title: Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms.
abstract: OBJECTIVE
  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.
authors: Mood and Anxiety Disorders Program, National Institutes of Health Intramural Research Program, Building 10, Room 3N210, MSC 1290, Bethesda, MD 20892, USA. mallingera@mail.nih.gov
authors: Alan G
authors: AG
authors: Mallinger
authors: Michael E
authors: ME
authors: Thase
authors: Roger
authors: R
authors: Haskett
authors: Joan
authors: J
authors: Buttenfield
authors: David A
authors: DA
authors: Luckenbaugh
authors: Ellen
authors: E
authors: Frank
authors: David J
authors: DJ
authors: Kupfer
authors: Husseini K
authors: HK
authors: Manji
mesh_terms: D000328:Adult; D018692:Antimanic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000523:psychology; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D016651:Lithium Carbonate / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010546:Perphenazine / Q000009:adverse effects / Q000627:therapeutic use; D011569:Psychiatric Status Rating Scales; D014700:Verapamil / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018692:Antimanic Agents; D014150:Antipsychotic Agents; D002121:Calcium Channel Blockers; D016651:Lithium Carbonate; D014700:Verapamil; D010546:Perphenazine