Nimodipine Decreases Frontal and Parietal Cortical Activity During Working Memory in Healthy Subjects
At a recent scientific meeting, researcher Kristin Bigos and colleagues described the effects of nimodipine, a treatment for brain hemorrhage, on the brain during working memory tasks. Nimodipine is a dihydropyridine L-type calcium channel blocker. Calcium channel blockers prevent calcium from entering cells in the heart and blood vessel walls, and they are often used to treat high blood pressure.
Nimodipine acts on the CACNA1C calcium influx gene. Certain genetic variations in this gene (particularly the rs1006737 A allele) have been linked to vulnerability to bipolar disorder, schizophrenia, depression, and autism. Carriers of the risk allele also have higher CACNA1C mRNA expression in the dorsolateral prefrontal cortex and exhibit more activity in the frontal and parietal regions of the brain during working memory tasks, suggesting inefficient brain processing in these regions. Bigos and colleagues found that 60mg/day of nimodipine decreased frontal and parietal cortical activity by 39.1% and 42.8%, respectively, during a working memory task, suggesting that nimodipine improved the efficiency of memory processing. Nimodipine’s positive effects were greater in those participants who had the CACNA1C risk allele.
Editor’s Note: Using a placebo-controlled off-on-off-on study design (meaning patients took placebo for a period, then nimodipine, then placebo again and nimodipine again), this editor (Robert M. Post), Peggy J. Pazzaglia and colleagues found that nimodipine had positive effects in both mania and depression in patients with bipolar disorder (described in the 2008 book Treatment of Bipolar Disorder: A Casebook for Clinicians and Patients by Robert M. Post and Gabriele S. Leverich). In a large randomized study of patients with bipolar disorder presented by Haroon R. Chaudhry at the 2010 meeting of the Society of Biological Psychiatry, lithium was associated with about a 50% response rate while the combination of lithium and nimodipine was associated with a 73% response rate.
It remains to be seen whether people with bipolar disorder who have the CACNA1C risk gene would respond better to nimodipine than those without the risk gene, and whether it would improve working memory more in the subgroup with the risk gene.
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.
Dopamine D2 and D3 Agonist Pramipexole May Enhance Cognitive Function in Bipolar I Disorder
Anil Malhotra from the Zucker Hillside Hospital found that pramipexole (Mirapex), a dopamine D2 and D3 agonist used in the treatment of Parkinson’s disease, improved measures of processing speed and working memory in euthymic bipolar patients (whose average age was 42) when compared with placebo in an adjunctive clinical trial.
Editor’s Note: Bipolar patients in a euthymic phase have consistently been shown to have some degree of cognitive dysfunction that is typically correlated with the number of prior depressive and/or manic episodes they have experienced. This is one of the first studies to directly target this cognitive dysfunction with a pharmacotherapeutic agent.
Pramipexole may be of additional value among depressed patients, because in two small, placebo-controlled studies, one led by Carlos Zarate at the National Institute of Mental Health and one led by Joseph F. Goldberg in New York, pramipexole has been shown to exert acute antidepressant effects in bipolar patients in the depressive phase of the illness. The new data from Malhotra raise the possibility that there could be a two-for-one benefit when pramipexole is used in the depressive phase of bipolar illness—improvement in both depression and cognition.
Other approaches to improving cognition in patients with bipolar disorder
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.
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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
