Applications of calcium channel blockers in psychiatry: pharmacokinetic and pharmacodynamic aspects of treatment of bipolar disorder

ABSTRACT

Introduction: Calcium channel blockers (CCBs) comprise a heterogeneous group of medications that reduce calcium influx and attenuate cellular hyperactivity. Evidence of hyperactive intracellular calcium ion signaling in multiple peripheral cells of patients with bipolar disorder, calcium antagonist actions of established mood stabilizers, and a relative dearth of treatments have prompted research into potential uses of CCBs for this common and disabling condition.

Areas covered: This review provides a comprehensive overview of intracellular calcium signaling in bipolar disorder, structure and function of calcium channels, pharmacology of CCBs, evidence of efficacy of CCBs in bipolar disorder, clinical applications, and directions for future research.

Expert opinion: Despite mixed evidence of efficacy, CCBs are a promising novel approach to a demonstrated cellular abnormality in both poles of bipolar disorder. Potential advantages include low potential for sedation and weight gain, and possible usefulness for pregnant and neurologically impaired patients. Further research should focus on markers of a preferential response, studies in specific bipolar subtypes, development of CCBs acting preferentially in the central nervous system and on calcium channels that are primarily involved in neuronal signaling and plasticity.

KEYWORDS:

• Bipolar disorder
• calcium channel blockers
• depression
• mania
• intracellular calcium
• nimodipine
• verapamil
• L-type channel

Article highlights

• Dysregulated intracellular calcium ion signaling has been reported in peripheral and neuronal cells from patients with bipolar mood disorders;

• Calcium channel gene alleles have been linked to bipolar mood disorders;

• Established mood stabilizers such as lithium and carbamazepine have calcium antagonist properties;

• The calcium channel antagonists verapamil and nimodipine have been found to have mood stabilizing properties. Isradipine also may have mood stabilizing effects. A number of small positive controlled studies and a few negative studies have been reported;

• Advantages of calcium channel blockers as potential treatments for bipolar mood disorders include minimal sedation and weight gain, lack of need for laboratory monitoring, and a more favorable profile during pregnancy. However, they require more frequent dosing than standard mood stabilizers;

• Some calcium channel blockers (e.g., those acting on P or Q channels) may be more specifically effective in mood disorders;

• Research is needed into profiles that predict a possible response to a calcium channel blocker such as calcium channel binding profiles, increased free intracellular calcium concentration in peripheral cells, or clinical features

Declaration of interest

S Dubovsky has received research support from the Tower Foundation, the Patrick Lee Foundation, Janssen, Otsuka, Neurim, Neurocrine, and Allergan. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.