A 20-month, double-blind, maintenance trial of lithium versus divalproex in rapid-cycling bipolar disorder

Am J Psychiatry. 2005 Nov;162(11):2152-61. doi: 10.1176/appi.ajp.162.11.2152.


Objective: The authors tested the hypothesis that divalproex would be more effective than lithium in the long-term management of patients with recently stabilized rapid-cycling bipolar disorder.

Method: A 20-month, double-blind, parallel-group comparison was carried out in recently hypomanic/manic patients who had experienced a persistent bimodal response to combined treatment with lithium and divalproex. Sixty patients were randomly assigned to lithium or divalproex monotherapy in a balanced design after stratification for illness type (bipolar I versus bipolar II disorder).

Results: Of the 254 patients enrolled in the open-label acute stabilization phase, 76% discontinued the study prematurely (poor adherence: 28%; nonresponse: 26% [of whom 74% remained depressed and 26% remained in a hypomanic/manic/mixed episode], intolerable side effects: 19%). Of the 60 patients (24%) randomly assigned to double-blind maintenance monotherapy, 53% relapsed (59% into depression and 41% into a hypomanic/manic/mixed episode), 22% completed the study, 10% had intolerable side effects, and 10% were poorly adherent. The rates of relapse into any mood episode for those given lithium versus divalproex were 56% and 50%, respectively; the rates were 34% and 29% for a depressive relapse and 19% and 22% for a hypomania/mania relapse. There were no significant differences in time to relapse. The proportion discontinuing prematurely because of side effects was 16% for lithium and 4% for divalproex.

Conclusions: The hypothesis that divalproex is more effective than lithium in the long-term management of rapid-cycling bipolar disorder is not supported by these data. Preliminary data suggest highly recurrent refractory depression may be the hallmark of rapid-cycling bipolar disorder.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Anticonvulsants / therapeutic use*
  • Bipolar Disorder / diagnosis
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / prevention & control
  • Double-Blind Method
  • Drug Therapy, Combination
  • Female
  • Follow-Up Studies
  • Humans
  • Lithium / therapeutic use*
  • Longitudinal Studies
  • Male
  • Patient Dropouts
  • Psychiatric Status Rating Scales
  • Secondary Prevention
  • Treatment Outcome
  • Valproic Acid / therapeutic use*


  • Anticonvulsants
  • Valproic Acid
  • Lithium