Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders.
Brain-penetrant calcium channel blockers are associated with a reduced incidence of neuropsychiatric disorders.
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DOI：
10.1038/s41380-022-01615-6
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发表时间：
2022-09
影响因子：
11
通讯作者：
Harrison, Paul J.
中科院分区：
文献类型：
--
作者：
Colbourne, Lucy;Harrison, Paul J.
钙通道阻滞剂(CCB)在穿透大脑的能力上有所不同。药物流行病学研究表明，CCB作为一类可能对某些精神和神经疾病的风险和结果有有益的影响。这似乎是合理的，但尚不清楚这种影响是否与他们的大脑外显率有关。为了解决这个问题，我们使用TriNetX电子健康记录网络来识别开出脑渗透剂CCB(BP-CCB)的人，或者那些服用氨氯地平的人，氨氯地平是一种脑渗透性低的CCB。我们创建了患者队列，这些患者在首次接触CCB之前，必须具有或不可能具有以下任何类别的ICD-10诊断记录：精神障碍；情感障碍(包括双相情感障碍和严重抑郁障碍)；焦虑症；物质使用障碍；睡眠障碍；精神错乱；痴呆症或运动障碍。队列配对的倾向性得分与年龄、性别、种族、血压、体重指数和一系列其他变量相匹配。结果是在两年的暴露期间测量这些疾病的发生率。匹配的队列大小从17,896到49,987不等。在没有精神或神经退行性疾病病史的人中，与氨氯地平相比，服用BP-CCBS的大多数疾病的发病率明显较低，风险比从0.64到0.88不等，总体风险比为0.88，即风险降低12%。在那些确实有精神疾病或神经退行性诊断的人中，差异要小得多，但再次表明，与氨氯地平相比，患有BP-CCBS的几种疾病的风险更低。这种差异在女性和60岁以下的人中更为明显。将BP-CCBS与维拉帕米和地尔硫卓进行比较，结果相似。我们还比较了BP-CCBS和血管紧张素受体阻滞剂，发现BP-CCBS的总体风险比为0.94，但不同疾病的影响不同，包括精神障碍和痴呆症的风险更高，但焦虑和睡眠障碍的风险更低。在一些分析中，有证据表明，即使在广泛的匹配之后，仍然存在残留的混淆，因为阴性对照结果显示，与对照队列相比，BP-CCB的发生率降低。总而言之，容易穿透大脑的CCB与不穿透大脑的CCB相比，神经精神障碍的发生率较低，尤其是第一次诊断。这可能反映了它们对神经元电压门控钙通道的阻断。这些发现鼓励使用现有的BP-CCB进行再利用试验，并表明具有增强的和更具选择性的中枢作用的新型BP-CCB可能对精神和神经退行性疾病具有更大的治疗潜力。
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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DOI：
10.1192/bjp.2020.249
发表时间：
2021-05
期刊：
The British journal of psychiatry : the journal of mental science
影响因子：
--
作者：
Harrison PJ;Colbourne L;Luciano S
通讯作者：
Luciano S
影响因子：
11
作者：
Cipriani, A.;Saunders, K.;Attenburrow, M-J;Stefaniak, J.;Panchal, P.;Stockton, S.;Lane, T. A.;Tunbridge, E. M.;Geddes, J. R.;Harrison, P. J.
通讯作者：
Harrison, P. J.
影响因子：
11
作者：
Clark, Michael B.;Wrzesinski, Tomasz;Tunbridge, Elizabeth M.
通讯作者：
Tunbridge, Elizabeth M.
影响因子：
7.3
作者：
Friden, Markus;Winiwarter, Susanne;Antonsson, Madeleine
通讯作者：
Antonsson, Madeleine
影响因子：
11.3
作者：
DUBOVSKY, SL;FRANKS, RD;MURPHY, J
通讯作者：
MURPHY, J