MEM 1003. L-type calcium channels affect several organ systems and are widely expressed in the CNS, thus influencing neuroplasticity and neuronal excitability. Lithium is known to act on calcium signaling pathways, and recent genome-wide association studies support an association between a common variation on the α 1C subunit of the L-type voltage-gated calcium channel gene and BP.26-28
In 2007, Memory Pharmaceuticals Corporation conducted a phase 2a study of MEM 1003, a novel L-type calcium channel antagonist, for acute mania in BP. Study participants (N = 84) were randomized to receive either MEM 1003 or placebo for 3 weeks. Despite positive tolerability and safety data, both primary and secondary outcome measures showed that MEM 1003 was ineffective in treating bipolar mania.4 These results, unfortunately, are in line with earlier failed studies that investigated calcium channel antagonists in the treatment of BP.29
N-acetylcysteine (NAC). While it is beyond the scope of this article to offer an intensive review of all agents, we do wish to briefly mention NAC, which affects the glutathione antioxidant system. In patients with BP, a subgroup analysis found that NAC led to remission of manic symptoms.30 Most studies, however, suggest that NAC has more robust effects on depressive symptoms.31
Adjunctive nutraceuticals. The expression “nutraceutical” was coined in 1989 and was defined as “a food (or part of a food) that provides medical or health benefits, including the prevention and/or treatment of a disease.”32 Nutraceuticals differ from dietary supplements because they are intended to not only supplement the diet but also to prevent and/or treat a particular disease or disorder. Many patients with BP (60%) who adhere to pharmacological treatment continue to experience recurring manic or depressive mood episodes while taking medications at recommended therapeutic doses. Thus, adjunctive neutraceuticals can act as agents with either super-additive or multi-target biologic effects or as agents with the potential to minimize adverse effects by reducing the necessary dose of conventional drugs.
Note that despite active research, no substantive evidence exists to support these notions. However, Sarris and colleagues33 recently conducted a systematic review of human clinical trials of nutraceuticals used adjunctively with standard pharmacotherapy in BP. Inclusion criteria (eg, open label, controlled, sample size greater than 10) narrowed 1710 studies to 18 that evaluated ω-3, NAC, inositol, and vitamins and minerals in combination with standard medications to treat BP (either mania or depression). Several nutraceuticals were found to improve bipolar mania, including a chelated mineral formula, l-tryptophan, magnesium, folic acid, and branched-chain amino acids (eg, leucine, isoleucine, and valine).
In contrast, the evidence did not support the adjunctive use of ω-3 in bipolar mania, although it may be useful in bipolar depression. Given that many of the trials involved small sample sizes and did not account for baseline dietary patterns, these positive results should be interpreted with caution. Likewise, significant heterogeneity between studies also prevented a meta-analysis of the findings.
While challenges in treating mania persist, the future discovery of novel therapeutic agents will likely expand our understanding of this devastating illness and provide key insights into future drug development.
Acknowledgments—The authors gratefully acknowledge the support of the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health, and thank the 7SE Research Unit of the NIMH-NIH for their support.