Are any serotonergic antidepressants (e.g., SSRIs, SNRIs TCAs, mirtazapine) safer than others in patients with hyponatremia? Which antidepressants are least likely to affect sodium levels?

Comment by InpharmD Researcher

Population-based analyses suggest mirtazapine and tricyclic antidepressants are associated with a lower risk of hyponatremia than SSRIs and SNRIs; however, an analysis of antidepressant-associated hyponatremia reported to the FDA adverse events reporting system (FAERS) suggests the risk of hyponatremia with mirtazapine use may be greater than suggested.

  

PubMed: antidepressants hyponatremia = 403 reults; antidepressants sodium levels = 717 results

Background

A 2018 commentary reviewed four population-based analyses regarding the incidence of hyponatremia secondary to antidepressant use. Although each study evaluated the association between antidepressant use and low sodium levels, the study populations, criteria for hyponatremia, and duration of antidepressant use are all different among studies. Trends from each study showed the risk of hyponatremia to be another within 2-4 weeks of starting antidepressants, and the risk appeared to decrease over time. After 3-6 months, the risk of hyponatremia is the same as patients not taking antidepressants. [1]

The overall risk of hyponatremia appears to be lower with tricyclic antidepressant use (TCA) and noradrenergic and specific serotonergic antidepressants (i.e., mirtazapine) compared to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). However, this data is obscured because not all of the studies differentiated between short-term and long-term antidepressant use. [1], [2], [3]

Another noradrenergic and specific serotonergic antidepressant, mianserin, also appears to have a lower risk of hyponatremia; however, this agent is not approved for use in the United States. Additionally, case reports suggest switching from an SSRI to mirtazapine is safe for patients with hyponatremia; however, it should be noted that severe hyponatremia has been reported with mirtazapine. Studies tend to show bupropion, trazodone, and tricyclic antidepressants to be the least implicated with hyponatremia. [1], [2], [3]

References:

[1] Lien Y-HH. Antidepressants and hyponatremia. The American Journal of Medicine. 2018;131(1):7-8. doi:10.1016/j.amjmed.2017.09.002
[2] Viramontes TS, Truong H, Linnebur SA. Antidepressant-Induced Hyponatremia in Older Adults. Consult Pharm. 2016;31(3):139-150. doi:10.4140/TCP.n.2016.139
[3] 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. doi:10.1016/j.psym.2014.01.010
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are any serotonergic antidepressants (e.g., SSRIs, SNRIs TCAs, mirtazapine) safer than others in patients with hyponatremia? Which antidepressants are least likely to affect sodium levels?

Please see Tables 1-2 for your response.

 

Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance-Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database

Design

Retrospective, database analysis

N=2,233

Objective

To quantify the strength of association between the use of different antidepressant drugs and hyponatremia by using information reported to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS)

Study Groups

  

Inclusion Criteria

Reported cases of hyponatremia, syndrome of inappropriate antidiuretic hormone (SIADH), and increased or decreased serum sodium or antidiuretic hormone levels; associated with antidepressant use (primary or secondary suspicion)

Exclusion Criteria

 None reported

Methods

This was an analysis of the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Cases were reports of hyponatremia or SIADH. Non-cases (controls) were all other reported adverse drug reactions during the same time period. The cases were further subclassified based on exposure to antidepressant medications (per Anatomical Therapeutic Chemical classification second-level code beginning N06A).

Duration

 2004 to 2018

Outcome Measures

 Association of antidepressants and hyponatremia; 

Baseline Characteristics

   Hyponatremia cases (n=13,307)

Other adverse drug reactions (n=2,771,223)

Age, years

 61.47 ± 20.2 49.1 ± 23.5

Female

57.3% 55.6%

Antidepressant use

 2,233 (38.3%) 220,773 (8.0%)

Results

  

Cases (N=2,233)

 Adjusted reported odds ratio (95% confidence interval)

Selective-serotonin reuptake inhibitors

Sertraline

Citalopram

Paroxetine

Escitalopram

Fluoxetine

Fluvoxamine

1,367 (61.2%)

356

339

241

234

180

17

 

2.40 (2.15–2.84)

3.09 (2.83–3.37)

2.72 (2.36–2.99)

2.51 (2.26–2.89)

1.87 (1.61–2.19)

2.56 (1.81–3.80)

Serotonin-norepinephrine reuptake inhibitors

Duloxetine

Venlafaxine

Desvenlafaxine

549 (24.6%)

292

227

30

 

2.38 (2.01–2.56)

1.90 (1.66–2.16)

0.97 (0.70–1.30)

Tricyclic antidepressants

Amitryptyline

Clomipramine

Doxepin

Imipramine

Trimipramine

113 (5.1%)

59

34

9

6

5

 

0.94 (0.75–1.25)

5.10 (3.62, 7.26)

0.90 (0.59–1.79)

0.99 (0.91–2.28)

4.01 (2.33–9.10)

Bupropion

36 (1.6%)

0.44 (0.29–0.63)

Mirtazapine

 230 (10.3%)

3.81 (3.51–4.39)

Mixed serotonergic antidepressants

Trazodone

Vortioxetine

Vilazodone

58 (2.6%)

39

12

7

 

0.61 (0.44–0.81)

1.72 (1.03–2.98)

1.62 (0.92–2.91)

The reported odds ratios were adjusted for sex, age, and concomitant medications associated with hyponatremia/SIADH.

The overall adjusted reporting odds ratio for the association between antidepressant drug use and hyponatremia was 1.91 (95% CI 1.83–2.00). The association was strongest for mirtazapine, followed by selective serotonin reuptake inhibitors, and lowest with serotonin-modulating antidepressant drugs.

Adverse Events

N/A

Study Author Conclusions

Hyponatremia is reported at a disproportionately higher level with classes of antidepressant drugs (noradrenergic and specific serotonergic antidepressant [mirtazapine] and serotonin modulators [vortioxetine]) that are in general considered to have a better profile of tolerability in terms of hyponatremia. With regard to the presented results, the risk of hyponatremia with mirtazapine appears to be greater than what was reported in the literature; however, confounding by indication cannot be ruled out.

This pharmacovigilance–pharmacodynamic analysis also indicates that inhibition of the serotonin transporter may not be involved in the hyponatremia linked to the use of antidepressant drugs

InpharmD Researcher Critique

This was a database analysis of cases of hyponatremia reported to the FDA, so this data may be limited by notoriety bias, selection bias, and under-reporting. The reporting odds ratios are influenced by potential confounders such as selective under-reporting, follow-up period bias, and exposure misclassification bias.

The impact of reporting is also influenced by the prevalence of prescribed medications. The severity of hyponatremia could not be ascertained. Additionally, this data may be confounded by the indications of antidepressant use.



References:

Mazhar F, Pozzi M, Gentili M, et al. Association of Hyponatraemia and Antidepressant Drugs: A Pharmacovigilance-Pharmacodynamic Assessment Through an Analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) Database. CNS Drugs. 2019;33(6):581-592. doi:10.1007/s40263-019-00631-5

 

Comparison of Risk (Odds Ratios) for Hyponatremia Among Antidepressants in Population-Based Studies
  Sweden (Farmand et al) Canada (Gandhi et al) Denmark (Leth-Møller et al) United Kingdom (Coupland et al)
New-onset (<29 days) Long-term (>85 days) New-onset (<30 days) New-onset (<14 days) Long-term (>180 days) New-onset (<28 days) Long-term (<85 days)

SSRI

Citalopram

Escitalopram

Sertraline

Paroxetine

Fluvoxamine

Fluoxetine

 

5.50

2.51

4.96

-

-

-

 

0.57

0.63

0.75

-

-

-

 

5.75

4.77

7.29

8.00

2.7

5.3

8.7

-

-

-

-

-

-

1.18

-

-

-

-

-

-

7.7

-

-

-

-

-

-

0.75

-

-

-

-

-

-

TCA

Amitriptyline

Nortriptyline

Clomipramine

1.59

-

-

-

0.77

-

-

-

-

-

-

-

5

-

-

-

1.35

-

-

-

2.6

-

-

-

0.67

-

-

-

SNRI

Duloxetine

Venlafaxine

 

-

5.29

 

-

0.95

 

8.0

-

6.3

-

-

1.62

-

-

-

-

-

-

-

0.44

NaSSA

Mirtazapine

 

2.54

 

0.76

 

3.17

3.2

-

0.96

-

-

-

-

0.31
NaSSA = noradrenergic and specific serotonergic antidepressant; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant

 

References:

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. Published 2011 Aug 2. doi:10.1136/bmj.d4551

Farmand S, Lindh JD, Calissendorff J, et al. Differences in Associations of Antidepressants and Hospitalization Due to Hyponatremia [published correction appears in Am J Med. 2021 Apr;134(4):554]. Am J Med. 2018;131(1):56-63. doi:10.1016/j.amjmed.2017.07.025

Gandhi S, Shariff SZ, 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(1):87-96. doi:10.1053/j.ajkd.2016.08.020

Leth-Møller 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. Published 2016 May 18. doi:10.1136/bmjopen-2016-011200

Lien Y-HH. Antidepressants and hyponatremia. The American Journal of Medicine. 2018;131(1):7-8. doi:10.1016/j.amjmed.2017.09.002