What is anxiety?

MANAGEMENT GUIDELINES FOR ANXIETY DISORDERS IN CHILDREN AND ADOLESCENTS Prabhat Sitholey1 , Anil Nischal2

Anxiety disorders represent one of the most common categories of psychopathology in children and adolescents. Apart from separation anxiety disorder, a well recognized problem of childhood, it is now widely accepted that generalized anxiety disorder, social phobia, specific phobia, posttraumatic stress disorder, obsessive compulsive disorder and panic disorder all occur during the childhood and adolescent years. Numerous studies examining the nature and treatment of anxiety disorders have appeared during the recent years. Significant advances in this area include the investigation of pharmacological agents and development of effective psychosocial interventions. Prevalence rates for having at least one childhood anxiety disorder vary from 6% to 20% over several large epidemiological studies (Costello et. al., 2004). Co-morbidity is extremely common among children and adolescent suffering from anxiety disorders. A recent study of children aged 8 - 13 years, having a primary diagnosis of anxiety disorder revealed that 79% of the sample also had another co-morbid anxiety disorder, mood disorder or behavior disorder (Kendall et. al., 2001). In view of such findings, consideration needs to be given to co-morbidities as their presence will guide selection of specific treatments. The objective of these guidelines is to provide up-to-date information about management of anxiety disorders. Literature was reviewed by a computerized search in the month of June 2007 using the keywords child, adolescent, anxiety disorder, treatment, and management. The search covered a period of 10 years (1997 through 2007).Articles retrieved and their relevant references were reviewed for the purpose of framing these guidelines. The information has been presented in two sections Assessment and Treatment. Certain statements in this guideline are followed by abbreviations MS or CG. MS stands for minimal standards and reflects that the statement is based on rigorous empirical evidence while CG stands for clinical guidelines indicating that the statement is based on empirical evidence and/or strong clinical consensus. ASSESSMENT Defining the boundary between extremes of normalcy and psychopathology is a dilemma that pervades all psychiatry. In many cases of childhood anxiety disorder this dilemma is at its zenith. The defining point for caseness is often ambiguous as many childhood anxieties are not only common but also have an adaptive role in human development. It is strongly recommended that psychiatric assessment of children and adolescents should routinely include screening questions about anxiety symptoms [MS]. If the screening indicates significant anxiety, then the clinician should do a formal evaluation to determine subtype of anxiety disorder, the severity of anxiety symptoms and functional 1. MD Professor and Head, 2. MD Assistant Professor, Department of Psychiatry, CSM Medical University UP, Lucknow, India (218)

impairment [MS] (Connolly et. al., 2007). Anxiety may be considered symptomatic when it is impairing and prevents / limits developmentally appropriate adaptive behavior. A useful rule for determining diagnostic threshold is the child's ability to recover from anxiety and to remain anxiety-free when the provoking situation is absent. The child's lack of flexibility in affective adaptation is an important pathological indicator. In addition, the degree of distress and dysfunction associated with anxiety also help in reaching a diagnosis. Anxiety disorders impair emotional, cognitive, physical and behavioral functioning in multiple areas and are usually chronic in nature. Hence, the child needs to be evaluated in context of his family, school, community, and culture. Important areas of assessment include history of onset and development of anxiety symptoms, associated stressors, medical history, school history, family psychiatric history and mental status examination. The psychiatric assessment should always consider differential diagnosis of physical conditions & psychiatric disorders that may mimic anxiety disorders [MS]. Early detection and effective treatment may reduce the impact of anxiety on academic and social functioning in youth and may reduce the persistence of anxiety into adulthood. INSTRUMENTS FOR ASSESSMENT Earlier, determination of childhood anxiety largely relied on rating scales or interviews inquiring about multiple unrelated fears and worries generating a count without a clear clinical meaning (Lapouse & Monk, 1958). The emphasis has now shifted to the study of diagnostic groups that reflect explicit clinical criteria. A comprehensive evaluation should include a detailed structured or semi structured psychiatric interview to establish the anxiety disorder diagnosis and detect co-morbid psychiatric disorders. In addition, clinical rating scales, self report scales and parent report instruments may be used to determine the type and severity of anxiety symptomatology. This practice also allows for monitoring of these symptoms over time. Over the last two decades there has been a proliferation of instruments to determine the presence of anxiety disorders in children or quantify levels of anxiety. Assessment instruments include paperand-pencil scales for children, parents and teachers, as well as child and parent interviews. Interested readers are referred to a review of commonly used instruments by Brooks & Kutcher, 2003. An overview is provided below. Rating scales: Rating scales serve diverse purposes. They are used to screen large groups, to examine the relative contribution of genetics and environment, to assess severity and as outcome measures of treatment efficacy. Rating scales that anteceded the present nosology of anxiety disorders were designed to assess a plethora of factors such as worry, physiological anxiety, fear of bodily harm, etc. rather than anxiety syndromes. These include the Revised Children's Manifest Anxiety Scale (RCMA; Reynolds &Richmond, 1985), the State Trait Anxiety Inventory for Children (STAIC; Spielberger, 1973) and the Revised Fear Survey Schedule for Children (FSSC-R; Scherer and Nakamura 1968; Ollendick 1983). In addition, the Child Behavior Checklist (CBCL; Achenback 1991) which generates a non specific factor of emotional disturbance, called the “internalizing factor" may be used as a rating scale. The limitations of the older rating scales and increasing interest in childhood anxiety disorders has led to development of more sensitive and diagnostically relevant measures of childhood anxiety. Recent efforts reflect the classification of anxiety disorders and a move towards specificity of content, with relevance to diagnostic grouping. Newer scales devised with these considerations include the Social Anxiety Scale for Children (La Greca et.al., 1988; La Greca & Stone, 1993) and for Adolescents( La Greca & Lopez, 1998), the Multidimensional Anxiety Scale for Children (MASC; March et. al., 1997; March & Albano,1998) and the Screen for Child Anxiety Related Emotional Disorders (SCARED), which has a parent version also (Birmaher et. al.,1997; Monga et. al., 2000). The MASC and SCARED appear to be promising for clinical purpose according to Research Unit on (219)

Pediatric Psychopharmacology Anxiety group study, 2001. A major clinical challenge is to differentiate between anxiety and depression. Anxiety scales do not adequately distinguish between children with anxiety disorders and those with other diagnosis (Klein, 1994). Therefore, though anxiety scales may provide an overall estimate of anxiety levels, they cannot be viewed as contributing to the diagnosis of anxiety disorders, and clinicians would be unwise to rely on them only for differential diagnostic decisions. Diagnostic Interviews: Several systematic diagnostic interviews for children and for parents as informants have been devised to meet different purposes and vary accordingly. The Diagnostic Interview Schedule for Children (DISC; Shaffer et. al, 1996) was developed for use in epidemiological studies. It is highly structured and can be used even by individuals who have no clinical training. A computer based version is also available. The Diagnostic Interview for Children and Adolescents (DICA; Herjanic & Reich, 1982; Reich et. al., 1991) is another highly structured instrument. The Child and Adolescent Psychiatric Assessment (CAPA; Angold & Costello, 1995) also devised for epidemiological studies, requires adequate training as it is less structured than DISC. The CAPA, in comparison to other instruments, additionally covers assessment of functioning in school, social relationship, etc. along with specific symptoms, allows for clarification of questions and more closely resembles usual clinical interview. The Kiddie Schedule for Affective Disorder and Schizophrenia (K-SADS) has been developed from a clinical perspective. Its present and lifetime version allows full latitude of inquiry. (Chambers et. al. 1985, Kaufmen et al, 1997). The Anxiety Disorder Interview Schedule for Children (ADIS) originally prepared to assess anxiety disorders has been expanded to provide diagnosis for other major disorders. This can be employed to collect detailed information in a flexible clinical fashion (Silverman & Albano 1996). All the instruments described above have demonstrated modest to adequate test-retest reliability with anxiety disorders faring no better or worse than most other diagnosis. There is little to guide selection of instruments in terms of better reliability or validity but the DISC is the most widely used worldwide.In Lucknow K-SADS-PL (Kaufmen et al, 1997) is the preferred tool. We understand that many of the above mentioned tools not be available easily, others might not be suitable for use in Indian population due to variety of reasons. The authors recommend use of K-SADS for diagnostic assessment, CGI for severity evaluation and CGAS (Shaffer et al, 1983) for global assessment of functioning as a minimal standard. Additionally, DOTES may be used for monitoring medication sideeffects (Campbell et al, 1985). Although conceived for research purposes, diagnostic interviews may be useful to clinicians as they provide a comprehensive coverage of symptomatic status, are excellent teaching tools and allow comparisons. In the end it needs to be said the though many instruments are available all of them have not been conclusively shown to distinguish between various anxiety disorders or anxiety disorders and other child psychiatric disorders. As such, a sufficient level of precision for diagnostic classification has not been reached. Available evidence only supports the diagnostic validity of social phobia but not other disorders. OUTLINE OF DIAGNOSTIC ASSESSMENT A. Obtain history from parents, patient, and other pertinent informants. 1. Note onset and development of symptoms and the context in which symptoms occur and are maintained. a. DSM - IV target symptoms, with particular attention to the following: i. Determination of whether anxiety is stimulus specific, spontaneous, or anticipatory. ii. Evaluation for avoidant behavior (degree of constriction of daily life). (220)

b. Biopsychosocial stressors. c. Co morbid psychopathological symptoms, maladaptive personality traits, and internal conflicts. d. Impact of symptoms on the daily life of the patient and family. e. Social and familial reinforcers of symptoms. 2. Emphasize developmental history with special consideration of the following: a. Temperament b. Ability to sooth self or be soothed. c. Quality of attachment. d. Adaptability. e. Stranger and separation responses. f. Childhood fears. 3. Obtain medical history, especially noting the following: a. Numbers of visits to physician or emergency room for these or other symptoms. b. Medications taken by the patient that could produce anxiety symptoms. c. Medical disorders 4. Obtain school history. a. Academic, athletic, social and behavioral functioning. b. Disparity between potential and actual achievement. c. Patterns of attendance. 5. Obtain social history. a. Environmental stressors such as disorganized home, presence of child abuse (physical, emotional or sexual) or neglect, mental or physical illness or death in family members, or exposure to danger or violence. b. History of separations and losses. c. Degree of involvement with peer group and social competence. 6. Obtain family history with particular attention to the following: a. Patient's past and present role in the context of family functioning. b. Family stresses, resources, and coping style. c. Family psychiatric history with emphasis on the following: i. Anxiety disorders (including obsessive compulsive disorders). ii. Mood disorders. iii. ADHD. iv. Psychoactive substance use disorders. v. Tic disorders. vi. Psychotic disorders. vii. Suicidal behavior. B. Interview the patient, including a mental status examination with special note of the following: 1. Patient's reports of symptoms, including self-assessment of impairment. 2. Objective signs of anxiety, including motor tension, autonomic hyperactivity, vigilance and scanning, variations in speech patterns and production and separation difficulty. 3. When developmentally appropriate, communication of anxiety through play and drawings. Play techniques can be used to understand a child fears and reasons for anxiety. C. Conduct family assessment. 1. Evaluation of family interactions and dynamics. 2. Assessment of parent -child relationship. (221)

D. Administer structured or semi structured interview for anxiety and comorbid diagnosis. E. Administer clinical, self-report, and parent-report instruments for severity of anxiety symptoms. F. Refer for IQ and psychological testing if indicated clinically and for learning disability, and speech and language testing if required and facilities are available. G. Conduct physical evaluation of the child or adolescent. 1. Physical examination. 2. Consultation and collaboration with family practitioner, pediatrician or other specialties as per need. 3. Evaluation of medical and neurological conditions as indicated. (See sec II.A below) DIFFERENTIAL DIAGNOSIS A. Consider physical conditions that may mimic anxiety disorders. 1. Documented hypoglycemic episodes. 2. Hyperthyroidism. 3. Cardiac arrhythmias 4. Caffeinism. 5. Pheochromocytoma. 6. Seizure disorders. 7. Migraine. 8. Central nervous system disorders (e.g., delirium or brain tumors). 9. Medication reactions: antihistamines, antiasthmatics, sympathomimetics, steroids, SSRIs, anti-psychotics (akathisia), and nonprescription preparations, including diet pills and cold medicines. B. Screen for psychiatric disorders that may be comorbid with or misdiagnosed as anxiety disorders. 1. Mood disorders. 2. ADHD. 3. Adjustment disorder. 4. Substance use disorders, including alcohol, nicotine, marijuana, cocaine, stimulants, inhalants, and hallucinogens. 5. Borderline or other personality disorders. 6. Eating disorders. 7. Somatoform disorders. 8. Tic disorders. 9. Trichotillomania. 10. Reactive attachment disorder. 11. Pervasive developmental disorders. 12. Schizophrenia. 13. Sleep Terror Disorder. C. Establish diagnosis of specific type of anxiety disorder. More than one may be present. (222)

1. 2.

Anxiety disorder beginning in childhood and adolescence: separation anxiety disorder. Anxiety disorders affecting children, adolescents and adults. a. Generalized anxiety disorder (inclusive over-anxious disorder of childhood). b. Specific phobia. c. Social phobia. d. Panic disorder. e. Obsessive - compulsive disorder. f. Posttraumatic stress disorder.

Treatment The evidence that childhood anxiety disorders cause suffering and impairment and may entail long term liability highlight the need for effective treatments. Some interventions, such as CBT, are based on theoretical models of anxiety while others such as medication, follow demonstrated efficacy in adult anxiety disorders. Child and adolescent psychiatrists usually employ an integration of several approaches in treating patients with anxiety disorders. In general, treatment planning should consider severity of and impairment produced by the anxiety disorder. A multimodal approach is advisable and psychotherapy should be considered an integral part of the management of childhood anxiety disorder [CG] (Connolly et. al., 2007). Literature is replete with case reports and studies evaluating various approaches. Wherever controlled studies are available, case reports have not been considered in framing the recommendations. We initially brief the different approaches followed by disorder-specific recommendations. BEHAVIOR THERAPY: Behavior therapy targets the patient's overt behavior and emphasizes treatment in context of family and school instead of focusing on intrapsychic conflicts. (Bernstein et. al., 1997). Etiology is not the focus of attention (Kazdin, 1991).Two comparative studies demonstrate efficacy of behavior therapy (systematic desensitization) in treatment of children with school refusal. (Miller, 1972; Blagg and Yule, 1984). CONGNITIVE BEHAVIOUR THERAPY: CBT is the most well studied intervention. It integrates the behavioral approach with an emphasis on changing the cognitions associated with the patient's anxiety. The basic notion is that distorted cognitions about the dangerousness of the environment underlie anxiety symptoms. The aim is to replace negative beliefs with more neutral realistic ones. The technique encourages the patients to restructure their thoughts into a more positive framework resulting in more assertive and adaptive behavior (Bernstein et. al., 1997). Cognitive interventions include identifying anxious feelings and thoughts, recognizing somatic responses to anxiety, and devising a plan to deal with these symptoms. Behavioral interventions include modeling, role-playing, relaxation techniques, exposure and rewards. CBT has been used for a variety of childhood anxiety disorders and is said to be effective (Roblek & Piacentini ,2005; Cartwright-Hatton et. al., 2004). Another major advantage of CBT is availability of treatment manuals that allow comparison across studies. The controlled studies of CBT may be divided into those that have used a no-treatment waiting list control group, and those that have compared CBT to a non-specific control intervention. Early trials often used waiting list controls. The problem with this methodology was that this confirms to patients that they require treatment, but withholds it. Another limitation is that this control does not reveal the specific usefulness of an intervention, because there is no way of determining whether treatment was effective because of its particular nature, or because of non-specific factors such as therapist's interest and concern, or the family mobilizing itself to bring the child for treatment. Even if control psychotherapy is used, it should be equivalently appreciated by recipients, so that treatment effects (223)

are not due to difference in treatment credibility. The most informative studies are those which rely on a comparison treatment that is reasonable and credible i.e. use attention controls. CBT was examined in two systematic studies by Kendall (Kendall 1994, Kendall et al. 1997) and he reported that the group receiving CBT had significantly better outcome. However, two other studies of CBT using attention controls reported no difference in efficacy (Last 1998; Silverman et. al., 1999). Other studies have examined parental involvement (Bernstein et. al.,2005, Spence et. al., 2000, Mendlowitz et. al. 1999) and report benefits of the same. In a study on family cognitive behavioral therapy for childhood anxiety disorders Wood et. al., 2006 report that family CBT may provide additional benefit over and above child-focused CBT. These findings provide preliminary support and encourage further research in parental participation in treatment for childhood anxiety. Many other studies are available, most of them suffer from methodological limitations, but there is evidence of improvement which is sustained over time (Kendall et al. 1996, Barrett et al.2001, Kendall et al. 2004). A recent review of CBT studies concluded that cognitive behavioral therapy appears an effective treatment for childhood and adolescent anxiety disorders in comparison to waiting list or attention control. There was no evidence for a difference between an individual, group or parental/family format. CBT can be recommended for the treatment of childhood and anxiety disorders, although with only just over half improving, there is a need for further therapeutic developments (James et. al., 2005). PSYCHOANALYSIS AND PSYCHODYNAMIC PSYCHOTHERAPY: Clinical data on psychoanalysis consists largely of case reports and most accounts report favorable results. Systematic studies of psychoanalysis (Heinicke and Ramsey-Klee, 1986; Target and Fonagy,1994) relevant to childhood anxiety disorders report improved capacity for relationships, frustration tolerance, balanced use of defenses and improvement in adaptation. Psychodynamic psychotherapy is a derivative of psychoanalysis with modifications such as less frequent appointments, greater participation of parents in treatment, and more explicit use of active support, practical guidance and environmental interventions (Bemporad, 1991). Anxious children generally benefit from mastering themes of separation, autonomy, self-esteem, and age appropriate behavior (Bernstein et al., 1997). Studies documenting efficacy in children are available (Muratori et. al.2003, Barett et. al., 1998, Hampe et al 1973, Miller et al, 1972). Overall, it is an effective but time consuming approach. Until recently this approach was widely practiced and accepted but has been overtaken by CBT now. PARENT CHILD INTERVENTIONS AND FAMILY THERAPY: Early temperamental traits of passivity, shyness, behavioral inhibition, fear & withdrawal in unfamiliar situations and insecure mother-child relation have been associated with increased risk of developing anxiety disorders during childhood (Capsi et al, 1995; Kagan et al 1988; Biederman et al, 1993; Warren et al, 1997; Prior et.al. 2000; Williams et. al. 1990). Therefore, attention to temperament and parent- child relationship is vital. Parent child interventions include helping parents encourage the child to face new situations, refraining from excessive criticism and intrusiveness, responding to child's emotional needs and encouraging child to engage in activities despite anxiety (Ginsburg et. al.,2002; Barrett P M, 1996; Crawford et. al. 2001). Family theory views anxiety symptoms in interpersonal terms and postulates that anxiety symptoms reflect problems in the family system (Last et. al. 1991). Bernstein et al .1990 in a study of 76 families identified family difficulties in areas of role performance, values and norms. It has been suggested that working with the family is a key to decrease anxiety symptoms experienced by the child. The aim of the therapy is to disrupt the dysfunctional family interactions that promote insecurity and to support areas of family competence (McDermott et. al. 1989). (224)

PHARMACOLOGICAL TREATMENT: Pharmacotherapy should preferably be used as adjunct to behavioral or psychotherapeutic interventions rather than as a sole intervention. This approach is important to prevent symptom return after discontinuation of medications. SSRI's have been extensively used for adult anxiety disorders and have documented safety and efficacy. Although several open trials of SSRI's in children have appeared, the most important study till date is a large multicentric, placebo controlled study (Research Unit on Pediatric Pharmacology Anxiety Group, 2001) documenting efficacy of fluvoxamine in children with mixed anxiety disorders (Social phobia, separation anxiety and generalized anxiety disorder), without major depression. 79% of the children on medication improved, as compared to 28% on placebo over a period of 8 weeks. Williams & Miller, 2003 after reviewing evidence state that the serotonin selective reuptake inhibitors should be considered firstline pharmacological treatment for anxiety disorders in children and adolescents [CG]. However, medications other than SSRIs may also be considered for treatment of anxiety disorders in children and adolescents [CG]. Klein, 1994 in his review of literature on TCAs states that the support for the efficacy of TCAs in children with separation anxiety is inconsistent. Bernstein el. at., 2000 reported efficacy of imipramine compared to placebo in adolescents with school refusal and anxiety disorders. Although there are reports supporting efficacy of benzodiazepines in childhood anxiety disorders, the safely profile of SSRIs and evidence of their recent usefulness weaken consideration of benzodiazepines. However, they may be used on short term basis for immediate respite from anxiety symptoms. Less commonly buspirone and â-blockers may be employed if required. At this time, there are no specific dosing guidelines for children and adolescents with anxiety disorder. Experts recommend starting at low doses, monitoring side effects closely, and then increasing the dose slowly on the basis of treatment response and tolerability. Clinicians need to appreciate that anxious child and anxious parents may be especially sensitive to any worsening in the child's somatic symptoms or emergence of even transient side effects of medications. Selection of medication is guided by several factors, primarily co morbidity and side effect profile (Connolly et. al., 2007). DISORDER SPECIFIC RECOMMENDATIONS Separation Anxiety Disorder, Generalized Anxiety Disorder and other Anxiety Disorders: Majority of pharmacological studies of children and adolescents with anxiety disorders enroll a mixed diagnostic group including with SAD, GAD and/or Social phobia. Several trials support efficacy of SSRIs in treatment of anxiety disorders in children. Efficacy and safety of fluovoxamine & Paroxetine in children and adolescent with SAD, GAD and/or social phobia, of sertraline for youth with GAD, and of fluoxetine for youth with SAD, GAD and/or social phobia has been documented in well designed trials (Reinblatt et.al.,2007; Seidel et.al.,2006; Muller et. al., 2005; Wagner et.al.,2004; Birmaher et. al. 2003; Brent D A, 2003; Pine DS, 2002; RUPP study, 2001; Rynn et. al. 2001). The most common side effects reported were abdominal discomfort and headache. No major problems were reported. Currently, an SSRI is the first line choice medication for children and adolescent with anxiety disorders, including those with SAD. Fluoxetine has also been reported to be clinically effective as maintenance treatment of anxiety disorders in children and adolescents (Clark et. al., 2005). Preliminary findings from controlled trials of extended release venlafaxine in treatment of youths with generalized anxiety disorder (Rynn et. al.2002, Rynn et. al.2007) and social phobia (Tourian et.al.2004) suggest it may be well tolerated and effective. Tricycles antidepressants are an alternative choice. However, scientific data for this group is much less convincing than that for SSRI's. Controlled studies for TCA's in SAD and/or school refusal report contrasting findings (Bernstein et. al. 1996). A study comparing CBT + Imipramine and CBT + placebo for adolescent school refusal with co-morbid anxiety and depression reported response rate of 70% and 28% respectively after 8 weeks of treatment. The point to be noted is that these patients did not suffer from pure anxiety problems (Bernstein et. al. 2000). Use of BZD's in treatment of youth with anxiety disorders is backed by limited (225)

data. Due to dependence potential this class of medications is reserved for short term use, typically in combination with an SSRI's or TCA while waiting for the onset of therapeutic effect of SSRI / TCA. It has been recommended that the SSRI should be continued for approximately one year after remission of target symptoms. Subsequently, during a low stress period a watchful medication free trial may be given. If relapse occurs SSRI should be immediately reinstated (Pine D S, 2002). In terms of psychotherapeutic interventions, CBT has the greatest empirical support (Albano et. al., 2002; Bernstein et. al., 2000; Dadds et. al. 2001; Velting et. al. 2004; Barrett PM, 1998; Kendall et. al. 1996; Last, 1998). The common components are 1. Education about nature of anxiety. 2. Activities to increase recognition of anxious thoughts and feelings. 3. Coping strategies such as adaptive self talk (cognitive-modification), progressive muscular relaxation and diaphragmatic breathing, and 4. Exposure to anxiety-provoking stimuli. The role of family therapy as a positive addition has also been documented along with efficacy in group format for SAD, GAD and social phobia (Barrett et. al. 1996; Dadds et. al. 2001; Kearney et. al. 2003). Data strongly supports short term efficacy of group/ individual CBT and SSRI's for youth with anxiety disorders. In anxiety disorders of mild severity, CBT should be initiated first, followed by SSRI in case of non-response. In practice, the two approaches are often combined for severe, impairing anxiety disorders. In cases of Generalized Anxiety Disorder CBT or CBT plus medication both are appropriate approaches based on severity of the case. Medication alone is not recommended. In mild to moderate cases CBT alone usually suffices (Connolly et. al., 2007). Social Phobia: CBT and SSRIs are the first line treatments. To our knowledge there is no published study examining efficacy of SSRIs in a sample of pure social phobia. However, studies of CBT in such samples are available and report CBT to be effective (Dadds et. al. 2001; Velting et. al. 2004; Beidal et. al. 2000). Depending on presentation, treatment may begin with CBT alone or CBT plus an SSRI (Mancini C. et. al., 2005). CBT here consists of social skills training, increased social opportunities, relaxation techniques, adaptive self-talk (cognitive restructuring), exposure and response prevention. Individual, group and school-based all interventions have found to be effective (Albano et. al. 1999; Masia et. al. 2001; Baer et. al. 2005) Specific Phobia: Treatment for specific phobias differs from CBT of SAD, GAD and social phobia. It primarily involves graded exposure to the feared stimuli, imaginary or actual, according to hierarchy constructed by the child progressing gradually from mild to most significant fears (Velting et. al. 2004). When exposure is paired with relaxation the technique is referred to as systematic desensitization. Other treatments include modeling, and cognitive exercises to facilitate adaptive thoughts. These also can be paired with graded exposure. Outcome studies report significant and sustained improvement with these approaches (Muris et. al. 1999; Bernstein et. al. 2005; Silvermann et. al. 1999; Berman et. al. 2000). Panic Disorder: CBT again is the first line of treatment. Components include 1. Education about the physical experience associated with panic attacks. 2. Breathing and relaxation exercises. 3. Interceptive exposure (i.e. exposure to cues associated with panic). 4. In vivo exposure. 5. Cognitive modification to reduce catastrophic misinterpretation. Ollendick, 1995 reported efficacy of this approach in a multiple-baseline design analysis. In practice an SSRI may be added to CBT (Masi et. al. 2001). Masi et. al. 2006 after reviewing the empirical evidence of pharmacotherapy in early-onset panic disorder, including selective serotonin re-uptake inhibitors, benzodiazepines and tricyclics conclude that the data supporting efficacy are still limited, and no controlled studies are available. Research in this area is wanting. (226)

Posttraumatic Stress Disorder Although only some of the children and adolescents exposed to traumatic life events develop fullblown posttraumatic stress disorder, many others experience some PTSD symptoms and associated functional impairments. A variety of psychopharmacological and psychosocial treatments are currently available for this group of anxiety disorders but the effectiveness of most of those interventions has not been adequately evaluated. Only trauma-focused cognitive behavioral interventions and SSRIs enjoy empirical evidence of efficacy. Psychotherapeutic treatments: Trauma-Focused CBT: Widely regarded as the first line treatment for PTSD. Several RCTs proving trauma focused CBT to be superior to other treatment are available. It decreases PTSD, depressive and behavioural symptoms, and /or functional impairment in traumatized children. Majority of research has been done on sexually abused children (Cohan et al, 2004). Typically 10-16 treatment sessions are given. The major components of this treatment are - Psycho education about traumatic reactions and PTSD - Stress-inoculation- including affective modulation, muscle relaxation, focused breathing, thought stopping, and cognitive coping techniques. - Gradual exposure- consisting of carefully calibrated efforts to encourage the child to recall and describe increasing details about the traumatic events as well as thoughts, feelings and physical sensations experienced at the time of the original trauma as well as during retelling. - Cognitive processing - Parental treatment component Eye Movement Desensitization And Reprocessing (EMDR): Variant of trauma focused CBT, in which exposure and cognitive reprocessing interventions are paired with directed eye movements; fewer sessions are required. Crisis Intervention: Consist of one to three sessions provided in the immediate aftermath of a traumatic event. It is often provided in a community setting and includes encouragement to discuss feelings, provision of emotional support and psycho education about common reaction to stress and advice about managing these reactions. Play Therapy: Therapists do not direct the form or content of child's play but rather interpret themes in it thought to be representative of certain inner conflicts. Other Techniques Psychodynamic & psychoanalytical technique Parent-child interaction therapy Dialectical behaviour therapy Relationship based conjoint parent-child treatment Pharmacological treatment: The data supporting efficacy of pharmacotherapy in early-onset panic disorder, including selective serotonin re-uptake inhibitors, benzodiazepines & tricyclics is limited (Masi et. al.,2006). Only one randomized trial has been conducted. This study evaluated the comparative impact of imipramine vs chloral hydrade on development of PTSD in acutely burnt children and demonstrated the efficacy of imipramine (Robert et. al, 1999). Several open trials have demonstrated clinical improvement with adrenergic blockers (PPNL), clonidine, dopamine antagonists (risperidone) and opiates. In practice SSRI's, TCA's, venlafaxine, bupropion or any of the above mentioned medications may be used. No information is available with regard to optimal length of treatment, need for maintenance treatment or use of multiple medications in treatment of childhood PTSD.

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Obsessive Compulsive Disorder: It is now being increasingly appreciated that although OCD in children is often chronic and can be severe, the outlook for patients receiving prompt diagnosis and appropriate treatment is quite positive. Considerable progress has been made in testing and refinement of both pharmacological and psychosocial treatments. Both forms of treatment are very effective in symptom relief and produce improvements in functioning, Clinical consensus suggests that combined treatment has added benefits. Treatments should begin with educating the family of the child about how to handle their child's behavior, which may be disrupting family life. On the internet www.ocdresource is a useful source of information about the disorder. If the disorder is hampering school performance, teachers need to be told about the child's problem and if possible be involved in the child's behavioral program. Choice of first line therapy depends on the symptom pattern, severity, and the patient's and family's preference. Whatever is used, it is important to urge flexibility, as combination therapy may be eventually required. Cognitive-Behavior Therapy: The technique of CBT needs to be modified in accordance with the developmental age of the child. CBT for pediatric OCD basically encompasses three techniques 1. Exposure and Response prevention 2. Cognitive therapy and 3. Relaxation training. ERP is the most recommended and effective approach. Cognitive therapy, which involves changing false beliefs, challenging reality of obsessions and necessity of compulsions, is usually ineffective as a sole treatment for OCD. However, it is a useful complement in most cases. Relaxation therapy is primarily used to manage anxiety produced by exposure but has no direct affect on O.C. Symptoms. Older children and adolescents respond well to CBT modeled on approaches used for adult OCD. However, younger children require a number of modifications. These include additional efforts to educate child and family about the nature of excessive anxiety and the role of treatment, sensitizing the child to the impact of OCD on his/her life and fostering motivation for change through his/her cooperation and perseverance in treatment, building a shared language to better communicate the nature of associated feelings or cognitions, and including behavioral rewards for maintaining engagement in treatment. Manuals for modified CBT for OCD suitable for children are available. Methodology, though undergoing continued refinement currently involves. 1. Daily exposure to cues avoided because of associated discomfort and rituals, and 2. Maintaining exposure and not ritualizing for at least an hour or until discomfort subsides. Developmentally modified forms of CBT for children appear to confer similar benefits in children as observed for adult population (O'Kearney et. al., 2006). Uncontrolled trials of CBT appear highly promising, with excellent response in up to 75% of the patients. Although, gains from ERP persist beyond discontinuation, booster treatment may help long term progress, and additional treatment may be needed for relapses brought on by stress. O'Kearney et. al., 2007 after reviewing evidence on benefits of cognitive-behavioural therapy for children and youth with obsessive-compulsive disorder report that CBT should be regarded as a first line equivalent to anti-OCD medication with the potential to lead to better outcomes when combined with medication than medication alone can provide. Additional studies are needed to further clarify CBT's benefits and to investigate how it can be made more available as a treatment option for children and youth who suffer from OCD. Pharmacological Treatment: Although pediatric trials of SSRIs have lagged behind those in adults, there is now extensive substantiation of the utility of pharmacotherapy in pediatric OCD. An initial trial of Serotonin Reuptake (228)

Inhibitor (SRI), most often an SSRI is the treatment of choice. If there is inadequate response at 10-12 weeks, another SSRI may be tried. Serotonergic Agents: Clomipramine was the first agent shown to be effective in O.C.D. A meta-analysis suggested that it may possess greater efficiency for pediatric OCD than the SSRIs (Allen, 1994; Practice Parameters for OCD, 1998). De Veaugh-Geis et.al, 1992 documented the efficacy of clomipramine in pediatric O.C.D in randomized controlled trial. However, being a tricyclic, it is associated with significantly greater risk of side effects and therefore is relegated to a second or third line treatment choice in children and adolescent with OCD. The evidence base supporting the efficacy and safely of SSRIs has considerably strengthened over the last few years (Geller et. al. 2004; Geller et. al. 2003; Practice Parameters for OCD, 1998). Anti-obsessive efficacy of fluoxetine, fluvoxamine and sertraline has been reported by controlled trials (March et.al.1998 Geller et. al. 2002; Liebowitz et. al. 2002, Riddle et. al. 2001). Similar benefits have been reported for Paroxetine (Geller et. al. 2003) and for Citalopram (Mukkades et. al. 2003). Low initial doses, with slow upward titration, are the rule. Patients should be told trials of more than one agent may be required, at times with augumenting agents. In controlled trials reduction in baseline symptom rating with treatment of upto 16 weeks has been relatively consistent, although modest, ranging from 18 to 44 percent (Geller et. al. 2003; Geller et. al. 2002; Liebowitz et. al. 2002; Riddle et. al. 2001). Studies including long term observation report continued symptom reduction upto one year. Data suggests that treatment benefits with SSRIs are stable and can be expected to strengthen in many with continued treatment. Overall, SSRIs have been found to be well tolerated by child and adolescent patients with OCD. However, almost 50% of the children and adolescents treated with an SSRI continue to have interfering symptoms and may require trials of alternative SSRIs, combined pharmacotherapy and addition of psychotherapeutic interventions. Augmenting Strategies and Adjunctive agents: Up to 50% childhood OCD cases show no or partial response to SRI treatment, even if two different SRIs are used (Geller et.al ,2003). Hence, augmentation strategies may be required. There are no randomized controlled trials of the utility of augmentation strategies in Pediatric OCD. However, based on experiences in adult patients, augmentation of an SRI might be considered for pediatric patients with a partial response or intolerance to higher doses. In adults, three agents, Clonazepam, Haloperidol, and Risperidone (Mc Dougle et.al., 1995; Pigott et.al.,1992) have been shown to be effective in controlled trials. These agents are worth a try. Another strategy, addition of a second concurrent SRI, has been used to a limited extent in children. An open table trial of six adolescents (Simeon et.al. 1990) combined fluoxetine and clomipramine and reported decreased doses requirement for both medications and fewer side effect. Figueroa et.al., 1998 described an open series of seven patients given clomipramine and SSRI (fluoxetine, sertraline or paroxetine) and followed through 5-22 months. Combination therapy appeared to be more effective than monotherapy for all cases. Adjunctive treatment may be indicated for children and adolescent with OCD with comorbidities. The comorbidity of tic disorders may require the addition of a-agonists or neuroleptics. Co-morbid anxiety symptoms are benefited by addition of BZDs or Buspirone. Depressive Symptoms may improve with lithium addition. Treatment Planning: Many experts and consensus guidelines recommend CBT as the first line approach for the majority of children and adolescents with OCD. However, more severe symptoms, comorbid depression or limited cooperation may prompt the clinician to consider medication alone or in combination with CBT. One half or more of the young patients with OCD usually require combined therapy at some point of (229)

time to achieve complete remission. OCD is often chronic and long-term medication treatment is often required to maintain symptom control (Leonard et.al. 1991). Whenever discontinuation is attempted, tapering should be gradual usually over several weeks. Long term (indefinite) drug maintenance is suggested after 2-4 relapses. Concomitant CBT has been observed to assist medication discontinuation in some patients (Stanley & Turner 1995; Wever & Rey 1997). Periodic resumption of CBT may be necessary to combat symptom exacerbation in response to stress or development transitions. In general, OCD in children & adolescent is very responsive to treatment. Majority of patients should experience significant relief and return to functioning. Reducing delays in diagnosis and aggressive treatment, often with combined approaches goes a long way in minimizing impact of the disorder on children development. Selective Mutism: Data on treatment of selective mutism is mostly limited to single case studies. Controlled trials are lacking. In spite of this, the conviction that behavioral techniques are an essential component of management of selective mutism is widespread. Reports describe successful use of techniques such as contingency management, stimulus fading, systematic desensitization, negative reinforcement and shaping. A combination of behavioral techniques is probably the most common and successful treatment approach (Anstending K, 1998; Dow et. al. 1995; Holmbeck et. al. 1992; Watson et. al. 1992). A hierarchy of situations in which the child has difficulty speaking is prepared. Then, the child is guided to systematically engage in speaking- related behaviors (e.g. mouthing speech, making sounds , whispering and so on.) in increasingly more difficult situations. With repeated attempts, associated anxiety dissipates through autonomic habituation. When the feared consequences of speaking fail to occur anxiety is further reduced. Typically, child is given rewards after attempts to engage in desired behaviors. The young age of most children with selective mutism and the fact that most of these children initially do not speak to the therapist necessitates parental involvement in treatment. Traditional anxiety-reducing behavioral techniques like shaping, gradual exposure and reinforcement are often used in initial sessions. Involvement of school personnel for providing regular communication and support in school is also highly recommended. Other Psychosocial therapies: Although behavior therapy is most commonly employed, accounts of successful treatment of selective mutism with use of play therapy, family therapy, psychodynamic therapy, and group therapy are also available (Watson et.al. 1992; Tatem et.al. 1995; Dow et. al.; Bozigar & Hansen, 1984; Anstendig et. al. 1998). These strategies may be used as per need. It is common for children with selective mutism to have some degree of speech or language difficulties which exacerbate speechrelated anxiety. In such cases speech therapy should be considered as an adjunct to other interventions. Pharmacological Treatments: SSRI medications appear to be effective. A double-blind, placebo controlled trial of fluoxetine in children with selective mutism indicated significant benefit (Black & Uhde, 1995). In addition, fluvoxamine was also found to be efficacious in a large multicentric study of anxiety disorders (RUPP Anxiety Group Study, 2001). Several open trials and case reports also support the use of SSRIs for selective mutism (Cartson et.al. 1999; Dow et. al. 1995). As of now, behavior therapy when available and practical should be considered the initial intervention strategy. In resistant cases, a combination treatment may be used.

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REVIEW

Open Access

Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders Martin A Katzman1*, Pierre Bleau2, Pierre Blier3, Pratap Chokka4, Kevin Kjernisted5, Michael Van Ameringen6, the Canadian Anxiety Guidelines Initiative Group on behalf of the Anxiety Disorders Association of Canada/ Association Canadienne des troubles anxieux and McGill University

Abstract Background: Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence reportedly as high as 31%. Unfortunately, anxiety disorders are under-diagnosed and under-treated. Methods: These guidelines were developed by Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE, PsycINFO, and manual searches (1980–2012). Treatment strategies were rated on strength of evidence, and a clinical recommendation for each intervention was made, based on global impression of efficacy, effectiveness, and side effects, using a modified version of the periodic health examination guidelines. Results: These guidelines are presented in 10 sections, including an introduction, principles of diagnosis and management, six sections (Sections 3 through 8) on the specific anxiety-related disorders (panic disorder, agoraphobia, specific phobia, social anxiety disorder, generalized anxiety disorder, obsessive-compulsive disorder, and posttraumatic stress disorder), and two additional sections on special populations (children/adolescents, pregnant/lactating women, and the elderly) and clinical issues in patients with comorbid conditions. Conclusions: Anxiety and related disorders are very common in clinical practice, and frequently comorbid with other psychiatric and medical conditions. Optimal management requires a good understanding of the efficacy and side effect profiles of pharmacological and psychological treatments.

Introduction Anxiety and related disorders are among the most common of mental disorders. Lifetime prevalence of anxiety disorders is reportedly as high as 31%; higher than the lifetime prevalence of mood disorders and substance use disorders (SUDs) [1-5]. Unfortunately, anxiety disorders are under-diagnosed [6] and under-treated [5,7,8]. These guidelines were developed to assist clinicians, including primary care physicians and psychiatrists, as well as psychologists, social workers, occupational therapists, and nurses with the diagnosis and treatment of anxiety and related disorders by providing practical, * Correspondence: [email protected] 1 Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1, Canada Full list of author information is available at the end of the article

evidence-based recommendations. This guideline document is not focused on any individual type of clinician but rather on assessing the data and making recommendations. Subsequent “user friendly” tools and other initiatives are planned. The guidelines include panic disorder, agoraphobia, specific phobia, social anxiety disorder (SAD), generalized anxiety disorder (GAD), as well as obsessive-compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Also included are brief discussions of clinically relevant issues in the management of anxiety and related disorders in children and adolescents, women who are pregnant or lactating, and elderly patients, and patients with comorbid conditions.

© 2014 Katzman et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Methods

Table 2 Treatment recommendation summary

These guidelines are based on a thorough review of the current literature and were developed by a panel of Canadian experts in anxiety and related disorders through a consensus process. Data on the epidemiology, diagnosis, and treatment (psychological and pharmacological) were obtained through MEDLINE searches of English language citations (1980–2012), using search terms encompassing the specific treatments and specific anxiety and related disorders. These searches were supplemented with data from PsycINFO and manual searches of the bibliographies of efficacy studies, meta-analyses, and review articles. Treatment strategies were rated on strength of evidence for the intervention (Table 1). A clinical recommendation for each intervention was then made, based on global impression of efficacy in clinical trials, effectiveness in clinical practice, and side effects, using a modified version of the periodic health examination guidelines (Table 2). The guidelines were initiated prior to the introduction of the American Psychiatric Association’s (APA) fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and the committee was sensitive to potential changes to the nosology of anxiety and related disorders and its impact on the guidelines. However, it was agreed that, since the evidence for treatment is based on studies using DSM-IV criteria (or earlier), the introduction of the DSM-5 would not fundamentally alter the evidence and recommendations at this time. Whether using DSM-5 diagnostic criteria for the inclusion patients in clinical trials in the future will have an impact on outcomes, remains to be seen. The panel of Canadian experts in anxiety and related disorders responsible for the development of these guidelines via consensus process included 10 psychiatrists and seven psychologists who were organized into subpanels based on their expertise in particular anxiety or related disorders as well as in treating specific patient populations. Preliminary treatment recommendations

First-line

Level 1 or Level 2 evidence plus clinical support for efficacy and safety

Second-line

Level 3 evidence or higher plus clinical support for efficacy and safety

Third-line

Level 4 evidence or higher plus clinical support for efficacy and safety

Table 1 Levels of evidence 1

Meta-analysis or at least 2 randomized controlled trials (RCTs) that included a placebo condition

2

At least 1 RCT with placebo or active comparison condition

3

Uncontrolled trial with at least 10 subjects

4

Anecdotal reports or expert opinion

Levels of evidence do not assume positive or negative or equivocal results, they merely represent the quality and nature of the studies that have been conducted. Level 1 and Level 2 evidence refer to treatment studies in which randomized comparisons are available. Recommendations involving epidemiological or risk factors primarily arise from observational studies, hence the highest level of evidence for these is usually Level 3. Recommendations, such as principles of care, reflect consensus opinion based on evidence from various data sources, and therefore are primarily Level 4 evidence.

Not Level 1 or Level 2 evidence for lack of efficacy recommended

and the evidence upon which they had been based were reviewed at a meeting of the panel in December 2012; subsequently, draft guidelines were prepared by the subpanels which were then circulated to the entire group for consensus ratification during 2013. Preliminary recommendations were also presented to the Canadian psychiatric community for input in September 2012 at the Canadian Psychiatric Association annual conference. These guidelines are presented in 10 sections, the first of which is this introduction. In the following section, the principles of diagnosis and management of anxiety and related disorders are covered. That section provides an overview of the differential diagnoses associated with anxiety and related disorders in general, discusses issues that affect all anxiety disorders, and presents the general advantages and disadvantages of psychological treatment and pharmacotherapy options. In the subsequent six sections (Sections 3 through 8), the specific diagnosis and management of the individual anxiety and related disorders (panic disorder, specific phobia, SAD, OCD, GAD, and PTSD) are reviewed and recommendations are made for psychological and pharmacological treatments. Section 9 discusses issues that may warrant special attention pertaining to anxiety and related disorders in children and adolescents, pregnant or lactating women, and the elderly. The last section of these guidelines addresses clinical issues that may arise when treating patients with anxiety and related disorders who are also diagnosed with comorbid psychiatric conditions such as major depressive disorder (MDD), bipolar disorder, or other psychoses, and attention deficit/hyperactivity disorder (ADHD), or medical comorbidities, such as pain syndromes, cardiovascular disease, and diabetes/metabolic syndrome.

Principles of diagnosis and management of anxiety and related disorders Epidemiology Prevalence and impact

Anxiety and related disorders are among the most common mental disorders, with lifetime prevalence rates as high as 31% [1-5] and 12-month prevalence rates of about 18% [3,4]. Rates for individual disorders vary widely. Women generally have higher prevalence rates

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for most anxiety disorders, compared with men [4,5,9]. Anxiety and related disorders are associated with an increased risk of developing a comorbid major depressive disorder [10-12]. Anxiety and related disorders put a significant burden on patients and their family members [13]. They are associated with substantial functional impairment, which increases as the severity of anxiety [14] or the number of comorbid anxiety disorders increases [7,15]. In addition, studies have demonstrated quality of life impairments in patients with various anxiety and related disorders [16,17]. Anxiety has a considerable economic impact on society as well, being associated with greater use of health care services [5,18] and decreased work productivity [18,19]. Importantly, studies report that about 40% of patients diagnosed with anxiety and related disorder are untreated [5,7].

Asking patients if they are feeling nervous, anxious or on edge, or whether they have uncontrollable worry, can be useful to detect anxiety in patients in whom the clinician suspects an anxiety or related disorder [7]. The DSM-5 suggests the questions shown in Table 4 for the identification of anxiety-related symptoms; items scored as mild or greater may warrant further assessment [26]. If anxiety symptoms are endorsed, they should be explored in more detail by including questions about the onset of the anxiety symptoms, associations with life events or trauma, the nature of the anxiety (i.e., worry, avoidance, or obsession), and the impact they have had on the patient’s current functioning. Table 5 presents suggested screening questions for individual anxiety and related disorders, from various validated screening tools [27-30], some of which are freely available online (e.g., http://www.macanxiety.com/ online-anxiety-screening-test).

Suicide risk

Conduct differential diagnosis

In large surveys, anxiety and related disorders were independently associated with a significant 1.7-2.5 times increased risk of suicide attempts [20-23]; however, data are conflicting as to whether the risk is moderated by gender [20,23]. Increased risk of suicide attempts or completed suicide has been reported for patients with panic disorder, PTSD [20,24], and GAD [24], even in the absence of a comorbid mood disorder. These data indicate that patients with an anxiety disorder warrant explicit evaluation for suicide risk. The presence of a comorbid mood disorder significantly increases the risk of suicidal behavior [22,25].

The differential diagnosis of anxiety and related disorders should consider whether the anxiety is due to another medical or psychiatric condition, is comorbid with another medical or psychiatric condition, or is medication-induced or drug-related [32]. When a patient presents with excessive or uncontrollable anxiety it is important to identify other potential causes of the symptoms, including direct effects of a substance (e.g., drug abuse or medication) or medical condition (e.g., hyperthyroidism, cardiopulmonary disorders, traumatic brain injury), or another mental disorder [26]. However, since comorbid conditions are common, the presence of some of these other conditions may not preclude the diagnosis of an anxiety or related disorder. Certain risk factors have been associated with anxiety and related disorders and should increase the clinician’s index of suspicion (Table 6) [4,9,33-37]. A family [33] or personal history of mood or anxiety disorders [34,35] is an important predictor of anxiety symptoms. In addition, family history is associated with a more recurrent course, greater impairment, and greater service use [33]. A personal history of stressful life events is also associated the development of anxiety and related disorders [36,37], in particular, childhood abuse [37]. Women generally have higher prevalence rates across all anxiety and related disorders, compared with men [4,5,9]. The median of age of onset is very early for some

Initial assessment of patients with anxiety

The management of patients presenting with anxiety symptoms should initially follow the flow of the five main components outlined in Table 3. Screen for anxiety and related symptoms

Anxiety and related disorders are generally characterized by the features of excessive anxiety, fear, worry, and avoidance. While anxiety can be a normal part of everyday life, anxiety disorders are associated with functional impairment; as part of the key diagnostic criteria for anxiety disorders is the requirement that the symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning [26].

Table 3 Overview of the management of anxiety and related disorders • Screen for anxiety and related symptoms • Conduct differential diagnosis (consider severity, impairment, and comorbidity) • Identify specific anxiety or related disorder • Psychological and/or pharmacological treatment • Perform follow-up

Table 4 General screening questions • During the past two weeks how much have you been bothered by the following problems? ○ Feeling nervous, anxious, frightened, worried, or on edge ○ Feeling panic or being frightened ○ Avoiding situations that make you anxious Adapted from reference [26].

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Table 5 Screening questions for specific anxiety and related disorders Panic disorder – MACSCREEN [29,30] • Do you have sudden episodes/spells/attacks of intense fear or discomfort that are unexpected or out of the blue? If you answered “YES” then continue • Have you had more than one of these attacks? • Does the worst part of these attacks usually peak within several minutes? • Have you ever had one of these attacks and spent the next month or more living in fear of having another attack or worrying about the consequences of the attack? SAD (Based on Mini-SPIN [28]) • Does fear of embarrassment cause you to avoid doing things or speaking to people? • Do you avoid activities in which you are the center of attention? • Is being embarrassed or looking stupid among your worst fears? GAD [31] • During the past 4 weeks, have you been bothered by feeling worried, tense, or anxious most of the time? • Are you frequently tense, irritable, and having trouble sleeping? OCD – MACSCREEN [29,30] Obsessions: • Are you bothered by repeated and unwanted thoughts of any of the following types: ○ Thoughts of hurting someone else ○ Sexual thoughts ○ Excessive concern about contamination/germs/disease ○ Preoccupation with doubts (“what if” questions) or an inability to make decisions ○ Mental rituals (e.g., counting, praying, repeating) ○ Other unwanted intrusive thoughts • If you answered “YES” to any of the above… Do you have trouble resisting these thoughts, images, or impulses when they come into your mind? Compulsions: • Do you feel driven to perform certain actions or habits over and over again, or in a certain way, or until it feels just right? Such as: ○ Washing, cleaning ○ Checking (e.g., doors, locks, appliances) ○ Ordering/arranging ○ Repeating (e.g., counting, touching, praying) ○ Hoarding/collecting/saving • If you answered “YES” to any of the above… Do you have trouble resisting the urge to do these things? PTSD – MACSCREEN [29,30] • Have you experienced or seen a life-threatening or traumatic event such as a rape, accident, someone badly hurt or killed, assault, natural or man-made disaster, war, or torture? If you answered “YES” then continue • Do you re-experience the event in disturbing (upsetting) ways such as dreams, intrusive memories, flashbacks, or physical reactions to situations that remind you of the event?

phobias and for separation anxiety disorder (seven to 14 years), but later for GAD, panic disorder, and PTSD (24-50 years) [1,2]. Loneliness [38], low education [38], and adverse parenting [39], as well as chronic somatic illnesses, such as cardiovascular disease, diabetes, asthma, and obesity may increase the risk for a lifetime diagnosis of anxiety [34,40]. Comorbid medical and psychiatric disorders Anxiety and related disorders frequently co-occur with other psychiatric disorders [3]. More than half of patients with an anxiety disorder have multiple anxiety disorders [3,15],

Table 6 Common risk factors in patients with anxiety and related disorders • • • • • •

Family history of anxiety [33] Personal history of anxiety or mood disorder [34,35] Childhood stressful life events or trauma [36,37] Being female [4,9] Chronic medical illness [34,40] Behavioral inhibition [41,42]

and almost 30% will have three or more comorbid anxiety or related disorders [3]. Anxiety is often comorbid with substance use and mood disorders [3,40]. An estimated 52% of patients with bipolar disorder [43], 60% of patients with MDD [44], and 47% of those with ADHD [45] will have a comorbid anxiety or related disorder. Therefore, anxiety disorders should be considered in these patients. The high frequency of comorbidity must be considered when diagnosing anxiety and related disorders since this can have important implications for diagnosis and treatment [32]. Anxiety disorders comorbid with other anxiety or depressive disorders are associated with poorer treatment outcomes, greater severity and chronicity [46-49], more impaired functioning [46], increased health service use [50], and higher treatment costs [51]. The impact tends to increase with an increasing number of comorbid conditions [46]. Patients with anxiety disorders have a higher prevalence of hypertension and other cardiovascular conditions, gastrointestinal disease, arthritis, thyroid disease,

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respiratory disease, migraine headaches, and allergic conditions compared to those without anxiety disorders [16,52]. Comorbid anxiety and related disorders have a significant impact on quality of life (QoL) in patients with medical conditions [52]. Baseline assessment Baseline assessment should include a review of systems, prescribed medications, over-thecounter agents, alcohol use, caffeine intake, and illicit drug use, in addition to evaluation of the anxiety symptoms and functioning [32]. Table 7 lists potential investigations that can be considered based on an individual patient’s presentation and specific symptoms (e.g., dizziness or tachycardia). Ideally, a physical examination and baseline laboratory investigations should be performed before pharmacotherapy is initiated, with repeat assessments according to best practice guidelines [32]. Patients with anxiety and related disorders should be monitored initially every one to two weeks and then every four weeks for weight changes and adverse effects of medications, as this is a major factor contributing to discontinuation of medication. Closer monitoring may be required in children younger than 10 years of age, older or medically ill patients, patients on medications associated with metabolic changes, and those on multiple medications [32]. Identify specific anxiety or related disorder

The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has been finalized by the American Psychiatric Association (APA) [26]. The new DSM-5 provides diagnostic criteria for psychiatric disorders based on scientific reviews of the literature, field trial data, internal evaluations, public comments, and a final review by APA’s Board of Trustees. The “anxiety disorders” chapter now includes panic disorder, agoraphobia, GAD, selective mutism, separation anxiety disorder, SAD (social phobia), specific phobia, substance/medication-induced anxiety disorder, as well as anxiety disorder due to another medical condition or not elsewhere classified. OCD and PTSD have been moved to separate chapters on obsessive-compulsive and

Table 7 Considerations for baseline laboratory investigations (as needed based on patient’s presenting symptoms) Basic lab tests • Complete blood count

• Fasting glucose

• Fasting lipid profile (TC, vLDL, LDL, HDL, TG)

• Thyroid-stimulating hormone

• Electrolytes

• Liver enzymes

If warranted • Urine toxicology for substance use Adapted from references [32,53]. HDL = high density lipoprotein; LDL = low density lipoprotein; TC = total cholesterol; TG = triglyceride; vLDL = very low density lipoprotein.

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related disorders and trauma- and stressor-related disorders, respectively [26]. Table 8 provides a brief summary of the key DSM-5 diagnostic features of the anxiety and related disorders that are included in these guidelines [26]. While the DSM-5 is the most up-to-date diagnostic criteria, it is important to note that the evidence for treatment is based on studies using DSM-IV criteria (or earlier) for inclusion of patients. However, most of the diagnostic criteria have not changed substantially (see Sections 3–9 for more information on diagnosis); the exception being agoraphobia, which is now designated as a separate diagnosis. Specific individual anxiety and related disorders should be diagnosed with the DSM-5 criteria in the sections devoted to each anxiety disorder. An accurate diagnosis is important to help guide treatment. Psychological and pharmacological treatment

Treatment options for anxiety and related disorders include psychological and pharmacological treatments. All patients should receive education about their disorder, efficacy (including expected time to onset of therapeutic effects) and tolerability of treatment choices, aggravating factors, and signs of relapse [32]. Information on self-help materials such as books or websites may also be helpful. The choice of psychological or pharmacological treatment depends on factors such as patient preference and motivation, ability of the patient to engage in the treatment, severity of illness, clinicians’ skills and experience, availability of psychological treatments, patient’s prior response to treatment, and the presence of comorbid medical or psychiatric disorders [32]. A brief overview of psychological and pharmacological treatments is provided below, with more specific recommendations in the individual sections for each anxiety and related disorder. Overview of psychological treatment Psychological treatments play an important role in the management of anxiety and related disorders. Regardless of whether formal psychological treatment is undertaken, patients should receive education and be encouraged to face their fears. Meta-analyses have demonstrated the efficacy of psychological treatments in group and individual formats in patients with panic disorder [54-56], specific phobia [57], SAD [58,59], OCD [60-63], GAD [55,64,65], or PTSD [66-69], particularly exposure-based and other cognitive behavioral therapy (CBT) protocols [70,71], as well as mindfulness-based cognitive therapy (MBCT) [72]. When choosing psychological treatments for individual patients, the forms of therapy that have been most thoroughly evaluated in the particular anxiety or related disorder should be used first. CBT is not a single approach to treatment, but rather a process that focuses on addressing the factors that

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Table 8 Key features of specific anxiety and related disorders Disorder

Key features

Panic disorder

• Recurrent unexpected panic attacks, in the absence of triggers • Persistent concern about additional panic attacks and/or maladaptive change in behavior related to the attacks

Agoraphobia

• Marked, unreasonable fear or anxiety about a situation • Active avoidance of feared situation due to thoughts that escape might be difficult or help unavailable if panic-like symptoms occur

Specific phobia

• Marked, unreasonable fear or anxiety about a specific object or situation, which is actively avoided (e.g., flying, heights, animals, receiving an injection, seeing blood)

Social anxiety disorder (SAD)

• Marked, excessive or unrealistic fear or anxiety about social situations in which there is possible exposure to scrutiny by others • Active avoidance of feared situation

Generalized anxiety disorder (GAD)

• Excessive, difficult to control anxiety and worry (apprehensive expectation) about multiple events or activities (e.g., school/work difficulties) • Accompanied by symptoms such as restlessness/feeling on edge or muscle tension

Obsessive–compulsive disorder (OCD)

• Obsessions: recurrent and persistent thoughts, urges, or images that are experienced as intrusive and unwanted and that cause marked anxiety or distress • Compulsions: repetitive behaviors (e.g., hand washing) or mental acts (e.g., counting) that the individual feels driven to perform to reduce the anxiety generated by the obsessions

Posttraumatic stress disorder (PTSD)

• Exposure to actual or threatened death, serious injury, or sexual violation • Intrusion symptoms (e.g., distressing memories or dreams, flashbacks, intense distress) and avoidance of stimuli associated with the event • Negative alterations in cognitions and mood (e.g., negative beliefs and emotions, detachment), as well as marked alterations in arousal and reactivity (e.g., irritable behavior, hypervigilance)

Adapted from reference [26].

caused and maintain the individual patient’s anxiety symptoms [73]. Some of the core components of CBT are shown in Table 9 [73]. CBT can be effectively delivered as individual or group therapy for most anxiety and related disorders. In addition, a variety of self-directed or minimal intervention formats (e.g., bibliotherapy/self-help books, or internet/ computer-based programs with or without minimal therapist contact) have demonstrated significant improvements in anxiety symptoms [74-79]. Meta-analyses have also shown that exposure therapy can be effectively administered in a virtual reality format [80,81]. These strategies may be particularly useful in cases where real-life exposure is difficult due to inconvenience, expense, or patient reluctance.

Psychotherapy and pharmacotherapy generally demonstrate about equivalent efficacy for the treatment of most anxiety and related disorders [71,82]. Results with combination therapy vary for the different anxiety disorders, and results have been conflicting [82,83] (see Sections 3– 9 for evidence and references regarding combination therapy). Therefore, current evidence does not support the routine combination of CBT and pharmacotherapy as initial treatment. However, when patients do not benefit from CBT or have a limited response, a trial of pharmacotherapy is advisable. Similarly, patients who show limited benefit from pharmacotherapy may benefit from CBT. All patients being treated with pharmacotherapy should be instructed to gradually face their fears (exposure to decrease avoidance).

Table 9 Components of cognitive behavioral interventions Exposure

• • • •

Safety response inhibition

• Patients restrict their usual anxiety-reducing behaviors (e.g., escape, need for reassurance) • Decreases negative reinforcement • Coping with anxiety without using anxiety-reducing behavior enhances self-efficacy

Cognitive strategies

• Cognitive restructuring, behavioral experiments, and related strategies target patients’ exaggerated perception of danger (e.g., fear of negative evaluation in SAD) • Provides corrective information regarding the level of threat • Can also target self-efficacy beliefs

Arousal management

• Relaxation and breathing control skills can help patient control increased anxiety levels

Surrender of safety signals

• Patient relinquishes safety signals (e.g., presence of a companion, knowledge of the location of the nearest toilet) • Patients learn adaptive self-efficacy beliefs

Adapted from reference [73].

Encourage patients to face fears Patients learn corrective information through experience Extinction of fear occurs through repeated exposure Successful coping enhances self-efficacy

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Overview of pharmacological treatment This section provides a general overview of some of the commonly recommended pharmacological agents. Evidence and recommendations for specific medications are described in the individual sections for each of the anxiety and related disorders. Table 10 shows medications that have Health Canada approved indications for use in different anxiety and related disorders [84], and dosing suggestions are shown in Additional file 1. Various antidepressants including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), noradrenergic and specific serotonergic antidepressants (NaSSAs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and reversible inhibitors of monoamine oxidase A (RIMAs) have demonstrated some efficacy in the treatment of anxiety and related disorders (see Sections 3–9 for evidence and references). SSRIs and SNRIs are usually preferred as initial treatments, since they are generally safer and better tolerated than TCAs or MAOIs [32]. Benzodiazepines may be useful as adjunctive therapy early in treatment, particularly for acute anxiety or agitation, to help patients in times of acute crises, or while waiting for onset of adequate efficacy of SSRIs or other antidepressants [32]. Due to concerns about possible dependency, sedation, cognitive impairment, and other side effects, benzodiazepines should usually be restricted

to short-term use, and generally dosed regularly rather than as-needed [32]. Several anticonvulsants and atypical antipsychotics have demonstrated efficacy in some anxiety and related disorders, but for various reasons, including side effects, as well as limited randomized controlled trial (RCT) data and clinical experience, these agents are generally recommended as second-line, third-line, or adjunctive therapies (see Sections 3–9 for evidence and references). The choice of medication should take into consideration the evidence for its efficacy and safety/tolerability for the treatment of the specific anxiety and related disorder, as well as for any comorbid conditions the patient might have, in both acute and long-term use. Safety and side effects Antidepressants: The most common side effects seen with SSRIs and SNRIs include headache, irritability, gastrointestinal complaints, insomnia, sexual dysfunction, weight gain, increased anxiety, drowsiness, and tremor [85-88]. Patients report that the most common bothersome side effects are sexual dysfunction, drowsiness, fatigue, and weight gain [87,88]. Most side effects occur early and transiently during the first two weeks of treatment, but others, such as sexual dysfunction and weight gain, may persist for the duration of treatment [85,87,89]. Use of SSRIs or SNRIs has been associated with an increased risk of upper gastrointestinal bleeding,

Table 10 Medications with Health Canada–approved indications for anxiety and related disorders Anxiety disorders

Panic disorder

Social anxiety disorder

Obsessive–compulsive disorder

Generalized anxiety disorder

Escitalopram (Cipralex®)

X

X

Fluoxetine (Prozac®)

X

Posttraumatic stress disorder

ANTIDEPRESSANTS SSRIs

Fluvoxamine (Luvox®)

X

Paroxetine (Paxil®)

X

X

Paroxetine CR (Paxil® CR)

X

X

Sertraline (Zoloft®)

X

X

X

X

X

TCAs Clomipramine

X

Other antidepressants Venlafaxine XR (Effexor® XR)

X

Duloxetine (Cymbalta®)

X

X X

AZAPIRONES Buspirone (BuSpar®, Buspirex®) BENZODIAZEPINES*

X X

Data from respective Canadian product monographs [84]. *Multiple generic and brand name products, consult product monographs: alprazolam, bromazepam, chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are indicated for anxiety disorders; alprazolam is also indicated for panic disorder. CR = controlled release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release.

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particularly when used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) [90,91]. SSRI use has also been associated with low bone mineral density [92,93], as well as an increased risk of fractures [94] and hyponatremia [95]. Abrupt discontinuation of SSRIs or SNRIs can lead to a discontinuation syndrome with gastrointestinal, psychiatric, vasomotor, and other symptoms [85,96]. Health Canada and the US Food and Drug Administration (FDA) require antidepressants to include a warning regarding an increased risk of suicidal ideation and behavior in children and adolescents [97,98]. The increased risk of suicidal behavior reported in pediatric patients [99] does not appear to be seen in adults, and may in fact be decreased [99,100]. Careful monitoring for evidence of self-harming or suicidal thoughts or behaviors is important in both adult and pediatric patients. SSRIs and SNRIs are generally better tolerated and safer than TCAs and MAOIs, having less anticholinergic effects, toxicity, lethality, and psychomotor or cognitive impairment [85,101]. MAOIs are generally reserved for second- or third-line treatment because of side effects, drug interactions, and dietary restrictions [32]. Anxiolytics: The most common side effects associated with benzodiazepines include primarily sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness [85]. Benzodiazepines are associated with withdrawal reactions, rebound, and dependence, with the risk being greater with short- and intermediate-acting compared to long-acting agents [102]. These agents should be used with caution in patients with SUDs [85,103]. Older patients (generally over 65 years of age) may be at high risk for falls and fractures due to psychomotor impairment associated with benzodiazepines [104,105]. Cognitive impairment has been reported [106], some of which may persist after cessation of therapy [107]. In particular, memory impairment has been associated with high-dose or high-potency benzodiazepines, particularly in older people [102,107]. Reported side effects of azapirones (buspirone) include dizziness, drowsiness, and nausea [32,108]. Atypical antipsychotics: Atypical antipsychotics are associated to varying degrees with weight gain, diabetes, and other metabolic side effects, including alterations in glucose and lipid levels [109-116]. Metabolic disturbances generally appear to be higher with olanzapine, intermediate with risperidone and quetiapine, and lower with aripiprazole, asenapine, lurasidone, and ziprasidone [109-114]. Atypical antipsychotics have varying sedative effects, with quetiapine, clozapine, asenapine, and olanzapine generally causing more sedation than ziprasidone, risperidone, lurasidone, or aripiprazole [111,115]. Data on cognitive effects are conflicting, with some studies suggesting improvements [111], while other data suggest greater

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cognitive dysfunction in patients using, versus those not using, antipsychotics [117]. Because of the risks of diabetes and weight gain, and the fact that there is limited RCT evidence of the efficacy of these agents in anxiety and related disorders, atypical antipsychotics are generally recommended as second-line, third-line, or adjunctive therapies (see Sections 3–9 for evidence and references). Anticonvulsants: Anticonvulsants are associated with gastrointestinal side effects, somnolence, weight gain, tremor, as well as dermatologic and hematologic side effects [111,118]. In addition, several anticonvulsants have a potential risk of serious rash, erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis [111]. Regular monitoring of serum medication levels and liver function is required for patients on divalproex [84,111]. Follow-up

Anxiety and related disorders are often chronic and a systematic approach to treatment should include patient education, assessment of comorbidities, and evidencebased pharmacological and psychological interventions with adequate monitoring and duration. Pharmacological treatment is often associated with a delay of about two to eight weeks in onset of symptom relief, with full response taking up to 12 weeks or more. Longer-term therapy has been associated with continued symptomatic improvement and the prevention of relapse, and therapy should be continued for at least 12-24 months for most patients [32]. Medication should be initiated at low doses and titrated to the recommended dosage range at one- to two-week intervals over four to six weeks. Once the therapeutic range has been achieved, improvement is usually seen over the next four to eight weeks. Followup should occur at two-week intervals for the first six weeks and monthly thereafter [32]. For a patient undergoing psychotherapy, the treatment schedule is structured around weekly contact with a therapist for about 12-20 weeks, although shorter protocols and minimal intervention programs have also proven effective (see Sections 3–9 for evidence and references). A followup appointment four weeks later and then every two to three months is usually sufficient [32]. Assessing response to treatment Therapy should seek to improve symptoms and distress. The optimal goal is full remission of symptoms and return to a premorbid level of functioning [32,85]. However, goals may need to be individualized for some patients with disorders that have been present since childhood as they may never have had adequate premorbid functioning. A response to therapy is often defined as a percentage reduction in symptoms (usually 25-50%) on an appropriate scale. Remission is often defined as loss of diagnostic status, a pre-specified low score on an appropriate disorder-specific scale, and

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no functional impairment in fully recovered patients as measured by a scale such as the Sheehan Disability Scale or SF-36 [32,119,120]. Objective scales can be used to help assess a patient’s progress. The Clinical Global Impression (CGI) scale is brief, comprehensive, and can easily be used at each appointment to assess improvement. The clinician-rated Hamilton Anxiety Rating Scale (HARS) can assess anxiety symptoms in general and is often used in clinical trials but is less practical in clinical practice. A variety of self-report and clinician-rated scales are available to assess the specific anxiety or related disorder.

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or related disorder, mood disorder, impulse-control disorder, or SUD [121,137]. MDD is very common, occurring in an estimated 35-40% of patients with panic disorder [121]. Panic disorder also frequently co-occurs with agoraphobia [138]. Panic disorder is more prevalent in patients with medical conditions, including thyroid disease, cancer, chronic pain, cardiac disease, irritable bowel syndrome, migraine, as well as allergic and respiratory diseases compared with the general population [85,139-141]. The presence of medical comorbidity is associated with greater severity of panic disorder symptoms and disability [140,142].

Panic disorder and agoraphobia Epidemiology

Diagnosis

The lifetime and 12-month prevalence of panic disorder have been estimated at 4.7-5.1% and 2.1-2.8%, respectively [121,122]. The estimated prevalence of panic attacks is considerably greater at 28.3% (lifetime) and 6.4-11.2% (12-month) [121,123]. Youth with panic attacks (which often do not meet diagnostic criteria for panic disorder) will frequently have or develop other psychiatric disorders including mood disorders (bipolar disorder and MDD), other anxiety or related disorders, SUDs, eating disorders, psychotic disorders, and personality disorders [122,124,125]. Annually, 8-10% of the general public will have a panic attack without ever developing any identifiable psychopathology [126]. About 40-70% of patients with panic disorder experience nocturnal panic (waking from sleep in a state of panic) [127]. Rates of 12-month and lifetime agoraphobia (without panic) are quite low, at 0.8% and 1.4%, respectively [2,3]. The risk of panic disorder and agoraphobia is higher in women than men, and patients who are middle-aged, widowed/divorced, and those of low income [122]. In the Canadian Community Health Survey 1.2 (CCHS 1.2) there were no differences in the rates of panic disorder or agoraphobia in urban versus rural settings [128]. Panic disorder has a negative impact on both psychological and physical functioning, and puts a substantial burden on the patient’s family [13]. Patients with panic disorder have more QoL impairment and dissatisfaction [16,17], greater likelihood of suicide attempts [20], and increased cognitive and emotional dysfunction [129-133] compared to healthy controls. Panic disorder is also associated with substantial societal costs [134], both in terms of health care utilization [135] and loss of workplace productivity [136]. In a 2012 survey, panic disorder conferred a substantial rate of work absenteeism (mean: 36.0 days/year) [136].

For a diagnosis of panic disorder, a patient must have had recurrent, unexpected panic attacks (Table 11), followed by at least one month of persistent concern or worry about further attacks or their consequences, or a significant maladaptive behavioral change related to attacks (Table 12) [26]. A panic attack continues to be considered a noncodable event in the DSM-5, with only minor revisions, including removal of the “10-minute” window, changing “hot flushes” to “heat sensations,” and the re-ordering of the list of symptoms to increase clinical utility [26,143]. Compared to the DSM-IV-TR [144], changes to the diagnostic criteria for panic disorder largely consisted of minor phrasing changes to improve clinical utility, with the most substantial change being the title of the disorder [26,143]. The DSM-5 now lists agoraphobia (anxiety about having a panic attack in certain situations, which are avoided or endured with marked distress) as a separate codable disorder, whereas previously panic disorder could be diagnosed as “panic disorder with agoraphobia” or “panic disorder without agoraphobia” [26,145]. For a diagnosis of agoraphobia, a patient must have intense fear about at least two different types of

Comorbidity

Patients with panic disorder, or those experiencing panic attacks, have significantly increased odds of being diagnosed with a comorbid disorder, including another anxiety

Table 11 DSM-5 criteria for panic attacks • An abrupt surge of intense fear or intense discomfort that reaches a peak within minutes, and includes ≥4 of the following symptoms: (1) Palpitations, pounding heart, or accelerated heart rate (2) Sweating (3) Trembling or shaking (4) Sensations of shortness of breath or smothering (5) Feelings of choking (6) Chest pain or discomfort (7) Nausea or abdominal distress (8) Feeling dizzy, unsteady, light-headed, or faint (9) Chills or heat sensations (10) Paresthesias (numbness or tingling sensations) (11) Derealization (feelings of unreality) or depersonalization (being detached from oneself) (12) Fear of losing control or going crazy (13) Fear of dying Adapted from reference [26].

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Table 12 DSM-5 diagnosis of panic disorder • The person has experienced both of the following: ○ Recurrent unexpected panic attacks ○ ≥1 of the attacks followed by ≥1 month of 1 or both of the following: • Persistent concern or worry about additional panic attacks or their consequences • Significant maladaptive change in behavior related to the attacks Adapted from DSM-5 [26].

situations, with the fear resulting from thoughts that escape may be difficult or help may be unavailable if panic-like symptoms occur (Table 13) [26,145]. The situations provoke anxiety and are avoided or endured with intense fear or anxiety, or may require that a companion be present. The resultant fear or anxiety is out of proportion to any actual danger from the situation, causes substantial functional impairment, and usually lasts for six months or longer [26]. While the most up-to-date DSM-5 diagnostic criteria are presented here, the treatment data described within this section are based on studies involving patients meeting DSM-IV panic criteria (or older). Establishing the context in which panic attacks occur, and whether there is any prior history of recurrent, unexpected panic attacks, is important for accurate diagnosis. Panic attacks frequently occur in other psychiatric disorders (e.g., MDD, PTSD), and medical conditions (e.g., cardiac, respiratory), and the DSM-5 has identified panic attacks as a specifier to be used in the absence of a diagnosable panic disorder [85]. Another disorder may better account for the panic attacks; for example, panic attacks in social situations may be SAD, those related to defined phobic objects or situations may be specific phobia, those related to reminders of traumatic events Table 13 DSM-5 diagnosis of agoraphobia • Marked fear or anxiety about ≥2 of the following 5 groups of situations: (1) Public transportation (e.g., traveling in automobiles, buses, trains, ships, or planes) (2) Open spaces (e.g., parking lots, market places, or bridges) (3) Being in shops, theatres, or cinemas (4) Standing in line or being in a crowd (5) Being outside of the home alone in other situations • The individual fears or avoids these situations due to thoughts that escape might be difficult or help might not be available in the event of panic-like symptoms • The agoraphobic situations almost always provoke fear or anxiety • The situations are actively avoided, require presence of a companion, or endured with marked fear or anxiety • The fear or anxiety is out of proportion to actual danger posed by agoraphobic situation • The fear, anxiety, or avoidance is persistent, typically lasting ≥6 months • The fear, anxiety, and avoidance cause clinically significant distress or functional impairment Adapted from DSM-5 [26].

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may be PTSD [26,85], and those related to being kidnapped by extraterrestrials may be schizophrenia [26]. Some medical conditions that can be associated with panic symptoms include hyper- or hypothyroidism, hypoglycemia, seizure disorders, and cardiac conditions [26,85]. Panic attacks may also be associated with intoxication or withdrawal from drugs of abuse, medications such as decongestants, stimulants, or beta-adrenergic agonist inhalers, or caffeine [85]. Psychological treatment

CBT has been extensively studied, and is an efficacious psychological treatment for panic disorder (Level 1) [56,70,146,147]. In fact, CBT was significantly favored over medications for the treatment of panic disorder in a meta-analysis [71]. In a meta-analysis of 42 studies, exposure and combinations of exposure, cognitive restructuring and other CBT techniques had the most consistent evidence of efficacy for the treatment of panic disorder [56]. Strategies that included exposure were the most effective for panic measures. For measures of agoraphobia, combined strategies were more effective than single techniques, which did not result in significant improvements. Factors that improved the effectiveness of treatments were the inclusion of homework and a follow-up program [56]. Another meta-analysis also found that CBT that included interoceptive exposure was superior to relaxation therapy for panic symptoms [55]. CBT can be effectively delivered in both individual and group settings [56,148,149]. Conducting exposure in virtual reality appears to be effective when used as part of a CBT protocol [150-154]. Minimal intervention formats, such as self-help books (bibliotherapy) [75,76,155-158], treatment via telephone/ videoconferencing [75,159-161], and internet-based CBT (ICBT) [75,79,162-169] have been shown to be more effective than wait-list or relaxation controls, as effective as face-to-face CBT, and may be cost-effective options particularly for agoraphobic patients who are unwilling or unable to attend a clinic. When using bibliotherapy, providing information all at one time was as effective as pacing [157], and therapist support does not appear to be essential [75,158]. Most ICBT programs have some therapist contact by either telephone or email, and once weekly contact appeared to be as effective as more frequent contact [168]. CBT panic disorder protocols usually involve 12-14 weekly sessions, but briefer strategies of six to seven sessions have been shown to be as effective [148,149,170]. In addition, compressing the duration of therapy by administering 13 sessions over three weeks has also been shown to be as effective as traditional weekly CBT [171]. Patients with higher baseline severity, disability, or comorbidity may have better outcomes with standard

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CBT [172]. CBT programs sometimes include one or more follow-up or “booster” sessions [170,173]. Predictors of decreased response to CBT were severity of panic disorder, strength of blood/injury fears, earlier age of initial onset of panic symptoms, comorbid social anxieties, and degree of agoraphobic avoidance [174,175]. Changes in symptoms are preceded by changes in beliefs during therapy [176], and change in beliefs and avoidance behaviors are considered key process variables [170,176]. Eye movement desensitization and reprocessing (EMDR) does not appear to offer advantages over the same strategy without the eye movement component for the treatment of panic disorder [177,178]. Combined psychological and pharmacological treatment

A meta-analysis of 21 trials found that combination psychotherapy and pharmacotherapy with antidepressants was superior to CBT or pharmacotherapy alone during the acute treatment phase and while medication was continued [179,180]. After termination of treatment, combined therapy was more effective than pharmacotherapy alone and was as effective as psychotherapy [179,180]. Prior meta-analyses have reported similar findings [54,146,181], suggesting that CBT alone or CBT combined with pharmacotherapy should be considered as first-line treatment. A meta-analysis of the combination of psychotherapy and benzodiazepines included only three trials, and found no benefit to combination therapy compared with psychotherapy or medication alone [182]. The follow-up data suggested that the combination might be inferior to behavior therapy alone [182]. Adding self-administered CBT to SSRI therapy did not result in significant improvements overall, but patients did report a significantly greater rate of decline in fear of bodily sensations compared to medication alone [183]. Early results suggest a benefit of MBCT as an adjunct to pharmacotherapy in relieving anxiety and depressive symptoms in patients with panic disorder [184,185]. Providing CBT sessions around the time of medication discontinuation was associated with a lower relapse rate during follow-up among patients treated with antidepressants [186]. In addition, CBT has been shown to be helpful in facilitating benzodiazepine discontinuation [187,188]. A cost-effectiveness study found that combined CBT and pharmacotherapy was associated with a robust clinical improvement compared to usual care, with only a moderate increase in costs [189]. In a RCT, buspirone enhanced the effects of CBT in the short-term, but had no significant benefit over CBT alone during long-term follow-up [190]. Data on the efficacy of d-cycloserine as an adjunct to CBT are conflicting, with one study suggesting significant benefits at posttreatment and one-month follow-up

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[191], while another found an acceleration of symptom reduction in severely ill patients but no significant improvement in outcomes overall [192] compared to CBT plus placebo. Another compound acting at the N-methyl-D-aspartate (NMDA) receptor, Org 25935, demonstrated no benefit over placebo in augmenting CBT for panic disorder [193]. Long-term effects of psychological treatment

In naturalistic long-term follow-up studies, the benefits of CBT were maintained for up to three years [148,169, 170,188]. At two-year follow-up, individual, group, and brief CBT were associated with lower relapse rates compared to the wait-list control [148]. A long-term follow-up study of patients who had become panic-free with exposure therapy found that 93% remained in remission after two years and 62% after 10 years [194]. A meta-analysis found that at six to 24 months followup, remission/response rates with the combination of psychotherapy and antidepressants continued to be superior to antidepressants alone, or to psychotherapy as long as therapy was continued [179,180]. Pharmacological treatment

The management of patients with panic disorder should follow the principles discussed in Section 2. Pharmacological interventions that have good evidence for efficacy in treating panic disorder include SSRIs, TCAs, and other antidepressants, as well as benzodiazepines. Treatments that have been investigated for use in panic disorder have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 14 and 15. First-line agents

SSRIs: Evidence from meta-analyses [195-197] and RCTs supports the use of the SSRIs citalopram [198-200], fluoxetine [201-204], fluvoxamine [195,205-210], paroxetine [211-219], and sertraline [183,220,221,223,224] (all Level 1), as well as escitalopram [198] and paroxetine controlled-release (CR) [225] (both Level 2) for the treatment of panic disorder. In meta-analyses, SSRIs demonstrated significant improvements in panic symptoms, agoraphobic avoidance, depressive symptomatology, and general anxiety [195-197,226]. Effect sizes for SSRIs and TCAs are similar [195,196], although dropout rates may be lower with SSRIs [195]. SNRIs: Venlafaxine extended-release (XR) has been shown to be useful in reducing the severity of panic disorder symptoms in RCTs (Level 1) [215,216,227-229]. Two studies found significantly greater rates of panicfree patients compared with placebo [215,216] while two did not [228,229]. Second-line agents

TCAs: There is good evidence from RCTs to support the use of the TCAs clomipramine [199,211,213,232,233]

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Table 14 Strength of evidence for pharmacotherapy for panic disorder Agent

Level of evidence

Agent

Level of evidence

Antidepressants SSRIs

TCAs

Citalopram [198-200]

1

Clomipramine [199,211,213,232,233]

1

Fluoxetine [201-204]

1

Imipramine [207,224,233-240]

1

Fluvoxamine [195,205-210]

1

MAOIs and RIMAs

Paroxetine [211-219]

1

Phenelzine [240]

2

Sertraline [183,220-224]

1

Moclobemide [204,232,241,242]

1* 3

Escitalopram [198]

2

Tranylcypromine [243]

Paroxetine CR [225]

2

Other antidepressants

SNRIs

Reboxetine [200,219,244]

1

Venlafaxine XR [215,216,227-229]

1

Mirtazapine [203,245,246]

2

Duloxetine [230]

3

Bupropion SR [247,248]

3*

Milnacipran [231]

3

Other therapies Anxiolytics Benzodiazepines Alprazolam [234,249-254]

1

Atypical antipsychotics Risperidone [217,267]

2

Olanzapine [268]

3

Clonazepam [218,250,255-258]

1

Quetiapine [267]

3

Lorazepam [251,259,260]

1

Adjunctive aripiprazole [269]

3

Diazepam [261-263]

1

Adjunctive olanzapine [270]

3

Adjunctive clonazepam [264,265]

1

Adjunctive risperidone [271]

3

Adjunctive alprazolam ODT [266]

3

Anticonvulsants

Other treatments Buspirone [254,282]

1 (-ve)

Divalproex [272-275] Levetiracetam [276]

Trazodone [283]

2 (-ve)

Gabapentin [277]

2 (-ve)†

Propranolol [262,284,285]

2 (-ve)

Tiagabine [278,279]

2 (-ve)

Adjunctive pindolol [286]

2

Carbamazepine [280]

3 (-ve)

Adjunctive divalproex [281]

3 3

3

*Conflicting data. †No significant superiority over placebo in overall population, but significant benefits in subgroup of more severely ill patients. CR = controlled release; MAOI = monoamine oxidase inhibitor; ODT = orally disintegrating tablets; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin– norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR = extended release; (-ve) = negative.

and imipramine [207,224,233-240] in panic disorder (Level 1). In meta-analyses, TCAs have demonstrated efficacy for the treatment of panic symptoms and agoraphobia [195-197,226]. Efficacy is generally equivalent to SSRIs, however, since TCAs tend to be less well tolerated and have higher discontinuation rates than SSRIs [195], they are recommended as second-line options.

Other antidepressants: Although there is level 1 evidence to support the use of reboxetine [200,219,244], limited experience with this agent in Canada, and its side effect profile, which includes dry mouth, constipation, and insomnia [244], led to its recommendation as a second-line option. Mirtazapine has demonstrated efficacy for the treatment of panic disorder in several open

Table 15 Recommendations for pharmacotherapy for panic disorder First-line

Citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, paroxetine CR, sertraline, venlafaxine XR

Second-line

Alprazolam, clomipramine, clonazepam, diazepam, imipramine, lorazepam, mirtazapine, reboxetine

Third-line

Bupropion SR, divalproex, duloxetine, gabapentin, levetiracetam, milnacipran, moclobemide, olanzapine, phenelzine, quetiapine, risperidone, tranylcypromine

Adjunctive therapy

Second-line: alprazolam ODT, clonazepam Third-line: aripiprazole, divalproex, olanzapine, pindolol, risperidone

Not recommended

Buspirone, propranolol, tiagabine, trazodone

CR = controlled release; ODT = orally disintegrating tablets; SR = sustained release; XR = extended release.

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trials [245,246] and one small RCT [203] (Level 2). It appears to be as effective as fluoxetine [203] and may be a useful second-line choice. Benzodiazepines: Alprazolam [234,249-254], clonazepam [218,250,255-258], lorazepam [251,259,260], and diazepam [261-263] have demonstrated efficacy for the treatment of panic disorder (Level 1). While it has been suggested that alprazolam may be more effective, a metaanalysis found no evidence that it was superior to other benzodiazepines for the treatment of panic disorder [252]. Although benzodiazepines are second-line options, they may be useful at any time during therapy for the short-term management of acute or severe agitation or anxiety. They may also be useful at the initiation of SSRI treatment to hasten response (Level 1) [264-266]. Third-line agents

MAOIs and RIMAs: Results with moclobemide for the management of panic disorder have been conflicting (Level 1). In clinical trials, moclobemide demonstrated efficacy similar to that of clomipramine and fluoxetine [204,232], but was not superior to placebo [241,242]. However, significant efficacy in more severely ill patients [241], suggests it may be useful in treatment-resistant patients. In a RCT, phenelzine was more effective than placebo and as effective as imipramine (Level 2) [240]. In a small randomized, uncontrolled trial, tranylcypromine demonstrated efficacy for patients with comorbid panic and social anxiety disorders (Level 3) [243]. Atypical antipsychotics: There is some evidence that atypical antipsychotics may have some benefits in the treatment of patients with refractory panic disorder [217,267,268]. In a RCT, risperidone monotherapy was as effective as paroxetine (Level 2) [217]. Open-label data also support the use of risperidone [267], olanzapine [268], and quetiapine [267]. There are also open-label data supporting the use of some atypical antipsychotics as adjunctive therapy (see below). Other therapies: The antidepressants duloxetine [230], milnacipran [231], and bupropion sustained release (SR) [247,248] have shown some efficacy in open trials, as have the anticonvulsants divalproex [272-275] and levetiracetam [276] (all Level 3). In a RCT, gabapentin was superior to placebo in patients who were more severely ill, but not in the overall group (Level 2, negative) [277]. These agents are recommended only as third-line options in patients with refractory panic disorder. Adjunctive therapy

There is good evidence that adjunctive clonazepam [264,265] (Level 1), and open-label evidence that adjunctive alprazolam orally-disintegrating tablet (ODT) [266] (Level 3), used short-term (1 h/day) or cause clinically significant distress or functional impairment • Specify patient’s degree of insight as to reality of OCD beliefs: ○ Good or fair insight (i.e., definitely or probably not true) ○ Poor insight (i.e., probably true) ○ Absent insight (i.e., completely convinced beliefs are true) • Specify if “tic-related” OCD Adapted from DSM-5 [26].

hair-pulling disorder (trichotillomania), and skin picking disorder [26]. Most of the other modifications to the OCD diagnostic criteria in the DSM-5 were minor wording changes designed to enhance clarity or further operationalize concepts that were considered too vague [26]. In particular, the definitions of obsessions and compulsions were clarified and simplified [26,654]. The requirement that the patient recognizes that the obsessions or compulsions are “excessive or unreasonable” has been deleted, since these terms are subject to interpretation and patients can have varying levels of insight. As a result, the previous DSMIV-TR specifier of “poor insight” has been expanded to include: good or fair, poor, and absent insight [26]. Finally, a specifier of “tic-related” OCD has been added [26]. While the most up-to-date DSM-5 diagnostic criteria are presented here, it is important to note that most of the treatment data described within this section are based on patients meeting DSM-IV criteria (or older). Psychological treatment

Meta-analyses support the beneficial effects of psychological treatment for OCD, mainly CBT, generally including exposure with response prevention (ERP) [60-63,70,71, 655-657]. CBT is equivalent or superior to pharmacotherapy [71,658-660]. Results with CBT were generally similar in comparisons of interventions with an emphasis on ERP and those with an emphasis on cognitive elements [60,63,655]. A treatment specifically designed to address fear of contamination with infectious substances, using a cognitive intervention that includes no direct exposure

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(“danger ideation reduction therapy, DIRT”), was found to be more efficacious than ERP [661,662]. Cognitive interventions may be important in patients who do not have overt compulsions, which can make ERP more difficult. One meta-analysis found that exposure in vivo combined with imaginal exposure was better than exposure in vivo alone [60]. Several meta-analyses have demonstrated no significant differences in efficacy between group and individual CBT [60,62,663]. However, results of head-to-head trials are conflicting, with some RCTs finding no significant differences in efficacy between group and individual therapy [663,664], and others showing individual therapy to be superior [665-667]. Differences in results may be explained by the fact that in individual therapy the therapist may have the advantage of being more aware of the patient’s dysfunctional beliefs, however, the group therapy setting may offer the advantages of group encouragement, reciprocal support, imitation, and interpersonal learning which may result in an increased motivation and reduced discontinuation of treatment [62]. An important practical question concerns the intensity and duration of treatment. The intensive ERP program described by Foa’s group involves 15 two-hour sessions scheduled five days a week over three weeks [658,668]. A similar program administered twice-weekly (a more practical approach for many patients and therapists) was as effective at the end of follow-up as the intensive fivedays/week strategy [669]. A step-care approach in which patients received six weeks of low-intensity counseling with ERP bibliotherapy followed by standard ERP for non-responders only was found to be as effective as initial therapy with standard ERP (17 sessions twice weekly), but was significantly less costly [670]. Other techniques that may be useful include acceptance and commitment therapy (ACT) [671], modular cognitive therapy (CT) addressing OCD beliefs [672,673], CT addressing obsessional doubt [674], organizational training [675,676], and mindfulness training [677]. RCTs on the benefits of adding motivational interviewing to CBT have been conflicting, with one showing no additional benefits [678], while another demonstrated improved symptom reduction and remission rates compared with CBT alone [679]. While EMDR was more effective than an SSRI in a RCT [680], data are limited and this technique is not generally recommended for patients with OCD. Data suggest that therapist-guided exposure is better than self-exposure [60]. While both treatment conditions showed significant symptom reduction, therapistadministered ERP was superior to self-administered ERP in improving OCD symptoms and self-reported functional impairment [681]. Other data suggest that ERP

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delivered by telephone is equivalent to face-to-face ERP [682]. Bibliotherapy in the form of self-help manuals delivered to patients via email has demonstrated significantly greater improvements in OCD symptoms compared with wait-list control groups in two RCTs [683,684]. ICBT is an easily accessible treatment that has the potential to reach untreated patients and motivate them for face-to-face psychotherapy if necessary [684,685]. Several RCTs have demonstrated that ICBT programs are significantly more effective than supportive therapy or relaxation control strategies [685-687]. ICBT was as effective as therapist-led CBT only when patients completed at least one self-exposure session [687]. ICBT was associated with significantly better outcomes when it included brief, scheduled, therapist-initiated telephone support compared with on-demand phone support [688]. Family accommodation (i.e., family members taking part in the performance of rituals, avoidance of anxietyprovoking situations, or modification of daily routines to assist a relative with OCD) has been associated with poorer response to both behavioral and pharmacological treatments [689]. Clinicians may want to consider targeting family accommodation in order to improve treatment outcomes for some patients. Although hoarding disorder is now a separate diagnosis [690], the limited data available on the treatment of hoarding will be mentioned in this section on OCD. One RCT found that group CBT significantly reduced hoarding and depression symptoms while bibliotherapy alone was associated with very limited improvements [691]. The addition of posttreatment, nonclinician, home assistance did not significantly improve outcomes.

Pharmacological treatment

Combined psychological and pharmacological treatment

Clomipramine: There is good evidence to support the use of clomipramine in the treatment of OCD (Level 1) [658,711,713,714,716-718,720,724,740,741]. Clomipramine has efficacy similar to SSRIs, but SSRIs are generally better tolerated [711,713,714,716-718,720,724]. Side effects and safety are issues with clomipramine and therefore it is recommended as a second-line choice. Common adverse effects include anticholinergic effects such as dry mouth, constipation, and blurred vision, as well as urinary retention, orthostatic hypotension, weight gain, and sedation [813,814]. The major safety concerns are cardiac arrhythmias, seizures, drug interactions, and toxicity in overdose [813,814]. Antidepressants: In RCTs, citalopram was more effective than placebo but less effective than psychotherapy (Level 2) [680,726]. Additional data from augmentation studies support the efficacy of citalopram for the treatment of OCD [727,728]. However, given that other SSRIs have much stronger evidence, citalopram was designated a second-line option. The only RCT data on

The combination of psychological and pharmacological treatment has been shown to be superior to medication alone [657,658,692-694], but not to CBT alone [83,658, 692,694,695]. These findings suggest that if pharmacotherapy is required or preferred, adding CBT to pharmacological treatment of OCD may enhance response rates and reduce relapse rates. Unlike in some anxiety and related disorders, there does not appear to be any contraindication to combining CBT with medications in patients with OCD [696], and combined treatment may improve relapse prevention [697]. Adding d-cycloserine may hasten the onset of improvements with ERP, with significant benefits over placebo during the first four or five ERP sessions [698-700], but this effect has not been seen in all studies [701]. Long-term effects of psychological treatment

Follow-up studies suggest that the benefits of CBT are maintained at one to five years of follow-up [664,695, 702-704].

The management of patients with OCD should follow the principles discussed in Section 2. SSRIs are recommended first-line pharmacological interventions for OCD, while SNRIs, clomipramine, and other antidepressants are recommended second- and third-line treatments. Treatments that have been investigated for use in OCD have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 26 and 27. First-line agents

SSRIs: Evidence from RCTs and meta-analyses support the use of SSRIs, including escitalopram [705-709], fluoxetine [660,710-716], fluvoxamine [711,713,714,717-719], paroxetine [705,720-722], and sertraline [659,710,711, 713,714,723-725] (all Level 1), in the treatment of OCD. In meta-analyses, response rates with SSRIs are generally twice those of placebo [809], at 40-60% with treatment versus 3 days but less than one month may be diagnosed as acute stress disorder (ASD), if the required ASD criteria are met [26]. Compared to the DSM-IV-TR [144], changes to the diagnostic criteria for PTSD in the DSM-5 include adjusting the symptom clusters, adding some new symptoms, and re-classifying PTSD as a ‘‘trauma- and stressor-related disorder’’ instead of an anxiety disorder [26,875]. In addition to PTSD, this new category also includes diagnostic criteria for reactive attachment disorder, disinhibited social engagement disorder, ASD, and adjustment disorders [26]. The DSM-5 diagnostic criteria for PTSD sharpens the definition of “traumatic event,” and there are now four symptom clusters rather than three with the “avoidance” and “numbing of responsiveness” being separated (Table 28). The DSM-5 also eliminated the acute and chronic PTSD specifiers. The PTSD diagnostic criteria apply to adults, adolescents, and children >6 years of age. A subtype has been added for children ≤6 years of age, as well as a dissociative symptoms specifier for patients of all ages [26]. While the most up-to-date DSM-5 diagnostic criteria are being presented here, it is important to note that the treatment data described within this section are based on patients meeting DSM-IV criteria (or older). PTSD is frequently comorbid with other psychiatric disorders, including other anxiety and related disorders, MDD, and SUDs, which may complicate diagnosis and management [849,859]. In addition, patients with PTSD frequently present with somatic symptoms and pain [859]. It is important to ask patients with psychological or somatic symptoms about trauma [32,859].

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Table 28 DSM-5 diagnosis of PTSD • The person has been exposed to actual or threatened death, serious injury, or sexual violation in ≥1 of the following ways: ○ Directly experienced or witnessed the traumatic event, learned that trauma occurred to close family member or friend (actual or threatened death must have been violent or accidental), experienced repeated exposure to aversive details of trauma • Presence of ≥1 of the following intrusion symptoms associated with the trauma: ○ Recurrent, involuntary, and intrusive distressing memories, distressing dreams, dissociative reactions (e.g., flashbacks), psychological or physiological distress at reminders of trauma • Persistent avoidance of stimuli associated with the trauma, including ≥1 of the following: ○ Avoidance of distressing memories or feelings and external reminders (e.g., people, places) of the trauma • Negative alterations in cognitions and mood associated with the trauma, including ≥2 of the following: ○ Inability to recall important aspect of the trauma, diminished interest or participation in activities, feeling of detachment or estrangement from others, persistent negative beliefs, distorted blame, and negative emotional state • Marked alterations in arousal and reactivity associated with the trauma, including ≥2 of the following: ○ Irritable or aggressive behavior, reckless or self-destructive behavior, hypervigilance, exaggerated startle response, problems with concentration, sleep disturbance • Duration of disturbance >1 month • Symptoms cause clinically significant distress or impaired functioning • Specify whether with dissociative symptoms (depersonalization or derealization) or with delayed expression (full criteria not met until at least 6 months after the event) Adapted from DSM-5 [26].

Prevention and early intervention

A number of studies have assessed early intervention with psychological and pharmacological strategies for the prevention of PTSD. Meta-analyses do not support the efficacy of wide spread use of single-session [876,877] or multiple-session [878] psychological debriefing after trauma in preventing or reducing the intensity of PTSD in individuals who have been exposed to a traumatic event but have not been identified as suffering from any specific psychological difficulties. In fact, these interventions may have an adverse effect on some individuals [876,878]. These findings pertain to individual debriefings only; there is insufficient evidence to comment on the utility of group debriefings. Conversely, meta-analyses have demonstrated the benefit of multisession trauma-focused-CBT (TF-CBT) in patients with ASD or PTSD [879,880]. Therefore, debriefing of all trauma victims is not recommended, rather, screening and treating appropriate individuals is preferred [876]. For the prevention of chronic PTSD in patients with ASD or acute PTSD, brief TF-CBT was more effective than both wait-list and supportive counseling interventions, but there was no evidence of the effectiveness of structured writing compared to minimal intervention [880]. There are few data on the use of pharmacotherapy for the prevention of PTSD. In a cohort study and a RCT, the early use of benzodiazepines following trauma was not beneficial, and may increase the risk of developing PTSD [881,882]. Similarly, retrospective data suggested that gabapentin or pregabalin had no effect on PTSD development [883]. Data from cohort studies on the use of the beta-blocker propranolol have been conflicting [884-888], but one small RCT did show a significant decrease in the severity of PTSD symptoms and lower

likelihood of developing subsequent PTSD [889]. SSRI therapy was significantly more effective than placebo in preventing PTSD symptoms according to parent reports but not child reports in a RCT in children [890]. Cohort studies suggest that the early use of morphine during trauma care may reduce the risk of the subsequent development of PTSD in children and adults [891-894]. Psychological treatment

Psychological therapies for PTSD generally include education about the disorder and its treatment, as well as exposure to cues relating to the traumatic event. Psychotherapy has demonstrated significant efficacy, although a metaanalysis suggested it may be less effective than pharmacotherapy in improving PTSD and comorbid depression symptoms [895]. Meta-analyses of over 30 RCTs of psychological interventions provide evidence of the efficacy of several CBT approaches for the management of chronic PTSD compared with wait-list or usual care control groups [66,67]. There was evidence that individual TF-CBT, EMDR, stress management, and group TF-CBT were effective, while other nontrauma focused psychological treatments (supportive therapy, nondirective counseling, psychodynamic therapy, and hypnotherapy) did not reduce PTSD symptoms as significantly [66,67]. Individual TF-CBT and EMDR appeared to be equally effective, but superior to stress management in the treatment of PTSD [66]. Another meta-analysis also found EMDR and TF-CBT were equally effective [68]. However, in a head-to-head RCT, EMDR resulted in faster recovery compared with the more gradual improvement with brief TF-CBT [896]. Cognitive therapy approaches have been used effectively in treating PTSD following sexual or interpersonal violence [897-901], civilian trauma [902-908], and military trauma [909-914].

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Cognitive processing therapy (CPT) is an effective protocol that combines cognitive therapy and written accounts [899-901,910-913]; however, an analysis of the components found no differences in outcomes with either component alone or the combined protocol [899]. Prolonged exposure (PE) is a widely studied CBT approach. A meta-analysis of 13 RCTs concluded that PE therapy was more effective than wait-list or psychological placebo control conditions, and as effective as other active treatments (e.g., CBT, CPT, EMDR) [69]. One study found that 30-minute imaginal exposure sessions were as effective as 60-minute sessions [915]. Imaginal appears to be as effective as in vivo exposure [69,916]. Data are conflicting as to the benefits of adding cognitive restructuring to exposure therapy; several studies suggest that exposure alone is superior to the combination [917-919], however, another large RCT found the combination to be significantly better than imaginal or in vivo exposure alone [916]. When used as an adjunct to exposure therapy, cognitive restructuring may improve non-fear problems like anger and guilt, and may be a useful adjunct in patients in which these emotions predominate [920,921]. Similarly, the addition of social emotional rehabilitation to exposure therapy did not improve PTSD symptoms but did improve social functioning in male combat veterans with chronic PTSD [922]. Meta-analyses and systematic reviews reveal two current limitations of CBT for PTSD. The first is that about one-third to one-half of patients experience substantial residual symptoms and functional impairments posttreatment, still report symptoms meeting diagnostic criteria at follow-up, or relapse and require booster sessions [923-925]. The second issue pertains to external validity. While CBT for PTSD has been shown to be efficacious in RCTs, there is a dearth of effectiveness studies to suggest that CBT can be generalized to many patients commonly found in clinical practice. Many RCTs have excluded patients with complex clinical profiles including childhood abuse histories, current SUDs, personality disorders, suicidality or self-injurious behavior, homelessness, refugees, intimate partner violence, and significant dissociative symptoms among others [926,927]. In this regard, Bradley et al. [923] found a positive association between the number of exclusion criteria and the strength of effect sizes, such that studies with stricter inclusion criteria tended to report larger treatment effects. Additionally, numerous studies fail to report whether patients experience any adverse effects from psychological treatments [66], or whether dropout rates (ranging between 0-50%) result from treatment demands. Dialectical behavior therapy (DBT), which was developed to reduce self-harm behavior in patients with BPD, was shown to be useful in patients with PTSD [928-930]. When used as a pretreatment, DBT reduced self-harm

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behaviors allowing over half of patients to become suitable candidates for PTSD treatment [929]. Another study [931] demonstrated some success with PE treatment of PTSD and comorbid substance abuse. Results of a recent expert clinician survey on best practices suggests that CBT is useful for fear-based PTSD, while this treatment approach may require an additional treatment module targeting affective regulation for patients presenting with a diagnosis of Disorders of Extreme Stress (DESNOS) or complex PTSD [932]. Internet-based treatments are being increasingly investigated, in part because they can be administered remotely and anonymously to under-served or disaster-stricken areas at a relatively low-cost [933]. RCTs have shown that therapist-assisted ICBT is more effective than wait-list or supportive care control strategies in improving PTSD symptoms, depression, anxiety, and disability [934-940]. In addition, a strong therapeutic relationship can be established through the internet, which improved the treatment process [936]. VRE therapy has also demonstrated some utility in improving PTSD symptoms [941-943]. Compared to face-to-face CBT, video-conference CBT was equally effective [944] but telehealth CBT was less effective [914]; however, both were effective compared with pre-treatment. Combined psychological and pharmacological treatment

Research evaluating combined treatment in PTSD is limited; a meta-analysis found only four small trials [945]. Combination SSRI plus psychotherapy was not superior to psychotherapy alone in two RCTs [946,947], but was superior to pharmacotherapy alone in the other two trials [948,949]. In contrast, a more recent RCT found that combination therapy was superior to psychotherapy alone [950]. The role of combining psychotherapy and medication requires further study. Adjunctive propranolol with trauma reactivation therapy was found to help prevent reconsolidation of the traumatic memory and thus decreased physiological responses and PTSD symptoms during subsequent follow-up in randomized and open trials [951,952]. Two RCTs have found that use of d-cycloserine did not enhance the overall treatment effects of exposure therapy [953,954], and may in fact decrease response to psychotherapy [954]. Long-term effects of psychological treatment

Open follow-up data of psychological treatments suggest that benefits are maintained at six- to 18-month assessments after treatment [923,955-958]. Longer-term follow-up of patients treated with EMDR showed that benefits were maintained at three years, with the majority of patients who had initially remitted being at full working capacity [959]. Very long-term follow-up showed that improvements in PTSD and related symptoms achieved with CPT and PE were maintained over an extended five to 10 year period [901].

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Pharmacological treatment

The management of patients with PTSD should follow the principles discussed in Section 2. Pharmacological interventions that have good evidence for efficacy in treating PTSD include fluoxetine, paroxetine, sertraline, and venlafaxine XR. Treatments that have been investigated for use in PTSD have been assessed according to the criteria for strength of evidence (Tables 1 and 2) and are summarized in Tables 29 and 30. First-line agents

Antidepressants (SSRIs & SNRIs): Evidence from metaanalyses [895,1060] and RCTs supports the use of the SSRI paroxetine [966-970] and the SNRI venlafaxine XR [975,989] (both Level 1) for the first-line treatment of

PTSD. Data with fluoxetine are mixed, with both positive [960-962] and negative [963-965] RCTs (Level 1, conflicting). Similarly, RCTs with sertraline have yielded both positive [971,972,975,976,978] and negative [973,974,977] results (Level 1, conflicting). However, there appear to be sufficient data from the larger RCTs to suggest that these agents can be effective first-line options. Conflicting results may be related to the types of traumas, symptom clusters, and comorbidities included in the various studies. Second-line agents

Antidepressants: The efficacy of mirtazapine was demonstrated in one small RCT (Level 2) [1000] and three open trials [999,1001,1002]. In a randomized, open-label

Table 29 Strength of evidence of pharmacotherapy for core symptoms of PTSD Agent

Level of evidence

Agent

Level of evidence

Antidepressants SSRIs

TCAs

Fluoxetine [960-965]

1*

Imipramine [992,993]

Paroxetine [966-970]

1

Amitriptyline [994]

2

Sertraline [971-978]

1*

Desipramine [970,995]

2*

Fluvoxamine [979-984] Escitalopram [985] Citalopram [974,986,787,988]

2 3 2 (-ve)

SNRIs

1

MAOIs and RIMAs Phenelzine [992,993,996] Moclobemide [997,998]

1* 3

Other antidepressants

Venlafaxine XR [975,989]

1

Mirtazapine [999-1002]

2

Duloxetine [990,991]

3

Reboxetine [984]

2

Bupropion SR [1003]

3

Tianeptine [997,1004]

3

Adjunctive bupropion SR [1005]

2 (-ve)

Other therapies Anxiolytics

Anticonvulsants

Benzodiazepines

Topiramate [1009,1010]

1*

Alprazolam [1006]

2 (-ve)

Lamotrigine [1011]

2

Clonazepam [881,1007,1008]

3 (-ve)

Carbamazepine [1012,1013]

Atypical antipsychotics

3

Divalproex [1014-1017]

1 (-ve) 2 (-ve)

Risperidone [1030]

2

Tiagabine [1018]

Aripiprazole [1031-1033] Quetiapine [1034,1035]

3 3

Adjunctive gabapentin [1019,1020] Adjunctive levetiracetam [1021]

4 4

Olanzapine [1036-1038]

2 (-ve)

Adjunctive pregabalin [1022]

4

Adjunctive risperidone [1039-1044]

1*

Adjunctive tiagabine [1023-1025]

Adjunctive olanzapine [1045]

2

Adjunctive topiramate [1026-1029]

4 2 (-ve)

Adjunctive aripiprazole [1033,1046,1047]

3

Other treatments

Adjunctive quetiapine [1048-1050]

3

Buspirone [1051,1052]

4

Trazodone [1053]

4

Memantine [1054] Adjunctive eszopiclone [1055]

4 2

Adjunctive clonidine [1056]

3

Adjunctive guanfacine [1057,1058]

1 (-ve)

Adjunctive zolpidem [1059]

2 (-ve)

*Conflicting data. MAOI = monoamine oxidase inhibitor; RIMA = reversible inhibitor of monoamine oxidase A; SNRI = serotonin–norepinephrine reuptake inhibitor; SR = sustained release; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; XR=extended release; (-ve) = negative.

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Table 30 Recommendations for pharmacotherapy for core symptoms of PTSD First-line

Fluoxetine, paroxetine, sertraline, venlafaxine XR

Second-line

Fluvoxamine, mirtazapine, phenelzine

Third-line

Amitriptyline, aripiprazole, bupropion SR, buspirone, carbamazepine, desipramine, duloxetine, escitalopram, imipramine, lamotrigine, memantine, moclobemide, quetiapine, reboxetine, risperidone, tianeptine, topiramate, trazodone

Adjunctive therapy

Second-line: eszopiclone, olanzapine, risperidone Third-line: aripiprazole, clonidine, gabapentin, levetiracetam, pregabalin, quetiapine, reboxetine, tiagabine Not recommended: bupropion SR, guanfacine, topiramate, zolpidem

Not recommended

Alprazolam, citalopram, clonazepam, desipramine, divalproex, olanzapine, tiagabine

SR = sustained release; XR = extended release.

trial, response rates were significantly higher with mirtazapine than sertraline [1001]. Fluvoxamine demonstrated efficacy for PTSD in open trials [979-983], and in a RCT was as effective as reboxetine (Level 2) [984]. Phenelzine was more effective than placebo in two RCTs [992,993], but not significantly different from placebo in a RCT crossover study (Level 1, conflicting) [996]. Caution is needed when using MAOIs because of the dietary restrictions and potential for drug interactions. Third-line agents

The following agents are recommended as third-line options because of limited data, side effects, or lack of clinical experience as a primary therapy for the treatment of PTSD. Antidepressants: In small RCTs, imipramine (Level 1) [992,993] and amitriptyline (Level 2) [994] demonstrated some efficacy in patients with PTSD. Data with desipramine are mixed, with one RCT showing significant benefit, which were comparable to paroxetine [970], and the other showing improvements in depression only [995]. While RCTs with the TCAs suggest some benefit with these agents, it appears to be limited. Reboxetine and fluvoxamine were equally effective in a small RCT (both Level 2) [984], and open-label studies suggest that bupropion SR [1003], duloxetine [990,991], escitalopram [985], moclobemide [997,998], and tianeptine [997,1004] (all Level 3) may be useful in PTSD. Anticonvulsants: Data on topiramate are mixed, with one RCT finding significant benefits over placebo [1010], while the other did not [1009] (Level 1, conflicting). There are also limited data suggesting efficacy of other anticonvulsants, including lamotrigine (Level 2) [1011] and carbamazepine (Level 3) [1012,1013]. Atypical antipsychotics: Some data suggest that the atypical antipsychotics, risperidone (Level 2) [1030], aripiprazole (Level 3) [1031,1032], and quetiapine (Level 3) [1034,1035] may be a useful alternative to SSRIs for some patients with PTSD. A meta-analysis of seven RCTs using atypical antipsychotics, either as monotherapy or adjunctively, concluded that these agents may be beneficial in the treatment of PTSD, particularly for the symptom of “intrusion” [1061].

Other therapies: Small, open case series have suggested benefits with trazodone [1053], buspirone [1051,1052], and memantine [1054] (all Level 4). Adjunctive therapies

Adjunctive strategies have generally been studied in patients who have had an inadequate response to adequate antidepressant therapy, and can be considered for patients with treatment-resistant PTSD. Second-line adjunctive therapies: In a RCT, adjunctive eszopiclone was significantly more effective than placebo in improving PTSD and sleep symptoms (Level 2) [1055]. There is RCT evidence for the use of adjunctive atypical antipsychotics, including risperidone (Level 1, conflicting) [1039-1044] and olanzapine (Level 2) [1045], for patients with treatment-resistant PTSD. While a number of small RCTs demonstrated benefits with adjunctive risperidone [1039-1042], a large, six-month trial in approximately 250 patients failed to show improvements in PTSD symptoms compared with placebo [1043]. Third-line adjunctive therapies: Open-label trials and case series suggest that adjunctive quetiapine [1048-1050] or aripiprazole [1033,1046,1047] (both Level 3) are useful in patients with refractory PTSD. Similarly, there are some data suggesting adjunctive anticonvulsants including: gabapentin [1019,1020], levetiracetam [1021], pregabalin [1022], or tiagabine [1023-1025] (all Level 4), as well as the alpha-adrenergic agonist clonidine (Level 3) [1056], can improve symptoms in patients with treatment-resistant PTSD. Not recommended adjunctive therapies: Small RCTs failed to show the superiority of adjunctive therapy with guanfacine (Level 1, negative) [1057,1058], bupropion SR [1005] (Level 2, negative), or zolpidem [1059] (Level 2, negative). While case series suggested that adjunctive topiramate [1026,1027,1029] may be effective in treatment-resistant PTSD, a RCT failed to show superiority over placebo [1028] (Level 2, negative). Treatments for specific PTSD-associated symptoms

Several agents have been used to target particular symptoms associated with PTSD. Prazosin has demonstrated significant efficacy for reducing trauma nightmares and improving sleep quality in patients with PTSD compared

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with placebo (Level 1) [1035,1062-1066]. Some openlabel data suggest that naltrexone may help reduce flashbacks (Level 3) [1067-1070], and fluphenazine may improve trauma re-experiencing symptoms (Level 3) [1037]. Cyproheptadine was not effective for nightmares or sleep problems in patients with PTSD and may actually exacerbate sleep disturbance (Level 2, negative) [1071]. Not recommended

In general, data do not currently support the use of divalproex [1014-1017] (Level 1, negative), alprazolam [1006], citalopram [974,986-988], olanzapine [1036-1038], tiagabine [1018] (all Level 2, negative), or clonazepam (Level 3, negative) [881,1007,1008]. Maintenance pharmacological treatment

Long-term therapy has been evaluated in relapseprevention and naturalistic follow-up studies. Relapseprevention studies are those in which responders to SSRI therapy are randomized to continued active treatment or placebo. A meta-analysis of three relapseprevention studies included 272 patients with PTSD, and found a highly significant reduction in relapse rates with continued SSRI treatment compared with placebo over approximately six months (odds ratio for relapse was 0.25) [497]. In RCT discontinuation studies, fluoxetine [1072,1073] and sertraline [1074] have demonstrated significantly lower relapse rates over six months in the range of 5-22% with active treatment compared to 16-50% with placebo [1072-1074]. However, in a small discontinuation RCT, tiagabine was not superior to placebo in preventing relapse [1075]. Open follow-up studies with paroxetine [1076] and sertraline [1077] have demonstrated sustained and continued improvement over six to 12 months of continued SSRI therapy. Biological and alternative therapies

In general, these therapies may be useful for some patients; however, more data are needed. Biological therapies: In RCTs, rTMS was effective as monotherapy or as an adjunct to SSRIs in patients with PTSD (Level 1) [1078-1080], and at least some improvements were maintained at two to three months after treatment [1078,1079]. Open prospective and retrospective data suggest that adjunctive electroconvulsive therapy may be helpful in patients with refractory PTSD (Level 3) [1081,1082]. Alternative therapies: In a RCT, acupuncture was more effective than a wait-list control and as effective as group CBT (Level 2) [1083]. Adjunctive use of symptom-oriented hypnotherapy [1059] or mantra repetition [1084] (both Level 2) improved PTSD symptoms in small trials; and in a small case series, patients with

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PTSD benefited from transcendental meditation (Level 4) [1085]. Summary

The lifetime prevalence of PTSD is around 6-9%; it is more frequent in women than in men, with an onset generally in the mid to late 20s. PTSD is associated with high rates of functional impairment, somatic complaints, suicide risk, and comorbid psychiatric disorders. A diagnosis of PTSD requires evidence of exposure to trauma, and is characterized by intrusive and dissociative symptoms. Evidence does not support the wide spread use of early intervention with psychological strategies for the prevention of PTSD. Debriefing of all trauma victims is not recommended, rather, screening and treating appropriate individuals is preferred. In general, there is little evidence supporting the use of pharmacotherapy for the prevention of PTSD, with most studies suggesting no preventive benefits. CBT is an effective first-line option for the treatment of PTSD. Effective approaches include TF-CBT, EMDR, PE, and stress management therapy. ICBT and VRE have also demonstrated efficacy. Benefits are maintained during long-term follow-up of up to one to 10 years after treatment. Research evaluating combined psychological and pharmacological treatments in PTSD is limited, and this requires further study. Pharmacotherapeutic approaches should begin with one of the first-line options which include SSRIs such as fluoxetine, paroxetine, or sertraline, or the SNRI venlafaxine XR. If response to optimal doses is inadequate or the agent is not tolerated, therapy should be switched to another first- or second-line agent, or a second-line agent should be added. Patients with PTSD may make few gains during treatment, and it is important to preserve even small gains achieved with initial therapy. Therefore, augmentation with second- or third-line agents may be important early in treatment. Patients who do not respond to multiple courses of therapy are considered to have treatment-refractory illness. In such patients it is important to reassess the diagnosis and consider comorbid medical and psychiatric conditions that may be affecting response to therapy. Third-line agents, adjunctive therapies, as well as biological and alternative therapies may be useful when patients fail to respond to an optimal treatment trial of first- and second-line therapies used alone and in combination.

Special populations Women during pregnancy and the postpartum period Epidemiology

Women have been found to be at higher risk for anxiety and related disorders than men [2]. Anxiety disorders during the perinatal period are increasingly gaining

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research attention. Although further investigation is needed, data from a large national survey suggest the overall prevalence of anxiety and related disorders is unchanged in women during pregnancy [1086]; however, other data have found an increased risk for individual disorders, such as GAD [1087,1088]. Similarly, some data suggest that anxiety disorders are also not more prevalent during the postpartum period [1086], but other studies suggest higher rates of OCD and GAD during this period [1089,1090]. In addition, PTSD can develop as a result of pregnancy complications that are experienced as traumatic [1091,1092]. Anxiety and related disorders during pregnancy or postpartum may have a negative impact on the pregnancy, the child, or the mother. While studies report that maternal anxiety disorders are associated with adverse pregnancy outcomes such as a shorter gestational age, premature delivery, or elective cesarean delivery [1093-1095], a meta-analysis found no relationship between anxiety symptoms per se and adverse perinatal outcomes [1096]. Anxiety symptoms during pregnancy have been associated with depressive symptoms, substance use, and anemia, as well as decreased use of prenatal vitamins [1093,1097-1099]. Parenting may also be affected by maternal anxiety and related disorders. Mothers with anxiety disorders have been found to be less promoting of psychological autonomy than those mothers without anxiety [1100]. Maternal anxiety has been found to be predictive of child cognitive development [1101], associated with behavioral/emotional problems in childhood [1101,1102], and maternal anxiety and related disorders have been found to be related to subsequent development of an anxiety disorder in the child [1103]. Treatment issues

Psychosocial treatments, with CBT specifically, have strong empirical support for the treatment of anxiety and related disorders [63,70,71,1104], but evidence of their efficacy in perinatal women with anxiety disorders is lacking. Cohort studies have shown beneficial effects of group CBT in pregnant women with B-I-I phobia [1105], and individual CBT in women with OCD in the postnatal period [1106]. Arch et al. argued that although exposurebased CBT or behavioral therapy may have been avoided in the past because of concerns of potential harm, they likely can be viable, safe alternatives in pregnancy [1107]. The lack of data on the use of structured psychosocial interventions for anxiety and related disorders during the perinatal period is a significant gap in the literature. It is important to consider the risks and benefits of pharmacotherapy during pregnancy and while breastfeeding during the postpartum period. Risks to the fetus and newborn should be weighed against that of the potential harm of untreated anxiety and related disorders, an area

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that is gaining increasingly more research attention. Treatment decisions should attempt to optimize outcomes for both mother and baby. Detailed recommendations on the use of psychiatric medications during pregnancy and lactation are available from the American Congress of Obstetricians and Gynecologists (ACOG) Practice Bulletin [1108]. Although it is over five years old, risks associated with various psychotropic medications are summarized [1108]. The FDA pregnancy risk category system has been criticized as being insufficient [1109] and is currently under the process of revision. The Canadian Hospital for Sick Children Motherisk website (http://www.Motherisk.org) is also a useful resource. Antidepressants: There appears to be little evidence of an association between maternal antidepressant use and increased risks of congenital malformations in general, and major congenital malformations in infants [1110-1113]. The exception is a statistically increased risk of cardiac defects with antidepressants, and with paroxetine specifically, although the clinical significance of this has been questioned [1108,1113-1117]. There have been reports of increased rates of spontaneous abortion following antidepressant use during pregnancy; in the most recent metaanalysis, this was not supported using data from studies with higher study quality but found by others who included all studies [1118-1120]. In terms of delivery outcomes, a recent meta-analysis found a statistically increased risk for preterm birth, lower gestational age, birth weight, and APGAR scores – but the effects were small, generally in the normal range, and of questionable clinical significance [1118]. However, data support an increased risk for poor neonatal adaptation syndrome (PNAS) [1121-1123], while findings of increased risk for persistent pulmonary hypertension in the antenatally exposed infant have not been consistent [1124-1127]. Systematic reviews suggest that overall prenatal exposure to antidepressants does not appear to be associated with changes in long-term neurocognitive or behavioral development in children [1128-1130] and that illness itself appears to play a role in negative outcomes (although this study examined the effects of maternal depression) [1131]. Two reports link prenatal antidepressant use to childhood autism spectrum disorders [1132,1133] and two others link bupropion exposure to childhood ADHD [1134,1135]. These studies have limitations and further research is required. In terms of breastfeeding, potential risks of antidepressant use during lactation must be weighed against the recognized benefits for the infant. Antidepressants are excreted into breast milk and although data are limited, the majority are found in very low amounts with few isolated instances of adverse signs [1108]. If antidepressant treatment is indicated, sertraline or paroxetine is preferred [1136]. Long-term data on potential neurobehavioral

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effects are lacking. Clinicians can consult LactMed at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen?LACT for the latest information available. Benzodiazepines: The data on benzodiazepines remain more limited. A recent meta-analysis did not find an increased risk of major malformations or cardiac defects following prenatal benzodiazepine exposure, but concluded the significant increase in risk of oral cleft remains based on data derived from case-control studies [1137], although another meta-analysis reported the absolute risk is small (55 years) with anxiety and related disorders are prescribed a benzodiazepine, which is higher than the rate of antidepressant use [1365-1367]. The very high use of these agents is a cause for concern since they are not a preferred longterm treatment strategy and elderly patients may be more sensitive to their negative effects [1365,1366]. Safety issues The elderly maybe more susceptible to adverse drug events and drug-drug interactions (DDIs) due to gradual age-related physiologic changes that affect the pharmacokinetic and pharmacodynamic properties of

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many medications [1368,1369]. Factors which may alter drug metabolism and plasma concentrations among elderly patients include frailty, reduced homoeostatic mechanisms, and psychosocial issues [1368]. Age-related changes in body composition can result in increases or decreases of drug volume distribution, and hepatic or renal dysfunction can impair drug metabolism and drug clearance [1369,1370]. All of these changes are highly variable in elderly patients, further complicating use of medications in this population [1368,1369]. A review of the literature found that almost half of available antidepressants are associated with age-related clearance changes and identified at least 45 medications that could interact with specific antidepressants [1371]. DDIs may be more common in older adults because of the greater number of concomitant medication they may be taking to treat multiple comorbid conditions. In one study of US community-dwelling older adults, almost 30% used at least five prescription medications, 80% used at least one prescription medication, and almost half used over-the-counter and dietary supplements [1372]. Psychotropic medications have been associated with an increased risk of fractures [1369,1373,1374]. In a metaanalysis, the RR of fractures was 1.34 for benzodiazepines, 1.60 for antidepressants, 1.54 for anticonvulsants, and 1.59 for antipsychotics [1373]. In a prospective cohort study (The Rotterdam Study) of subjects over 55 years of age, the risk of non-vertebral fractures was 2.35 for current SSRI use versus non-use [1375]. The increased risk for hip fracture associated with benzodiazepines was further increased with increasing dose and the use of concomitant interacting drugs [1369,1374]. There does not appear to be any difference between atypical antipsychotic agents in the increased risk of falls or fractures [1376]. An increased mortality risk has been associated with the use antipsychotics in older patients with dementia [1377-1379], which appears to be greater with conventional compared to atypical antipsychotics [1378-1380]. Antidepressants are frequently used to treat symptoms of anxiety in older adults who suffer from comorbid medical conditions such as heart disease. In a meta-analysis of SSRIs versus placebo or no antidepressant therapy in patients with coronary heart disease (CHD) and depression, SSRIs were associated with lower rates of all-cause mortality and readmissions for CHD, indicating that treatment may improve CHD prognosis [1381]. Clinicians should weigh the risks associated with antidepressants against the potential benefits when making prescribing decisions. Summary

While onset of anxiety and related disorders in late-life is uncommon, they do persist into older age and can have substantial impact on QoL and functionality. Older

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patients can present differently compared to younger patients, and diagnosis can be complicated by communication barriers, changes in role functioning, memory difficulties, and comorbid medical conditions. Few treatment studies are conducted in older patients; however, data suggest that psychological treatment and pharmacotherapy appear to be similarly effective in older patients. Using pharmacotherapy in elderly patients can be challenging, and should consider patient factors such as body mass, hepatic and renal function, comorbid conditions, and use of concomitant medications.

Anxiety with comorbid conditions Overview

Anxiety and related disorders often present together with other psychiatric or medical conditions [3,16,43, 1382,1383]. About 60-80% of patients with an anxiety disorder have at least one other comorbid psychiatric condition, which most commonly include another anxiety or related disorder, MDD, bipolar disorder, ADHD, and SUD [3]. The presence of comorbid disorders has a negative impact on most aspects of care. Patients with psychiatric comorbidities have more severe symptoms [46,1384], poorer treatment outcomes for both disorders [47,1385-1387], greater functional impairment [46,871,1384], poorer QoL [1388,1389], and an increased risk of suicide [652]. Medical conditions and pain disorders are also common comorbidities in patients with anxiety and related disorders. Medical conditions frequently reported in patients with anxiety and related disorders include cardiovascular disease, gastrointestinal disease, arthritis, respiratory disease, thyroid disease, migraine, and allergic conditions [16,52]. Patients with both anxiety disorders and medical conditions experience elevated disability, including more psychiatric comorbidity and depressive symptoms, as well as poorer interpersonal and physical functioning [52,142]. Patients with chronically painful conditions such as arthritis, back pain, or migraine are at a two- to four-fold higher risk of having an anxiety or related disorder, particularly panic disorder or PTSD [1390]. The high probability of comorbid disorders should be considered when diagnosing and treating patients with anxiety and related disorders. In patients with comorbid psychiatric conditions, such as another anxiety disorder or mood disorder, consider therapies that are effective for both disorders [32]. Benzodiazepines should be prescribed with additional caution in patients with comorbid SUDs. In patients with comorbid medical conditions, the clinician must weigh the benefits and risks of medication for the anxiety or related disorder, but should also consider the impact of untreated anxiety [32].

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Major depressive disorder (MDD) Q. What is the prevalence and impact of comorbid MDD and anxiety/related disorders?

MDD is very common in patients with anxiety, being reported in 20-36% of patients [121,310,360,1382]; and conversely, about 60% of patients with MDD will have a comorbid anxiety or related disorder [44]. In patients with anxiety, comorbid depression has been associated with more severe symptoms [46,1384], lower likelihood of remission [47], greater functional impairment [46,871,1384], an increased risk of suicide [652], and a greater risk of having another comorbid anxiety disorder [360]. Similarly, in patients with MDD, comorbid anxiety and related disorders were associated with poorer treatment outcomes including higher recurrence rates [1385-1387], poorer QoL [1391], and an increased risk of suicide [24,1387,1392,1393]. Q. What pharmacological treatment may be useful for patients with an anxiety/related disorder and comorbid MDD?

Guidelines generally recommend antidepressants (most commonly SSRIs and SNRIs) as first-line treatments in patients with both anxiety and depressive symptoms [32,1394]. SSRIs and SNRIs in patients with anxiety and related disorders, including panic disorder, GAD, OCD, or PTSD, with comorbid MDD have been shown to be effective in improving both disorders [224,723,1359,1395]. Among the atypical antipsychotics, quetiapine has been found to have efficacy as monotherapy in both MDD [1396] and GAD [1397], as well as MDD with anxiety [1398], while case series suggest that aripiprazole augmentation of antidepressants [496], and risperidone monotherapy [267] may also reduce comorbid depressive and anxiety symptoms. Bipolar disorder or psychoses Q. What is the prevalence and impact of comorbid bipolar disorder or psychoses with anxiety/related disorders?

Among patients with anxiety and related disorders, almost 14% also met criteria for bipolar I or II disorder [121]. However, among patients with bipolar disorder the rates of comorbid anxiety disorders are very high compared to the general population, and the DSM-5 notes anxiety disorders as the most common comorbidities in patients with bipolar disorder [26]. In epidemiological surveys, the lifetime comorbidity rates for any anxiety or related disorder among patients with bipolar disorder was 52% in Canada [43] and 60-75% in the US [1389,1399]. In a clinic population, the rate of anxiety and related disorders was 22% in patients with bipolar disorder, compared to 17% in patients with schizophrenia, and 30% in those with schizoaffective disorder [1400]. A meta-analysis of prevalence studies found that the rates of various anxiety disorders in patients with schizophrenia and related psychotic disorders ranged from 10-15% [1401].

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Comorbid anxiety and related disorders in patients with bipolar disorder were associated with a greater risk of MDD and drug use disorders, a poorer bipolar course, lower QoL, and lower psychosocial functioning [1388,1389]. Data are conflicting on the impact of anxiety and related disorders on suicidal tendencies in patients with bipolar disorder, with some analyses finding an increased risk [1389,1402], but not all [1403]. Similar findings have been reported in patients with schizophrenia, where comorbid anxiety and related disorders have been associated with more past SUDs, lower social adjustment and overall QoL, and greater suicidality [1404,1405]. Q. What pharmacological treatment may be useful for patients with an anxiety/related disorder and comorbid bipolar disorder or psychoses?

The management of patients with anxiety and related disorders and comorbid bipolar disorder, schizophrenia, or other psychosis should consider therapies that are effective for both disorders [32]. Atypical antipsychotics are recommended treatments for bipolar disorder and schizophrenia [111,1406], while the long-term use of antidepressants may destabilize patients with bipolar I disorder [111,1394]. Data in patients with a diagnosed anxiety or related disorder and comorbid bipolar disorder or psychosis are limited. In a RCT, risperidone monotherapy was shown to be no more effective than placebo for patients with bipolar and comorbid panic disorder or GAD [1407]. However, in a single-blind trial, olanzapine or lamotrigine when added to lithium demonstrated improvements in anxiety disorder symptoms in patients with remitted bipolar disorder [1408]; and in an open trial, switching to aripiprazole significantly improved social anxiety and psychosis in patients with SAD and schizophrenia [379]. In addition, atypical antipsychotics have demonstrated efficacy in RCTs in patients with anxiety and related disorders (see specific disorder sections for evidence), and data show that these agents can significantly reduce anxiety symptoms in patients with bipolar disorder [1409-1413]. Taken together, these data suggest these agents may be useful in comorbid patients. Anticonvulsants have also demonstrated efficacy in the treatment of some anxiety and related disorders (see specific disorder sections for evidence) and are often used for the treatment of bipolar disorder [111]. In patients with bipolar disorder, adjunctive valproate and gabapentin have demonstrated efficacy for the treatment of panic disorder [281,1414] and resulted in reductions in anxiety symptoms [1415,1416]. ADHD Q. What is the prevalence of comorbid ADHD and anxiety/ related disorders?

It is estimated that the lifetime rate of ADHD in children is 6-9%, with 70% persistence into adolescence and

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50-60% into adulthood [45,1417,1418]. In a communitybased survey, the estimated prevalence of current selfreported adult ADHD was 4.4% [45]. While ADHD has long been known to persist into adulthood [1419,1420], it has only recently become the focus of widespread clinical attention [1421-1423]. Of adults identified with ADHD in the National Comorbidity Survey-Replication (NCS-R), only one in 10 had received treatment within the previous year [45]. Of these individuals, it is estimated that approximately 47% meet criteria for an anxiety or related disorder within 12 months of assessment, with the most common being SAD (29.3%), followed by specific phobia (22.7%), PTSD (11.9%), panic disorder (8.9%), and GAD (8.0%) [45]. Patients with an anxiety or related disorder were reportedly four times more likely to meet criteria for ADHD than the general population [45]. Similar results were found in a Canadian survey of patients in an anxiety disorders clinic, where the rate of adult ADHD was 28% [378]. Q. What factors should be considered when treating patients with an anxiety/related disorder and comorbid ADHD?

When managing a patient with ADHD, it may be important to differentiate ADHD with anxious symptoms from comorbid ADHD and anxiety/related disorders. This can be challenging, as anxiety symptoms are frequently related to a sense of being overwhelmed or to compensatory skills in patients with ADHD. Stimulants may play a larger role in managing ADHD in patients with anxiety symptoms [1424,1425]; however, in an open trial, atomoxetine improved ADHD and comorbid symptoms of depression and anxiety [1426]. Treatment of patients with comorbid ADHD and an anxiety or related disorder may be more complicated. Generally, in patients with comorbid anxiety disorders and ADHD the diagnostic and treatment priority should be determined by the relative severity of symptoms and risks of each disorder [1427]. There are limited data on the role of stimulants in patients with ADHD and an anxiety disorder. In a RCT, atomoxetine significantly improved ADHD and SAD symptoms compared with placebo [487]. In separate open trials, adjunctive atomoxetine [1428] and adjunctive extended release mixed amphetamine salts [1429] significantly improved anxiety symptoms in patients with ADHD and GAD refractory to antidepressants alone. Medical comorbidities Q. What is the prevalence and impact of comorbid medical conditions and anxiety/related disorders?

Medical conditions are also common comorbidities that must be considered when prescribing medication for patients with anxiety and related disorders. Medical conditions are reported in over 60% of patients with anxiety

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and related disorders including cardiovascular diseases, gastrointestinal diseases, arthritis, respiratory diseases such as asthma, thyroid disease, migraine headaches, back pain, and allergic conditions [16,52,1430-1432]. Comorbidities are particularly common among patients with GAD, panic disorder, and PTSD [16,140,515, 517,1390,1433]. Patients with anxiety and related disorders and medical conditions experience more psychiatric comorbidity, depressive symptoms, and more severe anxiety disorder symptoms, as well as poorer interpersonal and physical functioning [52,140,142,515]. Q. What factors should be considered when treating patients with an anxiety/related disorder and comorbid chronic pain?

Chronically painful conditions (i.e., arthritis, back pain, and migraine) are commonly associated with anxiety [515,1390,1430,1434]. Patients with anxiety and related disorders are twice as likely to have painful physical symptoms compared to of those without, 45-60% versus 28% [515,1433]. About 60-70% of patients with anxiety disorders report migraine headaches [140,141]. For the management of anxiety and related disorders in patients with pain it may be helpful to consider treatments that have demonstrated efficacy in both anxiety disorders as well as pain. While there are few data available, duloxetine has demonstrated efficacy for both GAD and pain symptoms in RCTs [1435-1437]. TCAs, and to a lesser extent SSRIs, have been shown to reduce headache attacks in patients with migraine [1438], and provide moderate relief of neuropathic pain [1439]. Q. What factors should be considered when treating patients with an anxiety/related disorder and comorbid cardiovascular disease?

Although panic attacks can sometimes be mistaken for cardiovascular symptoms, it is important to be aware that patients with anxiety and related disorders do have a twoto three-times greater risk of cardiovascular disease compared to the general population [1431,1432]. In addition, anxiety disorders have been associated with increased risk of cardiovascular hospitalization rates and mortality risk [1440-1442]. In patients with cardiovascular or cerebrovascular comorbidity, it is important to consider the impact of treatments used for anxiety on heart rate, blood pressure, and lipid measures [1443-1445]. Q. What factors should be considered when treating patients with an anxiety/related disorder and comorbid diabetes and metabolic syndrome?

Patients with anxiety symptoms have an elevated risk of type 2 diabetes [1446]. While glycemic measures do not appear to be affected by anxiety symptoms [1447], some treatments, particularly some atypical antipsychotics, alter glucose parameters, lipid levels, and cause weight

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gain [109-116,1443]. Some antidepressants, including amitriptyline, mirtazapine, and paroxetine have also been associated with weight gain [1448].

Canadian Anxiety Guidelines Initiative Group Additional authors

Martin M. Antony1, Stéphane Bouchard2, Alain Brunet3, Martine Flament4, Sophie Grigoriadis5, Sandra Mendlowitz6, Kieron O’Connor7, Kiran Rabheru4, Peggy M.A. Richter5, Melisa Robichaud8, John R. Walker9 1 Department of Psychology, Ryerson University, Toronto, M5B 2K3, Canada; 2Department of Psychoeducation and Psychology, University of Québec in Outaouais, Gatineau, J9A 1L8, Canada; 3 Department of Psychiatry, McGill University, Montreal, H3A 1A1, Canada; 4 Department of Psychiatry, University of Ottawa, Ottawa, K1Z 7K4, Canada; 5 Department of Psychiatry, University of Toronto, Toronto, M5S 1A1, Canada; 6Department of Child Psychiatry, University of Toronto, Toronto, M5S 1A1, Canada; 7Department of Psychiatry, University of Montreal, Montreal, H3C 3J7, Canada; 8 Departments of Psychiatry and Psychology, University of British Columbia, Vancouver, V6T 2A1, Canada; 9 Department of Clinical Health Psychology, University of Manitoba, Winnipeg, R3E 3N4, Canada Email: Martin M. Antony - [email protected]; Stéphane Bouchard - [email protected]; Alain Brunet - [email protected]; Martine Flament - [email protected]; Sophie Grigoriadis - [email protected]; Sandra Mendlowitz - sandra. [email protected]; Kieron O’Connor - kieron. [email protected]; Kiran Rabheru - [email protected]; Peggy M.A. Richter - [email protected]; Melisa Robichaud - [email protected]; John R. Walker - [email protected] Additional contributors to the comorbidity section

Gordon Asmundson10, Larry J. Klassen11, Raymond W. Lam12, Roger S. McIntyre13, Isaac Szpindel14 10 Department of Psychology, University of Regina, Regina, S4S 0A2, Canada; 11Department of Psychiatry, Faculty of Medicine, University of Manitoba, Winnipeg, R3T 2N2, Canada; 12Department of Psychiatry, University of British Columbia, Vancouver, V6T 2A1, Canada; 13 Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, M5S 1A1, Canada; 14Attention and Learning Related Disorders, START Clinic, Toronto, M4W 2N4, Canada Email: Gordon Asmundson - [email protected]; Larry J. Klassen - [email protected]; Raymond W. Lam - [email protected]; Roger S. McIntyre [email protected]; Isaac Szpindel - [email protected]

Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1

Additional material Additional file 1: Suggested dosing ranges Dosing ranges of various psychiatric medications

List of abbreviations used AACAP: American Academy of Child and Adolescent Psychiatry; ABM: attention bias modification; ACOG: American Congress of Obstetricians and Gynecologists; ADHD: attention-deficit/hyperactivity disorder; APA: American Psychiatric Association; ASD: acute stress disorder; B-I-I: blood-injection-injury; BPD: borderline personality disorder; CBT: cognitive behavioral therapy; CBWT: cognitive behavioral writing therapy; CCHS: Canadian Community Health Survey; CHD: coronary heart disease; CPT: cognitive processing therapy; CR: controlled release; DBT: dialectical behavioral therapy; DDI: drugdrug interactions; DIRT: danger ideation reduction therapy; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; EMDR: eye movement desensitization and reprocessing; ERP: exposure with response prevention; FDA: Food and Drug Administration; GAD: generalized anxiety disorder; HARS: Hamilton Anxiety Rating Scale; HDL: high-density lipoprotein; ICBT: internet-based CBT; IPT: interpersonal therapy; IV: intravenous; LDL: lowdensity lipoprotein; MAOI: monoamine oxidase inhibitor; MBCT: mindfulnessbased cognitive therapy; MBT: mindfulness-based therapy; MDD: major depressive disorder; Mini-SPIN: Mini-Social Phobia Inventory; MRI: magnetic resonance imaging; N/A: not available; NaSSA: noradrenergic and specific serotonergic antidepressant; NCS-A: National Comorbidity Survey – Adolescent supplement; NCS-R: National Comorbidity Survey – Replication; NMDA: N-methyl-D-aspartate; NNT: number needed to treat; NPPO-REAC: neuro psycho physical optimization-radio electric asymmetric conveyor; NSAID: nonsteroidal anti-inflammatory drug; OCD: obsessive-compulsive disorder; ODT: orally disintegrating tablet; PNAS: poor neonatal adaptation syndrome; PTSD: posttraumatic stress disorder; QoL: quality of life; RCT: randomized controlled trial; REAC: radioelectric asymmetric conveyor; RIMA: reversible inhibitors of monoamine oxidase A; RR: relative risk; rTMS: repetitive transcranial magnetic stimulation; SAD: social anxiety disorder; SET: social effectiveness therapy; SHAT: spiritual-hypnosis assisted therapy; SNRI: serotonin–norepinephrine reuptake inhibitor; SR: sustained release; SSRI: selective serotonin reuptake inhibitor; SUD: substance use disorder; TC: total cholesterol; TCA: tricyclic antidepressant; TF-CBT: trauma-focused-CBT; TG: triglycerides; vLDL: very-low-density lipoprotein; VRE: virtual reality exposure; XL: extended release; XR: extended release; Y-BOCS: Yale-Brown Obsessive Compulsive Scale. Competing interests Unrestricted educational grants for the development of these guidelines were provided by Astra Zeneca Canada, Eli-Lilly Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier Canada Inc., Shire Canada, and Valeant Canada. None of the members received payment for participating in the development of these guidelines. The following authors do not have any competing interests to declare: AB, GA, JRW, KO, MMA, MF, LK, MR, SM. Advisory board/speaker’s bureau: Astra Zeneca (KK, KR, MK, P. Bleau, P. Blier, RWL, RSM), Biovail (RWL), Boehringer Ingelheim (MK), BMS (KK, KR, MK, P. Bleau, P. Blier, PC, RWL, RSM), Canadian Institutes of Health Research (CIHR) (RWL), Canadian Network for Mood and Anxiety Treatments (CANMAT) (RWL), Canadian Psychiatric Association (CPA) Foundation (RWL), Eli Lilly Canada (MK, P. Bleau, P. Blier, PC, SG, RWL, RSM, IS), France Foundation (RSM), GlaxoSmithKline (MK, P. Blier, RSM, SG), Janssen Ortho (KK, MK, P. Blier, PC, RSM), Labopharm (P. Blier), Litebook Company (RWL), Lundbeck (KK, KR, MK, P. Bleau, P. Blier, PC, RWL, RSM, SG), Lundbeck Institute (RWL), Organon (MK, RSM), Merck (P. Blier, RSM), Mochida (RWL), Otsuka (KK), Pfizer (P. Bleau, P. Blier, PC, RWL, RSM, SG), Pierre Fabre (P. Blier), Purdue (IS), Servier (P. Blier, RWL, SG), Shire (MK, RSM, IS), Solvay (MK), St. Jude’s Medical (RWL), Sunovion (KK, P. Blier), Takeda (P. Blier, RWL), UBC Institute of Mental Health/Coast Capital Savings (RWL), Valeant (P. Blier, IS), Wyeth (P. Bleau, MK, SG) Consultation fees: AstraZeneca (MK), BMS (MK), Boehringer Ingelheim (MK), Clinique et Développement In Virtuo Inc. (SB), Eli Lilly Canada (MK, SG),

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GlaxoSmithKline (MK, SG), Janssen Ortho (MK), Lundbeck (MK, PR, SG), Organon (MK), Pfizer (SG), Servier (SG), Shire (MK), Solvay (MK), Wyeth (MK, SG) Educational support: Astra Zeneca (RSM), BMS (RSM), CME Outfitters (RSM), Eli Lilly Canada (RSM, IS), France Foundation (RSM), I3CME (RSM), Merck (RSM), Optum Health (RSM), Pfizer (RSM), Physicians’ Postgraduate Press (RSM), Shire (IS) Research grants/clinical trial funding: AstraZeneca (KK, MK, P. Bleau, RSM, RWL), Biovail (RWL), BMS (KK, P. Bleau, RWL), Canadian Foundation for Innovation (MK), Canadian Institutes of Health Research (CIHR) (MK, RWL, SG), Canadian Network for Mood and Anxiety Treatments (CANMAT) (RWL), Canadian Psychiatric Association (CPA) Foundation (MK, RWL), Centre for Addiction and Mental Health Foundation (MK), CR Younger Foundation (SG), Eli Lilly Canada (MK, P. Bleau, PR, RSM, RWL), Genuine Health (MK), GlaxoSmithKline (MK), Janssen Ortho (MK, RSM), Litebook Company (RWL), Lundbeck (KK, MK, P. Bleau, RSM, RWL), Lundbeck Institute (RWL), Mochida (RWL), National Alliance for Research on Schizophrenia and Depression (NARSAD) (RSM), National Institutes of Mental Health (NIMH) (RSM), Ontario Ministry of Health (SG), Ontario Mental Health Foundation (SG), Organon (MK), Pfizer (P. Bleau, RSM, RWL), Roche (PR), Servier (RWL), Sick Kids Foundation (MK), Solvay (MK), St. Jude’s Medical (RWL), Shire (MK, RSM), Stanley Medical Research Institute (RSM), Takeda (RWL), UBC Institute of Mental Health/Coast Capital Savings (RWL), Wyeth (MK, P. Bleau) Unrestricted grants: Astra Zeneca Canada (MK), Eli Lilly Canada (MK), Janssen Inc. (MK), Lundbeck Canada (MK), Pfizer (MK), Purdue Pharma (MK), Servier Canada (MK), Shire Canada (MK), Valeant Canada (MK) Reimbursements, fees, funding, or salary: In the past five years, MVA received reimbursements, fees, funding, or salary from: Astra Zeneca, Biovail, Canadian Foundation for Innovation (CFI), Cephalon, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Hamilton Academic Health Sciences Organization (HAHSO) Innovation Grant (AFP Innovation Grant), Janssen Ortho, Labo Pharm, Lundbeck, National Institutes of Health (NIH), Novartis, Pfizer Inc., Servier, Shire, Sunovion, Valeant, Wyeth-Ayerst Stock/share ownership: Clinique et Développement In Virtuo Inc. (SB) Authors’ contributions We thank all co-authors for their considerable expertise in generating these guidelines. Authors who were members of the executive committee (MK, PB, PB, PC, KK, MVA) took part in teleconferences and a meeting in December 2012 to reach consensus on the strength of evidence and treatment recommendations. Draft guidelines were then developed by the core committee and revised by all co-authors. The entire content was subsequently circulated to all members of the Canadian Anxiety Guidelines Initiative Group for additional comments and approval during 2013. GA, LJK, RWL, RSM, and IS provided additional reviews of the comorbidity section. The final manuscript was then circulated to external reviewers (MP, DS, LDM) and revisions were made based on input from the core committee. Acknowledgements The consensus group would like to thank Astra Zeneca Canada, Eli-Lilly Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier Canada Inc., Shire Canada, and Valeant Canada for their generous support of the guideline process with unrestricted educational grants. Funds were used for editorial assistance and meeting logistics; none of the members received payment for participating in the guideline development process. The consensus group would also like to thank Pauline Lavigne and Steven Portelance who provided medical writing services on their behalf. Declarations The development and publication of these guidelines was supported by unrestricted educational grants provided by Astra Zeneca Canada, Eli-Lilly Canada, Janssen Inc., Lundbeck Canada, Pfizer Canada, Purdue Canada, Servier Canada Inc., Shire Canada, and Valeant Canada. None of the members received payment for participating in the development of these guidelines. This article has been published as part of BMC Psychiatry Volume 14 Supplement 1, 2014: Canadian Anxiety Disorders Guidelines Initiative: Clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessive-compulsive disorders. The full contents of the supplement are available online at http://www.biomedcentral.com/bmcpsychiatry/ supplements/14/S1.

Katzman et al. BMC Psychiatry 2014, 14(Suppl 1):S1 http://www.biomedcentral.com/1471-244X/14/S1/S1

Authors’ details 1 Department of Psychiatry, University of Toronto, Toronto, ON, M5S 1A1, Canada. 2Department of Psychiatry, McGill University, Montreal, QC, H3A 1A1, Canada. 3Department of Psychiatry and Cellular/Molecular Medicines, University of Ottawa, Ottawa, ON, K1Z 7K4, Canada. 4Department of Psychiatry, University of Alberta, Edmonton, AB, T6G 2R7, Canada. 5 Department of Psychiatry, University of British Columbia, Vancouver, BC, V6T 2A1, Canada. 6Department of Psychiatry and Behavioural Neuroscience, McMaster University, Hamilton, ON, L8N 3K7, Canada.

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doi:10.1186/1471-244X-14-S1-S1 Cite this article as: Katzman et al.: Canadian clinical practice guidelines for the management of anxiety, posttraumatic stress and obsessivecompulsive disorders. BMC Psychiatry 2014 14(Suppl 1):S1.

525674 research-article2014

JOP0010.1177/0269881114525674Journal of PsychopharmacologyBaldwin et al.

BAP Guidelines

Evidence-based pharmacological treatment of anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder: A revision of the 2005 guidelines from the British Association for Psychopharmacology

Journal of Psychopharmacology 1–­ 37 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0269881114525674 jop.sagepub.com

David S Baldwin1,2, Ian M Anderson3, David J Nutt4, Christer Allgulander5, Borwin Bandelow6, Johan A den Boer7,8, David M Christmas9, Simon Davies10, Naomi Fineberg11, Nicky Lidbetter12, Andrea Malizia13, Paul McCrone14, Daniel Nabarro15, Catherine O’Neill12, Jan Scott16, Nic van der Wee17 and Hans-Ulrich Wittchen18

Abstract This revision of the 2005 British Association for Psychopharmacology guidelines for the evidence-based pharmacological treatment of anxiety disorders provides an update on key steps in diagnosis and clinical management, including recognition, acute treatment, longer-term treatment, combination treatment, and further approaches for patients who have not responded to first-line interventions. A consensus meeting involving international experts in anxiety disorders reviewed the main subject areas and considered the strength of supporting evidence and its clinical implications. The guidelines are based on available evidence, were constructed after extensive feedback from participants, and are presented as recommendations to aid clinical decision-making in primary, secondary and tertiary medical care. They may also serve as a source of information for patients, their carers, and medicines management and formulary committees.

Keywords Anticonvulsants, antidepressants, antipsychotics, anxiety disorders, anxiolytics, benzodiazepines, cognitive behaviour therapy, evidence-based guidelines, generalised anxiety disorder, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, pregabalin, separation anxiety disorder, serotonin-noradrenaline reuptake inhibitor, social anxiety disorder, specific phobia, selective serotonin reuptake inhibitor, treatment.

1. Introduction The British Association for Psychopharmacology (BAP; www. bap.org.uk) aims to advance education and research in the science and practice of psychopharmacology by arranging scientific

meetings, fostering research and teaching, encouraging publication of research results, and providing guidance and information on matters relevant to psychopharmacology. As part of this

1Faculty

11Postgraduate

2Department

12Anxiety

of Medicine, University of Southampton, Southampton, UK of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa 3Neuroscience and Psychiatry Unit, University of Manchester, Manchester, UK 4Division of Experimental Medicine, Imperial College London, London, UK 5Karolinska Institutet, Stockholm, Sweden 6Department of Psychiatry and Psychotherapy, University of Goettingen, Goettingen, Germany 7Department of Nuclear Medicine and Molecular Imaging, University Medical Centre Groningen (UMCG), Groningen, The Netherlands 8PRA International Zuidlaren,The Netherlands 9Cambridge and Peterborough NHS Foundation Trust, Cambridge, UK 10Centre for Addiction and Mental Health, University of Toronto, Toronto, ON, Canada

Medical School, University of Hertfordshire, Hatfield, UK UK, Manchester, UK 13North Bristol NHS Trust, Bristol, UK 14Institute of Psychiatry, Kings College London, London, UK 15OCD Action, London, UK 16Newcastle University, Newcastle, UK 17Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands 18Institute of Clinical Psychology and Psychotherapy, Technical University Dresden, Dresden, Germany Corresponding author: David Baldwin, University Department of Psychiatry, University of Southampton, College Keep, 4-12 Terminus Terrace, Southampton, SO14 3DT, UK. Email: [email protected]

2 process the BAP has developed and periodically revised a series of consensus statements on the use of psychotropic drugs in patients with psychiatric and other disorders, with an emphasis on making concise and realistic recommendations based on a review of the evidence [IV] (Anderson et al., 2000, 2008; Barnes and Schizophrenia Consensus Group of British Association for Psychopharmacology, 2011; Burns and O’Brien., 2006; Goodwin, 2003, 2005; Goodwin et al., 2008; Lingford-Hughes et al., 2004, 2012; National Institute for Health and Clinical Excellence, 2011; O’Brien and Burns, 2010; Nutt et al., 2006; Wilson et al., 2010). Anxiety symptoms and disorders are common in community settings, and in primary and secondary medical care. The personal and societal burden associated with anxiety disorders is considerable, but many people who might benefit from treatment are not recognised or treated. Likely factors in this sub-optimal management include the range of different anxiety disorders, their co-morbidity with other disorders (particularly mood disorders), a widespread lack of awareness of anxiety disorders by affected individuals and health practitioners, and the low confidence of many practitioners in their management. Conversely, some patients with only mild or transient anxiety symptoms receive unnecessary or inappropriate treatment. Given the considerable room for improvement, the BAP previously produced evidence-based guidelines for the pharmacological treatment of anxiety disorders [IV] (Baldwin et al., 2005): this revision of those guidelines provides an update on key steps in diagnosis and treatment.

2. Caveats Clinical guidelines are systematically derived statements that aim to inform treatment decisions in clinical care. Recommendations are graded according to the strength of evidence, and whenever possible are derived from the findings of systematic reviews and randomised controlled trials. Principal recommendations apply to the management of ‘typical’ patients and hence apply much of the time: we therefore use expressions such as ‘clinicians should consider…’ in the summary boxes. But there are many patients and many clinical decision points where slavish adherence to guideline recommendations may be unhelpful and possibly harmful. In situations where the evidence is weaker we summarise potential management options, recognising that their implementation depends upon clinician experience, patient clinical features and preference, and local circumstance [IV] (Haynes et al., 2002). Some of our recommendations may be regarded as standards of clinical care that are largely driven by custom and practice: these are ‘standards’ which are intended to be applied routinely. There is often a tension between existing established clinical practice and the possible implications of new research findings for changing practice. Existing practice may be accepted on the basis of prolonged clinical experience but limited good quality evidence: new treatments may have proven superiority to placebo in methodologically robust randomised controlled trials, but lack comparator data against ‘established’ treatments. We attempt to strike a balance between the risks of advocating specific novel treatment recommendations that may prove premature and adhering to established routines when the evidence supporting them is questionable.

Journal of Psychopharmacology

3. Process for achieving consensus The revision of the original BAP guidelines started in February 2011, with a consensus meeting attended by experts in the field and representatives of patient groups (all who attended are named in the acknowledgments). Brief presentations were made on key areas, with an emphasis on systematic reviews and randomised controlled trials. Each presentation was followed by discussion, to identify areas of consensus or uncertainty. A literature review was then performed to ascertain the validity of the consensus points. Logistical factors made it impossible to perform a systematic review of all possible data from primary sources. Existing systematic reviews and randomised controlled trials were identified from MEDLINE and EMBASE searches and from the Cochrane Database, as well as from recent previous guidelines and reviews [IV] (Baldwin et al., 2011b; Bandelow et al., 2008a; Batelaan et al., 2012; Blanco et al., 2013; Fineberg et al., 2012; Ipser and Stein, 2012), through cross-referencing, and through discussion with experts in the field. We also drew on recent guidelines for generalised anxiety disorder, panic disorder, social anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder developed by the National Institute for Health and Clinical Excellence (2005, 2011a, 2011b, 2013). Particular attention was paid to research findings which had appeared since 2005, the year of publication of the original guidelines. Draft versions of the consensus statement, with recommendations based on the level of supporting evidence, were circulated repeatedly to the presenters and other participants and their comments were incorporated into the final version of the guidelines. Given the range and depth of the subject area it was not possible for all participants in the wider group to achieve full consensus on all points.

4. Levels of evidence and strength of recommendations The categories of evidence for causal relationships and the grading of recommendations have their origin in the methodology of the North of England Evidence-Based Guideline Development Project undertaken by the Centre for Health Services Research, University of Newcastle upon Tyne and the Centre for Health Economics, University of York [IV] (Shekelle et al., 1999). Given current debates about their competing merits, we have accorded a similar ‘level’ (‘I’) in the hierarchy of evidence to the findings of systematic reviews and to the results of randomised controlled trials, noting the evidence source which is available for each statement and recommendation (Table 1). Weaker levels of recommendations do not necessarily imply a reduced level of clinical importance. As in some previous guidelines we have included a category denoted as ‘S’ (representing a standard of care), for a recommendation that reflects important consensus on good clinical practice rather than on empirical evidence.

5. Aim and scope of the guidelines We hope the guidelines will prove relevant to most doctors treating patients with anxiety and related disorders, in primary, secondary and tertiary medical care settings. Each of the principal disorders – generalised anxiety disorder, panic disorder, specific

3

Baldwin et al. Table 1.  Levels of evidence and strength of recommendations. Categories of evidence relevant to treatment I [M] Evidence from meta-analysis of randomised double-blind placebo-controlled trials I [PCT] Evidence from at least one randomised double-blind placebo-controlled trial II Evidence from at least one randomised double-blind comparator-controlled trial (without placebo) III Evidence from non-experimental descriptive studies IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities Categories of evidence relevant to observational findings and associations I Evidence from large representative population samples II Evidence from small, well designed but not necessarily representative samples III Evidence from non-representative surveys, case reports IV Evidence from expert committee reports or opinions and/or clinical experience of respected authorities Strength of recommendations A Directly based on category I evidence (either I [M] or I [PCT]) B Directly based on category II evidence or an extrapolated recommendation from category I evidence C Directly based on category III evidence or an extrapolated recommendation from category I or II evidence D Directly based on category IV evidence or an extrapolated recommendation from other categories S Standard of clinical care

(or simple) phobia, social anxiety disorder (also known as social phobia), post-traumatic stress disorder, and obsessive-compulsive disorder – is considered in turn, following key steps in management (acute treatment; longer-term treatment; combination with psychological approaches; treatment resistance). The continued inclusion or otherwise of obsessive-compulsive disorder within the broad category of anxiety disorders is the subject of continuing debate, given evidence of its dissimilarity from other anxiety disorders and its resemblance to other conditions characterised by compulsivity and impulsivity: but the principles of pharmacological treatment of anxiety disorders and obsessive-compulsive disorder share many common features, and so we have chosen to retain obsessive-compulsive disorder within these guidelines. We also include separation anxiety disorder, given its inclusion within anxiety disorders in the Diagnostic and Statistical Manual (DSM5) (American Psychiatric Association, 2013), though evidence relating to its treatment in adults is at present very sparse. We also summarise the evidence for treatment of patients with health anxiety (‘illness anxiety disorder’), partly because of the overlap in clinical features with those of generalised anxiety disorder. We expect the guidelines will be most useful in informing decisions in primary and secondary care, regarding pharmacological treatment in patients aged between 18–65 years. The nature and prevalence of anxiety disorders changes during childhood and adolescence and the mean age of onset in adult patients varies between anxiety disorders. Most adults with anxiety disorders report an onset of symptoms in childhood or adolescence (Jones, 2013; Kessler et al., 2005), and some recommendations (for example those pertaining to obsessive-compulsive disorder and social phobia) will therefore be potentially applicable to adolescent patients. Similarly the recommendations are also likely to be pertinent to elderly patients although we did not specifically review evidence in those aged over 65 years.

6. Epidemiology of anxiety symptoms and disorders Anxiety symptoms are common in the general population and in primary and secondary medical care. Symptoms may be

mild, transient and without associated impairment in social and occupational function, but many patients are troubled by severe and persistent symptoms that cause significant personal distress, impair function and reduce quality of life. To meet the diagnosis of an anxiety disorder, patients have to experience a certain number of symptoms for more than a minimum specified period, the symptoms causing significant personal distress, with an associated impairment in everyday function. Most research in the field has been based on the diagnostic categories for anxiety disorders in the fourth edition of the Diagnostic and Statistical Manual (DSM-IV) [IV] (American Psychiatric Association, 1994) which are broadly similar to those in the tenth edition of the International Classification of Diseases (ICD-10) [IV] (World Health Organisation, 1992). The DSM system has recently been revised, and it is uncertain whether the approach to anxiety disorders within ‘ICD-11’ will differ substantially from ICD-10 or DSM-5. We give simplified versions of the principal clinical features of the anxiety disorders, post-traumatic stress disorder and obsessive-compulsive disorder in Table 2: a simple algorithm for initial delineation of anxiety and depressive symptoms into disorders is suggested in Figure 1. Epidemiological studies in the general population indicate that when taken together anxiety disorders have a 12-month period prevalence of approximately 14% [I] (Wittchen et al., 2011) (see Table 3), and a lifetime prevalence of approximately 21% [I] (Wittchen and Jacobi, 2005). Individual disorders are less frequent, with estimated 12-month prevalence rates ranging between 0.7% (obsessive-compulsive disorder) and 6.4% (specific phobia), and estimated lifetime prevalence rates between 0.8% (obsessive-compulsive disorder) and 13.2% (specific phobia). The age and sex distribution of individual disorders varies: for example, specific phobias are markedly more common in women than men across all age bands, whereas panic disorder is almost as frequent in men and women in middle age. Despite this variation within individual anxiety disorders, the pattern for all disorders taken together is fairly constant with an overall female: male ratio of approximately 2:1 across the age range.

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Table 2.  Principal clinical features of the anxiety disorders, post-traumatic stress disorder, and obsessive-compulsive disorder. Generalised anxiety disorder Generalised anxiety disorder is characterised by excessive and inappropriate worrying that is persistent (lasting more than a few months) and not restricted to particular circumstances. Patients have physical anxiety symptoms and key psychological symptoms (restlessness, fatigue, difficulty concentrating, irritability, muscle tension and disturbed sleep). Generalised anxiety disorder is often co-morbid with major depression, panic disorder, phobic anxiety disorders, health anxiety and obsessive-compulsive disorder. Panic disorder (with or without agoraphobia) Panic disorder is characterised by recurrent unexpected surges of severe anxiety (‘panic attacks’), with varying degrees of anticipatory anxiety between attacks. Panic attacks are discrete periods of intense fear or discomfort, accompanied by multiple physical or psychological anxiety symptoms. Panic attacks typically reach their peak within 10 min and last around 30–45 min. Most patients develop a fear of having further panic attacks. Around two-thirds of patients with panic disorder develop agoraphobia, defined as fear in places or situations from which escape might be difficult or in which help might not be available, in the event of having a panic attack. These situations include being in a crowd, being outside the home, or using public transport: they are either avoided or endured with significant personal distress. Social phobia (social anxiety disorder) Social phobia is characterised by a marked, persistent and unreasonable fear of being observed or evaluated negatively by other people, in social or performance situations, which is associated with physical and psychological anxiety symptoms. Feared situations (such as speaking to unfamiliar people or eating in public) are either avoided or are endured with significant distress. Specific phobia Specific, simple or isolated phobia is characterised by excessive or unreasonable fear of (and restricted to) single people, animals, objects, or situations (for example, dentists, spiders, lifts, flying, seeing blood) which are either avoided or are endured with significant personal distress. Separation anxiety disorder Separation anxiety disorder is characterised by fear or anxiety concerning separation from those to whom an individual is attached: common features include excessive distress when experiencing or anticipating separation from home, and persistent and excessive worries about potential harms to attachment figures or untoward events that might result in separation. Post-traumatic stress disorder Post-traumatic stress disorder is characterised by a history of exposure to trauma (actual or threatened death, serious injury, or threats to the physical integrity of the self or others) with a response of intense fear, helplessness or horror; with the later development of intrusive symptoms (such as recollections, flashbacks or dreams), avoidance symptoms (for example efforts to avoid activities or thoughts associated with the trauma), negative alterations in cognitions and mood, and hyper-arousal symptoms (including disturbed sleep, hypervigilance and an exaggerated startle response). Obsessive-compulsive disorder Obsessive-compulsive disorder is characterised by recurrent obsessive ruminations, images or impulses, and/or recurrent physical or mental rituals; which are distressing, time-consuming and cause interference with social and occupational function. Common obsessions relate to contamination, accidents, and religious or sexual matters; common rituals include washing, checking, cleaning, counting and touching. Illness anxiety disorder A somatic symptom related disorder characterised by excessive or disproportionate preoccupations with having or acquiring a serious illness, with excessive health-related behaviours and high levels of alarm about personal health status.

6.1. Course of anxiety symptoms and disorders

Significant anxietyrelated symptoms and impaired function,

Also moderate/ severe depression?

Yes

Treat depression

No Predominant symptom focus Trauma history and flashbacks?

Obsessions + compulsions

Uncontrollable worry about several areas

intermittent panic/anxiety attacks and avoidance

Fear of social scrutiny

Check for PTSD

Check for OCD

Check for GAD

Check for social phobia

Discrete Some object/ uncued/ situation spontaneous

Check for specific phobia

Check for panic disorder

Figure 1.  Suggested scheme for exploring a suspected anxiety disorder. GAD: generalised anxiety disorder; OCD: obsessive-compulsive disorder; PTSD: post-traumatic stress disorder.

Longitudinal studies in community samples indicate that many individuals with anxiety symptoms that are below the threshold for an anxiety disorder diagnosis experience an episodic condition with prolonged periods of remission: reappearance or worsening of symptoms being associated with adverse life events and other psychosocial stressors. By contrast, follow-up studies in patient groups demonstrate that anxiety disorders tend to run a chronic course, often over many years, with symptoms fluctuating in severity between periods of remission and relapse, the course of illness varying between disorders [II] (Bruce et al., 2005). Generalised anxiety disorder tends to run a waxing and waning course in non-clinical samples [I] (Angst et al., 2009), and a prolonged course in primary care [I] (Rodriguez et al., 2006): but may also ‘switch’ to other diagnoses particularly depression and somatoform disorders [II] (Rubio and Lopez-Ibor, 2007a). Social anxiety disorder tends to run a chronic course in primary [I] (Beard et al., 2010) and secondary medical care settings [II]

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Baldwin et al. Table 3.  Twelve-month prevalence of anxiety disorders within the European Union. Diagnosis (DSM-IV)

Inter-quartile range (%)

Best estimate (%)

Number affected (millions)a

Anxiety disorders Panic disorder Agoraphobia Social anxiety disorder Specific phobias Generalised anxiety disorder Obsessive-compulsive disorder Post-traumatic stress disorder

Not applicableb 0.4–2.0 0.4–2.0 1.1–4.4 3.4–7.1 0.6–2.2 0.5–1.1 0.7–2.5

14.0 1.8 2.0 2.3 6.4 1.7–3.4c 0.7 1.1–2.9d

61.5 7.9 8.8 10.1 22.7 8.9 2.9 7.7

aAccording

to Eurostat Directorate General of European Commission (Eurostat 2010) for the age groups used. data from single study. 95% confidence interval, 13.4–15.6%. cAge range 14–65 years, 1.7%; age 65+ years, 3.4%. dAge range 14–34 years, 2.9%; age range 35–65 years, 1.3%; age 66+ years, 1.1%. Best estimates represent consensus view of experts on most probable estimate from identified range. Full data available in Wittchen et al. (2011). DSM-IV refers to the Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association (1994). bAggregate

(Bruce et al., 2005; Ramsawh et al., 2009). For panic disorder, prospective studies reveal high degrees of symptom chronicity [I] (Batelaan et al., 2010b), relapse after remission [I] (Batelaan et al., 2010a), and ‘switching’ to other diagnoses [II] (Rubio and Lopez-Ibor, 2007b). Childhood separation anxiety disorder often resolves with entry into adolescence [I] (Copeland et al., 2014). Retrospective longitudinal studies in obsessive-compulsive disorder suggest a very poor outcome, though prospective studies in non-clinical [I] (Fineberg et al., 2013) and clinical samples [II] (Eisen et al., 2010; Kempe et al., 2007) indicate a more favourable prognosis. Cohort studies which have examined the course of symptoms following traumatic experiences suggest that posttraumatic stress disorder emerges in only a minority of affected individuals (for example, [II] Mayou et al., 2001) the course of established post-traumatic stress disorder is not established, though a chronic course was seen in almost one-half of adolescents and young adults [I] (Perkonigg et al., 2005).

Recommendations: increased awareness of anxiety disorders ● Become familiar with the main features of the anxiety disorders, post-traumatic stress disorder and obsessivecompulsive disorder: and with the main symptoms which distinguish between them [S] ● Develop systematic questions to ask about the nature, severity, duration, distress and associated impairment in patients with anxiety symptoms, to decide whether an anxiety disorder, post-traumatic stress disorder or obsessive-compulsive disorder is present [S] ● Become familiar with the fluctuating nature of symptoms in patients with anxiety disorders, and with the tendency for symptoms to change in nature over time [S]

6.2. Co-existing psychological symptoms and co-morbid mental disorders Anxiety symptoms often co-exist with other psychological symptoms, especially depressive symptoms, which are particularly

frequent among those individuals with more severe anxiety symptoms. Cross-sectional studies in European community and clinical settings [I] (Fehm et al., 2005; Goodwin, 2005; Lieb et al., 2005) and in UK primary medical care [I] (Nease and Aikens, 2003) reveal a significant correlation between measures of anxiety and depressive symptom severity. Many patients with anxiety disorders also simultaneously fulfil diagnostic criteria for another disorder, this pattern typically being named ‘co-morbidity’. High levels of co-morbidity are seen between the anxiety disorders, and with major depression [I] (Wittchen and Jacobi, 2005), bipolar disorder [II] (Gaudiano and Miller, 2005; Henry et al., 2003), schizophrenia (IV) (Buckley et al., 2009) substance misuse (Castle, 2008; Crippa et al., 2009; Robinson et al., 2009; Ziedonis et al., 2008) and physical illness [IV] (Davies et al., 2007; Roy-Byrne et al., 2008). The presence of a comorbid anxiety disorder is associated with both a longer time to recovery and with a greater risk of ending treatment prematurely in patients with major depression [II] (Brown et al., 1996). An early systematic review found that patients with comorbid conditions generally had worse outcomes than those with anxiety disorder or depressive disorder alone [I] (Emmanuel et al., 1998). This is supported by the findings of the US National Comorbidity Survey which demonstrated that individuals with comorbid generalised anxiety disorder and major depression were significantly more likely to remain symptomatic than individuals with depression or generalised anxiety disorder alone [I] (Kessler et al., 2008). Detection of co-morbid depression can sometimes lead to simultaneous recognition of an underlying primary anxiety disorder. For example, a French primary care study of the prevalence, recognition and treatment of social phobia found that detection rates were increased in the presence of comorbid depression (66%, compared with 53% in those without depression) [I] (Weiller et al., 1996). However the presence of a seemingly more pressing comorbid condition can result in sub-optimal treatment for the anxiety disorder. Data from a United Kingdom general practice cluster randomised controlled trial of the impact of mental health guidelines, which found that only 54% of patients with a ‘common mental disorder’ (depression or anxiety) were offered active treatment, revealed that patients with anxiety or mixed anxiety-depression were significantly less likely to be offered

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treatment than patients with depression alone [I] (Hyde et al., 2005). Analysis of a Dutch primary care database involving patients with a newly diagnosed anxiety disorder found that benzodiazepines were significantly more frequently prescribed in patients with psychiatric comorbid conditions, and antidepressants significantly more frequently prescribed in patients with comorbid physical illness: in both forms of comorbidity, the prescription pattern of benzodiazepines was inconsistent with current guideline recommendations [I] (Smolders et al., 2007). The presence of marked co-existing depressive symptoms is an important consideration in treatment decisions. Where anxiety symptoms are present within the context of a depressive disorder, antidepressant drug treatment is often effective in reducing anxiety (IV) (Anderson et al., 2008). Where depression follows or is comorbid with an anxiety disorder it is generally indicative of greater severity and associated with poorer prognosis (II) (Albus and Scheibe, 1993; Brown et al., 1995; Cowley et al., 1996; Erwin et al., 2002; Martinsen et al., 1998; Rief et al., 2000; Shalev et al., 1998). Clinical practice has usually been to direct treatment towards the depressive disorder in the first instance, choosing treatments that also have action against the symptoms of the anxiety disorder: though some guidance notes that when a patient has an anxiety disorder and comorbid depression or depressive symptoms, treating the anxiety disorder first should also be considered, as effective treatment of the anxiety disorder will often improve the depression or depressive symptoms (National Institute for Health and Clinical Excellence, 2011).

Recommendations: enquiring about coexisting symptoms and comorbid disorders ● Check for anxiety symptoms in patients presenting with symptoms of other mental disorders, including depression, bipolar disorder, psychosis and substance misuse [A] ● Remember that coexisting depressive symptoms in patients with anxiety disorders are associated with greater functional impairment and a longer duration of illness [B] ● Assess for comorbid depression and treat if depressive symptoms are of more than mild intensity [S]

7.  Detection of anxiety symptoms in primary medical care settings Within the setting of primary medical care (general practice), most patients with anxiety or depression have relatively mild and transient symptoms, which tend to resolve without the need for intervention: but many have severe, persistent and disabling symptoms, which are likely to benefit from psychological or pharmacological treatment. However, many patients with anxiety and depressive symptoms do not present to primary medical care services [I] (Andrews and Carter, 2001; Roness et al., 2005). Even when patients do consult their general practitioner, anxiety symptoms are usually not their presenting complaints. The general practitioner therefore faces a significant challenge, in detecting the sample of patients most in need of treatment,

from among the wider group, in many of whom intervention may be unnecessary. The limited detection of anxiety disorders in primary care has been observed in multiple countries over many years. A Dutch study found a low (47%) rate of detection of anxiety and depression, recognition being more likely in anxiety disorders of shorter duration [I] (Ormel et al., 1991). A German study, in which 5.3% of patients fulfilled diagnostic criteria for generalised anxiety disorder, and 1.6% for comorbid major depressive episode and generalised anxiety disorder, found that whilst the majority (over 70%) of affected individuals were recognised as having clinically significant emotional problems, accurate diagnosis was less common (34.4% for generalised anxiety disorder) [I] (Wittchen et al., 2002). A United States investigation of older patients with generalised anxiety disorder found low rates of recording of anxiety symptoms (34%) or anxiety disorder (9%) despite much use of health services [I] (Calleo et al., 2009). A Canadian study found the majority of ‘cases’ of anxiety disorder diagnosed through a structured clinical interview did not have a recorded diagnosis (generalised anxiety disorder, 71.0%; panic disorder, 85.8%; social anxiety disorder, 97.8%) [I] (Vermani et al., 2011). Limited recognition is partly related to difficulty in discussing emotional difficulties: many patients do not express emotional symptoms and many doctors find it hard to raise concerns about potential psychological distress. A United Kingdom general practice survey involving patients whose questionnaire scores indicated likely psychiatric ‘caseness’ found the vast majority had not mentioned emotional problems in the consultation, mainly through fears of either being unable to cope with the ensuing distress or of embarrassment, or through not wishing to trouble their doctor: but many also felt there would be either insufficient time, or the doctors could do nothing to help [II] (Cape and McCulloch, 1999). A United States primary care study found that doctors who were more sensitive to non-verbal communications were more likely to make diagnoses; but those who tended to ‘blame’ patients made fewer psychological assessments, and were less accurate in detecting distress [II] (Robbins et al., 1994). Fortunately general practice is structured in such a way that many patients present repeatedly, which provides an opportunity for recognition of symptoms at subsequent consultations, if an anxiety disorder is not detected at the first visit. In a United Kingdom longitudinal study of the detection of depression and anxiety which found that many ‘cases’ were not detected at the initial appointment, the vast majority of undetected cases of depression or anxiety were recognised at follow-up [I] (Kessler et al., 2002). A Dutch primary care practice survey found that patients with an anxiety disorder were less likely to be diagnosed than patients with a depressive episode, but the likelihood of diagnosis in both conditions increased with the number of consultations, and the expression of more severe psychological symptoms [I] (Verhaak et al., 2006).

Recommendations: increasing skills in detecting anxiety symptoms ● Remember that many patients are either reluctant to present with psychological symptoms or find it hard discuss emotional problems [A]

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● Be sensitive to non-verbal expression of psychological distress [B] ● Use the opportunity provided by repeated consultations in primary care to ask follow-up questions about possible anxiety symptoms when these were suspected but not established at earlier appointments [A] ● Routine screening of all patients for the presence of anxiety symptoms is not recommended [A]

8. Screening for anxiety disorders in primary care settings In theory, patients and health professionals might benefit from the use of screening tools for detecting anxiety disorders, which can lead to discussion of psychological symptoms at both the index and subsequent appointments. A Danish primary care study of the potential value of screening for common mental disorders found that disclosure of scores on screening questionnaires increased the recognition of mental disorders by doctors with moderate or low recognition rates; and also resulted in increased discussion of psychological concerns and planned follow-up consultations in patients who had ‘screened positive’ [I] (Christensen et al., 2005). However, use of screening questionnaires needs to be accompanied by other changes in practice structure, and it is uncertain whether routine screening and disclosure of ‘screened positive’ patients with anxiety disorders leads to improved clinical outcomes. An educational intervention involving this design, among United States primary care patients found no evidence for an improvement in patient outcomes [I] (Mathias et al., 1994). The criteria for diagnosing psychiatric disorders are mainly from clinical observations in psychiatric outpatients and inpatients and so may not be appropriate for routine use in screening for common mental disorders, among the more mildly ill patients in primary care. Primary care doctors often have reservations about the usefulness of DSM-IV criteria for diagnosis in primary care, and many of their patients are reluctant to accept any offered diagnoses or undergo psychotropic drug treatment [II] (Van Rijswijk et al., 2009). Although general practitioners sometimes find using screening questionnaires to be troublesome within a standard consultation, patients do not object to completing them [II] (Leydon et al., 2011). The use of questionnaires for detecting and following up patients with depressive symptoms has become part of routine primary care practice in the United Kingdom, suggesting that use of a similar questionnaire for detecting anxiety disorders is feasible in practice [IV] (Buszewicz and Chew-Graham, 2011).

9. Increasing awareness of anxiety disorders in particular patient populations When compared with the general population, anxiety disorders are more common among patients with other mental disorders, with chronic physical illness, and in certain demographic groups. Patients with long-standing socioeconomic problems, and those from certain ethnic populations, may be at greater risk of receiving sub-optimal care and treatment. A Dutch primary care

investigation, which included a nested case-control study of care received by patients with or without psychosocial problems, found that individuals with associated problems were significantly more likely to receive benzodiazepines and less likely to receive antidepressants: which may have contributed to their poorer outcomes [I] (Van Rijswijk et al., 2006). A crosssectional study of anxiety and depressive symptoms in Australian family practices found that unemployed patients, when compared to employed patients, were significantly more likely to report affective symptoms, to have greater symptom severity, to have previously undergone treatment and to be prescribed psychotropic medication: but were no more likely to be referred to mental health services than were employed patients [I] (Comino et al., 2000). Data from the United States indicate that black and Hispanic patients were less likely than white patients to receive care for depression and anxiety, or to receive antidepressant prescriptions (and for Hispanic patients, to undergo counselling) in primary care; and black patients were less likely than white patients to receive antidepressant prescriptions from a psychiatrist [II] (Lagomasino et al., 2011). Similar discrepancies were seen in a treatment review among United States primary care patients with anxiety disorders, where ‘non-white’ individuals were significantly less likely to receive treatment [II] (Weisberg et al., 2007). This situation may not necessarily apply in all countries, as a Dutch general practice study of the quality of care for anxiety and depression across ethnic minority groups found that all groups (with the exception of individuals originating from Surinam and the Antilles) were as likely to receive guideline-concordant medical care [I] (Fassaert et al., 2010).

Recommendations: paying particular attention to certain patient groups ● Remember that anxiety symptoms tend to persist longer in patients who are experiencing long-standing socioeconomic difficulties [B] ● Ensure that the presence of socioeconomic disadvantage or membership of a minority ethnic group among patients in your practice is not associated with a reduced chance of their undergoing evidence-based pharmacological or psychological treatment [S]

10. Identifying which patients with anxiety disorders should undergo treatment Many anxious individuals have mild symptoms of recent onset that are associated with stressful life events or troublesome situations, which will often improve without needing specific treatment. However, the chronic nature and significant associated disability of anxiety disorders means that most patients who fulfil the diagnostic criteria for an anxiety disorder – in terms of severity, duration, distress and impairment – are likely to benefit from some form of treatment, whether this is psychological or pharmacological. The need for treatment is influenced by the intensity and duration of illness, the impact of symptoms on everyday life, the presence of co-existing depressive symptoms and comorbid

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disorders, and the presence of concomitant medication; together with other features such as a good response to, or poor tolerability of, previous treatments. The choice of a particular treatment should be influenced by the supporting evidence base, by patient characteristics (such as co-morbid physical illness, previous response, or treatment contraindications), the preferences of patients and experience of doctors, and the local availability of any proposed intervention [IV] (Haynes et al., 2002). However, many patients with anxiety disorders who might benefit from treatment do not receive it. A United States longitudinal primary care study of the use of health services by patients with panic disorder found that 64% had undergone some form of intervention over 4–10 months, but only 22% had been given appropriate pharmacological treatment, and only 12% had received appropriate psychological treatment [II] (Roy-Byrne et al., 1999). The quality of treatment in those who do receive it may be enhanced through making an accurate diagnosis and by regular monitoring of progress. Another United States primary care study of the treatment of patients with panic disorder found that inadequate dosage and insufficient duration of treatment were both common, and suggested that enhanced patient education and an increased frequency of appointments would be more likely to facilitate adequate treatment than would physician education [II] (Roy-Byrne et al., 2002). A study of adherence to evidence-based guidelines for depression and anxiety disorders within the setting of Dutch primary medical care found that only 27% of patients with anxiety disorders received guidelineconsistent care: symptom severity had no influence on adherence, but documentation of a diagnosis by the general practitioner significantly increased the likelihood of receiving guidelineconsistent care [I] (Smolders et al., 2009). Media reports in many countries have raised concerns about the ‘medicalisation’ of anxiety, shyness, worrying and adjustment to trauma, and about the inappropriate prescribing of psychotropic drugs to patients who are experiencing life stresses or situational problems. This may be a factor in some settings, though most studies find a low level of inappropriate prescribing and a high level of unmet need. For example, a Norwegian primary care study involving over 1300 patients found some of evidence of ‘overtreatment’ (including inappropriate counselling, prescription of psychotropic medication, or specialist referral) in 11% of individuals without a formal psychiatric diagnosis, but also found substantial rates of ‘under-treatment’ for individuals with the diagnoses of major depressive episode (49%) or generalised anxiety disorder (64%) [I] (Olsson et al., 2006).

Recommendations: deciding when and which treatment is required ● Assess the severity and duration of anxiety symptoms, and the associated distress and impairment, when deciding which patients should be offered pharmacological or psychological treatment [S] ● Remember to ask about coexisting depressive symptoms and other potential comorbid disorders [S] ● Consider other factors such as the presence of physical illness, current concomitant medication, and a history of good response to, or poor tolerability of, previous treatments [S]

● Record the diagnosis and review this at subsequent appointments [A] ● The choice of a particular treatment should be influenced by the supporting evidence base, by clinical characteristics (such as treatment contraindications and expected impact of potential side effects), the preferences of patients, personal experience, and the local availability of any proposed intervention[S]

11. Anticipating common concerns about potential adverse effects of psychotropic drugs Many patients experience unwanted and distressing adverse effects of psychotropic drug treatment, such as sexual dysfunction with selective serotonin reuptake inhibitors (SSRIs), excessive perspiration with serotonin-noradrenaline reuptake inhibitors (SNRIs), drowsiness with pregabalin and the benzodiazepines, or weight gain with antipsychotic drugs. Others fear developing a tolerance or becoming dependent on medication, and so are reluctant to start, let alone continue, pharmacological treatment. In addition, many patients and health professionals and some commentators consider pharmacological intervention to be a merely symptomatic and not a definitive treatment. For these reasons, many of those who might benefit from treatment do not receive it, and many of those who do undergo treatment stop it early because of the emergence of unwanted effects. Opinions about the potential value and drawbacks of psychotropic drug treatment vary widely. A United States crosssectional study of patients with panic disorder attending primary care found high levels of willingness to see a psychiatrist or psychotherapist, or to undergo pharmacological treatment [III] (Johnson et al., 2000). However a United Kingdom primary care qualitative study of patients’ views on anxiety and depression found marked preferences regarding their perceived health needs, and much scepticism about the value of pharmacological treatments [II] (Kadam et al., 2001). Certain patient groups may be particularly reticent about starting or continuing psychotropic drug treatment. For example, in a United States study of beliefs about psychotherapy and psychotropic drug treatment for an anxiety disorder which found few differences between diagnostic groups, coexisting depression was associated with more favourable views regarding drug treatment, whereas individuals from black and minority ethnic groups were less favourably inclined towards pharmacological or psychological treatments [II] (Wagner et al., 2005). Adherence to prescribed treatment may be enhanced by providing relevant information about treatment and minimising administrative challenges. A qualitative study of experiences of care among groups of treatment-adherent and non-adherent economically disadvantaged patients with panic disorder found that providing information was empowering and reduced a sense of isolation; that patients used a continuing process to evaluate the benefits and risks of treatment; and that barriers to treatment were primarily logistical [II] (Craske et al., 2005). Another investigation of perceived barriers to care suggested that difficulties in the continuing treatment of panic disorder were primarily administrative, such as being uncertain where to seek help, worrying

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Baldwin et al. about potential costs, a lack of health insurance cover, and a delay in receiving appointments [II] (Mukherjee et al., 2006).

Recommendations: ascertaining attitudes to care and treatment ● Explore attitudes and expectations about pharmacological and psychological treatment and correct any misconceptions with patients prior to making a specific treatment recommendation [S] ● Review patient attitudes and experiences periodically during the course of treatment [B] ● Consider the administrative aspects of practice organisation to see whether these facilitate the care and treatment of patients with anxiety disorders [S]

12. Pharmacological treatments in patients with anxiety disorders It has often proved difficult to demonstrate the benefit of antidepressant drug treatment in patients with mild depressive symptoms and the same difficulty is likely to be seen in patients with milder forms of anxiety disorders. Randomised controlled trials across a range of anxiety disorders also often demonstrate a high placebo response [IV] (Baldwin et al., 2011b; Batelaan et al., 2012; Blanco et al., 2013; Fineberg et al., 2013, 2012; Ipser and Stein, 2012) which suggests that non-specific effects of assessment and monitoring can play a large part in overall improvement. It should be emphasised that treatment response is not immediate; that a transient worsening of symptoms can sometimes occur; that prolonged courses are needed to maintain an initial treatment response; and that psychotropic medications and psychological treatments can have additive effects in some disorders. The selection of a particular drug class (and of a specific drug within that class) should be determined principally by the evidence base supporting its use, and also by whether the patient has previous experience of treatment with that compound. The absence of a licensed indication does not necessarily mean an absence of evidence for the proposed treatment intervention: conversely it should not be assumed that all drugs within a class are likely to be efficacious in the treatment of a particular anxiety disorder, when one member of that class has proven efficacy [IV] (Aquilina et al., 2007; Baldwin and Kosky, 2007; Royal College of Psychiatrists, 2007). The presence of coexisting depressive symptoms of moderate or greater severity should guide treatment choice towards the prescription of antidepressant drugs rather than benzodiazepines.

12.1. SSRIs and SNRIs SSRIs have ‘broad spectrum’ efficacy in both short-term and long-term treatment, and are generally well tolerated; and for these reasons are widely considered to be the first-line pharmacological approach in patients with anxiety disorders or obsessivecompulsive disorder. However SSRIs have potentially troublesome adverse effects, including initial increased nervousness, insomnia, nausea and sexual dysfunction [I (M)] (Gartlehner et al., 2011; Serretti and Chiesa, 2009; Sinclair et al., 2009).

Fluoxetine and paroxetine are inhibitors of some cytochrome P450 enzymes and hence may interact with some other psychotropic drugs and treatments for physical illness [IV] (Muscatello et al., 2012). When stopped abruptly, and even when tapered slowly, SSRIs can produce a discontinuation syndrome characterised by dizziness, insomnia and flu-like symptoms [I (M)] (Baldwin et al., 2007; Schatzberg et al., 2006): this seems more likely with paroxetine and least likely with fluoxetine [II] (Tint et al., 2008). The SNRIs duloxetine and venlafaxine have proven efficacy in short-term and long-term treatment of generalised anxiety disorder [IV] (Baldwin et al., 2011b), and placebo-controlled trials indicate that venlafaxine is also efficacious in the acute treatment and prevention of relapse in panic disorder [IV] (Batelaan et al., 2012). Although the tolerability profiles of SSRIs and SNRIs in patients with anxiety disorders are not established fully, systematic reviews of studies in depressed patients suggest that duloxetine and venlafaxine may be less well tolerated than the SSRIs [I (M)] (Cipriani et al., 2012; Schueler et al., 2011). Both duloxetine and venlafaxine have been associated with discontinuation symptoms after abrupt withdrawal [I(M)] (Baldwin et al., 2007; Perahia et al., 2005) in adult patients, data being limited in children and adolescents [IV] (Hosenbocus and Chahal, 2011). Although evidence is mixed (Harrison et al., 2004; Mbaya et al., 2007; Thase, 1998) venlafaxine is sometimes associated with an increase in blood pressure, and monitoring is recommended with higher daily doses [IV] (Joint Formulary Committee, 2012). A systematic review [I (M)] (McIntyre et al., 2008) and the findings of pharmacoepidemiological studies [I (M)] (Strombom et al., 2008; Wernicke et al., 2008a, 2008b) provide no consistent evidence of an increased risk of hepatotoxicity with duloxetine, but it is recommended that duloxetine is avoided in patients with known liver disease and patients considered to be at risk of hepatic dysfunction [IV] (Joint Formulary Committee, 2012).

12.2. Other antidepressant drugs Certain tricyclic antidepressants (TCAs) [IV] (Baldwin et al., 2011b; Bandelow et al., 2008a; Batelaan et al., 2012; Blanco et al., 2013; Fineberg et al., 2012; Ipser and Stein, 2012) are efficacious in some anxiety disorders, but TCAs are associated with a greater burden of adverse effects than either SSRIs or SNRIs [IV] (Anderson et al., 2008), and for this reason should be generally be reserved for use after a non-response to or poor tolerance of initial treatment with an SSRI or SNRI. TCAs should be avoided in patients considered to be at risk of suicide, due to their potential fatal toxicity after overdose [IV] (Thanacoody and Thomas, 2005; Woolf et al., 2007). As with some SSRIs, many possible pharmacokinetic interactions limit their use in patients taking concomitant medication (listed in Appendix 1 of the British National Formulary, Joint Formulary Committee, 2012). As with other antidepressants, stopping TCAs abruptly can cause a discontinuation syndrome [IV] (Schatzberg et al., 2006). The traditional irreversible monoamine oxidase inhibitor (MAOI) phenelzine has proven efficacy in panic disorder and social phobia: but side effects and the need to follow dietary restrictions limit its use, so it should generally be reserved for when patients have not responded to, or proved intolerant of, other treatment approaches. Phenelzine overdose is potentially fatal [III] (White et al., 2008), and it should usually be avoided in patients considered to be at risk of suicide. Interactions involving

10 traditional MAOIs and serotonergic antidepressants such as SSRIs and clomipramine can be hazardous (Lane and Baldwin, 1997). Moclobemide, a reversible inhibitor of mono-amine oxidase A (RIMA) has proven efficacy in social phobia [IV] (Blanco et al., 2013) and some evidence of benefit in panic disorder [I (PCT)] (Ross et al., 2010): the reversibility of its action reduces the need for dietary restrictions at lower daily doses though avoidance of tyramine-containing foods is advisable at higher dosage [I (PCT)] (Dingemanse et al., 1998). Agomelatine has proven efficacy in acute treatment (Stein et al., 2008a) and prevention of relapse (Stein et al., 2012) in generalised anxiety disorder: sexual dysfunction is less likely than with SSRI or SNRI antidepressants [I (M)] (Serretti and Chiesa, 2009), as are discontinuation symptoms [I (PCT)] (Goodwin et al., 2009; Montgomery et al., 2004): elevations of hepatic enzymes occur in more than 1% of treated patients and regular monitoring of liver function tests is required in the early months of treatment [IV] (McAllister-Williams et al., 2010). The evidence for the efficacy of mirtazapine in patients with anxiety disorders is limited and inconsistent (Andrisano et al., 2013; Muehlbacher et al., 2005; Schutters et al., 2010), but in depressed patients treatment-emergent sexual dysfunction is probably less frequent than with SSRIs [I (M)] (Watanabe et al., 2011).

12. 3. Benzodiazepines Some benzodiazepines have proven efficacy in the treatment of patients with panic disorder, generalised anxiety disorder and social anxiety disorder [IV] (Baldwin et al., 2011b; Bandelow et al., 2008b; Batelaan et al., 2012; Blanco et al., 2013). However benzodiazepines can cause troublesome sedation and cognitive impairment in both short-term and long-term treatment, and tolerance and dependence can occur (especially in predisposed patients) with prolonged use: and it is hard to identify those patients at risk of developing long-term problems [IV] (Dell’Osso and Lader, 2012). It is uncertain whether benzodiazepines are efficacious in relieving depressive symptoms in patients with anxiety disorders but there is no evidence of efficacy for benzodiazepines in the acute treatment of patients with minor depression [I (M)] (Barbui et al., 2011) and antidepressants should therefore be preferred in patients with significant coexisting depressive symptoms. Benzodiazepines will usually be reserved for the further treatment of patients who have not responded to at least three previous treatments (such as after non-response to both an SSRI and an SNRI and a psychological intervention); but it has been argued that concerns about potential problems in long-term use should not prevent their use in patients with persistent, severe, distressing, and impairing anxiety symptoms, when other treatments have proved ineffective [IV] (Baldwin and Talat, 2012; Nutt, 2005).

12. 4. Pregabalin Pregabalin has proven efficacy in both acute treatment and prevention of relapse in generalised anxiety disorder [IV] (Baldwin et al., 2011b) and social anxiety disorder. In generalised anxiety disorder, it is efficacious in relieving depressive symptoms of mild to moderate intensity [I (M)] (Stein et al., 2008a), and in reducing the severity of sleep disturbance (Holsboer-Trachsler

Journal of Psychopharmacology and Prieto, 2013). Common adverse effects include drowsiness and dizziness though it may be better tolerated than other medications in the acute treatment of generalised anxiety disorder [I (M)] (Baldwin et al., 2011a). Long-term treatment is accompanied by weight gain in approximately 20% of patients [III] (Montgomery et al., 2013). It is not subject to hepatic metabolism and is excreted unchanged in the urine, which is a potential advantage in patients with hepatic impairment and in patients taking other drugs metabolised by the liver, but potentially disadvantageous in patients with renal disease. There is no known untoward interaction with lithium. Spontaneous reports of adverse sexual side effects are uncommon but the incidence of treatment-emergent sexual dysfunction with pregabalin is uncertain [IV] (Baldwin et al., 2013). Discontinuation symptoms after abrupt withdrawal of pregabalin have been reported, as has the abuse of pregabalin generally in individuals with a history of other substance abuse: but the relative potential for developing tolerance and abuse, when compared to with medications, is not established [IV] (Baldwin et al., 2013).

12. 5. Other agents Antipsychotic drugs are often prescribed to patients with anxiety disorders, but the strongest evidence for benefit is restricted to acute treatment and prevention of relapse with quetiapine in generalised anxiety disorder [IV] (Baldwin et al., 2011b), and the augmentation of SSRI antidepressants in patients with obsessivecompulsive disorder [IV] (Fineberg et al., 2012). The tolerability profile of antipsychotic drugs is such that they should generally be reserved for treatment after a non-response to other interventions [IV] (National Institute for Health and Clinical Excellence, 2011). The azapirone drug buspirone is efficacious in the acute treatment of generalised anxiety disorder [I (M)] (Chessick et al., 2006), as is the anti-histamine drug hydroxyzine [I (M)] (Guaiana et al., 2010), though neither has published evidence of efficacy in the prevention of relapse.

Recommendations: general aspects of pharmacological treatment ● Discuss the anticipated balance of potential benefits and potential risks of specific psychotropic medications with patients before starting treatment [S] ● Consider a SSRI for first-line treatment, as SSRIs are effective across the anxiety and related disorders, in both the short-term and long-term, and are generally well tolerated [A] ● Remain familiar with the evidence base for other classes of medication, as many patients do not respond to or are intolerant of SSRI treatment, but may respond to other classes of psychotropic drug [S] ● Discuss potential adverse effects early in treatment, including increased nervousness, worsened agitation, and review patient progress carefully over the first few weeks of treatment [A] ● Remember that benzodiazepines can be effective in many patients with anxiety disorders [A], but recognise that their use should generally only be short-term:

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Baldwin et al.



and only considered beyond this in patients who have not responded to a succession of other treatment approaches [S] ● Discuss the potential for experiencing discontinuation or withdrawal symptoms during unforeseen abrupt interruptions to treatment and after the planned end of pharmacological treatment [S]

13. Psychological treatments in patients with anxiety disorders Many patients with anxiety disorders or obsessive-compulsive disorder have a marked preference for psychological treatment approaches [II] (Patel and Simpson, 2010; Zoellner et al., 2009). Certain forms of psychotherapy, such as exposure therapy, cognitive therapy and cognitive behavioural therapy (CBT), have largely consistent evidence of efficacy in the treatment of anxiety disorders [I (M)] (Hofmann and Smits, 2008). An early systematic review of counselling for primary care patients with emotional problems (including anxiety, depression, and ‘stress’) indicates that the short-term (but not long-term) efficacy of counselling was greater than that of standard general practitioner care, with or without antidepressant treatment [I (M)] (Bower et al., 2001): though a subsequent meta-analysis suggests that short-term counselling is less beneficial than longer-term treatment with other psychological interventions [I (M)] (Cape et al., 2010). Some psychological interventions – such as psychodynamic psychotherapy - have not been subject to extensive controlled investigations (Leichsenring, 2005; Lewis et al., 2008). Psychodynamic psychotherapy was reported to be superior to applied relaxation in patients with panic disorder (Leichsenring et al., 2009; Milrod et al., 2007), but has been found less beneficial than CBT in generalised anxiety disorder (Durham et al., 1999) . Many evaluations of the efficacy of psychological treatments have not employed an optimal psychological placebo control treatment: the use of waiting list controls is inadequate to demonstrate potential efficacy. The efficacy of psychological and pharmacological approaches is broadly similar in the acute treatment of anxiety disorders. In some studies, relapse rates are lower after an initial response to cognitive therapy with exposure than after response to drug treatment. For these reasons, patients should be offered a choice of treatment approaches, selection being affected by patient clinical features, needs and preference, and by the local availability of services able to offer evidence-based psychological interventions [IV] (Haynes et al., 2002). In most anxiety disorders (generalised anxiety disorder, social anxiety disorder, post-traumatic stress disorder, obsessive-compulsive disorder) it is uncertain whether combining psychological and pharmacological treatments is associated with greater long-term benefit than that which is seen with either treatment approach when given alone. However, previous concerns that prescription of psychotropic drugs might reduce the efficacy of psychological treatment are probably unfounded: in some anxiety disorders systematic reviews suggest that psychotropic drug administration can enhance the short-term efficacy of cognitive-behavioural interventions. As with pharmacological approaches, it should be emphasised that response to psychological treatment is not immediate; that transient worsening of symptoms can sometimes

occur; that prolonged courses are often needed to maintain an initial treatment response; that dependence on the therapist may occur, with problems when treatment is stopped; and that encouraging short-term outcomes are no guarantee of good outcomes over the longer-term. Given uncertainty about the value of combination treatment and widespread constraints in the availability of mental health services, it may be best to plan sequential steps in patient management [IV] (National Institute for Health and Clinical Excellence, 2005, 2011). When psychological treatment is recommended, it should only be delivered by suitably trained and supervised staff, able to demonstrate that their clinical practice adheres to evidencebased treatment protocols [IV] (National Institute for Health and Clinical Excellence, 2005). The potential effectiveness of initiatives designed to increase the uptake of psychological interventions for patients with common mental health problems – such as the Improving Access to Psychological Therapies programme [IV] (Brown et al., 2010; Clark, 2011) in the United Kingdom – has not been established through formal randomised controlled trials. A general range of 8–20 h of sessions of CBT may be needed in the treatment of anxiety disorders. In generalised anxiety disorder and panic disorder, a typical treatment course consists of approximately 16–20 h, up to half of which can be conducted by the patient in supervised ‘homework’ sessions, over a period of approximately four months [IV] (National Institute for Health and Clinical Excellence, 2011). In social anxiety disorder a standard course should consist of up to 14 sessions of 90 min duration over the course of four months [IV] (National Institute for Health and Care Excellence, 2013). In post-traumatic stress disorder, a standard course of psychological treatment might involve 8–12 sessions of trauma-focused CBT, delivered at weekly intervals [IV] (National Institute for Clinical Excellence (NICE), 2005). In obsessive-compulsive disorder, a typical initial treatment course might include approximately 16 h of intervention based on exposure and response prevention, with longer and more intensive treatment in housebound patients [IV] (National Institute for Health and Clinical Excellence, 2005).

Recommendations: general aspects of psychological treatment ● Remember that the efficacy of psychological and pharmacological approaches is broadly similar in the acute treatment of patients with anxiety disorders [A] ● Discuss the anticipated balance of potential benefits and potential risks of specific psychological interventions with patients before starting treatment [S] ● Ensure that psychological treatments are only delivered by suitably trained and supervised staff, able to demonstrate that their clinical practice adheres to evidence-based treatment protocols [A] ● Remind patients that response to psychological treatment is not immediate and that a prolonged course is usually needed to maintain an initial treatment response [S] ● Plan sequential steps in patient management rather than combining treatments from the start, as it is uncertain whether combining is associated with greater longterm benefit [D]

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14. The role of self-help and complementary approaches in anxiety disorders Patient preference and the often sub-optimal effects of ‘standard’ pharmacological or psychological treatment approaches have encouraged the development of a range of self-help techniques and therapies in anxiety disorders; some undertaken as individuals, often through internet-based resources, and others in groups. Many patients and their carers derive considerable practical and emotional support from local self-help groups and national selfhelp organisations (such as the United Kingdom organisations Anxiety-UK and Obsessive Action): though formal evaluations of the effectiveness of participation in such groups are sparse [I (M)] (Pistrang et al., 2008). There have been relatively few randomised controlled trials of the efficacy and acceptability of self-help approaches undertaken as individuals, and few studies have been conducted in diagnostically homogenous groups, with reliable outcome measures and robust statistical analysis. An early systematic review of six randomised controlled trials found evidence for the efficacy of self-help in primary care patients with mixed anxiety disorders, greater efficacy being seen with more detailed instruction in use of self-help manuals [I (M)] (Van Boeijen et al., 2005). The findings of a systematic review of 21 studies in patients with depression or anxiety disorders suggest that guided self-help has similar effectiveness to face-to-face psychotherapy [I (M)] (Cuijpers et al., 2010): a subsequent systematic review of 31 randomised controlled trials in anxiety disorders indicates that selfhelp interventions are more effective than being placed on a waiting list, but less effective than therapist-administered treatments [I (M)] (Lewis et al., 2012). In addition, the evidence base for self-help approaches in young people with anxiety disorders is limited [IV] (Parslow et al., 2008; Rickwood and Bradford, 2012). In 2006, the UK National Institute for Clinical Excellence concluded that there was insufficient evidence to recommend the general introduction of computerised CBT for anxiety symptoms or disorders (National Institute for Health and Clinical Excellence, 2006): however the findings of a systematic review of 26 studies in individuals with depression or anxiety disorders suggest that internet-based interventions offer promise, in overall management [I (M)] (Griffiths et al., 2010); though there is a need to further investigate factors associated with beneficial outcomes (Andersson, 2012). Many patients with anxiety disorders wonder whether taking herbal preparations or nutritional supplements might prove beneficial, either instead of or in conjunction with standard pharmacological or psychological treatments. Systematic reviews find some evidence for the potential effectiveness of a number of ‘phytomedicines’, including Passiflora species extracts, Kava (Piper methysticum), and combinations of l-lysine and l-arginine (Lakhan and Vieira, 2010; Sarris et al., 2011b; Van der Watt et al., 2008). There is no current convincing evidence for the effectiveness of homoeopathic preparations in the treatment of patients with anxiety disorders [I (M)] (Davidson et al., 2011; Pilkington et al., 2006). Kava preparations appeared to have some beneficial effects in patients with generalised anxiety disorder but have been withdrawn in many countries due to potential hepatotoxic effects [IV] (Sarris et al., 2011a).

Journal of Psychopharmacology Other complementary approaches include regular exercise and interventions drawing on meditation techniques. A systematic review indicates that exercise training reduces anxiety symptoms in sedentary patients with long-term medical conditions [I (M)] (Herring et al., 2010); and regular walking may enhance the efficacy of group CBT, across a range of anxiety disorders [II] (Merom et al., 2008). In panic disorder, regular exercise is marginally superior to relaxation [I (PCT)] (Wedekind et al., 2010); but less effective than either the TCA clomipramine [I (PCT)] (Broocks et al., 1998) or group CBT [II] (Hovland et al., 2012). Preliminary evidence suggests that exercise training may be effective in obsessive-compulsive disorder (Abrantes et al., 2009), generalised anxiety disorder (Herring et al., 2012) and social anxiety disorder (Jazaieri et al., 2012). Meditation and yoga practices are often advocated, as part of the overall management of patients with anxiety disorders. Early systematic reviews found only minimal evidence for the effectiveness of meditation therapy [I (M)] (Krisanaprakornit et al., 2006) or mindfulness-based meditation [I (M)] (Toneatto and Nguyen, 2007). However another systematic review indicated that relaxation training (which often includes components of meditation) is effective in reducing anxiety symptoms in nonclinical and clinical groups [I (M)] (Manzoni et al., 2008): and the findings of two recent systematic reviews suggest that meditative therapies are effective in reducing anxiety symptoms (though their effect in anxiety disorders is uncertain) [I (M)] (Chen et al., 2012), and that mindfulness- and acceptance-based interventions are effective in reducing anxiety and co-existing depressive symptoms in patients with anxiety disorders [I (M)] (Vøllestad et al., 2012). Recommendations: approaches

self-help

and

complementary

● Remember that self-help approaches, such as use of internet-based educational resources, are potentially beneficial in patients with mild anxiety and depressive symptoms [A] ● Keep patients who use such resources under review as many will not improve, and so will need to undergo other forms of treatment [S] ● Enquire about the use by patients of herbal preparations or nutritional supplements, but remember that the evidence base for their use is relatively slight, when compared to the substantial evidence supporting the use of pharmacological and psychological interventions [S]

15. Costs of illness and costeffectiveness of treatment Anxiety disorders are associated with a substantial economic burden: both in health care systems (mainly direct costs of assessment, investigation, treatment and care), and in the wider society (including premature mortality, unemployment, reduced productivity losses) [I] (Andlin-Sobcki and Wittchen, 2005; Gustavsson et al., 2011; Wittchen et al., 2011). Using estimates to calculate the size of the population in the European Union that would be affected (69.1 million people), it was estimated that, in 2010, anxiety disorders (excluding post-traumatic stress disorder) cost close to €66

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Baldwin et al. billion [I] (Gustavsson et al., 2011). Treatment costs account for a small proportion of the overall costs of health care, and it has been argued that the increased costs of strategies to increase the recognition and evidence-based treatment in patients that would otherwise remain undetected and untreated would be small, compared to the saving arising from unemployment and reduced productivity at work [IV] (Baldwin et al., 2010; Issakidis et al., 2004). However there have been relatively few randomised controlled trials or systematic evaluations of the cost-effectiveness of pharmacological, psychological or self-help interventions across the broad range of anxiety disorders (Joesch et al., 2012; Konnopka et al., 2009; Lewis et al., 2012; Poirier-Bisson et al., 2010). Investigations of the costs of illness and cost-effectiveness of individual anxiety disorders are limited. The cost-effectiveness of Improving Access to Psychological Therapies (IAPT) services within the UK is not established [III] (McCrone, 2013; Mukuria et al., 2013). For generalised anxiety disorder, cost-effectiveness studies provide evidence for the value of CBT, certain antidepressants, and pregabalin (Bereza et al., 2009; Heuzenroeder et al., 2004; Iskedjian et al., 2008; Jorgensen et al., 2006; VeraLlonch et al., 2010). Cost-effectiveness studies in panic disorder provide evidence for the value of CBT (Heuzenroeder et al., 2004; Roberge et al., 2008) [II]; SSRI or tricyclic antidepressants (Heuzenroeder et al., 2004; McHugh et al., 2007); lifestyle approaches (Lambert et al., 2010) [III]; computerised interventions (Klein et al., 2009; McCrone et al., 2009; Mihalopoulos et al., 2005) and early intervention (Smit et al., 2009). Brief interventions (Klein et al., 2009), monotherapies (McHugh et al., 2007) and self-directed approaches (McCrone et al., 2009) may be more cost-effective than longer, combination treatment, or clinician-led approaches, respectively. Treatment studies in social anxiety disorder provide some evidence for the cost-effectiveness of internet-delivered approaches [II] (Hedman et al., 2011c; Titov et al., 2009), group CBT [II] (Hedman et al., 2011a), and for long-term treatment with the SSRI escitalopram in the prevention of relapse [I (PCT)] (Francois et al., 2008). The costeffectiveness of treatments for obsessive-compulsive disorder has been investigated only rarely, with limited evidence for the greater cost-effectiveness of ‘stepped care’ compared to standard CBT [II] (Tolin et al., 2011) and group CBT in children and adolescents [III] (Farrell et al., 2012). In post-traumatic stress disorder, there is only modelled or limited evidence, for the cost-effectiveness of trauma-focused CBT in the treatment of sexually abused children, which may be enhanced when combined with an SSRI [III] (Gospodarevskaya and Segal, 2012); and for virtual reality graded exposure therapy in combat-related trauma [III] (Wood et al., 2009).

16. Management of generalised anxiety disorder 16. 1. Recognition and diagnosis Generalised anxiety disorder is amongst the most common of mental disorders in primary medical care, and is associated with increased use of health services. However it is often not recognised, possibly because only a minority of patients present with anxiety symptoms (most present with physical symptoms), and doctors tend to overlook anxiety unless it is a presenting complaint [I] (Munk-Jorgensen et al., 2006). The

degree of functional impairment associated with generalised anxiety disorder is similar to that with major depression [I] (Wittchen et al., 2000). Patients with ‘co-morbid’ depression and generalised anxiety disorder have a more severe and prolonged course of illness and greater functional impairment (Tyrer et al., 2004). Patients with co-morbid depression are more likely to be recognised as having a mental health problem, though not necessarily as having generalised anxiety disorder [I] (Weiller et al., 1998; Wittchen et al., 2002).

16.2. Acute treatment The findings of systematic reviews [I (M)] (Baldwin et al., 2011b; National Institute for Health and Clinical Excellence, 2011) and randomised placebo-controlled trials of acute treatment of patients with generalised anxiety disorder together provide substantial evidence for the efficacy of many antidepressant drugs – including SSRIs (citalopram, escitalopram, paroxetine, sertraline), SNRIs (duloxetine, venlafaxine), the tricyclics imipramine and opipramol, trazodone, and agomelatine [IV] (Baldwin et al., 2011a). Other compounds with efficacy in placebo-controlled acute treatment studies include pregabalin [I (M)] (Wensel et al., 2012), some benzodiazepines (alprazolam, diazepam, lorazepam) [I (M)] (Martin et al., 2007), buspirone [I (M)] (Chessick et al., 2006), some antipsychotic drugs (quetiapine, trifluoperazine) [I (M)] (Lalonde and Van Lieshout, 2011) and the antihistamine hydroxyzine [I (M)] (Guaiana et al., 2010). Beta-blockers are often used in primary medical management of physical symptoms of anxiety but placebo-controlled evidence of efficacy in acute treatment of patients with generalised anxiety disorder is minimal [I (PCT)] (Meibach et al., 1987). There have been relatively few randomised comparatorcontrolled studies of acute treatment in generalised anxiety disorder [I (M)] (Baldwin et al., 2011b; National Institute for Health and Clinical Excellence, 2011) and most reveal no significant differences in overall efficacy between active compounds. An early analysis of randomised controlled trials of acute treatment found an overall mean effect size of 0.39: medications with higher effect sizes were pregabalin, hydroxyzine and SNRIs; and with lower effect sizes were benzodiazepines, SSRIs and buspirone [I (M)] (Hidalgo et al., 2007). The tentative findings of a mixed treatment comparison suggest fluoxetine, sertraline and pregabalin have some advantages over other medications: among currently licensed treatments in the United Kingdom, duloxetine, escitalopram and pregabalin may have some advantages over paroxetine and venlafaxine [I (M)] (Baldwin et al., 2011b). It is uncertain whether antidepressant drugs, pregabalin and benzodiazepines differ in their relative efficacy in reducing the severity of psychological or somatic anxiety symptoms [IV] (Baldwin et al., 2011a). The findings of fixed-dose randomised placebo-controlled trials provide some evidence of a dose-response relationship for pregabalin [I (M)] (Bech, 2007; Lydiard et al., 2010), but studies with antidepressant drugs provide no consistent evidence for a dose-relationship [IV] (Baldwin et al., 2011a). Although not an antidepressant, a post hoc pooled analysis of randomised placebo-controlled trials with pregabalin indicate that it is efficacious in reducing depressive symptom severity in patients with mild to moderate intensity of depressive symptoms [I (M)] (Stein et al., 2008b).

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16.3. Longer term treatment The findings of acute treatment studies indicate that the proportion of responding patients steadily increases over time [IV] (Baldwin et al., 2011a). Continuing with SSRI or SNRI treatment is associated with an increase in overall response rates: from 8–24 weeks with escitalopram or paroxetine [II] (Bielski et al., 2005); from 4–12 weeks with sertraline [I (PCT)] (Allgulander et al., 2004a) and from 8–24 weeks with venlafaxine [I (PCT)] (Montgomery et al., 2002). However, the findings of post hoc analyses of data from randomised double-blind placebo-controlled studies with duloxetine [I (M)] (Pollack et al., 2008), escitalopram [I (M) (Baldwin et al., 2009), and with alprazolam, pregabalin and venlafaxine [I (M) (Baldwin et al., 2011a) all suggest that response is likely only if there is an onset of effect within four weeks of treatment. The findings of randomised placebo-controlled relapseprevention studies in patients who have responded to previous ‘open’ acute treatment of varying lengths reveal a significant advantage for staying on active medication (agomelatine, duloxetine, escitalopram, paroxetine, pregabalin, quetiapine, venlafaxine, vortioxetine), when compared with switching to placebo, for periods of between 6–18 months (Baldwin et al., 2011b, 2012; Katzman et al., 2011; Rickels et al., 2010).

Journal of Psychopharmacology treatments with proven efficacy may be helpful [IV] (National Institute for Health and Clinical Excellence, 2011). The addition of pregabalin to SSRI or SNRI antidepressant drugs is superior to continued treatment with antidepressants alone [I (PCT)] (Rickels et al., 2012). The findings of small randomised placebo-controlled augmentation studies suggest that augmentation of antidepressants with antipsychotic drugs (olanzapine, quetiapine, risperidone) may be beneficial [I (PCT)] (Brawman-Mintzer et al., 2005; Pollack et al., 2006; Altamura et al., 2011), but the evidence for quetiapine augmentation is inconsistent [I (PCT)] (Khan et al., 2011; Simon et al., 2008), and uncertain for ziprasidone augmentation [I (PCT)] (Lohoff et al., 2010). Alternative treatments which have been found helpful in some patients include multi-faith spiritually based intervention [II] (Koszycki et al., 2010); Galphimia glauca (‘thyrallis’) [I (PCT)] (Herrera-Arellano et al., 2007), Matricaria recutita extract (chamomile) [I (PCT)] (Amsterdam et al., 2009), ‘Silexa’ lavender oil preparation [I (PCT)] (Woelk and Schlaefke, 2010), ‘relaxing room therapy’ [III] (Sherman et al., 2010), yoga-based breathing programme [III] (Katzman et al., 2012) and ‘balneotherapy’ (hydrotherapy with message) [III] (Dubois et al., 2010): but more investigation of these approaches is needed before they can be recommended.

16.4. Comparative efficacy of psychological, pharmacological, and combination treatments

Recommendations: managing patients with generalised anxiety disorder

Pharmacological or psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment [I (M)] (Bandelow et al., 2007a; National Institute for Health and Clinical Excellence, 2011). The efficacy of CBT and applied relaxation appears superior to that of other psychological interventions (National Institute for Health and Clinical Excellence, 2011). A randomised controlled trial found that augmentation of venlafaxine with CBT conferred no additional benefit, when compared with venlafaxine alone [II] (Crits-Christoph et al., 2011) but it is uncertain whether combining drug and psychological treatments is associated with greater overall efficacy than is seen with either treatment, when given alone [I (M)] (Bandelow et al., 2007a), and a ‘stepped care’ approach is recommended [IV] (National Institute for Health and Clinical Excellence, 2011). Anxiety symptom severity at follow-up after initial treatment is lower with CBT than with other forms of psychological treatment [III] (Durham et al., 2005): but the comparative efficacy of pharmacological and psychological approaches over the long-term is not established.

● Become familiar with the symptoms and signs of generalised anxiety disorder [S] ● Ask about the presence of coexisting depressive symptoms [A] ● Ask about long-standing anxiety in patients with depressive or unexplained physical symptoms [S] ● Assess any comorbid physical illness and enquire about excess alcohol consumption [S]

16. 5. Further management after nonresponse to initial treatment Many patients do not respond to first-line pharmacological or psychological interventions. There is only inconsistent evidence for a dose-response relationship with antidepressant drugs, but some patients who have not responded to an initial low dosage may respond to a higher daily dose. The efficacy of pregabalin when compared with placebo is more marked at higher daily doses (200 mg or higher) [I (M)] (Bech, 2007; Lydiard et al., 2010). Switching between pharmacological and psychological

Detection and diagnosis

Acute treatment ● Choose an evidence-based acute treatment [A] ○ pharmacological: most SSRIs (citalopram, escitalopram, paroxetine, sertraline), duloxetine, venlafaxine, pregabalin, agomelatine, quetiapine, some benzodiazepines (alprazolam, diazepam, lorazepam), imipramine, buspirone, hydroxyzine and trazodone [A] ○ psychological: cognitive-behaviour therapy, applied relaxation [A] ● Take account of patient clinical features, needs and preference and local service availability when choosing treatment, as pharmacological and psychological approaches have broadly similar efficacy in acute treatment [S] ● Consider an SSRI for first-line pharmacological treatment [A] ● SNRIs and pregabalin may be considered as alternative initial treatments if SSRIs are judged to be unsuitable [A] ● Remember that higher daily doses of pregabalin may be associated with greater response rates [A]

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● Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy [S] but recognise that an absence of clinical benefit within four weeks warns that a response to unchanged treatment is unlikely [A] Longer-term treatment ● Continue drug treatment for up to 18 more months in patients who have responded to treatment [A] ● Use a treatment approach that is known to be efficacious in preventing relapse [S] ● Recommend CBT over other forms of psychological treatment as it may reduce relapse rates better than other psychological treatments [C] ● Monitor effectiveness and acceptability regularly over the course of treatment [S] ● When stopping treatment, reduce the dose gradually over an extended period to avoid discontinuation and rebound symptoms [A]: in the absence of evidence a minimum of three months is recommended for this taper period [D] Combination of drugs and psychological treatment ● Routinely combining drug and psychological approaches is not recommended for initial treatment [A] When initial treatments fail ● Consider raising the dosage of pregabalin if the current dosage is well tolerated [A] ● Consider switching to another evidence-based treatment [D] ● Consider combining evidence-based treatments only when there are no contraindications [S] ● Consider pregabalin augmentation after a non-response to initial SSRI or SNRI treatment [A] ● Consider use of benzodiazepines after a non-response to SSRI, SNRI, pregabalin and buspirone treatment [S] ● Consider combining drug treatment and cognitivebehaviour therapy [D] ● Consider referral to regional or national specialist services in treatment refractory patients [S]

17. Management of panic disorder 17.1. Recognition and diagnosis Accurate diagnosis of panic disorder is dependent upon establishing the presence of recurring panic attacks (i.e. short-lived periods of severe psychological and physical symptoms of anxiety, typically peaking within 10 min and resolving within 30 min), at least some of which are, or have been, unexpected. There should be intervening periods of comparative freedom from anxiety between attacks; but the presence of associated concern, worry or change in behaviour due to an anticipated risk of having further panic attacks [IV] (Roy-Byrne et al., 2006). There is substantial overlap between panic disorder and agoraphobia, in community and clinical samples [I] (Goodwin et al., 2005; Wittchen et al., 2010). Patients with panic disorder are often not recognised or accurately diagnosed in primary [IV] (National Collaborating

Centre for Mental Health, 2011) or secondary medical care [I] (Burton et al., 2011; Deacon et al., 2008), despite their considerable use of emergency, cardiac, gastrointestinal, neurological and mental health services [IV] (Roy-Byrne et al., 2006). There is considerable co-morbidity with other mental disorders, including anxiety disorders, bipolar disorder and major depression [IV] (Roy-Byrne et al., 2006): co-morbid panic and depression is particularly common, and associated with greater disability and impairment, and increased use of health services [I] (Roy-Byrne et al., 2000).

17.2. Acute treatment Systematic reviews demonstrate that a range of pharmacological [IV] (Andrisano et al., 2013, Batelaan et al., 2012;), psychological [IV] (Schmidt and Keough, 2010) and combination [I (M)] (Furukawa et al., 2007; Watanabe et al., 2007) interventions are effective in the acute treatment of patients with panic disorder. Little is known about the efficacy of pharmacological or psychological treatment in patients with agoraphobia but without panic attacks (Perna et al., 2011). The findings of randomised doubleblind placebo-controlled trials of antidepressants indicate that all SSRIs (escitalopram, citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline); the SNRI venlafaxine; the selective noradrenaline reuptake inhibitor reboxetine; some TCAs (clomipramine, desipramine, imipramine, lofepramine); the MAOI phenelzine; some benzodiazepines (alprazolam, clonazepam, diazepam, lorazepam); and some anticonvulsants (gabapentin, sodium valproate) are all efficacious in acute treatment [IV] (Batelaan et al., 2012). The findings of randomised comparator-controlled studies provide some evidence for beneficial effects with mirtazapine [II] (Ribeiro et al., 2001) and moclobemide [II] (Kruger and Dahl, 1999; Tiller et al., 1999). The relative efficacy and tolerability of differing pharmacological treatments is uncertain, but there may be efficacy advantages for venlafaxine, and tolerability disadvantages for fluvoxamine and reboxetine [I (M)] (Andrisano et al., 2013). A post hoc analysis of findings from a randomised placebo-controlled trial suggests that escitalopram is superior to citalopram [I (PCT)] (Bandelow et al., 2007b); and randomised controlled trials suggest that some SSRIs (fluvoxamine, paroxetine) are more effective than some noradrenaline reuptake inhibitors (maprotiline, reboxetine) [II] (Bertani et al., 2004; Den Boer and Westenberg, 1988). Medications with a lack of efficacy in the acute treatment of patients with panic disorder include the antidepressant bupropion [I (PCT)] (Sheehan et al., 1983), the betablocker propranolol [I (PCT)] (Munjack et al., 1989); and buspirone[I (PCT)] (Sheehan et al., 1988). The potential value of antipsychotic drug monotherapy in acute treatment is unknown [I (M)] (Depping et al., 2010).

17.3. Longer term treatment The findings of acute treatment studies indicate that the proportion of responding patients steadily increases over time [IV] (Batelaan et al., 2012). Double-blind studies indicate that continuing SSRI or clomipramine treatment from 12–52 weeks is associated with an increase in overall treatment response rates [I (PCT)] (Ballenger, 1998; Lecrubier and Judge, 1997; Lepola et al., 1998). The relative effectiveness and acceptability of

16 differing medications over long-term treatment is uncertain, but a 12-month comparison of the efficacy and tolerability of differing SSRIs (citalopram, fluoxetine, fluvoxamine, paroxetine) suggests that fluvoxamine is less likely to be associated with weight gain or sexual adverse effects [III] (Dannon et al., 2007); and the findings of a randomised naturalistic parallel-group study of 34 months of continuation treatment with clonazepam or paroxetine suggest that clonazepam is marginally more effective and better tolerated [II] (Nardi et al., 2012). Placebo-controlled and other relapse-prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (fluoxetine, imipramine, paroxetine, sertraline, venlafaxine), compared to switching to placebo, for periods of up to six months: but the optimal duration of continuation treatment is uncertain [I (M)] (Donovan et al., 2010).

17.4. Comparative efficacy of psychological, pharmacological, and combination treatments The findings of pooled analyses and randomised controlled trials together indicate that pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment [I (M)] (Bandelow et al., 2007b; McHugh et al., 2009). In acute treatment, the combination of psychotherapy with antidepressants is superior to psychotherapy or an antidepressant, when either is given alone (Furukawa et al., 2007; Koszycki et al., 2011; Van Apeldoorn et al., 2010): the advantage over monotherapies persists as long as the antidepressant is continued, but combination treatment is more effective than antidepressant treatment alone, though no different to psychological treatment alone, in preventing relapse [I (M)] (Furukawa et al., 2007). Based on limited data, the combination of psychotherapy with a benzodiazepine is probably superior to a benzodiazepine when given alone during acute treatment, but the relative efficacy of combination treatment and monotherapies in the prevention of relapse is uncertain [I (M)] (Watanabe et al., 2007). However combination treatment appears no more cost-effective than antidepressant or CBT monotherapy [II] (McHugh et al., 2007). Exploratory placebo-controlled studies suggest that the addition of d-cycloserine may hasten the onset of effect [I (PCT)] (Siegmund et al., 2011) or increase overall effectiveness [I (PCT)] (Otto et al., 2010) of CBT in the acute treatment of patients with panic disorder.

17. 5. Further management after nonresponse to initial treatment Many patients do not respond to first-line pharmacological or psychological interventions. The findings of randomised fixeddose placebo-controlled studies suggest that higher daily doses of some antidepressants [I (PCT)] (paroxetine, fluoxetine: Ballenger et al., 1998; Michelson et al., 1998) but not others [I (PCT)] (citalopram, venlafaxine: Pollack et al., 2007; Wade et al., 1997) may be superior in efficacy to lower doses. However, the evidence to support dose escalation after an initial lack of response to lower doses is only limited [I (PCT)] (Michelson et al., 2001) or negative [I (PCT)] (Simon et al., 2009).

Journal of Psychopharmacology Switching between pharmacological and psychological treatments with proven efficacy may be helpful [IV] (National Institute for Health and Clinical Excellence, 2011). A single-blind crossover study in non-responders suggests that switching between citalopram and reboxetine may be worthwhile [II] (Seedat et al., 2003). A randomised placebo-controlled study found that pindolol augmentation of fluoxetine was superior to continued fluoxetine alone [I (PCT)] (Hirschmann et al., 2000). A small open study involving the addition of fluoxetine in patients taking a TCA, or vice versa, found some evidence of benefit [III] (Tiffon et al., 1994). Combined treatment with sodium valproate and clonazepam may be beneficial in patients who have not responded to several previous medications [III] (Ontiveros and Fontaine, 1992); as has the addition of olanzapine to other medications [III] (Sepede et al., 2006). Addition of lithium to clomipramine was found successful in a single case report [III] (Cournoyer, 1986). Augmentation of CBT with paroxetine may be superior to continuing with CBT alone, in patients who did not previously respond over 15 sessions [I (PCT)] (Kampman et al., 2002); and addition of group CBT may be beneficial in non-responders to pharmacological approaches [III] (Heldt et al., 2003; Otto et al., 1999; Pollack et al., 1994). However a small study in multiply treatment-resistant patients found no difference in effectiveness between the augmentation of medication with CBT or ‘medication optimisation’ (SSRI plus clonazepam) [I (PCT)] (Simon et al., 2009).

Recommendations: managing patients with panic disorder Detection and diagnosis ● Become familiar with the symptoms and signs of panic attacks and panic disorder [S] ● Ask about the presence of coexisting depressive symptoms [A] ● Assess the level of agoraphobic avoidance to help judge the severity of the condition [S] ● Ask about panic attacks and agoraphobia in patients with medically unexplained physical symptoms [D] Acute treatment ● Choose an evidence-based acute treatment [A] ○ pharmacological: all SSRIs, some TCAs (clomipramine, desipramine, imipramine, lofepramine) venlafaxine, reboxetine, some benzodiazepines (alprazolam, clonazepam, diazepam, lorazepam), some anticonvulsants (gabapentin, sodium valproate) [A] ○ psychological: cognitive-behaviour therapy [A] ● Avoid prescribing propranolol, buspirone and bupropion [A] ● Take account of patient clinical features, needs and preference and local service availability when choosing treatment, as pharmacological and psychological approaches have broadly similar efficacy in acute treatment [S] ● Consider an SSRI for first-line pharmacological treatment [S]

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● Consider increasing the dose if there is insufficient response, but remember that the evidence for a doseresponse relationship with SSRIs and venlafaxine is inconsistent [A] ● Initial side effects can be minimised by slowly increasing the dose or by adding a benzodiazepine for a few weeks [D] ● Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy [A] Longer-term treatment ● Continue drug treatment for at least six months in patients who have responded to treatment [A] ● Use an approach that is known to be efficacious in preventing relapse [S] ● Monitor effectiveness and acceptability regularly over the course of treatment [S] ● When stopping treatment, reduce the dose gradually over an extended period to avoid discontinuation and rebound symptoms [A]: in the absence of evidence a minimum of three months is recommended for this taper period [D] Combination of drugs and psychological treatment ● Consider combining cognitive therapy with antidepressants as this has greater efficacy and may reduce relapse rates better than drug treatment alone [A] ● Consider combining cognitive therapy with benzodiazepines (being mindful of potential long-term problems) as this probably has greater efficacy than drug treatment alone [A] When initial treatments fail ● Consider raising the dosage if the current dosage is well tolerated [A] ● Consider switching to another evidence-based treatment [D] ● Consider combining evidence-based treatments only when there are no contraindications [S] ● Consider combining evidence-based pharmacological and psychological treatments [A] ● Consider referral to regional or national specialist services in treatment refractory patients [S]

18. Management of specific phobia (also known as simple or isolated phobia) 18.1. Recognition and diagnosis Specific fears of objects, animals, people or situations are widespread in children, adolescents and adults, but only a minority of affected individuals reach the full diagnostic criteria for specific phobia. Specific (or simple or isolated) phobia has an estimated 12-month prevalence of 6.4% [I] (Wittchen et al., 2011), and had a lifetime prevalence of 9.4% in the United States National Epidemiologic Survey on Alcohol and Related Conditions [I] (Stinson et al., 2007). Many affected individuals have multiple fears, whose presence is associated with an earlier onset, greater

severity and impairment, and more frequent psychiatric comorbidity [I] (Burstein et al., 2012; Stinson et al., 2007). Most individuals with specific phobia do not present for treatment of that condition, presentation being more likely with comorbid anxiety or mood disorders [I] (Mackenzie et al., 2012).

18.1 Treatment The effectiveness and acceptability of psychological or pharmacological treatments for specific phobia has been relatively under-researched when compared to other anxiety disorders. The findings of a meta-analytic review of 33 randomised controlled treatment studies indicate that exposure-based therapies (particularly those involving in vivo exposure) are more effective than other psychological interventions: effectiveness being seen regardless of the nature of the specific phobia, and being somewhat greater with multiple rather than single sessions [I (M)] (Wolitzky-Taylor et al., 2008). Most patients respond to psychological approaches, but some may benefit from pharmacological treatment. The findings of small randomised placebo-controlled trials provide evidence for the efficacy of escitalopram [I (PCT)] (Alamy et al., 2008) and paroxetine [I (PCT)] (Benjamin et al., 2000). The findings of small randomised placebo-controlled studies suggest that the efficacy of exposure therapy can be enhanced through prior administration of d-cycloserine [I (PCT)] (Nave et al., 2012; Ressler et al., 2004): but not all evidence is consistent [I (PCT)] (Guastella et al., 2007), and its administration after a session is not associated with enhanced efficacy [I (PCT)] (Tart et al., 2013). Prior administration of naltrexone may reduce the effectiveness of exposure therapy [I (PCT)] (Kozak et al., 2007). It is unclear whether concomitant use of benzodiazepines enhances or reduces the efficacy of behavioural approaches.

Recommendations: managing patients with specific (or simple) phobia ● Become familiar with the symptoms and signs of specific phobia [S] ● Assess the number of fears, the level of anxiety, and the degree of impairment to judge severity [A] ● Ask about symptoms of comorbid disorders in treatment-seeking patients [A] ● Use psychological treatments based on exposure techniques as first-line treatment [A] ● Consider SSRI treatment for patients who have not responded to psychological interventions [A]

19. Management of social anxiety disorder (also known as social phobia) 19.1. Recognition and diagnosis Social anxiety disorder is often not recognised in primary medical care [I] (Weiller et al., 1996) but detection can be enhanced through the use of screening questionnaires in psychologically distressed primary care patients [I] (Donker et al., 2010; Terluin

18 et al., 2009). Social anxiety disorder is often misconstrued as mere ‘shyness’ but can be distinguished from shyness by the higher levels of personal distress, more severe symptoms and greater impairment [I] (Burstein et al., 2011; Heiser et al., 2009). The generalised sub-type (where anxiety is associated with many situations) is associated with greater disability and higher comorbidity, but patients with the non-generalised subtype (where anxiety is focused on a limited number of situations) can be substantially impaired [I] (Aderka et al., 2012; Wong et al., 2012). Social anxiety disorder is hard to distinguish from avoidant personality disorder, which may represent a more severe form of the same condition [IV] (Reich, 2009). Patients with social anxiety disorder often present with symptoms arising from comorbid conditions (especially depression), rather than with anxiety symptoms and avoidance of social and performance situations [I] (Stein et al., 1999). There are strong, and possibly two-way, associations between social anxiety disorder and dependence on alcohol and cannabis [I] (Buckner et al., 2008; Robinson et al., 2011).

19.2. Acute treatment The findings of meta-analyses and randomised placebocontrolled treatment studies indicate that a range of approaches are efficacious in acute treatment [IV] (Blanco et al., 2013). CBT is efficacious in adults [I (M)] (Hofmann and Smits, 2008) and children [I (M)] (James et al., 2005): cognitive therapy appears superior to exposure therapy [I (M)] (Ougrin, 2011), but the evidence for the efficacy of social skills training is less strong [IV] (Ponniah and Hollon, 2008). Antidepressant drugs with proven efficacy include most SSRIs (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), the SNRI venlafaxine, the MAOI phenelzine, and the RIMA moclobemide: nefazodone is not efficacious and the evidence for mirtazapine is inconsistent [I (M)] (De Menezes et al., 2011). The potential efficacy of tricyclic antidepressants is unknown. Some benzodiazepines (bromazepam and clonazepam, but not alprazolam) and anticonvulsants (gabapentin and pregabalin, but not levatiracetam), and the antipsychotic olanzapine also appear efficacious in acute treatment [IV] (Blanco et al., 2013). Neither the 5-hydroxytryptamine (5-HT1A) partial agonist buspirone, nor the beta-blocker atenolol are efficacious in generalised social anxiety disorder [IV] (Blanco et al., 2013), although a number of small single-dose placebo-controlled cross-over studies together suggest that beta-blockers can be beneficial in reducing anxiety symptoms in individuals with ‘performance anxiety’ (for example, when speaking in public), which overlaps with mild non-generalised social anxiety disorder) [IV] (Blanco et al., 2013). There have been relatively few randomised comparator-controlled studies of acute treatment and most reveal no significant differences in overall efficacy or tolerability between active compounds. In randomised placebo- and comparator- controlled studies, phenelzine was superior to placebo, but atenolol was not [I (PCT)] (Liebowitz et al., 1992); phenelzine was superior to placebo, but alprazolam was not [I (PCT)] (Gelernter et al., 1991); and escitalopram was found superior to paroxetine [I (PCT)] (Lader et al., 2004); venlafaxine and paroxetine had similar overall efficacy in two placebo-controlled studies [I (PCT)] (Allgulander et al., 2004b; Liebowitz et al., 2005).

Journal of Psychopharmacology

19.3. Longer term treatment The findings of acute treatment studies indicate that the proportion of responding patients increases steadily over time [IV] (Blanco et al., 2013). Double-blind studies indicate that continuing SSRI or SNRI treatment from 12–24 weeks is associated with an increase in overall treatment response rates [I (M)] (Lader et al., 2004; Stein et al., 2002a, 2003). A post hoc analysis of the clinical trial database for escitalopram indicates that response is unlikely if there is no onset of clinical effect within the first four weeks of treatment [I (PCT)] (Baldwin et al., 2009): however a post hoc analysis of the clinical trial database with paroxetine indicates that many non-responders to treatment at eight weeks become responders with a further four weeks of double-blind treatment [I (PCT)] (Stein et al., 2002a). The findings of randomised placebo-controlled relapse-prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (clonazepam, escitalopram, paroxetine, pregabalin, sertraline) for up to six months [IV] (Blanco et al., 2013).

19.4. Comparative efficacy of pharmacological, psychological and combination treatments Pharmacological and psychological treatments, when delivered singly, have broadly similar efficacy in acute treatment [I (M)] (Canton et al., 2012). However, acute treatment with cognitive therapy (group or individual) is associated with a reduced risk of symptomatic relapse at follow-up [I (M)] (Canton et al., 2012). It is unlikely that the combination of pharmacological with psychological treatments is associated with greater overall efficacy than with either treatment, when given alone, as only one in four studies of the relative efficacy of combination treatment found evidence for superior efficacy [I (PCT)] (Blanco et al., 2010). The findings of small randomised placebo-controlled studies suggest that the efficacy of psychological treatment may be enhanced through prior administration of d-cycloserine [I (PCT)] (Guastella et al., 2008; Hofmann et al., 2006) or cannabidiol [I (PCT)] (Bergamaschi et al., 2011).

19.5. Further management after nonresponse to initial treatment The findings of fixed-dose randomised controlled trials do not provide consistent evidence of a dose-response relationship with antidepressant drugs: but a fixed-dose study of pregabalin found that only the higher daily dosage was efficacious [I (PCT)] (Pande et al., 2004). A double-blind randomised controlled dosage escalation trial found no advantage for increasing to a higher daily dosage (120 mg) of duloxetine, when compared to continuing treatment with a lower (60 mg) dosage [II] (Simon et al., 2010). Switching between treatments with proven efficacy may be helpful [IV] (Blanco et al., 2013). An uncontrolled study of augmentation of SSRI treatment with buspirone found some evidence of beneficial effects [III] (Van Ameringen et al., 1996); but a placebo-controlled crossoverstudy of the augmentation of paroxetine with pindolol found no evidence of efficacy [I (PCT)] (Stein et al., 2001). A small

19

Baldwin et al. placebo-controlled study of the augmentation of paroxetine with clonazepam found the combination was marginally short of superiority, when compared to paroxetine alone [I (PCT)] (Seedat and Stein, 2004). Recommendations: managing patients with social anxiety disorder Detection and diagnosis ● Become familiar with the symptoms and signs of social anxiety disorder [S] ● Assess the level of distress and disability to help distinguish social anxiety disorder from shyness [A] ● Ask about the presence of coexisting depressive symptoms [A] ● Ask about social anxiety symptoms when patients present with depression, panic attacks restricted to social situations, or alcohol and cannabis misuse [A] Acute treatment ● Choose an evidence-based acute treatment [A] ○ pharmacological: most SSRIs (escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), venlafaxine, phenelzine, moclobemide, some benzodiazepines (bromazepam, clonazepam) and anticonvulsants (gabapentin, pregabalin), and olanzapine  ○ psychological: cognitive-behaviour therapy ● Avoid prescribing atenolol or buspirone in generalised social anxiety disorder [A] ● Take account of patient clinical features, needs and preference and local service availability when choosing treatment, as pharmacological and psychological approaches have broadly similar efficacy in acute treatment [S] ● Consider an SSRI for first-line pharmacological treatment [A] ● Routine prescription of higher doses of SSRIs is not recommended [A], but individual patients may benefit from higher doses [D] ● Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy [A] Longer-term treatment ● Use an approach that is known to be efficacious in preventing relapse [S] ● Continue drug treatment for at least six months in patients who have responded to treatment [A] ● Consider cognitive therapy with exposure as this may reduce relapse rates better than drug treatment [A] ● Consider cognitive therapy after response to drug treatment, in patients with a high risk of relapse [D] ● Monitor effectiveness and acceptability regularly over the course of treatment [S] Combination of drugs and psychological treatment ● Routinely combining drug and psychological approaches is not recommended for initial treatment in the absence of consistent evidence for enhanced efficacy over each treatment when given alone [A]

When initial treatments fail ● Consider raising the dosage if the current dosage is well tolerated [D] ● Consider switching to another evidence-based treatment [D] ● Consider combining evidence-based treatments only when there are no contraindications [S] ● Consider adding buspirone after partial response to an SSRI [C] ● Consider combining evidence-based pharmacological and psychological treatments [A] ● Consider benzodiazepines in patients who have not responded to other approaches [D] ● Consider referral to regional or national specialist services in treatment refractory patients [S]

20. Management of post-traumatic stress disorder 20.1. Recognition and diagnosis Exposure to potentially life-damaging traumatic events is common, in both genders, during childhood, adolescence and adult life [IV] (Nemeroff et al., 2006): but only a proportion of those exposed to trauma develop psychological sequelae. For example, the US National Comorbidity Survey found that 60.7% of men and 51.2% of women reported exposure to at least one traumatic event, but post-traumatic stress disorder had a lifetime prevalence of 7.8% [I] (Kessler et al., 1995). In the UK, post-traumatic stress disorder was present in only a minority of individuals exposed to motor vehicle accidents, at three-month (11%) and 12-month (5%) follow-up [I] (Mayou et al., 2001). The 12-month prevalence of post-traumatic stress disorder is estimated to be 1.1–2.9%, being more common in younger than older adults [I] (Wittchen et al., 2011). Post-traumatic stress disorder shows considerable co-morbidity with other mental disorders [I] (Loewe et al., 2011). Suicidal thoughts are common but the increased risk of completed suicide is probably due to the presence of comorbid depression [I (M)] (Krysinska and Lester, 2010). Post-traumatic stress disorder is associated with increased use of health services, but is often not recognised in primary or secondary care [I] (Liebschutz et al., 2007). Diagnosis can be established through eliciting the history of exposure to trauma (actual or threatened death, serious injury, or threats to the physical integrity of the self or others); with a response of intense fear, helplessness or horror; and the presence of ‘re-experiencing symptoms’ (such as intrusive recollections, flashbacks or dreams); avoidance symptoms (such as efforts to avoid activities or thoughts associated with the trauma); and hyper-arousal symptoms (including disturbed sleep, hypervigilance and an exaggerated startle response).

20.2. Prevention of post-traumatic disorder after experiencing trauma There is some scope for preventing the emergence of psychological post-traumatic symptoms in people subject to major trauma. Early administration of benzodiazepines after trauma may not

20 prevent the emergence of post-traumatic symptoms [III] (Gelpin et al., 1996). A small randomised placebo-controlled study found that acute administration of propranolol (160 mg/day) was superior to placebo in reducing subsequent post-traumatic symptoms and physiological hyper-activity to reminders of trauma, but not the emergence of post-traumatic stress disorder, at one month [I (PCT)] (Pitman et al., 2002). A naturalistic study suggests acute administration of propranolol (120 mg/day) prevented the emergence of syndromal post-traumatic stress disorder at two months [III] (Vaiva et al., 2003): but not all evidence is consistent [I (PCT)] (Nugent et al., 2010, Stein et al., 2007b). Intravenous administration of hydrocortisone has been found superior to placebo in preventing post-traumatic symptoms, in intensive care adult patients with septic shock (median interval, 31 months) [I (PCT)] (Schelling et al., 2001), in patients undergoing cardiac surgery (interval, six months) [I (PCT)] (Schelling et al., 2004), and in patients experiencing acute stress reactions following a range of traumatic experiences [I (PCT)] (Zohar et al., 2011). The findings of small randomised placebo-controlled treatment studies find evidence for the efficacy for sertraline [I (PCT)] (Stoddard et al., 2011), but not for gabapentin [I (PCT)] (Stein et al., 2007b) or escitalopram [I (PCT)] (Shalev et al., 2012), in preventing post-traumatic symptoms. The findings of systematic reviews suggest that trauma-focused CBT is potentially beneficial in preventing chronic post-traumatic symptoms, when provided within six months of the incident [I (M)] (Roberts et al., 2009); but approaches with limited efficacy include single-session ‘debriefing’ [I (M)] (Van Emmerik et al., 2002) and multiple-session early intervention [I (M)] (Roberts et al., 2009).

20.3. Acute treatment of post-traumatic disorder The findings of randomised placebo-controlled treatment studies indicate that there is evidence for the efficacy of a range of antidepressants including some SSRIs (fluoxetine, paroxetine, sertraline), amitriptyline, imipramine, mirtazapine, nefazodone, phenelzine and venlafaxine (Ipser and Stein, 2011). There is also evidence for the efficacy of the antipsychotics risperidone (Padala et al., 2006), olanzapine (Carey et al., 2012) and the anticonvulsant topiramate; (Yeh et al., 2011). Medications which have not been found efficacious in placebo-controlled trials include citalopram, alprazolam, and the anticonvulsants tiagabine and divalproex. However when 37 randomised placebo-controlled trials are subject to meta-analysis (restricted to comparisons of outcome data using validated scales), only paroxetine, sertraline and venlafaxine were found to have superiority over placebo [I (M)] (Ipser and Stein, 2011). Probably due to the small size of certain patient sub-groups (men vs women, civilians vs military veterans) neither paroxetine nor sertraline have been found consistently beneficial across all patient groups: though a post hoc analysis suggests that venlafaxine is potentially efficacious in reducing post-traumatic symptom severity in men and women, and across all trauma types [I (PCT)] (Rothbaum et al., 2008a). There have been few controlled comparisons of the effectiveness and acceptability of differing medications, though venlafaxine was found superior to placebo, when sertraline was not [I (PCT)] (Davidson et al., 2006b); reboxetine had similar effectiveness but lower overall tolerability than fluvoxamine [II]

Journal of Psychopharmacology (Spivak et al., 2006); and mirtazapine had somewhat greater than effectiveness than sertraline, in a randomised but ‘open’ trial [II] (Chung et al., 2004).

20.4. Longer term treatment Although many patients with post-traumatic stress disorder experience a prolonged illness, there is some uncertainty about the course of the condition, as most longitudinal studies in post-traumatic stress disorder are retrospective in design. Few prospective studies have been published, although the findings of a prospective study in adolescents and young adults with post-traumatic stress disorder or sub-threshold post-traumatic stress disorder indicate that around 50% will experience a chronic course of illness [I] (Perkonigg et al., 2005). The findings of acute and continuation treatment studies indicate that the proportion of responding patients increases steadily over time (Davidson et al., 2006a; Ipser and Stein, 2011; Londborg et al., 2001). A small number of randomised double-blind placebo-controlled relapse prevention studies find evidence for the efficacy of longer-term treatment, for fluoxetine [I (PCT)] (Martenyi et al., 2002) and sertraline [I (PCT)] (Davidson et al., 2005), but not tiagabine [I (PCT)] (Connor et al., 2006).

20.5. Comparative efficacy of pharmacological, psychological and combination treatments Meta-analyses demonstrate that trauma-focused CBT and eye movement desensitisation and reprocessing (EMDR) are both efficacious and superior to ‘stress management’ [I (M)] (Bisson and Andrew, 2007), and appear to have similar overall efficacy [I (M)] (Seidler and Wagner, 2006). There have been very few direct comparisons of the efficacy of psychological and pharmacological treatments, in either acute or long-term treatment of patients with post-traumatic stress disorder. A small unblinded 12-week comparison of paroxetine and trauma-focused CBT [III] (Frommberger et al., 2004) suggested that CBT may have certain advantages, in reducing the severity of post-traumatic and depressive symptoms. A systematic review of four studies of the combination of pharmacological with psychological treatments could find insufficient evidence to draw conclusions about the relative efficacy of combination treatment compared to monotherapy [I (M)] (Hetrick et al., 2010), although a more recent randomised placebo-controlled trial found evidence that paroxetine could enhance the effectiveness of prolonged (10 sessions) exposure therapy [I (PCT)] (Schneier et al., 2012). The findings of two randomised placebo-controlled studies of the potential augmentation of exposure therapy through administration of d-cycloserine could find no evidence of increased efficacy [I (PCT)] (De Kleine et al., 2012; Litz et al., 2012). The findings of two small exploratory randomised placebo-controlled trials in patients with treatment-resistant post-traumatic stress disorder suggest that the short-term efficacy of psychological treatment may be enhanced through concurrent administration of 3,4-methylenedioxymethamphetamine (MDMA) [I (PCT)] (Mithoefer et al., 2011; Oehen et al., 2013): with some evidence of persisting improvement at two-year follow-up [III] (Mithoefer et al., 2013).

21

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20.6. Further management after nonresponse to initial treatment Many patients with post-traumatic stress disorder do not respond to initial pharmacological or psychological treatment. Switching between treatments with proven efficacy may be beneficial [IV] (National Institute for Clinical Excellence (NICE), 2005). The findings of small randomised placebo-controlled augmentation studies provide evidence for the efficacy of the alpha-adrenergic agonist prazosin in reducing nightmares and other PSTD symptoms [I (PCT)] (Raskind et al., 2003), for olanzapine in reducing post-traumatic and depressive symptoms and sleep disturbance [I (PCT)] (Stein et al., 2002b) and risperidone in reducing comorbid ‘psychotic symptoms’ [I (PCT)] (Hamner et al., 2003), in reducing irritable aggression [I (PCT)] (Monnelly et al., 2003), and in reducing overall post-traumatic symptoms [I (PCT)] (Bartzokis et al., 2005; Rothbaum et al., 2008b). However a large randomised placebo-controlled trial found no evidence of benefit for risperidone augmentation of a range of pharmacological and psychological treatments [I (PCT)] (Krystal et al., 2011). Recommendations: managing patients with posttraumatic stress disorder Detection and diagnosis ● Ask about a history of traumatic events when patients present with psychological symptoms [S] ● Become familiar with the symptoms and signs of posttraumatic stress disorder [S] ● Ask about the presence of coexisting depressive symptoms [A] Prevention of post-traumatic symptoms ● After major trauma, discuss the potential for preventing the emergence of post-traumatic symptoms, and providing there are no contra-indications, consider preventive treatment with propranolol or sertraline [A] or traumafocused CBT [A] ● Do not recommend routine single-session or multiplesession ‘debriefing’ [A] Acute treatment of chronic post-traumatic stress disorder ● Choose an evidence-based acute treatment [A] ○ pharmacological: paroxetine, sertraline, venlafaxine [A] ○ psychological: trauma-focused individual CBT or EMDR [A] ● Consider an SSRI for first-line pharmacological treatment [A] ● Take account of patient clinical features, needs and preference and local service availability when choosing treatment, as the comparative efficacy of drug and psychological approaches is not established [S] ● Advise the patient that treatment periods of up to 12 weeks may be needed to assess efficacy [A]. Longer-term treatment ● Use an approach that is known to be efficacious in preventing relapse [S]

● Continue drug treatment for at least 12 months in patients who have responded to treatment [A] ● Monitor effectiveness and acceptability regularly over the course of treatment [S] Combination of drugs with psychological treatment ● Routinely combining drug and psychological approaches is not recommended for initial treatment in the absence of consistent evidence for enhanced efficacy over each treatment when given alone [A]: but paroxetine may enhance the effectiveness of exposure therapy [A] When initial treatments fail ● Consider raising the dosage if the current dosage is well tolerated [D] ● Consider switching to another evidence-based treatment [D] ● Consider combining evidence-based treatments only when there are no contraindications [S] ● Consider combining evidence-based pharmacological and psychological treatments [A] ● Consider augmentation of antidepressants with olanzapine [A] risperidone [A] or prazosin [A] ● Consider referral to regional or national specialist services in treatment refractory patients [S]

21. Management of obsessivecompulsive disorder 21.1. Recognition and diagnosis Obsessive-compulsive disorder has an estimated 12-month prevalence of 0.7–1.0% [I] (Kessler et al., 2012; Wittchen et al., 2011), and an estimated lifetime morbid risk of 2.7% [I] (Kessler et al., 2012). The female preponderance, early age of onset and typical presence of coexisting obsessions and compulsions are common features across societies, but the content of obsessions varies between cultures [I (M)] (Fontenelle et al., 2004). The disorder usually follows a chronic course, waxing and waning in severity; and has substantial co-morbidity with major depression and anxiety disorders [IV] (Zaudig, 2011), and with tic disorders [I] (Fibbe et al., 2012). Distinguishing obsessive-compulsive disorder from obsessive-compulsive personality disorder is difficult, and patients often fulfil diagnostic criteria for both conditions: their comorbidity is associated with greater illness severity [I] (Coles et al., 2008; Garyfallos et al., 2010; Lochner et al., 2011). Patients often present with symptoms arising from the co-morbid conditions, rather than with obsessional ruminations and compulsive rituals [I] (Torres et al., 2007).

21.2. Acute treatment of obsessivecompulsive disorder The findings of systematic reviews and meta-analyses of randomised double-blind placebo-controlled trials indicate that the TCA antidepressant clomipramine, and the SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) [I (M)] (Soomro et al., 2008) are all efficacious in acute treatment, in reducing symptom severity and in improving health-related quality

22 of life [IV] (Fineberg et al., 2012). Pharmacological approaches are efficacious in treating children and adolescents with obsessivecompulsive disorder [I (M)] (Watson and Rees, 2008). There have been few evaluations of the relative efficacy and tolerability of differing pharmacological treatments. The findings of meta-analysis suggest that the efficacy of clomipramine is on the margins of superiority over that of SSRIs [I (M)] (Ackerman and Greenland, 2002; National Institute for Health and Clinical Excellence, 2005) but in randomised controlled trials the tolerability of SSRIs is generally superior [IV] (Fineberg and Gale, 2005). The findings of a randomised comparator controlled trial suggest that paroxetine and venlafaxine had comparable effectiveness and acceptability [II] (Denys et al., 2003). Fixed-dose randomised controlled studies provide inconsistent evidence for a dose-response relationship with SSRIs, higher doses being associated with greater overall efficacy in some but not all studies: however the findings of meta-analysis of nine treatment studies involving SSRIs finds some evidence for greater efficacy (though poorer tolerability) with higher daily dosages [I (M)] (Bloch et al., 2010). Meta-analyses of controlled studies involving psychological treatment approaches find evidence for the efficacy of behaviour therapy based on exposure with response prevention alone, for cognitive restructuring alone, and for exposure with response prevention plus cognitive restructuring [I (M)] (RosaAlcazar et al., 2008). Internet-delivered CBT is superior to online supportive therapy [I (PCT)] (Andersson et al., 2012), though therapist-led CBT appears more effective than computerised CBT [I (M)] (Tumur et al., 2007). The relative effectiveness of individual and group CBT approaches is uncertain [I (M)] (Jonsson and Hougaard, 2009). Psychological approaches are efficacious in treating children and adolescents with obsessive-compulsive disorder [I (M)] (Watson and Rees, 2008).

21.3. Longer term treatment The findings of acute treatment studies indicate that the proportion of responding patients increases steadily over time. Long-term (up to 12 months) double-blind randomised controlled studies demonstrate an advantage for continuing with medication, in patients who have responded to acute treatment [I (PCT)] (Greist et al., 1995; Katz et al., 1990; Tollefson et al., 1994). A randomised placebocontrolled trial with paroxetine as an active comparator found that a low dosage of escitalopram only became efficacious in the second half of a 24-week study [I (PCT)] (Stein et al., 2007a). Most (but not all) placebo-controlled relapse-prevention studies in patients who have responded to previous acute treatment reveal a significant advantage for staying on active medication (escitalopram, fluoxetine at higher daily doses, paroxetine, sertraline), compared with switching to placebo, for up to 12 months [I (PCT)] (Fineberg et al., 2007), but the optimal duration of continuation treatment is uncertain [I (M)] (Donovan et al., 2010).

21.4. Comparative efficacy of pharmacological, psychological and combination treatments It is probable, but not certain, that the combination of pharmacological and psychological treatment is superior to psychological

Journal of Psychopharmacology approaches or medication, when either is given alone. The evidence for enhanced efficacy of exposure therapy with clomipramine compared with exposure alone is inconsistent (Foa et al., 2005; Marks et al., 1988; Rachman et al., 1979), though fluvoxamine has been shown to enhance the efficacy of exposure therapy [I (PCT)] (Cottraux et al., 1990) and multi-modal CBT [I (PCT)] (Hohagen et al., 1998). The combination of exposure and response prevention with varying SSRIs has been found superior to SSRI treatment alone [II] (Simpson et al., 2008); the addition of behaviour therapy after completion of acute treatment was superior to continuing with SSRI treatment alone in another study [II] (Tenneij et al., 2005); and the addition of CBT (but not CBT instructions) to SSRI treatment was found superior to medication management alone, in children and adolescents [II] (Franklin et al., 2011). However the value of combination treatment over psychological or pharmacological treatments given alone over the long term is uncertain. A series of small randomised placebo-controlled studies suggest that administration of d-cycloserine may hasten the response to CBT, but provide no evidence that the overall effectiveness of CBT is enhanced [I (PCT)] (Kushner et al., 2007; Storch et al., 2010; Wilhelm et al., 2008).

21.5. Further management after nonresponse to initial treatment Many patients do not respond to first-line pharmacological or psychological interventions. Switching between pharmacological or psychological treatments with proven efficacy is helpful in some patients. Increasing the dose of an SSRI, sometimes beyond formulary limits, may be beneficial (Ninan et al., 2006; Pampaloni et al., 2010). A placebo-controlled study found that intravenous clomipramine infusion was efficacious after non-response to oral clomipramine, but the necessary arrangements limit its usefulness in practice [I (PCT)] (Fallon et al., 1998). The findings of some, but not all, randomised double-blind placebo-controlled augmentation studies indicate that the addition of the antipsychotics aripiprazole, haloperidol, olanzapine, quetiapine or risperidone to continuing antidepressant treatment can be efficacious in patients who have not responded to initial treatment with clomipramine or SSRIs, the evidence currently being most strong for augmentation with risperidone [I (M)] (Dold et al., 2011). The findings of small randomised placebocontrolled augmentation studies with 5-HT3 antagonists provide evidence for the efficacy of the addition of ondansetron to fluoxetine [I (PCT)] (Soltani et al., 2010) and for the addition of granisetron to fluvoxamine [I (PCT)] (Askari et al., 2012). Three relatively small randomised placebo-controlled anticonvulsant augmentation studies indicate that the addition of topiramate to SSRIs reduces the severity of compulsions [I (PCT)] (Berlin et al., 2011), and of obsessive-compulsive symptoms [I (PCT)] (Mowla et al., 2010); and the addition of lamotrigine to SSRIs reduces the severity of obsessive-compulsive and affective symptoms [I (PCT)] (Bruno et al., 2012). The evidence for augmentation with pindolol is mixed, but placebo-controlled or comparator-controlled augmentation studies find no evidence for the efficacy of augmentation with buspirone, clonazepam, desipramine, inositol, liothyronine, lithium, naltrexone or oxytocin [IV] (Fineberg and Gale, 2005).

23

Baldwin et al. The findings of a randomised comparator-controlled trial of dextroamphetamine or caffeine augmentation of SSRI or SNRI antidepressants suggest both compounds were beneficial in reducing symptom severity [II] (Koran et al., 2009). Other potential but as yet unproven approaches in the management of patients with treatment-resistant obsessive-compulsive disorder include monotherapy with once-weekly morphine [I (PCT)] (Koran et al., 2005); and the glutamate-modulating compounds riluzole [III] (Coric et al., 2005; Pittenger et al., 2008), memantine [III] (Stewart et al., 2010), and glycine [I (PCT)(Greenberg et al., 2009). Some patients with treatment-refractory obsessive-compulsive disorder may benefit from deep brain stimulation and other neurosurgical approaches [IV] (Blomstedt et al., 2012; De Koning et al., 2011; Greenberg et al., 2010).

Recommendations: managing patients with obsessivecompulsive disorder Detection and diagnosis ● Become familiar with the symptoms and signs of obsessive-compulsive disorder [S] ● Assess the time engaged in obsessive-compulsive behaviour, the associated distress and impairment, and the degree of attempted resistance to confirm the diagnosis [S] ● Ask about obsessive-compulsive symptoms when patients present with depression [S] ● Ask about the presence of coexisting depressive symptoms [A] Acute treatment ● Choose an evidence-based acute treatment [A] ○ pharmacological: clomipramine and all SSRIs [A] ○ psychological: exposure therapy, cognitive-behaviour therapy, cognitive therapy [A] ● Take account of patient clinical features, needs and preference and local service availability when choosing treatment [S]: drug and psychological approaches have broadly similar efficacy in acute treatment ● Consider an SSRI for first-line pharmacological treatment [D] ● Consider increasing the daily dosage of SSRIs if there is insufficient response at lower dosage [A] ● Advise the patient that initial treatment periods beyond 12 weeks may be needed to assess efficacy [A] Longer-term treatment ● Use an approach that is known to be efficacious in preventing relapse [S] ● Continue drug treatment for at least 12 months in patients who have responded to treatment [A] ● Monitor effectiveness and acceptability regularly over the course of treatment [S] Combination of drugs with psychological treatments ● Consider combining an SSRI or clomipramine with an evidence-based psychological treatment when efficacy needs to be maximised [D]

When initial treatments fail ● Consider raising the dosage if the current dosage is well tolerated [A] ● Consider switching to another evidence-based treatment [D] ● Consider combining evidence-based treatments only when there are no contraindications [S] ● Consider combining evidence-based pharmacological and psychological treatments [A] ● Consider augmentation of an SSRI or clomipramine with an antipsychotic drug [A] ● Consider augmentation of an SSRI or clomipramine with a 5-HT3 antagonist [A] ● Consider augmentation of an SSRI with topiramate [A] or lamotrigine [A] ● Consider augmentation of an SSRI with morphine [A] ● Consider augmentation of an SSRI with riluzole [C] ● Consider referral to regional or national specialist obsessive-compulsive disorder services in treatment refractory patients [S]

22. Management of other anxiety disorders 22.1. Marked health anxiety (‘illness anxiety disorder’) The DSM-5 ((American Psychiatric Association, 2013) includes ‘illness anxiety disorder’ within the group of ‘somatic symptom and related disorders’. The condition is characterised by excessive concern over health, constant fear of undiagnosed disease that physicians may have missed, and the characteristic behaviours of repeated checking and need for medical reassurance. Pharmacological treatment is not normally acceptable to patients, as those with marked health anxiety are typically very sensitive to adverse effects of medication: but fluoxetine showed some benefit over placebo, though this was not pronounced and occurred late in treatment (8–12 weeks [I (PCT)] (Fallon et al., 2008). Psychological treatments have been found beneficial [I (M)] (Thomson and Page, 2007), and include behavioural stress management (Clark et al., 1998) ([II]), cognitive behaviour therapy, in both face-to-face and internet format (Hedman et al., 2011b; Seivewright et al., 2008; Sørensen et al., 2011) ([II]), and mindfulness –based CBT (McManus et al., 2012) ([II]). A recent large randomised controlled trial found efficacy for an adapted form of CBT in medical patients, in which significant benefits over standard care were still present two years after therapy had ended [II] (Tyrer et al., 2014).

22.2 Separation anxiety disorder in adults Though traditionally regarded as having an onset in childhood, separation anxiety disorder is now recognised as both continuing into and having an onset during adult life: and as such is grouped with other anxiety disorders within the DSM-5 (American Psychiatric Association, 2013). The efficacy of psychological or pharmacological treatment in adults with separation anxiety

24

Journal of Psychopharmacology

disorder has not been studied extensively, and treatment studies in children have often involved mixed diagnostic groups [IV] (Bögels et al., 2013). Psychological treatment studies in children find some evidence of benefit with CBT, parent-child interaction training, and ‘summer camp’ programmes [IV] (Ehrenreich et al., 2008). The findings of randomised placebo-controlled trials of pharmacological treatment in children with separation anxiety disorder provide no convincing evidence of benefit for any medication, although fluvoxamine (Walkup et al., 2001) and sertraline have been found efficacious among the separation anxiety disorder subgroup within mixed diagnostic samples (Walkup et al., 2008).

Recommendations: adolescents

treatment

of

children

and

● Reserve pharmacological treatments for children and teenagers who have not responded to psychological interventions, and in whom the anticipated benefits are expected to outweigh any potential risks [S] ● Choose from the same range of treatments as considered for adult patients, considering an SSRI for first-line pharmacological treatment: fluoxetine may be the SSRI with the best balance of potential benefit and risk [B] ● Ensure that the daily dosage takes account of the age and weight of the patient, and start with low dosage, recognising that more rapid metabolism may lead to the need for ‘adult’ doses [S] ● Monitor patients carefully, especially for any evidence of increased anxiety and agitation, and remember that many children and adolescents find it hard to describe emotional states and possible psychological adverse effects [D]

23. Special considerations in particular patient groups 23.1. Children and adolescents When compared with investigations in individuals aged between 18–65 years, there have been relatively few randomised placebocontrolled studies of the potential benefits and risks of psychotropic drug treatment in younger people, and little is known about the value of long-term treatment [I (M)] (Ipser et al., 2009). The findings of randomised placebo-controlled trials in children and adolescents indicate that SSRI treatment can be effective in children and adolescents with generalised anxiety disorder, separation anxiety disorder or social anxiety disorder [I (M)] (Dieleman and Ferdinand, 2008), and also in post-traumatic stress disorder [IV] (Strawn et al., 2010), and obsessive-compulsive disorder [IV] (Gentile, 2011). Psychological treatments also have evidence of efficacy [I (M)] (Gillies et al., 2012; James et al., 2005; Kircanski et al., 2011; Kowalik et al., 2011) but the relative efficacy of pharmacological and psychological treatment approaches, alone and in combination, is not established: although combination treatment was found optimal in obsessive-compulsive disorder (March et al., 2004). In 2004, the United Kingdom Committee on Safety of Medicines stated that the balance of risks and benefits for the treatment of depressive illness in people under the age of 18 years

was judged to be unfavourable for some SSRIs (escitalopram, citalopram, paroxetine and sertraline), mirtazapine and venlafaxine [IV] (Committee on Safety of Medicines, 2004), and advised caution when treating depressed adults aged 18–30 years with SSRIs. A recent meta-analysis cautiously concluded that the balance of benefit and risk in the treatment of depressed children and adolescents may be most favourable with fluoxetine [I (M)] (Hetrick et al., 2012). The balance of risks of harm and benefit in the treatment of children and adolescents with anxiety disorders, when compared to the treatment of depression, is more favourable [IV] (Holtkamp and Herpertz-Dahlmann, 2008). However careful monitoring is advisable, due to possible diagnostic uncertainty, the presence of co-morbid depression, problems associated with estimating the optimal dosage, and the difficulties young people might have in describing untoward effects of psychotropic drug treatment. It may be preferable to reserve pharmacological treatments for patients who do not respond to evidence-based psychological approaches.

23.2. Elderly patients and patients with cardiac or neurological disease Many elderly patients are troubled by anxiety symptoms, but anxiety disorders in those over 65 years may be less common than in younger age groups [IV] (Wolitzky-Taylor et al., 2010). When compared with investigations in individuals aged between 18–65 years, there have been relatively few randomised controlled studies of the potential benefits and risks of psychological or pharmacological treatment for anxiety disorders in older people [IV] (Oude Voshaar, 2013), and little is known about the relative effectiveness and acceptability of differing treatments, or about the value of long-term treatment [I (M)] (Goncalves and Byrne, 2012; Gould et al., 2012; Pinquart and Duberstein, 2007; Thorp et al., 2009). Clearance of many drugs is slower in the elderly, so lower doses may be required than in younger patients. Tricyclic antidepressants and some antipsychotic drugs are best avoided in patients with cardiac disease, as they can increase heart rate, induce orthostatic hypotension, slow cardiac conduction and have significant quinidine-like effects on conduction within the myocardium [IV] (Vieweg et al., 2009). Other type 1A antiarrhythmics (quinidine, moricizine) carry an increased risk of mortality in patients with ventricular arrhythmias and ischaemic heart disease, and TCAs should be regarded as relatively contraindicated in these situations. SSRIs have relatively minor effects on cardiovascular function and may have potentially beneficial effects on platelet aggregation (Bismuth-Evenzal et al., 2012; Lopez-Vilchez et al., 2009). Higher doses (more than 40 mg per day) of citalopram may be associated with a slightly increased risk of QT interval prolongation on the electrocardiogram, and should be avoided in patients with known cardiac risk factors including hypokalaemia and hypomagnesaemia [IV] (US Food and Drug Administration, 2012): though a recent large pharmacoepidemiological study found no evidence of elevated risks of ventricular arrhythmia or all-cause, cardiac or non-cardiac mortality associated with higher citalopram dosages [I] (Zivin et al., 2013). Anxiety symptoms and disorders have an increased prevalence in patients with common neurological conditions, including migraine [IV] (Buse et al., 2012), epilepsy [IV] (Beyenburg et al., 2005), and in the aftermath of stroke [I (M)] (Campbell Burton

25

Baldwin et al. et al., 2012). SSRI and SNRI antidepressants should be used with caution in patients with migraine undergoing prophylaxis with triptans [IV] (Evans et al., 2010). Despite widespread belief that antidepressant drugs can lower the seizure threshold, systematic review of data from placebo-controlled trials with psychotropic drugs, submitted to the United States Federal Drug Administration, indicates that that the frequency of seizures is significantly lower with most antidepressants than with placebo [I (M)] (Alper et al., 2007). Pharmacokinetic interactions between medications used for treating anxiety disorders and anticonvulsants are not uncommon and it is always advisable to establish the potential for untoward drug-drug interactions when treating epileptic patients with anxiety disorders [IV] (Muscatello et al., 2012). SSRI treatment may improve overall recovery after stroke [I (M)] (Mead et al., 2012), but little is known about the potential efficacy of psychological or pharmacological interventions in the treatment of anxiety disorders in the aftermath of stroke [I (M)] (Campbell Burton et al., 2011).

Recommendations: treatment in elderly and physically ill patients ● Remember that anxiety symptoms and disorders are common in elderly and physically ill patients, and that many individuals will benefit from evidence-based pharmacological or psychological treatments [S] ● Manage elderly patients in a broadly similar way to younger patients, being mindful of the possibility of drug interactions, the potential need for lower doses in patients with renal or hepatic impairment, and the risk of worsening any pre-existing cognitive impairment through the use of medications with sedative effects [S] ● Avoid prescribing tricyclic antidepressants to patients with cardiovascular disease [D]

23.3. Pregnant and breastfeeding women Anxiety disorders are not uncommon during pregnancy and in the post-partum period [I (M)] (Ross and McLean, 2006). Symptoms will remit during pregnancy in some women [III] (George et al., 1987). Many doctors consider the scope for withdrawing psychotropic drugs in pregnant women (particularly in the first trimester), and using psychological rather than pharmacological treatments, but in practice it is sometimes necessary to continue pharmacological treatment, in patients with severe anxiety disorders. The findings of a recent systematic review indicate that antidepressant drugs are associated with increased risk of spontaneous abortions, stillbirths, preterm deliveries, respiratory distress, endocrine and metabolic disturbance, with some evidence of a discontinuation syndrome and of an increased risk of cardiac defects; antipsychotics are associated with increased gestational weight and diabetes and with increased risk of preterm birth [I (M)] (Oyebode et al., 2012). However the overall evidence on the balance of risks and benefits of psychotropic drug treatment during pregnancy evolves over time and it is wise to seek advice from respected information sources. The BAP is producing guidance on the management of patients during the perinatal period (McAllister-Williams et al., in development).

Recommendations: women of child-bearing age ● Remember that anxiety disorders are common among women who wish to become pregnant [S] ● Keep familiar with the changing evidence base about the potential hazards of treatment of pregnant and breast-feeding women with psychotropic drugs [S] ● Consider carefully the anticipated benefits and risks of pharmacological and psychological treatments of anxiety disorders in pregnant women, including the potential relative and actual risks of harm to a developing child [S]

23.4. Referral to secondary and tertiary care mental health services Despite the availability of many evidence-based pharmacological and psychological treatments, a substantial proportion of patients will not respond fully to initial treatments, provided in primary medical care. The criteria for referral to secondary care mental health services should be sufficiently flexible to ensure that patients with disabling and treatment-resistant anxiety disorders can have equitable access to mental health specialists. Consensus between primary and secondary care about when referral of patients with anxiety disorders is advisable should be an explicit component of service commissioning procedures. Potential criteria for referral to secondary care mental health services include when the primary care practitioner feels insufficiently experienced to manage the patient’s condition; when two or more attempts at treatment have not resulted in sustained improvement; when there are severe coexisting depressive symptoms or a risk of suicide; when comorbid physical illness and concomitantly prescribed treatments could interact with prescribed psychotropic medication; and when proposed interventions are not available within primary care services. Some patients with complex, severe, enduring and treatment-resistant anxiety disorders do not respond to the range of treatment options delivered in secondary care mental health services, and these patients should be referred to tertiary care specialist services for patients with affective disorders.

Acknowledgements The authors would like to thank Susan Chandler and Lynne Harmer of the BAP office for organising the logistical aspects of the consensus meeting and for their support during the subsequent consensus process. Secretarial assistance for writing the consensus statement was provided by Magda Nowak (University of Southampton) The consensus group comprised Christer Allgulander, Ian Anderson, Spilios Argyropoulos, David Baldwin, Borwin Bandelow, Alan Bateson, David Christmas, Val Curran, Simon Davies, Hans den Boer, Lynne Drummond, Rob Durham, Nicol Ferrier, Naomi Fineberg, Matt Garner, Andrew Jones, Malcolm Lader, Alan Lenox-Smith, Glyn Lewis, Andrea Malizia, Keith Matthews, Paul McCrone, Stuart Montgomery, Marcus Munafò, David Nabarro, David Nutt, Catherine O’Neill, Jan Scott, David Taylor, Peter Tyrer, Nic van der Wee, Tom Watson, and Sue Wilson. The patient organisations OCD Action and Anxiety UK were represented at the meeting. Observers were also present from the Eli Lilly, Lundbeck, Pfizer and Servier pharmaceutical companies.

26 Conflict of interest All participants were asked to provide information about potential conflict of interest at the time of the consensus meeting

Funding This consensus statement received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

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Journal of Anxiety Disorders 28 (2014) 537–546

Contents lists available at ScienceDirect

Journal of Anxiety Disorders

Implicit associations in social anxiety disorder: The effects of comorbid depression夽 Judy Wong a , Amanda S. Morrison a , Richard G. Heimberg a,∗ , Philippe R. Goldin b , James J. Gross b a b

Adult Anxiety Clinic of Temple University, USA Stanford University, USA

a r t i c l e

i n f o

Article history: Received 31 August 2013 Received in revised form 13 April 2014 Accepted 19 May 2014 Available online 14 June 2014 Keywords: Social anxiety disorder Social phobia Depression Implicit associations Cognitive biases

a b s t r a c t Implicit associations of the self to concepts like “calm” have been shown to be weaker in persons with social anxiety than in non-anxious healthy controls. However, other implicit self associations, such as those to acceptance or rejection, have been less studied in social anxiety, and none of this work has been conducted with clinical samples. Furthermore, the importance of depression in these relationships has not been well investigated. We addressed these issues by administering two Implicit Association Tests (IATs; Greenwald, McGhee, & Schwartz, 1998), one examining the implicit association of self/other to anxiety/calmness and the other examining the association of self/other to rejection/acceptance, to individuals with generalized social anxiety disorder (SAD, n = 85), individuals with generalized SAD and a current or past diagnosis of major depressive disorder or current dysthymic disorder (n = 47), and nonanxious, non-depressed healthy controls (n = 44). The SAD and SAD-depression groups showed weaker implicit self-calmness associations than healthy controls, with the comorbid group showing the weakest self-calmness associations. The SAD-depression group showed the weakest implicit self-acceptance associations; no difference was found between non-depressed individuals with SAD and healthy controls. Post hoc analyses revealed that differences appeared to be driven by those with current depression. The SAD-only and SAD-depression groups did not differ in self-reported (explicit) social anxiety. The implications of these findings for the understanding of SAD-depression comorbidity and for the treatment of SAD are considered. © 2014 Elsevier Ltd. All rights reserved.

1. Introduction Social anxiety disorder (SAD) and major depressive disorder (MDD) are two of the most common mental disorders in the US (Kessler, Chiu, Demler, Merikangas, & Walters, 2005), with 12month prevalence rates of 6.8% and 6.7%, respectively (Kessler, Berglund, et al., 2005). SAD and MDD often occur together, and SAD precedes MDD in approximately 70% of individuals with both disorders (Kessler, Stang, Wittchen, Stein, & Walters, 1999; Schneier, Johnson, Hornig, Liebowitz, & Weissman, 1992). In one study, individuals with SAD were at 3.5 times higher risk than those without

夽 Portions of this paper were presented at the 2011 and 2012 meetings of the Association for Behavioral and Cognitive Therapies. ∗ Corresponding author at: Adult Anxiety Clinic, Department of Psychology, Weiss Hall, Temple University, 1701 North 13th Street, Philadelphia, PA 19122-6085, USA. Tel.: +1 215 204 7489; fax: +1 215 204 5539. E-mail address: [email protected] (R.G. Heimberg). http://dx.doi.org/10.1016/j.janxdis.2014.05.008 0887-6185/© 2014 Elsevier Ltd. All rights reserved.

to have a subsequent depressive disorder (Stein et al., 2001). In another study that followed adolescents into adulthood, the risk for depression was 2-fold in individuals with SAD compared to those without SAD and almost 3-fold compared to those with no anxiety disorder (Beesdo et al., 2007). Increasing our knowledge of depression comorbidity among persons with SAD is important because anxiety-depression comorbidity is associated with more chronic distress, greater risk of relapse, and more impaired psychosocial functioning than when the disorders present independently (e.g., Brown, Schulberg, Madonia, Shear, & Houk, 1996; Lewinsohn, Rohde, & Seeley, 1995; Reich et al., 1993; Ruscio et al., 2008). One particular focus is understanding the role of information processing biases in SAD with and without depression. 1.1. Attentional biases in social anxiety disorder Cognitive-behavioral models of SAD (e.g., Clark & Wells, 1995; Heimberg, Brozovich, & Rapee, 2010; Hofmann, 2007; see Wong, Gordon, & Heimberg, 2014, for a review and comparison of

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cognitive-behavioral models of SAD) posit that dysfunctional information processing contributes to the etiology and maintenance of the disorder. In fact, a large body of research documents the occurrence of one type of dysfunctional information processing, attentional bias toward social threat stimuli, in SAD (for a review, see Morrison & Heimberg, 2013; for a review of attentional bias toward threat stimuli in the anxiety disorders more generally, see Bar-Haim, Lamy, Pergamin, Bakermans-Kranenburg, & van Ijzendoorn, 2007). However, limited research suggests that the presence of depressive symptoms among individuals with social anxiety/SAD may alter the nature of this response. One study looked at the impact of depressive symptoms on attentional bias among socially anxious individuals using an emotional Stroop task (Grant & Beck, 2006). Socially anxious individuals without depressive symptoms showed greater Stroop interference for threat words relative to neutral and positive words. However, the socially anxious-dysphoric group did not exhibit this bias. To our knowledge, only two other studies have addressed this problem (LeMoult & Joormann, 2012; Musa, Lépine, Clark, Mansell, & Ehlers, 2003). Both administered a dot-probe task to individuals with SAD, SAD and a concurrent depressive disorder, and nonpatient controls. Musa et al. found results largely consistent with Grant and Beck. Patients with SAD showed the expected bias (i.e., vigilance) toward social threat words. Patients with SAD and concurrent depression showed no such bias and appeared similar to controls. In contrast to the 500 ms threat cue presentation duration employed by Musa et al., LeMoult and Joormann presented threat cues for either 7 ms or 1000 ms. They found evidence of attentional avoidance of angry faces in the depressed SAD group compared to the non-depressed SAD group for the supraliminal presentation. However, the meaning of these results is less than clear, given that neither SAD group differed from controls on these trials. In addition, no evidence of attentional bias, either vigilance or avoidance, in either SAD group was detected for subliminally presented angry face cues, nor for positive, sad, or disgust faces at either presentation time. Taken together, the pattern of results suggests that comorbid depression may nullify, or at least dampen, attentional biases associated with social anxiety at relatively brief exposures. When more time is permitted for stimulus processing, biases may be observed in the comorbid depression group, albeit in the opposite direction. Indeed, Mathews and MacLoed (2005) have suggested that early sensitivity to threat cues apparent in anxiety may by inhibited in depression, in which biases toward mood-congruent information are more commonly observed for stimuli that are presented for longer durations, potentially due to slower, more strategically directed processes such as rumination. Therefore, it appears prudent to consider whether concurrent depressive symptoms or depressive disorder have similar effects on other automatic cognitive biases in individuals with SAD. 1.2. Implicit associations and the Implicit Association Test (IAT) Implicit associations are another important type of biased cognitive processing that is receiving attention in research on psychopathology. Implicit associations are thought to represent stable memory constructs developed over time that contribute to schemas about the self (Beevers, 2005; Haeffel et al., 2007). The IAT, developed by Greenwald, McGhee, and Schwartz (1998), examines implicit attitudes that someone holds regarding the relationship between a concept or category (e.g., flowers) and an attribute (e.g., goodness). The IAT has been widely used to examine attitudes regarding different racial groups, genders, and sexual orientations (e.g., Devos & Banaji, 2005; Jellison, McConnell, & Gabriel, 2004; Nosek, Banaji, & Greenwald, 2002). During the typical administration of the IAT, participants make a series of response

choices involving a concept discrimination (e.g., flowers/insects) and an attribute discrimination (e.g., good/bad). Participants are instructed to respond rapidly with a right key press to items representing one concept and one attribute (e.g., flowers and good) and with a left key press to items from the remaining two categories (e.g., insects and bad). Participants then complete a second task in which key assignments for one of the pairs is switched. IAT response latencies are interpreted in terms of relative association strengths.1 It is assumed that responses are more rapid when the concept and attribute mapped onto the same key are strongly associated, whereas responses are assumed to be relatively slower when the concept and attribute mapped on the same key are less closely associated. The use of implicit measures, such as the IAT, may be particularly relevant with socially anxious individuals. Given that individuals with SAD experience heightened self-presentational concerns and fears of others’ evaluation, explicit self-report may yield an inaccurate or incomplete picture of their experiences. For example, it is a well-replicated phenomenon that persons with SAD report that they perform more poorly on behavioral tests than do other informants (e.g., Rapee & Lim, 1992; Rodebaugh, Heimberg, Schultz, & Blackmore, 2010; Rodebaugh & Rapee, 2005; Stopa & Clark, 1993). Implicit measures like the IAT may minimize – perhaps even circumvent – self-presentational biases and effects. 1.3. Implicit associations in social anxiety and depression Several studies have used the IAT to study implicit associations in socially anxious individuals. de Jong (2002) administered the IAT to female undergraduates high and low in social anxiety, using concept categories of self (e.g., I, self) and other (e.g., their, them) and attribute categories of low-esteem (e.g., bad, stupid) and highesteem (e.g., smart, valuable). Both high and low socially anxious groups performed faster categorizing self with high-esteem words than the reverse category pairings, although a significant interaction effect suggested that this pattern was stronger in the low socially anxious group. Similarly, another study found that high social anxiety participants did not exhibit negative implicit selfesteem; they responded more quickly to self-positive pairings than to self-negative pairings (Tanner, Stopa, & De Houwer, 2006). However, they did respond more slowly to self-positive pairings than those low in social anxiety. Notably, depressive symptoms did not impact IAT performance. Some researchers have also examined responses to an IAT in which self or other is paired with rejection or acceptance, an area of clear concern to persons with social anxiety. A self-rejection IAT was used by Teachman and Allen (2007) in their study of perceived peer acceptance/rejection and its relationship to implicit and explicit fear of negative evaluation in adolescents. Adolescents more easily associated the self with acceptance than with rejection. Clerkin and Teachman (2010) examined the responses to the same IAT of socially anxious undergraduates to whom they provided training to modify implicit associations. Because all participants were socially anxious, it was not possible to compare their responses to those of a non-anxious sample, but similar to the adolescent sample of Teachman and Allen (2007), they more easily associated the self with acceptance than rejection. However, trained participants demonstrated strengthened self-acceptance

1 As noted by Pinter and Greenwald (2005), it is important to keep in mind that “the standard interpretation of any IAT measure involves relative strengths of associations of the two contrasted concept categories with the two contrasted attribute categories” (p. 75, italics added). Throughout this paper, we will refer to IAT results using simplified descriptors (e.g., flowers-good) to increase readability. However, results are always referring to the relative strength of associations (e.g., flowersgood/insects-bad).

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associations and were more likely to complete an impromptu speech than students who had not received the implicit association training. Few studies of implicit attitudes in social anxiety have examined clinical samples. Gamer, Schmukle, Luka-Krausgrill, and Egloff (2008) took a step in this direction when they recruited socially anxious students who completed four weeks of cognitivebehavioral group therapy at a university counseling center and were administered the IAT before and after treatment. Their responses were compared to non-anxious students who received no treatment. Participants were asked to categorize self-other words and anxiety-calmness words. Consistent with previous findings, socially anxious participants and non-anxious controls were faster in the self-calm pairings than in the self-anxiety pairings on both IAT administrations. However, socially anxious participants had weaker self-calm implicit associations than non-anxious controls at baseline. In addition, self-calm implicit associations had strengthened following treatment, as socially anxious participants no longer differed from controls. To date, only one study has used the IAT to examine comorbid anxiety and depression in a diagnosed sample. Glashouwer and de Jong (2010) compared implicit beliefs in a mixed anxiety disorder group, those with a current diagnosis of MDD, those with an anxiety disorder and comorbid MDD, and a healthy control group. Participants were part of the Netherlands Study of Depression and Anxiety (Penninx et al., 2008). An IAT measured implicit self-anxiety associations. As with previous IAT studies, all groups exhibited faster reaction times on self-calm trials than on self-anxiety trials. The anxious group showed weaker self-calm associations than the depressed and control groups. The authors made no hypotheses regarding the effect of comorbidity on IAT scores, but the comorbid group had the weakest self-calm associations, although not significantly different from the anxious group (after Bonferroni correction). Implicit associations have also been studied in relation to depression. For example, in the study by Glashouwer and de Jong (2010), an IAT was also administered in which self versus other words were paired with words representing depression or elation. Although depressed participants exhibited faster reaction times on self-elation trials than on self-depression trials, they also demonstrated weaker self-elation associations than the anxiety and control groups. Several additional studies have examined the implicit associations of persons at cognitive risk for depression (e.g., Haeffel et al., 2007; Steinberg, Karpinski, & Alloy, 2007) or previously depressed persons in reaction to a negative mood induction (e.g., Gemar, Segal, Sagrati, & Kennedy, 2001; Meites, Deveney, Steele, Holmes, & Pizzagalli, 2008). A full review of this literature is beyond the scope of this paper, but see a metaanalysis of implicit cognition in depression by Phillips, Hine, and Thorsteinsson (2010). The general conclusion to be drawn from these studies is that the implicit associations of self to positive attributes of depressed/formerly depressed/at-risk-for-depression persons are weaker than those of non-depressed persons. This is important to the current research because it supports the idea that comorbid depression may confer additional risk for cognitive bias in socially anxious persons, unlike the somewhat mixed findings for attentional bias toward social threat. 1.4. Present study Research has demonstrated the utility of the IAT and provided the groundwork for understanding implicit associations in SAD. However, little is known about implicit associations in those with SAD and comorbid depression. Furthermore, no studies have examined implicit attitudes in a sample of clinically diagnosed, treatment-seeking individuals with SAD and depression. Of the

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studies reviewed above, the majority have been conducted with analog samples, and only two have examined the impact of depressive symptoms. Tanner et al. (2006) found no effect of depression on the implicit associations of socially anxious persons. Glashouwer and de Jong (2010) examined a mixed anxiety group and did not focus specifically on SAD. Given the high comorbidity of SAD and MDD, and the impairment associated with this comorbidity, it is crucial that we increase our understanding of the associated cognitive processes so that we can expand our theoretical models and enhance our treatment approaches. One step toward this, and a goal of the current study, was to examine implicit associations among treatment-seeking patients with SAD and comorbid depression (i.e., MDD or dysthymia), compared to patients with SAD but no history of depression, and to healthy controls. We used two IATs, one measuring associations of self/other with anxiety/calmness and the other measuring associations of self/other with rejection/acceptance. Based on results from previous studies, we hypothesized that individuals with SAD would exhibit weaker self-calm associations than healthy controls. We also hypothesized that the comorbid group would exhibit weaker self-calm associations than healthy controls. Studies on implicit associations in depression suggest that the comorbid group might have even weaker self-calm associations than the SAD group, but the empirical support for this hypothesis is not strong. The self-rejection IAT used here was similar to the one used by Clerkin and Teachman (2010) and Teachman and Allen (2007) and has yet to be studied in a clinical sample of persons with SAD. Our interest in this IAT comes in part from the literature on interpersonal rejection sensitivity (e.g., Downey & Feldman, 1996; Leary, 2006). Those with high levels of interpersonal rejection sensitivity are thought to have high expectations for rejection by others and to place high value on being accepted (Downey & Feldman, 1996). Rejection sensitivity has been primarily studied as a risk factor for depression (e.g., Ayduk, Downey, & Kim, 2001; Boyce & Parker, 1989), but it may be an underlying personality trait in those with social anxiety as well (Harb, Heimberg, Fresco, Schneier, & Liebowitz, 2002). We sought to explore how a clinical sample would perform on the self-rejection IAT, and whether there would be differences between the SAD and SAD-depression groups, given the potential importance of rejection sensitivity in both social anxiety and depression.

2. Method 2.1. Participants Participants were 136 individuals with a primary diagnosis of generalized SAD and 44 healthy controls (HC group). Among those with SAD, 47 individuals had a current or past diagnosis of major depressive disorder (MDD) or current dysthymic disorder (SAD + Dep group), and 85 individuals had no current or past diagnosis of depression (SAD group). Four individuals with SAD who met criteria for a diagnosis of past dysthymic disorder were not included in the current study due to poor inter-rater reliability on the diagnostic measure (see Section 2.2). All participants with SAD were enrolled in one of two randomized controlled trials for the treatment of SAD. In one trial, participants (n = 74) were randomly allocated to receive individually administered cognitive-behavioral therapy (CBT) for SAD or to a waitlist control condition (see Goldin et al., 2012). In the other trial, participants (n = 62) were randomly assigned to complete either mindfulness-based stress reduction (MBSR) or to an active comparison condition of aerobic exercise (see Jazaieri, Goldin, Werner, Ziv, & Gross, 2012). Measures included in the present analyses were administered prior to randomization.

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Participants were included in the treatment studies if they met criteria for a principal diagnosis of generalized SAD according to the Anxiety Disorders Interview Schedule for DSM-IV, Lifetime version (ADIS-IV-L; Di Nardo, Brown, & Barlow, 1994; see below). Additional diagnoses, including MDD and dysthymia, were also assessed with the ADIS-IV-L. Participants were excluded for current pharmacotherapy or psychotherapy; history of medical disorders or head trauma; and current psychiatric disorders other than generalized anxiety disorder, obsessive compulsive disorder (OCD), agoraphobia without a history of panic attacks, specific phobia, MDD, or dysthymic disorder. In Goldin et al. (2012), participants were also excluded for current MDD or OCD, as well as previous CBT treatment. In Jazaieri et al. (2012), participants were excluded for previous completion of an MBSR course or regular meditation practice or exercise regimen. With regard to depression diagnoses in the SAD + Dep group, most met diagnostic criteria for past MDD only (57.4%), current MDD only (21.3%), current MDD and current dysthymia (10.6%), current dysthymia only (8.5%), or past MDD and current dysthymia (2.1%). HC participants had no history of any psychiatric problems assessed by the ADIS-IV-L and were selected to match participants with SAD in the Goldin et al. (2012) study in terms of sex, race, age, and years of education. Participants were recruited via community bulletin boards web-based community listings, and referrals from mental health clinics and providers. 2.2. Materials 2.2.1. Anxiety Disorders Interview Schedule for DSM-IV, Lifetime Version (ADIS-IV-L) The ADIS-IV-L (Di Nardo et al., 1994) is a widely used, semistructured diagnostic interview that assesses current and past episodes of anxiety and related disorders. For each diagnosis, the interviewer provides a Clinician’s Severity Rating (CSR), which is a 9-point, Likert-type rating that ranges from 0 to 8; scores of 4 or greater indicate that the patient has met criteria for a DSMIV diagnosis. In a reliability study of a mixed diagnostic group, the ADIS-IV-L indicated good to excellent inter-rater agreement for current disorders (range of ’s = .67–.86) and lifetime disorders (range of ’s = .58–.83), except dysthymia (e.g.,  = .36 as a lifetime diagnosis; Brown, Di Nardo, Lehman, & Campbell, 2001). All individuals administering the ADIS-IV-L had satisfied training criteria outlined by Brown et al. (2001) and were experienced clinicians with at least masters-level training in clinical psychology. 2.2.2. Brief Fear of Negative Evaluation Scale (BFNE) The BFNE (Leary, 1983) is a 12-item self-report measure that was designed to assess the degree to which people experience apprehension at the prospect of being evaluated negatively. Participants rate each item using a five-point, Likert scale from 1 (Not at all characteristic of me) to 5 (Extremely characteristic of me). Sample items include “I am afraid that people will find fault with me” and “Sometimes I think I am too concerned with what other people think of me.” Research suggests that the reverse-scored items have inferior validity and that only the eight straightforwardly worded items be used (BFNE-S; Rodebaugh et al., 2004; Weeks et al., 2005). The BFNE-S demonstrated excellent internal consistency in a sample of patients with SAD (˛ = .92) and in a nonanxious control sample (˛ = .90; Weeks et al., 2005). The BFNE-S demonstrated adequate internal consistency in all three of our groups (HC: ˛ = .92; SAD: ˛ = .92; SAD + Dep: ˛ = .77). 2.2.3. Social Interaction Anxiety Scale (SIAS) The SIAS (Mattick & Clarke, 1998) is a 20-item self-report scale designed to measure fears of social interactions. Participants are asked to rate each item using a Likert scale from 0 (not at all

characteristic or true of me) to 4 (extremely characteristic or true of me). Sample items include “I feel tense if I am alone with just one person” and “I find it difficult to disagree with another’s point of view.” The SIAS has been widely used in the assessment of social anxiety and has shown good reliability and validity in a number of studies (e.g., Brown et al., 1997; Mattick & Clarke, 1998; Safren, Turk, & Heimberg, 1998). Rodebaugh, Woods, and Heimberg (2007) have reported that the straightforward items of the SIAS are more valid indicators of social interaction anxiety than the reverse-scored items, which appear to be more strongly related to the construct of extraversion, and therefore suggest utilizing only the 17 straightforward items (SIAS-S) to calculate the total score. In the current sample, internal consistency of the SIAS-S was good in all three groups (HC: ˛ = .90; SAD: ˛ = .88; SAD + Dep: ˛ = .88). 2.2.4. Beck Depression Inventory – II (BDI-II) The BDI-II (Beck, Steer, Ball, & Ranieri, 1996; Beck, Steer, & Brown, 1996) is a 21-item self-report instrument which assesses the existence and severity of depressive symptoms. Participants rate the severity of each symptom, such as sadness and loss of interest, over the past two weeks on a 0–3 scale, with higher scores indicating greater severity. The BDI-II has been used extensively and has demonstrated good internal consistency in outpatient and undergraduate populations (e.g., Beck, Steer, Ball, et al., 1996; Beck, Steer, & Brown, 1996; Storch, Roberti, & Roth, 2004), as it did in the three groups in the current sample (HC: ˛ = .73; SAD: ˛ = .91; SAD + Dep: ˛ = .91). 2.2.5. Implicit Association Test Participants completed two IATs administered via computer. In both IATs, the concept discrimination was between self and other. In one IAT, the attribute discrimination was between anxiety and calmness, and in the other IAT, it was between acceptance and rejection. Stimuli from the self category were I, own, my, me, and self. Stimuli from the other category included them, others, you, your, and they. Items from the anxiety category included afraid, anxious, uncertain, nervous, and fearful, and items from the calmness category included calm, restful, balanced, relaxed, and at ease. Items representing the acceptance category were loved, welcomed, admired, included, and respected, and items representing the rejection category included forgotten, alienated, deserted, shunned, and disliked. The IAT procedure was modeled after Egloff and Schmukle’s (2002) “IAT-Anxiety.” Within each IAT, there were five blocks of trials. In the first block, participants completed 20 practice trials categorizing the concept discrimination (i.e., self/other). In the second block, an additional 20 practice trials were completed for categorizing the attribute stimuli. The fourth block was also a practice block of 20 trials for categorizing self/other items with the key assignment switched. The third and fifth blocks were each comprised of 40 critical trials in which participants categorized items into two combined categories. In the third block, items for self and the positive attribute were to be categorized on the left and in the fifth block items for self and the negative attribute were to be categorized on the right. We chose not to counterbalance the order of the pairings to remain consistent with the procedure of Egloff and Schmukle (2002). They argue that the advantages of this type of procedure may outweigh the disadvantages. Specifically, they suggest that, although we cannot interpret the IAT score in absolute terms, this type of consistent ordering optimizes comparison between participants and thus “generates an ordering according to the (relative) size of the IAT effect” (p. 1443). Participants were instructed that they would be asked to make a series of category judgments. On each trial, a stimulus word was presented in the center of the screen and category labels presented in the upper left and right sides of the screen. Participants were

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Table 1 Demographic information and self-report measures by diagnostic group. Variable

SAD

SAD + Dep

Healthy controls

Test statistic

% female % Caucasian Age (SD) Years education (SD) BFNE-S (SD) SIAS-S (SD) BDI-II (SD)

52.9 45.9 33.8 (9.1) 16.9 (2.1) 31.5 (5.6) 46.5 (9.8) 11.4 (9.0)

40.4 63.8 32.7 (7.5) 16.2 (2.1) 32.5 (3.8) 48.6 (9.4) 19.4 (10.4)

54.5 40.9 33.5 (9.8) 17.3 (2.0) 13.6 (4.6) 16.4 (6.5) 1.2 (1.8)

2 = 2.4 2 = 5.6 F = 0.2 F = 3.4* F = 204.1** F = 173.9** F = 52.4**

Note. SAD – social anxiety disorder; SAD + Dep – SAD with current or past depression; % Caucasian – proportion of individuals who self-identified as Caucasian versus nonCaucasian; BFNE-S – Brief Fear of Negative Evaluation Scale, straightforward item total; SIAS-S – Social Interaction Anxiety Scale, straightforward item total; BDI-II – Beck Depression Inventory – II. * p < .05. ** p < .001.

instructed to use the Q key on the left side of the keyboard and the P key on the right side of the keyboard for their responses. They were told to keep their index fingers on the Q and P keys throughout the task and to respond as quickly and accurately as possible. They were also told that if they made an error they would see a red X and that the task would continue. Each of the IATs exhibited excellent reliability overall and within each group (anxiety/calmness IAT: overall ˛ = .94, SAD + Dep ˛ = .94, SAD ˛ = .94, HC ˛ = .94; acceptance/rejection IAT: overall ˛ = .95, SAD + Dep ˛ = .96, SAD ˛ = .95, HC ˛ = .95). 2.3. Procedure Participants first provided written informed consent. Diagnostic status was determined with the ADIS-IV-L. Participants also completed a demographics questionnaire and the BDI-II at this appointment. After leaving the laboratory, participants were emailed a link to complete an online battery of self-report questionnaires, which included the social anxiety questionnaires reported in the current study. At a later appointment, participants completed the two versions of the IAT. Participants always completed the anxiety/calmness IAT prior to the acceptance/rejection IAT. The order of the tasks was kept consistent across participants for the same reason explained above regarding ordering of key assignments. 3. Results

endorsed greater depression than the SAD group [BDI-II: t(127) = 4.57, p < .001]; however, they did not differ in self-reported social anxiety [BFNE-S: t(121) = 1.10, p = .27; SIAS-S: t(121) = 1.12, p = .26]. 3.2. IAT data scoring and reduction Response latencies from the IAT were scored according to the algorithm developed by Greenwald, Nosek, and Banaji (2003). Specifically, trials with response latencies greater than 10,000 ms were first deleted. Participants for whom more than 10% of trials had latencies less than 300 ms would then have been deleted, but there were no such individuals in the sample. Then, each error latency was replaced with an error penalty computed as the mean latency of correct responses for that block + 600 ms. These error penalty latencies were used from this point forward. Next, “inclusive” standard deviations for all trials in the critical blocks (i.e., blocks 3 and 5) were calculated. Then the mean latency for responses in each of the critical blocks was calculated. A D score for each IAT was calculated by subtracting the mean latency for selfanxiety and self-rejection associations from the mean latency for self-calmness and self-acceptance associations, respectively, and then dividing this difference by the appropriate inclusive standard deviation. This method of calculating a D score helps to account for overall response latency as well as improve the psychometric properties of the IAT (Lane, Banaji, Nosek, & Greenwald, 2007). Greater IAT scores indicate greater self-calmness or self-acceptance associations.

3.1. Participant characteristics 3.3. IAT results See Table 1 for descriptive statistics and omnibus tests comparing the three groups. Groups did not differ on age or sex; however, there were significant differences among the groups with regard to years of education completed and ethnicity (i.e., Caucasian versus non-Caucasian). Follow-up t-tests revealed the SAD + Dep group reported fewer years of education than the HC group, t(81) = 2.60, p = .01. The SAD group did not differ in years of education from either of the other two groups, ps > .06. The omnibus chi-square test for ethnicity approached significance (p = .06), so we completed follow-up tests, which revealed a greater proportion of Caucasian than non-Caucasian individuals in the SAD + Dep group than the HC group, 2 = 4.79, p = .04. The SAD group did not differ on ethnicity compared with either the SAD + Dep group, 2 = 3.91, p = .07, or the HC group, 2 = 0.29, p = .71. With regard to symptom measures, omnibus tests were all significant (see Table 1). In follow-up tests, the HC group reported significantly lower social anxiety and depression than both the SAD group [BFNE-S: t(114) = 17.14, p < .001, SIAS-S: t(115) = 17.30, p < .001; BDI-II: t(122) = 7.22, p < .001] and the SAD + Dep group [BFNE-S: t(83) = 20.76, p < .001; SIAS-S: t(82) = 17.92, p < .001; BDIII: t(87) = 11.11, p < .001]. As expected, the SAD + Dep group

Within-group bivariate correlations between the two IATs and between each of the IATs and self-reports of social anxiety (SIAS-S) and depression (BDI-II) are shown in Table 2. The IAT scores correlated with each other within the SAD group and within the HC group, but not within the SAD + Dep group (p = .06). Only three correlations between IAT scores and self-report measures emerged as significant. In the SAD + Dep group, both IAT scores correlated with depression, with greater self-calmness and greater self-acceptance scores associated with lower depression. In the SAD group, greater self-calmness associations were associated with lower social anxiety. See Fig. 1 for mean IAT scores for each task by group. Because there was a significant difference among the groups for years of education and a near significant difference in ethnicity (i.e., Caucasian versus non-Caucasian), we first examined whether these demographic characteristics were related to implicit associations on either IAT, which would dictate whether they be included as covariates in the IAT data analyses. Bivariate correlations revealed that years of education was not significantly related to either anxiety/calmness IAT scores, r = .09, p = .24, or acceptance/rejection

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Table 2 Bivariate correlations of the IATs by diagnostic group. Anxiety/Calmness Implicit Association Test

3.4. Post hoc analyses Acceptance/Rejection Implicit Association Test

Social anxiety disorder (SAD) A/R IAT .44*** SIAS-S −.25* BDI-II .20

−.15 −.07

Social anxiety disorder + Depression (SAD + DEP) A/R IAT .28 SIAS-S −.02 BDI-II −.45**

−.23 −.35*

Healthy control (HC) A/R IAT .66*** SIAS-S −.04 BDI-II −.19

−.20 −.26

Note. SIAS-S – Social Interaction Anxiety Scale, straightforward item total; BDI-II – Beck Depression Inventory – II. Because of the use of listwise deletion, the sample sizes differ from those reported for the primary analyses (SAD = 69, SAD + Dep = 44, HC = 32). * p < .05. ** p < .01. *** p < .001.

Self-Calmness/Acceptance IAT Scores

IAT scores, r = .11, p = .18, nor was ethnicity related to either anxiety/calmness IAT scores, r = −.03, p = .74, or acceptance/rejection IAT scores, r = .11, p = .16. Therefore, analyses did not control for either years of education or ethnicity. Likewise, we did not control for self-reported social anxiety given that the two SAD groups did not differ on either social anxiety self-report measure. A one-way analysis of variance (ANOVA) comparing the three groups on implicit self-calmness associations was significant, F(2, 173) = 7.30, p < .01, 2 = 0.08. Follow-up t-tests revealed that the SAD + Dep group had the weakest self-calmness associations [compared to the HC group: t(89) = 3.76, p < .001, Cohen’s d = 0.80; compared to the SAD group: t(130) = 2.37, p = .02, Cohen’s d = 0.44]. The SAD group also exhibited weaker self-calmness associations than the HC group, t(127) = 1.99, p < .05, Cohen’s d = 0.36. Results for the acceptance/rejection IAT were similar but not identical. A one-way ANOVA comparing the three groups’ implicit self-acceptance associations was significant, F(2, 173) = 3.13, p < .05, 2 = 0.04. Levene’s test for equality of variances was significant, so reported follow-up t-tests were based on the test that did not assume equal variances. Such t-tests revealed that the SAD + Dep group exhibited weaker self-acceptance associations than the HC group, t(86.54) = 2.75, p < .01, Cohen’s d = 0.59, and the SAD group, t(118.52) = 1.98, p = .05, Cohen’s d = 0.35. The SAD group and HC group did not differ on self-acceptance associations, t(102.48) = 0.91, p = .36, Cohen’s d = 0.17.

Given that approximately half of the SAD + Dep group comprised individuals with remitted depression (n = 27), we explored whether the above results differed if the SAD + Dep group was split into its two subgroups (i.e., SAD + Current Dep, SAD + Past Dep). A one-way ANOVA comparing the four groups’ implicit self-calmness associations was significant, F(3, 172) = 5.43, p < .01, 2 = .09. Follow-up t-tests were largely consistent with the previous analysis, in that both of the SAD + Dep groups exhibited weaker self-calmness associations than the HC group, ps < .05. In addition, the two SAD + Dep groups did not differ from one another, t(45) = 1.19, p = .24, Cohen’s d = 0.35. However, whereas the SAD + Current Dep group continued to exhibit weaker self-calmness associations than the SAD group, t(103) = 2.69, p < .01, Cohen’s d = 0.53, the SAD + Past Dep group did not differ from the SAD group, t(110) = 1.23, p = .22, Cohen’s d = 0.23. This final comparison suggests the previously observed differences between the SAD and SAD + Dep groups in self-calmness associations may be driven by those with current depression. With regard to the acceptance/rejection IAT, the omnibus ANOVA was again significant, F(3, 172) = 3.70, p = .01, 2 = .06. Follow-up t-tests revealed significant divergences from previous analyses. Here, the SAD + Current Dep group exhibited weaker selfacceptance associations than the other three groups [compared to the SAD + Past Dep group: t(45) = 2.76, p < .01, Cohen’s d = 0.82; compared to the SAD group, t(103) = 2.69, p < .01, Cohen’s d = 0.53; compared to the HC group, t(62) = 3.73, p < .01, Cohen’s d = 0.95]. In contrast, the SAD + Past Dep group did not differ from the SAD group, t(110) = 0.30, p = .77, Cohen’s d = 0.06, or from the HC group, t(69) = 1.10, p = .28, Cohen’s d = 0.26. Given that the two SAD + Dep groups and the SAD group did not differ from one another on selfreported social anxiety as assessed with the SIAS-S, ps > .30, these results clearly suggest that current depression is driving the difference in self-acceptance associations observed previously. 4. Discussion The current study was the first to examine implicit associations of the self in a clinical, treatment-seeking sample of individuals with generalized SAD with and without comorbid depression. In line with hypotheses, a diagnosis of SAD was associated with the strength of the anxiety-calmness IAT effect. Individuals with SAD exhibited weaker self-calmness associations than non-anxious, non-depressed healthy controls. In addition, those with SAD and comorbid depression showed the weakest self-calmness associations compared to both individuals with SAD without a history of depression and healthy controls. When we looked more specifically at the depression subgroups in post hoc analyses, both the

0.8 0.7 0.6 0.5 0.4

SAD

0.3

SAD+Dep

0.2

Healthy Controls

0.1 0

Calmness/Anxiety

Acceptance/Rejecon IAT

Fig. 1. Scores on two Implicit Association Tests (IATs) for individuals with social anxiety disorder (SAD), social anxiety disorder and a current and/or past diagnosis of depression (SAD + Dep), and healthy controls (error bars are standard errors).

J. Wong et al. / Journal of Anxiety Disorders 28 (2014) 537–546

SAD-past depression and SAD-current depression groups showed weaker self-calmness associations than the healthy controls. However, whereas the SAD-current depression group showed weaker self-calmness associations than the SAD-only group, the SAD-past depression group did not. On the self-rejection/acceptance IAT, the SAD-current depression group showed the weakest self-acceptance associations. However, in this analysis, self-acceptance associations did not differ among individuals with SAD and remitted depression, non-depressed individuals with SAD, and healthy controls. These findings suggest that current depression has a significant effect on both self-calmness and self-acceptance associations in socially anxious individuals. Notably, self-reported (explicit) level of social anxiety did not differ between the SAD-only and SAD-depression groups. Our findings that individuals with SAD demonstrate weaker selfcalmness associations than non-anxious controls replicate results from previous studies using non-clinical samples (e.g., Gamer et al., 2008; Glashouwer & de Jong, 2010). The lack of significant difference between the SAD group and healthy controls on the selfacceptance IAT was unexpected. This implicit association has been far less examined in relation to social anxiety than has the selfcalmness association. Only two studies (Clerkin & Teachman, 2010; Teachman & Allen, 2007) have utilized the self-acceptance IAT, but the nature of these specific studies make predictions based upon them somewhat difficult. Teachman and Allen examined implicit self-acceptance associations among adolescents (ages 13–18) as part of a larger longitudinal investigation of adolescent social development in familial and peer contexts (Allen, Porter, & McFarland, 2006), whereas Clerkin and Teachman focused on the utility of training implicit associations in socially anxious college students. Although the implicit self-acceptance associations of the socially anxious participants improved with training, the authors did not examine the implicit self-acceptance associations of socially anxious participants versus healthy controls. Because fear of negative evaluation and rejection are highly related to SAD (APA, 2013; Harb et al., 2002), we expected to see this difference, which did not appear. It is also of interest that recent research (Mallott, Maner, DeWall, & Schmidt, 2009; Maner, DeWall, Baumeister, & Schaller, 2007) has demonstrated that non-anxious persons react to social rejection with an increase in prosocial behavior and the desire to affiliate with others whereas those with high levels of social anxiety do not show this pattern of response but rather are characterized by social withdrawal in the face of social exclusion. Further research on the implicit self-acceptance associations of persons with SAD appears warranted. 4.1. The impact of comorbid depression In our primary analyses, the SAD-depression group showed the weakest self-calmness associations compared to non-depressed SAD individuals and healthy controls. However, post hoc analyses revealed that the difference between the SAD-depression and SADonly groups was driven by those with current depression; those with remitted depression were no different from socially anxious persons without a history of depression. With regard to rejection/acceptance implicit associations, the impact of current comorbid depressive was robust. Surprisingly, the SAD-only, SAD-past depression, and healthy control groups did not differ on self-acceptance associations. The SAD-current depression group had the weakest self-acceptance associations, weaker than any of the other groups. That comorbid depression should have an effect here follows from the literature on rejection sensitivity as a risk factor for depression (Ayduk et al., 2001; Boyce & Parker, 1989; Downey & Feldman, 1996), although it is unclear why only those with current depression exhibited a difference from the SAD-only group. It is possible that current depression may be more

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closely linked with the expectation of negative outcomes, or at least greater certainty about such outcomes, than social anxiety with or without past depression, and that this was reflected in our findings. More than two decades ago, Alloy, Kelly, Mineka, and Clements (1990) proposed a cognitive explanation for when and why anxiety and depression co-occur. They theorized that differing degrees of certainty about one’s ability to control important outcomes (i.e., helplessness) and negative-outcome expectancies (i.e., hopelessness) resulted in a pure anxiety, mixed anxiety-depression, or pure depression presentation. They argued that those who experience anxiety are uncertain of their helplessness. Those who are certain of their helplessness and of negative outcomes primarily experience depression. Those in a mixed depression-anxiety state were theorized to be more certain of their helplessness but uncertain about negative outcomes. If we apply this helplesshopelessness theory to explain the self-acceptance IAT results, it could be argued that those with comorbid depression held more negative outcome expectancies and were therefore more likely to expect rejection. Non-depressed individuals with SAD, in contrast, may have had relatively weaker negative outcome expectancies. Social anxiety-relevant implicit associations may be more negative and/or stable among socially anxious individuals when depression is present. Like the attentional bias research reviewed earlier (Grant & Beck, 2006; LeMoult & Joormann, 2012; Musa et al., 2003), this suggests that the presence of depressive symptoms may modify maladaptive cognitive processes in those with social anxiety. Similar to the arguments of Mathews and MacLoed (2005) presented in the introduction, Musa et al. (2003) noted that their findings of nullified attention bias to threat at relatively brief exposure durations suggests that anxiety and depression are associated with biases at different stages of information processing – preattentive and selective attention processes are affected in anxiety, and effortful, controlled processes are more likely to be disrupted in depression. In the IAT, although the processes under study are implicit in nature and thereby outside of conscious awareness, stimuli are presented at durations sufficient for more elaborative processing. As such, our findings that individuals with SAD with current comorbid depression exhibited less positive implicit associations than individuals with SAD with no depression, who themselves exhibited less positive implicit associations than healthy controls (at least in the case of self-calmness associations), appear to converge with this theory. Further, our results suggest that SAD with current comorbid depression may represent a more severe instantiation of social anxiety despite the fact that this was not reflected in our study on explicit self-report measures of social anxiety, nor has it been consistently apparent in the studies on attentional bias. At present, it is unclear why those with SAD and remitted depressed performed similarly to socially anxious individuals without a history of depression, but not to those with current depression, on both IAT tasks. Research on information processing biases comparing currently to formerly depressed individuals is, to our knowledge, scant. A handful of studies suggest that currently and formerly depressed individuals exhibit similar attention biases (Fritzsche et al., 2010; Gupta & Kar, 2012; Joormann & Gotlib, 2007) and memory biases toward sad stimuli (Fritzsche et al., 2010; Gupta & Kar, 2012). However, in the one study that has examined implicit associations found that on a self-esteem IAT, those with remitted depression exhibited higher implicit self-esteem than those with current depression and those without a history of depression (Franck, De Raedt, & De Houwer, 2008). More research is needed to investigate whether implicit biases associated with depression are better characterized as a state marker of a depressive episode, or a trait-like characteristic of people at risk for depression.

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4.2. Limitations and future directions It should be noted that there are limitations in using the IAT as a paradigm for examining implicit associations. As mentioned earlier, the IAT was designed to measure relative association strengths and was not meant to measure the difference in evaluative associations with a single target concept (e.g., acceptance versus rejection associations with the self). Karpinski (2004) points out that while some target concepts have obvious and meaningful complementary pairs (e.g., young-old), others do not (e.g., Santa Claus). He contends that in many instances, the unspecified other is not a meaningful complement to the self target concept for the research hypothesis being tested. Pinter and Greenwald (2005) counter by arguing that the other has been found to have a neutral valence. However, given that the other may be perceived by socially anxious individuals as a threatening stimulus, we would likely benefit from examining implicit self associations that are not tied to an other when studying SAD. As an alternative method, Karpinski and Steinman (2006) developed a Single Category IAT (SC-IAT) that eliminates the need for a second contrast category. Preliminary examinations of the SCIAT suggest it shows acceptable reliability and validity (Karpinski & Steinman, 2006). Therefore, a potential next step would be for future studies of social anxiety and implicit associations to compare the SC-IAT to traditional IAT measures. In addition to limitations of the IAT, there were also some methodological limitations to the current study. For one, other stimuli, chosen to be consistent with previous studies, included the words “you” and “your.” Respondents may have potentially confused these words as belonging to the self category, thus adding noise to the IAT results. Also, the order of administration of the IATs used in the study was not counterbalanced, and the acceptancerejection IAT always followed the anxiety-calmness IAT. Practice effects may have weakened the acceptance-rejection IAT effect. In summary, the present results underscore the utility of examining implicit cognitions in our attempts to better understand and treat SAD, alone and when it is comorbid with current depression. The self-calmness and self-acceptance IATs differentiated among groups, but the specific patterns of results differed. Differences between the SAD-only and SAD-current depression groups could reflect differences in specific schema or provide an implicit index of severity of social anxiety that might complement typically employed explicit measures. Future research should look further into the malleability of maladaptive implicit associations and examine the relationship between these associations and behavior. Clerkin and Teachman (2010) demonstrated that selfacceptance associations among socially anxious college students could be strengthened by training and that trained participants were more likely to complete an impromptu speech than untrained participants. Replicating these findings in a clinical sample of persons with SAD could have important implications for treatment. One interesting avenue to pursue would be to investigate whether the addition of implicit association training to more commonly applied cognitive behavioral treatments would be most beneficial for persons with SAD and comorbid depression. Funding This research was supported by NIMH Grant R01 MH076074 awarded to James J. Gross, Ph.D. Conflict of interest None of the authors have any direct or indirect conflicts of interest, financial or personal relationships or affiliations to disclose.

The authors wish to thank Hooria Jazaieri and Faith Brozovich for their assistance at various phases of data analysis and manuscript preparation.

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Living with Anxiety Understanding the role and impact of anxiety in our lives Mental Health Awareness Week 2014

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The truth is that anxiety is at once a function of biology and philosophy, body and mind, instinct and reason, personality and culture. Even as anxiety is experienced at a spiritual and psychological level, it is scientifically measurable at the molecular level and the physiological level. It is produced by nature and it is produced by nurture. It’s a psychological phenomenon and a sociological phenomenon. In computer terms, it’s both a hardware problem (I’m wired badly) and a software problem (I run faulty logic programs that make me think anxious thoughts)”.1

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1. Scott Stossell ‘My Age of Anxiety’.

Contents 05 Executive summary 08 Introduction 08 What is anxiety? 10 Anxiety and modernity 13 Living with Anxiety: Stephanie 15 Anxiety disorders in the UK 18 Living with anxiety: Ian 20 The state of the nation: Anxiety in the UK 28 Living with anxiety: Jane 30 Managing anxiety 36 A new age of anxiety? 40 Useful resources and information 42 References

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Acknowledgements This report was written by Paul Swift, Dr Eva Cyhlarova, Isabella Goldie and Chris O’Sullivan. Others who contributed to this report include Paul Bristow, Joanna Carson, Hanna Biggs and Jenny Edwards, CBE.

Foreword We all experience anxiety; it is a natural human state and a vital part of our lives. Anxiety helps us to identify and respond to danger in ‘fight or flight’ mode. It can motivate to us face up to dealing with difficult challenges. The ‘right’ amount of anxiety can help us perform better and stimulate action and creativity. But there is another side to anxiety. Persistent anxiety causes real emotional distress and can lead to us becoming unwell and, at worst, developing anxiety disorders such as panic attacks, phobias and obsessional behaviours. Anxiety at this level can have a truly distressing and debilitating impact on our lives and impact on our physical as well as our mental health. Some commentators have described this as ‘The Age of Anxiety’. The Mental Health Foundation’s survey, commissioned for this report, backs up this sense of widespread heightened anxiety. Alarmingly, almost 1 in 5 people revealed that they feel anxious ‘nearly all of the time’ or ‘a lot of the time’. More than half of us have noticed that ‘people are more anxious today than they were 5 years ago.’ The survey highlights ‘finance, money and debt’ as the most common source of anxiety, perhaps reflecting the impact of the recession and austerity on public mental health and well-being. Anxiety is one of the most common mental health problems in the UK and it is increasing. Yet it remains under-reported, under-diagnosed and undertreated. A good ability to cope with anxiety is key to resilience in the face of whatever life throws at us. However, experiencing it too much or too often means we risk becoming overwhelmed, unable to find balance in our lives or to relax and recover. Our ability to find some inner peace has never been more important to our well-being. This report is about framing anxiety as an essential aspect of our humanity and part of the natural human emotional response to circumstances in our lives. It is also about challenging the stigma that still gets in the way of our reaching out for help and support when our levels of anxiety become a real problem. As individuals and society we need to understand and engage with anxiety better, recognising when it is helpfully alerting us to pay attention, and ensuring we have coping strategies when its negative impact becomes too great. We need to recognise when the people around us, our friends, family members and colleagues, are experiencing distressing levels of anxiety or at risk of this because of life events and circumstances. Local public health strategies need to identify the points at which people are most likely to experience high anxiety and to offer a range of help that is simple, quick to access and non-stigmatising. We encourage public health commissioners to check the list of the most common sources of anxiety in this survey and 3

use them to help identify the best places and partnerships to reach out to those 1 in 5 people who feel anxious nearly all the time or most of the time. We consider there could be great benefit in public policy becoming “anxiety aware”, adjusting its strategies and styles of interaction with the public in order to prevent and reduce anxiety. If we truly recognised the mounting costs of anxiety distress to people, their children’s futures, to communities and employers, we would act now. In today’s “Age of Apps” where many people are living dual lives, partly online, then we can develop new and innovative digital approaches to living better with anxiety, particularly to invest in the mental and emotional well-being of our children and young people. We hope that this report will act as a catalyst for a growth in self-help resources to enable us all to manage our response to increasingly anxious thoughts.

Jenny Edwards CBE Chief Executive Mental Health Foundation

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Executive summary

―― While 2.6% of the population experience depression and 4.7% have anxiety problems, as many as 9.7% suffer mixed depression Anxiety is a familiar emotion because it is part and anxiety, making it the most prevalent of everyone’s experience. Its natural function is to mental health problem in the population alert us to potential threats, allowing us to evaluate as a whole. and respond to them in appropriate ways. This heightened state of readiness can also help people ―― About 1.2% of the UK population experience perform better and stimulate creative impulses. panic disorders, rising to 1.7% for those Anxiety is often regarded as an artefact of modern experiencing it with or without agoraphobia. societies, one that is increasingly represented in visual arts, music, literature and social media. ―― Around 1.9% of British adults experience a phobia of some description, and women For some people anxiety triggers inappropriate are twice as likely to be affected by this or disproportionate responses to perceived problem as men. threats, leading to persistent and intrusive symptoms associated with anxiety disorders, such as panic, phobias and obsessive behaviours, ―― Agoraphobia affects between 1.5% and 3.5% of the general population in its fully which often have a debilitating effect on their developed form; in a less severe form, up lives. Anxiety is one of the most prevalent mental to one in eight people experience this. health problems in the UK and elsewhere, yet it is still under-reported, under-diagnosed and under―― Post-Traumatic Stress Disorder (PTSD) treated. This report explores the intersection affects 2.6% of men and 3.3% of women. between popular perceptions of anxiety, the experience of anxiety in people’s everyday ―― Obsessive Compulsive Disorders (OCD) lives and the impact of anxiety disorders. affect around 2–3% of the population. The experience of anxiety often involves ―― Generalised Anxiety Disorder affects interconnected symptoms and disorders. It is between 2–5% of the population, yet estimated that one in four people in the UK will accounts for as much as 30% of the experience a mental health problem each year, mental health problems seen by GPs. while one in six experience a neurotic disorder such as anxiety or depression. Anxiety disorders Previous survey evidence suggests that: are also estimated to affect 3.3% of children and young adults in the UK. The prevalence of the ―― Although, on average, women rate their life most common forms of anxiety are given below. satisfaction higher than men, their anxiety levels are significantly higher than men. ―― People in their middle years (35 to 59) report the highest levels of anxiety compared to other age groups. ―― People in the older age groups tend to be happier and less anxious. ―― People with a disability are, on average, more anxious than people without a disability. 5

―― Unemployed people report significantly higher anxiety levels than those in employment. ―― People in the lowest income groups report significantly higher anxiety levels than those in the higher income groups. ―― On average, all ethnic groups report higher levels of anxiety than people who describe themselves as White British. ―― Young people aged 16–24 are more likely to report lower levels of anxiety compared with adults generally. ―― Women and young adults aged 20–29 are the most likely to seek help for anxiety from their GP. Our specially commissioned survey of over 2,000 members of the public found that: ―― Almost one in five people feel anxious all of the time or a lot of the time.

―― Around a fifth of people who are anxious have a fear of unemployment. ―― Younger people are much more likely to feel anxious about personal relationships. ―― Older people are more likely to be anxious about growing old, the death of a loved one and their own death. ―― The youngest people surveyed (aged 18–24) were twice as likely to be anxious about being alone than the oldest people (aged over 55 years). ―― One-fifth of people who have experienced anxiety do nothing to cope with it. ―― The most commonly used coping strategies are talking to a friend, going for a walk, and physical exercise. ―― Comfort eating is used by a quarter of people to cope with feelings of anxiety, and women and young people are more likely to use this as a way of coping.

―― Only one in twenty people never feel anxious. ―― Women are more likely to feel anxious than men. ―― The likelihood of feeling anxious reduces with age. ―― Students and people not in employment are more likely to feel anxious all of the time or a lot of the time. ―― Financial issues are a cause of anxiety for half of people, but this is less likely to be so for older people. ―― Women and older people are more likely to feel anxious about the welfare of loved ones. ―― Four in every ten employed people experience anxiety about their work. 6

―― A third of the students in the survey said they cope by ‘hiding themselves away from the world’. ―― People who are unemployed are more likely to use coping strategies that are potentially harmful, such as alcohol and cigarettes. ―― Fewer than one in ten people have sought help from their GP to deal with anxiety, although those who feel anxious more frequently are much more likely to do this. ―― People are believed to be more anxious now than they were five years ago. ―― There is a tendency to reject the notion that having anxious feelings is stigmatising. ―― People who experience anxiety most frequently tend to agree that it is stigmatising.

―― Just under half of people get more anxious these days than they used to and believe that anxiety has stopped them from doing things in their life.

We recommend a stepped care approach be adopted to ensure that support for living with anxiety is provided in the least stigmatising and most inclusive way possible including:

―― Most people want to be less anxious in their day-to-day lives.

―― Universal approaches to learning to live well with anxiety should be built into school curriculums from primary 1 onwards, including an understanding of the role of anxiety in our lives, and techniques for managing stresses associated with school (such as peer relationships, exams and transitions).

―― Women and younger people are more likely to say that anxiety has impacted on their lives. Surveys suggest we live in an ‘age of anxiety’ which reflects a shared mood about the defining aspects of modern life: our work, the way we raise children, our attitudes to people who are disadvantaged, the future of public services, the threat of terrorism, and so on. At another level, there is evidence of the hidden impact of more severe forms of anxiety upon the lives of a significant number of people. Our understanding of anxiety disorders has improved in recent years due to research, the development of more sophisticated diagnostics, effective treatments, and the emergence of a genuine voice for people living with anxiety. While these developments are encouraging, our own work suggests that there are still gaps that need to be addressed in the provision of support for people who experience anxiety.

―― Peer-led approaches should be promoted within universal settings such as employment, schools and universities, in recognition of the importance that young people place on support from peers and the unique level of empathetic understanding that can be provided by those with a common experience. ―― Access to good quality self-help approaches should be made available across the UK through quality-assured and co-designed digital platforms to ensure they are fit for purpose for those who choose not to use face-to-face services (young people, people in full time employment). ―― GP training and anxiety-related guidance should be assessed for equalities impact and adapted alongside groups of people who are at highest risk of developing problematic anxiety and least likely to have their needs met by current service provision. ―― A sample of psychological services should be audited to establish how well current referral processes are working, who is accessing these, and who is falling through the gaps. This audit should include IAPT (Improving Access to Psychological Therapies) in England and Wales and initiatives to improve access in Scotland.

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―― Agencies offering support to people with anxiety should make greater use of peer mentors and advice and information that is explicitly based on the life experiences of people who live with anxiety. We also recommend that research be commissioned to better understand: ―― The nature and understanding of anxiety for different groups in society (women, people with long-term conditions, older people, people from black and minority ethnic communities), and whether current approaches and interventions can be found to address specific needs. ―― The relationship between unemployment, financial distress, and anxiety. The Department of Work and Pensions should develop strategies to prevent people who are not working from becoming marginalised from the workforce. Processes for accessing social welfare for those unable to work due to disability should be assessed for their impact on anxiety levels. ―― The impact of technological advancements in self-management for anxiety.

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Introduction In this report we want to get deeper under the skin of ‘anxiety’, one of our most unwelcomed emotional states, and understand the role that it plays in our lives―for better and for worse. It is not our intent to present the case for eradicating anxiety, for being anxious is an important part of what it means to be human. We are often anxious about those aspects of our lives that we care most about: our health; our ability to clothe and feed ourselves and our family; and our ability to be connected and valued by others. Anxiety helps us to get up in the morning and motivates us to step out of our comfort zone.

around us, or from professionals. However, as we come to understand anxiety better, there is much that we can do as individuals to take steps to reduce its hold over us, and to learn to appreciate our full range of emotions without fear that they will overtake us.

What is anxiety?

Everyone has feelings of anxiety at some point in their life, whether it is about preparing for a job interview, meeting a partner’s family for the first time, or the prospect of parenthood. While we associate anxiety with alterations to our mental state, experienced as worry or apprehension perhaps, and physical symptoms such as raised However, we often go to great lengths to avoid heart rate and adrenaline, we also understand being anxious, feeling a sense of failure if we don’t that it is likely to affect us only temporarily until keep our worrying thoughts under tight control. the source of our anxiety has passed or we have There may be times when these thoughts get learnt to cope with it. Anxiety is therefore one away from us and begin to feel overwhelming. of a range of emotions that serves the positive For some they may become habitual, leading function of alerting us to things we might need to to regular uncomfortable, or even distressing, worry about: things that are potentially harmful. physical symptoms. Patterns of avoidance may More importantly, these emotions help us to build up, that can have a limiting effect on our lives. evaluate potential threats and respond to them in an appropriate way, perhaps by quickening Anxiety can also be exhilarating. Putting ourselves our reflexes or focusing our attention. into situations that make us anxious can feel like an ordeal at the time, but getting through to Fear, like anxiety, is a familiar emotion precisely the other side can bring an incredible sense of because it is part of everyone’s experience achievement. Our most important moments in life and we consider it an essential component are usually not achieved without some sleepless of our humanity, yet it is also a psychological, nights. Being a new parent, our wedding days, physiological and behavioural state we share passing exams, and learning to drive bring great with animals when confronted by a threat to our rewards, but it is unlikely that these were achieved wellbeing or survival. Fear increases the body’s without some feelings of apprehension. arousal, expectancy, and neurobiological activity, and triggers specific behaviour patterns designed Anxiety is an emotional state that can work for to help us cope with an adverse or unexpected us as well as against us. It is something we all situation. But how do we distinguish anxiety have in common, but where we often differ is in from fear, given that the two are often how we perceive these feelings of arousal and used interchangeably? how we respond to them. Our life circumstances, our upbringing and our personalities can all be factors in why one person’s exciting fairground ride will leave another person in abject terror. Feeling anxious isn’t a sign of failure and there are times when it is important to ask for help from those 9

“If fear is fearful of something particular and determinate, then anxiety is anxious about nothing in particular and is indeterminate. If fear is directed towards some distinct thing in the world, spiders or whatever, then anxiety is anxious about being-in-the-world as such. Anxiety is experienced in the face of something completely indefinite. It is, Heidegger insists, ‘nothing and nowhere’” (Critchley, 2009).

While fear often has a specific, immediate context which provokes classic ‘fight or flight’ reflexes— the automatic fear response occurs faster than conscious thought, releasing surges of adrenaline which can subside quickly once the perceived or actual threat has passed—anxiety connotes lingering apprehension, a chronic sense of worry, tension or dread, the sources of which may be unclear. It can be a vague, unpleasant emotion experienced in anticipation of some ill-defined misfortune. The committee charged with reviewing the diagnostic criteria for the latest version of the Diagnostic and Statistical Manual of Mental Disorders (DSM)2 similarly distinguish anxiety as “a future-oriented mood state associated with preparation for possible, upcoming negative events” from fear which “is an alarm response to present or imminent danger (real or perceived)”; but add “importantly, these descriptions represent prototypes of fear and anxiety that lie at different places upon a continuum of responding. Along such a continuum, symptoms of fear vs. anxiety are likely to diverge and converge to varying degrees” (Craske et al., 2009). Another writer, expressing the distinction in less esoteric terms, suggests “the sudden re-arrangement of your guts when an intruder holds a knife to your back (fear), is different from the mild nausea, dizziness and butterflies in your stomach as you’re about to make a difficult phone call (anxiety).”3 This report is concerned with the way that different types of anxiety, found at various points on the continuum, are experienced by individuals and how they are represented to the wider public. It explores the everyday manifestations as well as what happens when anxiety becomes more than a temporary experience, and instead is experienced as either a series of debilitating episodes or a constant presence in someone’s

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2. Published by the American Psychiatric Association, the DSM offers standard criteria for the classification of mental disorders for use by clinicians, researchers, pharmaceutical companies, policymakers, etc. The latest version, DSM-V, was published in May 2013. 3. From Harriet Lerner, The Dance of Connection blog October 11th 2009.

life. Anxiety disorders such as panic, phobias and obsessive behaviours may be triggered by traumatic memories, irrational hatred of specific objects, proximity to particular situations or physical locations, or a persistent worry that something bad will happen in the future. A defining characteristic of anxiety disorders is that psychological symptoms, such as irritability, difficulties concentrating and depression, become persistent and intrusive. Many people also experience physical symptoms, like heart palpitations, sweating, tensions and pain, heavy and rapid breathing, dizziness, fainting, indigestion, stomach aches, sickness and diarrhoea; in acute cases, people have described how it felt as though they were dying. The lives of those with the most severe forms of anxiety can become completely dominated by their condition, meaning they find it difficult to relax or achieve regular patterns of sleep, becoming stuck in circular patterns of thought that impair their ability to maintain preferred lifestyles, hold down a job or sustain personal relationships.

Anxiety and modernity Although it is the most common sign of mental distress in nearly every country in the world, anxiety is often presented as an artefact of modern Western societies; Norman Mailer, for example, suggested that “the natural role of twentiethcentury man [sic] is anxiety”. The concept of anxiety per se was first brought to prominence as a philosophical and psychoanalytic concept in the first part of the twentieth century. Freud was a seminal figure in the development of Western thinking about anxiety, which he conceived of as a state of inner tension from which humans are driven to escape. At a most basic level, anxiety is a signal to the ego (the aspect of personality that deals with reality) that something overwhelmingly awful is about to happen and that it needs to employ a defence mechanism in response. Freud saw this as deriving from an infant’s mental helplessness, which is a counterpart of its biological helplessness. Humans learn to cope with anxiety prompted by ‘real’ threats, such as fear of being bitten by a dog, either by avoiding situations likely to contain the threat, or by physically withdrawing from them. Freud’s typology also included neurotic anxiety arising from an unconscious fear that we will lose control of libidinal impulses, leading to inappropriate behaviour, and moral anxiety, arising from a fear of violating our own moral or societal codes. Moral anxiety, he suggested, manifests itself as guilt or shame. The task of psychoanalysis is therefore to strengthen the ability of the ego to find ways of coping with anxiety such as ‘denial’, ‘rationalisation’, ‘regression’ (to a childhood state) or ‘projection’. Within the existentialist philosophical tradition, ‘angst’, from the German word for anxiety, is held to be a negative feeling arising from the experience of human freedom and responsibility in a world where faith and traditional social bonds have been undermined. Kierkegaard’s classic example of existential angst is of a person standing on the edge of a high cliff or building;

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along with the fear of accidentally falling, the person feels an irrational impulse to deliberately fling themselves over the edge. The emotion the person feels upon realising that he or she has this option is angst. Kierkegaard described the burden of making moral choices as a consequence of free will “the dizziness of freedom”. Existential psychology therefore proceeds from the presumption that anxiety stems from a crisis in the exercise of free will, which might be manifested in anxiety about one’s mortality, the inevitability of loss, or about accepting personal responsibility for one’s thoughts, feelings and actions.

Freudian psychoanalysts would recognise as classical defence mechanisms: “they learn to seal their anxiety off from public view”. According to Daniel Smith, “they learn to cork their anxiety within themselves like acid in a vial. It isn’t pleasant. The human mind isn’t Pyrex, it can corrode. But it works.”6

Perhaps more significantly, the testimony of people living with anxiety affords us a more rounded appreciation of the role that it plays in shaping their lives; as Scott Stossel, author of My Age of Anxiety, puts it, “anxiety can be a spur to achievement as well as a barrier. Picture a bell 4 That anxiety “somehow feels new” may be curve with extreme anxiety on the far right and extreme lack of anxiety on the far left. If you’re explained partly by the fact that anxiety has been the subject of significant scientific research for less too anxious to the point where it’s physically than half a century, while the psychiatric profession and mentally debilitating, then your performance first codified diagnostic criteria for all the different suffers. If you’re not anxious enough, if you’re not disorders as recently as 1980, with the publication engaged and slightly activated by anxiety, as it were, then your performance also suffers.”7 of DSM-III. Subsequent advances in diagnostic techniques, coupled with the development of effective pharmacological treatments and The voices of people living with the more acute psychological therapies, have prompted primary forms of anxiety help us to conceive of anxiety healthcare professionals to more readily identify as something more than simply a condition that anxiety in their patients. requires diagnosis and treatment. How individuals engage with their anxiety, how they manage it and Anxiety is now recognised as one of the most represent it to the wider world lifts anxiety beyond prevalent mental health problems in the UK, the realm of medicine and science and into yet there is good evidence that it is still undera broader sociological and cultural context. reported, under-diagnosed and under-treated. One reason may be that, unlike many other mental health issues, people whose lives are affected have not yet found a voice that articulates the full range of experiences of anxiety, not just those of people living with anxiety disorders. In recent years, this has begun to change, as writers, bloggers and campaigners have provided us with an insight into “Britain’s silent epidemic”5 by describing the lived experience of anxiety, the complexities and nuances of the various disorders, the symptoms that are associated with them, and the effect that anxiety has upon their lives. For example, some people living with anxiety describe feelings of shame and embarrassment 4. Rachel Cooke, The Observer, Sunday 15th September 2013. at their physical symptoms, such as excessive 5. The Observer, Sunday 15th September 2013. perspiration, which lead them to adopt what 6. From Monkey Mind: A Memoir of Anxiety by Daniel Smith, quoted 12

in The Observer, Sunday 15th September 2013. 7. Scott Stossel ‘May Age of Anxiety’.

“For as long as I can remember I have suffered from a deep feeling of anxiety which I have tried to express in my art. Without anxiety and illness I should have been like a ship without a rudder” (Edvard Munch). The representation of these more acute forms of anxiety within the arts has long been established as a powerful creative force in a way that fear rarely is.8 From the “dizziness of freedom” has flowed a rich artistic tradition since the beginning of the twentieth century, starting with the close relationship between early modernist artists and psychoanalysis and the rise of art practices within psychiatric hospitals, which in turn had a significant impact on the development of art history. Writers have also recognised anxiety as a “handmaiden to creativity”,9 either as the motivating spirit acknowledged by Graham Greene, for example, or as the animating theme of novels by Virginia Woolf, Franz Kafka and Haruki Murakami. Most notably, the First World War poets, many with the experience of early psychiatric treatments for trauma, brought the subjective experience of severe anxiety disorders into the public realm. In another sphere, musicians as diverse as Leonard Bernstein, Marvin Gaye and Radiohead have represented anxiety in their work, while The King’s Speech demonstrates that a debilitating social anxiety can be the subject matter of a commercially successful film as well as a critically acclaimed one.

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In 2009, the Mental Health Foundation published In The Face of Fear, which addressed the questions of how fear and anxiety affect our health and society, and what we can do about it. At that time, fear seemed a natural response to the dramatic banking crisis of the previous year and the potential socio-economic consequences that few at the time could predict, except that it was likely to be the deepest recession for a generation. Indeed, research carried out for In The Face of Fear found that “people perceive our world as having become more frightening and frightened”. In 2014, five years on, we are exploring whether and how that mood of fear has translated into a more persistent sense of apprehension and, taking a broader perspective, how that fits into our historical understanding of anxiety. We do this by asking: do we live in age of anxiety? In doing so, we want to draw attention to the way that anxiety affects the lives of the people who live with it and consider the contribution of anxiety to our culture. This report explores the intersection between popular perceptions of anxiety, the experience of anxiety in people’s everyday lives, and the impact of anxiety disorders. In doing so, we have reviewed the research evidence on anxiety disorders, commissioned a survey of public views, and collected people’s stories about their own experiences. The following chapters set out the scale and nature of anxiety in the UK and how it is currently managed, interspersed with case studies describing what it is like to live with anxiety. We hope that the report will contribute to a wider understanding of the role that anxiety plays in our lives and stimulate discussion about the public health implications of learning to live well with anxiety.

8. Later this year, the Anxiety Arts Festival will explore anxiety, its causes, how it affects our lives and how it can act as a motivating force for creativity. 9. Attributed to Aldous Huxley.

Living with anxiety: Stephanie, journalist, mid-20s Your greatest strength is also your greatest weakness. I’ve always had a natural tendency to be on edge, to be extremely aware of my surroundings. I’m alert all of the time and, although a predisposition to being quite observant is great for your career, it isn’t always the best for your personal relationships. As a writer, your job is to see the things that other people don’t necessarily see. It’s because of your ability to notice anything and everything that you are able to draw conclusions, notice trends or comment on various social phenomena. I had a brilliant upbringing and a really supportive family. But Mum and Dad were in the process of getting divorced when I went off to university, so there I was, worried about putting on weight while I had a lot going on at home. I started to spend more and more time at the gym because exercise was a great stress relief (and the endorphins didn’t hurt either). I started to see results in weight loss, which made me want to do a bit more and then a bit more. I guess, because I’m a perfectionist, if I was going to do something, I was going to do it well! My weight loss was drastic, but it never got to the stage where I was hospitalised. But I was very well aware that my behaviour was not normal; even then I didn’t lose that logical side of me. Mum and Dad could see what was happening and did encourage me to see a psychologist. It really really helped. When I got the diagnosis (anorexia nervosa/bulimia nervosa with mild anxiety disorder), it was a shock. I was surprised to find out that I had an anxiety disorder, and it was the eating disorder that was the symptom, not the other way around.

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In my sessions with my psychologist, she used CBT10. Good old CBT, it works every time! I’m a big champion of it. The best techniques for me are the ones that make me separate my emotions from the thoughts; to realise that what I’m feeling inside isn’t necessarily an accurate representation of what the situation is. So, if I’m feeling stressed out of my mind, I take a step back and notice that I’m feeling stressed, then take another step back and notice that I’m having the thought of feeling stressed. That simple dissociation between “I think, therefore I am” really helps. The heightened anxiety I felt during my parents’ divorce lasted for about a year before I got into CBT. Then, within six months I got back to being more like myself. I found that for me, the central issue affecting my anxiety is control; more specifically, the lack of control is what precipitates my anxiety. It definitely flares up when I’m stressed. I used to repress everything to the point where I would become overwhelmed with emotion—I would cut off—but that doesn’t ever help because you eventually explode; it has to come out at some stage. Now I allow myself to feel stressed or anxious for a little period because I know that ultimately it will subside. I let it wash over me, but then stop it because I know that the body can only be in a state of stress for so long; it ultimately calms itself down.

People deal with anxiety in different ways. For some, it’s addiction; mine is an eating disorder. Your weight and your food intake is something that will never be out of your control, and that’s why you find comfort with it. I know it will never completely go away—it’s part of my chemistry—but doing CBT helped me and prevented me from going too far and over-thinking things. It helped me to acknowledge that a thought is simply a thought rather than the truth. Now I can gauge where I am in my overall wellbeing by my drive to watch what I eat or how I exercise. Now, if I have dessert, that’s okay. The more that food or weight is in the forefront of my mind, the more I know that I need to change something in my life that is causing me that stress.

I’ve had a couple of years now of being more mindful and trying to observe myself from a bird’seye perspective. I know what my limits are now. Having recently moved to London, there were definitely times last year when I fell back into my old patterns of thinking because I was chronically stressed about my job situation and repressed my feelings of loneliness, missing creature comforts, yet wanting to be this strong person. I was too proud to acknowledge that I was having a tough time. I’d never really admit to friends how I was feeling deep down, because that then meant I’d have to admit to myself that I had a problem again. So, I went home and had a couple of booster sessions with my counsellor.

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10. Cognitive Behavioural Therapy (CBT): is one of a broad range of psychotherapies or ‘talking therapies’ that aims to change the way that you think and behave.

Anxiety disorders in the UK The best estimates suggest that: one in four people in the UK will experience a mental health problem each year; one in six will experience a common mental health problem such as anxiety or depression; and that these figures have steadily increased over the past 20 years. Estimates of the number of people who experience anxiety vary because of the different methods for gathering data and the different criteria used in identifying it. Some surveys rely on self-reporting: people’s own assessments of their emotional state. While the results can help us appreciate the general mood of a population and the distribution of anxiety within a population, such surveys lack the consistency of a diagnostic threshold. However, reports based on service data will, by definition, only include those willing and able to seek help for their anxiety and rely on the correct identification by professionals of the presence of a problem. Estimating the prevalence of anxiety problems is further complicated by the fact that, in diagnostic terms, anxiety is the common thread linking a range of disorders, from agoraphobia to obsessive compulsive disorder. Some disorders are linked (for example, agoraphobia and panic disorders), while each displays particular characteristics which themselves impact on people’s lives.

What are the most common anxiety disorders? The experience of anxiety often involves a bundle of interconnected symptoms and disorders characterised by confusing circularity between the triggers to anxiety and the responses that it invokes. Scott Stossel’s “bundle” includes emetophobia, a fear of vomiting (especially in public), which is a condition that according to Anxiety UK is not widely diagnosed even though it is fairly prevalent. This is the aspect of his anxiety that is most debilitating, he says, because it is entwined with agoraphobia caused specifically by a fear of being sick far from home as well as nausea, a commonly experienced physical symptom of many forms of anxiety. While the separate elements to the bundle may not, in themselves, have a decisive impact on his life, the effects of their interaction can be devastating. This can be seen more clearly in people diagnosed with co-morbid depression and anxiety, which often results from a downward spiral in which anxiety leads to low mood which in turn intensifies the anxiety. The most recent national survey of mental health in the UK indicates that while 2.6% of the population experience depression and 4.7% have anxiety problems, as many as 9.7% suffer mixed depression and anxiety, making it the most prevalent mental health problem among the population as a whole (McManus et al., 2009). Previous surveys conducted in 1993 and 2000 showed an increase in the prevalence of mixed anxiety and depressive disorders, but only small changes between 2000 and 2007 (Self et al., 2012). Panic is an exaggeration of the body’s normal response to fear, stress or excitement. Panic attacks are a period of intense fear in which symptoms develop abruptly and peak rapidly. Panic attacks have been described as a form of “emotional short-circuiting” (Servian-Schreiber, 2005) whereby the limbic brain suddenly takes over the body’s functioning, leading to overwhelming sensations, which might include

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a pounding heart, feeling faint, sweating, shaky limbs, nausea, chest pains, breathing discomfort and feelings of losing control. Adrenaline overwhelms the cognitive functions that would normally help the brain assess the real nature of the threat to the body. The effects can be so severe that people experiencing panic attacks believed they were dying. It is estimated that about 1.2% of the UK population experience panic as a separate disorder (Goodwin et al., 2005), rising to 1.7% for those experiencing it with agoraphobia (Skapinakis et al., 2011).

developed form; in a less severe form up to one in eight people, i.e. about 7 million in the UK, may be troubled by some agoraphobic symptoms.

Post-Traumatic Stress Disorder (PTSD), or syndrome, is a psychological reaction to a highly stressful event outside the range of everyday experience, such as military combat, physical violence, or a natural disaster. The symptoms usually include depression, anxiety, flashbacks, recurrent nightmares, and avoidance of situations that might trigger memories of the event. One study of UK armed forces personnel deployed to Afghanistan found that of 1,431 participants, A phobia is an intense and irrational fear of a 2.7% were classified as having probable PTSD, specific object or situation, such that it compels while a household survey of UK adults estimated the person experiencing it to go to great lengths a prevalence of 2.6% in men and 3.3% in women. to avoid it. Phobias can be about harmful things Whilst a range of studies investigating the health or situations that present a risk, but they can also challenges of asylum seekers and refugees be of harmless situations, objects or sometimes have found that PTSD levels can be as much as animals. Social phobia can include a fear of being 10 times higher than the age-matched general judged, scrutinised or humiliated in some way. It population (Fazel et al., 2005). A range of stressors can show itself with a fear of doing certain things have been identified as impacting adversely on in front of others, such as public speaking. mental health, including those experienced preAccording to the Office for National Statistics, around 1.9% of British adults experience a phobia migration, such as torture, traumatic bereavement and imprisonment, but also post-migration factors of some description, and women are twice as such as discrimination, detention, destitution likely as men to be affected by this problem. and delayed decision making in the asylum process (McColl et al., 2008). One study of women Although agoraphobia is often associated with asylum seekers in Scotland and Belgium found a fear of open spaces, the main feature is intense that 57% were above the cut-point for PTSD anxiety triggering a panic response in situations where escape is perceived as difficult or potentially symptomatology (Scottish Refugee Council et al., 2009). embarrassing, or where help may not be readily available; indeed, such crises often occur in confined spaces. People with agoraphobia appear Obsessive Compulsive Disorder (OCD) affects around 2–3% of the population and is to experience two distinct types of anxiety― characterised by unwanted, intrusive, persistent panic, and the anticipatory anxiety related to fear or repetitive thoughts, feelings, ideas, sensations of future panic attacks. Agoraphobia can have a dramatic limiting effect upon the lifestyle of people (obsessions), or behaviours that makes the sufferer feel driven to do something (compulsions) living with the condition, as they seek to avoid to get rid of the obsessive thoughts. This only situations that make them anxious; for example, provides temporary relief and not performing only using places where exit routes are known or staying close to exits. In extreme cases, individuals the obsessive rituals can cause great anxiety. A are so fearful they become homebound altogether. person’s level of OCD can be anywhere from mild to severe, but if severe and left untreated, it can Onset of agoraphobia is usually between the destroy a person’s capacity to function at work, ages of 18 and 35 and affects between 1.5% at school or even to lead a comfortable existence and 3.5% of the general population in its fully in the home. 17

Generalised Anxiety Disorder (GAD) is the most commonly diagnosed anxiety disorder and usually affects young adults. Women are more likely to be affected than men. While feelings of anxiety are normal, people with GAD find it hard to control them, to such an extent that it impinges upon their daily life. It causes sufferers to feel anxious about a wide range of situations and issues, rather than one specific event. Unlike a phobia, which focuses upon a specific object or situation, generalised anxiety is diffuse and pervades the sufferer’s daily life. Although GAD is less intense than a panic attack, its duration and the mental and physical symptoms, such as irritability, poor concentration and the effects of disrupted sleep patterns, mean that people with the disorder often find it difficult to live the life they would prefer to live. GAD affects 2–5% of the population and has increased slightly since 1993 (Self et al., 2012), yet accounts for as much as 30% of the mental health problems in people seen by GPs, which explains why an analysis of people seeking help through primary care suggests a higher prevalence rate of 7.2% (Martin-Merino et al., 2010).

lifestyle choices such as smoking, drinking too much alcohol, and a poor diet (Mental Health Foundation, 2009).

Children and young adults Anxiety disorders are estimated to affect 3.3% of children and young adults in the UK (about 290,000) and while we cannot be sure whether children and young adults today are more anxious than previous generations, mental health problems in young people are surprisingly common, disabling and run a chronic course (Cresswell et al., 2010; Hagell et al., 2013). Cohort studies carried out from 1974 show significant increases in emotional problems such as depression and anxiety amongst young people, and in 2004 it was estimated that 4% of children and young people had an emotional disorder (anxiety or depression) (Green et al., 2005). The absence of similar research in the last eight years means that it is difficult to assess the impact of the financial crisis on levels of anxiety amongst young people. Nevertheless, in 2004, children and young people with ‘emotional disorders’ were found to be living in significantly poorer households compared to other children and were more likely Anxiety and health The true impact of anxiety can be masked when it to be educationally disadvantaged (Green et al., is the symptom of other more obvious or treatable 2005). One commentator has concluded that physical problems which are likely to be prioritised such “mental health problems have important implications for every aspect of young people’s in any subsequent medical intervention. Anxiety lives including their ability to engage with problems are common amongst cardiovascular education, make and keep friends, engage in patients; for example, panic disorder is up to 10 times more prevalent amongst people with chronic constructive family relationships and make their obstructive pulmonary disease than in the general own way in the world” (Hagell et al., 2013). population (Livermore et al., 2010, cited by Naylor The results of a major study revealed that et al., 2012). People with GAD have been found children and adolescents with an autistic to be at higher risk of coronary heart disease, spectrum disorder were at particularly high risk while anxiety has also been linked to increased of experiencing problematic levels of anxiety. incidence of gastrointestinal problems, arthritis, Nearly 40% were estimated to have clinically migraines, allergies, and thyroid disease. People elevated levels of anxiety or at least one anxiety with anxiety disorders are four times as likely as disorder, with specific phobia most common others to develop high blood pressure, and many studies have shown a relationship between anxiety at nearly 30%, followed by OCD in 17%, social anxiety disorder and agoraphobia in nearly 17% and reduced white blood cell function, a sign of immune system weakness. There is also emerging and GAD in 15% (Van Steensel et al., 2011). evidence of a link between stress and Alzheimer’s disease. Anxiety is also associated with unhealthy 18

Living with anxiety: Ian, Environmental Trust Manager, mid-30s I heard a psychologist on the radio say that having anxiety is like sticking your head above a trench every day. Mine is not that severe; it is more like getting ready for a job interview, a feeling that I have to perform more highly than in reality I actually have to. Some days it is worse than others, but it is not often that I’m away from thoughts that distract me from letting go or having a good time; there is always something at the back of my mind saying you’ve got to sort this or that out. What we are talking about is GAD. My head says I’m under attack and physically I feel like I’m under attack. I start holding my breath, shallow breathing, my heart starts beating faster, pacing up and down. I get shaking―not like my cup of tea would go everywhere―but more like a buzz, a readiness, as though I’m preparing for something. Maybe I ramble on a bit; that’s a product of it. It’s energysapping although I still manage to find energy. It’s only recently that I’ve realised there is something that needs to be explored a bit more deeply. I’m currently working with a CBT therapist, talking about the time when I first noticed my anxiety, trying to recognise whether it was a particular incident that triggered it or whether I’ve had it from a younger age. My gut feeling is that I’ve always had a tendency to be anxious. My grandmother was anxious and I wonder if there is something genetic there. I was quite shy and reserved at school but it became more pronounced when I went to university. It was less about the stress of moving away from home, although that may have contributed to it, and more uncertainty about me and my place in the world. While I was at university my GP prescribed antidepressants, but I wasn’t comfortable taking them. I didn’t have a diagnosis; I just used to think that I’m not quite hitting the right note, not quite getting satisfaction from what I do, or that I’m flawed in 19

some way. Having experienced life a bit more, I’ve noticed patterns of stress for which I sought counselling. I didn’t really nail down a diagnosis and acceptance of GAD until about 3 years ago. That led to me to get involved with Anxiety UK and they put me in touch with one of their cognitive behavioural therapists and I’m currently looking at ways to change the way I think and instil new behaviours and habits. It has taken me a while to get to that point. Anxiety is always there, but it is heightened when there is a transition or anything new, so at a micro-level it could be a social situation I am not entirely comfortable with. So there are different levels of anxiety. When you hear the word anxiety, classically you think of worry and you would be able to see it, but anxiety can be internalised as well. So when I am there with my family at a social event, it might be the most natural, comfortable thing in the world, but in my mind somewhere I’ve got doubts and worries and anxieties that aren’t showing.

I do think that sport is a great medicine. I’d love to do 30 minutes of exercise a day, but the GAD means that I feel I have to do X, Y and Z before I can find time to do some exercise. It’s a form of perfectionism which means that you can’t start something until you’ve lessened the anxious feeling about these things that are pressing because the world will blow up if you don’t do those. Then you can think about exercising. It’s difficult to get a well-rounded routine. I find that taking on responsibilities helps. So I’ve taken on the responsibility to take this seriously. I used to go out and drink and that didn’t help, so now I don’t drink, or very rarely.

I haven’t ever stopped and that has been one of the problems. Constantly doing things is something I feel is necessary as a way of preventing things going wrong. But that is actually a negative thing because I haven’t been able to say, ‘hang on Ian look at yourself a little bit more, think some more positive thoughts because it has all been a bit of a rush’. Even if GAD gives me fear-fuelled oomph, I’d definitely swap it for peace My personality is positive by default; however, of mind, clarity, and the yearning to just… be. I’m GAD interrupts my fun and placid temperament often left feeling sad, isolated and frustrated at and replaces positivity with negative thoughts that the difficult task of simply enjoying life. I’m not good enough. Sometimes I wonder what part of it is me and what part of it is GAD. I do get a lot of things done, and then I think: is it good that I have GAD? You know what they say: if you want something done, give it to a busy person. Well, that happens to me. But really I could use the energy in much more productive ways. People have said “You need to learn to say no”, but part of me on the negative side goes, “If I do say no then what will people think of me?” The other part of me says “I really want to get involved in this; I’m going to do it”. And I know, because of the way I am, that if I do agree to do something I’ll worry about it. So I agreed to put on the local carnival alongside holding down my full-time job, as well as juggling a social life. I’m naturally an organised person and I do have a passion for my local community, but my worry about doing a bad job and worry about what people will think of me spurred me on to put on a good schedule of events. 20

The state of the nation: anxiety in the UK

―― People in the older age groups tend to be happier and less anxious (Understanding Society, 2013).

To get a picture of the extent and causes of anxiety ―― The anxiety levels of people with a disability amongst the general population of Britain in early are higher, on average, than those of people April 2014, we commissioned a survey of 2,330 11 without a disability (ONS, 2013). adults. The survey complements upon recent large-scale survey evidence about anxiety, which ―― Unemployed people report significantly suggests that: higher anxiety levels than those in employment (ONS, 2013). ―― Although, on average, women rate their life satisfaction higher than men, their anxiety levels are significantly higher than men (Self ―― People in the lowest income groups report significantly higher anxiety levels than those et al., 2012; the Office for National Statistics in higher income groups (ONS, 2014). (ONS), 2013). ―― People in their middle years (35 to 59) report ―― On average, all ethnic groups reported higher levels of anxiety than people describing the highest levels of anxiety compared to themselves as White British (Hicks, 2013). other age groups (Self et al., 2012; ONS, 2013). ―― Young people aged 16–24 are more likely to report lower levels of anxiety compared with adults generally (Potter-Collins & Beaumont, 2012; ONS, 2014). ―― Women and adults aged 20–29 are most likely to seek help from their GP for anxiety. (Martin-Merino et al., 2010). For the purposes of the survey, we defined ‘anxious’ as generally feeling worried, nervous, or uneasy. The survey explored how often people feel anxious, the causes of their anxiety, what they do about it, and the impact of anxiety on their lives. The findings presented an opportunity to map the scale of anxiety across a representative sample of the population, and analyse responses by age, gender, social class and employment status.

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11. Source: YouGov Plc. April 2014. Total sample size was 2,330 adults. Fieldwork was undertaken between 9th and 10th April 2014. The survey was carried out online. The figures have been weighted and are representative of all GB adults (aged 18+).

How often do people feel anxious? ―― Almost one in five people feel anxious nearly all of the time or a lot of the time. ―― Only one in twenty people say they never feel anxious. ―― Women are more likely to feel anxious than men. ―― The likelihood of feeling anxious tends to decline with age. ―― Students and people not in employment are more likely than those who are working or retired to feel anxious all of the time or a lot of the time.

In general which ONE, if any, of the following statements do you think BEST describes your experience with anxiety in your everyday life? (n=2,330) I feel anxious nearly all of the time I feel anxious a lot of the time I feel anxious some of the time I rarely feel anxious I never feel anxious Don’t know

4% 14% 41% 34% 5% 1%

The frequency of anxious feelings decreased incrementally through the age groups of respondents, while the proportion of those saying they rarely or never feel anxious increased with age, from 25% of 18–24 year olds at the lower end of the scale, to 49% of those aged 55 years When asked to describe how frequently they experience anxiety in their everyday life, our survey or older at the upper end. People not working for other reasons than being unemployed (such as found that 19% of people feel anxious either a lot of the time or all of the time. For this group, anxiety long-term disability) were three times more likely is something that almost two-thirds (61%) of them (12%) to experience anxious feelings all of the time than the survey sample as a whole (4%). experience on a daily basis and a third (33%) Students (26%), people who are unemployed experience it at least once a week. There was a (30%), and people not working for other reasons marked difference between the experiences of men and women however, in that almost a quarter (33%) were more likely to feel anxious a lot of the time or all of the time compared to the of the women surveyed (22%) feel anxious a lot survey sample as a whole (19%). or all of the time, compared to 15% of the men. A further 41% of people in the survey feel anxious some of the time, meaning that six of every ten respondents said they feel anxious at least some of the time. Women were more likely to experience this frequency of anxiety (68%) compared to men (51%). Additionally, 47% of men said they are either rarely or never anxious in their everyday lives, compared to 31% of women.

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What causes anxiety? ―― Nearly half of the people who said they feel anxious in their everyday life said that financial issues are a cause of anxiety, but this is less likely to be so for older people (those over 55 years). ―― Women and older people are more likely to feel anxious about the welfare of loved ones. ―― Four in every ten people who are currently employed said they experience anxiety about issues to do with their work. ―― Around one-fifth of people who are anxious have a fear of unemployment. ―― Younger people are more likely to feel anxious about personal relationships. ―― Older people are more likely to be anxious about growing old, the death of a loved one, and their own death. ―― The youngest people surveyed (those aged between 18 and 24) were twice as likely to be anxious about being alone than the oldest people (aged 55 and over).

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We asked people to identify the causes of their anxiety. Almost half of those surveyed (45%) said that financial issues (i.e. money/finance/debt) cause them to feel anxious. The survey highlighted a marked decline in anxiety about finances amongst people aged 55 years and older: nearly one-third (32%) of this age group cited finances as a cause compared to more than half for each of the other age categories. Discounting people who are retired (who are half as likely as others to say financial issues are a cause of their anxiety), this shows that not only are financial issues a significant factor in anxiety for people of working age, but also suggests that people in part-time employment (53%), the unemployed (53%), and people not working for other reasons (55%) are slightly more likely to have anxious feelings about money. The survey findings further suggest that people in social grades C2D&E (49%) may be more likely to feel anxious because of financial issues than people in social grades AB&C1 (42%). Work issues, such as long hours, were identified by just over a quarter of people (27%) as a cause of anxiety and 17% said that the fear of losing their job or unemployment caused them to feel anxious. Anxiety related to work appears to be consistent across working life and then, as one might expect, diminishes sharply as people approach and enter retirement. Indeed, significantly higher proportions of those in either full- or part-time employment cited work issues (39%) and fear of unemployment (22%) as a cause of anxiety compared to the survey sample as a whole.

Which, if any, of the following specifically cause you to feel anxious in your everyday life? (n=2,184) Money/finance/debt Welfare of my loved ones/children Other work issues (e.g. long hours etc.) Personal relationships Growing old Death of a loved one Fear of losing my job/unemployment Fear of being alone/isolation My own death Fear of crime/personal safety Other Don’t know/can’t recall

45% 36% 27% 26% 25% 22% 17% 16% 16% 14% 14% 6%

Anxiety related to family and relationships featured prominently in the survey. Personal relationships were said to be a cause of anxious feelings for 26% of people who said they feel anxious in everyday life, but significantly more so for people aged 18–24 (44%) and students (46%), and significantly less so for people aged over 55 years (15%). Just over one-third of those surveyed (36%) identified the welfare of a loved one or children as a cause of anxiety, but significantly more women (44%) than men (28%) cited this as a cause, and the likelihood of citing it increased with age so that almost half of people aged over 55 years (47%) said that this was a cause of anxiety. Age was also a factor in anxiety about growing old, with 36% of those aged 55 years and above saying they were anxious about this, compared to just 15% of 18–24 year olds. Similarly, 29% of the people surveyed from the oldest age group felt anxious about the death of a loved one, compared to 13% from the youngest age group, and twice as many from the oldest age group (19%) were anxious about their own death, compared to the youngest age group (10%). However, the survey also threw up an interesting anomaly around fear of being alone/isolation. We might hypothesise that this would be a particular source of anxiety for older people, yet young people aged 18–24 (28%) were twice as likely to mention it than people in the 55 years and over age group whose response (14%) was lower than the survey sample as a whole (16%). This may be suggestive of the importance placed on belonging to a peer group by young people. Women (19%) were slightly more likely than men (13%) to mention this as a cause of feeling anxious, while students (27%), people working part-time (23%) and people not working for reasons other than unemployment (23%) were also more likely to have anxious feelings about being alone.

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How do people cope with their anxiety? ―― Nearly one-fifth of people who have experienced anxiety do nothing to cope with it.

Which, if any, of the following do you do/use to “cope” with your feelings of anxiety in your everyday life? (n=2,184)

Talk to a friend or relative 30% Go for a walk 30% Comfort eating 24% Physical activity/exercise 23% Hide away from the world 18% ―― Comfort eating is used by a quarter of people Alcohol 16% (24%) to cope with feelings of anxiety and Relaxation/meditation techniques 13% women and young people are more likely Cigarettes 10% to use this as a way of coping. Visit my GP 7% Other 11% ―― Almost one-third of students in the survey Don’t know 2% said they cope by ‘hiding themselves away from the world’. The most common coping strategy was talking ―― People who are unemployed are more likely to a friend or relative, used by 30% of people who to use coping strategies that are potentially feel anxious in their everyday life, although women harmful, such as alcohol and cigarettes, (38%) were more likely to do this than men (21%), than those who are currently employed. and younger people (42%) were more likely to do so than people in older age groups. This may ―― Fewer than one in ten people (7%) have also be an indication of the central role of peer sought help from their GP to deal with relationships in the lives of young people. anxiety, although those who feel anxious more frequently are much more likely The survey explored people’s use of three active to do this. approaches to coping with stress. Almost one-third of all respondents (30%) said they would go for We asked people who have experienced anxiety a walk to cope with anxiety, a little under a quarter in their lives to identify the different ways they said they would undertake a physical activity or do cope with it. Just under one in five (19%) do not some exercise (23%), while fewer (13%) would do, or use, anything to cope with anxiety in their use relaxation or meditation. While these ways everyday lives. The findings revealed an inverse of coping were employed fairly consistently across relationship between the frequency with which all groups, the results suggest that people from people experience anxiety and how active they social grades AB&C1 (27%) may be more likely are in seeking ways to cope with it; so 32% of to undertake physical activities to deal with anxiety people who rarely have anxious feelings said that than people from social grades C2D&E (19%). they do nothing to cope with those feelings, while only 6% of people who live with anxiety all the The survey also included four potentially harmful time do nothing about it. The proportion of men coping strategies. Of these, comfort eating, was not using coping strategies was higher (24%) employed by 24% of those surveyed and women than for women (16%), and older people (28%) (29%) were more likely to cope in this way than are less prone to using coping strategies than men (18%). People in the younger age groups younger people. were much more likely to use comfort eating ―― The most commonly used coping strategies included talking to a friend, going for a walk, and physical exercise.

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than people in the older age groups. A similar pattern across age and gender emerged in relation to hiding away from the world, which was cited by 18% of respondents. Students were more likely than other groups to hide themselves away; 31% of students in the survey said they use this as a coping strategy. The pattern of usage for alcohol ( just over one in six people) and cigarettes (one in ten people) was not significantly different across age groups or between men and women. The findings suggest that unemployment may be a factor in determining the types of strategies that people use to cope with anxious feelings. Unemployed people were more likely than other groups to use potentially harmful strategies: about a quarter (23%) said they would hide away from the world, use alcohol (27%) and use cigarettes (23%). In contrast, people who are retired are much less likely than any of the other groups to use any of these potentially harmful coping strategies to cope with their anxiety. Visiting a GP to deal with anxiety was an option taken up by just 7% of respondents who had reported anxious feeling at some point in their lives, a proportion that was consistent across gender and age groups. Yet those experiencing anxiety most frequently were over five times more likely to visit their GP than the survey sample as a whole, while those experiencing anxiety a lot of the time were more than twice as likely to visit their GP. Despite this apparently low rate of self-referral usage to GP services, 27% of those surveyed agreed that a problem with anxiety is something they would see a GP about. Agreement amongst women was higher (31%) than amongst men (23%), and more than half (56%) of those experiencing anxiety nearly all of the time agreed that anxiety is something they would visit their GP about.

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Perceptions of anxiety

The impact of anxiety

―― People are believed to be more anxious now than they were 5 years ago.

―― Just under half of people get anxious more often these days than they used to and believe that anxiety has stopped them from doing things in their life.

―― There is a tendency to reject the notion that having anxious feelings is stigmatising. ―― People who experience anxiety most frequently tend to agree that it is stigmatising. The survey found strong agreement with the proposition that people are more anxious now than they were five years ago; as one might expect, agreement is strongest amongst people who experience anxiety most frequently (72%). People were also asked to indicate the extent of their agreement with statements addressing aspects of stigma that may be attached to anxiety. Just over a quarter of respondents (26%) felt that feeling anxious is a sign of not being able to cope, but almost twice as many (50%) disagreed with this sentiment. Slightly more people (29%) agreed that they would be embarrassed to tell someone they have anxieties, but again just under half (46%) indicated that they would not be embarrassed. There was an even stronger rejection of the notion that feeling anxious is something to be ashamed of; just 10% of people agreed with this sentiment, while nearly three-quarters (74%) of them disagreed. However, people experiencing anxious feelings most frequently were much more likely to agree with these stigmatising views of anxiety, while, conversely, respondents who had never experienced anxious feelings were much more likely to disagree with the proposition that they would be embarrassed to tell someone they have anxieties (57%).

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―― Most people want to be less anxious in their day-to-day lives. ―― Women and younger people are more likely say that anxiety has impacted on their lives in these ways. We asked three questions of those people who had experienced feelings of anxiety about the impact it has upon their lives. More people agreed (47%) than disagreed (31%) that they get more anxious these days than they used to and there were similar levels of agreement that feelings of anxiety had stopped them from doing things in their lives. There was a more clearly defined tendency for people to agree (57%) than disagree (14%) when asked if they would like to be less anxious in their day-to-day lives. In each of these domains, the tendency for agreement was larger for women compared to men and for people in the younger age groups compared to the older age groups. People experiencing anxiety on a frequent basis were also more likely to agree than disagree with these statements.

The state of the nation Our survey provides an important insight into the impact that anxiety has upon people’s everyday lives. The findings suggest that feelings of anxiety are experienced widely and form part of a familiar emotional landscape for people taking part in the survey. The survey highlights those areas of people’s lives most likely to generate feelings of anxiety; stresses and worries about families and personal relationships are a major cause of anxiety, while financial issues and workrelated matters feature prominently in people’s concerns. Overall, people believe that society is more anxious than it was five years ago and many of those who have experienced anxiety in their own lives say that they are more anxious than they used to be. However, the message from people taking part in our survey is that anxiety is not something to be ashamed of or embarrassed about, or that anxious feelings should be interpreted as a sign that someone is unable to cope. This perhaps tells us something about the level of awareness about anxiety that now exists amongst the general public and their potential receptiveness to initiatives to address the problems posed by anxiety. An important message to emerge from the survey is that people find a variety of ways of coping with feelings of anxiety that fall short of seeking professional help. Although we made no attempt to gauge the effectiveness of these strategies, the preferences expressed for simple human interaction and physical activity may suggest that people deal with feelings of anxiety in ways that have proved helpful with other emotional crises. The survey also maps a less positive tendency for some people to use potentially harmful coping strategies, notably comfort eating or social withdrawal.

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The survey identifies discrete groups within the populations for whom anxiety may be persistent and at times debilitating, or for whom anxiety has a disproportionate impact. It suggests that there is a small but significant group of people for whom anxious feelings are a constant presence that may provoke a heightened sense of stigma, yet they are also more active than most in seeking ways to cope with them and are more likely to call upon primary care services for help. This group will include people who have a recognised anxiety disorder, whether diagnosed or not, as well as those at risk of experiencing acute episodes of anxiety. The survey suggests that gender, age and employment status may be factors in shaping the experience of anxiety in the UK. It reconfirms that anxiety has a disproportionate effect upon the lives of women compared to men in terms of the frequency of anxious feelings, the source of their anxiety and their preferences for coping with it. Women are also more likely to report that their anxiety has had a negative impact upon their lives by, for example, stopping them doing things. Similarly, younger people are more likely to be affected by anxiety than people from older groups, while people in the oldest age group (55 years and over), and especially retired people, are markedly less likely to be affected. Finally, the survey does suggest that people who are not employed are more likely to experience anxiety more frequently than those in work, are more likely to be anxious about financial matters, and be more likely to cope in ways that are potentially harmful.

Living with anxiety: Jane, Volunteer, early 50s I was probably considered a shy child, but I didn’t have any major problems in childhood. I had one or two good friends although I wasn’t really comfortable in big groups and I did panic if I was ever invited to parties or if there was a big group thing in class. My anxiety has always been social anxiety, so it has prevented me from doing a lot of things. It really came to a head in my teenage years―that traditional transition stage when I was doing exams. That was when it really started to kick in and I couldn’t go to school, I couldn’t sit my exams, so I left and I got a job through a relative. But I struggled with the work so I had to leave. I tried college and had to leave that too. I felt very ashamed and very embarrassed about having anxiety and it was something I tried desperately to cover up. Of course the more I tried to cover it up, the more anxious I became. I thought there was a real stigma around anxiety at the time; I didn’t realise that young people of my age had similar experiences and feelings. I thought it was just something that affected adults. My father suffered with anxiety and it was something he was ashamed of. He tried to cover it up and wouldn’t talk about it. So I picked up on that as being something to be embarrassed about. My GP diagnosed anxiety―it wasn’t social anxiety then, it was just anxiety―and he gave me valium; I was about 17 at the time. I was also referred to a psychologist at the local hospital, but I really didn’t understand what the psychologist or psychiatrist was telling me; it was very unpleasant. The tablets worked while I was taking them, but once I stopped taking them, all the symptoms came back and I still had all the very negative frightening thoughts―it didn’t help those. I had a lot of physical symptoms, blushing and sweating which people would comment on, so I became more and more withdrawn. Eventually, I stopped going out, so I lost friends, had no social life, no relationships and became quite housebound. My anxiety has meant that I haven’t been able to work 29

for a long time and even looking for a job is really really difficult for me. I wanted to do something because I’m on benefits and I wanted to give something back, also to feel better in myself, to boost my own self-esteem. I am a member of Anxiety UK and I’ve been working as a volunteer on their helpline for about 4 years now. I decided to do some volunteering to help me practise my coping skills. I was always terrified of doing it and then somebody gave me a push and said “You’ve got to make an effort now”. I had a major panic attack the first day I was here, but one of the staff took me outside and had a chat with me; they said, “It’s OK, it’s understandable, we’ve seen this before, it’s not only you that this has happened to”. Just hearing that―that it happens to other people as well― made all the difference. Everybody here has experience of anxiety or, if they haven’t, they have a special interest in it, so I don’t have to hide it. That was the biggest thing: not having to hide it. I could have anxiety attacks with all the symptoms and nobody would make any comments about it. The people here have encouraged me and given me support, and that has really helped me build my self-esteem and confidence. The biggest change has been coming here because it’s such a supportive environment. Peer support is the main thing that helps me cope, but I’ve also done an online CBT course. I’ve seen some therapists, but it may be part of my anxiety, I just feel uncomfortable with therapists being in the room; I feel trapped. I think it’s my social anxiety. So I’ve not been able to concentrate on what they are saying because I’ve been focused on my anxiety and wanting to leave. Doing it online there were no distractions and I really seemed to take that in. I’ve used those CBT techniques and breathing control. There is some excellent self-help online. So it’s been a combination of things.

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Because it has been there for such a long time, anxiety has taken root. Maybe I have an anxious nature, so it is always going to be a part of my life. But now I understand it a lot better, I know I am not the only one who has it―that helps a lot―and it doesn’t worry me as much because I have some coping techniques and know what I can do to reduce my anxiety. Working here I can give people hope because when they ring up they often think that anxiety is going to ruin their lives and they are never going to get better. I tell them, from my many years’ experience, “You can learn to manage it, it doesn’t have to control you, you can still get on with your life. If you nip it in the bud when it starts, you have a better chance of it not getting really bad. Don’t be frightened of it and don’t bottle it up; share it with someone you feel comfortable with”. I also contribute to a course at a local university, helping to train therapists of the future. The fact that I can use my anxiety in a positive way like this is a massive thing for me because for so many years I felt ashamed and embarrassed about it. So to be able to talk about it openly and for my experience to be embraced―they really want to hear it―that’s been tremendous for me. And in general, I think it makes you a more caring person, I really do.

Managing anxiety “A person cannot just simply decide not to be anxious anymore” (Anxiety Care UK). Although anxiety can be a debilitating condition, it is not an illness and therefore is no more susceptible to being ‘cured’ than other emotional states that serve important functions as part of the human survival kit. Our survey illustrates how people experiencing anxiety in their everyday lives often find the personal resources to cope through simple remedies such as talking things through or doing a physical activity, although the finding that people from social grades C2D&E are less likely to engage in a physical activity may suggest an inequality in access to such resources. This gives pause for thought when considering emerging evidence on the benefits of this form of coping strategy on wellbeing more generally (Mental Health Foundation, 2013) and in managing stress levels specifically (Gerber and Puhse, 2009). These self-help strategies are less likely to work for more acute disorders even though most are highly treatable and full recovery is an achievable goal. Medicines can ameliorate the worst symptoms and aid the recovery process, but are less useful in helping people to manage the threat of relapse in the longer term. Lingering symptoms, vulnerability to ‘normal’ anxiety, and stress-related intensification of symptoms and anxiety contribute to a continuous risk of relapse, but these are factors that are directly addressed by psychological therapies which have been shown to improve the long-term outcomes for people who seek this type of help. In 2010 it was estimated that there were 8.2 million diagnosed cases of anxiety disorder in the UK (Fineberg et al., 2013) yet only about one-third to half of sufferers receive treatment (McCrone et al., 2008). One of the problems of tackling anxiety disorders in the UK is the fact that despite the incidence of anxiety symptoms rising between 1998 and 2008, the incidence of GP recorded anxiety diagnoses fell over the same 31

period (Walters et al., 2012). A number of reasons for this apparent under-recording have been suggested, including an increased preference by GPs for recording the symptoms of anxiety rather than specific diagnoses. Others have suggested a preference for broad diagnostic labels, such as ‘anxiety states’, which may reflect a lack of training, a belief that the distinctions in anxiety states are not meaningful in primary care practice, or reluctance to use formal diagnoses which may be perceived as stigmatising for patients (Walters et al., 2012). Others have pointed to structural problems in the pathways that exist between primary and specialist services following implementation of the National Service Framework for Mental Health (Cohen, 2008). This introduced the Improving Access to Psychological Therapies (IAPT) programme, which is designed to provide services for those suffering from anxiety and depression disorders; during the year 2012–13, more than three-quarters of a million people in England were referred to IAPT services nationally. Yet there is evidence that only half of the people referred to IAPT services go on to receive treatment, while for those that remain, about half show significant improvements or recover (Richards and Borglin, 2011). Somewhere along the line a great many people who experience anxiety are either not getting the treatment they require or are choosing not to complete the course of therapy. At the same time, the treatment of co-morbid health and anxiety problems in acute patients appears to be seriously under-developed. For example, while 42% of patients with cardiovascular disease are currently provided with rehabilitation, only 16% of these programmes have a psychological component, despite 31% of these patients experiencing significant anxiety problems (Naylor et al., 2012). New collaborative approaches involving a number of health professionals working together with a patient are likely to help and have been associated with significant improvements in depression and anxiety outcomes compared with usual care (Archer et al., 2012).

Several different treatments are available to ease the psychological and physical symptoms of anxiety, including psychological therapies and medication, as well as a range of guided selfhelp strategies and exercise on prescription. The National Institute for Health and Care Excellence (NICE) recommends a ‘stepped care’ approach to treatment, starting with interventions that are the least intrusive of those likely to be effective (NICE, 2012). However, the evidence about the most effective ways of treating anxiety is mixed and we know little about the treatment preferences of those seeking help with anxiety. This is worth further exploration, as one American review found evidence for enhanced outcomes for those receiving the treatment of their choosing and a marked preference for psychotherapeutic support over other forms of treatment (McHugh et al., 2013).

Health Foundation (2013) that exercise can be particularly effective in reducing the symptoms of clinical anxiety when combined with CBT, although a review of 7 RCTs found no effect for interventions comprising aerobic exercise only (Bartley et al., 2013). Media link: Gretchen Reynolds ‘How Exercise Can Calm Anxiety’ (New York Times).

Cognitive Behavioural Therapy When someone is distressed or anxious, the way they see and evaluate themselves can become negative. Cognitive behavioural therapy (CBT) helps people to understand the link between negative thoughts and mood and how altering their behaviour can enable them to manage anxiety and feel in control. It is the most effective non-pharmacological treatment for reducing the symptoms of almost all mental health Keeping active problems, but especially anxiety and depression Studies on participation in leisure activities have (Stuhlmiller and Tolchard, 2009; Olatunji et al., shown improvements in self and life satisfaction, 2010), for people with anxieties about their health which helps in reducing depression and anxiety (Tyrer et al., 2013), and leads to more general and enhances a person’s sense of wellbeing improvements in the quality of life of people (Haworth, 2010), while the evidence about the experiencing anxiety (Hoffman et al., 2014). effectiveness of exercise alone is mixed. According CBT has also been shown to be effective with to Sport England, participation in physical activity children and young people, although it is not and sport has been shown to be effective in yet clear whether it is more effective than other reducing depression, anxiety, psychological treatments for these younger age groups distress and emotional disturbance. Low to (James et al., 2013). moderate physical exercise can reduce anxiety and have both short and long-term beneficial One feature of CBT is that it is a short-term therapy effects on psychological health. Taking part in and, it is claimed, can be delivered effectively sport and spectating can have a positive impact by primary care therapists either face-to-face on the wellbeing and happiness of young people or as part of a self-help programme (Høifødt et (ONS, 2014). A major limitation in the evidence al., 2011). There is evidence that CBT delivered base is that while numerous studies and metain primary care settings has a moderate effect analyses show that exercise is associated with on reducing symptoms of anxiety (Seekles et reduced anxiety in clinical settings, not enough al., 2013). NICE therefore recommends CBT for research has been done to map the effect of anxiety and panic disorders, and the availability exercise on anxiety in real life (Anderson and of it has expanded rapidly in England under Shivakumar, 2013). A recent systematic review the government-funded Improving Access to of relevant Randomised Controlled Trials (RCTs) Psychological Therapies (IAPT) programme. The concluded that exercise is effective in conjunction Scottish Mental Health Strategy (2012–15) has with other treatments (Jayakody et al., 2014), also committed to improving and monitoring confirming the conclusions of the Mental access to psychological therapies with an 32

important focus on older people, where there remains an equity issue across the UK despite an emerging evidence base of effectiveness in treating anxiety and depression in later life (McMurchie et al., 2013). Media link: Jane Feinmann ‘Coping with anxiety – on the cheap’ (the Daily Telegraph). Mindfulness Mindfulness is a variation of CBT in that it focuses on changing the relationship between the anxious person and his or her thoughts, rather than changing the thoughts themselves. Using meditation and similar techniques, it can help people break out of the ‘automatic pilot mode’ that leads to negative ways of thinking and responding. Instead, it is about helping people to experience the world in the ‘here and now’. It does this by addressing the bodily symptoms experienced when someone is anxious, but rather than avoiding or withdrawing from these feelings, he or she remains present and fully experiences them and in this way is able to observe their reactions in a different way. One guide to mindfulness provides a useful analogy:12

“It may be helpful to think of this approach in terms of a radio. That is, imagine that the negative thoughts that drift into your mind are coming from a loud radio that is tuned to a station where the thoughts are very negative and seem to be shouting at you. The skill in mindfulness is not so much about trying to turn the radio off, but changing the way you listen to the radio. In this way the volume of the radio station can be reduced, and therefore seem less disruptive and distressing.”

Reviews of studies into Mindfulness Behavioural Therapy (MBT) have found the approach has a strong positive effect upon mood and symptoms of people with anxiety disorders (Hoffman et al., 2010; Vollestad et al., 2012). Media link: Julie Myerson ‘How mindfulness based cognitive behaviour therapy changed my life’ (the Guardian).

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12. From the Centre for Interventions’ information sheets.

Guided self-help Guided self-help has become an increasingly popular way of offering treatment because of its low cost, adaptability to different forms of digital and social media and its acceptability to people who might otherwise not receive treatment (Andrews et al., 2010) either for reasons connected with their anxiety or because of time pressure from commitments such as caring. Most guided self-help is based on cognitive behavioural approaches and aims to help the person experiencing anxiety achieve a level of recovery whereby they are able to understand the nature of their anxiety and what is happening physiologically to them. They are then helped to develop the necessary skills to tolerate and cope with it, by challenging unhelpful thinking, evaluating their bodily symptoms realistically and managing graded self-exposure to the source of their anxiety. Computerised CBT can be supported by reminders from a non-clinical technician or practice nurse, or guided by a clinician via telephone, email, live links such as Skype, or posts on a private forum. Many areas of the country also have self-help groups that offer peer support. Andrews et al. (2010) point out that a major advantage of this form of CBT is the level of treatment fidelity that can be achieved. Similarly, an evaluation of an online mindfulness course has shown promising results in terms of the acceptability of the means of delivering help to people who might otherwise not receive treatments and its ability to decrease the anxiety experienced by course participants (Krusche et al., 2013).

There is good evidence that guided self-help is effective for: ―― Certain types of disorder, such as social phobia and panic disorder (Van’t Hof et al., 2009; Lewis et al., 2012; Mayo-Wilson and Montgomery, 2013). ―― Reducing the symptoms of some anxietyrelated conditions and improving quality of life outcomes (Haug et al., 2013; Stubbings et al., 2013). ―― Children with anxiety disorders (Creswell et al., 2010). ―― People who are motivated (Newman et al., 2011). ―― Those who have lower level anxiety problems (Newman et al., 2011). ―― People who are not able or are not willing to use other services for people with anxiety disorders (Mayo-Wilson and Montgomery, 2013). There are doubts as to the long-term effectiveness of these approaches compared to face-to-face approaches (Coull and Morris, 2011; Haug et al., 2013) and there is a lack of evidence of their usefulness with older people or people with more severe conditions (Newman et al., 2011). Nevertheless, there are good reasons to believe that where face-to-face CBT treatment is not available or where individuals would choose not to use such a service for reasons of control, stigma or convenience, then it makes sense to make self-help treatment widely available. The range and diversity of self-help approaches and methods of engagement means that individuals have the ability to select those that work best for their specific needs. As we engage in more complex ways with technology then it seems probable that we will see more innovation develop in this field of support. More research is

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needed, but a recent co-production project funded by NHS Greater Glasgow and Clyde et al. found that young people valued digital approaches to self-help and peer support and recommended increased development of digital assets aimed specifically at and co-designed by young people (NHS Greater Glasgow and Clyde et al., 2013). For the past three years, The Mental Health Foundation has worked with the Paul Hamlyn Foundation, Comic Relief and Nominet Trust to deliver the Innovation Labs programme,13 working with technology companies, mental health organisations and young people to co-design and deliver seven tools to support young people address mental health concerns. Throughout the process, the value of technology to young people has been demonstrated, as has their ability to manage risk and challenge in online spaces.

Such developments recognise the new ways that people want to access support, but also the importance of providing a safe and quality assured space to do so. At the same time it is critical that digital spaces for mental health don’t merely replicate online what is available offline. A nuanced understanding of the way different audiences use technology is needed to best leverage opportunities. Equally, digital services need to be an opt in for those who are keen to use them, and not an opportunity to remove or ‘reframe’ existing services by forcing people online when they aren’t comfortable with that modality. In time this may create cost-savings, but this should be a collateral benefit and not a driver of digital innovation in mental health.

We have also seen the development of scaled technology-based tools for people to self-manage mental ill health, including anxiety. A range of products exist, with many health authorities in the UK having engaged the services of companies like Big White Wall14 to provide a validated, well controlled online community for self-management and self-exploration online. In Scotland, a different approach is being developed with the Scottish Government, NHS 24 and New Media Scotland collaborating on the development of Project Ginsberg. Ginsberg will provide a route for people who use technology to gain insight into their lives, using a range of apps and tools to better self-manage distress. Ginsberg will provide an online platform that will provide a selection of digital products, including access to diagnostic, treatment and monitoring tools that people can access independently of face-to-face services.

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13. www.innovationlabs.org.uk 14. www.bigwhitewall.com

Peer support Peer support is a system of giving and receiving help founded on key principles of respect, shared responsibility, and mutual agreement of what is helpful” (Mead, 2003). The benefits of peer support have been evidenced in a number of studies in relation to supporting individuals to self-manage their mental health problems and for those whose mental health is most at risk, such as isolated older people, people with dementia and young carers. Identified key benefits of peer support are the ability for the peer mentor to provide support based on empathetic understanding and from a position of having previous experience of developing coping skills for the particular set of problems encountered. Most of the research regarding people experiencing mental health problems has not been specific to anxiety. However, there are indications from work in relation to young people during transitions and people adapting to life with long-term conditions that peer support can provide a helpful approach in learning to cope with the anxiety that uncertainty brings.

Medication Among patients diagnosed with anxiety, approximately two-thirds are treated with medication, anti-depressants accounting for almost 80% of prescriptions made out to this group (Martin-Merino et al., 2010). Pharmacological interventions have been found to be effective at improving quality of life by reducing the symptoms of anxiety for some patients (Hofmann et al., 2013), although not for a significant number (Ravindran and Stein, 2010). Medication is generally not as effective for older adults as it is for younger adults (Wetherall et al., 2013).

NICE suggests that for particular kinds of anxiety, such as panic, social phobia and obsessions, GPs should prescribe anti-depressants, especially certain SSRIs (selective serotonin reuptake inhibitors). SSRIs appear effective in treating social phobia over the short term and the long term (Stein et al., 2004), while augmentative medications appear to be useful in the treatment of GAD, which is a more chronic condition (Chessick et al., 2006). Due to high rates of UK Governments are recognising the benefits of treatment resistance, there is interest in new peer support and over recent years there has been pharmacological treatment options such as a move to embed peer support approaches within second-generation antipsychotics (Depping et al., specialist mental health services as an additional 2010). Additionally, beta-blockers and tranquilisers layer of support. The advancements in digital are sometimes prescribed in the short term to technology may see further innovations in relation treat the physical symptoms without reducing to peer support available online and is an area the psychological symptoms of anxiety. worthy of fuller investigation in relation to anxiety. For fuller consideration of the role of peer support, see the Mental Health Foundation’s Need 2 Know Peer Support Briefing available to download from the Mental Health Foundation website.

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“The storm has died away, and still we are restless, uneasy, as if the storm were about to break. Almost all the affairs of men remain in a terrible uncertainty. We think of what has disappeared, and we are almost destroyed by what has been destroyed; we do not know what will be born, and we fear the future, not without reason… Doubt and disorder are in us and with us. There is no thinking man, however shrewd or learned he may be, who can hope to dominate this anxiety, to escape from this impression of darkness” (Paul Valery, Crisis of the Mind, 1919).

A new ‘Age of Anxiety’? The term ‘age of anxiety’ has been applied to several periods in modern history and is taken to mean a period of time marked by uncertainty about how we make sense of life. It is often used to refer to the period spanning the two world wars. Previous generations, particularly in the West, had believed that the trajectory of human society was inexorably upwards, fuelled by the civilising influences of faith, education and science in the service of industry and commerce. The First World War dealt a shattering blow to those old certainties and the long period of economic and political turmoil that followed is often characterised as a time of despair and darkness. It was also marked by a flowering of the visual arts, the emergence of the social sciences as a discipline, and the development of psychiatric medicine. Are we living in similar times? The shock of the recent economic crisis may have prompted fear and anxiety in the short term, but some longer term research suggests that the prevalence of anxiety disorders is largely impervious to the vicissitudes of the economy, suggesting instead that social trends such as divorce and crime may have greater explanatory validity (Twenge, 2000). While the notion of anxiety disorders undoubtedly relates to the individual human condition, is it possible to speak more generally of anxiety as a sociological phenomenon, a mood or emotion that permeates a community of people? Can an understanding of the state of the nation’s mood give us an insight into the effects of wider economic and social forces? In 2010, the Government introduced a new measure of wellbeing to broaden the indicators of economic development in the UK. It is intended that these indicators be used to inform the public about the nation’s wellbeing and “lead to government policy that is more focussed not just on the bottom line but on all those things that make life worthwhile” (Number10, 2010; Hicks, 2011). One of the measures used in the first of these wellbeing surveys relates to anxiety,

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because being anxious “is widely used as an indicator of poor mental wellbeing, a widely used generic measure of health status” (Dolan et al., 2011). This is important for the ‘bottom line’ because anxiety disorders are estimated to cost the UK economy £10.1bn annually15 in direct medical costs as well as indirect costs such as lost productivity due to absence from work or early retirement (Fineberg et al., 2013). For example, during 2011, around 27.4 million working days were lost due to minor illnesses such as coughs, colds and flu, while as many as 13.3 million working days were lost due to stress, depression and anxiety. Moreover, the group of people diagnosed with anxiety and depression has one of the lowest rates of employment (27.2%) of groups with a disability defined under the Disability Discrimination Act. People suffering anxiety are heavier users of primary care services than other users of those services (Martin-Merino et al., 2010) and the presence of an anxiety disorder significantly increases the costs of providing care to people with long-term conditions (Naylor et al., 2012). Our survey showed that worries about money and jobs are significant components of feelings of anxiety and that employment status directly effects how people assess their own anxiety; working conditions, job satisfaction and job security are known factors in people’s assessment of their own anxiety levels (Bryan, 2012; Oguz et al., 2013). The Office for National Statistics (ONS), which is charged with collecting data to inform the wellbeing indicator, has detected subtle changes between 2011–12 and 2012–13: a small decrease in people rating their lives as unsatisfactory corresponding with a small decrease in the same sample reporting high levels of anxiety.16 Yet the significant decrease in levels of anxiety amongst people in employment was not shared by people of working age who were unemployed (ONS, 2013). This may reflect a shift in mood as the worst of the recession passes, albeit short of outright optimism about the future.

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The ‘age of anxiety’ narrative is attractive because it appeals to our sense of zeitgeist, a desire to find a shared mood about the defining aspects of modern life; our work, the way we raise children, our attitudes to people who are disadvantaged, the future of public services, the threat of terrorism and so on. But there is a danger that in concentrating too much on the cultural significance of anxiety, we miss the continuing hidden impact of anxiety upon the lives of a great many people. For those living with the chronic forms of anxiety, it is more than a social index that rises and falls over time. Even within the last decade we have achieved a much better appreciation of this, even though we still lack definitive answers about the causes of anxiety disorders. We know more about the complexity of anxiety disorders, their symptomologies, manifestations and the multiplicity of factors that may be at play when someone experiences anxiety. Our understanding has been enhanced by a number of developments.

Firstly, a recognition by the medical and scientific communities that anxiety is worthy of attention. The collective clinical gaze has fallen upon particular aspects of anxiety: developing diagnostic consistency, the epidemiology of the various conditions that fall within the diagnostic criteria, causation and treatment. New technologies have helped, so genetics is now at the stage of suggesting heredity as a possible factor in anxiety. Secondly, the available options for managing anxiety are now more sophisticated and nuanced and we have a more robust evidence base for assessing the effectiveness of treatments, therapeutic interventions and coping strategies. In particular, the utility of psychological approaches, especially CBT, in managing anxiety either through a therapeutic relationship or as part of a self-help programme has been established and there is still great scope for expanding the availability of these.

15. At 2010 prices. 16. Both findings statistically significant at the 0.05 level.

Thirdly, the public profile of anxiety has been raised as part of a wider public debate about mental health and what we, as a society, need to do about it. There are a number of strands to this from campaigning and awareness-raising by organisations such as Anxiety UK, to greater interest from the news media and the emergence of a distinctive voice for people who experience anxiety through books and social media. These have helped tackle perceptions of stigma that have been associated with anxiety in the past. While these developments are encouraging, our own work suggests that there are still gaps that need to be addressed in the provision of support for people who experience anxiety. We know, for example, that people approaching primary care services do not always get the responses they need, including accurate diagnosis and referral to appropriate specialists, and too many people fail to complete courses of treatment when they do.

Recommendations We therefore make recommendations regarding approaches to helping people with anxiety and the research that is required to further our understanding of the experience of living with anxiety. A stepped care approach should be adopted to ensure that support to live with anxiety is provided in the least stigmatising and most inclusive way possible, including: ―― Universal approaches to learning to live well with anxiety should be built into school curriculums from primary 1 onwards, including an understanding of the role of anxiety in our lives and techniques for managing stresses associated with school (such as peer relationships, exams and transitions). ―― Peer-led approaches should be promoted within universal settings such as employment, schools and universities, in recognition of the importance that young people place on support from peers and the unique level of empathetic understanding that can be provided by those with a common experience. ―― Access to good quality self-help approaches should be made available across the UK through quality assured and co-designed digital platforms to ensure they are fit for purpose for those who choose not to use face-to-face services (young people, people in full time employment). ―― GP training and anxiety-related guidance should be assessed for equalities impact and adapted alongside groups of people who are at highest risk of developing problematic anxiety and least likely to have their needs met by current service provision.

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―― A sample of psychological services should be audited to establish how well referral processes are working, who is accessing these, and who is falling through the gaps. This audit should include IAPT in England and Wales and initiatives to improve access in Scotland. ―― Agencies offering support to people with anxiety should make greater use of peer mentors and advice and information that is explicitly based on the life experiences of people who live with anxiety. Research should be commissioned to better understand: ―― The nature and understanding of anxiety for different groups in society (women, people with long-term conditions, older people, people from black and minority ethnic communities), and whether current approaches and interventions can be found to address specific needs. ―― The relationship between unemployment, financial distress, and anxiety. The Department of Work and Pensions should develop strategies to prevent people who are not working from becoming marginalised from the workforce. Processes for accessing social welfare for those unable to work due to disability should be assessed for their impact on anxiety levels. ―― The impact of technological advancements in self-management for anxiety. Perhaps the most important conclusion to be drawn from this report is the importance of framing anxiety as an essential aspect of our humanity. All of us could trace a mental bell curve like the one described by Scott Stossell to plot the positive and negative uses to which we put our stock of anxiety, both the creative impulses and the destructive ones. The findings of our survey 40

show how anxiety stems as much from concern for family, friends and relationships as it does from the demand of the outside world. Most people instinctively seek solace and comfort in human interaction when confronted with anxious thoughts and feelings, and we know that these are the most effective ways of dealing with them. But anxiety can cause us to withdraw from society and look for solutions in ways that may harm us. We can glimpse in all of this the vital function that anxiety plays in alerting us to threats to the things that we hold most dear, as well as the material things ( jobs, money, possessions) that we need to sustain a modern existence. The testimony of people living with anxiety demonstrates how they cope and manage anxiety so that it remains a vital component of who they are without coming to define them. There remains a significant amount of work to be done across society to equip ourselves and bring our children up to live with anxiety, not only focusing our attention on the point where it becomes an identified problem, but ensuring that we are able to get the most out of life. Living to our full potential not limited by the fear of anxiety.

Useful resources and information Books about the lived experience of anxiety Scott Stossel (2014) My Age of Anxiety: Fear, Hope, Dread, and the Search for Peace of Mind published by Heinemann. Daniel Smith (2013) Monkey Mind: A Memoir of Anxiety published by Simon & Schuster.

Self-help guides Northumberland Tyne and Wear NHS Foundation Trust has a self-help guide that has been commended by the BMA and has been well reviewed by people accessing it online. For more information and to download a copy, click here. The NICE Guide to self-help resources for generalised anxiety disorder is available to download here. Radio and television programmes and films

Blogs about living with anxiety BBC Radio 4 Woman’s Hour Programme. Claire Eastham’s Blog weallmadhere. Psychological therapies The time to change blog about anxiety. Directory of IAPT services. The Anxiety No More website and a blog by its founder Paul David.

The Counselling Directory has a number of articles about anxiety. An online mindfulness course is available at Be Mindful Online. Mental Health Foundation How to overcome fear and anxiety. A video about anxiety from the NHS Choices website. Anxiety Care UK website. Tips on physical activity from the MIND website.

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National organisations offering help, advice and information Anxiety UK 08444 775 774 anxietyuk.org.uk Anxiety Care anxietycare.org.uk British Association for Behavioural and Cognitive Psychotherapies (BABCP) 01617054304 babcp.com Can provide a list of qualified therapists. British Association for Counselling and Psychotherapy (BACP) 01455 883300 bacp.co.uk Information about counselling and therapy. See the itsgoodtotalk website for details of local practitioners. The British Psychological Society 01162549568 bps.org.uk Produces a directory of chartered psychologists. Mindfulness Based Cognitive Therapy mbct.co.uk  Information about the therapy, classes in Mindfulness and training. NICE (National Institute for Health and Care Excellence) nice.org.uk  Information and guidelines on recommended treatments for different disorders. No Panic Helpline 08001388889 nopanic.org.uk Provides a helpline, step-by-step programmes, and support for those with anxiety disorders.

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Samaritans24-hour helpline 08457909090 email: [email protected] samaritans.org Emotional support for anyone feeling down, experiencing distress or struggling to cope. UK Council for Psychotherapy (UKCP) 02070149955 psychotherapy.org.uk Has a voluntary register of qualified psychotherapists. The Young Minds website has information for parents concerned about a child’s anxiety, including a helpline (0808 802 5544) Monday to Friday 9.30am-4pm.  YouthNet runs The Site which offers young adults help with a range of problems, including anxiety.

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McCrone, P., Dhanasiri, S., Patel, A., Knapp, M. and Lawton-Smith, S. (2008) Paying The Price: the cost of mental health care in England to 2026, London: King’s Fund. McHugh, R., Whitton, S., Peckham, A., Welge, J. and Otto, M. (2013) Patient preference for psychological vs pharmacologic treatment of psychiatric disorders: a meta-analytic review, The Journal Of Clinical Psychiatry 74 (6), 595–602. McManus, S., Meltzer, H., Brugha, T., Bebbington, P. and Jenkins, R. (2009) Adult psychiatric morbidity in England, 2007: Results of a household survey, Leeds: The NHS Information Centre for health and social care. McMurchie, W., Macleod, F., Power, K., Laidlaw, K. and Prentice, N. (2013) Computerised cognitive behavioural therapy for depression and anxiety with older people: a pilot study to examine patient acceptability and treatment outcome, International Journal of Geriatric Psychiatry [online]. Available at: http://onlinelibrary.wiley. com/doi/10.1002/gps.3935/pdf. Martín-Merino, E., Ruigómez, A., Wallander, M.A., Johansson, S., García-Rodríguez, L.A. (2010) Prevalence, incidence, morbidity and treatment patterns in a cohort of patients diagnosed with anxiety in UK primary care, Family Practice 27 (1), 9–16. Mayo-Wilson, E. and Montgomery, P. (2013) Media-delivered cognitive behavioural therapy and behavioural therapy (self-help) for anxiety disorders in adults, The Cochrane Database Of Systematic Reviews 9. Mental Health Foundation (2009) In the face of fear. How fear and anxiety affect our health and society, and what we can do about it, London: Mental Health Foundation. Mental Health Foundation (2013) Let’s Get Physical: the impact of physical activity on wellbeing, London: Mental Health Foundation. NHS Greater Glasgow & Clyde, Young Scot, Snook & Mental Health Foundation (2013) Project 99: Exploring internet based approaches to support young mental health in Greater Glasgow & Clyde [online]. Available at: http://www.wegot99.com/wp-content/uploads/2013/12/finalreport-draft-v11-interactive.pdf. National Institute for Clinical Excellence (2011) Generalised anxiety disorder and panic disorder (with or without agoraphobia) in adults: management in primary, secondary and community care (NICE clinical guideline 113), London: NICE.

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Magellan’s Clinical Practice Guideline for the Assessment and Treatment of Generalized Anxiety Disorder in Adults

©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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Magellan Clinical Practice Guideline Task Force Thomas G. Carlton, M.D. Nancy D. Donachie, M.D. Kathleen Frampton, R.N., B.S.N., M.P.H. Gary Henschen, M.D. Pamela E. Kumar, R.N., B.S.N. Kathryn Kvederis, M.D., D.F.A.P.A. Louis A. Parrot, M.D., Ph.D. Clifton A. Smith, D.O., M.S. Fatimah A. Tahil, M.D., M.P.H. Fred Waxenberg, Ph.D.

Table of Contents Purpose of This Document .............................................................................. 3 Provider Feedback ........................................................................................... 3 Executive Summary ........................................................................................ 4 Generalized Anxiety Disorder in Adults Assessment .............................................................................................. 9 Diagnosis and Treatment Planning.......................................................... 14 Patient and Family Education ................................................................. 14 Psychotherapy Treatments ...................................................................... 15 Pharmacology Treatments ....................................................................... 21 Combined Treatments ............................................................................. 36 Monitor Progress and Address Sub-optimal Recovery .............................. 38 References .................................................................................................... 40

©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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Purpose of This Document Magellan Health (Magellan) has developed the Clinical Practice Guideline Assessment and Treatment of Generalized Anxiety Disorders (GAD) in Adults for use by providers working with Magellan members who may have these disorders. This guideline is a research-based document that covers the psychiatric management of adult patients with GAD. It reviews clinical features, epidemiology, assessment and treatment planning including psychotherapy and pharmacotherapy. For detailed information on the management of children and adolescents with GAD, see the American Academy of Child and Adolescent Psychiatry (AACAP) Practice Parameter for the Assessment and Treatment of Children and Adolescents with Anxiety Disorders (2007). The purpose of this document is to summarize recommendations from a literature review conducted on GAD through April 2014. The rationale for this summary, presented in table format, offers clinicians evidence- and consensus-based guidance on assessment and treatment of GAD in one location for ease of use and reference. However, clinicians also should become familiar with the content of the articles referenced in the document. As with all guidelines, this document is intended to augment, not replace, sound clinical judgment. As a matter of good practice, providers should note clinically sound exceptions to this practice guideline in the member’s treatment record, with documentation of the clinical reasoning for making the exception. Magellan periodically requests treatment records from providers in order to monitor compliance with clinical practice guidelines. Additionally, this guideline does not supersede Food and Drug Administration (FDA) determinations or other actions regarding withdrawal or approval of specific medications or devices, and their uses. It is the responsibility of the treating clinician to remain current on medication/device alerts and warnings that are issued by the FDA and other regulatory and professional bodies, and to incorporate such information in his or her treatment decisions.

Provider Feedback Magellan welcomes feedback on our clinical practice guidelines. We take all suggestions and recommendations into consideration in our ongoing review of the guidelines. Comments may be submitted to: Clinical Operations Coordinator Re: CPG Magellan Health 6950 Columbia Gateway Dr. Columbia, Maryland 21046 [email protected]

©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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Executive Summary (A discussion of additions/changes in this updated guideline.) This update to Magellan’s Clinical Practice Guideline for the Assessment and Treatment of Generalized Anxiety Disorder (GAD) in Adults includes findings from peer reviewed studies from November 2011 through April 2014. The new Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM-5™) reorganized the criteria for GAD while leaving it virtually unchanged. The DSM-5 distinguishes GAD from nonpathological anxiety indicating that worries associated with GAD are excessive and usually interfere significantly with psychosocial functioning. Occurring even without precipitants, they are more pervasive, distressing and pronounced with longer duration. Worries are also more likely to be accompanied by physical symptoms, e.g., restlessness, being on edge. Patients with GAD may also have several psychic and somatic symptoms including suicidality. Assessment scales such as the Generalized Anxiety Disorder Severity Scale and the Hamilton Anxiety Scale may be efficient tools for screening for GAD and assessing its severity in clinical practice and research. Gibbons et al. reported that a new computerized adaptive test for GAD, CAT-ANX, based on multidimensional item response theory, allows the specific items administered and the number of items to vary from individual to individual, leading to a decrease in the number of items required for a fixed level of measurement uncertainty. Each patient’s items are selected from a large bank of test items based on prior item responses. The DSM-5 notes that childhood adversities and parental overprotection, although associated with GAD, have not been identified as specific to GAD and are not sufficient for making a diagnosis of GAD. Other associated factors include neuroticism, harm avoidance, genetic factors and physiological factors. DSM-5 notes that one-third of the risk of experiencing GAD is genetic. According to the DSM-5, individuals diagnosed with GAD are most likely to have met the criteria for other anxiety disorders and unipolar depressive disorders. A recent study by Zbozinck et al. reviewed data from the Mini International Neuropsychiatric Interview (MINI) to determine whether symptom overlap may inflate rates of co-morbidity between GAD and major depressive disorders (MDD). Patients with GAD and MDD share symptoms of difficulty sleeping, difficulty concentrating, being easily fatigued and psychomotor agitation. Investigators found that the co-morbid GAD/MDD group endorsed the overlapping symptoms more than a MDD group but not the GAD group. The co-morbid group endorsed the overlapping symptoms more than the non-overlapping symptoms. Zbozinck et al. suggested that rates of co-morbidity between GAD and MDD may be inflated due to the symptom overlap. The 2011 National Institute for Health and Clinical Excellence (NICE) guidelines stress the importance of a comprehensive assessment of all patients suspected of having GAD, considering not only the number, severity and duration of symptoms, but also the degree of distress and functional impairment. The guideline’s recommendations include active monitoring of the individual’s symptoms and functioning, indicating how active monitoring may improve less severe presentation and avoid the need for additional interventions. ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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Psychotherapy Treatments A recent randomized controlled trial by Norton et al. investigated the efficacy of a 12week transdiagnostic cognitive behavioral therapy (CBT) group treatment compared to a 12-week established diagnosis-specific group CBT treatment for panic disorder, social anxiety disorder and GAD. Individuals with these disorders were randomized to the transdiagnostic CBT group (received treatment deemphasizing diagnostic labels and focusing on confronting feared stimulation – including psychoeducation, cognitive restructuring and exposure therapy) or the diagnosis-specific group (received treatment specifically targeting the individual diagnosis). Results showed effects of transdiagnostic CBT were as strong as those of diagnosis-specific CBT on outcome measures. Researchers suggested that a single transdiagnostic CBT applicable to more than one anxiety disorder may encourage more mental health practitioners to adopt CBT for the treatment of all three disorders. Patel et al. have noted that CBT is the cornerstone for treatment of adults with GAD, suggesting that if it is not effective, other therapies, e.g., relaxation training, worry exposure or exposure therapy, or short-term psychodynamic psychotherapy, may augment or replace it. A study by Paxling et al. addressed the content of therapist e-mails in therapist-guided internet-based cognitive behavioral therapy (iCBT) for GAD. In this randomized trial, three therapists delivered iCBT to participants diagnosed with GAD. Different therapist behaviors had an impact on module completion. Allowing deadline flexibility was found to be associated with negative outcome whereas task reinforcement was associated with a positive outcome. Investigators suggested the need for larger studies addressing the impact of e-mail support given in addition to traditional therapy. Bandelow has suggested that internet-based CBT should not be recommended for the treatment of GAD as trials have not compared it to traditional CBT in which the patient and therapist are in personal contact. A recent randomized controlled trial conducted by Bush et al. used the Pittsburgh Sleep Quality Index (PSQL) as an outcome measure in a study examining the response to CBT compared to enhanced usual care in older adults with GAD. Participants were randomized to treatment with CBT (including psychoeducation, motivation interviewing, relaxation training, cognitive restructuring, exposure, problem-solving skills training and behavioral sleep management) or to enhanced usual care (including telephone conversations with a therapist focusing on safety monitoring and providing support). Outcomes measured by the PSQL administered at 3-months posttreatment and over a 12-month interval showed that participants who received CBT for anxiety experienced improvement on scores of sleep quality, sleep latency and sleep disturbances than those who received enhanced usual care. Researchers noted, however, that CBT did not achieve improvement in sleep duration, daily functioning or the use of sleep medications. Brenes et al. examined the effects of CBT delivered by telephone (CBT-T) to older participants with GAD, panic disorder, combined GAD and panic disorder, or anxiety disorder not otherwise specified. In this randomized controlled trial, participants were randomized to CBT-T (including telephone therapy sessions and a treatment workbook, a telephone therapy session and discussion with therapist) or to information-only comparison (including written information on anxiety disorders and a list of referral options). Findings of this study included: 1) participants receiving CBT-T demonstrated greater improvement in self-report and clinician-rated worry and anxiety symptoms than those in the information-only group; and 2) participants receiving CBT-T experienced greater reductions in insomnia and anxiety than the information-only group. This effect ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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did not continue six months after treatment completion. Researchers suggested a longer intervention and also suggested that CBT-T may be helpful in a stepped-care to late-life anxiety as older adults often prefer psychotherapy to pharmacotherapy. CBT-T does not require attendance at regular face-to-face therapy sessions which older adults may not be able to attend. In another study, participants were randomized to an 8-week program of manualized Mindfulness-Based Stress Reduction (MBSR) or to an attention control, Stress Management Education (SME) to compare the effects of the two treatments. MBSR included group in-class practices, e.g., breath-awareness, gentle Hatha yoga and BodyScan exercises, focusing on present experience and treating the body gently. Participants were also instructed in present-focused awareness while eating, bathing or cleaning. SME was taught in a didactic format comprising both class and home activities, e.g., stress physiology, time management techniques, sleep physiology and factors that buffer the impact of stress. Both MBSR and SME resulted in significant reduction in anxiety symptoms as measured by the Hamilton Anxiety Scale, but MBSR was associated with greater reduction in anxiety as measured by the Clinical Global Impression of severity and Improvement and the Beck Anxiety Inventory compared to SME. Researchers suggested that MBSR may result in greater resilience to stressful psychological challenges and reduce anxiety symptoms in patients with GAD. Pharmacology Treatments Strongest evidence of clinical efficacy in the treatment of GAD has been found for the first-line treatments for GAD: SSRIs – escitalopram, paroxetine, sertraline; SNRIs – venlafaxine and duloxetine; and the calcium channel modulator - pregabalin. Secondline treatment options include buspirone, benzodiazepines, i.e., alprazolam and diazepam, and the antihistamine hydroxyzine. Quetiapine, an atypical antipsychotic, is used as monotherapy in GAD and is reserved for treatment-refractory cases. Bandelow et al., in a practical summary of the World Federation of Biological Psychiatry (WFSBP) guidelines, advises that the benzodiazepines should only be used for long-term treatment after other drugs or CBT have failed. Berger et al. compared healthcare costs of patients with GAD who received treatment with a benzodiazepine adjunctive to antidepressants to costs of patients who did not receive concomitant therapy, finding that healthcare costs increased following benzodiazepine treatment. Further, they noted that approximately half of the increase in cost was associated with known sequelae of long-term treatment with benzodiazepines. A later systematic review and meta-analysis performed by Offidani et al. analyzed whether controlled comparisons support the current prescribing pattern favoring newer antidepressants (SSRIs and SNRIs) over benzodiazepines. Researchers reported studies showing no significant differences in response rates between patients receiving benzodiazepines, venlafaxine XR, or placebo, although more adverse events (and discontinuations of treatment) occurred in patients taking venlafaxine XR than in those treated with benzodiazepines. Another study reviewed by Offidani et al. showed that both lorazepam and paroxetine treatments were effective in reducing anxiety-related psychiatric symptoms; however, somatic features improved significantly only in those taking lorazepam. Researchers noted serious side effects of treatment with SSRIs, e.g., sexual dysfunction, weight gain, risk of osteoporosis, hyponatremia, gastrointestinal bleeding and potential for drug interactions. They also noted a potential advantage of SSRIs over benzodiazepines: the associated lower impairment in cognitive and psychomotor skills. Nonetheless, they concluded that literature does not support the ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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pattern favoring newer antidepressants over benzodiazepines in the treatment of anxiety disorders. Bandelow et al. have reviewed literature demonstrating the efficacy of escitalopram, paroxetine, and sertraaline, while also noting associated adverse effects that may impair compliance. Researchers have suggested that SSRIs be taken in the morning to avoid nocturnal restlessness and insomnia at the beginning of treatment. Bandelow et al. have also reviewed literature reporting the results of randomized trials demonstrating the efficacy of SNRIs, indicating that adverse effects may impair compliance. Mezhebovsky et al. conducted a large study to evaluate the efficacy and tolerability of quetiapine XR monotherapy in older patients with GAD. Patients were randomized to quetiapine XR or to placebo over a 9-week treatment period and a 2-week drugdiscontinuation period. Treatment was initiated at 50 mb/day with dose adjustment made based on efficacy and tolerability. Results of this study showed significant benefits over placebo (reduced anxiety symptoms at week 9 as measured by the Hamilton anxiety Rating Scale). Additionally, significantly improvements were seen with quetiapine XR as early as week 1, suggesting it may reduce anxiety symptoms within a timeframe similar to benzodiazepines. Mezhebovsky et al. concluded that quetiapine XR monotherapy is an effective, short-term treatment in older persons with GAD, improving anxiety symptoms as well as quality of life. A small study by Chen et al., including patients with an anxiety disorder or a mood disorder with anxiety symptoms who were randomized to quetiapine XR as an adjunct to treatment with antidepressants (escitalopram, paroxetine, venlafaxine, duloxetine and mirtazapine) or to a placebo plus antidepressant, found a short-term benefit at 4-weeks in the group treated with quetiapine XR as an adjunct to antidepressant treatment. At 8-weeks, there were no significant differences between the two groups based on changes in anxiety symptoms. Researchers suggested further studies are needed. Pregabalin’s effect on sleep disturbance in patients with GAD was studied in a recent review by Holsboer-Trachsler and Pieto). A review of the results of seven randomized controlled trials found that treatment with pregabalin is associated with improvement in sleep, functioning, and quality of life in patients with GAD. Adverse effects, including sedation, were mild to moderate and limited to the first 2-3 weeks of treatment. Levitan et al. reviewed two studies investigating the efficacy of the novel antidepressant, agomelatine, for treatment-resistant GAD. The studies showed that agomelatine demonstrated higher rates of response and anxiety remission than placebo at 12 weeks, and patients randomized to continuing agomelatine after week 16 showed a lower incidence of relapse than the placebo group. A more recent literature search and review indicates that potential interactions with a number of compounds necessitate caution when prescribing agomelatine. This updated guideline also discusses plantbased medicines that show evidence for anxiolytic effects. Sarris et al. discuss the use of these anxiolytics, cautioning that some may have mild and serious adverse effects. Wetherell et al. examined whether sequenced treatment with escitalopram and CBT boosts response and prevents relapse in older adults with GAD. Patients started on escitalopram were randomized to one of four groups: 1) escitalopram augmented with CBT followed by maintenance escitalopram; 2) escitalopram alone followed by maintenance escitalopram; 3) escitalopram augmented with CBT followed by maintenance placebo; and 4) escitalopram alone followed by maintenance placebo. Findings showed that treatment with escitalopram followed by augmentation with CBT ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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resulted in greater improvement in decreasing symptoms of worry measured by the Penn State Worry Questionnaire than escitalopram alone. Patients receiving maintenance escitalopram had a significantly lower relapse rate than those receiving placebo. Among patient receiving maintenance placebo, those receiving escitalopram augmented with CBT had lower rates of relapse than those who had escitalopram alone. Wetherell et al. concluded that in older patients with GAD, antidepressant medication augmented with CBT reduces pathological worrying and relapse, even when antidepressant treatment is stopped after augmentation, noting that CBT could be an option for older patients who prefer to discontinue antidepressants. Bandelow et al. recommend that development of the treatment plan for GAD should be affected by several conditions, e.g., preferences of patients, co-morbidity, severity of the illness, substance use disorders, suicide risk and history of prior treatment. Recommendations also include providing information and support to both individuals with GAD, their families and their caregivers.

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Generalized Anxiety Disorder in Adults: Recommendations Based on Recent Literature Review Magellan conducted a review of the clinical literature on assessment and treatment of GAD in adults. Key relevant recommendations from this literature are summarized below. Magellan encourages providers to be familiar with this information and consult the referenced research articles.

GENERALIZED ANXIETY DISORDER (GAD) IN ADULTS PROCEDURE

RECOMMENDATIONS

Assessment

Generalized anxiety disorder (GAD) is a common condition with a life-time prevalence 4.3%-5.9% and a 1-year prevalence of 0.2%4.3% (Bandelow et al., 2013; Kessler, Chiu, et al. 2005). In other countries, the 12-month prevalence ranges from 0.4%-3.6%. (APA, 2013).The age of onset of GAD differs from that of other anxiety disorders, with the majority of cases presenting between 35 to 45 years of age. Peaking in middle age, the prevalence of the diagnosis declines across the later years of life, although GAD may be the most common anxiety disorder among the older population (aged 55 to 85 years). Typically, symptoms fluctuate in intensity over time, but GAD is usually a chronic condition where patients report reduced quality of life related to general physical, mental and social health and being unable to function as usual an average of 1.5 to 5.4 days per month (Collins et al., 2009; Baldwin, 2004). GAD appears to be more common in primary care than in the general population, suggesting that patients with GAD are high users of primary care resources. GAD is diagnosed twice as often in women as in men; in clinical settings, 55%-60% of those with GAD are women (APA, 2013). Prevalence rates are higher in white and Native American persons than in black, Asian and Hispanic individuals (Newman et al., 2013). Although GAD does “stand on its own as a disorder with distinct onset, course, impairment and prognosis…” it is one of the most highly co-morbid psychiatric conditions (Hales et al., 2010, para. 2). According to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5™) published by the American Psychiatric Association in 2013, GAD is an anxiety disorder characterized by persistent, excessive and difficult-to-control anxiety and worry about a number of activities or events (APA, 2013). The worry and anxiety are out of proportion to the actual likelihood or impact of the anticipated events, its focus often

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shifting from one concern to another during the course of the disorder. Having difficulty in controlling the worry, the individual’s worrisome thoughts may interfere with attention to tasks at hand. Worries may be about everyday, routine life circumstances, e.g., job responsibilities, health and finances, health of family members, their children’s misfortunes or minor matters, e.g., chores around the house or tardiness in meeting appointments. GAD is distinguished from non-pathological anxiety as worries associated with GAD are excessive and usually interfere significantly with psychosocial functioning. They may occur without precipitants, and are more pervasive, distressing, and pronounced with longer duration. Worries associated with GAD are much more likely to be accompanied by physical symptoms, e.g., restlessness or feeling keyed up or on edge. Constant worry and related impairment in social, occupational or other important areas of functioning lead to subjective stress (APA, 2013). GAD may be accompanied by several psychic and somatic symptoms including suicidality. Other features supporting diagnosis of GAD include muscle tension, and somatic symptoms, e.g., nausea, diarrhea, sweating, irritable bowel syndrome, headaches and exaggerated startle response. Clinical presentations often include somatic illness, pain, fatigue, depression and problems with sleeping. Diagnosis of GAD must meet the following DSM-5 criteria: • Persistent and excessive anxiety and worry about common events or activities occur on more days than not, for six months or more. Worry may focus on finances, marriage, children, personal or family health, job performance or security. The extent of anxiety is in excess of what might be considered reasonable given the reality of the situation. • Difficulty controlling worry is associated with at least three of the following six symptoms: restlessness or feeling keyed up or on edge, easy fatigability, difficulty concentrating or mind going blank, irritability, muscle tension and sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep). •

Clinically significant distress or impairment in social, occupational or other important areas of functioning are caused by the anxiety, worry or physical symptoms. Diagnosis of GAD should be made only when the focus of anxiety or worry is unrelated to disorders, such as worry about entering a social situation (social anxiety disorder) or as a response to an identified stressor (adjustment disorder), having a panic attack (as in panic disorder), gaining weight (as in anorexia nervosa), being contaminated (as in obsessive-compulsive disorder), having multiple physical complaints (as in somatization disorder) or having a serious illness (as in

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hypochondriasis). Also, in GAD, the worry does not occur exclusively during post-traumatic stress disorder. Anxiety, worry or physical symptoms cause clinically significant distress or impairment in social, occupational or other important area of function. •

The disturbance is not due to the direct physiological effects of a substance, e.g., a drug of abuse, a medication, or a general medical condition, e.g., hyperthyroidism.

•

The disturbance is not better explained by another mental disorder, e.g., panic disorder, social phobia, obsessivecompulsive disorder, separation anxiety disorder, posttraumatic stress disorder, body dysmorphic disorder, illness anxiety disorder, schizophrenia or delusional disorder (APA, 2013). Patients with GAD may present with symptoms other than anxiety, e.g., pain or sleep disturbance, leading to a misdiagnosis. Assessment Scales – Evidence from a criterion-standard study found that the seven-item anxiety scale (GAD-7) has reliability, criterion, construct, factorial and procedural validity, and may be an efficient tool for screening for GAD and assessing its severity in clinical practice and research (Spitzer, 2006; Kroenke et al., 2010). Two other symptom severity measurement instruments have been developed and tested for GAD. The Generalized Anxiety Disorder Severity Scale (DGSS) is comprised of eight GAD symptoms for assessment of frequency and intensity. The DGSS demonstrated good internal reliability with the Hamilton Anxiety Scale (HAM-A) and Clinical Global Impression Severity Scale (CGI-S) (Stein, Fincham et al., 2009). The newly developed Daily Assessment of Symptoms-Anxiety (DAS-A) scale was also shown to have validity as a new instrument to assess onset of symptomatic improvement in GAD (Feltner et al., 2009). A new computerized adaptive test for GAD, CAT-ANX, based on multidimensional item response theory, allows the specific items administered and the number of items to vary from individual to individual, leading to a dramatic decrease in the number of items required for a fixed level of measurement uncertainty. Items are selected for each patient from a large bank of test items based on prior item responses (Gibbons et al., 2013). Epidemiological Data – Data from the U.S. National Co-morbidity Survey Replication (NCS-R) showed that GAD prevalence rates changed when using a broader definition of episode from the required 6 months. Community epidemiological data for the range of 1-12 months showed that lifetime prevalence changed from 6.1% to 4.2-12.7%; 12 month prevalence changed from 2.9% to 2.25.5%; and 30 day prevalence changed from 1.8% to 1.6-2.6%. Cases with episodes of 1-5 months did not differ greatly from those with episodes greater than or equal to 6 months in onset, persistence, impairment, co-morbidity, parental GAD or socio©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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demographic correlates. These findings suggest that a large number of people suffer from a GAD-like syndrome with episodes of less than 6 months duration and question the basis for excluding these people from a diagnosis of GAD (Kessler, Brandenburg, et al. 2005). DSM-5 continues to include excessive anxiety and worry (apprehensive expectation) occurring for at least 6 months as part of the diagnostic criteria for GAD (APA, 2013). Risk Factors – One study found that GAD (co-morbid or pure) was associated with several risk factors across multiple domains of risk during childhood: maternal internalizing symptoms, i.e., the mother’s symptoms of anxiety and depression manifesting as insomnia, hopelessness, tension, somatic complaints, low socioeconomic status, maltreatment, internalizing, conduct problems and negative emotionality (Moffit, Caspi, et al. 2007). Although childhood adversities and parental overprotection have been shown to be associated with GAD, DSM-5 notes that these factors have not been identified as specific to GAD and are not sufficient for making a diagnosis of GAD (APA, 2013). Temperamental factors, e.g., behavioral inhibition, neuroticism and harm avoidance, are associated with GAD, as are genetic and physiological factors. According to DSM-5, one-third of the risk of experiencing GAD is genetic. Although there is cultural variation in the expression of GAD, there is a lack of information about whether the propensity for excessive worrying is related to culture (APA, 2013). Co-morbid Psychiatric Conditions – Individuals meeting the criteria for GAD are most likely to have met the criteria for other anxiety disorders and unipolar depressive disorders which share the same risk factors, although independent pathways are also possible (APA. 2013). Other less common co-morbidities include substance use, conduct, psychotic, neurodevelopmental and neurocognitive disorders (APA, 2013). The co-morbidity rate with major depression is about 59% and 56% with other anxiety disorders (Hales et al., 2010; Canadian Psychiatric Association Guideline, 2006). One study showed that the generalized anxiety disorder – major depression disorder (GAD-MDD) co-morbidity may affect more of the adult population and constitute a greater health burden than previously thought. Another study of the association between GAD and MDD demonstrated that generalized anxiety usually began before or concurrently in 37% of depression cases, but depression began before or concurrently in 32% of anxiety cases. Also, cumulatively, 72% of lifetime anxiety cases had a history of depression, but 48% of lifetime depression cases had anxiety. This study challenged the prevailing notion of a predominant pattern in which generalized anxiety usually develops into depression by showing that depression develops into generalized anxiety almost as often (Moffitt, Harrington, et al. 2007). In addition, the co-occurrence of GAD and bipolar disorder ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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was reported from baseline data of the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) Study. The investigation revealed that 18% of subjects with bipolar disorder had a lifetime occurrence of GAD (somewhat higher for bipolar I than for bipolar II disorder) and 51% of bipolar patients had at least one type of lifetime anxiety disorder (Simon, 2009). A more recent study addressed the symptom overlap of participants (n=1218) meeting diagnostic criteria for GAD, MDD, or both, to investigate whether co-morbidity may be explained by overlapping diagnostic criteria. Data in the study included symptom profiles of participants with GAD, MDD, and co-morbid GAD/MDD. DSM-5 diagnostic criteria for GAD and MDD share four symptoms: difficulty sleeping, difficulty concentrating, being easily fatigued and psychomotor agitation. Authors reviewed data from the Mini International Neuropsychiatric Interview (MINI) to determine whether the co-morbid GAD/MDD group endorsed the overlapping symptoms more than the non-overlapping symptoms, and whether the co-morbid GAD/MDD group endorsed the overlapping symptoms more than GAD only or MDD only groups. Results showed that the GAD/MDD group endorsed the overlapping symptoms more that the MDD group but not the GAD group and the co-morbid group endorsed the overlapping symptoms more than the non-overlapping symptoms. Findings suggested that symptom overlap may inflate rates of co-morbidity between GAD and MDD; alternatively it may represent the shared psychopathology underlying the conditions (Zbozinek et al., 2012). Co-morbid Physical Conditions – Anxiety disorders have been shown to be independently associated with several physical conditions. Results from a large study, The German Health Survey, revealed that after adjusting for socio-demographic factors and other common mental disorders, the presence of an anxiety disorder was significantly associated with thyroid disease, respiratory disease, gastrointestinal disease, arthritis, migraine headaches and allergic conditions. Co-morbidity was also shown to be significantly associated with poor quality of life and disability (Sareen, Jacobi, et al. 2006). Suicide Ideation and Suicide Attempt – Two studies demonstrated that as a group of disorders, anxiety disorders were highly prevalent among those with suicidal behavior in large community samples. One study showed that anxiety disorders were independent risk factors for suicidal behavior, even after adjusting for co-morbidity with common mental disorders. Also, the presence of an anxiety disorder in combination with a mood disorder was associated with increased likelihood of suicidal behavior, compared with those with mood disorder alone (Hawgood et al., 2008; Sareen, Cox, et al. 2005). Another study of adolescents and young adults aged 16-18, 19-21 and 21-25 years ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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showed that anxiety disorders were associated with moderate increases in suicidal behavior and may account for approximately 7-10% of this population’s rate of suicidal behaviors. There was evidence to suggest that GAD was more strongly associated with suicidal ideation, and that panic disorder was more strongly associated with suicide attempts, than other anxiety disorders. Also, the rates of suicidal behavior increased in proportion to the number of anxiety disorders present (Boden, 2006). A more recent study explored independent association between specific anxiety disorders (including GAD) and suicide attempts and ideation using a process that simulated a case-control study and made use of the National Co-morbidity Survey Replication and the National Epidemiologic Survey on Alcohol and Related Conditions. This study presented evidence that each anxiety disorder, e.g., GAD, is associated with suicide ideation and suicide attempts beyond the effects of co-occurring mental disorders (Thibodeau et al., 2013). Diagnosis and Planning

It is important to identify the diagnosis of GAD as early as possible in order to plan and begin treatment.

Patient and Family Education

All patients who are suspected of having GAD should receive a comprehensive assessment, not relying solely on the number, severity and duration of symptoms, but also considering the degree of distress and functional impairment (National Institute for Health and Clinical excellence (NICE), 2011). Patients should receive education from their physician about the nature of GAD, options for treatment, and general prognosis. Physicians should identify alleviating and aggravating factors as well as signs of relapse for each patient. In addition, information on local self-help and support groups, self-help reading material describing evidence-based treatment strategies, and other resources such as websites, may be helpful. To support informed decision-making, patients should be informed about effectiveness, common side effects of medications, probable duration of treatment, any costs they might incur, and what to expect when treatment is discontinued (Canadian Psychiatric Association Guideline, 2006). Along with educating the patient, the individual’s symptoms and functioning should be actively monitored. Education and active monitoring may have the effect of improving less severe presentations and may avoid the need for further interventions (NICE, 2011). • One study examined whether telephone-based collaborative care for patients with panic disorder and/or GAD improves clinical and functional outcomes more than the usual care provided by primary care providers. Care managers called patients at regular intervals and provided them with psychoeducation; assessed preferences for guideline-based care, monitored treatment responses, and informed physicians of their patients’ care preferences and progress via an electronic

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medical record. Compared with the outcomes achieved by primary care physicians’ usual care for panic and GAD, the telephone-based collaborative intervention significantly reduced anxiety and depressive symptoms, improved mentalhealth related quality of life, and improved employment patterns during the 12-month course of follow-up (Rollman, 2005). Psychotherapy Treatments

The efficacy of Cognitive Behavioral Treatments (CBT) for anxiety in adults has been supported as a consistent and empirically validated form of psychotherapy for GAD in the Consensus Statement on Generalized Anxiety Disorder from the International Consensus Group on Depression and Anxiety (Ballenger, 2001). Additionally, the Canadian Psychiatric Association Clinical Practice Guidelines on the Management of Anxiety Disorders (2006) notes that CBT research demonstrates that it is more effective than no treatment and non-specific psychological methods for GAD, and that the magnitude of benefits is comparable to those reported in studies of antidepressant drugs. In addition, these guidelines note that CBT appears to be beneficial in both individual and group settings where the benefits tend to be maintained during 6 months to 2 years of follow-up. Several common problems have been identified among individuals with GAD, including intolerance of uncertainty, poor problem-solving approaches, and beliefs that worry is a helpful way to deal with problems. The aforementioned guidelines note that CBT interventions targeting these aspects were effective in clinical trials (Canadian Psychiatric Association Guideline, 2006). Important research findings on psychotherapy for the treatment of GAD include studies on CBT, Worry Exposure, Applied Relaxation, Muscle Relaxation, Short-term Psychodynamic Psychotherapy and Mindfulness-based Therapy summarized as follows: •

One meta-analysis looking at the efficacy of CBT compared to pharmacological therapy showed no significant differences in their efficacy in the treatment of GAD. The attrition rates were lower for CBT, which indicated that it was better tolerated by patients. Also, because most comparisons of CBT treatments were with the benzodiazepine drug class, more research is needed to compare CBT to other psychotropic agents, i.e., Selective Serotonin Reuptake Inhibitors (SSRIs), Selective Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs) and buspirone (Mitte, 2005).

•

Another meta-analytic review of CBT in adults across all anxiety disorders showed that cognitive therapy and exposure therapy alone, in combination or combined with relaxation training, were efficacious across the anxiety disorders with no differential efficacy for any treatment components for any specific diagnoses. When comparing across diagnoses, outcomes for GAD and post-traumatic stress disorder (PTSD)

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were superior to those for social anxiety disorder (Norton, 2007). •

A large meta-analysis reviewed some 27 studies that examined the efficacy of CBT versus placebo in the treatment of all adult anxiety disorders. In comparing the average effect size estimates of CBT, treatment efficacy for both anxiety symptoms (Hedges’ g = 0.51) and depressive symptoms (Hedges’ g = 0.38), GAD ranked among the lowest effect sizes with the exception of panic disorder. The strongest effect size estimates for CBT were for obsessive-compulsive disorder and acute stress disorder (Hofman et al., 2008).

•

One study combined meta-analysis to determine overall effect size of CBT in the treatment of both GAD and panic disorder and meta-regression to determine the factors that had an impact on this effect size. The study findings showed that CBT is significantly less effective for patients with a severe form of both disorders. Also, trials that compared CBT to a wait-list control group found significantly larger effect sizes than those comparing CBT to an attention placebo, but not to a pill placebo. Also, these findings noted that most studies used psychologists as providers and recommended that more studies are needed with other professional groups as well as other modes of administration, e.g., telephone, computer (Haby, 2005). Previous studies have suggested that transdiagnostic CBT for anxiety disorders reduces symptoms of anxiety. A recent randomized clinical trial by Norton and Barrera investigated the efficacy of a 12-week transdiagnostic CBT group treatment compared with a 12-week well-established diagnosis-specific group CBT treatment for panic disorder, social anxiety disorder, and GAD. Participants (n=46) with the above disorders were randomized either to the transdiagnostic CBT group or the diagnosis-specific CBT group. Participants in the transdiagnostic CBT condition received treatment that deemphasized diagnostic labels and focused on challenging and confronting feared stimulation. It included psychoeducation, cognitive restructuring and exposure therapy. Participants in the diagnosis-specific CBT group received group CBT treatment specifically targeting individual diagnoses of panic disorder, social anxiety disorder and GAD. The results of this trial showed effects of transdiagnostic CBT at least as strong as those of diagnosis-specific CBT on most outcome measures. Researchers noted the shared clinical features and underlying processes among the anxiety disorders and suggested that a single transdiagnostic CBT applicable to more than one anxiety disorder may increase the adoption rate of evidence-based CBT by mental health practitioners. They concluded that the almost identical outcomes across transdiagnostic and diagnosis-specific groups provides preliminary evidence supporting the efficacy of

•

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transdiagnostic CBT in the treatment of social anxiety disorder, GAD and panic disorder, suggesting that transdiagnostic treatments may be extended to include other anxiety disorders (Norton et al., 2012). •

CBT is considered the cornerstone of treatment of adults with GAD with the goal of helping patients identify distressing/ dysfunctional beliefs and thought patterns with more rational and realistic views (Patel et al., 2013). Authors noted other nondrug therapies which can augment or replace CBT if it is not effective, e.g., relaxation training, worry exposure or exposure therapy, short-term psychodynamic psychotherapy.

•

Internet and computer-based CBT delivery formats continue to be developed in an effort to increase patient access to this type of therapy. One large meta-analysis studied the effects of 22 studies of computerized CBT models against a control condition for patients with the following disorders: major depression, panic disorder, social phobia or GAD. The mean effect size superiority for the four diagnostic groups (Hedges g) was 0.88 and specifically for GAD was 1.12 (2 studies; n=198) showing short- and long-term benefits, good patient adherence and satisfaction with computerized CBT despite decreased clinician contact (Andrews et al., 2010). Similarly, a randomized controlled trial of 8 week internet-delivered CBT (n=89) consisting of a self-help program based on CBT principles and applied relaxation along with therapist guidance revealed significant improvement compared with the control group on measures of worry, anxiety and depression at both the 1- and 3-year follow up (Paxling et al., 2011).

•

An exploratory study addressed the content of therapist emails in therapist-guided internet-based cognitive behavioural therapy (iCBT) for GAD (Paxling et al., 2013). Authors examined almost 500 e-mails from three therapists providing support to patients (n=44) diagnosed with GAD in a randomized controlled trial. Online text modules, e.g., applied relaxation, worry exposure, problem solving, and cognitive restructuring, communicated CBT strategies to the participants in order to reduce problems related to excessive worrying. Homework assignments were included and at the end of each week the patient responded by providing information about their progress and related problems. The therapist replied to the e-mail with feedback and answers to any patient questions. In this study, the therapist e-mails to patients were analyzed and therapist behaviors were coded as follows: deadline flexibility, task reinforcement, alliance bolstering, task prompting, psychoeducation, self-disclosure, self-efficacy shaping, and empathetic utterance. Investigators indicated that distinct therapist behaviour exists in online therapy. Lenience regarding deadlines was negatively associated with treatment outcome, and task reinforcement correlated with module completion and positive outcomes.

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•

Investigators suggested further studies with a larger sample size are needed along with studies addressing the impact of email support given in addition to traditional face-to-face therapy (Paxling et al., 2013).Bandelow et al. suggested that internet-based CBT should not be recommended for the treatment of GAD as trials have not compared it to traditional CBT in which the patient and therapist are in personal contact (Bandelow et al., 2013). A systematic review of 27 clinical trials (total n=2,373) evaluating both pharmacological (14 studies using various agents, i.e., antidepressants, anticonvulsants, buspirone, piperazine/azapirone anxiolytic or quetiapine) and psychotherapeutic interventions (13 studies – 12 studies using CBT in at least one study arm and one study comparing community treatment vs. modular psychotherapy) for GAD in adults aged 55 and over demonstrated that pooled treatment effects were similar for either type of intervention and that patients benefited from the active intervention when compared to waiting list, usual care or minimal contact conditions. These effects however, were lost for psychotherapeutic interventions when other active conditions were employed as comparators, i.e., discussion group, medical management, (Goncalves et al., 2011).

•

There are emerging new approaches in the cognitive behavioral treatment of GAD as it is a chronic condition that remains the least-successfully treated of the anxiety disorders, i.e., client returning to normative levels on key outcome measures. These concerns have led to the development of new treatments that expand CBT approaches in order to better target the function of worry and the nature of GAD (Roemer, 2007). One metaanalysis that focused specifically on the efficacy of CBT for pathological worry among clients with GAD showed that CBT is effective, with the largest treatment gains evidenced for younger adults and for those who underwent individual CBT treatment (Covin, 2007).

•

Stand-alone worry exposure therapy (WE) without further CBT interventions was evaluated in a randomized controlled study of 73 patients with GAD. Subjects were allocated to either WE or applied relaxation (AR) for 15 sessions. Results showed that patients in both groups exhibited distinct improvements on all primary and secondary measures where symptoms of anxiety, depression, excessive worrying, negative metacognitive appraisal of worrying and thought suppression were reduced. These treatment effects were stable at six month and one year follow-up (Hoyer et al., 2009).

•

A randomized clinical trial of elderly patients (n=134) examined the effect of CBT relative to enhanced usual care (EUC) conducted in a primary care setting. Patients who received EUC were telephoned biweekly during the first three months of the study by the same therapist to provide support,

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ensure patient safety and remind them to call staff if symptoms worsened. Findings showed that patients receiving CBT had greater improvement in worry severity, depressive symptoms, and general mental health than those receiving EUC. Mean change in GAD severity following CBT was meaningful but not significantly than following EUC (Stanley et al., 2008). •

A later study examined the psychometric properties of the Pittsburgh Sleep Quality Index (PSQI, a comprehensive selfreport measure of sleep quality and impairment, comparing the component scores of older adults (n=134) with GAD to those (n=82) without GAD (Bush et al, 2012). PSQI scores showed that participants with GAD experienced greater sleep difficulties than those without GAD. Researchers then used the PSQI as an outcome measure in a trial examining the response to CBT compared to enhanced usual care (EUC) in older adults (n=134) with principal or co-principal GAD. Participants were randomized to receive either CBT (consisting of 10 individual sessions including psychoeducation, motivational interviewing, relaxation training, cognitive restructuring, exposure, problem-solving skills training and behavioral sleep management) or EUC (consisting of biweekly telephone conversations with a therapist, focusing on safety monitoring and providing support). At posttreatment (3months) and over a 12 month interval, the Pittsburgh Sleep Quality Index (PSQI), a comprehensive self-report measure of sleep quality and impairment, was administered to each group. Participants who received CBT for anxiety experienced greater reductions (improvement) on scores of sleep quality, sleep latency and sleep disturbances than those who received enhanced usual care. Researchers noted that although CBT for anxiety alleviated some aspects of sleep difficulty over time, it did not improve improvement in sleep duration, daily functioning or use of sleep medications (Bush et al., 2013).

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Another study examined the effects of cognitive behavioral therapy delivered by telephone (CBT-T) to older adults diagnosed with a diagnosis of GAD, panic disorder, combined GAD and panic disorder, or anxiety disorder not otherwise specified (Brenes et al., 2012). Participants (n=60) were randomized to CBT-T or information-only comparison. CBT-T was comprised of telephone therapy sessions and a treatment workbook. After the participant received a workbook chapter addressing a specific topic, e.g., treatment rationale, relaxation techniques, problem-solving, behavioral activation and relapse prevention, a telephone therapy session was conducted during which the content of the chapter was reviewed and the participant could ask questions. Homework was reviewed and discussed along with recommendations by the therapist. Participants randomized to information-only received written information on anxiety disorders and a list of referral options.

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This study found that participants who received CBT demonstrated greater improvement in self-report and clinicianrated worry and anxiety symptoms than participants in information only. They also experienced greater reductions in insomnia and anxiety sensitivity. Follow-up data (6-months after treatment completion) indicated no significant differences in the reductions in anxiety sensitivity and insomnia between the two conditions, suggesting that a longer intervention or more intense follow-up may be needed. Researchers suggested that CBT-T may be useful in a stepped care to late-life anxiety as older adults often prefer psychotherapy to pharmacotherapy and many are unable to attend regular face-to-face therapy sessions. They also suggested that more follow-up sessions should be integrated into telephone treatment (Brenes et al., 2012). •

A clinical review of muscle tension in GAD evaluated 13 controlled studies and found that muscle relaxation therapy and CBT are the most effective treatments for GAD. The investigators indicated that the efficacy of muscle relaxation therapy for GAD lies primarily in its function of stressreduction and in helping to distract from excessive worry by focusing on the muscles. Authors suggested that other therapies using cognitive distraction should be developed and studied for the treatment of GAD and muscle tension (Pluess et al., 2009).

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Short-term psychodynamic psychotherapy and CBT were compared with regard to treatment outcome. Patients with GAD were randomly assigned to receive either CBT (n=29) or short-term psychotherapy (n=28) according to treatment manuals on a weekly basis for 30 weeks. Results showed both CBT and short-term psychodynamic psychotherapy yielded significant, large and stable improvements using the primary outcome measures symptoms of anxiety and depression. CBT was superior in secondary measures of trait anxiety, worry and depression. According to investigators, these findings remained stable at the 12-month follow-up. Researchers noted that outcomes in psychodynamic psychotherapy may be optimized by employing a stronger focus on the process of worrying as is the case in CBT (Salzer et al., 2010). Investigators also proposed the conceptualization of worry in psychodynamic psychotherapy as “a mechanism of defense that protects the subject from fantasies or feelings that are even more threatening than the contents of his or her worries” (Salzer et al., 2010, p.5; Salzer et al. 2011). Mindfulness-based therapy (MBT) was developed to help individuals counter experiential avoidance strategies by use of a mental state characterized by nonjudgmental awareness of present moment experiences using techniques derived from Buddhist meditation and traditional yoga practices (Hofmann et al., 2010). A meta-analytic review of 39 studies of 1,140

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patients was conducted on patients who received this treatment (including both mindfulness-based cognitive therapy and stress reduction) for a range of conditions, e.g., GAD, cancer, depression and other medical or psychiatric disorders. Overall findings showed that in patients with anxiety and mood disorders, MBT was associated with effect sizes of 0.97 and 0.95 (Hedge’s g) for improving anxiety and mood symptoms, respectively. Results from the 7 studies that evaluated anxiety disorders specifically, i.e., GAD, GAD comorbid with panic disorder or social anxiety disorder) significant treatment effects were found for reducing anxiety symptoms (Hedge’s g=0.97) and depressive symptoms (Hedge’s g=0.75) in those patients who demonstrated elevated level of depressive symptoms at pre-treatment (Hofmann et al., 2010). •

Pharmacology Treatments

In a later trial, participants aged 18 or older (n=93) with GAD were randomized to an 8-week program of manualized Mindfulness-Based Stress Reduction (MBSR) or to an attention control, Stress Management Education (SME) to compare the effects of the two treatments (Hoge et al., 2013). MBSR was comprised of group in class practices, e.g., breath-awareness, gentle Hatha yoga and Body-Scan exercises, which focused on present experience and treating the body gently. Participates were also instructed in daily home practice, e.g., presentfocused awareness while eating, bathing or cleaning. SME, which did not include any mindfulness components, was taught in a didactic format comprising both class and home activities, e.g., stress physiology, time management techniques, sleep physiology, nutrition and factors that buffer the impact of stress. Findings showed that both MBSR and SME led to significant reductions in anxiety symptoms as measured by the Hamilton Anxiety Scale (HAM-A). Anxiety symptoms as measured by the Clinical Global Impression of Severity and Improvement (CGI-S and CGI-I) the Beck Anxiety Inventory (BAI), and the pre- and –post-treatment Trier Social Stress Tests were significantly reduced in the MBSR group compared to the SME group. Researchers suggested that MBSR, which may result in increased resilience to stressful psychological challenges and reduce anxiety symptoms in patients with GAD, should be studied further in larger trials (Hoge et al., 2013).

In 2008, the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders-Revised were published to include treatment recommendations for GAD (Bandelow et al., 2008). The WFSBP Task Force rank-ordered clinical trials based on the quality of evidence for efficacy and risk/benefit assessment. Strong evidence of clinical efficacy in the treatment of GAD was found for first-line pharmacological treatments for GAD, i.e., SSRIs – escitalopram, paroxetine,

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sertraline; SNRIs – venlafaxine and duloxetine; and the calcium channel modulator – pregabalin. Second-line treatment options include buspirone (for augmentation), benzodiazepines, i.e., alprazolam and diazepam, and the antihistamine hydroxyzine. An atypical antipsychotic, i.e., quetiapine may be used as monotherapy in GAD and is reserved for treatment-refractory cases (Patel et al., 2013, Bandelow et al., 2012, Bandelow et al., 2013). Only when all other drugs or CBT have failed, benzodiazepines, i.e., diazepam and lorazepam, can be used for long-term treatment (Allgulander 2010; Bandelow et al., 2008, Bandelow et al., 2012). The WFSBP Guidelines ranked the tricyclic antidepressant (TCA) imipramine as a secondary drug of choice, despite its efficacy, due to the higher toxicity and adverse event burden. In addition, these guidelines cited strong evidence and recommended the benzodiazepines, alprazolam and diazepam, for treatmentresistant cases with no history of addiction and as adjuncts for immediate relief of anxiety during the initiation of other agents and for use in episodes of acute exacerbation. The WFSBP Guidelines also indicated that the antihistamine, hydroxyzine, is effective but has sedating properties. Lastly, these guidelines specified that in treatment-refractory GAD patients, augmentation of SSRI treatment with risperidone and olanzapine (SGAs) may be used (Allgulander 2010; Bandelow et al., 2008). An effect-size analysis of 21 double-blind placebo controlled trials of pharmacologic treatments for GAD showed that mean effect sizes (ES) by drug (or drug classes) were as follows: pregabalin (0.50); antihistamines (0.45); SNRIs (0.42); benzodiazepines (0.38); SSRIs (0.36) and azapirones (0.17) (Hidalgo et al., 2007). Moreover, all of these drugs precipitate response (50% improvement in symptom severity) in approximately two-thirds of patients and remission (a reduction in symptom severity clinical measurement scores to the normal range) in approximately one-half of the responders, or one-third of total patients (Collins et al., 2009; Hidalgo et al., 2007). An earlier published summary of all peer-reviewed meta-analyses and randomized placebo-controlled trials on the pharmacological treatment of GAD concluded that trials with escitalopram, paroxetine, sertraline and venlafaxine indicate that treatment with Selective Serotonin Reuptake Inhibitors (SSRIs) and Selective Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs) can be efficacious in the acute management of GAD. There was also some evidence for the efficacy of certain benzodiazepines, buspirone, imipramine, hydroxyzine and trifluoperazine (Baldwin, 2005). Similarly, The International Consensus Group on Anxiety and Depression recommends an SSRI, SNRI or non-sedating tricyclic antidepressant (TCA) as the first-line pharmacotherapy for the treatment of GAD (Rickels, 2006; Ballenger, 2001). The U.S. Food and Drug Administration (FDA) approved the following drugs in their respective classes for the treatment of ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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GAD: (1) azapirone anxiolytic – buspirone, (2) SNRIs – venlafaxine and duloxetine, (3) SSRIs – paroxetine and escitalopram, (4) benzodiazepines – diazepam, lorazepam and alprazolam, (5) first generation antipsychotic (FGA) – trifluoperazine, (6) antihistamine – hydroxyzine. Findings support pharmacological treatment for patients with GAD for at least six months and up to a year (Collins et al., 2009; Davidson 2009; Baldwin, 2005). In spite of some convincing efficacy data, the Psychopharmacologic Drugs Advisory Committee of the FDA voted against first-line treatment of GAD with quetiapine due to the potential metabolic consequences of maintenance treatment, the potential for extrapyramidal adverse events and the risk of sudden death due to ventricular arrhythmia (Allgulander, 2009). In 2010, The International Psychopharmacology Algorithm Project (IPAP) published a psychopharmacological treatment algorithm to be used for all patients in the treatment of GAD. It addresses the needs of patients who may achieve a good response, partial response, non-response or loss of previous response (Davidson et al., 2010). The IPAP consultants developing the algorithm indicated that once the diagnosis of GAD has been established, an evaluation for co-morbidities should be done at this point, and at every subsequent point of assessment throughout the course of treatment. This includes a careful evaluation for suicidality, insomnia, substance abuse, non-compliance, childbearing potential, elderly patient problems and cultural issues. They also recommended that that stabilization of co-morbid disorders should be attempted prior to treatment of GAD (Davidson et al., 2010). Proposed Treatment Steps: Several conditions, e.g., patient’s preference, severity of illness, co-morbidity, concomitant medical illnesses, substance use disorders, risk of suicide, history of prior treatments, cost issues and availability of types of treatment, may affect the development of the treatment plan (Bandelow et al., 2012). Information and support should be provided to individuals with GAD, their families and caregivers. The following summarizes important clinical information from the decision points and action steps conveyed in the IPAP review and treatment algorithm for GAD: (Davidson et al., 2010; IPAP GAD Algorithm Flowchart, 2009). •

Expert consensus indicates that an SSRI or SNRI monotherapy may be the initial choice of medication of a treatment-naive patient presenting with GAD. Other antidepressants, e.g., imipramine and trazodone, have shown efficacy, but are not recommended as first-line treatments due to poor tolerability and high risk of potential serious side effects.

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If rapid response is warranted, or insomnia is predominant symptom, a concomitant benzodiazepine may be used for a short period of time in patients with no history of substance abuse.

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Response time to antidepressant drug treatment in GAD is usually 4-12 weeks. A partial response should occur by the initial evaluation point after 4-6 weeks with adequate dosing.

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In cases where there is a good response after an adequate trial, medications should be continued for at least one year, in order to reduce the risk of relapse. Current state of knowledge permits the prescriber to increase dose, augment, switch or wait longer when there has been a partial response. A switching strategy should be considered where adequate drug trial has not elicited at least a 25% symptom improvement from baseline using a valid clinical measurement scale.  Augmenting agents: atypical antipsychotics (risperidone and olanzapine), benzodiazepines, antihistamine (hydroxyzine), buspirone or anticonvulsant agent, tiagabine (use with caution for patients with a history of seizure disorder or predisposition).  Switching to another antidepressant within the same class or to a different class e.g., SSRI to SNRI or SNRI to SSRI.  Psychotherapy may be added to the regimen. Insomnia must also be addressed when evaluating a partial response with the suggested use of hypnotic agents: nonbenzodiazepine GABAergic hypnotic drugs, benzodiazepines, trazodone or mirtazapine. A sedating antihistamine may be added. Patient should be counseled on possible lifestyle changes.

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If the patient has improved or achieves remission with these new drugs, continue treatment for one year.

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At this stage, if there is still a partial or non-response, the clinician must evaluate for the presence of a significant comorbid disorder. Recommended drugs are as follows:  Co-morbid depression – adequate dose of an antidepressant or augmentation with bupropion, buspirone, atypical antipsychotic, or the nutritional supplement, chromium picolinate. Severe depression may need ECT.  Co-morbid stable bipolar disorder – add mood stabilizer, anticonvulsant or atypical antipsychotic drug. May need laboratory monitoring.  Co-morbid panic disorder – add TCA or SSRI/SNRI or benzodiazepine.  Co-morbid social anxiety disorder – add benzodiazepine, serotonin-reuptake inhibitor (SRI), atypical antipsychotic, pregabalin or anticonvulsant agent, levetiracetam.  Co-morbid obsessive-compulsive disorder – add SSRI or clomipramine.  Co-morbid posttraumatic stress disorder – add SSRI, SNRI, atypical antipsychotic or sympatholytic drug,

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prazosin. If there is no co-morbid disorder, switch to another combination that includes SSRI, SNRI, noradrenergic and specific serotonergic antidepressant (NaSSa), or TCA or add a third drug of different class from the other two. Psychotherapy may be added to the regimen at this phase of treatment. Other important research findings on recommended drugs to treat GAD are summarized below: Benzodiazepines – Evidence-based reviews have demonstrated that benzodiazepines are an effective and rapid treatment for many patients with GAD (Baldwin, 2005; Mitte, 2005; Chessick, 2007). However, the benzodiazepines have limited efficacy in the treatment of GAD and co-morbid depression (Baldwin, 2005). Baldwin et al. concluded that treatment with benzodiazepines should be for a short-term duration (up to 4 weeks) in order to avoid the risk of physical dependence and withdrawal resulting from long-term usage. Other unwanted effects of benzodiazepines may include sedation, memory disruption and psychomotor impairment, with an associated increased risk of traffic accidents. Other safety concerns with the use of benzodiazepines in the elderly population have been noted due to the high incidence of falls, hip fracture, withdrawal difficulties and increased risk of cognitive impairment (Davidson et al., 2010; Collins et al., 2009: Pollack et al., 2009; Baldwin, 2005; Mitte, 2005). A recent study compared healthcare costs of patients with GAD who received treatment with a benzodiazepine adjunctive to antidepressants with costs of those who did not receive concomitant therapy. Researchers found that healthcare costs increased in patients following benzodiazepine treatment and noted that approximately half of the increase in costs was associated with known sequelae of long-term treatment with benzodiazepines, e.g., care associated with accidents (Berger et al., 2012). In a later study, Offidani et al. performed a systematic review and meta-analysis to analyze whether controlled comparisons support the current prescribing pattern favoring newer antidepressants (SSRIs, SNRIs) over benzodiazepines (Offidani et al., 2013). In one study comparing the efficacy of benzodiazepines to venlafaxine XR and placebo in patients with GAD (n=540), results showed no significant differences in response rates between groups. Discontinuations of treatment, due to adverse events, occurred more often in patients taking venlafaxine XR than in those treated with benzodiapepines. In another study, researchers evaluated the efficacy of treatment with lorazepam, paroxetine or placebo in patients with GAD (n=169) over four weeks. Results showed that both lorazepam and paroxetine treatments were effective in reducing anxiety-related psychiatric symptoms. Somatic features improved significantly only in those taking lorazepam. Researchers ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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noted serious and bothersome side effects of treatment with SSRIs, e.g., high rates of sexual dysfunction, weight gain, osteoporosis, hyponatremia, gastrointestinal bleeding and potential for drug interactions. Researchers suggested that the only potential advantage of SSRI versus benzodiazepines is the associated lower impairment in cognitive and psychomotor skills. They concluded that literature lends no support to the pattern favoring newer antidepressants over benzodiazepines in the treatment of anxiety disorders (Offidani et al., 2013). Azapirones – Two meta-analyses have shown that buspirone (an azapirone anxiolytic with partial agonist properties at 5-HT1A receptors) has comparable efficacy to benzodiazepines in the treatment of GAD and seems to be a suitable alternative for longterm treatment of the condition with side effects that are mild and non-serious (Baldwin, 2005; Mitte, 2005). Another meta-analytic review showed that buspirone appears to be useful in the treatment of GAD, particularly for those patients who had not been on a benzodiazepine, because it may be less effective than benzodiazepines. Also, these findings were inconclusive about buspirone’s long-term efficacy and its superiority to antidepressants, psychotherapy or kava (Chessick, 2007). Currently, buspirone is rarely used as monotherapy in GAD but is more frequently used as augmentation to first-line agents due to its slow onset of action, variable tolerability and overall lack of benefit against other co-morbid disorders (Davidson et al., 2010; Pollack, 2009). Selective Serotonin Reuptake Inhibitors (SSRIs) – Several SSRI antidepressant drugs are currently used in the treatment of GAD. Efficacy findings with the best levels of evidence support escitalopram, paroxetine-immediate release and sertraline. The IPAP consultants noted that of these three aforementioned agents, sertraline has the best safety data in pregnancy and lactation ( Davidson et al., 2010; Bandelow et al., 2008). Studies have been conducted to determine whether some of the SSRIs have more advantages than the others: •

A published review of research findings from paroxetine clinical trials (3 short-term and 1 long-term relapse study) showed that it is an effective short- and long-term treatment agent for GAD, demonstrating substantial patient improvement in family, social and work functionality, achieving remission, and in relapse prevention. Researchers note that paroxetine has demonstrated efficacy in depression and in several anxiety disorders (e.g., panic, OCD, social anxiety and PTSD) making it a favorable option to treat core symptoms of GAD along with disorders that are commonly co-morbid with it (Rickels, 2006).

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Study findings support the clinical efficacy of short-term treatment with sertraline, resulting in significant improvement in both psychic and somatic anxiety symptoms, including quality of life and work productivity (Allgulander, 2004). A study comparing the efficacy of sertraline and paroxetine in the treatment of GAD showed no difference in therapeutic efficacy or tolerability (Ball, 2005). Another study showed there were no differences in efficacy between escitalopram (10-20 mg./day) and paroxetine (20-50 mg./day) in the treatment of GAD. However, patients treated with paroxetine reported significantly more side effects (e.g., insomnia, constipation, sexual dysfunction, weight gain) than with escitalopram (Bielski, 2005). A randomized, single-blind trial comparing sertraline (50100mg./day) and buspirone (10-15 mg./day) in elderly patients (n=46) showed that they were both efficacious and well tolerated for the treatment of GAD in this population (Mokhber et al., 2010). GAD patients who were treatment responders were prescribed escitalopram for 24-76 weeks. Findings showed that escitalopram (20 mg./day) significantly reduced the risk of relapse in these patients – risk of relapse was 4.04 times higher in the placebo group (Allgulander, 2005).

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A randomized controlled study of 177 adults, aged 60 years and older, evaluated the use of escitalopram 10 to 20 mg./day against placebo during 12 weeks in the treatment of GAD. Researchers found a statistically significant difference in the mean cumulative response rate (i.e., decrease in anxiety symptoms and improvement in role functioning) for escitalopram (69%) compared with placebo (51%). Response rates were not significantly different when using an intention-to-treat (ITT) analysis. Further study is necessary to assess safety and efficacy compared to longer term treatment (Lenze et al., 2009).

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In a recent review of literature, Bandelow et al. reported the results of randomized trials including various treatments of GAD. They reported a number of controlled trials demonstrating the efficacy of the SSRIs escitalopram, paroxetine, and sertraline. Although SSRIs are generally well tolerated they noted adverse effects that may impair compliance and suggested that they should be taken in the morning to avoid nocturnal restlessness and insomnia at beginning of treatment (Bandelow et al., 2013).

Selective Serotonin and Norepinephrine Re-uptake Inhibitors (SNRIs) – Venlafaxine extended release (XR) was the first SNRI antidepressant to receive FDA approval for the treatment of GAD followed by duloxetine (Collins et al., 2009; Davidson 2009; ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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Baldwin, 2005). •

An open trial demonstrated equal efficacy and tolerability during 8 weeks in patients with GAD who received venlafaxine XR or paroxetine. Double-blind, placebocontrolled, comparison studies are needed to draw definitive conclusions (Kim, 2006).

•

A trial of duloxetine showed its superiority to placebo in the short-term management of GAD with its demonstrated efficacy, safety and tolerability leading to improvement in symptom severity and functioning. The adverse effects most frequently associated with duloxetine were nausea, dizziness and somnolence. Another study, which pooled data from two multi-center trials, evaluated the efficacy of duloxetine (60-120 mg./day) in patients with GAD and significant pain symptoms. It showed that the drug is effective in reducing anxiety symptoms, pain severity and in improving patient functioning (Rynn, 2007). Retrospectively derived pooled data from five studies reported efficacy of venlafaxine XR in patients with GAD who are age 65 and older, but there were findings of intolerance in frail elderly subjects (Davidson et al., 2010). Further post hoc analysis of previous duloxetine clinical trial data assessed painful physical symptoms in patients with GAD using two 9-10 week efficacy trials (n=840) and one relapse prevention trial (n=887) comprising both a 26week open-label treatment phase and a 26-week doubleblind, placebo-controlled treatment continuation phase. Findings showed that both short- and long-tern duloxetine treatments were associated with improvement in painful physical symptoms in GAD. Additionally, patients who responded to duloxetine treatment and subsequently discontinued treatment experienced a worsening of painful symptoms (Beesdo et al., 2009). Another large (n=668) clinical trial of adult patients treated with duloxetine compared to placebo (n=495) showed an almost 2:1 rate of substantial return to normative functioning and quality of life, i.e., global role functioning, subjective well-being and perceived health (Pollack et al., 2007). A non-inferiority comparison of duloxetine 60-mg./day and venlafaxine extended-release (XR) 75-227 mg./day for the treatment of adults with GAD pooled data from nearly identical 10-week, multicenter, randomized, placebocontrolled, double-blind studies. Non-inferiority trials are designed to analyze the amount of drug/placebo difference between two treatments. An independent expert consensus panel determined the statistical and clinical criteria for non-inferiority and clinical response (i.e., > 50% reduction in HAMA Rating Scale total score). Findings showed that duloxetine 60-120 mg./day met all of the criteria for non-

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inferiority and exhibited a similar safety and tolerability profile compared with venlafaxine XR 75-225 mg./day (Allgulander et al., 2008). A systematic review of studies in the use of duloxetine substantiated the drug’s effectiveness for anxiety disorders with or without concomitant major depression. Specifically, the GAD studies confirmed duloxetine’s short-term effectiveness, long-term efficacy, early response to treatment at first and second weeks of therapy and efficacy/tolerability in the elderly (Mancini et al., 2010). A recent review of literature reported the results of randomized trials demonstrating the efficacy of SNRIs (Bandelow et al., 2013). In all but one trial, venlafaxine was effective against GAD. Duloxetine was also found to be effective against GAD in controlled trials. Researchers cautioned that adverse effects, e.g., nausea, sleep problems, agitation, may impair compliance (Bandelow et al., 2013).

Tricyclics (TCAs) – In a 2003 Cochrane review of antidepressants used to treat GAD, Kapczynski et al. noted that the tricyclic antidepressant, imipramine, has been studied as early as 1988 for its comparative effectiveness against alprazolam, and in a later study (1993) compared to trazodone, diazepam and placebo. Published results of these early studies demonstrated that imipramine was effective in alleviating such symptoms as dysphoria, anticipatory negative thinking, apprehension and worry. This Cochrane meta-analytic review concluded that available evidence suggests that imipramine, venlafaxine and paroxetine are superior to placebo in treating GAD in adults. Sertraline had been shown to be superior to placebo in treating GAD in children and adolescents. This study was not able to assess the differences in efficacy between imipramine and venlafaxine, or venlafaxine and paroxetine, as there were no direct comparisons of these agents in this review. This review also noted findings suggesting that paroxetine and imipramine are similar in terms of efficacy and tolerability (Kapczinski, 2003). While imipramine is effective in the treatment of GAD, it is currently considered a second-line option due to its lower tolerability profile and potential lethality in overdose (Davidson et al., 2010; Bandelow et al., 2008). Noradrenergic and specific serotonergic antidepressant (NaSSA) – Findings from a trial of mirtazapine (fixed dose 30 mg. for 12 weeks) supported its efficacy and tolerability for the treatment of GAD. Further randomized placebo-controlled studies are needed to explore the utility of this agent in the treatment of anxiety disorders (Gambi, 2005). Mirtazapine may be considered to treat insomnia in patients with GAD who have had an otherwise good ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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response to SRI drugs (Davidson et al., 2010).

Antipsychotics – A published literature review on the efficacy of typical and atypical antipsychotics for primary and co-morbid anxiety symptoms or disorders noted that there is fair evidence that typical antipsychotics, especially trifluoperazine, were effective in the short-term treatment of GAD (Gao, 2006).Using annual data from the 1996-2007 National Ambulatory Medical Care Survey, a study reported that across this 12-year period, antipsychotic prescriptions in visits for anxiety disorders increased from 10.6% to 21.3% particularly among new patients (Comer et al., 2011). The investigators noted the availability of SGA drugs with improved anxiolytic prosperities and fewer short-term anticholinergic and extrapyramidal effects than first generation agents while offering less sedation have contributed to this trend. In addition, authors reported that “across drug classes, antipsychotic medications ranked near the top in off-label use, drug safety concerns and inadequate supporting evidence” (p. 1064, Comer et al., 2011). •

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Data from a small (N=30) open-label, flexible-dose study of adjunctive risperidone suggest that augmentation of an adequate dose of an SSRI, SNRI or benzodiazepine, with low-dose risperidone initiated at least eight weeks prior to the study, may be a useful option for patients with GAD, panic disorder and social anxiety disorder refractory to adequate initial pharmacotherapy. Results showed significant reduction in anxiety symptoms, and while two patients reported mild akathisia (one was persistent), no patients developed dystonias (Simon, 2006). Olanzapine, risperidone and quetiapine immediate-release (IR) have all been studied as adjunctive agents to antidepressants and/or anxiolytics in the treatment of refractory GAD with inconsistent results (Gao et al., 2009). However, quetiapine extended-release (XR) 150 mg./day monotherapy yielded consistent anxiolytic effects across three studies that were superior to placebo and as effective as paroxetine 20 mg./day and escitalopram 10 mg./day but with an earlier onset of action. Also, in a 52-week treatment of GAD, quetiapine-XR was superior to placebo in the prevention of anxiety relapses (Gao et al., 2009; Bandelow et al., 2008). One study investigated the efficacy of atypical antipsychotic monotherapy in mood disorders co-morbid with GAD. Patients (n=111) with bipolar disorder co-morbid with GAD (88%) or panic disorder (59%) were randomly assigned to receive risperidone 0.5 mg.-4 mg./day or placebo monotherapy for 8 weeks. Out of the 63 patients who completed the study, there were no statistically significant

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differences between risperidone or placebo on the primary outcome measure for anxiety or secondary outcome measures for panic depression, mania and disability (Gao et al., 2009). •

A more recent meta-analysis on the treatment of GAD with atypical antipsychotics (SGAs) suggests that existing data do not support their usage as augmentation therapy for refractory GAD. Five studies (n=912) demonstrated that SGA augmentation (using olanzapine, risperidone or quetiapine) did not demonstrate superiority against placebo for clinical response or remission and showed that these patients were 43% more likely to discontinue treatment. Conversely, four studies (n=1383) that examined quetiapine XR monotherapy (150 mg.) demonstrated that patients were 31% more likely to respond, and 44% more likely to achieve remission than the placebo group. In addition, patients in the quetiapine group were 30% more likely to leave the study before completion. Investigators stressed that while quetiapine monotherapy may be efficacious, issues with adverse effects and tolerability must be considered in clinical practice (Lalonde et al. 2011). In addition, two other systematic reviews on the use of SGAs for the treatment of refractory GAD emphasized the need for both larger and more rigorous clinical trials on safety and efficacy in order to recommend their usage (Samuel et al, 2010; Lorenz et al., 2010).

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With a lifetime prevalence of 6% in older patients, GAD is both undertreated and under investigated (Mezhebovsky et al., 2012). In a recent, large study, researchers evaluated the efficacy and tolerability of quetiapine XR monotherapy in older patients (n=450), aged 66 and greater) with GAD. Patients were randomized to quetiapine XR (50-300 mg/day) or placebo over a 9-week treatment period and a 2-week drug-discontinuation period. Treatment was initiated at 50 mg/day with dose adjustment made on the basis of efficacy and/or tolerability. Efficacy evaluations were based on the changes in the Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impressions-Severity of Illness (CGI-S), and the Montgomery Asberg Depression Rating Scale (MADRS). Results showed significantly reduced HAM-A scores at week 9 with quetiapine XR versus placebo. Significant improvements were also seen with quetiapine XR as early as week 1, suggesting the reduction of anxiety symptoms within a timeframe similar to benzodiazepines. In patient-reported outcomes, quetiapine XR was associated with significant improvements versus placebo. Researcher concluded that quetiapine XR monotherapy is an effective short-term treatment in older patients with GAD, improving anxiety symptoms, psychic and somatic symptoms, health-related

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quality of life, sleep quality and pain versus placebo (Mezhebovsky et al., 2013). •

A small study evaluated the feasibility of augmenting antidepressant treatment with quetiapine XR in patients with either a primary anxiety disorder or a mood disorder with co-morbid anxiety symptoms (Chen et al., 2012). Patients receiving treatment with an antidepressant, i.e., escitalopram, paroxetin, venlafaxine, duloxetine, and mirtazapine, were randomized to quetiapine (50-300 mg/day) or placebo for 8 weeks. Although efficacy evaluations based on changes in the HAM-A and CGI-S showed no significant differences between the quetiapine XR and placebo groups at 8 weeks, treatment with quetiapine XR as an adjunct to treatment with an antidepressant provided a short-term benefit at 4 weeks. Researchers cautioned that the results should be considered preliminary due to the small sample size, recommending further studies (Chen et al., 2012).

As noted in the Assessment section, GAD may be the most common anxiety disorder in the elderly. Clinicians should be aware of a FDA Alert that was issued notifying health care professionals that both conventional and atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis (FDA Alert 6/16/08). Non-benzodiazepine hypnotics – Zolpidem extended-release coadministered with escitalopram in patients insomnia and comorbid GAD was studied in a multicenter, double-blind, parallelgroup trial. Patients (n=383) received open-label escitalopram 10mg./day and were randomized to either adjunctive zolpidem extended-release 12.5 mg. or placebo. Findings showed that combination zolpidem and escitalopram improved all measures of sleep to a significantly greater degree than escitalopram and placebo. Improvements were also seen in many measures of daytime functioning and quality of life. Zolpidem extended-release did not significantly augment the anxiolytic effects of the escitalopram and there was no associated rebound upon withdrawal of therapy (Fava et al., 2009). Anticonvulsants – As noted earlier, the World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for the Pharmacological Treatment of Anxiety, Obsessive-Compulsive and Post-Traumatic Stress Disorders-Revised classify pregabalin as a first-line treatment for GAD. Conversely, the IPAP pharmacological algorithm consultants do not yet support the position of pregabalin due to a relative lack of clinical experience in use for treatment of GAD to date and a deficiency of data to establish ©2008-2014 Magellan Health, Inc. This document is the proprietary information of Magellan Health, Inc. and its affiliates.

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efficacy for co-morbid conditions (Davidson et al., 2009). While pregabalin is not indicated for treatment of GAD in the United States, it is indicated for this use in Europe (Pollack, 2009). • A study compared pregabalin (300 mg./day, 450 mg./day and 600 mg./day) to alprazolam 1.5 mg./day and placebo. The pregabalin treatment was associated with significant end-point improvement on the Hamilton Anxiety Rating Scale (HAM-A), which was comparable to alprazolam at all three doses at the end of four weeks of treatment and two follow-up visits during drug discontinuation (Rickels, 2005). • A recent literature review of the evidence on the role of anticonvulsant drugs in the treatment of anxiety disorders showed that the strongest evidence (level 1 – meta-analysis and replicated randomized controlled trials) was for pregabalin in GAD with or without co-morbidity (Mula, 2007). •

Pooled data were analyzed from six double-blind, placebocontrolled trials where response to treatment for GAD was evaluated for three fixed-dose pregabalin groups (150, 300450, 600 mg./day) and for a benzodiazepine group. In the high-insomnia subgroup, the anxiolytic efficacy of pregabalin 300-600 mg. was comparable with alprazolam/lorazepam. Whereas the 150 mg. dose of pregabalin was associated with improvement in anxiety measurement scores, it did not have a significant effect on insomnia symptoms (Montgomery et al., 2009).

•

Another pooled analysis of the same six trials (above) examined the efficacy of pregabalin in depressive symptoms associated with GAD through a post-hoc analysis of the existing clinical trial database. Findings showed that in patients with GAD, pregabalin reduced associated symptoms of depression in the 150, 300-450 and 600 mg./day groups where pregabalin 300-450 mg./day dosage demonstrated the most beneficial response (Stein, Baldwin et al., 2009). A more recent meta-analysis examined 7 trials of GAD patients (n=1,352) using pregabalin compared to placebo and calculated an overall effect size of 0.364 (Hedge’s g), an effect size of 0.349 on psychic anxiety symptoms, and 0.239 on somatic anxiety symptoms. Investigators concluded that while pregabalin is an effective treatment for GAD, they also noted these effect sizes are smaller than earlier studies even though their findings were based on participants taking the largest doses of the drug during the clinical trial (Boschen 2011). A recent review summarized the results of clinical trials and pooled analyses providing data on pregabalin’s effect on sleep disturbance in patients with GAD (Holsboer-Trachsler and Prieto, 2013). Sleep disturbance, i.e., difficulty falling or

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staying asleep, or restless, unsatisfying sleep, is a symptom of GAD in DSM-5. Hiksbier-Trachsler and Prieto noted that insomnia, associated with impairment in both functioning and quality of life, is an important target for effective treatment of GAD. A review of the results of seven randomized controlled trials found that treatment with pregabalin is associated with improvement in sleep among patients with GAD as well as improved functioning and quality of life. Adverse events were mild to moderate and limited to the first 2-3 weeks of treatment. One of these, sedation, occurs in some patients but the incidence is lower compared to benzodiazepines. Authors concluded that pregabalin is a treatment option for patients with GAD who present with insomnia (Holsboer-Trachsler and Prieto, 2013). Tiagabine is a selective gamma-aminobutyric acid (GABA) reuptake inhibitor that increases synaptic GABA availability. Study conclusions were mixed. While tiagabine demonstrated efficacy in one randomized controlled trial, it did not show benefit in subsequent combined analysis of three additional trials (Davidson et al., 2010; Pollack, 2009).

Novel Agents - Antidepressants may have many shortcomings in the treatment of anxiety states in that they do not work quickly, may have significant side effects, e.g., nausea, agitation, sexual dysfunction, and may be associated with distressing symptoms upon discontinuation. Therefore, the search for novel pharmacological agents for GAD continues (Starcevic, 2007). Riluzole, a presynaptic glutamate release inhibitor used in the treatment of amyotrophic lateral sclerosis (ALS), has demonstrated very promising results in reducing symptoms of anxiety in GAD patients in a recent clinical trial. An 8-week, open-label, fixed-dose trial of riluzole in 18 outpatients with GAD resulted in a significant reduction in anxiety symptoms where 67% of patients responded and 44% entered remission by the end of the study (Pollack, 2009; Gao et al., 2009). Another novel agent, the corticotropin-releasing factor receptor-1 antagonist (CRF), pexacerfont (100mg./day) was studied in patients (n=294) with GAD (after receiving a one week loading dose of 300 mg./day) in a randomized trial comparing it to placebo or escitalopram (20 mg./day) in a 2:2:1 ratio, i.e., a halfpowered comparator arm. Response rates for pexacerfont, placebo and escitalopram were 42, 42, and 53% respectively, leading researchers to conclude that the novel agent did not demonstrate anxiolytic properties (Coric et al., 2010). The novel antidepressant, agomelatine, which has both a serotonergic and a melatonergic mechanism of action (Stein, 2012), has been considered to be a promising option for treatmentresistant GAD. Authors reviewed two studies that investigated the efficacy of agomelatine in the treatment of GAD. In a 12-week, randomized, controlled trial examining the efficacy of agomelatine

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in patients (n=121) with GAD, researchers found that in a 12-week treatment period, agomelatine demonstrated higher rates of response and anxiety remission than placebo. Another trial evaluating the efficacy of agomelatine in preventing relapses in patients with GAD over six months, found that patients randomized to continue agomelatine after week 16 showed a lower incidence of relapse at the endpoint than the placebo group (Levitan et al., 2012). A more recent literature search and review noted that although preliminary data indicate agomelatine as a promising option for both acute and long-term treatment of GAD, caution is needed when prescribing and using it in patients with psychiatric or medical co-morbidities, due to potential interactions with a number of compounds. They suggest studies are needed, especially in special populations such as elderly patient with GAD (Buoli et al., 2014). Complementary and Alternative Medicine (CAM) – At the present time, Piper methysticum (kava), has been the most widely used and studied herbal medicine for the treatment of GAD and other anxiety disorders. Reported meta-analytic findings of 11 randomized controlled trials of kava monopreparations (60-280 mg.) demonstrated significant anxiolytic activity compared to placebo in all but one trial (Sarris et al., 2009). Kava is currently restricted from use in the United Kingdom, Canada and the European Union due to concerns about hepatoxicity reported in some 93 cases resulting in the call for removing kava from overthe-counter public use to prescription only (Sarris et al., 2009). • The first randomized, double-blind, placebo-controlled efficacy and tolerability trial of Matricaria recutita (Chamomile extract) was conducted using 57 outpatients with mild to moderate GAD where 28 patients received chamomile and 29 patients received placebo. Chamomile (220 mg) or placebo therapy was initiated daily at week 1 and increased to 2 tablets daily during the second week. Patients with a 50% reduction or less in HAM-A scores from baseline were increased 1 tablet each week up to week 5 if they still continued to have a 50% reduction or less in symptom improvement (up to 5 capsules daily during week 5-8 of therapy). Results showed that patients had a significantly greater reduction in mean total HAM-A scores with chamomile versus placebo treatment (Amsterdam et al., 2009). •

A more recent comprehensive review of plant-based medicines assessed in human clinical trials revealed evidence for anxiolytic effects for 21 plants (Sarris et al., 2013). This review reported evidence supporting the use of the following plant-based anxiolytics: piper methysticum (kava), matricaria recutita (chamomile), ginkgo biloba, scutellaria lateriflora (skullcap), silybum marianum (milk thistle), passiflora incarnata (passionflower), withania somniferum (ashwaghanda), galphimia glauca (galphimia),

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centella asiatica (gotu cola), rhodiola rosea (roseroot), echinacea spp (purple cone flower), melissa officinalis (lemon balm), and echium amoenum (Iranian borage). In one 15-week, controlled, double blind randomized trial, patients (n=191) with GAD were randomized to one of the following treatments: 1) 2-4 capsules of dried galphimia (350 or 700 mg/day) or 2) lorazepam in capsule form (1 -2 mg). Anxiety scores on Hamilton Anxiety Scale were significantly reduced for galphimia treatment compared with lorazepam over the course of the 15 week period. Authors cautioned that some anxiolytic plants may have mild adverse effects, e.g., digestive disturbance, headaches and skin reactions. Serious adverse effects may include liver toxicity associated with kava (Sarris et al., 2013). Combined Treatments

Both the Canadian Psychiatric Association Clinical Practice Guidelines on the Management of Anxiety Disorders (2006) and The International Psychopharmacology Algorithm Project (IPAP) report and psychopharmacological treatment algorithm indicated that there is no current evidence to support the routine combination of CBT and pharmacology in the treatment of GAD. Pharmacological or psychological treatments have broadly similar efficacy in the acute treatment of GAD, but the comparative efficacy of combined drug and psychological approaches for a long-term period is not established. Both the IPAP report/algorithm and the Canadian Guideline recommend that as in other anxiety disorders, when patients with GAD do not benefit from CBT or have a limited response, a trial of pharmacotherapy is advisable. Similarly, patients who show limited benefit from pharmacotherapy may benefit from CBT. The Canadian Guideline also emphasizes that studies are required to evaluate whether CBT reduces the rate of relapse when pharmacologic treatment is discontinued (Davidson et al., 2009; IPAP GAD Algorithm Flowchart, 2009; Canadian Psychiatric Association, 2006). A later study assessed the efficacy of combined treatment including CBT and venlafaxine XR in patients with GAD. Patients (n=117) were randomly offered or not offered an option of adding CBT (12-weeks) in addition to venlafaxine XR (Crits-Christoph et al., 2011). Only one-third of those offered CBT chose to receive the therapy including techniques such as applied relaxation/selfcontrol desensitization; training in self monitoring of environmental, somatic, affective, imaginal and thought cues; slowed diaphragmatic breathing; and development of coping selfstatement to respond to cues. Results of the study showed no evidence of additional benefit for the combined CBT and venlafaxine XR compared to venlafaxine XR alone in treating patients with GAD (Crits-Christoph et al., 2011). An area of emerging interest and research is the sequential treatment of pharmacotherapy and CBT as a two-staged intensive

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approach to the treatment of anxiety disorders and mood disorders (Pull, 2007). In reviewing published studies of sequential use of pharmacotherapy and psychotherapy in mood and anxiety disorders, Fava et al. noted that available studies on anxiety disorders (panic disorder and obsessive-compulsive disorder) do not substantiate long-term benefits from the sequential combination of pharmacotherapy and psychotherapy as was demonstrated for recurrent unipolar depression (Fava, 2005). Since the sequential approach has not yet been applied to GAD, social phobia and post-traumatic stress disorder, Fava suggests the need for such research in the treatment of these conditions. • A trial evaluated the specific effectiveness of CBT combined with medication tapering, i.e., benzodiazepine discontinuation, among GAD patients compared to GAD patients receiving nonspecific psychological therapy with medication tapering. Those patients receiving CBT had a markedly better benzodiazepine cessation rate (75% to 37%), with this group’s discontinuation rate being twice as high. The number of patients who no longer met GAD criteria was also greater in the CBT group. The addition of specific CBT components targeting manifestations of the disorder, apprehension related to ending medication, and behavioral and cognitive factors involved in the maintenance of excessive worry may facilitate benzodiazepine cessation among patients suffering from GAD (Gosselin, 2006). •

A large randomized controlled trial (n=1004) of adults being treated in 17 primary care clinics for anxiety disorders (panic, generalized anxiety, social anxiety, and posttraumatic stress disorder) were treated with Coordinated Anxiety Learning and Management (CALM) or usual care (UC) for three to 12 months. Usual care consisted of treatment by a patient’s physician with limited familiarity with evidenced-based psychotherapy, or referral to a mental health specialist. The CALM intervention was designed to allow patient choice of CBT, medication or both; it also included real-time web-based outcomes monitoring to optimize treatment decisions and care management to promote medication adherence. Investigators reported that CALM compared with UC resulted in greater improvement in anxiety symptoms, depression symptoms, functional disability and quality of care during the 18 months of follow-up (Roy-Byrne et al, 2010).

•

A recent study examined sequenced treatment with escitalopram and CBT to learn whether this treatment boosts acute response and prevents relapse in adults aged 60 and older with GAD (Wetherell et al., 2013). Participants with GAD (n=73) were treated with escitalopram over 12 weeks followed by randomization to one of four conditions: 1) 16 weeks of escitalopram (10-20 mg/day) combined with 16 sessions of CBT followed by 28 weeks of maintenance escitalopram, 2) 16 weeks of escitalopram (10-20 mg/day) alone followed by 28 weeks of maintenance escitalopram, 3) 16 weeks of

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escitalopram (10-20 mg/day) combined with 16 sessions of CBT followed by 28 weeks of pill placebo, or 4)16 weeks of escitalopram (10-20 mg/day) alone followed by 28 weeks of pill placebo. This study showed that a sequence of escitalopram followed by augmentation with CBT resulted in greater improvement in pathological worry as measured by the Penn State Worry Questionnaire than those on escitalopram alone. However, escitalopram followed by augmentation with CBT did not lead to higher rates of response on a measure of anxiety symptoms. Participants receiving maintenance escitalopram had a significantly lower relapse rate than those receiving placebo. In addition, among participants taking maintenance placebo, those who received escitalopram augmented with CBT had lower rates of relapse than those who had escitalopram without CBT. Researchers concluded that antidepressant medication augmented with CBT reduces pathological worrying and relapse risk in older patients with GAD, even when antidepressant treatment is stopped after augmentation. They suggested that for older patients who prefer to discontinue antidepressants, CBT could be an option. Further they noted that CBT could be an alternative to augmentation with antipsychotic medications which are increasingly used in treating anxiety disorders (Wetherell et al., 2013). Monitor Progress and Address Sub-optimal Recovery

1. Psychiatric Co-morbidity and Recovery/Recurrence – Findings from a 12-year prospective study that examined the long-term course of GAD showed that it is a chronic anxiety disorder with low probability (0.58) of achieving recovery. After 12 years, 42% of GAD patients remained in their intake episode. Of those who did recover, nearly one-half subsequently had a recurrence. Researchers noted that these results are clearly inconsistent with earlier assumptions, reflected in the DSM-III criteria, that GAD is a residual and innocuous condition that usually does not lead to significant impairment. Rather, the long-term course appears to be chronic in nature, with more recent studies showing significant impairment across multiple domains. For those patients suffering with major depressive disorder co-morbid with anxiety disorder, the likelihood of recovering from the depression is reduced (Bruce, 2005). 2. Pharmacology and Relapse – One of the main problems with the pharmacotherapy of anxiety states is a high rate of relapse upon discontinuation of the medication. Strategies have been proposed to improve this situation – longer pharmacological treatment in order for remission to occur (Starcevic, 2007). Also, there is evidence to suggest that early lack of improvement (at weeks 1 and 2) on a drug may be a strong negative predictor of improvement at the 8th week. These findings were demonstrated for all three agents in a comparative trial of placebo, diazepam and a serotonin

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receptor (5HT-1A) partial agonist (Rynn, 2006). (N.B. Refer to previous discussion of the WFSBP Guidelines on page 9 and summarization of the IPAP psychopharmacological treatment algorithm on page 10,11 for strategies to manage treatment resistance and more recent meta-analysis findings on SGA augmentation efficacy for refractory GAD on page 15). 3. Standard Tools to Assess Response – The Canadian Psychiatric Association’s Clinical Practice Guidelines on the Management of Anxiety Disorders (2006) notes that the 14-item Hamilton Anxiety Rating Scale (HARS) can be used by clinicians to assess GAD illness severity and response to therapy. Self-rated tools may also be appropriate for GAD, such as the Penn State Worry Questionnaire and the Generalized Anxiety Disorder Questionnaire-IV. The Canadian guideline also notes that response to clinical trials of pharmacotherapy is often defined as a Clinical Global Improvement (CGI) score of < 2 (very much or much improved) or a 50% reduction in the HARS score. Remission is usually defined as a HARS score < 7 (no or minimal anxiety), and full recovery in GAD should be defined as no longer meeting the diagnostic criteria for the disorder (symptom resolution), as well as a return to pre-morbid functioning in all aspects of life (Canadian Psychiatric Association Guideline, 2006).

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Curr Psychiatry Rep (2015) 17:531 DOI 10.1007/s11920-014-0531-3

ANXIETY DISORDERS (A PELISSOLO, SECTION EDITOR)

The Role of Emotion and Emotion Regulation in Social Anxiety Disorder Hooria Jazaieri & Amanda S. Morrison & Philippe R. Goldin & James J. Gross

# Springer Science+Business Media New York 2014

Abstract Many psychiatric disorders involve problematic patterns of emotional reactivity and regulation. In this review, we consider recent findings regarding emotion and emotion regulation in the context of social anxiety disorder (SAD). We first describe key features of SAD which suggest altered emotional and self-related processing difficulties. Next, we lay the conceptual foundation for a discussion of emotion and emotion regulation and present a common framework for understanding emotion regulation, the process model of emotion regulation. Using the process model, we evaluate the recent empirical literature spanning self-report, observational, behavioral, and physiological methods across five specific families of emotion regulation processes—situation selection, situation modification, attentional deployment, cognitive change, and response modulation. Next, we examine the empirical evidence behind two psychosocial interventions for SAD: cognitive behavioral therapy (CBT) and mindfulnessbased stress reduction (MBSR). Throughout, we present suggestions for future directions in the continued examination of emotion and emotion regulation in SAD.

Keywords Emotion . Emotion regulation . Emotion dysregulation . Process model . Social anxiety disorder (SAD) This article is part of the Topical Collection on Anxiety Disorders H. Jazaieri (*) Department of Psychology, Institute of Personality and Social Research, University of California, Berkeley, 4152 Tolman Hall, Berkeley, CA 94720-1650, USA e-mail: [email protected] A. S. Morrison : J. J. Gross Department of Psychology, Stanford University, Stanford, CA, USA P. R. Goldin Betty Irene Moore School of Nursing Science, University of California, Davis, Sacramento, CA, USA

Introduction Social anxiety disorder (SAD) is associated with severe impairments in nearly every realm of the patient’s life [1], making it the fifth most disabling psychiatric disorder [2]. Although prevalent [3] and chronic [4], SAD is often undertreated [5]. Current estimates suggest that as many as 80 % of individuals meeting diagnostic criteria for SAD will receive no treatment over the course of their lifetimes, while those who eventually pursue treatment do so in their late 20s, which is typically more than a decade after symptom onset [6]. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; pp. 202–203), a diagnosis of SAD is warranted when the following key features are present: a marked and persistent fear of social and performance situations (criterion A); the individual fears that behaviors or anxiety symptoms will be negatively evaluated by others (criterion B); social situations almost always provoke fear or anxiety within the individual (criterion C); feared situations are avoided and, when not avoided, endured with intense fear or anxiety (criterion D); the fear or anxiety experienced by the individual is out of proportion to the actual threat posed by the social situation (criterion E); the fear, anxiety, or avoidance is persistent—lasting for 6 months or longer (criterion F); and the fear, anxiety, or avoidance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning (criterion G) [7]. Many have posited that SAD involves emotion dysregulation or difficulties with emotion regulation [8, 9]. The diagnostic criteria for SAD suggest altered emotional and selfrelated processing difficulties; however, the DSM criteria for SAD do not specifically point to regulatory difficulties. Only recently has clinical research focused on emotion and emotion regulation in SAD and how treatments can facilitate adaptive emotion regulation efforts.

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In this review, we first provide a conceptual and theoretical foundation for examining emotion and emotion regulation, introducing the process model of emotion regulation, which we utilize as a framework for understanding the occurrence of emotion dysregulation in SAD. We then evaluate two psychosocial interventions, which are designed to promote adaptive emotion regulation. Throughout, we highlight studies that use a variety of measures, including patient self-reports, observational/behavioral data, and physiological indices. Where possible, we also highlight areas for continued research.

Emotion and Emotion Regulation One of the most difficult questions facing the field of affective science is defining exactly what an emotion is and what it is not [10••]. Emotions are one type of affective response among many, including moods and stress responses [11]. They are briefer than moods and include a broader set of responses than are typically included within stress responses. There are several core features of emotions that are worth noting [12]. First, emotions include situational antecedents or an internal or external activating event. Second, emotions require conscious or preconscious attention to the activating event. Third, there is implicit or explicit subjective appraisal of whether an emotion is useful (or not) in achieving the present goal(s). Fourth, emotions unfold over time and promote relevant action urges, physiological activation (central and peripheral), and, in some cases, expressive behaviors. Emotion regulation refers to efforts made to influence the particular emotions one has, when one has them, and how these emotions are (or, in some cases, are not) experienced and/or expressed [13]. In contrast, emotion dysregulation is conceptualized as a state in which despite one’s best efforts, emotion-regulatory attempts fail to achieve emotion-related goal(s), and the person is unable to make the necessary corrections to achieve the emotion-related goal(s) [12]. Emotion dysregulation has been closely tied to psychopathology, especially mood and anxiety disorders [14]. Three core features of emotion regulation are important to note [12]. First, although theories and research tend to emphasize downregulation of negative emotions, positive emotion regulation, that is, influencing the intensity and/or duration of positive emotions, is also relevant to consider. Second, emotion regulation can be a conscious, intentional, effortful process or it can be a process that occurs without conscious awareness. Third, emotion-regulatory processes must be evaluated within their specific contexts and in light of one’s regulatory goal(s) to determine whether they are “adaptive” or “maladaptive.” Emotion-regulatory processes can be organized into groups based on when they have their primary impact on the emotion-

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generative process [15]. The most common framework for understanding emotion regulation is the process model of emotion regulation (see Fig. 1), which includes five specific families of emotion regulation processes—situation selection, situation modification, attentional deployment, cognitive change, and response modulation. Situation selection refers to efforts made to influence emotion by either increasing or decreasing the likelihood of encountering a given situation where particular emotions are likely elicited. Situation modification refers to efforts made to alter one’s emotions by changing external, physical features in the environment. Attentional deployment refers to efforts made to alter one’s emotions by directing one’s attention in a particular way in a given situation. Cognitive change refers to efforts made to alter one’s emotions by modifying the subjective meaning of the situation. Lastly, response modulation refers to efforts made to alter physiological, experiential, or behavioral responses in a situation. Table 1 depicts a “maladaptive” and “adaptive” example of each of these five strategies. It bears emphasizing that emotion-regulatory strategies are neither “adaptive” nor “maladaptive” but must be considered within the context and goal(s) operative in a given situation [16]. A recent meta-analysis highlighted considerable variation both between and within families of emotion regulation processes [17••]. Relatedly, although much less is known about this empirically, presumably in most situations, individuals are using multiple strategies in a single situation, either in sequence or simultaneously. Research suggests that being able to apply a variety of emotion-regulatory strategies in a flexible manner is what constitutes “adaptive” emotion regulation and promotes health and well-being [18, 19••].

Emotion and Emotion Regulation in SAD Emotion regulation difficulties in SAD have been documented on both intra- and interpersonal levels. Individuals with SAD exhibit a limited repertoire of strategies and are thought to have deficits that are relevant to specific aspects of SAD [20]. However, some researchers have suggested a more general disturbance in emotion-regulatory neural circuits in SAD [21]. In the sections that follow, we use the process model of emotion regulation [15] as a framework for understanding emotion dysregulation in SAD. Situation Selection Situation selection refers to the decision to approach or avoid a specific context that may generate unwanted emotional responses. In SAD, situation selection involves the avoidance of feared social and performance situations. Often, patients predict that future situations and related emotional responses will be negative. Compared to those without SAD, patients

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Fig. 1 The process model of emotion regulation. Reprinted with permission from Guilford Press

interpret social situations as being more threatening and arrive at more catastrophic conclusions [8]. These distorted interpretations lead to avoidance of social and performance situations. One study that examined memories of autobiographical social situations in patients with SAD and healthy controls found that patients demonstrated greater avoidance of present situations that resemble situations they have encountered in the past [22]. When compared to healthy controls, patients with SAD self-report greater use of situation selection when recalling past social anxiety-evoking situations [23]. Research suggests that social isolation and limited approach behavior, particularly of activities or situations where positive emotions may be generated [24], are characteristic of SAD. Clinically, aside from rare circumstances where the patient is caught off guard by the situation or the potential consequences for avoiding the situation are very high (e.g., giving a presentation at work or risk getting fired), patients craft their daily lives to strategically select the situations they wish to avoid. Avoidance “works” because it creates immediate, shortterm relief from having to encounter the feared stimuli. Accordingly, patients judge the avoidance of the situation as a “success” since the situation and emotion (fear/anxiety) are avoided; yet the maladaptive avoidance behavioral pattern is reinforced. The utilization of situation selection not only avoids the feared environment, but it also avoids experiencing

the feared emotion of anxiety. Consequently, the patient does not have the opportunity to increase tolerance to the seemingly intolerable situation/emotion. Situation Modification Once a patient has entered a social or performance situation, situation modification can become operative. Situation modification refers to modifying the situation to influence which emotions will or will not occur. Maladaptive situation modification can take several forms in SAD, the most common of which is engaging in safety behaviors. These are covert or overt behaviors employed with the intention of reducing threatening emotional states and maintaining a sense of safety. Safety behaviors include a broad range of behaviors and are common in anxiety disorders more generally. There are a variety of subtypes of safety behaviors in SAD, for example, behaviors that involve avoidance or impression management [25] and attempts to reduce the likelihood of negative evaluation from others [8]. Cognitive models of SAD posit that safety behaviors contribute to the maintenance of anxiety and negative beliefs about social situations. A recent study showed that as concerns about “public exposure and scrutiny of negative self-attributes” increased, so did safety behaviors [26]. While safety behaviors may make situations less threatening or awkward for the patient, these behaviors can be problematic

Table 1 Maladaptive and adaptive emotion regulation in social anxiety disorder Situation selection Maladaptive ER Avoid going to the meeting in order to avoid feeling anxious during the meeting Adaptive ER

Situation modification Attentional deployment

Cognitive change

Response modulation

Enter the meeting Browse the Internet on one’s Use cognitive Inhibit and push away room and move a laptop/smartphone to reappraisal skills to one’s anxious thoughts, chair to the corner avoid engaging with others convince oneself feelings, and physical and sit away from before the meeting begins that this job does sensations others not matter Go to the meeting in order Enter the meeting Look at objects in the Use cognitive Inhibit the urge to act on to feel satisfaction for room, open a bottle meeting room—pictures reappraisal skills to the emotion of anger participating in one’s job of cold water, and on the walls, colors, and actively challenge when the manager start drinking to textures in environment to distorted, anxious starts the meeting cool down help feel more comfortable thoughts 15 min late, again before the meeting begins

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and perceived as unskillful. They can inadvertently increase anxiety and cause patients to appear less appealing to others, thus providing more “evidence” for the patient’s catastrophic beliefs and predictions [27, 28]. Situation modification or safety behaviors are valiant efforts to regulate uncomfortable emotions but are coupled with consequences that perpetuate affective disturbance. Encouragingly, research suggests that when instructed to reduce safety behaviors, patients with SAD perceived and actually received more positive responses in a social interaction then when not instructed to reduce safety behaviors [29]. Research has also demonstrated that patients instructed to eliminate the use of safety behaviors during cognitive behavioral therapy (CBT) had greater reductions in social anxiety symptoms following treatment compared to those who continued with safety behaviors [30]. Taken together, these findings suggest that when instructed, patients can reduce safety behaviors, resulting in both intra- and interpersonal benefits. Attentional Deployment Once in a social situation, an individual may direct attention in a particular way to influence emotions. There are many choices in terms of where an individual can place his or her attention—e.g., the immediate environment (social or nonsocial objects) versus the self (e.g., internal sensations). Meta-analyses indicate that biased attention toward threat is characteristic of anxiety disorders in general [31] and specific information processing biases have been documented in SAD [32]. For example, SAD has been associated with general (rather than specific) biases in emotion recognition [33], increased self-focused attention, and atypical self-referential processing [34]. The attentional bias to negative information observed in SAD has been implicated in enhancing maladaptive emotion regulation and may increase emotional vulnerability and potential for psychopathology [35]. Although attentional bias toward threat causally contributes to impaired emotion regulation in SAD, not all forms of attentional deployment in the context of threat are problematic. For example, in a laboratory induction of deliberate attentional avoidance of negative information, emotional responses to a speech stressor were adaptively regulated and socially anxious participants displayed beneficial behavioral consequences as a result during the speech performance [36]. By attending to non-threatening cues, reductions in self-reported, behavioral, and physiological measures of anxiety are possible [37]. This suggests selective attention to information can be an adaptive form of emotion regulation in some circumstances, at least in the short term. Difficulty disengaging attention from threatening aspects of a situation may maintain SAD [38]. However, it may be possible to retrain attentional bias from negative information in SAD [39], thereby reducing social anxiety symptoms [40, 41]. Furthermore, CBT is also

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beneficial for patients who are slower to disengage from negative stimuli [42]. The role of various forms of maladaptive and adaptive attentional deployment in SAD is an important area for continued research. Cognitive Change Cognitive change is one of the main targets of CBT for SAD [43]. It involves utilizing cognitive skills (e.g., perspective taking, reframing the meaning of thoughts and situations, challenging interpretations) to modify the meaning of stimuli that generate emotional reactions. Cognitive reappraisal is the most researched form of cognitive change and is largely considered to be an “adaptive” emotion-regulatory strategy. When employed appropriately, cognitive reappraisal can modify emotional reactions to anxiety-provoking situations and enhance psychological flexibility and emotional well-being [11]. On the other hand, difficulty employing reappraisal is considered a core mechanism in the maintenance of psychopathology in individuals with anxiety and mood disorders [44]. Compared to healthy adults, patients with SAD report being less skillful at using cognitive change strategies [23]. Neuroimaging studies have begun to elucidate specific brain circuit deficits during cognitive reappraisal in patients with SAD. Compared to healthy adults, patients with SAD have difficulty recruiting cognitive control prefrontal cortex (PFC) brain networks when reappraising reactivity to harsh facial expressions [45]. Specifically, there can be delayed recruitment of PFC regions and lesser inverse PFC-amygdala functional connectivity when reappraising negative selfbeliefs [46]. However, a recent study found that CBT can modify these deficits by increasing brain signal magnitude, timing, and functional connectivity of the PFC-amygdala during cognitive reappraisal [47]. These results suggest deficient cognitive reappraisal processes in SAD can be restored when appropriate training is employed [46, 45]. Current models suggest that self-focused appraisal can be a successful emotion regulation strategy for patients with SAD [48]. However, one recent study suggests that one’s beliefs about being negatively evaluated (rather than self-focused attention) produce changes in behavior that results in “poor social performance and subsequent rejection” [49]. Thus, examining the exact nature of the patient’s distorted beliefs (e.g., beliefs of being negatively evaluated rather than distorted self-focused beliefs more generally) may be a fruitful area of continued research. In another recent study utilizing a 2-week daily diary to examine emotions, social events, and emotion regulation in social anxiety, the use of cognitive reappraisal to reduce distress resulted in fewer negative social events on the following day for participants with lower social anxiety but did not influence the daily lives of participants with high social anxiety [50•]. This suggests that there may be

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important subgroups of indiviudals who will benefit from the use of cognitive reappraisal. Additionally, the timing of acquisition of reappraisal skills during CBT appears to be an important marker of treatment response [51•]. Additional research is needed to understand whether introducing reappraisal earlier in treatment can be beneficial for patients with SAD. A more fine-grained analysis of the type of belief and subsequent reappraisal, patient symptom severity, and the timing of reappraisal skill acquisition are areas for future research. Response Modulation After an emotion occurs, response modulation refers to strategies to modify one or more components of the emotional response (e.g., experience, behavior, physiology). One form of response modulation is expressive suppression, whereby the individual inhibits outward expressions of the emotion, such as facial behavior. Another form of response modulation is experiential avoidance, which involves altering, avoiding, or concealing anxious thoughts and feelings, and is common in patients with SAD [52]. When compared to healthy controls, patients with SAD report greater use of expressive suppression and less skill in employing response modulation in social situations [23]. Research suggests that patients with SAD engage in response modulation to both negative [53] and positive [54] emotions, perhaps due to the underlying fear of negative or positive evaluation. In experience sampling studies, patients with SAD report fewer positive experiences on days they reported engaging in more experiential avoidance [24]. Similarly, patients report fewer positive social events and less positive emotion on days following the use of greater positive emotion suppression [50•]. Non-acceptance of emotional responses has been associated with social interaction and social performance anxiety [20]. Suppression often leads to less warm and outgoing behavior, which may in turn elicit less friendly behaviors (even rejection) from others, which subsequently generates negative emotions [8]. However, the use of emotion suppression strategies during CBT is not a marker of treatment response in patients with SAD [51•] and CBT has been shown to be beneficial even for patients endorsing particularly high levels of experiential avoidance [55, 56].

Clinical Perspective The emphasis on emotions in psychological treatments is not a new idea [57, 58]. To date, many formal treatment programs and clinical interventions have been developed to address emotion dysregulation [59–65], and there is evidence for the usefulness of emotion regulation training in psychotherapy for

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SAD [21]. Here, we focus on two distinct psychosocial interventions for SAD: CBT and mindfulness-based stress reduction (MBSR).

Cognitive Behavioral Therapy Based on Aaron Beck’s pioneering work [66, 67], CBT utilizes cognitive and behavioral strategies to break the maladaptive cycle that exists among distorted thoughts, emotions, and behaviors. CBT includes training in cognitive restructuring of maladaptive beliefs (cognitive change) and behavioral strategies such as exposure to avoided situations (situation selection) and is an effective treatment for many types of psychological problems. To a lesser degree, CBT also works toward modifying maladaptive patterns of situation modification, attentional deployment [68], and response modulation emotion-regulatory strategies. CBT is the gold-standard intervention for SAD [43]. Emotion regulation strategies have been shown to predict, moderate, and mediate treatment response to CBT. This should inspire clinicians to consider matching treatments to people with different emotion regulation difficulties or to enhance the efficacy of existing treatments by capitalizing on the specific emotion regulation strategies that appear to show the largest and most consistent effects. While research has demonstrated that patients with SAD endorse more negative and fewer positive self-views and emotions when compared to healthy controls, CBT can modify this pattern. Moderator analyses show that CBT works quite well for patients who endorse lower psychological flexibility [55]. Mediator analyses have begun to identify specific mediators of the impact of CBT for SAD on social anxiety symptom reduction. A recent randomized controlled trial of CBT for SAD has shown that reductions of maladaptive interpersonal beliefs [69] as well as increases in cognitive reappraisal selfefficacy [70•] and positive self-views [71] during treatment mediate reductions in social anxiety symptoms. Importantly, increases in cognitive reappraisal self-efficacy [70•] and positive self-views [71] also predict reduction of social anxiety symptoms 1-year post-CBT. A more nuanced analysis examined weekly change across 16 sessions of individual CBT and found that weekly social anxiety decreases were associated with decreases in utilizing suppression and increases in using cognitive reappraisal successfully during treatment and that weekly increases in using cognitive reappraisal successfully predicted post-CBT reduction in social anxiety symptom severity [72]. Neurally, studies have shown that CBT reduces negative emotion experience and allows for greater and quicker recruitment of reappraisalrelated brain regions [47]. Furthermore, there is some evidence that CBT may be mediated by top-down regulation and decreased emotional reactivity [73].

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This growing body of literature on CBT for SAD is encouraging and yet there is still much to be done—for example, some initial research suggests that there may be an interesting relationship between the specific treatment phases of CBT (e.g., cognitive vs. cognitive+behavioral exposures) and the use of maladaptive versus adaptive emotion-regulatory strategies in patients with SAD [74]. A more detailed examination of phases of CBT and the interaction between maladaptive and adaptive emotion-regulatory strategies is warranted. Furthermore, as the field of psychology moves toward transdiagnostic treatments, continued research examining blends of adaptive components across existing interventions will be needed. Cognitive behavioral conceptualizations of SAD may benefit from integrating constructs aligned with alternative treatments. For example, researchers have begun to examine the role of trait mindfulness in CBT for SAD [75]. One study found that cognitive restructuring and mindfulness strategies together reduced post-event processing, a ruminative and anxiety-maintaining cognitive process common among individuals with SAD, and improved affect [76]. Others have begun to directly compare CBT to alternative mindfulnessbased treatments for SAD [56, 55]. Mindfulness-Based Stress Reduction MBSR was originally developed by Jon Kabat-Zinn, Ph.D., for adults suffering from chronic pain [MBSR; 77] and has since become a widely accepted and empirically supported intervention for many psychological and medical disorders [78]. In MBSR, individuals cultivate the mental quality of mindfulness—a non-judgmental, flexible, and presentmoment attentional focus. Through training and practice, the exercises taught in MBSR are thought to reduce the habitual tendency to automatically and compulsively engage in and react to mental states and external environments [79]. Several meta-analyses have shown that MBSR reliably decreases symptoms of stress, anxiety, and depression and increases well-being across clinical and non-clinical samples [80–82] and is associated with increased positive and decreased negative affective states [78, 83, 84]. MBSR yields symptom improvement in mixed samples of individuals with anxiety disorders [85], though only a few studies have targeted a specific anxiety disorder [86, 87], and even fewer have focused specifically on SAD. Mindfulness-based approaches and interventions for SAD improve mood, functionality, and quality of life and reductions in fear of negative evaluation [88, 89]. A recent study found that in patients with generalized SAD, MBSR decreased social anxiety and depressive symptoms, decreased perceived stress and loneliness, and increased self-esteem and satisfaction with life [90]. As noted above, in an effort to address treatment non-responders or those who will not participate in traditional treatments, researchers are increasingly interested in examining the role of

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trait mindfulness in patients with SAD and comparing mindfulness-based interventions to the current gold-standard treatment of CBT for SAD. Interestingly, in one trial of MBSR for SAD, patients did not achieve the rate of response on core symptoms of SAD when compared to group CBT, though MBSR was as efficacious as CBT in improving subjective well-being, mood, and overall functioning [91]. Neuroimaging data have begun to illuminate the neural mechanisms through which MBSR influences emotion regulation in SAD. Following MBSR, patients with SAD reported decreased negative emotion experience in addition to reduced amygdala activity and increased activity in attentional deployment brain regions [92]. These findings suggest that MBSR may reduce emotional reactivity and enhance emotion regulation in patients with SAD. Additionally, in a recent randomized controlled trial comparing MBSR to an aerobic exercise (AE) stress reduction program, MBSR resulted in greater reductions in negative emotions when patients were asked to engage in present-moment focused meta-cognitive attention regulation in the context of negative self-beliefs embedded in autobiographical, anxiety-provoking social situations. Interestingly, more meditation practice during MBSR was associated with greater decreases in negative emotion and social anxiety symptom severity, as well as increases in attentionrelated regions when implementing the attention regulation strategy [93]. This suggests that mindfulness meditation training may improve clinical symptoms and emotion reactivity through augmentation of meta-cognitive attention regulation ability in patients with SAD. In a related analysis [94], results indicated that during a self-referential processing experimental task, compared to AE, MBSR yielded greater reductions in self-endorsement of negative self-views which in turn was related to a reduction in social anxiety symptom severity. Neurally, the MBSR group displayed an increased attentionrelated posterior cingulate cortex/precuneus response. These findings suggest that MBSR may train adaptive self-referential processing in patients with SAD.

Conclusion From our review, it is apparent that emotion dysregulation exists in SAD. Without intervention, clinical symptoms and difficulties persist and significantly impact the individual’s life. Fortunately, treatments for SAD exist which include components that address difficulties with emotion regulation. Despite these interventions, treatment non-responders and those who are unable or unwilling to participate in traditional forms of treatment still exist. Future research must develop alternative interventions and refine existing interventions to improve the efficacy and acceptability of treatments for individuals with SAD. Given the emerging research we have

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reviewed, it appears that investigating the role of emotion and emotion dysregulation in SAD has much to offer in this area. Compliance with Ethics Guidelines Conflict of Interest Hooria Jazaieri, Amanda S. Morrison, Philippe R. Goldin, and James J. Gross declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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