Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia



      Selective serotonin reuptake inhibitors (SSRIs) and other antidepressants are important as a cause of hyponatremia. However, most studies have focused on the effect on sodium levels regardless of clinical symptoms, or have been too small to be able to discriminate between the effects of specific antidepressant drugs. The objective of the present study was to investigate the association between different groups of antidepressants and the risk of hospitalization due to hyponatremia.


      In this register-based case-control study of patients in the general Swedish population, we identified 14,359 individuals with a main diagnosis of hyponatremia. For every case, 4 matched controls were included (n = 57,382). To investigate the temporal aspects of drug-induced hyponatremia, antidepressant exposure was divided into patients with newly initiated and ongoing treatment. Univariable and multivariable logistic regression was used to analyze the association of antidepressant use and hospitalization.


      For newly initiated antidepressants, adjusted odds ratios (95% confidence interval) for a main diagnosis of hyponatremia compared with controls were: citalopram 5.50 (4.71-6.44); sertraline 4.96 (3.81-6.48); venlafaxine 5.28 (3.20-8.83); tricyclic antidepressants 1.59 (1.13-2.24); and mirtazapine 2.54 (2.04-3.16). Adjusted odds ratio (confidence interval) for individuals with ongoing treatment ranged from 0.57 (0.52-0.63) for citalopram to 1.08 (0.85-1.36) for other SSRIs.


      There was a strong association between newly initiated treatment with SSRIs or venlafaxine and hospitalization due to hyponatremia. The association for tricyclic antidepressants and mirtazapine was small to moderate. In contrast, there was no evidence that ongoing treatment with antidepressants increases the risk for hospitalization due to hyponatremia.


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        • Upadhyay A.
        • Jaber B.L.
        • Madias N.E.
        Incidence and prevalence of hyponatremia.
        Am J Med. 2006; 119: S30-S35
        • Adrogue H.J.
        • Madias N.E.
        N Engl J Med. 2000; 342: 1581-1589
        • Liamis G.
        • Milionis H.
        • Elisaf M.
        A review of drug-induced hyponatremia.
        Am J Kidney Dis. 2008; 52: 144-153
        • De Picker L.
        • Van Den Eede F.
        • Dumont G.
        • et al.
        Antidepressants and the risk of hyponatremia: a class-by-class review of literature.
        Psychosomatics. 2014; 55: 536-547
        • Siegler E.L.
        • Tamres D.
        • Berlin J.A.
        • et al.
        Risk factors for the development of hyponatremia in psychiatric inpatients.
        Arch Intern Med. 1995; 155: 953-957
        • Kirby D.
        • Harrigan S.
        • Ames D.
        Hyponatraemia in elderly psychiatric patients treated with Selective Serotonin Reuptake Inhibitors and venlafaxine: a retrospective controlled study in an inpatient unit.
        Int J Geriatr Psychiatry. 2002; 17: 231-237
        • Movig K.L.
        • Leufkens H.G.
        • Lenderink A.W.
        • et al.
        Association between antidepressant drug use and hyponatraemia: a case-control study.
        Br J Clin Pharmacol. 2002; 53: 363-369
        • Jung Y.E.
        • Jun T.Y.
        • Kim K.S.
        • et al.
        Hyponatremia associated with selective serotonin reuptake inhibitors, mirtazapine, and venlafaxine in Korean patients with major depressive disorder.
        Int J Clin Pharmacol Ther. 2011; 49: 437-443
        • Leth-Moller K.B.
        • Hansen A.H.
        • Torstensson M.
        • et al.
        Antidepressants and the risk of hyponatremia: a Danish register-based population study.
        BMJ Open. 2016; 6: e011200
        • Gandhi S.
        • Shariff S.Z.
        • Al-Jaishi A.
        • et al.
        Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
        Am J Kidney Dis. 2017; 69: 87-96
        • Coupland C.
        • Dhiman P.
        • Morriss R.
        • et al.
        Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
        BMJ. 2011; 343: d4551
        • Movig K.L.
        • Leufkens H.G.
        • Lenderink A.W.
        • et al.
        Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly.
        Eur J Clin Pharmacol. 2002; 58: 143-148
        • Wilkinson T.J.
        • Begg E.J.
        • Winter A.C.
        • et al.
        Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people.
        Br J Clin Pharmacol. 1999; 47: 211-217
        • The Swedish Board of Health and Welfare
        Instructions on the choice of primary and secondary diagnosis.
        (Available at)
        • Hillier T.A.
        • Abbott R.D.
        • Barrett E.J.
        Hyponatremia: evaluating the correction factor for hyperglycemia.
        Am J Med. 1999; 106: 399-403
        • The National Board of Health and Welfare
        The National Patient Register.
        (Available at)
        Date accessed: April 1, 2017
        • Wettermark B.
        • Hammar N.
        • Fored C.M.
        • et al.
        The new Swedish Prescribed Drug Register—opportunities for pharmacoepidemiological research and experience from the first six months.
        Pharmacoepidemiol Drug Saf. 2007; 16: 726-735
        • R Core Team
        R: A Language and Environment for Statistical Computing.
        2013 (Available at)
        Date accessed: May , 2015
        • Movig K.L.
        • Leufkens H.G.
        • Lenderink A.W.
        • et al.
        Validity of hospital discharge International Classification of Diseases (ICD) codes for identifying patients with hyponatremia.
        J Clin Epidemiol. 2003; 56: 530-535
        • Gandhi S.
        • Shariff S.Z.
        • Fleet J.L.
        • et al.
        Validity of the International Classification of Diseases 10th revision code for hospitalisation with hyponatraemia in elderly patients.
        BMJ Open. 2012; 2
        • Holland-Bill L.
        • Christiansen C.F.
        • Ulrichsen S.P.
        • et al.
        Validity of the International Classification of Diseases, 10th revision discharge diagnosis codes for hyponatraemia in the Danish National Registry of Patients.
        BMJ Open. 2014; 4: e004956
        • Brownfield M.S.
        • Greathouse J.
        • Lorens S.A.
        • et al.
        Neuropharmacological characterization of serotoninergic stimulation of vasopressin secretion in conscious rats.
        Neuroendocrinology. 1988; 47: 277-283
        • Leibowitz S.F.
        • Eidelman D.
        • Suh J.S.
        • et al.
        Mapping study of noradrenergic stimulation of vasopressin release.
        Exp Neurol. 1990; 110: 298-305
        • Stimmel G.L.
        • Dopheide J.A.
        • Stahl S.M.
        Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects.
        Pharmacotherapy. 1997; 17: 10-21

      Linked Article

      • Corrigendum to “Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia” AmJMed, 131(01);56-63
        The American Journal of MedicineVol. 134Issue 4
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          Regarding the authors’ previously published paper on the association of antidepressants and hospitalization due to hyponatremia: In preparation of a new manuscript based on the same data published, 2 errors have been discovered in the dataset. Instead of only including patients with a primary diagnosis of hyponatremia, some cases with hyponatremia as a secondary diagnosis had been included. When corrected, the number of cases admitted with a primary diagnosis of hyponatremia were 11,213 instead of 14,359 as reported in the manuscript, and thus the number of matched controls was 44,801 instead of 57,382.
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