Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults

Diana M. Sobieraj, PharmD; Brandon K. Martinez, PharmD; Adrian V. Hernandez, MD, PhD; Craig I. Coleman, PharmD; Joseph S. Ross, MD, MHS; Karina M. Berg, MD, MS; David C. Steffens, MD, MHS; William L. Baker, PharmD


J Am Geriatr Soc. 2019;67(8):1571-1581. 

In This Article

Abstract and Introduction


Objectives: To assess adverse effects of pharmacologic antidepressants for treatment of major depressive disorder (MDD) in adults 65 years of age or older.

Objectives: Systematic review and meta-analysis.

Setting: Specialist or generalist outpatient setting, rehabilitation facility, and nursing facilities.

Participants: Persons 65 years and older with MDD.

Intervention: Selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine compared with another antidepressant, placebo, or nonpharmacologic therapy.

Measurements: Adverse events, arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, QTc prolongation, serious adverse events, and withdrawals due to adverse events.

Results: Nineteen randomized controlled trials and two observational studies were included. Most studies evaluated treatment of the acute phase (<12 wk) of MDD of moderate severity. SSRIs led to a statistically similar frequency of overall adverse events vs placebo (moderate strength of evidence [SOE]), but SNRIs caused more overall adverse events vs placebo (high SOE) during the acute treatment phase. Both SSRIs and SNRIs led to more study withdrawals due to adverse events vs placebo (SSRIs low SOE; SNRIs moderate SOE). Duloxetine led to a more falls vs placebo (moderate SOE) during 24 weeks of acute and continuation treatment of MDD.

Conclusion: In patients 65 years of age or older with MDD, treatment of the acute phase of MDD with SNRIs, but not SSRIs, was associated with a statistically greater number of overall adverse events vs placebo. SSRIs and SNRIs led to a greater number of study withdrawals due to adverse events vs placebo. Duloxetine increased the risk of falls that as an outcome was underreported in the literature. Few studies examined head-to-head comparisons, most trials were not powered to evaluate adverse events, and results of observational studies may be confounded. Comparative long-term studies reporting specific adverse events are needed to inform clinical decision making regarding choice of antidepressants in this population.


The prevalence of depression in community-based adults 65 years of age and older is 15% to 20% in the United States, although estimations are subject to bias; depression prevalence of more than 50% in older nursing home residents was reported.[1,2] In addition to the modest efficacy provided by antidepressant medications, clinicians must consider the safety risks associated with the treatments.[3]

The American Geriatrics Society (AGS) regularly compiles the AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults.[4] This list identifies medications that are best avoided for most adults with specific conditions, or used with caution, at lower doses, or with careful monitoring. In 2019, this list recommended that clinicians avoid prescribing selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) to older adults with a history of falls or fractures, regardless if used as an antidepressant.[4] There may be situations when use of these medications may be appropriate, however, and clinicians and patients must carefully weigh both benefits and potential harms.[5] Suggested alternatives to TCAs and SSRIs include serotonin norepinephrine reuptake inhibitors (SNRIs) and bupropion.[6] However, the AGS also recommended using SSRIs and SNRIs with caution due to the potential to exacerbate or cause hyponatremia as a result of the syndrome of inappropriate antidiuretic hormone (SIADH).[4]

Given these concerns of potential adverse effects in the older population and recognizing that some patients will require treatment of major depressive disorder (MDD), understanding which antidepressants have been studied with respect to safety and how their safety compares is important for clinicians. We performed a systematic review and meta-analysis to assess adverse effects of pharmacologic antidepressants for the treatment of MDD in adults 65 years of age or older.