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: Hyponatremia associated with antipsychotic drugs is a rare but potentially life-threatening adverse drug reaction; the underlying pharmacological mechanism has not yet been explained. METHODS: We investigated the relationship between pharmacological targets of antipsychotic drugs and the occurrence of hyponatremia by conducting a nested case-control study using the Food and Drug Administration Adverse Event Reporting System database. Multiple logistic regression was used to determine the associations between antipsychotics receptor occupancy and hyponatremia. We also performed a systematic review of clinical studies on this association. RESULTS: Of 139 816 reports involving at least 1 antipsychotic, 1.1% reported hyponatremia. Olanzapine was the most frequently suspected drug (27%). A significant positive association was found between dopamine D(3), D(4), and hyponatremia, while adrenergic α (1), serotonin 5-HT(1A), and 5-HT(2A) receptor occupancies were negatively associated. A multivariable stepwise regression model showed that dopamine D(3) (adj. odds ratio = 1.21; 95% CI = 1.09–1.34; P < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT(2A) occupancy (Adj. odds ratio = 0.78; 95% CI = 0.68–0.90; P < .01) exhibited a protective effect against hyponatremia. Among the 11 studies included in the systematic review, incidence rates of hyponatremia diverged between 0.003% and 86%, whereas the odds of developing hyponatremia from effect studies ranged between 0.83 and 3.47. CONCLUSIONS: Antipsychotic drugs having a combined modest occupancy for D(3) and 5-HT(2A) receptors and higher levels of D(3) receptor occupancy correspond to different degrees of risk for hyponatremia. Based on the few, relatively large-scale available studies, atypical antipsychotics have a more attenuated risk profile for hyponatremia.