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

Systematic Review Draft
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Open for comment through Jun 13, 2018

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Purpose of the Review

To assess adverse events of first-line antidepressants in the treatment of major depressive disorder in adults 65 years or older.

Key Messages

  • Acute treatment (<12 weeks) with
    • Serotonin norepinephrine reuptake inhibitors (SNRIs) (duloxetine, venlafaxine), but not selective serotonin reuptake inhibitors (SSRIs) (escitalopram, fluoxetine) led to a greater number of adverse events compared with placebo.
    • SSRIs (citalopram, escitalopram and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of patients withdrawing from studies due to adverse events compared with placebo
    • Details of the contributing adverse events in RCTs were rarely reported to more clearly characterize what adverse events to expect.
  • Acute and continuation treatment (24 weeks) with the SNRI duloxetine most likely increases the risk of falls.
  • Observational evidence 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.
  • RCT data is limited due to short duration and being underpowered. Observational studies were non-placebo comparison. Long term, rigorous comparative studies are needed.

Structured Abstract

Objective. To assess select adverse events of first-line antidepressants in the treatment of major depressive disorder (MDD) in adults 65 years or older. First-line antidepressants included in this review are selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone and vortioxetine.

Data sources. MEDLINE®, Embase®, Cochrane Central, and PsychINFO bibliographic databases from earliest date through December 11, 2017; 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 select outcomes.

Results. Nineteen RCTs and two observational studies reported in 41 articles were included. Studies were mostly acute treatment (<12 weeks) of moderate severity MDD in patients 65 years and older, required to be free from uncontrolled medical comorbidities or psychological conditions, and relied on spontaneous reporting of adverse events. Evidence was scarce and conclusions are based often on single studies; particularly for specific adverse events. None of the RCTs were powered or designed to capture adverse events.

Acute treatment with SSRIs (escitalopram and fluoxetine) led to a similar frequency of adverse events compared with placebo but SNRIs (duloxetine and venlafaxine) were found to cause a greater number of adverse events compared with placebo (high SOE). Both SSRIs (citalopram, escitalopram and fluoxetine) and SNRIs (duloxetine and venlafaxine) led to a greater number of study withdrawals due to adverse events compared with placebo (moderate SOE). Details of the contributing adverse events were rarely reported to more clearly characterize what adverse events to expect. We were unable to detect differences in any specific adverse events comparing SSRIs with placebo, SSRIs with SNRIs or within the SSRI class, but this was based on single RCTs. Duloxetine was the only SNRI with specific adverse event data reported in RCTs, and led to a greater number of falls compared with placebo (moderate SOE) during 24 weeks of acute and continuation treatment. We identified single RCTs for any given outcome studying bupropion, mirtazapine, trazadone or vortioxetine, limiting our ability to detect difference in adverse events for these interventions. Observational evidence 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.

Conclusions. In patients 65 years or older with MDD, acute treatment with SNRIs (duloxetine and venlafaxine), but not SSRIs (escitalopram and fluoxetine), led to a greater number of adverse events compared with placebo. Characterizing the comparative safety of first-line antidepressants further is difficult because trials were not powered to evaluate adverse events and observational studies may be confounded. Comparative, long-term, well-designed studies that report specific adverse events are needed to help better inform decision making in this population.