title: A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development.
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.
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: A
authors.identifier: 0000-0001-5179-8321
authors.initials: A
authors.lastname: Cipriani
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: K
authors.initials: K
authors.lastname: Saunders
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: M-J
authors.initials: MJ
authors.lastname: Attenburrow
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: J
authors.initials: J
authors.lastname: Stefaniak
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: P
authors.initials: P
authors.lastname: Panchal
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Stockton
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
authors.forename: T A
authors.initials: TA
authors.lastname: Lane
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Tunbridge
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: J R
authors.initials: JR
authors.lastname: Geddes
authors.affiliation: Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.|Oxford Health NHS Foundation Trust, Warneford Hospital, Oxford, UK.
authors.forename: P J
authors.initials: PJ
authors.lastname: Harrison
mesh_terms: D001714:Bipolar Disorder / Q000188:drug therapy*; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000235:genetics; D004311:Double-Blind Method; D006801:Humans; D017275:Isradipine / Q000627:therapeutic use; D009553:Nimodipine / Q000627:therapeutic use; D014700:Verapamil / Q000627:therapeutic use
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D009553:Nimodipine; D014700:Verapamil; D017275:Isradipine