Journal of the American Academy of Child & Adolescent Psychiatry
Volume 48, Issue 5 , Pages 519-532, May 2009

A Double-Blind, Randomized, Placebo-Controlled Trial of Divalproex Extended-Release in the Treatment of Bipolar Disorder in Children and Adolescents

Dr. Wagner is with the University of Texas Medical Branch; Dr. Redden is with the Abbott Laboratories; Dr. Kowatch is with the University of Cincinnati Medical Center; Dr. Wilens is with the Massachusetts General Hospital; Dr. Segal is with the Segal Institute for Clinical Research; Dr. Chang is with the Stanford University School of Medicine; Drs. Vigna, Abi-Saab, and Saltarelli are with Abbott Laboratories and the Divalproex ER Pediatric Mania Group; and Dr. Wozniak is with Advanced Clinical Research Services

Accepted 29 December 2008.

Disclosure: Dr. Wagner is or has been a consultant to or an advisory board member of Abbott Laboratories, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen, Jazz Pharmaceuticals, Johnson & Johnson, Novartis, Ortho-McNeil, Otsuka, Pfizer, Solvay, and Wyeth. She receives research support from the National Institute of Mental Health. She received honoraria for consultation regarding the study design. Dr. Kowatch is a member of the speakers' bureau for AstraZeneca and serves as a consultant to Forest, GlaxoSmithKline, Medscape, and Physicians Postgraduate Press. He receives support from the National Alliance for Research on Schizophrenia and Depression, the National Institute of Child Health and Human Development, the National Institute of Mental Health, and the Stanley Foundation. Dr. Wilens receives grant support from Abbott, McNeil, Eli Lilly, the National Institutes of Health/National Institute on Drug Abuse, Merck, and Shire. He is a member of the speakers' bureaus of Eli Lilly, McNeil, Novartis, and Shire. He is a consultant to Abbott, McNeil, Eli Lilly, the National Institutes of Health/National Institute on Drug Abuse, Novartis, Merck, and Shire. He received honoraria for consultation regarding this study design. Dr. Chang serves as a consultant to Abbott, AstraZeneca, GlaxoSmithKline, Eli Lilly, and Otsuka; has received research support from Abbott, AstraZeneca, GlaxoSmithKline, Eli Lilly, and Otsuka; and is a member of the speakers' bureaus and advisory boards of Abbott, AstraZeneca, and Eli Lilly. Dr. Wozniak is a former employee of Abbott and receives financial compensation in the form of pension, stocks, and stock options. Drs. Redden, Vigna, Abi-Saab, and Saltarelli are employees of Abbott Laboratories. Dr. Segal reports no conflicts of interest.

Abstract 

Objectives

To compare the efficacy and safety of divalproex extended-release (ER) to placebo in a 28-day double-blind study of bipolar disorder in children and adolescents and evaluate the safety of divalproex ER in a 6-month open-label extension study.

Method

In the double-blind study, 150 patients (manic or mixed episode, aged 10-17 years) with baseline Young Mania Rating Scale (YMRS) score of 20 or higher were randomized to once-daily placebo or divalproex ER, which was titrated to clinical response or serum valproate concentration of 80 to 125 μg/mL. Sixty-six patients enrolled in the extension study.

Results

In the double-blind study, a treatment effect was not observed with divalproex ER based on change in mean YMRS score (divalproex ER −8.8 [n = 74]; placebo −7.9 [n = 70]) or secondary measures. Divalproex was similar to placebo based on incidence of adverse events. Four subjects treated with divalproex ER and three treated with placebo discontinued because of adverse events. Mean ammonia levels increased in the divalproex ER group, but only one patient was symptomatic. In the long-term study, YMRS scores decreased modestly (2.2 points from baseline). The most common adverse events were headache and vomiting.

Conclusions

The results of the study do not provide support for the use of divalproex ER in the treatment of youths with bipolar I disorder, mixed or manic state. Further controlled trials are required to confirm or refute the findings from this study.

Key Words:  bipolar disorder , divalproex ER , treatment

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 This study was supported by a grant from Abbott Laboratories.The authors thank the other members of the Divalproex ER Pediatric Mania Group, as follows, for their enrollment of patients and participation in this study (both the double-blind and long-term studies unless otherwise indicated): Grant Belnap, M.D., Eagle, ID (long-term study only); Deborah Bergen, M.D., Wichita, KS; Guy Brannon, M.D., Shreveport, LA; Michael Greenbaum, M.D., Libertyville, IL; Sanjay Gupta, M.D., Olean, NY; Robert Hendren, D.O., Sacramento, CA (double-blind study only); Willis Holloway Jr., M.D., Oklahoma City, OK; Ali Kashfi, M.D., P.A., Altamonte Springs, FL; Bennett Leventhal, M.D., Chicago, IL (double-blind study only); Melisa Martinez, M.D., Galveston, TX; Sohail Punjwani, M.D., North Miami, FL; Robert Riesenberg, M.D., Atlanta, GA (double-blind study only); Michael Rieser, M.D., Lexington, KY; Adelaide Robb, M.D., Washington, DC; Franco Sicuro, M.D., St. Louis, MO; Deborah Simkin, M.D., Destin, FL; and William Terry, M.D., Boise, ID (double-blind study only).Clinical trial registration information–An Outpatient Study of the Effectiveness and Safety of Depakote ER in the Treatment of Mania/Bipolar Disorder in Children and Adolescents. URL: http://clinicaltrials.gov. Unique identifier: NCT00067262. Evaluate the Safety of Depakote Extended Release Tablets in the Treatment of Mania Associate With Disorder in Children and Adolescents. URL: http://clinicaltrials.gov. Unique identifier: NCT00195767.

PII: S0890-8567(09)60069-1

doi:10.1097/CHI.0b013e31819c55ec

Journal of the American Academy of Child & Adolescent Psychiatry
Volume 48, Issue 5 , Pages 519-532, May 2009

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