Study Design and Implementation

This study was designed as a two-phase, multicenter, randomized, controlled trial for children and adolescents between the ages of 7 and 17 years who had separation or generalized anxiety disorder or social phobia. Phase 1 was a 12-week trial of short-term treatment comparing cognitive behavioral therapy, sertraline, and their combination with a placebo drug. Phase 2 is a 6-month open extension for patients who had a response in phase 1.

The authors designed the study, wrote the manuscript, and vouch for the data gathering and analysis. Pfizer provided sertraline and matching placebo free of charge but was not involved in the design or implementation of the study, the analysis or interpretation of data, the preparation or review of the manuscript, or the decision to publish the results of the study.

Study Subjects

Children between the ages of 7 and 17 years with a primary diagnosis of separation or generalized anxiety disorder or social phobia (according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision [DSM-IV-TR]16), substantial impairment, and an IQ of 80 or more were eligible to participate. Children with coexisting psychiatric diagnoses of lesser severity than the three target disorders were also allowed to participate; such diagnoses included attention deficit–hyperactivity disorder (ADHD) while receiving stable doses of stimulant and obsessive–compulsive, post-traumatic stress, oppositional–defiant, and conduct disorders. Children were excluded if they had an unstable medical condition, were refusing to attend school because of anxiety, or had tried but had not had a response to two adequate trials of SSRIs or an adequate trial of cognitive behavioral therapy. Girls who were pregnant or were sexually active and were not using an effective method of birth control were also excluded. Children who were receiving psychoactive medications other than stable doses of stimulants and who had psychiatric diagnoses that made participation in the study clinically inappropriate (i.e., current major depressive or substance-use disorder; unmedicated ADHD, combined type; or a lifetime history of bipolar, psychotic, or pervasive developmental disorders) or who presented an acute risk to themselves or others were also excluded.

Recruitment occurred from December 2002 through May 2007 at Duke University Medical Center, New York State Psychiatric Institute–Columbia University Medical Center–New York University, Johns Hopkins Medical Institutions, Temple University, University of California, Los Angeles, and Western Psychiatric Institute and Clinic–University of Pittsburgh Medical Center. The protocol was approved and monitored by institutional review boards at each center and by the data and safety monitoring board of the National Institute of Mental Health. Subjects and at least one parent provided written informed consent.

Interventions

Cognitive behavioral therapy involved fourteen 60-minute sessions, which included review and ratings of the severity of subjects' anxiety, response to treatment, and adverse events. Therapy was based on the Coping Cat program,17,18 which was adapted for the subjects' age and the duration of the study.19 Each subject who was assigned to receive cognitive behavioral therapy received training in anxiety-management skills, followed by behavioral exposure to anxiety-provoking situations. Parents attended weekly check-ins and two parent-only sessions. Experienced psychotherapists, certified in the Coping Cat protocol, received regular site-level and cross-site supervision.

Pharmacotherapy involved eight sessions of 30 to 60 minutes each that included review and ratings of the severity of subjects' anxiety, their response to treatment, and adverse events. Sertraline (Zoloft) and matching placebo were administered on a fixed–flexible schedule beginning with 25 mg per day and adjusted up to 200 mg per day by week 8. Through week 8, subjects who were considered to be mildly ill or worse and who had minimal side effects were eligible for dose increases. Psychiatrists and nurse clinicians with experience in medicating children with anxiety disorders were certified in the study pharmacotherapy protocol and received regular site-level and cross-site supervision. Pill counts and medication diaries were used to facilitate and document adherence.

Combination therapy consisted of the administration of sertraline and cognitive behavioral therapy. Whenever possible, therapy and medication sessions occurred on the same day for the convenience of subjects.

Objectives

Study objectives were, first, to compare the relative efficacy of the three active treatments with placebo; second, to compare combination therapy with either sertraline or cognitive behavioral therapy alone; and third, to assess the safety and tolerability of sertraline, as compared with placebo. We hypothesized that all three active treatments would be superior to placebo and that combination therapy would be superior to either sertraline or cognitive behavioral therapy alone.

Outcome Assessments

We obtained demographic information, information on symptoms of anxiety, and data on coexisting disorders and psychosocial functioning using reports from both the subjects and their parents and from interviews of subjects and parents at the time of screening, at baseline, and at weeks 4, 8, and 12. The interviews were administered by independent evaluators who were unaware of study-group assignments.

We used the Anxiety Disorders Interview Schedule for DSM-IV-TR, Child Version,20 to establish diagnostic eligibility. The categorical primary outcome was the treatment response at week 12, which was defined as a score of 1 (very much improved) or 2 (much improved) on the Clinical Global Impression–Improvement scale,21 which ranges from 1 to 7, with lower scores indicating more improvement, as compared with baseline. A score of 1 or 2 reflects a substantial, clinically meaningful improvement in anxiety severity. The dimensional primary outcome was anxiety severity as measured on the Pediatric Anxiety Rating Scale, computed by the summation of six items assessing anxiety severity, frequency, distress, avoidance, and interference during the previous week.22 Total scores on this scale range from 0 to 30, with scores above 13 indicating clinically meaningful anxiety. The Children's Global Assessment Scale23 was used to rate overall impairment. Scores on this scale range from 1 to 100; scores of 60 or lower are considered to indicate a need for treatment, and a score of 50 corresponds to moderate impairment that affects most life situations and is readily observable. Agreement among the raters was high for anxiety severity (r=0.85) and diagnostic status (intraclass correlation coefficient=0.82 to 0.88) on the basis of a videotaped review of 10% of assessments by independent evaluators that were performed at baseline and at week 12.

Adverse Events

Adverse events were defined as any unfavorable change in the subjects' pretreatment condition, regardless of its relationship to a particular therapy. Serious adverse events were life-threatening events, hospitalization, or events leading to major incapacity. Harm-related adverse events were defined as thoughts of harm to self or others or related behaviors.

All subjects were interviewed at the start of each visit by the study coordinator with the use of a standardized script. Identified adverse events and harm-related events were then evaluated and rated by each subject's study clinician. This report presents data on all serious adverse events, all harm-related adverse events, and moderate and severe (i.e., functionally impairing) adverse events that occurred in 3% or more of subjects in any study group. The data and safety monitoring board of the National Institute of Mental Health performed a quarterly review of reported adverse events.

Given the greater number of study visits (and hence more reporting opportunities) and the unblinded administration of sertraline in the combination-therapy group, the test of the adverse-event profile of sertraline focused on statistical comparisons between sertraline and placebo and sertraline and cognitive behavioral therapy.

Randomization and Masking

The randomization sequence in a 2:2:2:1 ratio was determined by a computer-generated algorithm and maintained by the central pharmacy, with stratification according to age, sex, and study center. Subjects were assigned to study groups after being deemed eligible and undergoing verbal reconsent with a study investigator. Subjects in the sertraline and placebo groups did not know whether they were receiving active therapy, nor did their clinicians. However, subjects who received combination therapy knew they were receiving active sertraline. The study protocol called for independent evaluators who completed assessments to be unaware of all treatment assignments.

Statistical Analysis

On the basis of previous studies,10-15 we hypothesized that 80% of children in the combination-therapy group, 60% in either the sertraline group or the cognitive-behavioral-therapy group, and 30% in the placebo group would be considered to have had a response to treatment at week 12. We determined that we needed to enroll 136 subjects in each active-treatment group and 70 subjects in the placebo group for the study to have a power of 80% to detect a minimum difference of 17% between any two study groups in the rate of response, assuming an alpha of 0.05 and a two-tailed test with no adjustment for multiple comparisons.

Analyses were performed with the use of SAS software, version 9.1.3 (SAS Institute). For categorical outcomes (including data regarding adverse events), treatments were compared with the use of Pearson's chi-square test, Fisher's exact test, or logistic regression, as appropriate. Logistic-regression models included the study center as a covariate. For dimensional outcomes, linear mixed-effects models (implemented with the use of PROC MIXED) were used to determine predicted mean values at each assessment point (weeks 4, 8, and 12) and to test the study hypotheses with respect to between-group differences at week 12. In each linear mixed-effects model, time and study group were included as fixed effects, with linear and quadratic time and time-by-treatment group interaction terms. Each model also began with a limited number of covariates (e.g., age, sex, and race), followed by backward stepping to identify the best-fitting and most parsimonious model. In all models, random effects included intercept and linear slope terms, and an unstructured covariance was used to account for within-subject correlation over time. All comparisons were planned and tests were two-sided. A P value of less than 0.05 was considered to indicate statistical significance. The sequential Dunnett test was used to control the overall (familywise) error rate.24

We analyzed data from all subjects according to study group. Sensitivity analyses were performed with the last observation carried forward (LOCF) and multiple imputation assuming missingness at random. Results were similar for the two missing-data methods. We report the results of the LOCF analysis because the response rates were lower and hence provide a more conservative estimate of outcomes.