Journal Article Annotations
2024, 1st Quarter

Psychonephrology

Annotations by Shivali Patel, MD, Sahil Munjal, MD.
April, 2024

Comparative Safety of Antidepressants in Adults with CKD.

PUBLICATION #1 — Psychonephrology

Comparative Safety of Antidepressants in Adults with CKD.

Nanbo Zhu, Hong Xu, Tyra Lagerberg, Kristina Johnell, Juan Jesús Carrero, Zheng Chang

Abstract: Clin J Am Soc Nephrol. 2023 Dec 1;19(2):178-188. doi: 10.2215/CJN.0000000000000348. Online ahead of print.

Background:
Depression is prevalent in patients with CKD and is related to poor prognosis. Despite the widespread use of antidepressants in the CKD population, their safety remains unclear.

Methods:
We identified adults with CKD stages G3-5 (eGFR <60 ml/min per 1.73 m2 not treated with dialysis) and incident depression diagnosis during 2007-2019 from the Stockholm Creatinine Measurements project. Using the target trial emulation framework, we compared the following treatment strategies: (1) initiating versus not initiating antidepressants, (2) initiating mirtazapine versus selective serotonin reuptake inhibitors (SSRIs), and (3) initiating SSRIs with a lower dose versus a standard dose.

Results:
Of 7798 eligible individuals, 5743 (74%) initiated antidepressant treatment. Compared with noninitiation, initiation of antidepressants was associated with higher hazards of short-term outcomes, including hip fracture (hazard ratio [HR], 1.23; 95% confidence interval [CI], 0.88 to 1.74) and upper gastrointestinal bleeding (HR, 1.38; 95% CI, 0.82 to 2.31), although not statistically significant. Initiation of antidepressants was not associated with long-term outcomes, including all-cause mortality, major adverse cardiovascular event, CKD progression, and suicidal behavior. Compared with SSRIs, initiation of mirtazapine was associated with a lower hazard of upper gastrointestinal bleeding (HR, 0.52; 95% CI, 0.29 to 0.96), but a higher hazard of mortality (HR, 1.11; 95% CI, 1.00 to 1.22). Compared with the standard dose, initiation of SSRIs with a lower dose was associated with nonstatistically significantly lower hazards of upper gastrointestinal bleeding (HR, 0.68; 95% CI, 0.35 to 1.34) and CKD progression (HR, 0.80; 95% CI, 0.63 to 1.02), but a higher hazard of cardiac arrest (HR, 2.34; 95% CI, 1.02 to 5.40).

Conclusions:
Antidepressant treatment was associated with short-term adverse outcomes but not long-term outcomes in people with CKD and depression.

Annotation

The finding:
This study aimed to assess the safety of antidepressants in patients with depression and non-dialysis dependent chronic kidney disease (CKD) stages III-V. Antidepressant initiation was associated with a non-statistically significant increased risk of hip fractures and upper GI bleed but not associated with all-cause mortality, major adverse cardiovascular events, CKD progression, or suicidal behavior. Additionally, initiation of SSRIs at approximately 50% of the standard dose was associated with a non-statistically significant reduced risk of CKD progression and upper GI bleeding but a higher risk of cardiac arrest. Finally, mirtazapine was associated with a lower risk of upper GI bleed but a higher risk of mortality compared to SSRIs.

Strength and weaknesses:
Authors emulated the analyses of target trials (initiating versus not initiating antidepressant treatment, initiating mirtazapine versus SSRI treatment, and initiating SSRI treatment with a lower dose versus a standard dose) to reduce confounding and bias. Additionally, a large population was examined for this study, with a good covariate balance. However, given the limited power of this study, it is difficult to disentangle the impact of antidepressants on short-term and long-term outcomes from those of moderating variables, including age, comorbid medical pathologies, concomitant medications, and substance use. Moreover, the study did not focus on antidepressant efficacy in this population and did not report the specific SSRIs used, making it difficult to contextualize if the benefits of antidepressant initiation outweighed risks. Apart from mirtazapine, the study also did not examine the safety of other non-SSRI antidepressants in patients with CKD and depression, including SNRIs and bupropion, or the safety of augmenting agents like atypical antipsychotics. Finally, given that the study population was residents from Stockholm, Sweden, results may not be generalizable to the general population.

Relevance:
As up to 25% of patients with CKD are affected by depression, it is important for C-L psychiatrists treating this population to consider the short-term and long-term risks of antidepressant initiation. Though antidepressants were not associated with long-term renal, cardiovascular, or mortality outcomes, given associated short-term bleeding and fracture risks, initiating antidepressants at lower than standard doses and gradual titration is recommended. However, further studies are needed given the non-statistically significant findings.