A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.

A Cipriani,S Stockton,J R Geddes,M-J Attenburrow,K Saunders,P Panchal,T A Lane,P J Harrison,J Stefaniak,E M Tunbridge

doi:10.1038/mp.2016.86

Abstract

l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes.

Highlights

Bipolar disorder is a common mental disorder with a lifetime prevalence of up to 4.4%.1 Mood stabilisation and prophylaxis is the principal aim of treatment
Studies reports have continued to emerge since that time regarding L-type calcium channels (LTCC) antagonists in bipolar disorder, the only evidence that has been systematically assessed concerns verapamil in the treatment of mania, with the data not demonstrating superiority over placebo.[9]
We found six randomised controlled trials (RCTs) compared to the only previous systematic review including LTCC antagonist studies in the treatment of bipolar disorder,[9] which found just one

Summary

Introduction

Bipolar disorder is a common mental disorder with a lifetime prevalence of up to 4.4%.1 Mood stabilisation and prophylaxis is the principal aim of treatment. Calcium signalling has long been implicated in bipolar disorder, following reports of altered levels of calcium in cerebrospinal fluid in patients with mania,[4,5] and the observation that long-term lithium treatment is associated with altered calcium metabolism, including hyperparathyroidism.[6] These reports, taken together with the similarities in the mechanism of action of lithium and calcium channel blockers, prompted investigations of these drugs (primarily verapamil) beginning in the 1980s as potential treatments for bipolar disorder. This was facilitated by the fact that verapamil and other drugs that block L-type calcium channels (LTCC) were already available and in use for the treatment of hypertension and angina.[7,8] studies reports have continued to emerge since that time regarding LTCC antagonists in bipolar disorder, the only evidence that has been systematically assessed concerns verapamil in the treatment of mania, with the data not demonstrating superiority over placebo.[9]

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Conclusion