Endoxifen, a New Treatment Option for Mania: A Double-Blind, Active-Controlled Trial Demonstrates the Antimanic Efficacy of Endoxifen

Abstract

The protein kinase C (PKC) signaling system plays a role in mood disorders and PKC inhibitors such as endoxifen may be an innovative medicine for bipolar disorder (BP) patients. In this study we show for the first time the antimanic properties of endoxifen in patients with bipolar I disorder (BPD I) with current manic or mixed episode. In a double-blind, active-controlled study, 84 subjects with BPD I were randomly assigned to receive endoxifen (4 mg/day or 8 mg/day) or divalproex in a 2:1 ratio. Patients orally administered 4 mg/day or 8 mg/day endoxifen showed significant improvement in mania assessed by the Young Mania Rating Scale as early as 4 days. The effect remained significant throughout the 21-day period. At study end point, response rates were 44.44% and 64.29% at 4 mg/day and 8 mg/day of endoxifen treatment, respectively. Thus, endoxifen has been shown as a promising novel antimanic or mood stabilizing agent.

Figure 1

Chemical structure of endoxifen.

Figure 2

Study design.

Figure 3

(a) Mean change in baseline from total YMRS score. (b) Percent change from the baseline to each subsequent assessment in the total YMRS score. T1 = endoxifen 4 mg/day; T2 = endoxifen 8 mg/day; R = divaloproex 1,000 mg/day.

Figure 4

(a) Plasma concentration profile of endoxifen at two doses of 4 mg/day and 8 mg/day. (b) Pharmacokinetic–pharmacodynamic relationship. AUC values were calculated from plasma concentration–time curve of endoxifen. Each AUC value represents the average of those from 24 (4 mg/day group) or 28 (8 mg/day group) patients.