Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults

Project Summary Title and Description

Title
Adverse Effects of Pharmacologic Treatments of Major Depression in Older Adults
Description
Objective. To assess select 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 select outcomes. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings. Results. Nineteen RCTs and two observational studies reported in 41 articles were included. Studies mostly evaluated treatment of the acute phase (<12 weeks) of MDD which 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 XR (moderate SOE) led to 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 compared with 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) during 24 weeks 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 compared with TCAs (amitriptyline or nortriptyline) (low SOE, NNT 13) as did mirtazapine compared with paroxetine (low SOE, NNT 9). Vortioxetine had fewer adverse events compared 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 with MDD, 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 compared with 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 difference 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 decisionmaking in this population.
Attribution
N/A
Authors of Report
N/A
Methodology description
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. 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. Number needed to harm (NNH) is reported for graded outcomes with statistically significant findings.
PROSPERO
CRD42018088648
DOI
10.26300/dxjn-p932
Notes
Pubmed link to final report: https://www.ncbi.nlm.nih.gov/books/NBK539624/ Weblink to final report: https://effectivehealthcare.ahrq.gov/topics/depression-harms/research Data for this project was entered retrospectively by uploading data from other software.
Funding Source
AHRQ

Key Questions

1. KQ 1. In older adults with major depressive disorder, what are the adverse effects and comparative adverse effects of pharmacologic treatments?
2. KQ 2. In subgroups of older adults (e.g., age, sex, race, comorbidities) with major depressive disorder, what are the adverse effects and comparative adverse effects of pharmacologic treatments?

Associated Extraction Forms

Associated Studies (each link opens a new tab)

TitleAuthorsYear
A double-blind study of paroxetine compared with fluoxetine in geriatric patients with major depression.1993
Escitalopram in the treatment of depressed elderly patients.2005
Paroxetine and fluoxetine effects on mood and cognitive functions in depressed nondemented elderly patients.2002
A double-blind, placebo-controlled study of venlafaxine and fluoxetine in geriatric outpatients with major depression.2006
Evaluation of two-dimensional gas chromatography-time-of-flight mass spectrometry for the determination of multiple pesticide residues in fruit.2003
Escitalopram prevents relapse in older patients with major depressive disorder.2007
Efficacy of citalopram in the prevention of recurrent depression in elderly patients: placebo-controlled study of maintenance therapy.2002
Antidepressant pharmacotherapy in the treatment of depression in the very old: a randomized, placebo-controlled trial.2004
A double-blind, placebo-controlled treatment trial of citalopram for major depressive disorder in older patients with heart failure: the relevance of the placebo effect and psychological symptoms.2009
Comparative efficacy and safety of sertraline versus nortriptyline in major depression in patients 70 and older.1999
Comparison of the tolerability and efficacy of citalopram and amitriptyline in elderly depressed patients treated in general practice.1998
Paroxetine in the treatment of elderly depressed patients in general practice: a double-blind comparison with amitriptyline.1992
Safety and tolerability of duloxetine at 60 mg once daily in elderly patients with major depressive disorder.2008
Efficacy and tolerability of venlafaxine in geriatric outpatients with major depression: a double-blind, randomised 6-month comparative trial with citalopram.2004
Comparative efficacy of sertraline vs. fluoxetine in patients age 70 or over with major depression.1999
Double-blind, randomized comparison of mirtazapine and paroxetine in elderly depressed patients.-- Not Found --
Double-blind, placebo-controlled evaluation of extended-release bupropion in elderly patients with major depressive disorder.2010
Acute and long-term treatment of late-life major depressive disorder: duloxetine versus placebo.2014
A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder.2012
Antidepressant use and risk of adverse outcomes in older people: population based cohort study.2011
Comparison of treatment persistence, hospital utilization and costs among major depressive disorder geriatric patients treated with escitalopram versus other SSRI/SNRI antidepressants.2008

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