This entire article is available in PDF format to paid subscribers (certain restrictions apply).
If you have not already registered for Full Text Access to The Journal, then visit our registration page.

A 6-Month, Double-Blind, Maintenance Trial of Lithium Monotherapy Versus the Combination of Lithium and Divalproex for Rapid-Cycling Bipolar Disorder and Co-Occurring Substance Abuse or Dependence

David E. Kemp, M.D.; Keming Gao, M.D., Ph.D.; Stephen J. Ganocy, Ph.D.; Omar Elhaj, M.D.; Sarah R. Bilali, M.A.; Carla Conroy, B.A.; Robert L. Findling, M.D.; and Joseph R. Calabrese, M.D.

Objective: To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder and comorbid substance abuse and/or dependence.

Method: A 6-month, double-blind, parallel-group comparison was carried out in patients who met DSM-IV criteria for (1) bipolar I or II disorder; (2) alcohol, cannabis, or cocaine abuse within the last 3 months or dependence within the last 6 months; (3) rapid cycling during the 12 months preceding study entry; and (4) a history of at least 1 manic, hypomanic, or mixed episode within 3 months of study entry and who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy. The study was conducted at an outpatient mood disorders program between October 1997 and October 2006.

Results: Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%, nonresponse: 25%, intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% (N=17) relapsed (24% [N=4] into depression and 76% [N=13] into a manic/hypomanic/mixed episode), 26% (N=8) completed the study, and 19% (N=6) were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (not significant). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% (N=9) and 53% (N=8), respectively. The rate of depressive relapse in both arms was 13% (N=2), while the rate of relapse into a manic, hypomanic, or mixed episode was 44% (N=7) for lithium monotherapy and 40% (N=6) for the combination of lithium and divalproex.

Conclusion: A small subgroup of patients in this study stabilized after 6 months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of rapid-cycling bipolar disorder in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.

Trial Registration: clinical Identifier: NCT00194129.


(J Clin Psychiatry 2009;70(1):113-121. Online Ahead of Print December 30, 2008. doi:10.4088/JCP.07m04022)

Received Dec. 27, 2007; accepted April. 24, 2008. From Case Western Reserve University, University Hospitals Case Medical Center, Cleveland, Ohio (Drs. Kemp, Gao, Ganocy, Findling, and Calabrese and Mss. Bilali and Conroy); and Louis Stokes Cleveland Department of Veterans Affairs Medical Center, Brecksville, Ohio (Dr. Elhaj).

Supported by National Institutes of Health (NIH) grants R01MH-50165 (Dr. Calabrese) and P20MH-66054 (Drs. Calabrese and Findling) and in part by NIH grant 1KL2RR024990 (Dr. Kemp), and by an International Society for Bipolar Disorders Research Fellowship Award (Dr. Kemp). Study medication was provided by Abbott.

Presented in part at the 45th annual meeting of the American College of Neuropsychopharmacology; Dec. 37, 2006; Hollywood, Fla.

The authors acknowledge Daniel J. Rapport, M.D., University of Toledo, Ohio, for data collection. Dr. Rapport has no financial or other relationships relevant to the subject of this article.

Financial disclosure appears at the end of the article.

Corresponding author and reprints: David E. Kemp, M.D., 10524 Euclid Ave., 12th Floor, Cleveland, OH 44106 (e-mail: