CNS Drugs

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Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance–Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database

  • Faizan Mazhar
  • Marco Pozzi
  • Marta Gentili
  • Marco Scatigna
  • Emilio Clementi
  • Sonia RadiceEmail author
  • Carla Carnovale
Original Research Article



Hyponatraemia induced by antidepressant drugs is a rare but potentially life-threatening adverse reaction. Whether it is associated with all or only some antidepressant drugs is still unclear. This needs to be clarified to guide antidepressant therapies, especially in patients with electrolytic imbalances.


The primary objective of this study was to quantify the strength of association between the use of different antidepressant drugs and hyponatraemia by using information reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). The secondary objective was to investigate the putative relationship between different antidepressant pharmacological targets and the risks of hyponatraemia induced by antidepressant drugs using the ‘pharmacovigilance–pharmacodynamic’ method.


We used the FAERS database to conduct a case/non-case analysis on spontaneous reports, focusing on events of hyponatraemia/syndrome of inappropriate antidiuretic hormone secretion (SIADH) reported in connection with the use of antidepressant drugs. Risk was expressed as a measure of disproportionality using the reporting odds ratio while adjusting for sex, age and concomitant medications associated with hyponatraemia/SIADH. We assessed to what extent the receptor-binding properties of antidepressant drugs could associate with the reporting odds ratios of hyponatraemia/SIADH of antidepressant drugs, building a linear regression model that included as independent variables the binding affinities (pKi) to the serotonin transporter, dopamine transporter, norepinephrine transporter, and serotonin 5-HT2C, 5-HT2A and 5-HT1A, and α1- and α2-adrenergic receptors.


There were 2233 reports identified. The adjusted reporting odds ratio for the association between antidepressant drug use and hyponatraemia was 1.91 (95% confidence interval 1.83–2.00). The association was strongest for mirtazapine, followed by selective serotonin reuptake inhibitors, and lowest with serotonin-modulating antidepressant drugs. A significant linear correlation was found between the adjusted reporting odds ratios for hyponatraemia and pKi for the adrenergic receptors α1 and α2.


Hyponatraemia is reported at a disproportionately higher level with classes of antidepressant drugs (noradrenergic and specific serotonergic antidepressant [mirtazapine] and serotonin modulators [vortioxetine]) that are in general considered to have a better profile of tolerability in terms of hyponatraemia. With regard to the presented results, the risk of hyponatraemia with mirtazapine appears to be greater than what was reported in the literature; however, confounding by indication cannot be ruled out. Our pharmacovigilance–pharmacodynamic analysis also indicates that inhibition of the serotonin transporter may not be involved in the hyponatraemia linked to the use of antidepressant drugs.


Compliance with Ethical Standards


This study was supported by the Centre of Pharmacovigilance of Regione Lombardia (MEAP project, Monitoraggio degli eventi avversi nelle popolazioni a rischio, to Emilio Clementi) and by the Italian Ministry of Health (RC 2018 to Marco Pozzi). Faizan Mazhar is supported by the 33rd cycle Ph.D. programme in “Scienze Farmacologiche Sperimentali e Cliniche”, Università degli Studi di Milano.

Conflict of Interest

Faizan Mazhar, Marco Pozzi, Marta Gentili, Marco Scatigna, Emilio Clementi, Sonia Radice and Carla Carnovale have no conflicts of interest that are directly relevant to the content of this article.

Supplementary material

40263_2019_631_MOESM1_ESM.docx (117 kb)
Supplementary material 1 (DOCX 116 kb)


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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Faizan Mazhar
    • 1
  • Marco Pozzi
    • 2
  • Marta Gentili
    • 1
  • Marco Scatigna
    • 3
  • Emilio Clementi
    • 1
    • 2
  • Sonia Radice
    • 1
    Email author
  • Carla Carnovale
    • 1
  1. 1.Pharmacovigilance Service, Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences L. Sacco, “Luigi Sacco” University HospitalUniversity of Milan ASST Fatebenefratelli-SaccoMilanItaly
  2. 2.Scientific Institute, IRCCS E. MedeaBosisio PariniItaly
  3. 3.Specialisation School of Clinical Pharmacology and ToxicologyUniversità di MilanoMilanItaly

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