The Role of Calcium in Genetic Vulnerability, Pathophysiology, and Treatment Of Bipolar Illness
One of the most consistent findings in biological psychiatry is that levels of intracellular calcium in blood elements (platelets and white cells) are higher than normal in patients with mood disorders, particularly bipolar disorder. These data are now supported by genome-wide association studies that have identified a relationship between alterations in a calcium channel and vulnerability to bipolar illness. The specific alteration is in the alpha-IC subunit of the L-type calcium channels, otherwise referred to as CACNA1C. These findings were initially reported by one group funded by the Welcome Trust, a charitable organization that funds health research, in a series of studies that included thousands of patients and controls. Investigator Pamela Sklar later replicated these findings in another large independent sample.
At the 65th Annual Scientific Convention of the Society of Biological Psychiatry, investigator Tyson Tragon reported that there were higher levels of CACNA1C in the cingulate cortex in autopsy specimens of those with bipolar illness than in controls. In a study of mice, some of which had the gene for the glutamate receptor subunit GLuR6 knocked out (i.e. production of the gene was artificially limited), the researchers found that the L-type dihydropyridine calcium channel blocker nimodipine decreased hyperactivity, amphetamine super-sensitivity, risk-taking behavior, and aggression in those with the gene removed. The dihydropyridine-type drugs like nimodipine also decreased stress-related immobilization in the wild type (the animal with normal genes) but not the knockout animals (the ones lacking GLuR6). These data suggest that alterations in a subunit of the dihydropyridine-responsive L-type calcium channel are a risk factor for bipolar illness, a brain abnormality in those who have the illness, and relevant to behavioral/pharmacological models.
Several research groups have noted that treatment with the L-type calcium channel blocker nimodipine (Nimotop) can sometimes have positive effects in mania and depression in those poorly responsive to lithium carbonate. This has been documented by Pazzaglia and Post in double blind off-on-off-on clinical trials (i.e. during off trials patients received placebo and during on trials patients received nimodipine, but the raters were unaware which pill the patient had received). In several instances, a positive response continued when the patient was switched from nimodipine to another dihydropyridine, isradapine (DynaCirc), but not when patients were switched to a different L-type calcium channel blocker, the phenylalkylamine verapamil (sold under the names Calan, Covera, Isoptin, and Verelan), which acts at a slightly different site on the channel.
Editors Note: These data are reviewed in detail in the 2008 book by myself (Post) and Leverich, Treatment of Bipolar Disorder: A Casebook for Clinicians and Patients, published by WW Norton. Taken together, the findings make it likely that the calcium channel plays a role in the pathophysiology and treatment of bipolar disorder. Those with the CACNA1C gene are at risk for the development of bipolar disorder, patients with the illness have high levels of intracellular calcium in their blood elements and high levels of CACNA1C in the brain (through which too much calcium presumptively flows into cells), and a drug which blocks this type of calcium influx, nimodipine, is an effective treatment for some patients with the illness.
Combination of Nimodipine and Lithium Is Superior to Lithium Alone and to Nimodipine Plus Valproate or Carbamazepine
In line with these findings is a new study by Haroon R. Chaudhry et al. on nimodipine in bipolar disorder. This research group randomized a large group of bipolar subjects to: lithium alone, N= 49; lithium plus nimodipine, N= 55; valproate plus nimodipine, N=54; and carbamazepine plus nimodipine, N=52. They found evidence of a good response to all of these treatment options, but the combination of lithium and nimodipine was superior to the other treatments at the p < 0.05 level, with a 73% response rate to this combination compared with 61% to nimodipine with valproate, 54% to nimodipine with carbamazepine, and 59% to lithium alone.
Editor’s note: These data are clinically important for several reasons. Combination treatment with lithium plus nimodipine has again been shown to be superior to lithium monotherapy, as was originally reported by Manna in a non-randomized study published in 1991. Manna found that one year on the combination was superior to both one year of lithium alone and one year of nimodipine alone. While combinations have generally been shown to be superior to monotherapy in a number of studies (as summarized in the last BNN), controlled studies to determine which combinations are preferable to others had not previously been carried out.
Pazzaglia and myself (Post) had reported that the combination of nimodipine plus carbamazepine was beneficial to a number of patients with treatment-refractory bipolar illness, and had postulated that the blockade of calcium influx through the L-type calcium channel may have been strengthened by carbamazepine’s effects on calcium influx, including slowing calcium entry through the glutamate NMDA receptor. While lithium and valproate also share this ability to slow calcium influx through the NMDA receptor, lithium has many other effects on intracellular calcium and other systems. What makes the combination of nimodipine and lithium superior to nimodipine in combination with either carbamazepine or valproate in Chaudhry’s study is not yet clear.
Nimodipine is a dihydropyridine L-type channel blocker and has an excellent side-effects profile that makes it better tolerated than lithium. For example, lithium can be associated with increases in tremor, gastrointestinal distress, weight gain, thyroid suppression, diabetes insipidus, and impairment in glomular filtration (renal function, as indicated by slow increases in creatinine in a small subgroup of patients on very long-term lithium treatment). Nimodipine does not cause any of these side effects, and thus is a potentially useful adjunct to lithium, particularly for those who are unable to tolerate lithium doses that are sufficient to achieve a complete remission.
Nimodipine is FDA-approved only for the treatment of subarachnoid hemorrhage and is inordinately expensive compared with the other dihydropyridines, which are used for the treatment of high blood pressure. Thus, one treatment suggestion is to optimize treatment with nimodipine, then see if the same response can be achieved with other agents of the dihydropyridine class, such as isradipine (DynaCirc) or amlodipine (Norvasc). Both nimodipine and isradipine have short half-lives and require dosing three times daily as opposed to amlodipine, which can be administered once a day. In the double-blind studies mentioned above, we saw responsiveness to nimodipine cross to isradipine in some patients, while such cross-responsivity to amolodipine has not yet been demonstrated in systematic crossover trials in individual patients.
The evolving ANK-3 gene story
Another gene, ANK3, has also been found to be a vulnerability factor to bipolar illness in two large gene-wide association studies. Melanie P. Leussis reported at the 65th Annual Scientific Convention of the Society of Biological Psychiatry that in an animal model, when ANK3 was knocked-in partially (i.e. the gene production was increased artificially by molecular genetic techniques), the animal engaged in bipolar-like behaviors that could be partially reversed with lithium treatment. Together, the data with CACNA1C and ANK3 thus begin to suggest that some findings from the genome-wide association studies may be further supported by direct studies in patients with bipolar disorder and by animal models.
In the case of the CACNA1C gene, the convergent evidence that nimodipine treatment, which blocks the increase in calcium influx through the dihydropyridine-type calcium channel CACNAIC, is an effective treatment strengthens the evidence that the calcium channel plays a role in the etiology and treatment of bipolar disorder. The fact that CACNA1C is increased in the brains of patients in bipolar disorder compared to other patient groups and controls provides further direct evidence for a link between the calcium channel and bipolar illness.
However, it is now thought that multiple genes, each of small effect, contribute to the vulnerability to bipolar disorder, and it remains to be seen how powerful a relationship may exist between the CACNAIC gene and bipolar disorder, and whether those with the gene would be more specifically responsive to treatments such as nimodipine which act directly at this site.