Sertraline in Children and Adolescents With Obsessive-Compulsive Disorder A Multicenter Randomized Controlled Trial John S. March, MD, MPH; Joseph Biederman, MD; Robert Wolkow, MD; Allan Safferman, MD; Jack Mardekian, PhD; Edwin H. Cook, MD; Neal R. Cutler, MD; Roberto Dominguez, MD; James Ferguson, MD; Betty Muller, MD; Robert Riesenberg, MD; Murray Rosenthal, DO; Floyd R. Sallee, MD, PhD; Hans Steiner, MD; Karen D. Wagner, MD, PhD Context.—The serotonin reuptake inhibitors are the treatment of choice for pa- APPROXIMATELY 1 in 200 young per- tients with obsessive-compulsive disorder; however, empirical support for this as- sons has obsessive-compulsive disorder sertion has been weaker for children and adolescents than for adults. (OCD),1 which many believe to be the 2 Objective.—To evaluate the safety and efficacy of the selective serotonin reup- paradigmatic neuropsychiatric illness. take inhibitor sertraline hydrochloride in children and adolescents with obsessive- Individuals with OCD experience obses- sions, which are recurrent and persis- compulsive disorder. tent thoughts, images, or impulses that Design.—Randomized, double-blind, placebo-controlled trial. are egodystonic, intrusive, and, for the Patients.—One hundred eighty-seven patients: 107 children aged 6 to 12 years most part, acknowledged as senseless.3 and 80 adolescents aged 13 to 17 years randomized to receive either sertraline (53 children, 39 adolescents) or placebo (54 children, 41 adolescents). See also p 1784 and Patient Page. Setting.—Twelve US academic and community clinics with experience con- ducting randomized controlled trials. Intervention.—Sertraline hydrochloride was titrated to a maximum of 200 mg/d Common obsessions are generally ac- during the first 4 weeks of double-blind therapy, after which patients continued to companied by distressing negative af- fects, such as fear, disgust, doubt, or a receive this dosage of medication for 8 more weeks. Control patients received feeling of incompleteness, and include placebo. contamination fears, scrupulosity, fear Main Outcome Measures.—The Children’s Yale-Brown Obsessive Compul- of harm to self or others, symmetry sive Scale (CY-BOCS), the National Institute of Mental Health Global Obsessive urges, or hoarding urges. Not surpris- Compulsive Scale (NIMH GOCS), and the NIMH Clinical Global Impressions of ingly, persons with OCD typically at- Severity of Illness (CGI-S) and Improvement (CGI-I) rating scales. tempt to ignore, suppress, or neutralize Results.—In intent-to-treat analyses, patients treated with sertraline showed sig- obsessive thoughts and associated feel- nificantly greater improvement than did placebo-treated patients on the CY-BOCS ings by performing compulsions, which (adjusted mean, −6.8 vs −3.4, respectively; P = .005), the NIMH GOCS (−2.2 vs −1.3, are repetitive, purposeful behaviors that respectively; P = .02), and the CGI-I (2.7 vs 3.3, respectively; P = .002) scales. Sig- are usually performed according to cer- tain rules or in a stereotyped fashion to nificant differences in efficacy between sertraline and placebo emerged at week 3 temporarilyneutralizeoralleviateobses- and persisted for the duration of the study. Based on CGI-I ratings at end point, 42% sions and their accompanying dysphoric of patients receiving sertraline and 26% of patients receiving placebo were very affects.4 Compulsions can be observable much or much improved. Neither age nor sex predicted response to treatment. The behaviors (eg, hand washing) or covert incidence of insomnia, nausea, agitation, and tremor were significantly greater in mental acts (eg, counting). Among chil- patients receiving sertraline; 12 (13%) of 92 sertraline-treated patients and 3 (3.2%) dren and adolescents with OCD, few re- of 95 placebo-treated patients discontinued prematurely because of adverse medi- ceive a correct diagnosis and even fewer cal events (P = .02). No clinically meaningful abnormalities were apparent on vital receive appropriate treatment.1 sign determinations, laboratory findings, or electrocardiographic measurements. An extensive empirical literature Conclusion.—Sertraline appears to be a safe and effective short-term treatment demonstrates that the potent serotonin reuptake inhibitors (SRIs) clomipra- for children and adolescents with obsessive-compulsive disorder. minehydrochloride,5 fluoxetine,6 fluvox- JAMA. 1998;280:1752-1756 amine,7 paroxetine,8 and sertraline hy- drochloride9 areeffectivetreatmentsfor From the Departments of Psychiatry and Psychol- Decatur, Ga (Dr Riesenberg); Department of Psychia- adults with OCD. Although empirical ogy, Duke University Medical Center, Durham, NC (Dr try, Medical University of South Carolina, Charleston (Dr support is more limited, pharmaco- March); the Department of Psychiatry, Massachusetts Sallee); Department of Psychiatry, Stanford University, General Hospital, Boston (Dr Biederman); Pfizer Inc, New Stanford, Calif (Dr Steiner) and the Department of Psy- therapy for children and adolescents 10 York, NY (Drs Wolkow, Safferman, and Mardekian); the chiatry, University of Texas Medical Branch, Galveston with OCD also relies on SRIs. The ear- Departments of Psychiatry and Pediatrics, University of (Dr Wagner). Dr Ferguson is in private practice in Mur- liest pediatric studies were conducted Chicago, Chicago, Ill (Dr Cook); California Clinical Tri- ray, Utah, and Dr Rosenthal is in private practice in San als, Beverly Hills (Dr Cutler); the Department of Psy- Diego, Calif. with the tricyclic compound clomipra- 5 11 chiatry, University of Miami, Miami, Fla (Dr Dominguez); Reprints: John S. March, MD, MPH, Pediatric Psychia- mine. In the mid 1980s, Flament et al Department of Psychiatry, Tulane University, New Or- try, Duke University Medical Center, Box 3527, Durham, reported that clomipramine was statis- leans, La (Dr Muller); Biobehavioral Research Center, NC 27710 (e-mail: [email protected]). tically superior to 1752 JAMA, November 25, 1998—Vol 280, No. 20 Sertraline and Obsessive-Compulsive Disorder—March et al ©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 placebo in a placebo-controlled, double- gators obtained assent of the child or ado- Compulsive Scale (CY-BOCS), the blind, crossover study. Leonard et al12 lescentandwritteninformedconsentfrom NIMH GOCS, and the NIMH Clinical then showed that clomipramine was su- parents or legal guardians. Global Impression of Severity of Illness perior to the predominantly noradrener- Inclusion and Exclusion Criteria (CGI-S) and Improvement (CGI-I) gic reuptake inhibitor desipramine hy- scales. The CY-BOCS is identical in form drochloride. Subsequently, an 8-week Patients were male and female outpa- andscoringtothewidelyusedadultYale- multicenter, double-blind, parallel com- tients aged 6 to 17 years who met full Di- Brown Obsessive Compulsive Scale,22 parison of clomipramine vs placebo led to agnostic and Statistical Manual of Men- but the questions are slightly modified tal Disorders, Revised Third Edition 23 US Food and Drug Administration ap- 21 forageappropriateness. TheCY-BOCS proval of clomipramine for the treatment (DSM-III-R) diagnostic criteria for OCD scale ranges from 0 to 40, with a score of of OCD in children and adolescents aged on clinical interview. At the baseline visit, 20 indicating moderate severity of obses- 10 years and older.13 patients were required to have a score of sive and compulsive symptoms and a Unfortunately, clomipramine causes a at least 7 on the National Institute of Men- score of 10 or below indicating subclinical tal Health Global Obsessive Compulsive wide spectrum of anticholinergic, antihis- 22 OCD. The NIMH GOCS has been exten- taminergic, and antiadrenergic adverse Rating Scale (NIMH GOCS), indicating sively used in both adult22 and pediatric12 effects, including excessive sedation, at least moderate impairment in global OCD trials. It assesses severity of OCD weight gain, adverse cardiovascular ef- functioning from OCD, and a score of 17 symptoms in relation to their functional fects, and an increased risk for drug-in- or less plus a score of 0 (none) or 1 (mini- impact.24 Scores of 1 to 3 indicate minimal ducedseizures.14 Thesedifficultiesencour- mal) on item 1 (depressed mood) of the 24- impairment, scores of 7 or more indicate agedthesearchformoreeffectiveandbet- item Hamilton Depression Scale, indicat- clinically meaningful OCD symptoms, ter-tolerated treatments for young per- ing the absence of significant depression. and scores of 13 to 15 indicate very severe sons with OCD.15 One such agent is the Baseline electrocardiographic and labora- obsessive and compulsive behaviors. The selective serotonin reuptake inhibitor tory results were required to be normal NIMH CGI scales provided clinician- (SSRI) sertraline, a naphthylamino com- or not clinically significant if outside the rated overall summary: the CGI-S scale pound that specifically blocks neuronal re- normal range. ranges from 1 (normal, not at all ill) to 7 uptake of serotonin via competitive inhi- Patients having a primary psychiatric (extremelyill)andtheCGI-Iscaleranges bition at the presynaptic serotonin trans- disorder other than OCD on clinical inter- from 1 (very much improved judgments) porter.16 Controlled trials of sertraline in view were excluded, as were those with to 7 (very much worse judgments).25 adultswithOCDdemonstratethatsertra- medical contraindications to treatment Efficacy measures were obtained on line is more effective than placebo17