The Role of Calcium in Genetic Vulnerability, Pathophysiology, and Treatment Of Bipolar Illness

February 1, 2011 · Posted in Neurobiology, Risk Factors · Comment 

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.

Nimodipine Table

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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.   Read more