Pediatr Drugs 2007; 9 (4): 227-237

Pediatr Drugs 2007; 9 (4): 227-237 1174-5878/07/0004-0227/$44.95/0

THERAPY IN PRACTICE

© 2007 Adis Data Information BV. All rights reserved.

Social Anxiety Disorder in Children and Adolescents Epidemiology, Diagnosis, and Treatment Sarosh Khalid-Khan, Maria-Paz Santibanez, Carolyn McMicken and Moira A. Rynn Department of Psychiatry, Mood and Anxiety Disorders Clinic, University of Pennsylvania, Philadelphia, Pennsylvania, USA

Contents Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 1. Definition and Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 2. Epidemiology, Course, and Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 3. Co-Morbidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 4. Diagnosis of Social Phobia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 4.1 Self-Report Instruments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229 4.2 Clinician-Administered Assessments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 5. Treatment of Pediatric Social Anxiety Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 5.1 Psychosocial Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 230 5.1.1 In Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232 5.2 Pharmacologic Treatments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.2.1 Selective Serotonin Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 233 5.2.2 Serotonin Norepinephrine Reuptake Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.3 Benzodiazepines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.4 Monoamine Oxidase Inhibitors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.5 Gabapentin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.6 Pregabalin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.7 Nefazodone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.8 Antidepressant Treatment and the Development of Suicidal Thinking/Behaviors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 234 5.2.9 Medication Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 6. Combined Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 235

Abstract

Social anxiety disorder (SOC) is characterized by marked and persistent fear of one or more social performance situations in which the person is exposed to unfamiliar people or to possible scrutiny. The person fears that she or he might act in a way that will be humiliating or embarrassing. Children and adolescents with this disorder often have great impairment in their academic performance, social skills, peer relationships, and family life. Early diagnosis is vital. Primary care providers are in a unique situation to first diagnose and treat SOC in children and adolescents. There is evidence of successful pharmacologic and psychosocial treatment in pediatric SOC. Serotonin reuptake inhibitors, which are considered first-line medications for SOC, have shown promising results in openlabel and double-blind trials. Studies have demonstrated that psychosocial treatments, specifically cognitivebehavioral therapy and group therapy, are efficacious in pediatric SOC. There is some evidence that the use of combination therapy, both pharmacology and psychosocial treatment, is beneficial in the management of pediatric SOC.

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Khalid-Khan et al.

Social anxiety disorder (SOC), also known as social phobia, is a relatively common and frequently debilitating condition in children, adolescents, and adults that develops early in life and often goes undiagnosed. Primary care providers are in a unique position to not only diagnose this condition but also to address the treatment needs of children and adolescents. This article focuses on the epidemiology, diagnosis, and treatment of SOC in childhood and adolescence in a general clinical setting. A search for relevant literature was conducted via PubMed using the following terms: ‘childhood,’ ‘social anxiety disorder,’ ‘treatments.’

or evaluative situations. Avoidant behavior may begin in childhood and become increasingly maladaptive through adolescence and early adulthood; however, the authors of the DSM-IV caution clinicians about applying an avoidant personality disorder diagnosis in children because avoidant behavior may be developmentally appropriate or disappear with age. In rare cases socially anxious children and adolescents may fail to speak in feared social situations, despite having normal verbal language abilities. This condition, known as selective mutism,[1] is often identified by the school and leads to academic and social impairment. 2. Epidemiology, Course, and Prognosis

1. Definition and Classification SOC, as defined by the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) [DSM-IV],[1] is characterized by the following: • marked and persistent fear about being subjected to embarrassment or humiliation in social situations such as public speaking, starting or holding conversations, eating in front of others, dating, playing sports, going to parties, or any other circumstance that may involve being scrutinized or evaluated by others; • when exposed to these situations, children and adolescents experience intense anxiety that interferes with their normal functioning; • the fears are excessive or unreasonable; • the child or adolescent avoids feared social or performance situations whenever possible, or endures them with intense distress; • the duration of illness is at least 6 months; • and the symptoms cannot be better explained by another condition. SOC has two subclassifications: generalized and non-generalized. Generalized SOC (GSOC) refers to individuals who experience anxiety and fear across most social situations. Non-generalized SOC involves specific social or performance situations only, such as fear of public speaking. GSOC tends to occur earlier in life and has a poorer prognosis.[2] Research suggests that a temperamental style with shyness, social inhibition, and avoidance behavior in childhood may be a risk factor for the later development of SOC.[3,4] A study by Chavira et al.[5] in which structured interviews were conducted showed that adults with shyness demonstrated a high prevalence of GSOC. Retrospective studies have found that adults with GSOC rate themselves as being shy and anxious as children. This supports the notion that shyness seems to exist on a SOC spectrum. GSOC also frequently overlaps with a diagnosis of avoidant personality disorder, another DSM-IV diagnosis that describes a more pervasive pattern of social inhibition and avoidance of social © 2007 Adis Data Information BV. All rights reserved.

SOC has been identified as one of the most prevalent mental illnesses, following substance abuse and depression.[4] Epidemiologic findings show that in the pediatric primary healthcare setting anxiety disorders are very common ranging from 1% to 10%[6-8] but are unrecognized and under-treated.[9,10] In community settings, rates of SOC in youth range from 0.5% to 4%[11,12] and from 3% to 6.8% in primary care settings.[7-9] Recent research suggests that lifetime prevalence rates in adolescents in the US and Germany are between 5% and 15%.[13,14] Although the age of onset is usually in the early teens with a mean age of onset of 15.5 years,[15] children as young as 8 years old have been diagnosed with the disorder.[16] Once developed, SOC tends to have a chronic course and does not remit without intervention. Specifically, children with this disorder may have few friends, limited involvement in outside activities, somatic symptoms, and difficulty attending school with associated academic under-achievement.[17] 3. Co-Morbidity Individuals with SOC are at a significant risk for co-morbidity.[18] A recent study[19] reported that the onset of SOC prior to age 15 years was associated with a higher risk of co-morbidity than development of SOC later in life. Most commonly these individuals will develop another anxiety disorder, such as panic disorder or agoraphobia,[18] major depressive disorder, and substance abuse. Studies[20] have shown that in children aged 7–13 years with SOC, 60% had an additional psychiatric diagnosis, of whom 36% had an anxiety disorder as follows: generalized anxiety disorder 10%; attention deficit hyperactivity disorder 10%; specific phobia 10%; and selective mutism 8%. Those individuals who develop comorbid disorders will also have an increased risk of suicidal ideation and suicide attempts.[18] The cost of inadequately treating SOC is significant. In addition to the development of co-morbid mental disorders such as depression and substance abuse, children and adolescents with this illness are at risk for educational or occupational under-achievement, and failure to achieve financial and emotional indepenPediatr Drugs 2007; 9 (4)

Child and Adolescent Social Anxiety Disorder

dence. The challenge of preventing the consequences of SOC lies in early diagnosis. 4. Diagnosis of Social Phobia Parents may bring the adolescent with SOC to the pediatrician usually with concern that the adolescent is increasingly avoiding social interactions with their peers and enduring them with great distress. This distress is often manifested in physical symptoms such as blushing, abdominal discomfort (‘butterflies’), palpitations, and/or trembling in social and performance situations. The adolescent may have a gradual deterioration in school grades due to a lack of participation in classroom activities and also may be avoiding engaging in activities previously considered to be enjoyable, such as sports. In more severe cases adolescents may refuse to go to school altogether, because of the discomfort caused by physical anxiety symptoms and the fear that everyone is scrutinizing and ridiculing them. In some cases, the adolescent may become very oppositional because of extreme anxiety and become physically aggressive when forced by caretakers to participate in activities or to go to school. In younger children, physical symptoms of anxiety at times of social interaction or the beginning of school can be a cue for exploration of further symptoms of SOC. In extreme cases, young children may have temper tantrums when required to be in a situation that is anxiety provoking, such as going to school, and this can lead to a chronic pattern of refusing to attend school. Another manifestation of childhood social anxiety is selective mutism, where the child will not talk in school and will only speak to family members at home. The diagnostic evaluation should entail a complete gathering of information through an interview of the child or adolescent and a separate interview with the parents/caregivers if time permits. Current symptoms (severity, duration, and functional impairment), psychiatric history, previous and current medical history, development milestones, family history and environment, school and social achievements, and relationships should be reviewed. Different triggers or stressors should also be identified. These stressors could be any change in life circumstances that places the socially anxious individual in a new situation; for example, the family moving, placing the youngster in a new neighborhood and new school and forcing him or her to make new friends while also dealing with the loss of old friends. The diagnostic evaluation should also include an assessment for different mood disorders to identify co-morbidity. The primary care physician tends often to be the first professional that parents confide in regarding their child’s behavior and development. Thus, general practitioners have an obligation to successfully screen for mental health problems in young people. If shyness is present and SOC is suspected, a self-rating instrument such as the Social Anxiety Scale for Adolescents (SAS-A) for © 2007 Adis Data Information BV. All rights reserved.

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adolescents aged 13–17 years and the Fear Survey Schedule for Children-Revised (FSSC-R) for individuals aged 8–18 years may be helpful to identify or clarify the presence of social anxiety symptoms. An instrument such as the Multi-Dimensional Anxiety Scale for Children (MASC) or the Screen for Child Anxiety Related Emotional Disorders (SCARED) can be used as a general screening measure for more than one anxiety disorder. Clinician rating scales such as the Liebowitz Social Anxiety Scale for Adolescents (LSAS-A) may be used to further establish the diagnosis and assess the severity of symptoms. As a result of time limitations in a busy primary care practice, it may not be feasible to use the clinician-administered scales. Sections 4.1 and 4.2, respectively, provide more details on available self-report instruments and clinician-administered assessments. 4.1 Self-Report Instruments

Self-report scales offer the child or adolescent the opportunity to provide information about their symptoms, fears, worries, and related behaviors in a non-threatening manner. Often the clinician will learn more about the child through this method of inquiry than through direct questioning. In addition, reviewing the child’s responses to the questions from the self-report form can serve as a place to start when initiating a dialogue with the child about his or her anxiety. These scales are easy to administer and some of them include a version for the parent as well as the patient. It is helpful to use self-report instruments as screening tools to distinguish SOC from other anxiety disorders. Self-report measures that target social anxiety are more informative regarding a child’s level of social anxiety than those with a broader diagnostic focus. Scales that are more specific to SOC include the Social Phobia and Anxiety Inventory in Children (SPAI-C)[21] and the SAS-A.[22] Examples of anxiety scales that assess a broad range of anxiety symptoms include the MASC[23] and SCARED.[24] All of the following scales can be used in the primary care setting in the waiting room; however, the MASC, SAS-A, and SPAI-C may be the easiest to employ in the primary care setting since they are brief. The MASC is a 39-item, four-point, Likert-style, self-report scale for ages 8–18 years. It includes a parent version. The MASC has main factors and subfactors including: (i) physical symptoms (tense/restless and somatic/autonomic); (ii) harm avoidance (anxious coping and perfectionism); (iii) social anxiety (humiliation/ rejection and public performance fears); and (iv) separation anxiety. The validity of the various subscales of the MASC has been documented. The MASC is useful in identifying youth who might benefit from a more detailed assessment. SCARED is a 38-item scale that is used as a screening tool for generalized anxiety disorder, separation anxiety disorder, panic disorder, SOC, and school phobia for individuals aged 9–18 years. It has a three-point, Likert-type scale with items describing the Pediatr Drugs 2007; 9 (4)

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degree to which statements are true. Findings from previous and current versions of the SCARED support its discriminative properties.[24] The SAS-A consists of 18 anxiety-related items and four items that assess social preferences and activities. It has a five-point Likert scale and three subscales: Fear of Negative Evaluation (FNE), Social Avoidance and Distress Specific to New Situations (SAD-New), and Generalized Social Avoidance and Distress (SAD-General). This scale is used in adolescents aged 13–17 years. The SAS was found to have adequate internal consistency and test-retest reliability. In addition, the validity of the SAS-A has been supported by correlations with various measures of social functioning.[25,26] The SPAI-C is a self-report measure that is designed to specifically measure cognitive, physiologic, and behavioral symptoms of social anxiety as described in the DSM-IV[1] in children aged 8–13 years. In this inventory, five factors are identified: (i) assertiveness; (ii) general conversation; (iii) public performance; (iv) physical/cognitive symptoms; and (v) behavioral avoidance.[27] The SPAI-C has been found to have sound psychometric properties, including adequate test-rerest reliability and internal consistency.[22] The FSSC-R[28] has a three-point scale assessing specific fears in children with eight fear categories including school, social, and physical fears (i.e. fear of failure and criticism), fear of the unknown, fear of injury and small animals, fear of danger and death, and medical fears. It is used in children aged 8–18 years. This scale has been shown to have good reliability and adequate discriminant validity.[29] The Child Behavior Checklist (CBCL) has 118 items covering a wide range of symptoms.[30] Patient’s report on child’s competencies and behavioral/emotional problems based on the child’s activities, social relations, and school performance. The Revised Children’s Manifest Anxiety Scale (RCMAS) is used for children aged 8–18 years and has 37 items to measure chronic anxiety. It focuses on three anxiety factors: physiologic manifestations of anxiety; worry and oversensitivity; and problems with fear and concentration. It has shown adequate retest reliability in studies.[31] 4.2 Clinician-Administered Assessments

Clinician-administered assessments can be very cumbersome to perform in a primary care setting. The LSAS-A, a modified version of the adult LSAS, is the only assessment that is specific and specialized to SOC and can be completed within a reasonable amount of time. It can be used as an outcome assessment tool and is used for ages 13–17 years. The LSAS is the first clinicianadministered scale developed for the assessment of fear and avoidance associated with SOC. The LSAS-A is a semi-structured scale that measures fear and avoidance of different social and perform© 2007 Adis Data Information BV. All rights reserved.

ance situations that have been adapted to an adolescent’s school and social life. The LSAS-A has demonstrated adequate psychometric properties and has been shown to be sensitive to treatment effects.[32] The Anxiety Disorders Interview Schedule-Revised DSM-IV, Parent and Child Versions (ADIS-P; ADIS-C)[33] is a semi-structured interview based on DSM-IV classification of psychopathology.[34] It includes a child and a parent interview. In addition to providing the diagnosis, the ADIS requires the clinician to provide a clinician severity rating (CSR), which is the clinician’s estimate of the degree of functional impairment present due to the disorder. The interview has shown inter-rater reliability and re-test reliability and it has shown sensitivity to treatment effects in studies of youth with anxiety disorders.[35,36] The Pediatric Anxiety Rating Scale (PARS)[37] was designed to assess the frequency, severity, and associated impairment of separation anxiety, generalized anxiety and social anxiety symptoms in youngsters aged 6–17 years. A 50-item symptom checklist groups items using a 6-point scale from 0 for none and 1–5 for minimal to extreme for each dimension. The dimensions include the number of symptoms, frequency, severity of distress associated with anxiety symptoms, severity of physical symptoms, avoidance, and interference at home and out of home.[37] 5. Treatment of Pediatric Social Anxiety Disorder There is limited literature on treatments specifically for pediatric SOC. Given that SOC is a prevalent and debilitating disorder in childhood and the possibility that early onset may result in a greater severity of symptoms later in life, it is important that effective treatments are developed for children. The evidence to date on safe and efficacious treatment options for the pediatric population are reviewed in this section; a brief review of psychosocial treatments is followed by a more in-depth review of pharmacologic treatments. 5.1 Psychosocial Treatments

Most of the psychosocial treatment studies examining childhood anxiety disorders were designed to include all anxiety disorders, not just SOC; only a handful of studies have enrolled children who have met the specific diagnostic criteria for SOC.[38] This may be due to the fact that these anxiety disorders are highly co-morbid in children and adolescents and it appears that these disorders do respond to the same treatments. It is, therefore, difficult to generalize these results to children with SOC since they represent a very small portion of the entire sample.[38] In addition, most of the literature on the psychosocial treatment of childhood and adolescent SOC addresses variations of behavioral and cognitive-behavioral therapy (CBT).[38] The treatments that have been developed to date have been modifications of adult intervention programs. Pediatr Drugs 2007; 9 (4)


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Table I. Childhood anxiety disorders: randomized cognitive-behavioral therapy (CBT) trials Study

Diagnosis of study participants (no. of participants)

Intervention

Trial design

Primary outcome measures

Comments

Barrett et al.[42]

OAD (30), SAD (30), SOC (19)

Individual CBT CBT-FAM WL

RCT WL

RCMAS, FSSC-R, CBCL

Both active treatments beneficial, CBT superior on primary outcome measures

Biedel et al.[17]

SOC (67)

Individual and group CBT Nonspecific treatment control

RCT

SPAI-C, ADIS

Active treatment significantly better in multiple domains

Flannery-Schroeder and Kendall[40]

GAD (21), SAD (11), SOC (5)

Individual CBT Group CBT WL

RCT WL control

RCMAS, CBCL

Both individual and group CBT yielded lower rates of anxiety disorders and enhanced coping abilities

Hayward et al.[44]

SOC (35)

Group CBT No treatment control

RCT

SPAI-C, ADIS

Active treatment showed significant improvement

Kendall[52]

OAD (30), SAD (8), AVD (9)

Individual CBT WL

RCT WL control

RCMAS, FSSC-R, CBCL-I

Individual CBT with lower rates of anxiety disorder than WL

Kendall et al.[43]

OAD (55), SAD (22), AVD (17)

Individual CBT WL

RCT WL control

RCMAS, STAIC

Similar results to above study

Shortt et al.[53]

GAD (42), SAD (19), SOC (10)

Family group CBT RCT WL

RCMAS, CBCL

Active treatment showed significant improvement in all outcomes

Silverman et al.[45]

GAD (12), SOC (15), OAD (29)

Group CBT WL

RCMAS, FSSC-R, CBCL

Group CBT yielded significant improvements across all primary outcome domains

RCT WL control

ADIS = Anxiety Disorders Interview Schedule-Revised DSM-IV, Parent and Child Versions; AVD = avoidant disorder; CBCL = Child Behavior Checklist; CBT-FAM = CBT with a family treatment component; FSSC-R = Fear Survey Schedule for Children-Revised; GAD = generalized anxiety disorder; OAD = overanxious disorder; RCMAS = Revised Children’s Manifest Anxiety Scale; RCT = randomized controlled trial; SAD = separation anxiety disorder; SOC = social anxiety disorder; SPAI-C = Social Phobia and Anxiety Inventory in Children; STAIC = State Trait Anxiety Inventory for Children; WL = wait-list.

All of the studies have evaluated the target treatment program against wait-list control groups rather than an alternative treatment or placebo. The empirical study of psychosocial treatments for anxiety disorders in adolescents is growing but still incomplete. Specific treatments have employed cognitive-behavioral group therapy for SOC in adolescents,[39] social effectiveness therapy for children,[17] and ‘coping cat’ child behavior therapy.[40] Overall, most clinical researchers now believe that CBT is the treatment of choice for youth with internalizing disorders including SOC.[41] Study investigators have modified these treatment programs in their own way. For example, Barrett et al.[42] adapted Kendall’s ‘coping cat’[40] for an Australian child population, renaming it ‘coping koala.’ Despite the modifications, all these interventions share four common components: psychoeducation, exposure, skill building, and homework assignments. Psychoeducation is the first part of treatment in which information is provided about SOC to the youngster and the parents in a supportive manner. The three components (cognitive, somatic, and behavioral) of anxiety are explained as well as specific symptoms © 2007 Adis Data Information BV. All rights reserved.

of SOC. The anxiety symptoms are differentiated from normal anxiety with emphasis on the maladaptive patterns of anxiety symptoms and avoidance behaviors. Explanations are provided about the importance of exposing oneself to fearful social situations in order to get habituated to them. Exposure therapy is the systematic confrontation of fearful social situations. A hierarchy of phobic stimuli is made, which is individualized. Skill-building tasks may include relaxation training, problem-solving skills, cognitive restructuring techniques, and assertiveness building.[43] Between sessions, homework assignments are given to continue the learning process and refine and generalize skills to everyday situations. A brief review of eight randomized clinical trials using CBT interventions is presented and summarized in table I. All studies had an active treatment group; results were compared with those from either a wait-list or no-treatment control condition[17,44,45] or an active placebo-controlled condition.[39,46-49] In addition, several studies compared more than one active treatment.[39,40,46-51] Most of the studies employed some variation of the ‘coping cat’ CBT Pediatr Drugs 2007; 9 (4)

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program developed by Kendall et al.[40] ‘Coping cat’ CBT is the most studied of all treatments of childhood anxiety disorders to date. Kendall and colleagues[43,52] conducted two studies with youth with mixed anxiety disorders but having avoidant disorders (SOC in DSM-IV). In the first study,[52] 47 children with an anxiety disorder were randomly assigned to either individual CBT or waitlist control. In the latter group, participants did not receive active treatment but were on a wait list to receive treatment in the near future. Results showed that at post-treatment, the majority of the CBT group no longer met diagnostic criteria for an anxiety disorder compared with only 5% in the wait-list group. One-year follow-up assessment revealed maintenance of gains. In the second study,[43] 94 children with mixed anxiety disorders were randomly assigned to either individual CBT or wait-list control. In this study at post-treatment, 54% of children treated with CBT no longer met diagnostic criteria for an anxiety disorder compared with 6% in the wait-list group. Barrett et al.[42] adapted Kendall’s treatment program[40] and assigned 79 children with anxiety disorders randomly to either CBT, CBT with a family treatment component (CBT-FAM), or a wait-list control condition. In the latter group, participants did not receive active treatment but were on a wait list to receive treatment some time in the future. In the CBT-FAM group, 84% of children were free of any diagnosis, in the CBT group, 57.1% and in the wait-list group, 26%. Significant differences were seen from pretreatment to post-treatment between all three groups on the percentage of children meeting diagnostic criteria. Silverman et al.[45] conducted a study of 104 children with an anxiety disorder. Parents were involved in this treatment study. The sample was randomly assigned to individual CBT in one of the three following groups: comparison of contingency management, self-control training, and education support as a psychosocial placebo condition. There were no significant differences between the three conditions. All three conditions indicated significant improvements from pre- to post-treatment on parent and child self-report measures, with no differences between groups. This study highlights the importance of having alternative treatment or placebo-controlled conditions rather than only waitlist controls. Flannery-Schroeder and Kendall[40] conducted a study comparing individualized CBT, group CBT, and a wait-list control condition in 37 children with an anxiety disorder. In terms of posttreatment criteria of primary anxiety disorders, results were significantly better in both treatment groups than in the wait-list control group, but no differences were present between the two treatment groups. In the individualized CBT group, 73% of patients no longer met the criteria for a primary anxiety disorder, compared with 50% in those receiving group CBT, and only 8% in the waitlist control group. © 2007 Adis Data Information BV. All rights reserved.

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A few studies have targeted social and performance fears specifically in youth. Beidel et al.[17] developed an intervention called the Social Effectiveness Therapy for Children (SET-C). SET-C combines social skills training with exposures performed in individual and group sessions. Sixty-seven children (8–12 years) with SOC were randomly assigned to either SET-C or a nonspecific, active intervention called Testbusters[39] for 12 weeks. Children in the SET-C group at post-treatment were significantly more improved than in the Testbusters group with improved social interaction and decreased fears of socializing. Moreover, only 5% of children in the Testbusters group did not meet criteria for SOC compared with 67% in the SET-C group. These gains were maintained when children were seen at 6-months follow-up. A second trial targeting SOC in adolescents was performed by Hayward et al.[44] This study involved random assignment of 35 adolescent females to either cognitive behavior group therapy for adolescents (CBGT-A) or a no-treatment control group. Adolescents in the CBGT-A group showed significant improvement in social anxiety symptoms with a higher percentage of adolescents not meeting diagnostic criteria compared with the control group. At 1-year follow-up, the gains in the CBGT-A group were not maintained.[44] Shortt et al.[53] conducted a family-based group cognitivebehavioral treatment (FGCBT) called the FRIENDS program. In this randomized clinical trial, 71 children (6–10 years) with separation anxiety, generalized anxiety or SOC were assigned to FRIENDS for 10 weeks or a wait-list control group. At the end of treatment 69% of children in the FGCBT group were diagnosisfree compared with 6% in the wait-list group. These improvements were maintained at 1-year follow-up. 5.1.1 In Summary

Despite the successful results in treating anxiety disorders, these studies have some limitations. First, most of the studies compared the treatment against a wait-list condition rather than another active treatment. Second, only a handful of participants had SOC in most of these studies. Third, there was a wide range in the age of the participants (from 6 to 16 years). Most psychosocial treatments need to be modified for a particular development age. Future research needs to focus on controlled trials of combined treatments (i.e. comparisons of medication, CBT, and the combination of pharmacotherapy and CBT) to determine whether combined treatment is more effective for symptom reduction than either medication or CBT alone. Also, follow-up controlled studies are needed to determine the long-term benefits of CBT, whether booster sessions of CBT lead to reduced relapse rates, and whether early treatment in childhood prevents later psychiatric disorders in adulthood. In addition, studies that have diverse populations and a wide age range are needed to evaluate if these protocols can be generalized to other populations. Pediatr Drugs 2007; 9 (4)


CBT is considered effective but it is not simplistic. It requires a person to have considerable training and expertise to help youth and parents make effective behavioral changes over a specified period of time. There are very limited resources available to implement CBT in a clinical setting and the CBT protocols used in most of the research trials are difficult to implement in community clinics. Therefore, for a primary care provider, having a CBT specialist available may not always be possible. Because of the lack of availability of CBT, pharmacologic treatment may be the treatment of choice by default in many settings. 5.2 Pharmacologic Treatments

Most psychopharmacology studies of treatment for pediatric anxiety disorders have examined the efficacy of antidepressant agents. Similar to the psychosocial studies, the majority of these trials have studied the safety and efficacy of these medications for multiple anxiety diagnoses such as generalized anxiety disorder, separation anxiety disorder, and SOC and not specifically for SOC. 5.2.1 Selective Serotonin Reuptake Inhibitors

Selective serotonin reuptake inhibitors (SSRIs) have been used more commonly in recent years because of their efficacy, safety, and tolerability compared with other antidepressants. The SSRIs used in the pediatric population include fluoxetine, paroxetine, sertraline, citalopram, escitalopram, and fluovoxamine. There are very few randomized, double-blind, placebo-controlled trials of SSRIs in children with SOC. The few trials that exist enrolled participants with multiple anxiety disorders. An open-label trial examined the efficacy of fluoxetine over a 9-week period in 21 children (aged 5–14 years) diagnosed with selective mutism, which is considered to be a variant of SOC.[54] The children had a current diagnosis of separation anxiety disorder, generalized anxiety disorder, avoidant disorder, or SOC. The mean daily dose of fluoxetine was 28.1 mg/day (range 20–60 mg/ day). After treatment, 76% of the patients showed marked improvement in anxiety symptoms. These data have to be considered cautiously because of the small sample size and the uncontrolled study design. A major limitation of the study is the lack of a randomized controlled trial methodology. Randomized controlled trials are needed to determine the long-term risks and benefits of fluoxetine for this group. No suicidal ideation was reported in this trial. In a 12-week, double-blind study of fluoxetine in 16 children aged 6–12 years with selective mutism, results showed a significant improvement in children treated with fluoxetine 0.6 mg/kg/ day compared with placebo based on parent ratings.[55] However, clinician and teacher ratings indicated no significant differences between the two groups. All children met diagnostic criteria for avoidant disorder or SOC. This study showed that fluoxetine may © 2007 Adis Data Information BV. All rights reserved.

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be beneficial and safe in the treatment of children with selective mutism. Side effects were minimal with no suicidal ideation reported. In a more recent study, 128 children aged 6–17 years who met the criteria for SOC, separation anxiety disorder, and/or generalized anxiety disorder with or without co-morbid attention deficit disorder/attention deficit hyperactivity disorder were randomly assigned to receive fluvoxamine or placebo for 8 weeks.[56] The dose of fluvoxamine was increased 50 mg/week to a maximum of 300 mg/day. The children in the fluvoxamine group had significant reductions in symptoms of anxiety and higher rates of clinical response than the children receiving placebo. On the PARS, which was the main outcome measure, significant between-group differences were detectable by week 3 and increased through to week 6. Fluvoxamine was generally well tolerated but was associated with a greater incidence of gastrointestinal symptoms (abdominal discomfort, nausea, vomiting) and increased levels of motor activity than placebo. All of these adverse events were mild. Five children receiving fluvoxamine withdrew due to adverse events such as sedation, somatic discomfort, or hyperactivity. No suicidal ideation was reported in this trial. Two studies have examined the efficacy of SSRIs for specifically treating SOC. The first was an 8-week, open-label trial of sertraline (dosage range between 50 and 200 mg/day; mean dosage was 123.2 mg/day) in 14 adolescents aged 11–17 years.[57] Treatment responders were patients who received an endpoint Clinical Global Impressions Improvement (CGI-I) scale score of ‘much improved’ or ‘very much improved.’ After treatment, 36% of the adolescents were responders and 29% were partial responders. In general, sertraline was well tolerated in this group of subjects. The second study was a randomized, double-blind, placebocontrolled, multicenter trial of paroxetine.[58] 329 children (aged 8–11 years) and adolescents (aged 12–17 years) with SOC were randomly assigned to receive paroxetine (10–50 mg/day) or placebo for 16 weeks. Almost 78% of patients receiving paroxetine were defined as responders (CGI-I score of 1 or 2) compared with 38% with placebo (p < 0.001). Patients receiving paroxetine also showed a significantly greater reduction in symptoms on selfreports (LSAS-A). The benefit of paroxetine was apparent within the first 4 weeks of treatment. Adverse events that occurred twice as often in patients taking paroxetine than in patients taking placebo were insomnia, decreased appetite, and vomiting. Other behavioral adverse events included agitation (1.8% for paroxetine and 1.3% for placebo), manic reaction (1.8% and 0%), and emotional lability (2.5% and 1.3%). Four paroxetine-treated patients who had emotional lability as an adverse event had expressed suicidal ideation or had threatened suicide. Two of these patients also reported self-harm behavior. The author reported that none of these cases were considered serious, no suicide attempts were involved, and none were attributed to the study medication. Pediatr Drugs 2007; 9 (4)

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5.2.2 Serotonin Norepinephrine Reuptake Inhibitors

A recently conducted, double-blind, placebo-controlled, parallel-group trial studied the efficacy, safety, and tolerability of venlafaxine extended release in the treatment of 293 child and adolescent outpatients with GSOC.[59] Patients, aged 8–17 years, were randomly assigned to treatment with venlafaxine extended release (dosage range 37.5–225 mg/day) or placebo for 16 weeks. Seventy-six percent of patients receiving venlafaxine extended release were responders compared with 54% of patients receiving placebo (based on the CGI score) [p = 0.001]. Compared with placebo, the venlafaxine extended release-treated subjects’ response was statistically superior. Adverse events included dizziness, anorexia, asthenia, and nausea. One patient experienced a serious adverse event of suicidal ideation and two events of selfinjury. No suicide attempts, suicides or events of hostility occurred in this study. Among the placebo-treated patients, only one patient had a serious adverse event (intentional injury, scratch marks on the wrist).

SSRIs) leading to hypertensive crises, postural hypertension, insomnia, paresthesias, and sedation. Presently, given the lack of research in children and adolescents and the adverse effects of these agents, monoamine oxidase inhibitors are not a treatment of choice for this population. 5.2.5 Gabapentin

Gabapentin is a novel anticonvulsant agent (a γ-aminobutiric analog) with an unknown mechanism of action. At this time, the efficacy of gabapentin has not been studied in children with SOC or other anxiety disorders, therefore gabapentin is not a first-line treatment of choice for this population. Gabapentin has not been studied in randomized controlled trials in adults with SOC. 5.2.6 Pregabalin

Pregabalin is currently being studied for the treatment of adult anxiety disorders and randomized controlled trials are underway. No evidence is currently available in children.[62] 5.2.7 Nefazodone

5.2.3 Benzodiazepines

In a 6-week, open-label study, 12 children (aged 9–16 years) with overanxious disorder and avoidant disorder participated in a trial consisting of a baseline placebo period (1 week), alprazolam therapy for 4 weeks, a drug-tapering period (1 week), and a postdrug placebo period (1 week).[60] The alprazolam mean dosage was 1.5 mg/day. Significant improvements were seen in clinicians ratings for the anxiety (p < 0.01), depression (p < 0.01), and psychomotor excitation (p < 0.05) factors of the Brief Psychiatric Rating Scale for Children (BPRSC). A 4-week, double-blind, placebo-controlled trial assessed the efficacy and safety of alprazolam in children and adolescents (aged 8–16.9 years) with overanxious disorders (n = 21) or avoidant disorder (n = 9).[61] The initial dose was 0.25mg for patients with a bodyweight of 40kg. The maximum dosage permitted was 0.04 mg/kg/day (ranging from 1.04 to 3.5 mg/day). Based on CGI-I ratings at the end of the study, alprazolam appeared to be superior to placebo in both overanxious disorder and avoidant disorder; however, the difference was not statistically significant. Adverse effects reported were mild dry mouth and feelings of tiredness. Presently, the data for the use of benzodiazepines for pediatric social anxiety are inconclusive. Some clinicians use benzodiazepines as adjunct treatment with an SSRI in order to provide the child relief from physical anxiety symptoms and to allow time for the positive effects of the SSRIs to occur. 5.2.4 Monoamine Oxidase Inhibitors

Monoamine oxidase inhibitors have not been studied in the treatment of children and adolescents with SOC. These agents have serious adverse effects such as life-threatening interactions with tyramine-containing foods and concomitant medications (e.g. © 2007 Adis Data Information BV. All rights reserved.

A case report of a 15-year-old female patient showed improvement on nefazodone (up to 400 mg/day) in treating SOC after 8 weeks.[63] However, because of a history of elevated liver function tests and induced hepatic failure seen in adults treated with this compound and the lack of data in children at this time, nefazodone is not a treatment of choice for pediatric SOC. In Summary

There are very few pharmacotherapy trials in general and even fewer randomized, double-blind, placebo-controlled trials in childhood anxiety disorders. Most of the available studies need to be replicated to confirm the efficacy of studied medications in children, and long-term studies are needed to determine the effects of these medications over long periods of time. We do not have information on how these medications affect the developing brain. It also remains difficult to predict which children are most likely to require pharmacotherapy. In particular, with antidepressants, the appropriate maintenance therapy is not known nor is the duration of treatment required to reach remission. 5.2.8 Antidepressant Treatment and the Development of Suicidal Thinking/Behaviors

In 2004 the US FDA issued a warning regarding the use of antidepressants (fluoxetine, paroxetine, citalopram, escitalopram, venlafaxine extended release, venlafaxine, fluvoxamine, nefazodone, mirtazapine, bupropion, and sertraline) in pediatric patients because of data showing that these medications may increase suicidal ideation and/or suicide attempts in depressed pediatric patients. The FDA conducted a meta-analysis of placebocontrolled clinical trials for pediatric major depression, anxiety, and obsessive compulsive disorder to examine if there was a relationship between the use of antidepressants and the emergence of suicidality. The FDA did not include patients with SOC in this Pediatr Drugs 2007; 9 (4)


analysis. This analysis showed a 1.8-fold increase in the risk of new onset or worsening of suicidal ideation or suicide attempts in pediatric patients treated with antidepressants compared with patients receiving placebo.[64] Given these data, the FDA required a warning on every antidepressant label with information for physicians, instructing them to monitor closely pediatric patients receiving antidepressant treatment for possible worsening of depression and suicidality, especially at the beginning of the therapy or when the dosage is changed. Physicians must always assess suicidal ideation before starting antidepressants and be aware of symptoms such as abrupt onset of increased anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, severe restlessness, hypomania, and mania that may increase the risk of worsening of depression and the emergence of suicidality. Physicians must also instruct patients and their families to be alert for the emergence of these symptoms.

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Currently, the National Institute of Mental Health-funded multicenter, Child and Adolescent Multimodal Treatment Study (CAMS) is taking place in the US.[68] CAMS is a randomized controlled trial of children and adolescents aged 7–17 years with anxiety disorders including separation anxiety disorder, SOC, and generalized anxiety disorder, in which CBT, sertraline, CBT plus sertraline, and placebo are compared. CAMS consists of two phases. Phase I is a 12-week, short term efficacy trial comparing the different treatments and phase II involves 6-month maintenance treatment for responders to the three active treatments. No preliminary data are yet available; this trial will provide information on the success of using a combined treatment compared with monotherapies in children diagnosed with anxiety disorders, including SOC. 7. Conclusion

5.2.9 Medication Management

There are no specific laboratory tests that are required when prescribing SSRIs. However, an additional concern for the prescribing clinician is the risk of drug-drug interactions. The SSRIs inhibit specific isoenzymes in the cytochrome P450 system (2D6, 1A2, 2C, and 3A4); this differs for each medication.[65] It is important for the clinician to obtain a detailed medication history, including over-the-counter medications. There is a lack of information about the amount of medication required to treat SOC. It is recommended while prescribing SSRIs to initiate the medication at a low dose; for example, sertraline should be administered at a daily dose of 25mg for the first 7 days in children, and then increased to 50mg, increasing slowly thereafter as clinical response dictates. Once a therapeutic dosage is reached, this dose should be maintained for 6–8 weeks to assess its efficacy. It is recommended that patients are seen weekly for the first 4 weeks, then once every 2 weeks until week 12, then as needed thereafter. If one SSRI is not effective after 8 weeks at the maximum dose, a second SSRI or a serotonin norepinephrine reuptake inhibitor (SNRI) could be used. There have been withdrawal symptoms reported with the discontinuation of SSRIs, including nausea, headache, dizziness, and agitation.[66] Therefore, these medications should not be abruptly discontinued. 6. Combined Treatment Only one open-label trial has studied combination treatment in children with SOC.[67] In this study, 12 children aged 8–17 years received citalopram (maximum dosage of 40 mg/day) plus eight brief psychoeducational and behavioral counseling sessions for 12 weeks. Eighty-three percent (n = 10) of the children improved, suggesting the potential benefit of combining pharmacologic and psychosocial interventions in the treatment of social phobia.[67] © 2007 Adis Data Information BV. All rights reserved.

There are current data demonstrating the efficacy of antidepressants (SSRIs and SNRIs) and CBT in the short-term treatment of pediatric SOC. However, more research is needed on the longterm effects of these treatments. Also, additional research is needed to evaluate the efficacy of combination treatment in children and adolescents diagnosed with SOC. There are no data available to shed light on the question of whether or not the sequencing of therapies or combinations of therapies leads to a difference in treatment outcome. Because of the lack of research as to what modality is most effective, clinical guidelines are suggested here. How a clinician decides which type of treatment to start first may be determined by the clinician’s particular expertise, which may be in pharmacotherapy or CBT. If there is mild impairment, a psychosocial intervention, preferably CBT (if available), is a reasonable approach. This treatment should be tried for approximately 4 months. If a 50% reduction in anxiety symptoms is not achieved, it would be reasonable to consider a medication, i.e. an SSRI. It is reasonable for primary care providers who diagnose SOC in children in their clinics to start with pharmacotherapy and to maximize this treatment until remission occurs. Clinicians should closely monitor the emergence of suicidal ideation, since some studies have reported children and adolescents to develop these symptoms. Benzodiazepines may be a second-line treatment for SOC or they may be used in severe cases as adjunctive therapy to SSRIs to relieve severe symptoms until the onset of effects with SSRIs. Acknowledgments No sources of funding were used to assist in the preparation of this review. Dr Moira Rynn has served as a consultant to and received research grants from Wyeth, Pfizer, and Eli Lilly. Pediatr Drugs 2007; 9 (4)

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Correspondence: Dr Sarosh Khalid-Khan, Mood and Anxiety Disorders Clinic, University of Pennsylvania, 3535 Market Street, Suite 670, Philadelphia, PA 19104, USA. E-mail: [email protected]

Pediatr Drugs 2007; 9 (4)