Hyponatremia Following Antipsychotic Treatment: In Silico Pharmacodynamics Analysis of Spontaneous Reports From the US Food and Drug Administration Adverse Event Reporting System Database and an Updated Systematic Review

Background: Hyponatraemia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction (ADR); the underlying pharmacological mechanism has not been explained yet. Methods: We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatraemia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System (FAERS) database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatraemia. We also performed a systematic review of clinical studies on this association. Results: Of 139,816 reports involving at least one antipsychotic, 1.1% reported hyponatraemia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D3, D4 and hyponatraemia, while adrenergic α1, serotonin 5-HT1A, and 5-HT2A receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D3 (Adj. Odds Ratio=1.21; 95% CI=1.09-1.34; p<0.05) predicted the risk for hyponatraemia (p<0.05), while serotonin 5-HT2A occupancy (Adj. OR=0.78; 95% CI=0.68-0.90; p<0.01) exhibited a protective effect against hyponatraemia. Among the eleven studies included in the systematic review, incidence rates of hyponatraemia diverged between 0.003 % and 86%, whereas the odds of developing hyponatraemia from effect studies ranged between 0.83 to 3.47. Conclusions: Antipsychotic drugs having a combined modest occupancy for D3 and 5-HT2A receptors and higher levels of D3 receptor occupancy, correspond to different degrees of risk for hyponatraemia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatraemia.