Hyponatremia Associated with the Use of Common Antidepressants in the All of Us Research Program

Abstract

Selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and norepinephrine-dopamine reuptake inhibitor (NRI) antidepressants can cause hyponatremia through syndrome of inappropriate antidiuretic hormone secretion (SIADH). This study assesses the differential risks of hyponatremia associated with commonly prescribed SSRIs (fluoxetine, paroxetine, sertraline, citalopram, escitalopram), SNRIs (duloxetine, venlafaxine) and NRI (bupropion), as well as omeprazole as a reference, with a retrospective observational cohort study in the All of Us Research Program, a national multicenter research cohort containing de-identified electronic health records (EHR). Participants who had been prescribed monotherapy with any of eight common antidepressants were included, with each drug considered as a separate arm indexed with a start date. Events were defined as the first occurrence of a low plasma sodium measurement or a clinical diagnosis recorded for either hyponatremia or SIADH. Those who did not have events were censored at their last plasma sodium measurement. A total of 17,439 individuals were exposed to one of the eight antidepressants as monotherapy. The overall incidences for hyponatremia were 0.87% in the first 30 days and 10.5% in the first 3 years in the antidepressant arms. Compared to sertraline, duloxetine (hazard ratio [HR] = 1.37 [1.19-1.58]) and escitalopram (HR = 1.16 [1.01-1.33]) were associated with the highest overall risk of hyponatremia, and bupropion (HR = 0.83 [0.73-0.94]) and paroxetine (HR = 0.78 [0.65-0.93]) were associated with the lowest risk. The risks were unchanged after adjusting for comorbidity and polypharmacy. Such information could help guide providers in managing patients and their risks of hyponatremia when on common antidepressants.

Figure 1

The study design. (a) A flowchart for inclusions and exclusions in the cohort building. ESRD: end‐stage renal diseases. (b) A design diagram to illustrate the temporality of variables. Years on the timeline are for example purposes only; actual timelines of exposure vary by individual. Drug 2: The prescription of a second antidepressant. Hypo‐Na: A hyponatremia event (defined by an abnormal laboratory sodium measurement or a diagnostic code. Rx: An EHR mention (such as prescription) of the study drug.

Figure 2

A forest plot to compare the risks of hyponatremia among the SSRI, SNRI, and NRI drugs with reference drug omeprazole and sertraline, with a glucose‐adjusted sodium value of ≤ 134 mEq/L as the cut‐off for hyponatremia. CI., confidence interval; HR, hazard ratio.

Figure 3

Differential risks of hyponatremia among the SSRI, SNRI, and NRI drugs. (a, b) The cumulative incidence of hyponatremia with glucose‐adjusted sodium ≤ 134 mEq/L (a) and ≤ 130 mEq/L (b) as cut‐offs; the red vertical dash lines are the 3‐year marks as a reference; y axis: Cumulative Hazard. (c, d) The chronological change of differential risks for hyponatremia between different antidepressants with Nelson Aalen Hazard plots (y axis: Hazard within the timeframe). (c) Early events since the initiation of the medications (bandwidth = 15 days). (d) Events during long‐term follow‐up when duloxetine and sertraline were compared (bandwidth = 12 months, Shades: 95% confidence interval).