A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

Cipriani, Andrea; Saunders, Kate E. A.; Attenburrow, Mary-Jane; Stefaniak, James D.; Panchal, Priyanka; Stockton, Sarah; Lane, TA; Tunbridge, Elizabeth M.; Geddes, John; Harrison, Paul J.

doi:10.1038/mp.2016.86

Cited by 91 publications

(90 citation statements)

References 99 publications

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“…Firstly, characterization of the complement of full-length CACNA1C isoforms is a necessary first step towards understanding how its transcript profile might be altered by a risk variant or disease state. Secondly, calcium channel blockers, which have Ca V 1.2 as one of their primary targets, are licensed for cardiovascular indications and have possible utility as a therapeutic strategy for psychiatric disorders [54][55][56][57] . Since the Ca V 1.2 proteins that arise from CACNA1C splicing show differential sensitivity to the existing calcium channel blockers 52 it may be possible to selectively target disease-relevant CACNA1C isoforms and/or those that are differentially expressed in the brain vs. the periphery, to provide novel psychotropic agents that are both more potent and are freer from peripheral side effects.…”

Section: Discussionmentioning

confidence: 99%

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Clark

Wrzesiński

Garcia

et al. 2018

Preprint

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RNA splicing is a key mechanism linking genetic variation and complex diseases, including schizophrenia. Splicing profiles are particularly diverse in the brain, but it is difficult to accurately identify and quantify full-length isoforms using standard approaches. CACNA1C is a large gene that shows robust genetic associations with several psychiatric disorders and encodes multiple, functionally-distinct voltage-gated calcium channels via alternative splicing. We combined long-range PCR with nanopore sequencing to characterise the full-length coding sequences of the CACNA1C gene in human brain. We show that its splice isoform profile varies between brain regions and is substantially more complex than currently appreciated: we identified 38 novel exons and 83 high confidence novel isoforms, many of which are predicted to alter protein function. Our findings demonstrate the capability of long-read amplicon sequencing to effectively characterise human splice isoform diversity, while the accurate characterisation of CACNA1C isoforms will facilitate the identification of disease-linked isoforms.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

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Section: Discussionmentioning

confidence: 99%

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Clark

Wrzesiński

Garcia

et al. 2018

Preprint

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“…Regarding sleep it has been shown, that a specific CACNA1C gene is associated with sleep quality and may be associated with sleep latency, which is prolonged in CH patients . Thus, L‐type calcium channel antagonists may normalize sleep . A recent study from our own group found that CH patients taking verapamil had a later nocturnal attack peak compared to CH patients not taking verapamil (02:43 AM compared to 01:53 AM) .…”

Section: Side Effects and Safetymentioning

confidence: 96%

“…A single neuron will typically express different receptor subfamilies . CCBs are currently used in the treatment of neurological and psychiatric disorders such as epilepsy, Parkinson’s disease, dementia, bipolar disorder, and long‐term depression . Dementia and Parkinson’s diseases are neurodegenerative disorders, whereas CH, epilepsy, depression, and bipolar disorders have a cyclic nature with a possible, common hypothalamic link .…”

Section: Side Effects and Safetymentioning

confidence: 99%

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives

et al. 2019

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Objective A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. Background Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. Methods A Pubmed search was conducted: “Verapamil”[Mesh] and “Cluster Headache”[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled‐trials or open labels studies), safety, and mechanism of effect. Results Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open‐label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open‐label studies support a dose‐dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene‐related peptide. Conclusion Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood.

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“…A recent review found no evidence that verapamil, an L-type calcium channel blocker usually prescribed for cardiovascular pathology, was effective in the management of acute mania. 38 However, the review suggests that this might be due to poor blood-brain barrier permeability of verapamil. There are also concerns about cardiovascular side effects of using L-type calcium channel blockers in bipolar disorder.…”

Section: It Wasmentioning

confidence: 99%

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis

et al. 2017

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IntroductionGabapentin has been extensively prescribed off-label for psychiatric indications, with little established evidence of efficacy. Gabapentin and pregabalin, a very similar drug with the same mechanism of action, bind to a subunit of voltage-dependent calcium channels which are implicated in the aetiopathogenesis of bipolar disorder, anxiety and insomnia. This systematic review and meta-analysis aims to collect and critically appraise all the available evidence about the efficacy and tolerability of gabapentin and pregabalin in the treatment of bipolar disorder, insomnia and anxiety.Methods and analysisWe will include all randomised controlled trials (RCTs) reported as double-blind and comparing gabapentin or pregabalin with placebo or any other active pharmacological treatment (any preparation, dose, frequency, route of delivery or setting) in patients with bipolar disorder, anxiety or insomnia. For consideration of adverse effects (tolerability), single-blind or open-label RCTs and non-randomised evidence will also be summarised. The main outcomes will be efficacy (measured as dichotomous and continuous outcome) and acceptability (proportion of patients who dropped out of the allocated treatment). Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least 2 independent reviewers. We will conduct a random-effects meta-analysis to synthesise all evidence for each outcome. Heterogeneity between studies will be investigated by the I2 statistic. Data from included studies will be entered into a funnel plot for investigation of small-study effects. No subgroup analysis will be undertaken, but we will carry out sensitivity analyses about combination treatment, psychiatric comorbidity, use of rescue medications and fixed versus random-effects model.Ethics and disseminationThis review does not require ethical approval. This protocol has been registered on PROSPERO (CRD42016041802). The results of the systematic review will be disseminated via publication in a peer-reviewed journal.

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A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

Cited by 91 publications

References 99 publications

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives

Biological rationale and potential clinical use of gabapentin and pregabalin in bipolar disorder, insomnia and anxiety: protocol for a systematic review and meta-analysis

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