Identifying Antidepressants Less Likely to Cause Hyponatremia: Triangulation of Retrospective Cohort, Disproportionality, and Pharmacodynamic Studies

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.