Protein Kinase C Inhibition in the Treatment of Mania
2008; American Medical Association; Volume: 65; Issue: 3 Linguagem: Inglês
10.1001/archgenpsychiatry.2007.43
ISSN1538-3636
AutoresAyşegül Yıldız, Sebnem Guleryuz, Donna P. Ankerst, Döst Öngür, Perry F. Renshaw,
Tópico(s)Pharmacological Effects and Toxicity Studies
ResumoContext 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:NCT00411203and isrctn.org Identifier:ISRCTN97160532
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