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, a significant decrease in serum sodium levels was observed for selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine among SSRIs and milnacipran among SNRIs. In the disproportionality analysis, a significant increase in hyponatremia reports was observed for SSRIs and SNRIs, but not for mirtazapine, fluvoxamine, and milnacipran. Finally, pharmacoepidemiological–pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. These data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia.