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 D3, D4, and hyponatremia, while adrenergic α 1, 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 < .05) predicted the risk for hyponatremia (P < .05), while serotonin 5-HT2A 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 D3 and 5-HT2A receptors and higher levels of D3 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.

中文翻译：

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抗精神病药物治疗后的低钠血症：美国食品和药物管理局不良事件报告系统数据库自发报告的计算机药效学分析和更新的系统评价

背景与抗精神病药物相关的低钠血症是一种罕见但可能危及生命的药物不良反应。潜在的药理机制尚未得到解释。方法 我们通过使用食品和药物管理局不良事件报告系统数据库进行嵌套病例对照研究，调查抗精神病药物的药理靶点与低钠血症发生之间的关系。多元逻辑回归用于确定抗精神病药物受体占据与低钠血症之间的关联。我们还对这种关联的临床研究进行了系统评价。结果 在涉及至少一种抗精神病药物的 139 816 份报告中，1.1% 报告了低钠血症。奥氮平是最常被怀疑的药物（27%）。发现多巴胺 D3、D4 和低钠血症之间存在显着正相关，而肾上腺素 α1、5-羟色胺 5-HT1A 和 5-HT2A 受体占据呈负相关。多变量逐步回归模型显示多巴胺 D3（调整优势比 = 1.21；95% CI = 1.09–1.34；P < .05）可预测低钠血症的风险（P < .05），而血清素 5-HT2A 占用率（Adj. 优势比 = 0.78；95% CI = 0.68–0.90；P < .01）对低钠血症具有保护作用。在纳入系统评价的 11 项研究中，低钠血症的发生率在 0.003% 和 86% 之间存在差异，而从效果研究中发生低钠血症的几率在 0.83 和 3.47 之间。结论 抗精神病药物对 D3 和 5-HT2A 受体具有适度的占有率以及较高水平的 D3 受体占有率与不同程度的低钠血症风险相对应。根据为数不多的、相对大规模的可用研究，非典型抗精神病药的低钠血症风险更小。