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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.

Pharmacogenomics, which is derived from genome-wide association studies (GWAS), and pharmacogenetics, which involves candidate gene association studies (CGASs), are proving increasingly useful in personalized cancer care. Research in psychiatric applications has primarily involved genetic polymorphisms of P450 CYP enzymes, which mediate oxidative metabolism, particularly CYP2D6, which is involved in the metabolism of at least 30 psychotropic medications. This work has been supplemented by genotyping of proteins for the drug efflux pump P-glycoprotein (P-gp), serotonin receptors, and the serotonin reuptake pump.This review covers principles of pharmacogenetics and pharmacogenomics, previous analyses of pharmacokinetic and pharmacodynamics studies, newer studies of the predictive value of genetic testing in the treatment of depression, obstacles to implementation of genetic testing in predicting treatment response and side effects, and suggestions for future research.Studies of multiple genes have produced some positive results in groups of patients, but genetic testing does not yet seem to be applicable to choosing medications for a specific patient.

Major depressive disorder (MDD), one of the most common disorders in medical practice and one of the leading causes of disability worldwide, is frequently comorbid with anxiety disorders. Vortioxetine (Lu AA21004) is a new antidepressant that combines a number of neurotransmitter reuptake and receptor effects that have been thought to predict efficacy as a treatment for depressive and anxiety disorders.This review summarizes the pharmacology and neurobiology of vortioxetine. Studies of its efficacy and tolerability in major depression and generalized anxiety disorder are critically reviewed.Despite the fact that industry-sponsored studies are more likely than other clinical trials to support efficacy of the experimental drug, results have been mixed. Some studies supported that vortioxetine is superior to placebo in the treatment of MDD and some do not. Two studies supported the efficacy of vortioxetine in the treatment of generalized anxiety disorder and two do not. The incidence of sexual dysfunction has varied considerably in different studies, but cardiac effects and psychomotor impairment seem to be minimal. Advantages of vortioxetine over existing antidepressants are not yet clear.

A proprietary combination of the atypical antipsychotic drug olanzapine and the serotonin reuptake inhibitor fluoxetine (OFC, Symbyax) was approved for the treatment of bipolar depression based on a double-blind, placebo-controlled comparison of olanzapine, OFC, and placebo.This review considers published controlled and uncontrolled studies of the efficacy, pharmacodynamics, pharmacokinetics, interactions, and adverse effects of OFC. Beyond previously reviewed efficacy studies, an open-label 7-week study of 161 bipolar depressed patients (93% bipolar I), and an 8-week double-blind study of 833 bipolar I depressed patients with an open-label extension were identified. The structure and limitations of clinical trials of OFC are critically addressed.OFC trades simplicity of administration for loss of flexibility of dosing and lack of a generic preparation, both of which are available for olanzapine and fluoxetine separately. Clinical trials are limited by short-term follow-up, exclusive use of symptom rating scale scores, limitation of subjects to those with depression that is not overly complex or comorbid, lack of consideration of subsyndromal hypomania and mood cycling, and high dropout rates. In the absence of comparisons to mood stabilizers combined with each other and/or antidepressants, the role of OFC in the treatment of bipolar depression remains unclear.