Zarate CA Jr et al. (2007) Efficacy of a protein kinase C inhibitor (tamoxifen) in the treatment of acute mania: a pilot study. Bipolar Disord 9: 561–570

The protein kinase C (PKC) signaling cascade has been identified as a direct biochemical target for the treatment of mania. Preclinical studies and early clinical trials have shown that the anticancer agent tamoxifen, a relatively selective PKC inhibitor that can cross the blood–brain barrier, exerts an antimanic effect in a mouse model of mania. Zarate et al. have now examined the effect of tamoxifen in a double-blind pilot trial of 16 inpatients in the manic phase of bipolar disorder.

Study participants received flexible dosing of tamoxifen (20–140 mg; n = 8) or placebo (n = 8) for 21 days. At the end of the study period, a significant difference was seen between the effects of tamoxifen and placebo on manic symptoms (Cohen's d = 1.08, 95% CI 0.45–1.71; P = 0.001). After 3 weeks of therapy, 63% of patients in the treatment group showed a clinical response—defined as at least a 50% reduction from baseline in Young Mania Rating Scale total score—compared with 13% of those receiving placebo (P = 0.12). Notably, patients receiving tamoxifen showed improvement in symptoms as early as 5 days after the start of treatment. Therapy was generally well tolerated.

The authors conclude that the results of this small pilot study are proof of the concept that direct inhibition of PKC could form the basis of fast-acting medications for the manic phase of bipolar disorder. Further studies in this setting are warranted.