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

Ayşegül Yildiz, Sebnem Guleryuz, Donna Pauler Ankerst, Dost Öngür, Perry F. Renshaw

Research output: Contribution to journalArticle

148 Scopus citations

Abstract

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: clinicaltrials.gov Identifier: NCT00411203 and isrctn.org Identifier: ISRCTN97160532.

Original languageEnglish (US)
Pages (from-to)255-263
Number of pages9
JournalArchives of General Psychiatry
Volume65
Issue number3
DOIs
StatePublished - Mar 1 2008

ASJC Scopus subject areas

  • Arts and Humanities (miscellaneous)
  • Psychiatry and Mental health

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