Gene for Calcium Channel Linked to Bipolar Disorder in Several Ways
No one gene explains the risk of developing bipolar disorder. Many genes are involved, each with a small effect. However, the effects of one particular gene have been validated in multiple different ways. The gene is called CACNA1C, and it codes for one subunit of the dihydropyridine L-type calcium channel. Calcium channels are structures on the membranes of neurons that allow calcium to enter cells and alter their excitability.
Different people can have different variants of the CACNA1C gene, depending on which nucleotides appear there: valine (Val) or methionine (Met). One particular variant (known as the Met/Met single nucleotide polymorphism, rs1006737) has been associated with executive function deficits compared to the Val/Val variant in multiple tests in patients with bipolar disorder. Executive function refers to abilities like planning, organizing, and retaining information. This was reported by Soeiro-de-Souza et al. in the journal Acta Psychiatrica Scandinavica in 2013.
Importantly, CACNA1C has also been linked to risk of bipolar disorder, a finding that was replicated in several large genome-wide association studies (GWAS). Autopsy studies of people who had been diagnosed with bipolar disorder show more calcium channels in their brains. The Met/Met variant of the CACNA1C gene also lets more calcium ions into cells. Those who have the gene variant also show differences in some brain structures known to be involved in the modulation of emotions compared to those without the variant.
In addition to these findings, more than a dozen studies report increased intracellular calcium in the white blood cells of people with bipolar disorder compared to controls. To the extent that these increases in intracellular calcium reflect changes in neurons, this would be consistent with the findings about CACNA1C. High levels of calcium influx and the associated intracellular calcium may increase cellular excitability and potentially dysregulate normal neuronal functioning.
The final piece of evidence linking altered calcium channel regulation to bipolar disorder is a direct therapeutic test of a drug that blocks calcium influx through the dihydropyridine L-type calcium channel. There is evidence that nimodipine, which selectively blocks dihydropyridine L-type calcium channels, has therapeutic effects in bipolar disorder.
Double-blind off-on-off-on studies by Pazzaglia et al. (1993, 1998) and this editor Post and Leverich (2008), in which patients’ mood is rated while alternating between taking either placebo or nimodipine on a double-blind basis, have shown that the drug has both antimanic and antidepressant efficacy, including in patients with ultra-rapid and ultra-ultra rapid or ultradian cycling (cycling multiple times within one day).
Other open case studies in adults (Brunet et al. 1990, Goodnick 1995) and one in a teenager (Davanzo et al. 1999) with ultradian cycling support the double blind findings, as these patients also responded to nimodipine when other treatments had failed.
The combination of nimodipine and lithium may be particularly effective. A randomized study by Chaudhry et al. (2010) observed several different treatments including lithium alone, lithium plus nimodipine, valproate plus nimodipine, and carbamazepine with nimodipine, with about 50 participants in each group. Chaudhry found about a 50% response rate to lithium alone, but a 73% response rate on the combination of lithium plus nimodipine. (In two other randomized groups of about 50 patients each, those receiving nimodipine in combination with either valproate or carbamazepine only showed about a 50% response rate.) An earlier retrospective series showed that a year on the combination of nimodipine and lithium was more effective than a year on either drug alone, also suggesting additive effects of the drugs in combination.
Very early evidence had suggested that nimodipine had some positive effects on cognition in advanced Alzheimer’s disease compared to placebo (a finding that was never pursued further). Nimodipine increases levels of the peptide somatostatin in cerebrospinal fluid, which are low in both depression and Alzheimer’s disease.
Implications for Treatment
Nimodipine is worth a try in patients who respond well to lithium but cannot tolerate it or cannot take full therapeutic doses of it because of renal dysfunction. In research by Stephen Dubovsky, a history of a good prior response to lithium actually predicted a positive response to L-type calcium channel blockers. However, as noted above, nimodipine is also effective in some patients with a history of nonresponse to lithium.
Nimodipine might be useful in those with treatment-resistant ultra-rapid and ultradian cycling, although further studies with these groups are needed.
Nimodipine should also be tested in clinical trials to see if it could help prevent or reverse some of the cognitive deficits associated with bipolar disorder.
In a young person who is at high risk for bipolar disorder because they have a parent with the disorder, a test for high intracellular calcium or the CACNA1C variant Met/Met (neither of which is readily available at this time) could provide added evidence of risk, so that early intervention using family focused therapy (FFT) and/or medications might be considered if symptoms develop.
Whether early intervention with nimodipine could help prevent the onset of full-blown mania in a child who has bipolar illness not otherwise specified (BP NOS), which is often accompanied by multiple mood switches in a single day, and is at high risk for converting to bipolar I or II disorder within several years should also be studied.
Pharmacogenetic studies should assess whether those with the Met/Met variant of CACNA1C are more responsive than those without this variant to the effects of nimodipine on mood stabilization or cognition. If this proved to be the case, it would be a step toward “personalized medicine,” i.e. predicting in advance what drugs might work best for a given individual based on genetic or other laboratory testing.
