Adverse Effects of First-line Pharmacologic Treatments of Major Depression in Older Adults

Objective. To assess selected adverse events of antidepressants in the treatment of major depressive disorder (MDD) in adults 65 years old or older. Antidepressants included in this review, as determined by expert opinion, are selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, and vortioxetine.

Data sources. MEDLINE®, Embase®, Cochrane Central, and PsycINFO® bibliographic databases from earliest date through May 15, 2018; hand searches of references of relevant studies; www.clinicaltrials.gov; and the International Controlled Trials Registry Platform.

Review methods. Two investigators screened abstracts and subsequently reviewed full-text files. We abstracted data, performed meta-analyses when appropriate, assessed the risk of bias of each individual study, and graded the strength of evidence (SOE) for each comparison and selected outcomes. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings.

Results. Nineteen randomized controlled trials (RCTs) and two observational studies reported in 41 articles were included. Studies mostly evaluated treatment of the acute phase (<12 weeks) of MDD that was of moderate severity in patients 65 years and older, required subjects to be free from uncontrolled medical comorbidities or psychological conditions, and relied on spontaneous reporting of adverse events. Evidence was scarce and conclusions (based on statistical significance) for a given comparison and outcome are based often on a single study, particularly for specific adverse events. None of the RCTs were powered or designed to capture adverse events and most RCTs studied low doses of antidepressants. Observational data were limited by residual confounding.

SSRIs (escitalopram and fluoxetine, moderate SOE), vortioxetine (high SOE), and bupropion extended release (moderate SOE) had a statistically similar frequency of adverse events compared with placebo, whereas SNRIs (duloxetine and venlafaxine) were found to cause a greater number of adverse events (high SOE, NNH 10) compared with placebo during treatment of the acute phase of MDD. Both SSRIs (citalopram, escitalopram, and fluoxetine) and SNRIs caused a greater number of withdrawals due to adverse events than placebo (SSRIs, low SOE, NNH 11; SNRIs, moderate SOE, NNH 17). Duloxetine led to a greater number of falls compared with placebo (moderate SOE, NNH 10) over 24 weeks of treatment. A single observational study provided evidence on long-term use of antidepressants (low SOE) and suggested increased risk of adverse events (SSRIs), falls (SSRIs, SNRI venlafaxine, mirtazapine, trazadone), fractures (SSRIs, SNRI venlafaxine, mirtazapine), and mortality (SSRIs, SNRI venlafaxine, mirtazapine, trazadone) compared to no antidepressant.

Evidence for the comparative harms of different antidepressants was limited to single RCTs, mostly studying treatment of the acute phase of MDD (<12 weeks). Comparing SSRIs to each other or SSRIs to SNRIs showed statistically similar rates of adverse events (moderate SOE). SSRIs (paroxetine, citalopram, sertraline) had fewer withdrawals due to adverse events than tricyclic antidepressants (amitriptyline or nortriptyline) (low SOE, number needed to treat [NNT] 13), as did mirtazapine compared with paroxetine (low SOE, NNT 9). Vortioxetine had fewer adverse events than with duloxetine (high SOE, NNT 6).

Increasing age was associated with greater incidence of serious adverse events with escitalopram (low SOE). The increased risk of falls on duloxetine may be associated with the presence of cardiopulmonary conditions (low SOE).

Conclusions. In patients 65 years of age or older, treatment of the acute phase of MDD with SNRIs (duloxetine and venlafaxine) led to a greater number of adverse events compared with placebo, while adverse events were statistically similar to placebo with SSRIs (escitalopram, fluoxetine), vortioxetine, and bupropion. SSRIs (citalopram, escitalopram, and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of study withdrawals due to adverse events than placebo, and duloxetine increased the risk of falls. Further characterization of the comparative safety of antidepressants is difficult because few studies were identified, comparisons were based on statistical significance, trials were not powered to identify small differences in adverse events, and observational studies may be confounded. Comparative, long-term, well-designed studies that report specific adverse events are needed to better inform decision making in this population.