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Antidepressants and Hyponatremia

  • Yeong-Hau H. Lien
    Correspondence
    Requests for reprints should be addressed to Yeong-Hau H. Lien, MD, PhD, Arizona Kidney Disease and Hypertension Center, 4511 N. Campbell Avenue, Suite 100 Tucson, AZ 85718.
    Affiliations
    Department of Medicine, College of Medicine, University of Arizona, Tucson

    Arizona Kidney Disease and Hypertension Center, Tucson
    Search for articles by this author
Published:September 15, 2017DOI:https://doi.org/10.1016/j.amjmed.2017.09.002
      See related Article, p. 56
      It is well known that antidepressants can cause hyponatremia, particularly in elderly patients. This complication can be serious, with delirium, seizure, or even death. In the classic study by Fabian et al,
      • Fabian T.J.
      • Amico J.A.
      • Kroboth P.D.
      • et al.
      Paroxetine induced hyponatremia in older adults: a 12-week prospective study.
      paroxetine, a selective serotonin reuptake inhibitors (SSRI), was found to induce hyponatremia in 12% of elderly patients within a mean duration of 9 days. The findings of urine sodium, urine osmolality, and serum antidiuretic hormone levels are consistent with the syndrome of inappropriate antidiuretic hormone secretion.
      • Fabian T.J.
      • Amico J.A.
      • Kroboth P.D.
      • et al.
      Paroxetine induced hyponatremia in older adults: a 12-week prospective study.
      Over last 20 years newer antidepressants have been added to the market. The so-called second-generation antidepressants include SSRIs, serotonin–norepinephrine reuptake inhibitors, noradrenergic and specific serotonergic antidepressants (NaSSAs), and others. They have different pharmacologic mechanisms and are better tolerated than tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors
      • Mulrow C.D.
      • Williams Jr, J.W.
      • Chiquette E.
      • et al.
      Efficacy of newer medications for treating depression in primary care patients.
      and thus largely replace the older antidepressants. Whether all antidepressants cause hyponatremia equally has been questioned
      • De Picker L.
      • Van Den Eede F.
      • Dumont G.
      • et al.
      Antidepressants and the risk of hyponatremia: a class-by-class review of literature.
      but is still controversial after multiple population-based studies published in recent years.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      In this issue of The American Journal of Medicine, Farmand et al
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      add another population-based study, using 10-year hospital data from the National Patient Register of Sweden to investigate the association between various antidepressants and hyponatremia.
      The unique patient entry criteria for this study was that hyponatremia had to be the primary diagnosis for hospitalization (ie, patients with secondary hyponatremia associated with severe medical conditions were excluded). To validate this diagnosis-based approach, the authors sampled 104 consecutive patients with a primary diagnosis of hyponatremia in 1 hospital. The diagnosis error was significant, approximately 11%; however, hyponatremia was quite severe, with a mean serum sodium level of 121 meq/L and 77% of patients having a serum sodium level <125 meq/L. Surprisingly, approximately 25% of the 14,359 hospitalized patients with a primary diagnosis of hyponatremia were taking antidepressants, and among them, approximately one-third were newly started on antidepressants.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      The mean age for those new antidepressant users was 76 years, and 80% were women. The top 5 comorbidities were ischemic heart disease, diabetes, cerebral vascular disease, congestive heart failure, and alcoholism. These data suggest that elderly women with high comorbidities, particularly cardiovascular comorbidities, are prone to develop severe hyponatremia after starting antidepressants. Unfortunately, these patients are exactly the majority who need antidepressants.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      To understand whether all antidepressants cause hyponatremia equally, the results of all 4 recent population-based studies are listed in the Table.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      Although all studies address the association between antidepressants and hyponatremia, the study populations, criteria for hyponatremia, and duration of antidepressant use are all different among studies.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      The odds ratio for each class or individual antidepressant therefore should not be compared across studies. Overall, hyponatremia risk is much higher within 2-4 weeks of starting antidepressants, and the risk seems to diminish over time. By 3-6 months the hyponatremia risk is the same as for patients who do not take antidepressants.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      As for each class of antidepressant, the risk of hyponatremia seems to be lower with TCAs and NaSSAs when compared with SSRI and serotonin–norepinephrine reuptake inhibitors.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      Because the risks for new and long-term use of antidepressants are widely different, the data for individual antidepressants in the British
      • De Picker L.
      • Van Den Eede F.
      • Dumont G.
      • et al.
      Antidepressants and the risk of hyponatremia: a class-by-class review of literature.
      and Danish
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      studies are not shown, because those data mixed new use and long-term use of antidepressants together. According to 2 other studies,
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      beside TCAs, mirtazapine seems to have a lower risk for hyponatremia. Another NaSSA, mianserin (not approved in the United States), was found to have no added risk for hyponatremia in the Danish study.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      Whether the lowered hyponatremia risk for the NaSSAs is related to their effects on neurotransmitters remains to be investigated. There are case reports supporting that switching from SSRIs to mirtazapine was safe for patients with hyponatremia
      • Jagsch C.
      • Marksteiner J.
      • Seiringer E.
      • Windhager E.
      Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion.
      • Mogi T.
      • Yoshino A.
      • Ikemoto G.
      • Nomura S.
      Mirtazapine as an alternative for selective-serotonin-reuptake-inhibitor-induced syndrome of inappropriate secretion of antidiuretic hormone.
      ; however, severe hyponatremia after mirtazapine use has also been reported.
      • Cheah C.Y.
      • Ladhams B.
      • Fegan P.G.
      Mirtazapine associated with profound hyponatremia: two case reports.
      While we are waiting for more studies, switching to mirtazapine seems to be reasonable for patients with profound hyponatremia in a hospital setting, where serum sodium levels and state of depression can be monitored closely.
      TableComparison of Risk for Hyponatremia Among Antidepressants in 4 Population-Based Studies
      AntidepressantsSweden
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      Canada,
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.


      New (<30 d)
      Denmark
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      Britain
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      New (<29 d)Long-term (>85 d)New (<14 d)Long-term (>180 d)New (<28 d)Long-term (>85 d)
      SSRI8.71.187.70.75
       Citalopram5.50.575.8
       Escitalopram2.50.634.78
       Sertraline5.00.757.3
       Paroxetine8.0
      Low events and odd ratio calculated from Table S7 of the cited reference.6
       Fluvoxamine2.7
      Low events and odd ratio calculated from Table S7 of the cited reference.6
       Fluoxetine5.3
      Low events and odd ratio calculated from Table S7 of the cited reference.6
      TCA1.60.7751.352.60.67
       Amitriptyline
       Nortriptyline
       Clomipramine
      SNRI6.31.62
       Duloxetine8.0
      Low events and odd ratio calculated from Table S7 of the cited reference.6
       Venlafaxine5.30.95
      NaSSA3.2
      NaSSA includes mirtazapine and mianserin.5
      0.96
      NaSSA includes mirtazapine and mianserin.5
       Mirtazapine2.50.763.17
      Other6.3
      Other includes venlafaxine and mirtazapine.3
      0.62
      Other includes venlafaxine and mirtazapine.3
      Study population: Sweden: Population based case–control study with patients aged >18 years with hospitalization due to hyponatremia (2005-2014)
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      ; Canada: Population based case–control study with patients aged >65 years receiving antidepressants (2003-2012)
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      ; Denmark: residents aged >18 years (1998-2012)
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      ; Britain: Patients aged >65 years with depression (1996-2007).
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      Hyponatremia definition as primary outcome: Sweden: Hospitalization with hyponatremia as primary diagnosis
      • Farmand S.
      • Lindh J.
      • Calissendorff J.
      • et al.
      Differences in associations of antidepressants and hospitalization due to hyponatremia.
      ; Canada: Hospitalization with hyponatremia as 1 diagnosis
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      ; Denmark: Na <135 mEq/mL
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      ; Britain: Diagnosis of hyponatremia.
      • Coupland C.
      • Dhiman P.
      • Morriss R.
      • et al.
      Antidepressant use and risk of adverse outcomes in older people: population based cohort study.
      Duration of antidepressant therapy: new and long-term therapy for each study defined as in Table.
      NaSSA = noradrenergic and specific serotonergic antidepressant; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant.
      * Low events and odd ratio calculated from Table S7 of the cited reference.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      NaSSA includes mirtazapine and mianserin.
      • Leth-Moller K.B.
      • Hansen A.H.
      • Torstensson M.
      • et al.
      Antidepressants and the risk of hyponatremia: a Danish register-based population study.
      Other includes venlafaxine and mirtazapine.
      • De Picker L.
      • Van Den Eede F.
      • Dumont G.
      • et al.
      Antidepressants and the risk of hyponatremia: a class-by-class review of literature.
      The take-home message is that we need to be careful when we start elderly patients on antidepressants. Patients who are prone to develop hyponatremia owing to high cardiovascular comorbidities are likely to develop hyponatremia after taking antidepressants. Unfortunately, no practice guidelines for initiation of antidepressants are currently available for primary care physicians who are prescribing most antidepressants.
      • Gandhi S.
      • Shariff S.Z.
      • Al-Jaishi A.
      • et al.
      Second-generation antidepressants and hyponatremia risk: a population-based cohort study of older adults.
      Informing patients about the risk of hyponatremia, preventive fluid moderation or restriction, and following serum sodium at 1 or 2 weeks should be considered. For hospitalized patients with severe hyponatremia, it is critical to take a detailed history of antidepressant use, particularly the duration of new antidepressant use. The management of antidepressant-induced hyponatremia depends on whether antidepressants can be stopped. If not, can switching to mirtazapine be an option?

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      Linked Article

      • Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia
        The American Journal of MedicineVol. 131Issue 1
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          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.
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