背景:苯二氮卓的使用很常见,尤其是老年人。苯二氮卓类药物对认知有明确的急性不良反应,但对神经变性和痴呆风险的长期影响仍不确定.
方法:我们纳入了基于人群的鹿特丹研究的5443名认知健康(MMSE≥26)参与者(57.4%的女性,平均年龄70.6岁)。从1991年至基线(2005-2008年)使用苯二氮卓类药物来自药房配药记录,从中我们确定了药物类型和累积剂量。苯二氮卓的使用定义为在药房记录开始和研究基线之间的抗焦虑药(ATC代码:N05BA)或镇静催眠药(ATC代码:N05CD)的处方。累积剂量计算为所有处方的规定每日剂量的总和。我们使用Cox回归确定了到2020年与痴呆风险的关联。在4836名重复脑部MRI的参与者中,我们使用线性混合模型进一步确定了苯二氮卓类药物的使用与神经影像学标志物变化的相关性.
结果:在所有5443名参与者中,2697(49.5%)在基线前15年的任何时间使用苯二氮卓类药物,其中1263人(46.8%)使用抗焦虑药,530(19.7%)镇静催眠药,904例(33.5%)同时使用;345例(12.8%)参与者在基线评估时仍在使用.在平均11.2年的随访中,726名参与者(13.3%)发展为痴呆。总的来说,与从未使用苯二氮卓类药物相比,使用苯二氮卓类药物与痴呆风险无关(HR[95%CI]:1.06[0.90-1.25]),无论累积剂量。任何使用抗焦虑药的风险估计都比镇静催眠药高(HR1.17[0.96-1.41]vs0.92[0.70-1.21]),与高累积剂量抗焦虑药的相关性最强(HR[95%CI]1.33[1.04-1.71])。在成像分析中,目前使用苯二氮卓类药物在横截面上与海马的脑容量较低有关,杏仁核,和丘脑,并纵向加速海马体的体积损失,杏仁核的程度较小。然而,影像学检查结果因苯二氮卓类药物类型或累积剂量而异.
结论:在这个基于人群的认知健康成年人样本中,苯二氮卓类药物的总体使用与痴呆风险增加无关,但潜在的类依赖性不良反应以及与神经变性亚临床标志物的关联可能需要进一步研究.
BACKGROUND: Benzodiazepine use is common, particularly in older adults.
Benzodiazepines have well-established acute adverse effects on cognition, but long-term effects on neurodegeneration and dementia risk remain uncertain.
METHODS: We included 5443 cognitively healthy (MMSE ≥ 26) participants from the population-based Rotterdam Study (57.4% women, mean age 70.6 years). Benzodiazepine use from 1991 until baseline (2005-2008) was derived from pharmacy dispensing records, from which we determined drug type and cumulative dose. Benzodiazepine use was defined as prescription of anxiolytics (ATC-code: N05BA) or sedative-hypnotics (ATC-code: N05CD) between inception of pharmacy records and study baseline. Cumulative dose was calculated as the sum of the defined daily doses for all prescriptions. We determined the association with dementia risk until 2020 using Cox regression. Among 4836 participants with repeated brain MRI, we further determined the association of benzodiazepine use with changes in neuroimaging markers using linear mixed models.
RESULTS: Of all 5443 participants, 2697 (49.5%) had used
benzodiazepines at any time in the 15 years preceding baseline, of whom 1263 (46.8%) used anxiolytics, 530 (19.7%) sedative-hypnotics, and 904 (33.5%) used both; 345 (12.8%) participants were still using at baseline assessment. During a mean follow-up of 11.2 years, 726 participants (13.3%) developed dementia. Overall, use of
benzodiazepines was not associated with dementia risk compared to never use (HR [95% CI]: 1.06 [0.90-1.25]), irrespective of cumulative dose. Risk estimates were somewhat higher for any use of anxiolytics than for sedative-hypnotics (HR 1.17 [0.96-1.41] vs 0.92 [0.70-1.21]), with strongest associations for high cumulative dose of anxiolytics (HR [95% CI] 1.33 [1.04-1.71]). In imaging analyses, current use of benzodiazepine was associated cross-sectionally with lower brain volumes of the hippocampus, amygdala, and thalamus and longitudinally with accelerated volume loss of the hippocampus and to a lesser extent amygdala. However, imaging findings did not differ by type of
benzodiazepines or cumulative dose.
CONCLUSIONS: In this population-based sample of cognitively healthy adults, overall use of
benzodiazepines was not associated with increased dementia risk, but potential class-dependent adverse effects and associations with subclinical markers of neurodegeneration may warrant further investigation.