Abstract
Impulsive aggressive behavior is common in psychiatric disorders and accounts for significant morbidity and mortality. However, little systematic treatment data exist from placebo-controlled trials for this symptom domain. This was a multicenter, randomized, double-blind, placebo-controlled study in which outpatients with a score of ⩾15 on the Aggression scale of the Overt Aggression Scale-Modified (OAS-M) and who fulfilled DSM-IV criteria for Cluster B personality disorder (n=96), intermittent explosive disorder (n=116), or post-traumatic stress disorder (n=34) were randomized to divalproex sodium or placebo for 12 weeks duration. Based on average OAS-M Aggression scores over the last 4 weeks of treatment, a treatment effect was not observed in the intent-to-treat data set (combined across the three psychiatric disorders), but was observed in both intent-to-treat and evaluable data sets for patients with Cluster B personality disorders. In the Cluster B evaluable data set, statistically significant treatment differences favoring divalproex were also observed for component items of the OAS-M Aggression score, including verbal assault and assault against objects, as well as OAS-M Irritability score, and Clinical Global Impression (CGI)-Severity at multiple time points throughout the study. No treatment group difference was noted for overall premature discontinuation rate; however, across psychiatric diagnoses, 21 (17%) patients in the divalproex group prematurely discontinued because of an adverse event, as compared to 4 (3%) patients in the placebo group (p<0.001). While a treatment effect was not observed when all diagnostic groups were combined, in a large subgroup of patients with Cluster B disorders, divalproex was superior to placebo in the treatment of impulsive aggression, irritability, and global severity.
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Acknowledgements
We thank the other investigators, as follows, for their enrollment of patients and participation in this study: Kathleen Brady, MD, Medical University of South Carolina, Charleston, SC; Lori Davis, MD, Tuscaloosa VAMC, Tuscaloosa, AL; James Ferguson, MD, Pharmacology Research Clinic, Salt Lake City, UT; Jeffrey S Kelsey, MD, Emory University, Atlanta, GA; Steven Lindley, MD, National Center for PTSD, Menlo Park, CA; Gopinath Mallya, MD, McLean Hospital, Belmont, MA; John Marshall, MD, Wisconsin Psychiatric Institute and Clinics, Madison, WI; Jeffrey A Mattes, MD, Psychopharm Research, Princeton, NJ; Gerard F Moeller, MD, University of Texas Health Science Center, Houston, TX; George Nurnberg, MD, University of New Mexico Health Sciences Center, Albuquerque, NM; Frederick Petty, MD, Dallas VAMC, Dallas, TX; Mark Rapaport, MD, University of California, La Jolla, CA; Rudolph Steven, DO, San Diego, CA; Christopher Reist, MD, Long Beach VAMC, Long Beach, CA; Carlos Zarate, MD, University of Massachusetts, Worcester, MA; and Mark Zimmerman, MD, Rhode Island Hospital, Providence, RI.
The DSMB members for this study were: Dennis Charney, MD, National Institute of Mental Health, Bethesda, MD; Judith Jones, MD, PhD, The Degge Group, Ltd, Arlington, VA; James Neaton, PhD, School of Public Health, University of Minnesota, Minneapolis, MN; Larry Siever, MD, Bronx VA Medical Center (116A), Bronx, NY; and Debbie Wentworth, School of Public Health, University of Minnesota, Minneapolis, MN.
Dr Hollander has received research grants from Abbott Laboratories, Bristol Myers Squibb, Eli Lilly and Company, Pfizer Laboratories, Solvay, and Wyeth-Ayerst. He has served as a consultant to and member of the Speakers Bureau of Abbott Laboratories, Solvay, and Wyeth-Ayerst.
Dr Swann has received grant support from Abbott Labo-ratories, Glaxo SmithKline, UCB Pharma, Bristol Myers Squibb, Eli Lilly, and Shire Laboratories. He has served as a consultant for Abbott Laboratories, Pfizer Laboratories, Shire Laboratories, UCB Pharma, Glaxo SmithKline, Novartis, Eli Lilly, and Bristol Myers Squibb. He has served on Speakers’ Bureaus for Abbott Laboratories, Janssen Pharmaceuticals, Novartis, Glaxo SmithKline, and Pfizer Laboratories.
Dr Coccaro is a consultant to Abbott Laboratories and to Eli Lilly Pharmaceuticals. He is a member of the Speakers Bureau for Abbott Laboratories, Eli Lilly Pharmaceuticals, Glaxo SmithKline, and Forest Pharmaceuticals and has received research grants from Abbott Laboratories and Eli Lilly Pharmaceuticals.
Dr McElroy is a consultant to Abbott Laboratories and is a member of the company's Speakers Bureau and Divalproex Advisory Board. She has also received research grants from Abbott Laboratories, and Eli Lilly and Company.
Dr Nemeroff reports the following: Grants/Research: Abbott Laboratories; AstraZeneca; Bristol-Myers-Squibb; Forest Laboratories; Janssen Pharmaceutica; Eli Lilly; GlaxoSmithKline; NARSAD; NIMH; Organon; Pfizer Pharmaceuticals; Pharmacia-Upjohn; Stanley Foundation/NAMI; and Wyeth-Ayerst.
Consultant: Abbott Laboratories; Acadia Pharmaceuticals; AstraZeneca; Bristol-Myers-Squibb; Cephalon Pharmaceuticals; Corcept; Cypress Biosciences; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Eli Lilly; Merck; Mindsense; Neurocrine Biosciences; Novartis; Organon; Otsuka; Pharmacia-Upjohn; Sanofi; Somerset; Vela Pharmaceuticals; and Wyeth-Ayerst.
Speakers Bureau: Abbott Laboratories; AstraZeneca; Bristol-Myers-Squibb; Eli Lilly; Forest Laboratories; GlaxoSmithKline; Janssen Pharmaceutica; Organon; Pfizer Pharmaceuticals; and Wyeth-Ayerst.
Stockholder: Corcept and applies only to Dr. Nemeroff Drs Tracy, Wozniak, and Sommerville are employees of Abbott Laboratories.
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This study was supported by a grant from Abbott Laboratories, Abbott Park, IL. These data were presented in part at the 2002 Annual Meeting of the American Psychiatric Association, Philadelphia, PA, USA, May 18–23, 2002.
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Hollander, E., Tracy, K., Swann, A. et al. Divalproex in the Treatment of Impulsive Aggression: Efficacy in Cluster B Personality Disorders. Neuropsychopharmacol 28, 1186–1197 (2003). https://doi.org/10.1038/sj.npp.1300153
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DOI: https://doi.org/10.1038/sj.npp.1300153
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