Protein kinase C inhibitor tamoxifen new concept in the treatment of mania

Abstract

Existing evidence suggests that two structurally dissimilar anti-manic agents, lithium and valproate, attenuate protein kinase C-PKC function in a therapeutically relevant time frame, whereas promanic psychostimulants activate PKC. PKC plays a major role in the regulation of neuronal excitability, neurotransmitter release, long-term alterations in gene expression and plasticity. Recently, two scientifically rigorous, placebo-controlled, randomized trials of a PKC inhibitor drug: tamoxifen in mania have been carried out. Both trials, which were carried out independently, indicate that tamoxifen has strong antimanic properies. In the first trial intent-to-treat analysis of available measures on 66 subjects indicated that tamoxifen yielded a mean Young Mania rating Scale-YMRS decrease of 5.84 points/week (0.73 CGI-Mania points/week) compared to a mean increase of 1.50 (YMRS) and 0.10 (CGI-Mania) points/week with placebo; both drug-placebo contrasts differed significantly (p<0.001). The second study conducted at the NIMH with 16 manic patients reported a mean YMRS decrease of 18.3 ± 4.29 points with tamoxifen compared to a mean increase of 4.67 ± 4.08 YMRS points with placebo over 3 weeks. These two proof of concept trials on the role of ‘PKC’ in development and treatment of mania along with all the previous genomic, preclinical, and clinical work represents an example of thoughtful drug development and improved understanding of the pathophysiology of bipolar illness. This first target specific anti-manic treatment strategy via measurable effects of the disease or the test drug on the target: PKC may also lead to identification of a biomarker indicative of the disease state and potential treatment responders.