Anxiety disorders are remarkably common among pediatric patients1,2 and are associated with significant morbidity3 and increased risk of suicidality in adolescents.4,5 Effective diagnosis and treatment of pediatric anxiety disorders are critical for reducing psychosocial morbidity,3,6 suicidality, and the risk of secondary mood disorders.7
This article summarizes open-label studies and randomized controlled trials (RCTs) of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors, atypical anxiolytics, and benzodiazepines in children and adolescents with generalized anxiety disorder (GAD), social phobia, separation anxiety disorder, and panic disorder. Although we focus on psychopharmacologic treatments, the best outcomes generally are observed with multimodal treatments that combine psychotherapy and pharmacotherapy.
Generalized anxiety disorder
Researchers have evaluated SSRIs, benzodiazepines, and buspirone in pediatric patients with GAD. In a double-blind, placebo-controlled trial of 22 patients age 5 to 17, sertraline, 50 mg/d, was associated with improvement in Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scores over 9 weeks.8 The Child-Adolescent Anxiety Multimodal Study compared cognitive-behavioral therapy (CBT) to sertraline or sertraline plus CBT in 488 patients age 7 to 17, 78% of whom had GAD.9 Sertraline monotherapy was superior to placebo and not statistically different from CBT, while combination treatment was superior to both monotherapy conditions in improving CGI score. In both trials, sertraline was well tolerated.
One study evaluated fluoxetine, 5 to 40 mg/d, or CBT in 14 youths with GAD; both treatments improved symptoms.10 In a study of 320 GAD patients age 6 to 17, venlafaxine extended-release (XR) initiated at 37.5 mg/d was associated with improved HAM-A scores.11 In general, venlafaxine was well tolerated; adverse effects included increased blood pressure, asthenia, pain, anorexia, somnolence, weight loss, and possibly treatment-emergent suicidal ideation.
Two RCTs of buspirone, 15 to 60 mg/d, that evaluated 559 children and adolescents age 6 to 17 with GAD did not observe significant differences between buspirone and placebo.12 By contrast, 2 open-label studies of youths with anxiety suggested improvement associated with buspirone.12 Treatment-emergent adverse events included nausea, stomachache, and headache.
Clinical trials of benzodiazepines in anxious children and adolescents have yielded mixed results. A 4-week, open-label trial of alprazolam, 0.5 mg to 1.5 mg/d, in 12 adolescents with overanxious disorder—the DSM-III forerunner of GAD—found improvements in anxiety, depression, psychomotor excitation, and hyperactivity, but patients experienced sedation, activation, headache, and nausea.13 However, a double-blind RCT in 30 youths age 8 to 16 found no statistically significant difference between alprazolam and placebo.14 Alprazolam generally was well tolerated; fatigue and dry mouth were reported, but no withdrawal symptoms. Additionally, benzodiazepine use may be associated with tolerance and—in young children—disinhibition.
Social phobia
Researchers have evaluated paroxetine, citalopram, fluoxetine, and venlafaxine for treating social phobia in pediatric patients. In an RCT, 78% of paroxetine-treated patients with social phobia responded compared with 38% for placebo over 16 weeks. Adverse events—including withdrawal symptoms—were twice as likely in patients who received paroxetine. Additionally, 4 paroxetine patients exhibited suicidal ideation vs 0 patients who received placebo.15
In an RCT of 293 children and adolescents age 8 to 17 with social phobia, venlafaxine XR was initiated at 37.5 mg/d and titrated to 112.5 mg/d, 150 mg/d, or 225 mg/d, depending on body weight.16 The venlafaxine group experienced significantly improved anxiety symptoms and the medication generally was well tolerated, although 3 venlafaxine-treated patients developed suicidal ideation compared with 0 in the placebo group.
An RCT compared Social Effectiveness Therapy for Children (SET-C) and fluoxetine, 10 to 40 mg/d, for 139 patients age 7 to 17 with social phobia.17 SET-C is a CBT for children and adolescents that focuses on increasing interpersonal skills and becoming more comfortable in social situations; it involves psychoeducation, social skills training, and exposure exercises. At endpoint, 53% of patients in the SET-C group no longer met diagnostic criteria for social phobia. Fluoxetine was well tolerated; no severe adverse events were reported.
In an open-label study of sertraline (mean dose = 123 mg/d) for 14 young persons with social phobia, 36% of patients responded and 29% partially responded at 8 weeks.18 Adverse events generally were mild and included nausea, diarrhea, and headache. In a 12-week study, 12 pediatric patients with social phobia received citalopram, 10 to 40 mg/d, and eight 15-minute counseling sessions. At endpoint, clinicians rated 83% of patients as much improved or very much improved. The medication generally was well tolerated.19
Separation anxiety disorder
In a 4-week, double-blind crossover pilot study, researchers randomly assigned 15 children age 7 to 13 with separation anxiety disorder to clonazepam, up to 2 mg/d, or placebo.20 There was no significant difference in CGI-I score between clonazepam and placebo. Side effects—including drowsiness, irritability and “oppositional behavior”—were more frequent in patients treated with clonazepam.