Verapamil augmentation of lithium treatment improves outcome in mania unresponsive to lithium alone: preliminary findings and a discussion of therapeutic mechanisms

Calcium channel blocking drugs (CCBs) have long been advocated as a treatment for mania, but data on their efficacy have been inconsistent. The literature in this area has been summarized in several recent reviews. Levy and Janicak (1) concluded that while early work on verapamil demonstrated positive results for acute mania, later better-controlled studies (including their own) did not support its efficacy. They noted further that verapamil’s efficacy as an augmentation therapy has yet to be adequately studied. Keck et al. (2) pointed out both positive and negative findings for antimanic efficacy of two CCBs (verapamil and nimodipine), and concluded that further studies would be needed to establish CCBs as efficacious in the treatment of mania. In a selected review on the treatment of rapid cycling bipolar disorder, Post et al. (3) suggest a role for CCBs as part of a complex combination treatment strategy for managing this condition. They also pointed to earlier work by Manna (4) demonstrating that the combination of lithium and nimodipine was more effective than either agent alone in long-term administration. In another review on rapid cycling disorder, Dubovsky (5) summarized studies of nimodipine and suggested as a strategy the addition of CCBs to treatment with other mood stabilizers. In the time since these reviews were written, Wisner et al. (6) reported that 9 of 11 women with manic or mixed symptoms showed an antimanic response to verapamil, Yingling et al. (7) described successful treatment of a pregnant bipolar woman with nimodipine, and Giannini et al. (8) reported that combining magnesium oxide with verapamil was more effective for reducing manic symptoms than was verapamil alone. The theoretical rationale for using CCBs as antimanic agents rests on previous observations that intracellular calcium is elevated in mania (9), a situation that could potentially be corrected by blocking cellular calcium influx. The majority of previous studies on CCBs for treatment of acute mania have used verapamil specifically. However, it is important to note that in addition to its effect on L-type calcium channels, verapamil can inhibit protein kinase C (PKC) activity (10–12). The PKC signaling pathway has an important role in regulating neuronal function, and moreover, preclinical biochemical and behavioral data support the notion that PKC activation may result in manic-like behaviors, whereas PKC inhibition may be antimanic (13–15). Given that the prototypical antimanic agents, lithium and valproate, have been found to bring about isozyme-selective reductions in PKC levels (16–18), attenuation of PKC activity could be an important mechanism of antimanic drug action. Indeed, recent preliminary studies have suggested that tamoxifen, a drug that potently inhibits PKC (in addition to its more well-known effect as a selective estrogen receptor modulator), produces clinical improvement in acutely manic patients (19–21). Moreover, in one of these studies, medroxyprogesterone (a hormonal modulator without PKC inhibition) produced lesser, nonsignificant improvement of manic symptoms (20). Most recently, a whole genome association study of bipolar disorder has been conducted, utilizing North American bipolar pedigrees as a test sample, and German bipolar subjects as the replication sample. This study found a highly significant association (p ~ 10−8) of diacylglycerol kinase eta (DGKH) with bipolar disorder (22). These findings are particularly noteworthy, since diacylglycerol (DAG) is the major activator of PKC. Our original purpose in conducting this study was to investigate treatment options for the significant proportion of patients who either do not respond adequately or cannot tolerate the adverse effects associated with therapeutic doses of lithium. While a number of other treatments are available, including several anticonvulsants and antipsychotics, issues of effectiveness, tolerability, and safety contribute to an ongoing need for the development of new therapeutic alternatives. Thus, the goal of this investigation was to perform a controlled (double-blind, random assignment) comparison of verapamil versus continued-lithium treatment in bipolar manic patients who were unresponsive to three weeks of initial treatment with lithium (± perphenazine). Subsequently, patients who failed to respond to the single agents being tested were treated with combined verapamil and lithium. Within this framework, the overall aim of this investigation was to assess the acute treatment efficacy of verapamil, either alone or in combination with lithium, in patients who initially failed to respond to a course of lithium therapy.