Rationale

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

Algorithm

Explanation

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 men^7,47 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.

Precautions

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

• Click to download a PDF of In Depth Analysis

Artifacts for implementers

• Click to download a PDF of the flow diagram
• Click to download the computable Drools code and associated OMOP Value sets
• Click to download the computable CQL code
• Click to view the SSRI and SNRI value set
• Click to view the Thiazide and Thiazide-like diuretics value sets
• Click to view the Haloperidol value sets
• Click to view the Antineoplastic value sets
• Click to view the Risperidone value sets
• Click to view the Quetiapine value sets
• Click to view the Antiepileptic value sets
• Click to view the Amiodarone value set
• Click to view the history of Hepatic cirrhosis SNOMED, ICD10CM, ICD9CM
• Click to view the history of HIV / AIDS value sets: SNOMED,ICD10CM
• Click to view the history of heart failure value sets: SNOMED, ICD9CM
• Click to view the history of pneumonia value sets: SNOMED, ICD10CM, ICD9CM
• Click to view the history of adrenal insufficiency value sets: SNOMED, ICD10CM, ICD9CM
• Click to view the history of malignancy value sets: SNOMED, ICD10CM, ICD9CM
• Click to view the value set for sodium concentration lab measurement
• Click to add comments or ask questions on the Discussion forum
• Click to view a PDF short implementation guide

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References

1. Movig KL, Leufkens HG, Lenderink AW, Egberts AC. Serotonergic antidepressants associated with an increased risk for hyponatraemia in the elderly. Eur J Clin Pharmacol. 2002;58(2):143-148. PMID: 12012148
2. Liamis G, Milionis H, Elisaf M. A review of drug-induced hyponatremia. Am J Kidney Dis. 2008;52(1):144-153. PMID: 18468754
3. Liamis G, Filippatos TD, Elisaf MS. Thiazide-associated hyponatremia in the elderly: what the clinician needs to know. J Geriatr Cardiol. 2016;13(2):175-182. PMID: 27168745
4. Filippatos TD, Makri A, Elisaf MS, Liamis G. Hyponatremia in the elderly: challenges and solutions. Clin Interv Aging. 2017;12:1957-1965. PMID: 29180859
5. Hwang KS, Kim GH. Thiazide-induced hyponatremia. Electrolyte Blood Press. 2010;8(1):51-57. PMID: 21468197
6. Farmand S, Lindh JD, Calissendorff J, et al. Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia. Am J Med. 2018;131(1):56-63. PMID: 28803926
7. Sonnenblick M, Friedlander Y, Rosin AJ. Diuretic-induced severe hyponatremia. Review and analysis of 129 reported patients. Chest. 1993;103(2):601-606. PMID: 8432162
8. Friedman E, Shadel M, Halkin H, Farfel Z. Thiazide-induced hyponatremia. Reproducibility by single dose rechallenge and an analysis of pathogenesis. Ann Intern Med. 1989;110(1):24-30. PMID: 2491733
9. Chow KM, Szeto CC, Wong TY, Leung CB, Li PK. Risk factors for thiazide-induced hyponatraemia. Qjm. 2003;96(12):911-917. PMID: 14631057
10. Barber J, McKeever TM, McDowell SE, et al. A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation? Br J Clin Pharmacol. 2015;79(4):566-577. PMID: 25139696
11. Nadal J, Channavajjhala SK, Jia W, Clayton J, Hall IP, Glover M. Clinical and Molecular Features of Thiazide-Induced Hyponatremia. Curr Hypertens Rep. 2018;20(4):31. PMID: 29637415
12. Glover M, Clayton J. Thiazide-induced hyponatraemia: epidemiology and clues to pathogenesis. Cardiovasc Ther. 2012;30(5):e219-226. PMID: 21884020
13. Viramontes TS, Truong H, Linnebur SA. Antidepressant-Induced Hyponatremia in Older Adults. Consult Pharm. 2016;31(3):139-150. PMID: 26975593
14. Clayton JA, Rodgers S, Blakey J, Avery A, Hall IP. Thiazide diuretic prescription and electrolyte abnormalities in primary care. Br J Clin Pharmacol. 2006;61(1):87-95. PMID: 16390355
15. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. 2018;71(19):e127-e248. PMID: 16390355
16. Bak S, Tsiropoulos I, Kjaersgaard J, Andersen M, Mellerup E, Hallas J. Selective serotonin reuptake inhibitors and the risk of stroke: a population-based case-control study. Stroke. 2002;33:1465-1473. PMID: 12052976
17. Yuet WC, Derasari D, Sivoravong J, Mason D, Jann M. Selective Serotonin Reuptake Inhibitor Use and Risk of Gastrointestinal and Intracranial Bleeding. J Am Osteopath Assoc. 2019;119(2):102-111. PMID: 30688347
18. Bogner HR, Cary MS, Bruce ML, et al. The role of medical comorbidity in outcome of major depression in primary care: the PROSPECT study. Am J Geriatr Psychiatry. 2005;13(10):861-868. PMID: 16223964
19. 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. International Journal of Geriatric Psychiatry. 2002;17(3):231-237. PMID: 11921151
20. Movig KL, Leufkens HG, Lenderink AW, et al. Association between antidepressant drug use and hyponatraemia: a case-control study. Br J Clin Pharmacol. 2002;53(4):363-369. PMID: 11966666
21. Hix JK, Silver S, Sterns RH. Diuretic-associated hyponatremia. Semin Nephrol. 2011;31(6):553-566. PMID: 22099512
22. Rosner MH. Severe Hyponatremia Associated with the Combined Use of Thiazide Diuretics and Selective Serotonin Reuptake Inhibitors. The American Journal of the Medical Sciences. 2004;327(2):109-111. PMID: 14770031
23. Ware JS, Wain LV, Channavajjhala SK, et al. Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. J Clin Invest. 2017;127(9):3367-3374. PMID: 28783044
24. Rodenburg EM, Hoorn EJ, Ruiter R, et al. Thiazide-associated hyponatremia: a population-based study. Am J Kidney Dis. 2013;62(1):67-72. PMID: 23602191
25. Chapman MD, Hanrahan R, McEwen J, Marley JE. Hyponatraemia and hypokalaemia due to indapamide. Med J Aust. 2002;176(5):219-221. PMID: 11999238
26. Yong TY, Huang JE, Lau SY, Li JY. Severe hyponatremia and other electrolyte disturbances associated with indapamide. Curr Drug Saf. 2011;6(3):134-137. PMID: 11999238
27. Dhalla IA, Gomes T, Yao Z, et al. Chlorthalidone versus hydrochlorothiazide for the treatment of hypertension in older adults: a population-based cohort study. Ann Intern Med. 2013;158(6):447-455. PMID: 23552325
28. De Picker L, Van Den Eede F, Dumont G, Moorkens G, Sabbe BG. Antidepressants and the risk of hyponatremia: a class-by-class review of literature. Psychosomatics. 2014;55(6):536-547. PMID: 25262043
29. Siegler EL, Tamres D, Berlin JA, Allen-Taylor L, Strom BL. Risk factors for the development of hyponatremia in psychiatric inpatients. Arch Intern Med. 1995;155(9):953-957. PMID: 7726704
30. Leth-Moller KB, Hansen AH, Torstensson M, et al. Antidepressants and the risk of hyponatremia: a Danish register-based population study. BMJ Open. 2016;6(5):e011200. PMID: 27194321
31. Choi J-S, Lee HW, Lee JY, Jung HY. Rapid-onset hyponatremia induced by duloxetine in a middle-aged male with depression and somatic symptoms. Psychiatry Investig. 2012;9(1):83-84. PMID: 22396690
32. Dirks AC, van Hyfte DM. Recurrent hyponatremia after substitution of citalopram with duloxetine. J Clin Psychopharmacol. 2007;27(3):313. PMID: 17502788
33. Kruger S, Lindstaedt M. Duloxetine and hyponatremia: a report of 5 cases. J Clin Psychopharmacol. 2007;27(1):101-104. PMID: 17224730
34. Mussig K, Morike K, Haring HU. Severe and symptomatic hyponatremia following duloxetine treatment. J Psychopharmacol. 2009;23(3):338-339. PMID: 18562431
35. Wilkinson TJ, Begg EJ, Winter AC, Sainsbury R. Incidence and risk factors for hyponatraemia following treatment with fluoxetine or paroxetine in elderly people. British journal of clinical pharmacology. 1999;47(2):211-217. PMID: 10190657
36. Ladino M, Guardiola VD, Paniagua M. Mirtazapine-induced hyponatremia in an elderly hospice patient. J Palliat Med. 2006;9(2):258-260. PMID: 16629552
37. Shepshelovich D, Schechter A, Calvarysky B, Diker-Cohen T, Rozen-Zvi B, Gafter-Gvili A. Medication-induced SIADH: distribution and characterization according to medication class. Br J Clin Pharmacol. 2017;83(8):1801-1807. PMID: 28168757
38. Jagsch C, Marksteiner J, Seiringer E, Windhager E. Successful mirtazapine treatment of an 81-year-old patient with syndrome of inappropriate antidiuretic hormone secretion. Pharmacopsychiatry. 2007;40(3):129-131. PMID: 17541890
39. Bavbek N, Kargili A, Akcay A, Kaya A. Recurrent hyponatremia associated with citalopram and mirtazapine. Am J Kidney Dis. 2006;48(4):e61-62. PMID: 16997047
40. Coupland C, Dhiman P, Morriss R, Arthur A, Barton G, Hippisley-Cox J. Antidepressant use and risk of adverse outcomes in older people: population based cohort study. BMJ. 2011;343:d4551. PMID: 21810886
41. Varela Pinon M, Adan-Manes J. Selective Serotonin Reuptake Inhibitor-Induced Hyponatremia: Clinical Implications and Therapeutic Alternatives. Clin Neuropharmacol. 2017;40(4):177-179. PMID: 28622213
42. Makam AN, Boscardin WJ, Miao Y, Steinman MA. Risk of thiazide-induced metabolic adverse events in older adults. J Am Geriatr Soc. 2014;62(6):1039-1045. PMID: 24823661
43. Clark BA, Shannon RP, Rosa RM, Epstein FH. Increased susceptibility to thiazide-induced hyponatremia in the elderly. J Am Soc Nephrol. 1994;5(4):1106-1111. PMID: 7849250
44. Spital A. Diuretic-induced hyponatremia. Am J Nephrol. 1999;19(4):447-452. PMID: 10460932
45. Sharabi Y, Illan R, Kamari Y, et al. Diuretic induced hyponatraemia in elderly hypertensive women. J Hum Hypertens. 2002;16(9):631-635. PMID: 12214259
46. Yeates KE, Singer M, Morton AR. Salt and water: a simple approach to hyponatremia. Cmaj. 2004;170(3):365-369. PMID: 14757675
47. Huang CC, Chung CM, Hung SI, et al. Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia. Medicine (Baltimore). 2015;94(34):e1422. PMID: 26313793
48. Lu X, Wang X. Hyponatremia induced by antiepileptic drugs in patients with epilepsy. Expert Opin Drug Saf. 2017;16(1):77-87. PMID: 27737595
49. Gandhi S, McArthur E, Mamdani MM, et al. Antiepileptic drugs and hyponatremia in older adults: Two population-based cohort studies. Epilepsia. 2016;57(12):2067-2079. PMID: 27896804
50. Dutta P, Parthan G, Aggarwal A, et al. Amiodarone induced hyponatremia masquerading as syndrome of inappropriate antidiuretic hormone secretion by anaplastic carcinoma of prostate. Case Rep Urol. 2014;2014:136984. PMID: 24818037
51. Berghmans T. Hyponatremia related to medical anticancer treatment. Support Care Cancer. 1996;4(5):341-350. PMID: 8883227
52. Schmitz PH, de Meijer PH, Meinders AE. Hyponatremia due to hypothyroidism: a pure renal mechanism. Neth J Med. 2001;58(3):143-149. PMID: 11246114
53. Tang WW, Kaptein EM, Feinstein EI, Massry SG. Hyponatremia in hospitalized patients with the acquired immunodeficiency syndrome (AIDS) and the AIDS-Related complex. The American Journal of Medicine. 1993;94(2):169-174. PMID: 8430712