Contents lists available at ScienceDirect European Journal of Internal Medicine journal homepage: www.elsevier.com/locate/ejim Antipsychotics and severe hyponatremia: A Swedish population–based case–control study Henrik Falhammar a,b, ⁎ , Jonatan D. Lindh c , Jan Calissendorff a,b , Jakob Skov a , David Nathanson b,d , Buster Mannheimer d a Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden b Department of Endocrinology, Metabolism and Diabetes, Karolinska University Hospital, Stockholm, Sweden c Department of Laboratory Medicine, Division of Clinical Pharmacology, Karolinska University Hospital Huddinge, Karolinska Institutet, Stockholm, Sweden d Department of Clinical Science and Education at Södersjukhuset, Karolinska Institutet, Stockholm, Sweden ARTICLE INFO Keywords: Risperidone First-generation antipsychotics Second-generation antipsychotics Hyponatremia SIADH Adverse reaction ABSTRACT Background: Antipsychotics have been claimed to cause hyponatremia. The risk associated with individual an- tipsychotics, or groups (first-generation [FGAs] or second-generation [SGAs] antipsychotics), is not well-docu- mented. The objective of this study was to investigate the association between antipsychotics and hospitalization due to hyponatremia. Methods: The general Swedish population was the base of this register–based case–control study. Comparisons were made between patients hospitalized with a principal diagnosis of hyponatremia (n = 14,359) and matched controls (n = 57,383). Multivariable logistic regression adjusting for concomitant drugs, medical conditions, previous hospitalizations and socioeconomic factors was performed to investigate the association between hy- ponatremia and antipsychotic use. In addition newly initiated (≤90 days) or ongoing use was analysed sepa- rately. Results: Compared to controls, the adjusted OR (95%CI) for hospitalization due to hyponatremia was for any antipsychotic 1.67(1.5–1.86). Individuals on FGA were more likely to experience severe hyponatremia (2.12[1.83–2.46]) than those on any SGA (1.32[1.15–1.51]). No increased risks, neither as newly initiated nor ongoing therapy, were found for risperidone (0.86[0.56–1.31] and 0.83[0.67–1.02]) and aripiprazole (1.16[0.30–4.46] and 0.62[0.27–1.34]), respectively. Conclusions: There was an association between antipsychotic therapy and hospitalization due to hyponatremia. The association was stronger for FGAs than SGAs. Risperidone was not associated with an increased risk. 1. Background Hyponatremia is the most common electrolyte disturbance affecting 15–30% of hospitalized patients [1]. Symptoms range from mild, non- specific symptoms such as lethargy, agitation and confusion to severe life-threatening symptoms such as seizures, coma and ultimately death due to brain oedema [2–4]. Medications are often the cause of hypo- natremia resulting in hospitalization. Thiazide diuretics, anti- depressants and antiepileptic drugs are the most frequent culprits [5–7]. In addition, antipsychotics can occasionally lead to severe hy- ponatremia [5,8–10]. Since decreased sodium values can result in symptoms resembling those seen in psychiatric conditions, including dementia, hyponatremia may be difficult to recognise [8]. First-generation (typical) antipsychotics (FGAs) have been available for over 6o years and produce a combination of strong D2-antagonism together with anticholinergic and antihistaminergic effects [11]. Due to adverse reactions, second-generation (atypical) antipsychotics (SGAs) were developed with lower affinity to D2-receptors in combination with potent 5-HT 2A receptor action in addition to variable affinity to other receptors. Antipsychotic drugs have been associated with hyponatremia in schizophrenia and other severe mental illnesses [9]. Most reports on antipsychotic-induced hyponatremia have been case report/series [8,12–14], with only a few exceptions [9,10,15]. Hence, quantitative data on the risk of drug-induced hyponatremia, comparing different antipsychotics, is utterly scare [11]. We believe it is of clinical im- portance to fill this knowledge gap. The aim of this study was primarily to investigate the association between treatment with antipsychotic drugs and hospitalization due to https://doi.org/10.1016/j.ejim.2018.11.011 Received 2 October 2018; Received in revised form 24 November 2018; Accepted 27 November 2018 ⁎ Corresponding author at: Department of Molecular Medicine and Surgery, D02:04, Karolinska Institutet, SE-171 76 Stockholm, Sweden. E-mail address: henrik.falhammar@ki.se (H. Falhammar). European Journal of Internal Medicine xxx (xxxx) xxx–xxx 0953-6205/ © 2018 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. Please cite this article as: Falhammar, H., European Journal of Internal Medicine, https://doi.org/10.1016/j.ejim.2018.11.011