Antimanic Treatment With Tamoxifen Affects Brain Chemistry: A Double-Blind, Placebo-Controlled Proton Magnetic Resonance Spectroscopy Study

Abstract

BackgroundThe antimanic efficacy of a protein kinase C inhibitor, tamoxifen, has been tested in several clinical trials, all reporting positive results. However, mechanisms underlying the observed clinical effects require further confirmation through studies of biological markers. MethodsWe investigated the effect of tamoxifen versus placebo on brain metabolites via a proton magnetic resonance spectroscopy study. Scanning was performed in 48 adult manic patients with bipolar disorder type I (mean Young Mania Rating Scale score of 37.8 ± 5.8) at baseline and after 3 weeks of double-blind treatment. We hypothesized that alleviation of manic symptoms would improve the levels of markers associated with brain energy metabolism (creatine plus phosphocreatine [total creatine (tCr)]) and neuronal viability (N-acetylaspartate). ResultsThe Young Mania Rating Scale scores decreased from 38.6 ± 4.5 to 20.0 ± 11.1 in the tamoxifen group and increased from 37.0 ± 6.8 to 43.1 ± 7.8 in the placebo group (p < .001). Proton magnetic resonance spectroscopy measurements revealed a 5.5% ± 13.8% increase in tCr levels in dorsomedial prefrontal cortex in the tamoxifen group and a 5.3% ± 13.1% decrease in tCr in the placebo group (p = .027). A significant correlation between the Young Mania Rating Scale score change and tCr percent change was observed in the whole group (Spearman rho = .341, p = .029). Levels of both tCr and N-acetylaspartate in the responder group were increased by 9.4% ± 15.2% and 6.1% ± 11.7%, respectively, whereas levels in the nonresponder group were decreased by 2.1% ± 13.2% and 6.5%± 10.5%, respectively (p < .05). ConclusionsTamoxifen effectively treated mania while increasing brain tCr levels, consistent with involvement of both excessive protein kinase C activation and impaired brain energy metabolism in the development of bipolar manic states.