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.
RCT Entities:
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.
Authors: Cristiana T Trinconi; Juliana Q Reimão; Jenicer K U Yokoyama-Yasunaka; Danilo C Miguel; Silvia R B Uliana Journal: Antimicrob Agents Chemother Date: 2014-02-18 Impact factor: 5.191