Hyponatremia is one of the most common electrolyte disorders observed in psychiatric and geriatric patients.1-5 and it is associated with increased mortality. It occurs in approximately 8% of persons ≥ 55 years of age and the incidence increases to 12% for those over 75 years of age.3,5

Thiazide diuretics, thiazide-like diuretics, and antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), are widely known to affect sodium retention, with the resulting hyponatremia often requiring hospitalization.5-13 Also, severe thiazide-induce hyponatremia (TIH) (serum sodium < 115 mEq/L) can be fatal,12 and accounts for more than 90% of cases reported between 1962 to 1990.7 A cross-sectional observational study found that TIH occurs in approximately one in seven patients taking thiazide diuretics in primary care setting.14 Thiazide diuretics are commonly used because they are recommended by the American College of Cardiology as first-line therapy for hypertension treatment,15 and are commonly prescribed due to low cost and excellent cost-effectiveness.12 The ubiquitous use of thiazides has resulted in TIH being a major concern in the elderly.5,11 Similarly, SSRIs are widely used for treatment of depression due to their low incidence of side-effects, ease of dosing, safety, tolerability and wide range of indications, including anxiety, major depression, obsessive-compulsive disorder, and posttraumatic stress disorder.16,17

Thus, thiazide and SSRI/SNRI are likely to be prescribed concurrently in patients with multiple conditions including depression and hypertension.18 Studies have shown that combined use of SSRI/SNRI with thiazide-type diuretics increases the risk of hyponatremia over either drug alone.19,20



Generally, hyponatremia is caused by cation reduction, excess water retention or sodium shift; and severe hyponatremia may occur when these mechanisms happen at the same time.21 SSRIs induce hyponatremia through inducing the syndrome of inappropriate antidiuretic hormone secretion (SIADH).22 Thiazide diuretics cause hyponatremia by inhibiting urinary dilution through reduction of NaCl reduction at the distal renal tubules,3,5,7,21-23 stimulation of ADH release,21,22 increased proximal water reabsorption and reduction of glomerular filtration.21 Thiazides can also exacerbate hyponatremia in patients with underlying SIADH .3 There are case reports of severe hyponatremia associated with concurrent used of a SSRI and a thiazide diuretic, strongly suggesting the synergistic actions of both drug classes.22

Evidence of hyponatremia has been reported by several studies. A population-based study reported that the risk of development of hyponatremia was approximately 5 times higher in patients taking thiazide compared to those without thiazide exposure (HR=4.95; 95% CI 4.12-5.92).24 Moreover, the risk of severe hyponatremia was over 8 times higher for patients taking thiazide (HR=8.28; 95% CI,4.69-14.61).24 The prevalence and severity of the TIH incidence varies by thiazide and thiazide-like drugs. Some of the most frequently reported medications are hydrochlorothiazide alone, the combination of hydrochlorothiazide and amiloride (Moduretic®), a combination of hydrochlorothiazide and triamterene (Dyazide®), indapamide, and bendroflumethiazide,10,25,26 possibly due to the increased use of these drugs. A study reported hospitalization due to hyponatremia was almost two times higher in chlortalidone compared to hydrochlorothiazide treated patients (adjust HR=1.68, 95% CI, 1.24-2.28).27 However, there is no other compelling data to indicate that one thiazide ( or thiazide-like diuretic) is more likely to cause hoponatremia than another. Thus, providers should consider all thiazides and thiazide-like agents can interact with SSRI/SNRI. Moreover, the onset of TIH is usually within the first two weeks after initiating a thiazide diuretic,7,12 but it can be longer for some patients.10 For instance, a systematic review of 102 articles found the mean time to onset of TIH of 19 days after starting therapy.10

Antidepressants have variable association with increased risk of hyponatremia. Hyponatremia occurs more frequently with SSRIs and SNRIs as compared to other antidepressant classes.6,20 A review of the literature published in 2014 reported that incidence rates of hyponatremia was between 0.06% and 40% for SSRIs and 0.08% and 70% for venlafaxine, with the wide variation in incidence due to differences in sodium cutoff values, study designs, and populations.28 The risk of hyponatremia was 5.6 times higher (95% CI, 2.6-11.6) for patients with depression taking either SSRIs or venlafaxine compared to those did not take either SSRI or venlafaxine.19 Among SSRIs, fluoxetine appears to be the most strongly associated with the development of hyponatremia (OR=21.4, 95% CI, 5.3- 86.9),29 followed by citalopram (OR=5.50; 95% CI, 4.71-6.44), and then sertraline (OR=4.96, 95% CI, 3.81-6.48).6 Among SNRI class, clomipramine and venlafaxine have the strongest association with hyponatremia with odds ratios of 4.15 (95% CI, 2.56-6.74) and 2.04(95% CI, 1.79-2.33), respectively compared to those not receiving antidepressants.30 There are also case reports of the occurrence of hyponatremia with duloxetine.31-34 Similar to TIH, antidepressant induced hyponatremia usually occurs within the first two weeks of therapy and gradually decreases over time.1,30,35 For example, compared to no antidepressants, the incidence rate ratio of developing hyponatremia within 14 days (IRR14) and >180 days (IRR>180) are IRR14= 8.72 [7.97-9.54] and IRR180=1.18[1.14-1.23] for SSRIs; and IRR14= 6.31[4.77-8.36] and IRR180=1.62 [1.46-1.79] for SNRIs.30

In addition, evidence suggests that combined use of SSRI/SNRI with thiazide-type diuretic increases the risk of hyponatremia over either drug alone.19,20,28 Risk for hyponatremia is much greater for SSRIs with thiazides (OR = 11.2, 95%, 2.2-58.1) compared to no diuretic or SSRIs.19

Hyponatremia can also possibly happen with mirtazapine. A case-control study reported that risk of  hyponatremia is 2.5 time higher for mirtazapine exposure compared to controls, (OR=2.54, 95%CI, 2.04-3.16),6 but the prevalence is low likely due to infrequent use of the drug.28 Isolated cases of possible mirtazapine-induced hyponatremia have been reported.36,37 In one case, a patient with probably citalopram hyponatremia (with positive dechallenge) was put on mirtazapine with no recurrence of hyponatremia.38 In another case switching from citalopram to mirtazapine resulted in recurrence of hyponatremia.39

The clinical evidence suggests that tricyclic antidepressants (TCA) are less likely to result in hyponatremia.6,20 Two studies report the odds of hyponatremia associated tricyclic antidepressants to be between 1.05 (95% CI, 0.87-1.27) and 1.87 (95% CI, 0.56-6.24) compared to controls, but they appear to be not statistically significant.1,40

Isolated cases (including one confirmed by rechallenge) suggest that bupropion may cause hyponatremia. However, more evidence is needed to establish the extent to which it is less likely than SSRI/SNRI to cause hyponatremia, but in one case of hyponatremia normalized after the patient was switched from sertraline to bupropion.41

Mianserin is unlikely to associated with hyponatremia. A retrospective cohort study of 72,509 patients in Denmark with hyponatremia suggested that mianserin was not assoiciated with hyponatremia.30 Also, there is little information to suggest that nonselective monoamine oxidase inhibitors (MAOIs) antidepressants cause hyponatremia.

Beyond medications, there are numerous risk factors for hyponatremia. For patients with pre-existing TIH, recurrent hyponatremia can occur very quickly (within six hours) after a single dose thiazide re-challenge.8 The risk of hyponatremia is 3.67 times (95% CI, 2.13-6.33) for sodium levels between 135-139 mEq/L as compared to higher sodium level > 140 mEq/L.42 Evidence also suggested that elderly individuals with a previous history of TIH have impaired urinary dilution capacity are more susceptible to recurring TIH.5 Re-challenging with a thiazide should be avoided if possible, and when thiazide medications are necessary then a low dose is recommended for patients with risks factors for TIH.3 Considering the synergistic effect of SSRI/SNRI and thiazide diuretics among patients with pre-existing hyponatremia, adding either an SSRI/SNRI or a thiazide diuretic is likely to substantially increase the risk of worsening hyponatremia. If the combination cannot be avoided, monitor electrolyte status and symptoms carefully.

Epidemiological studies and case reports provide evidence that hyponatremia occurs more frequently in elderly women and those on restricted sodium intake.3,5,7,9,10,12,14,21,23,24,43-46 Multiple studies report the average age of hyponatremia development is 73-80 years, and about 70-80% are female.3,10,12,23 Women are 4-5 times more likely to experience hyponatremia compared to men7,47 and the risk are 3-4 times higher in individuals 70 years of age or greater.12,14 In addition, the prevalence of A396T variant of SLCO2A1 was twice as frequent in TIH cases as in controls. The A396T variant appears to be a risk factor for TIH possibly due to the combination of increased water permeability in the collecting duct caused by SLCO2A1 activity reduction and impairment of urinary dilution caused by thiazide.23 These risk factors should be considered when prescribing these medications.


Many other medications and some disease states have been associated with an increased risk of hyponatremia. The association is well documented for antiepileptics (OR= 2.98, 95% CI,1.54-5.76),3,48,49 amiodarone,50 angiotensin-converting enzyme (ACE) inhibitor,10,11 angiotensin-receptor blockers (ARBs),10,11,47 and some anti-neoplastic agents.51 Heart failure, hepatic cirrhosis, pneumonia, AIDs, hypothyroidism, hyperglycemia, adrenal insufficiency, and certain malignancies have been associated with an increased risk of hyponatremia.1,3,52,53

Supporting documentation

Artifacts for implementers



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Created: 11/1/2019
Last revision: 11/1/2019
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