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

Abstract

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 (RCBD) and comorbid substance abuse and/or dependence. Method A 6-month, double-blind, parallel group comparison was carried out in recently manic/hypomanic/mixed patients 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. 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% relapsed (24% into depression and 76% into a manic/hypomanic/mixed episode), 26% completed the study, and 19% 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 (p=NS). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% and 53%, respectively. The rate of depressive relapse in both arms was 13%, while the rate of relapse into a manic, hypomanic, or mixed episode was 44% for lithium monotherapy and 40% for the combination of lithium and divalproex. Conclusion A small subgroup of patients in this study stabilized after six 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 RCBD in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013

“…In a small RCT involving 31 patients with rapidcycling BD and comorbid SUD who were stabilized on the combination of lithium plus divalproex, there was no significant difference in mood relapse rates between patients randomized to continue combination therapy and those who received lithium alone (181). An analysis of 98 patients from the acute open-label phase of this study found that these patients have a poor response to treatment and a high burden of serious medical comorbidity (327).…”

“…In a six-month RCT, patients with BD (recent manic episode), SUD, and rapid cycling, who were responders to lithium plus divalproex, were randomized to continue combination therapy or lithium alone (181). Of 149 patients enrolled into the openlabel acute stabilization phase, 31 were assigned to maintenance treatment and 55% relapsed.…”

Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder

“…Lithium and/or divalproex have level 3 evidence 617, 682, 685, 686, 687. Quetiapine failed to provide any benefit in terms of mood and anxiety symptoms in a small subsample of highly comorbid patients with BD.…”

“…A combination of divalproex and lithium is the only treatment for alcohol use disorder comorbid with BD that meets criteria for level 2 evidence 682, 683. In a small RCT, there was a significant reduction in the number of drinks per drinking day, as well as per heavy drinking day, in the combination group compared to the group with lithium alone when adherence to treatment was added as a covariate.…”

“…Lithium or divalproex, either alone or in combination, were proven useful in small studies addressing cocaine use disorder682, 685, 686, 687, 707, 708 (level 4). Quetiapine in monotherapy or in combination with the ongoing treatment shows evidence of efficacy for cocaine, amphetamine and methamphetamine use disorder709, 710, 711 (level 3).…”