Selective serotonin reuptake inhibitors and risk of epilepsy after traumatic brain injury – A population based cohort study

ObjectiveTraumatic brain injury (TBI) is common and associated with a marked increased risk of developing epilepsy. Animal studies indicate that treatment with selective serotonin reuptake inhibitors (SSRIs) may increase the risk of epilepsy after TBI. The aim of this study was to investigate whether use of SSRIs modifies the risk of epilepsy after TBI.MethodsThis was a cohort study of 205,715 persons, who suffered a TBI in Denmark from 1996 to 2013. For each person with TBI, we matched 10 reference persons (N = 2,057,150) who were alive on the day of TBI and who had the same age and gender but had no history of TBI. We used a stratified Cox regression to calculate the relative risk of epilepsy after TBI for persons exposed to TBI, SSRI or both after adjustment for income, civil status, medical and neurological comorbidities, severe mental disease, and substance abuse.ResultsThe risk of epilepsy was 5.61 times higher for persons who used SSRI at time of TBI (adjusted Hazard Ratio (aHR): 5.61 (95% CI: 4.88; 6.45)), 3.23 times higher for persons who had a TBI but did not use SSRI at time of TBI (aHR: 3.23 (95% CI: 3.12;3.35)), and 1.31 times higher for persons who used SSRI but had no TBI (aHR: 1.31 (95% CI: 1.18; 1.45)) compared to persons unexposed to both TBI and SSRI.ConclusionsThis large population based cohort study showed that people using SSRI at the time of a TBI had higher risk of developing epilepsy compared to people not using SSRI at the time of TBI. The results are in line with those of animal studies and calls for further studies to evaluate whether the association is due to SSRIs or to the underlying disease (e.g. depression or anxiety).

研究背景：创伤性脑损伤（Traumatic Brain Injury, TBI）十分常见，且会显著增加癫痫发病风险。动物实验研究显示，选择性5-羟色胺再摄取抑制剂（Selective Serotonin Reuptake Inhibitor, SSRIs）的治疗可能会提升创伤性脑损伤后癫痫的发病风险。本研究旨在探讨选择性5-羟色胺再摄取抑制剂的使用是否会改变创伤性脑损伤后癫痫的发病风险。
研究方法：本研究为队列研究，纳入1996年至2013年丹麦境内205715名创伤性脑损伤患者。为每例创伤性脑损伤患者匹配10名对照个体（总对照人数为2057150名），这些对照个体在创伤性脑损伤发生当日仍存活，年龄、性别与病例组匹配，且无创伤性脑损伤病史。本研究采用分层Cox回归模型，在校正收入、婚姻状况、内科与神经系统合并症、重型精神疾病及物质滥用等混杂因素后，计算创伤性脑损伤患者、使用选择性5-羟色胺再摄取抑制剂者以及同时暴露于两者人群的癫痫相对发病风险。
研究结果：与未暴露于创伤性脑损伤和选择性5-羟色胺再摄取抑制剂的人群相比，创伤性脑损伤急性期使用选择性5-羟色胺再摄取抑制剂者的癫痫发病风险升高5.61倍（校正后风险比（adjusted Hazard Ratio, aHR）：5.61，95%置信区间（Confidence Interval, CI）：4.88~6.45）；仅发生创伤性脑损伤但未在急性期使用选择性5-羟色胺再摄取抑制剂者的癫痫发病风险升高3.23倍（aHR：3.23，95% CI：3.12~3.35）；仅使用选择性5-羟色胺再摄取抑制剂但无创伤性脑损伤史者的癫痫发病风险升高1.31倍（aHR：1.31，95% CI：1.18~1.45）。
研究结论：这项基于大人群的队列研究显示，创伤性脑损伤急性期使用选择性5-羟色胺再摄取抑制剂的人群，相较于创伤性脑损伤急性期未使用该类药物的人群，癫痫发病风险更高。本研究结果与动物实验研究结论一致，后续需开展进一步研究以明确该关联是由选择性5-羟色胺再摄取抑制剂本身所致，还是由潜在基础疾病（如抑郁症或焦虑症）引发。