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.

Study Highlights

WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

✓ PKC inhibitors are new compounds for the treatment of bipolar I disorder and mood‐stabilizing agents.

WHAT QUESTION DID THIS STUDY ADDRESS?

✓ The study addressed the efficacy and safety of endoxifen at two doses in the treatment of patients with bipolar disorder I.

WHAT THIS STUDY ADDS TO OUR KNOWLEDGE?

✓ This prospective clinical trial demonstrated that endoxifen, a protein kinase C inhibitor, acts rapidly and demonstrated for the first time an antimanic activity in patients with bipolar disorder I. Endoxifen was well tolerated by patients. Furthermore, the endoxifen amount required for the antimanic activity is 125–250‐fold less than divalproex (active‐control), a commonly used drug for the treatment of this disease.

HOW THIS MIGHT CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

✓ This is the first clinical study to elucidate the safety and antimanic effects of endoxifen in patients with bipolar I disorder. These findings on endoxifen deserve to be studied in a phase III trial.

The protein kinase C (PKC) is a family of serine/threonine kinases, which are known to play a vital role in cell signaling pathways. It regulates multiple neuronal processes implicated in mood regulation.¹, ² In current clinical practice, antidepressants and mood stabilizers have been shown to modulate the PKC pathway. Disrupted PKC activity has been found both in postmortem brains and platelet from patients with mood disorders. Accumulating evidence suggests an imbalance of the PKC signaling system in mood disorders. Thus, PKC may be a novel molecular target for the development of innovative medicine for bipolar disorder (BP). This is a chronic, debilitating illness that affects 0.4% to 4% of the US population.³, ⁴ The causes of BP are still unknown and no agent has been specifically developed on the basis of an understanding of the pathophysiology of the illness or mechanism of action for effective treatments. However, several drugs have been approved such as lithium, valproate, carbamazepine, and atypical antipsychotics for the treatment of acute bipolar mania.⁵ While these drugs have provided relief for many individuals with BP, significant issues with tolerability and efficacy still remain. The clinicians, for example, may find themselves in situations in which better‐tolerated agents are less effective, and vice versa. Also, the adherence to the treatment is affected by adverse effects such as sedation and weight gain. Therefore, there is an urgent need to develop novel and more effective treatments for BP.

Two placebo‐controlled, randomized trials of a PKC inhibitor drug, tamoxifen, were carried out independently.⁶, ⁷ These studies indicated that tamoxifen has strong antimanic properties both in men and women. Tamoxifen is extensively metabolized predominantly by the cytochrome P450s (CYP450) system to several primary and secondary metabolites including active metabolite endoxifen.⁸ We reported earlier the endoxifen (Figure ​1)1) synthesis and its superior inhibitory PKC activity compared with tamoxifen. Endoxifen showed fourfold higher potency in inhibiting the PKC activity compared with tamoxifen.⁹ Endoxifen, being the active metabolite of tamoxifen, is not dependent on drug‐metabolizing enzymes such as CYP450 and especially major polymorphic isozyme CYP2D6. In addition, the avoidance of CYP2D6‐mediated drug metabolism represents an early Go / No Go decision criteria in central nervous system (CNS) drug discovery efforts because of its potential for variable patient safety and drug efficacy arising from genetic polymorphisms and its involvement in the metabolism of many existing drugs.

Figure 1

Chemical structure of endoxifen.

To the best of our knowledge, this is the first report that describes the findings of a randomized, double‐blind, active‐controlled clinical trial to evaluate efficacy and safety of endoxifen in BPD I patients with current manic or mixed episode.