Background: The antimanic efficacy of a protein kinase C (PKC) inhibitor, tamoxifen, has been tested in several clinical trials, all reporting positive results. However, mechanisms underlying the observed clinical effects requires further confirmation through studies of biological markers.
Methods: We investigated the effect of tamoxifen versus placebo on brain metabolites via a proton (1H) magnetic resonance spectroscopy (MRS) study. Forty-eight adult bipolar I manic patients (mean Young Mania Rating Scale (YMRS) score of 37.8±5.8) were scanned at baseline and following 3 weeks of double-blind treatment. We hypothesized that manic symptom alleviation would improve the levels of markers associated with brain energy metabolism (creatine plus phosphocreatine [total creatine; tCr]) and neuronal viability (N-acetylaspartate [NAA]).
Results: The YMRS 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<0.001). 1H MRS measurements revealed a 5.5±13.8% increase in the dorsomedial prefrontal cortex (DMPFC) tCr levels in the tamoxifen group and a 5.3±13.1% decrease in tCr in the placebo group (p=0.027). A significant correlation between the YMRS score change and tCr percent change was observed in the whole group (Spearman ρ=0.341, p=0.029). Both tCr and NAA levels in the responder group were increased by 9.4±15.2% and 6.1±11.7%, whereas levels in the non-responder group were decreased by 2.1±13.2% and 6.5±10.5%, respectively (p<0.05).
Conclusions: Tamoxifen effectively treated mania while it also increased brain tCr levels, consistent with involvement of both excessive PKC activation and impaired brain energy metabolism in the development of bipolar mania.
Clinical trial registration: Registry name: ClinicalTrials.gov URL: https://clinicaltrials.gov/ct2/show/NCT00411203?term=NCT00411203&rank=1 Registration number: NCT00411203.
Keywords: MRS; Tamoxifen; bipolar mania; creatine; dorsomedial prefrontal cortex; protein kinase C.