Nimodipine improves cortical efficiency during working memory in healthy subjects

Zink, Caroline F.; Giegerich, Mellissa; Carta, Kayla; Ginkel, Marcus van; O’Rourke, Molly Patricia; Singh, Eesha; Fuchs, Edward J.; Hendrix, Craig W.; Zimmerman, Eric I.; Breakey, Jennifer C.; Marzinke, Mark A.; Hummert, Pamela; Pillai, Jay J.; Weinberger, Daniel R.; Bigos, Kristin L.

doi:10.1038/s41398-020-01066-z

Cited by 14 publications

(14 citation statements)

References 38 publications

(41 reference statements)

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“…In particular, a gain-of-function mutation (99) in CACNA1C, which encodes for the alpha subunit of the L-type Ca 2+ channel, Cav1.2, is consistently linked to increased risk of schizophrenia and bipolar disorder (69,81,(100)(101)(102). This gain-offunction in Cav1.2 is associated with inefficient dlPFC function (103) and poor working memory and executive control in healthy controls and especially in patients (104,105). In the heart, Cav1.2 is central to the "fight or flight" stress response, where its activation by noradrenergic beta-AR-PKA signaling drives internal Ca 2+ release from the sarcoplasmic reticulum, increasing muscle contraction (106).…”

Section: Gain-of-function Alterations In Gene Products That Normally ...mentioning

confidence: 99%

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

Arnsten¹,

Woo²,

Yang³

et al. 2022

Biological Psychiatry

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Section: Gain-of-function Alterations In Gene Products That Normally ...mentioning

confidence: 99%

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

Arnsten¹,

Woo²,

Yang³

et al. 2022

Biological Psychiatry

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“…50 Nimodipine has also been linked to improved cortical efficiency during working memory tasks, indicating this may have therapeutic value for the treatment of negative symptoms, such as cognitive dysfunction. 51 Finally, we highlight that Riluzole, an antiglutamatergic agent targeting the KCNN3 hit, was found to be effective in treating negative symptoms in a randomized control trial for schizophrenia. 52 The therapeutic potential of a pharmacological intervention targeting the glutamatergic system is further supported by increasing evidence linking this system to psychiatric risk.…”

Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

T-SEM of 11 Major Psychiatric Disorders: Identification of Gene Expression Patterns for Cross-Disorder Risk and Drug Repurposing

Grotzinger¹,

Singh

Lam

et al. 2022

Preprint

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Importance: Psychiatric disorders display high levels of comorbidity and genetic overlap, necessitating multivariate approaches for parsing convergent and divergent psychiatric risk pathways. Identifying gene expression patterns underlying cross-disorder risk also stands to propel drug discovery and repurposing in the face of rising levels of polypharmacy. Objective: To identify gene expression patterns underlying genetic convergence and divergence across psychiatric disorders along with existing pharmacological interventions that target these genes. Design: This genomic study applied a multivariate transcriptomic method, Transcriptome-wide Structural Equation Modeling (T-SEM), to investigate gene expression patterns associated with four genomic factors indexing shared risk across 11 major psychiatric disorders. Follow-up tests, including overlap with gene sets for other outcomes and phenome-wide association studies, were conducted to better characterize T-SEM results. Public databases describing drug-gene pairs were used to identify drugs that could be repurposed to target genes found to be associated with cross-disorder risk. Main Outcomes and Measures: Gene expression patterns associated with genomic factors or disorder-specific risk and existing drugs that target these genes. Results: In total, T-SEM identified 451 genes whose expression was associated with the genomic factors and 41 genes with disorder-specific effects. We find the most hits for a Thought Disorders factor defined by bipolar disorder and schizophrenia. We identify 39 existing pharmacological interventions that could be repurposed to target gene expression hits for this same factor. Conclusions and Relevance: The findings from this study shed light on patterns of gene expression associated with genetic overlap and uniqueness across psychiatric disorders. Future versions of the multivariate drug repurposing framework outlined here have the potential to identify novel pharmacological interventions for increasingly common, comorbid psychiatric presentations.

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“…However, whether any CCBs produce significant effects on the neuronal voltage-gated calcium channels at clinically used doses has been questioned [ 60 , 61 ]. Recent evidence using functional MRI provides some evidence that they do [ 62 ] but further studies are required [ 63 ]. The fact that BP-CCBs were associated with lower risk across a diverse range of disorders suggests that the mechanism involves some facet of a shared underlying brain substrate, whilst the fact that the benefits of BP-CCBs were much greater in reducing incidence of first rather than subsequent diagnoses suggests they work primarily to reduce vulnerability to the onset of illness rather than affecting their course.…”

Section: Discussionmentioning

confidence: 99%

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

Colbourne

Harrison

2022

Mol Psychiatry

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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.

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Nimodipine improves cortical efficiency during working memory in healthy subjects

Cited by 14 publications

References 38 publications

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

Unusual Molecular Regulation of Dorsolateral Prefrontal Cortex Layer III Synapses Increases Vulnerability to Genetic and Environmental Insults in Schizophrenia

T-SEM of 11 Major Psychiatric Disorders: Identification of Gene Expression Patterns for Cross-Disorder Risk and Drug Repurposing

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

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