The new england journal of medicine established in 1812 december 25, 2008 vol. 359 no. 26 Cognitive Behavioral Therapy, Sertraline, or a Combination in Childhood Anxiety John T. Walkup, M.D., Anne Marie Albano, Ph.D., John Piacentini, Ph.D., Boris Birmaher, M.D., Scott N. Compton, Ph.D., Joel T. Sherrill, Ph.D., Golda S. Ginsburg, Ph.D., Moira A. Rynn, M.D., James McCracken, M.D., Bruce Waslick, M.D., Satish Iyengar, Ph.D., John S. March, M.D., M.P.H., and Philip C. Kendall, Ph.D.* Abstract Background Anxiety disorders are common psychiatric conditions affecting children and ado- From the Johns Hopkins Medical Institu- lescents. Although cognitive behavioral therapy and selective serotonin-reuptake in- tions, Baltimore ( J.T.W., G.S.G.); New York State Psychiatric Institute–Columbia Uni- hibitors have shown efficacy in treating these disorders, little is known about their versity Medical Center, New York (A.M.A., relative or combined efficacy. M.A.R.); the University of California at Los Angeles, Los Angeles (J.P., J.M.); Methods Western Psychiatric Institute and Clinic– University of Pittsburgh Medical Center, In this randomized, controlled trial, we assigned 488 children between the ages of Pittsburgh (B.B., S.I.); Duke University 7 and 17 years who had a primary diagnosis of separation anxiety disorder, general- Medical Center, Durham, NC (S.N.C., J.S.M.); the Division of Services and In- ized anxiety disorder, or social phobia to receive 14 sessions of cognitive behav- tervention Research, National Institute ioral therapy, sertraline (at a dose of up to 200 mg per day), a combination of ser- of Mental Health, Bethesda, MD (J.T.S.); traline and cognitive behavioral therapy, or a placebo drug for 12 weeks in a 2:2:2:1 Baystate Medical Center, Springfield, MA (B.W.); and Temple University, Philadel- ratio. We administered categorical and dimensional ratings of anxiety severity and phia (P.C.K.). Address reprint requests to impairment at baseline and at weeks 4, 8, and 12. Dr. Walkup at the Division of Child and Adolescent Psychiatry, Department of Results Psychiatry and Behavioral Sciences, Johns Hopkins Medical Institutions, 600 N. Wolfe The percentages of children who were rated as very much or much improved on the St., Baltimore, MD 21287. Clinician Global Impression–Improvement scale were 80.7% for combination ther- *The study investigators are listed in the apy (P<0.001), 59.7% for cognitive behavioral therapy (P<0.001), and 54.9% for Appendix. sertraline (P<0.001); all therapies were superior to placebo (23.7%). Combination therapy was superior to both monotherapies (P<0.001). Results on the Pediatric This article (10.1056/NEJMoa0804633) was published at www.nejm.org on October Anxiety Rating Scale documented a similar magnitude and pattern of response; 30, 2008. combination therapy had a greater response than cognitive behavioral therapy, which was equivalent to sertraline, and all therapies were superior to placebo. Ad- N Engl J Med 2008;359:2753-66. Copyright © 2008 Massachusetts Medical Society. verse events, including suicidal and homicidal ideation, were no more frequent in the sertraline group than in the placebo group. No child attempted suicide. There was less insomnia, fatigue, sedation, and restlessness associated with cognitive behavioral therapy than with sertraline. Conclusions Both cognitive behavioral therapy and sertraline reduced the severity of anxiety in children with anxiety disorders; a combination of the two therapies had a superior response rate. (ClinicalTrials.gov number, NCT00052078.) n engl j med 359;26 www.nejm.org december 25, 2008 2753 The New England Journal of Medicine Downloaded from nejm.org at WEILL CORNELL MEDICAL LIBRARY on April 19, 2012. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. The new england journal of medicine nxiety disorders are common in cebo free of charge but was not involved in the children and cause substantial impairment design or implementation of the study, the analy- in school, in family relationships, and in sis or interpretation of data, the preparation or A 1,2 social functioning. Such disorders also predict review of the manuscript, or the decision to pub- adult anxiety disorders and major depression.3-6 lish the results of the study. Despite a high prevalence (10 to 20%3,7,8) and substantial morbidity, anxiety disorders in child- Study Subjects hood remain underrecognized and undertreated.1,9 Children between the ages of 7 and 17 years with An improvement in outcomes for children with a primary diagnosis of separation or generalized anxiety disorders would have important public anxiety disorder or social phobia (according to health implications. the criteria of the Diagnostic and Statistical Manual of In clinical trials, separation and generalized Mental Disorders, fourth edition, text revision anxiety disorders and social phobia are often [DSM-IV-TR]16), substantial impairment, and an grouped together because of the high degree of IQ of 80 or more were eligible to participate. overlap in symptoms and the distinction from Children with coexisting psychiatric diagnoses other anxiety disorders (e.g., obsessive–compulsive of lesser severity than the three target disorders disorder). Efficacious treatments for these disor- were also allowed to participate; such diagnoses ders include cognitive behavioral therapy10,11 and included attention deficit–hyperactivity disorder the use of selective serotonin-reuptake inhibitors (ADHD) while receiving stable doses of stimulant (SSRIs).12,13 However, randomized, controlled tri- and obsessive–compulsive, post-traumatic stress, als comparing cognitive behavioral therapy, the oppositional–defiant, and conduct disorders. Chil- use of an SSRI, or the combination of both thera- dren were excluded if they had an unstable medi- pies with a control are lacking. The evaluation of cal condition, were refusing to attend school be- combination therapy is particularly important be- cause of anxiety, or had tried but had not had a cause approximately 40 to 50% of children with response to two adequate trials of SSRIs or an these disorders do not have a response to short- adequate trial of cognitive behavioral therapy. term treatment with either monotherapy.14,15 Girls who were pregnant or were sexually active Our study, called the Child–Adolescent Anxi- and were not using an effective method of birth ety Multimodal Study, was designed to address the control were also excluded. Children who were re- current gaps in the treatment literature by evalu- ceiving psychoactive medications other than stable ating the relative efficacy of cognitive behavioral doses of stimulants and who had psychiatric diag- therapy, sertraline, a combination of the two thera- noses that made participation in the study clini- pies, and a placebo drug. This article reports the cally inappropriate (i.e., current major depressive results of short-term treatment. or substance-use disorder; unmedicated ADHD, combined type; or a lifetime history of bipolar, Methods psychotic, or pervasive developmental disorders) or who presented an acute risk to themselves or Study Design and Implementation others were also excluded. This study was designed as a two-phase, multi- Recruitment occurred from December 2002 center, randomized, controlled trial for children through May 2007 at Duke University Medical Cen- and adolescents between the ages of 7 and 17 years ter, New York State Psychiatric Institute–Colum- who had separation or generalized anxiety disor- bia University Medical Center–New York Univer- der or social phobia. Phase 1 was a 12-week trial sity, Johns Hopkins Medical Institutions, Temple of short-term treatment comparing cognitive be- University, University of California, Los Angeles, havioral therapy, sertraline, and their combina- and Western Psychiatric Institute and Clinic–Uni- tion with a placebo drug. Phase 2 is a 6-month open versity of Pittsburgh Medical Center. The proto- extension for patients who had a response in col was approved and monitored by institutional phase 1. review boards at each center and by the data and The authors designed the study, wrote the manu- safety monitoring board of the National Institute script, and vouch for the data gathering and analy- of Mental Health. Subjects and at least one parent sis. Pfizer provided sertraline and matching pla- provided written informed consent. 2754 n engl j med 359;26 www.nejm.org december 25, 2008 The New England Journal of Medicine Downloaded from nejm.org at WEILL CORNELL MEDICAL LIBRARY on April 19, 2012. For personal use only. No other uses without permission. Copyright © 2008 Massachusetts Medical Society. All rights reserved. cognitive Behavioral Therapy and Sertraline in Childhood Anxiety Interventions isting disorders and psychosocial functioning us- Cognitive behavioral therapy involved fourteen ing reports from both the subjects and their 60-minute sessions, which included review and rat- parents and from interviews of subjects and par- ings of the severity of subjects’ anxiety, response ents at the time of screening, at baseline, and at to treatment, and adverse events. Therapy was weeks 4, 8, and 12. The interviews were adminis- based on the Coping Cat program,17,18 which was tered by independent evaluators who were unaware adapted for the subjects’ age and the duration of of study-group assignments. the study.19 Each subject who was assigned to re- We used the Anxiety Disorders Interview Sched- ceive cognitive behavioral therapy received training ule for DSM-IV-TR, Child Version,20 to establish in anxiety-management skills, followed by behav- diagnostic eligibility. The categorical primary out- ioral exposure to anxiety-provoking situations. come was the treatment response at week 12, Parents attended weekly check-ins and two parent- which was defined as a score of 1 (very much only sessions. Experienced psychotherapists, cer- improved) or 2 (much improved) on the Clinical tified in the Coping Cat protocol, received regular Global Impression–Improvement scale,21 which site-level and cross-site supervision.