Division of Pharmacology, Department of Biomedical Sciences, Nihon University School of Medicine, Tokyo, Japan.
Division of Genomic Epidemiology and Clinical Trials, Clinical Trials Research Center, Nihon University School of Medicine, Tokyo, Japan.
Clin Pharmacol Ther. 2022 Jun;111(6):1258-1267. doi: 10.1002/cpt.2573. Epub 2022 Mar 29.
Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine's Clinical Data Warehouse (2004-2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change -1.00 ± 0.23 mmol/L, P < 0.001) or serotonin-noradrenaline reuptake inhibitor (SNRI; -1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004-2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58-5.45) and SNRIs (5.66, 4.38-7.31), but not for mirtazapine (1.08, 0.74-1.58), fluvoxamine (1.48, 0.94-2.32), and milnacipran (0.85, 0.45-1.62). Finally, pharmacoepidemiological-pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = -0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.
抗抑郁药已知会导致低钠血症，但对于特定的抗抑郁药，存在相互矛盾的证据。为了确定不太可能导致低钠血症的抗抑郁药，我们进行了一项整合回顾性队列、不适当性和药效学研究的三角研究。在日本大学医学院临床数据仓库（2004-2020 年）≥ 60 岁患者的回顾性队列研究中，观察到在开始使用选择性 5-羟色胺再摄取抑制剂（SSRI；平均变化-1.00±0.23mmol/L，P < 0.001）或 5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI 后 30 天内血清钠水平显著下降；-1.01±0.31mmol/L，P = 0.0013），而去甲肾上腺素和特异性 5-羟色胺能抗抑郁药（米氮平）则没有下降；+0.55±0.47mmol/L，P = 0.24）。在 SSRI 中，氟伏沙明的血清钠水平没有下降（+0.74±0.75mmol/L，P = 0.33），在 SNRI 中，米那普仑的血清钠水平也没有下降（+0.08±0.87mmol/L，P = 0.93）。在日本药物不良事件报告数据库（2004-2020 年）≥ 60 岁患者的不适当性分析中，SSRIs（报告比值比 4.41，95%置信区间 3.58-5.45）和 SNRIs（5.66，4.38-7.31）的低钠血症报告显著增加，但米氮平（1.08，0.74-1.58）、氟伏沙明（1.48，0.94-2.32）和米那普仑（0.85，0.45-1.62）则没有增加。最后，药物流行病学药效学分析显示，血清钠水平下降与 5-羟色胺转运体（SERT）结合亲和力之间存在显著相关性（r = -0.84，P = 0.02），这表明米氮平、氟伏沙明和米那普仑对 SERT 的结合亲和力较低，是造成上述差异的原因。尽管还需要进一步的研究，但我们的数据表明，米氮平、氟伏沙明和米那普仑不太可能导致低钠血症。
