CACNA1C (CaV1.2) and other L-type calcium channels in the pathophysiology and treatment of psychiatric disorders: Advances from functional genomics and pharmacoepidemiology.

A role for voltage-gated calcium channels (VGCCs) in psychiatric disorders has long been postulated as part of a broader involvement of intracellular calcium signalling. However, the data were inconclusive and hard to interpret. We review three areas of research that have markedly advanced the field. First, there is now robust genomic evidence that common variants in VGCC subunit genes, notably CACNA1C which encodes the L-type calcium channel (LTCC) CaV1.2 subunit, are trans-diagnostically associated with psychiatric disorders including schizophrenia and bipolar disorder. Rare variants in these genes also contribute to the risk. Second, pharmacoepidemiological evidence supports the possibility that calcium channel blockers, which target LTCCs, might have beneficial effects on the onset or course of these disorders. This is especially true for calcium channel blockers that are brain penetrant. Third, long-range sequencing is revealing the repertoire of full-length LTCC transcript isoforms. Many novel and abundant CACNA1C isoforms have been identified in human and mouse brain, including some which are enriched compared to heart or aorta, and predicted to encode channels with differing functional and pharmacological properties. These isoforms may contribute to the molecular mechanisms of genetic association to psychiatric disorders. They may also enable development of therapeutic agents that can preferentially target brain LTCC isoforms and be of potential value for psychiatric indications.

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

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.

Onset and recurrence of psychiatric disorders associated with anti-hypertensive drug classes.

The major anti-hypertensive (AHT) drug classes have been associated with differential risks of psychiatric disorders. However, existing data are limited largely to depression, and confounding variables have not always been controlled for. We sought to fill the evidence gap, using TriNetX Analytics, an electronic health records network. Amongst 58.6 million patients aged 18-90 years, patients prescribed a calcium channel blocker (CCB) were compared with those taking a diuretic, angiotensin-converting enzyme inhibitor (ACEI), angiotensin receptor blocker (ARB), or ß-blocker. Cohorts were propensity score-matched for age, sex, race, and blood pressure. Over a 2-year exposure period, we measured the incidence and risk ratio of a first diagnosis (ICD-10 codes), or a recurrence, of psychotic, affective, and anxiety disorders, as well as substance use disorders and sleep disorders. Cohort sizes ranged from 33,734 to 322,814. CCBs were associated with a lower incidence of psychotic, affective, and anxiety disorders than ß-blockers (risk ratios 0.69-0.99) and a higher incidence than ARBs (risk ratios 1.04-2.23) for both first and recurrent diagnoses. Comparisons of CCBs with ACEIs or diuretics showed smaller risk ratios that varied between disorders, and between first episode and recurrence. AHT classes were also associated with the incidence of substance use and sleep disorders. Results remained largely unchanged after more extensive cohort matching for additional potential confounders. In a secondary analysis, a comparison between ARBs and ACEIs showed lower rates of psychotic, affective, and substance use disorders with ARBs, but higher risks of anxiety and sleep disorders. In conclusion, AHT classes are differentially associated with the incidence of psychiatric disorders. ARBs show the most advantageous profile and ß-blockers the least. The apparent beneficial effects of ARBs merit further study.

Incidence of neurodegenerative and cerebrovascular diseases associated with antihypertensive drug classes.

Antihypertensive drugs (AHTs) are associated with lowered risks of neurodegenerative diseases and stroke. However, the relative risks associated with different AHT classes are unclear. Using an electronic health record network with 34 million eligible patients, we compared rates of these disorders over a 2-year period, in propensity score-matched cohorts of people taking calcium channel blockers (CCBs) compared with those taking other AHT classes. CCBs were associated with a higher incidence of all disorders compared with renin-angiotensin system agents, and a higher incidence of dementia and cerebrovascular disease compared with diuretics. CCBs were associated with a lower incidence of movement disorders and cerebrovascular disease compared with beta-blockers. The data show that AHT classes confer differential risks of neurodegenerative and cerebrovascular diagnoses.

Rates of delirium associated with calcium channel blockers compared to diuretics, renin-angiotensin system agents and beta-blockers: An electronic health records network study.

BACKGROUND: Antihypertensive drugs, especially calcium channel blockers, have been associated with differential rates of a number of neuropsychiatric outcomes. Delirium is commonly attributed to medication, including antihypertensive drugs, but delirium incidence has not been compared directly between antihypertensive drug classes. METHODS: Using a federated electronic health records network of 25.5 million people aged 50 years or older, we measured rates of delirium over a two-year period in patients prescribed calcium channel blockers compared to the other main antihypertensive drug classes. Extensive propensity score matching was used to create cohorts matched for a range of demographic factors and delirium risk factors. Negative control outcomes were also measured. RESULTS: Cohort sizes ranged from 54,000-577,000. Delirium was more common with calcium channel blockers than with renin-angiotensin system agents (~40% higher) but less common than with beta-blockers (~20% lower). These differences remained when patients with a range of other delirium risk factors were excluded, and they were not paralleled by the negative control outcomes. Comparisons between calcium channel blockers and diuretics produced inconclusive results. CONCLUSIONS: Calcium channel blockers are associated with higher rates of delirium than renin-angiotensin system agents, but lower rates compared to beta-blockers. The findings add to the list of factors which may be considered when choosing antihypertensive drug class.

The neuropathology of bipolar disorder: systematic review and meta-analysis.

Various neuropathological findings have been reported in bipolar disorder (BD). However, it is unclear which findings are well established. To address this gap, we carried out a systematic review of the literature. We searched over 5000 publications, identifying 103 data papers, of which 81 were eligible for inclusion. Our main findings can be summarised as follows. First, most studies have relied on a limited number of brain collections, and have used relatively small sample sizes (averaging 12 BD cases and 15 controls). Second, surprisingly few studies have attempted to replicate closely a previous one, precluding substantial meta-analyses, such that the latter were all limited to two studies each, and comprising 16-36 BD cases and 16-74 controls. As such, no neuropathological findings can be considered to have been established beyond reasonable doubt. Nevertheless, there are several replicated positive findings in BD, including decreased cortical thickness and glial density in subgenual anterior cingulate cortex, reduced neuronal density in some amygdalar nuclei, and decreased calbindin-positive neuron density in prefrontal cortex. Many other positive findings have also been reported, but with limited or contradictory evidence. As an important negative result, it can be concluded that gliosis is not a feature of BD; neither is there neuropathological evidence for an inflammatory process.

The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS): study protocol for a randomised controlled, experimental medicine study.

BACKGROUND: The discovery that voltage-gated calcium channel genes such as CACNA1C are part of the aetiology of psychiatric disorders has rekindled interest in the therapeutic potential of L-type calcium channel (LTCC) antagonists. These drugs, licensed to treat hypertension and angina, have previously been used in bipolar disorder, but without clear results. Neither is much known about the broader effects of these drugs on the brain and behaviour. METHODS: The Oxford study of Calcium channel Antagonism, Cognition, Mood instability and Sleep (OxCaMS) is a high-intensity randomised, double-blind, placebo-controlled experimental medicine study on the effect of the LTCC antagonist nicardipine in healthy young adults with mood instability. An array of cognitive, psychiatric, circadian, physiological, biochemical and neuroimaging (functional magnetic resonance imaging and magnetoencephalography) parameters are measured during a 4-week period, with randomisation to drug or placebo on day 14. We are interested in whether nicardipine affects the stability of these measures, as well as its overall effects. Participants are genotyped for the CACNA1C risk polymorphism rs1006737. DISCUSSION: The results will clarify the potential of LTCC antagonists for repurposing or modification for use in psychiatric disorders in which cognition, mood and sleep are affected. TRIAL REGISTRATION: ISRCTN, ISRCTN33631053 . Retrospectively registered on 8 June 2018 (applied 17 May 2018).