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Double-Blind, Placebo-Controlled Trial of Divalproex Monotherapy in the Treatment of Symptomatic Youth at High Risk for Developing Bipolar Disorder
Robert L. Findling, M.D.; Thomas W. Frazier, Ph.D.; Eric A. Youngstrom, Ph.D.; Nora K. McNamara, M.D.; Robert J. Stansbrey, M.D.; Barbara L. Gracious, M.D.; Michael D. Reed, Pharm.D.; Christine A. Demeter, M.A.; and Joseph R. Calabrese, M.D.
Objective: To determine if divalproex sodium was superior to placebo in the treatment of symptomatic youths who suffer from a bipolar spectrum disorder and who also have a parent with a diagnosis of a bipolar illness.
Method: Youths, ages 5 to 17 years, meeting DSM-IV criteria for bipolar disorder not otherwise specified (NOS) or cyclothymia who also had at least 1 biological parent with bipolar illness were randomly assigned in a double-blind fashion to receive treatment with either divalproex sodium or placebo for up to 5 years. Study participation ended if the subject required additional clinical intervention, if the patient developed treatment-related adverse events, or if the participant was not adherent with study procedures. The primary outcome measure was time to study discontinuation for any reason. The study was conducted from August 1997 to April 2003.
Results: Fifty-six youths with a mean (SD) age of 10.7 (3.1) years were randomly assigned and received either divalproex sodium (N = 29) or placebo (N = 27). In spite of statistical power of 80% to detect hazard ratios of 2.2 or larger, the treatment groups did not significantly differ in survival time for discontinuation for any reason (p = .93) or discontinuation due to a mood event (p = .55). Changes in mood symptom ratings and psychosocial functioning from baseline to study discontinuation did not differ between groups (most significant p > .14). However, both groups did show improvements in mood symptoms and psychosocial functioning over time (all p values < .002). One patient, from the placebo group, ended study participation due to an adverse event.
Conclusion: These results suggest that, although well tolerated, divalproex sodium does not produce clinically meaningful improvements in the treatment of symptomatic youths suffering from either bipolar NOS or cyclothymia who are at genetic risk for developing bipolar disorder.
(J Clin Psychiatry 2007;68:781-788)
Received Aug. 18, 2006; accepted Oct. 17, 2006. From the Departments of Psychiatry (Drs. Findling, McNamara, Stansbrey, and Calabrese and Ms. Demeter) and Pediatrics (Drs. Findling and Reed), Case Western Reserve University, and the University Hospitals of Cleveland (Drs. Findling, McNamara, Stansbrey, Reed, and Calabrese), Cleveland, Ohio; the Department of Psychology, John Carroll University, University Heights, Ohio (Dr. Frazier); the Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill (Dr. Youngstrom); and Strong Memorial Hospital, University of Rochester Medical Center, Rochester, N.Y. (Dr. Gracious).
This study was primarily supported by The Stanley Medical Research Institute, Chevy Chase, Md. The study was also supported in part by a National Institute of Mental Health Developing Centers for Interventions and Services Research grant (P 20 MH-66054). Nursing and pharmacy activities were supported in part by a National Institute of Child Health and Human Development Pediatric Pharmacology Research Unit contract (HD 31323-05). Medications were provided in part by Abbott Laboratories, Abbott Park, Ill.
Financial disclosure appears at the end of the article.
Corresponding author and reprints: Robert L. Findling, M.D., Child and Adolescent Psychiatry, University Hospitals of Cleveland, 11100 Euclid Ave., Cleveland, OH 44106-5080 (e-mail: email@example.com).