Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders

Abstract

Calcium channel blockers (CCBs) differ in their ability to penetrate into the brain. Pharmacoepidemiological studies suggest that CCBs as a class may have beneficial effects on the risks and outcomes of some psychiatric and neurological disorders. It is plausible but unknown whether this effect relates to their brain penetrance. To address this, we used the TriNetX electronic health records network to identify people prescribed a brain-penetrant CCB (BP-CCB), or those given amlodipine, a CCB with low brain penetrability. We created cohorts of patients who, prior to first CCB exposure, either had to have, or could not have had, a recorded ICD-10 diagnosis in any of the following categories: psychotic disorder; affective disorder (including bipolar disorder and major depressive disorder); anxiety disorder; substance use disorder; sleep disorder; delirium; dementia, or movement disorder. Cohort pairs were propensity score matched for age, sex, race, blood pressure, body mass index, and a range of other variables. The outcomes were the incidence of these disorders measured over a two-year exposure period. Matched cohort sizes ranged from 17,896 to 49,987. In people with no prior history of psychiatric or neurodegenerative disorder, there was a significantly lower incidence of most disorders with BP-CCBs compared to amlodipine, with risk ratios ranging from 0.64 to 0.88 and an overall risk ratio of 0.88, i.e. a risk reduction of 12%. In people who did have a prior psychiatric or neurodegenerative diagnosis, differences were much smaller, but again showed lower risks for several disorders with BP-CCBs compared to amlodipine. The differences were somewhat more marked in women and in people less than 60 years old. Results were similar when comparing BP-CCBs with verapamil and diltiazem. We also compared BP-CCBs with angiotensin receptor blockers, and found an overall risk ratio of 0.94 in favour of BP-CCBs, but with differential effects across disorders including a higher risk of psychotic disorder and dementia, but a lower risk for anxiety and sleep disorders. In some analyses, there was evidence of residual confounding even after the extensive matching, in that negative control outcomes showed a reduced incidence with BP-CCBs relative to the comparator cohort. In summary, CCBs that readily penetrate the brain are associated with a lower incidence of neuropsychiatric disorders, especially first diagnoses, compared to CCBs which do not. This may reflect their blockade of neuronal voltage-gated calcium channels. The findings encourage repurposing trials using existing BP-CCBs, and suggest that novel BP-CCBs with enhanced and more selective central actions might have greater therapeutic potential for psychiatric and neurodegenerative disorders.

Heart-brain connections: Phenotypic and genetic insights from magnetic resonance images

“…For example, in a meta-analysis of 209 studies, antihypertensive medications were found to reduce dementia risk by 21% ( 126 ). Brain-penetrant calcium channel blockers were associated with a lower incidence of neuropsychiatric disorders ( 127 ). The CMR and brain MRI traits prioritized in our heart-brain analyses could be helpful in identifying potential therapeutic targets and evaluating the therapeutic potential (or side effects) of existing antihypertensive drugs and heart disease medications for mental health and neurodegenerative disorders.…”

Comment on: “Risk of Erectile Dysfunction in Male Patients with Gout Treated with Febuxostat or Allopurinol: A Propensity Score-Matched Cohort Study”

“…Major depressive disorder (F32-F33) [5] instead of depression (F32) alone should be listed. Psychotic disorders (F20-F29), affective disorders (F30-F39), anxiety disorders (F40-48), substance use disorder (F10-F19), delirium (F05, R40.0, R41.0), dementia (F01-F03, G30, G31.0, G31.2, G31.83), and movement disorder (G20-G26) could also be considered in the analysis [19]. After adjusting for the psychologic factors, the results would better reflect organic ED that is drug induced.…”

Substantiated therapy of pre-dementia cognitive impairment with calcium-channel blockers

“…На сегодняшний день многие исследования показали, что Ca2+-дисгомеостаз и потеря синапсов являются ранним событием, лежащим в основе цитотоксичности нейронов, и возникают раньше, чем отложение бляшек и нейрофибриллярных клубочков [24][25][26][27][28]. Двухлетнее наблюдение за пациентами, принимаю щими различные блокаторы кальциевых каналов, показало снижение риска развития деменции, психотических и аффективных расстройств [29]. При этом риски развития неврологических и психических заболеваний были на 12% ниже у лиц, принимаю щих селективные блокаторы кальциевых каналов с высокой проникаю щей способностью в мозговой кровоток, например нимодипин.…”