Protein kinase C inhibition in the treatment of mania: a double-blind, placebo-controlled trial of tamoxifen

Arch Gen Psychiatry. 2008 Mar;65(3):255-63. doi: 10.1001/archgenpsychiatry.2007.43.


Context: Findings that protein kinase C (PKC) activity may be altered in mania, and that both lithium carbonate and valproate sodium inhibit PKC-associated signaling in brain tissue, encourage development of PKC inhibitors as candidate antimanic agents.

Objective: To perform a controlled test of antimanic efficacy of the centrally active PKC inhibitor tamoxifen citrate.

Design: Three-week, randomized, double-blind, placebo-controlled, parallel-arms trial.

Setting: A university medical center inpatient psychiatric unit in Izmir, Turkey.

Patients: Sixty-six patients aged 18 to 60 years, diagnosed as having DSM-IV bipolar I disorder on the basis of the Structured Clinical Interview for DSM-IV, currently in a manic or mixed state, with or without psychotic features, with initial scores on the Young Mania Rating Scale (YMRS) greater than 20.

Intervention: Treatment with tamoxifen or identical placebo tablets for up to 3 weeks. Adjunctive lorazepam was allowed up to 5 mg/d.

Main outcome measures: Primary: change in YMRS scores; secondary: change in Clinical Global Impressions-Mania scores, weekly ratings of depression and psychosis, and adjunctive use of lorazepam.

Results: The 21-day trial was completed by 29 of 35 subjects randomized to receive tamoxifen (83%) and 21 of 31 given placebo (68%) (P = .25). Intent-to-treat analysis of available measures on all 66 subjects indicated that tamoxifen treatment yielded mean decreases in scores on the YMRS and Clinical Global Impressions-Mania of 5.84 and 0.73 point per week, respectively, compared with mean increases of 1.50 and 0.10 point per week, respectively, with placebo; both drug-placebo contrasts differed significantly (P < .001).

Conclusions: Tamoxifen demonstrated antimanic properties and was remarkably well tolerated. The findings encourage further clarification of the role of PKC in the pathophysiologic mechanism of bipolar I disorder and development of novel anti-PKC agents as potential antimanic or mood-stabilizing agents.

Trial registration: Identifier: NCT00411203 and Identifier: ISRCTN97160532.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors / therapeutic use*
  • Tamoxifen / therapeutic use*
  • Treatment Outcome


  • Antimanic Agents
  • Protein Kinase Inhibitors
  • Tamoxifen
  • Protein Kinase C

Associated data

  • ISRCTN/ISRCTN97160532