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

Abstract

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 (2004Warehouse ( -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,), 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.

Benzodiazepine-related dementia risks and protopathic biases revealed by multiple-kernel learning with electronic medical records

“…Unlike patients of large hospitals in many other countries, a substantial proportion of these patients continued to be regularly and holistically cared for over a long period of time. We have observed previously reported clinical effects of drugs as well as unattended effects in over 10 previous analyses with this database (for reference, see the most recent ones 30 – 32 ), and we therefore expected generalisable knowledge to be drawn from it.…”

The risk of antidepressant-induced hyponatremia: A meta-analysis of antidepressant classes and compounds

“…Studies that reported on the mean time of hypoNa manifesting in SSRIs mentioned durations of 9 days (within 1–14 days) to 24 days (within 7–42 days) [ 19 , 20 ]. As to the possible underlying psychopharmacological mechanisms, duloxetine has been demonstrated to have a very high affinity for SERT inhibition [ 15 , 21 ]. Venlafaxine has less affinity for SERT inhibition than duloxetine and probably has about the same potency for SERT inhibition as paroxetine [ 22 ].…”

“…Looking for underlying mechanisms of hypoNa, Nagashima et al examined the correlations between antidepressants and serum sodium levels through their actions on serotonin transporter (SERT) inhibition and found a correlation between decreases in serum sodium levels and the binding affinity for SERT, with mirtazapine showing the lowest binding affinity for SERT [15]. Mirtazapine is known for its atypical receptor profile; more precisely, its primary therapeutic action is presynaptic α2-antagonism; it also blocks several postsynaptic serotonin (5HT) receptors (5HT2A, 5HT2C, 5HT3) and histamine 1 receptors [17].…”

Vitamin D supplementation is effective for olanzapine-induced dyslipidemia

“…This database includes detailed diagnostic, demographic, and laboratory data for inpatients and outpatients. We received written informed consent and agreement for the secondary use after anonymization at three hospitals affiliated with the NUSM ( Nagashima et al, 2022 ). Similar to the JMDC claims data analysis, the pre-prescription period of olanzapine was defined as the period within 12 months of the first prescription.…”

“…Furthermore, to improve the drawbacks of FAERS (lacking time stamps and the population size of patients who were prescribed the specified drugs), another source of real-world clinical big data, insurance claims from JMDC Inc., was utilized in our recently published studies ( Nagaoka et al, 2021 ; Siswanto et al, 2021 ). In the present study, in addition to the FAERS and JMDC databases, electronic medical records stored in the clinical data warehouse of Nihon University School of Medicine (NUSM’s CDW) containing detailed demographic, diagnostic, and laboratory data from patients at three hospitals affiliated with NUSM ( Nagashima et al, 2022 ) were also used. Electronic medical records can provide continuous clinical information, leading to unattainably precise outcomes of the onset pattern of specific drug-induced adverse effects, treatment significance, and validated medication safety.…”