Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms

Bipolar Disord. 2008 Dec;10(8):856-66. doi: 10.1111/j.1399-5618.2008.00636.x.


Objectives: Attenuation of protein kinase C (PKC) is a mechanism common to both established (lithium, valproate) and some novel (tamoxifen) antimanic agents. Verapamil, although primarily known as a calcium channel blocker, also has PKC inhibitory activity. Verapamil has shown antimanic activity in some but not all studies. Therefore, we investigated verapamil, used alone or as an adjunctive treatment, in manic patients who did not respond to an initial adequate trial of lithium.

Methods: Each study phase lasted three weeks. Subjects were treated openly with lithium in Phase 1 (n = 45). Those who failed to respond were randomly assigned to double-blind treatment in Phase 2 with either verapamil (n = 10) or continued-lithium (n = 8). Phase 2 nonresponders (n = 10) were assigned to combined verapamil/lithium in Phase 3.

Results: Response in Phase 2 did not differ significantly between verapamil and continued-lithium. During Phase 3, response to combined treatment was significantly better than overall response to monotherapy in Phase 2 (Fisher's Exact test, p = 0.043). Mania ratings improved during combined treatment in Phase 3 by 88.2% (linear mixed model analysis, F = 4.34, p = 0.013), compared with 10.5% improvement during Phase 2.

Conclusions: In this preliminary investigation, verapamil monotherapy did not demonstrate antimanic efficacy. By contrast, the combination of verapamil plus lithium was highly efficacious. Our findings thus suggest that verapamil may have potential utility as an adjunct to lithium. This effect may be mediated by additive actions on PKC inhibition, which may be an important mechanism for antimanic agents in general.

Trial registration: NCT00518947.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Antimanic Agents / adverse effects
  • Antimanic Agents / therapeutic use*
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / therapeutic use
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / psychology
  • Calcium Channel Blockers / adverse effects
  • Calcium Channel Blockers / therapeutic use*
  • Double-Blind Method
  • Drug Resistance
  • Drug Therapy, Combination
  • Female
  • Humans
  • Lithium Carbonate / adverse effects
  • Lithium Carbonate / therapeutic use*
  • Male
  • Middle Aged
  • Perphenazine / adverse effects
  • Perphenazine / therapeutic use
  • Psychiatric Status Rating Scales
  • Verapamil / adverse effects
  • Verapamil / therapeutic use*


  • Antimanic Agents
  • Antipsychotic Agents
  • Calcium Channel Blockers
  • Lithium Carbonate
  • Verapamil
  • Perphenazine

Associated data