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

Department of Psychiatry, Dokuz Eylül University, Huzur Mah, Saffet Baba Sok, No. 27/12 PK: 35320 Narlidere, Izmir, Turkey.
Archives of general psychiatry (Impact Factor: 14.48). 04/2008; 65(3):255-63. DOI: 10.1001/archgenpsychiatry.2007.43
Source: PubMed


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.
To perform a controlled test of antimanic efficacy of the centrally active PKC inhibitor tamoxifen citrate.
Three-week, randomized, double-blind, placebo-controlled, parallel-arms trial.
A university medical center inpatient psychiatric unit in Izmir, Turkey.
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.
Treatment with tamoxifen or identical placebo tablets for up to 3 weeks. Adjunctive lorazepam was allowed up to 5 mg/d.
Primary: change in YMRS scores; secondary: change in Clinical Global Impressions-Mania scores, weekly ratings of depression and psychosis, and adjunctive use of lorazepam.
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).
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. Identifier: NCT00411203 and Identifier: ISRCTN97160532.

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Available from: Ayşegül Yildiz, Jan 15, 2014
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    • "In rodents, the non-selective PKC inhibitor tamoxifen has been shown to reduce the hyperlocomotion elicited by amphetamine (Einat et al., 2007; Sabioni et al., 2008). In addition, preliminary clinical trials demonstrating that tamoxifen rapidly improved manic symptoms of bipolar patients (Bebchuk et al., 2000; Kulkarni et al., 2006; Zarate et al., 2007; Yildiz et al., 2008; Amrollahi et al., 2010) suggest that PKC inhibition might be a relevant antimanic strategy. "
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