November 6, 2019

Higher Frequency of Adverse Events in Older Patients on Antidepressant Drugs

Results of a recent meta-analysis
Drugs intended to treat depression symptoms in the elderly may have adverse psychological and non-psychological effects. Alternative naturopathic treatments may be beneficial in this population.


Sobieraj DM, Martinez BK, Hernandez AV, et al. Adverse effects of pharmacologic treatments of major depression in older adults. J Am Geriatr Soc. 2019;67(8):1571-1581.


To assess the adverse effects of pharmacologic antidepressants used to treat major depressive disorder (MDD) in adults 65 years of age or older.


Meta-analysis of 19 randomized controlled trials and 2 observational studies, most of which considered treatment in the acute phase (<12 weeks) of MDD of moderate severity.


Patients 65 years or older with MDD taking lower-limit dosing of antidepressant medications including selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), bupropion, mirtazapine, trazodone, vilazodone, or vortioxetine were compared to those receiving another antidepressant, placebo, or nonpharmacologic therapy.

Study Parameters Assessed

Adverse events under treatment for MDD, such as arrhythmias, cognitive impairment, falls, fractures, hospitalization, mortality, and QTc prolongation, were assessed. Serious adverse events and withdrawals due to adverse events were also evaluated.

Primary Outcome Measures

The different pharmacological treatments were compared with regard to the frequencies of adverse events.

Key Findings

There were 3 key findings in this meta-analysis:

  1. In patients 65 years of age or older, both SSRIs and SNRIs were associated with significantly more study withdrawals due to overall adverse events than placebo.
  2. In the acute phase of treatment (<12 weeks), patients prescribed SNRIs, but not SSRIs, experienced a higher frequency of adverse events compared to placebo.
  3. The SNRI duloxetine specifically and significantly increased the number of falls in senior patients, especially those with cardiovascular disease, a fact that was underreported in the original studies.

Practice Implications

Significant depression symptoms are prevalent in older persons, with rates of 15% to 20% in community-based adults and higher in those with a medical illness or in an institution.1 Depression symptoms in seniors may present differently than in non-seniors. As a result, depression might not meet the usual criteria for major depression. In general, older patients experience more somatic complaints and cognitive symptoms, with fewer complaints of a sad or dysphoric mood. Frequently, depression in elderly persons is seen as agitation, hypochondriasis, or dementia syndrome, and these may often appear without complaints of sadness.2,3

Prescription antidepressants are a concern for older patients due to the slower clearance of medications as well as the greater likelihood of interactions, since this population generally takes more medications. The American Geriatric Society recommends that SSRIs and tricyclic antidepressants (TCA) should not be prescribed to seniors with a history or significant risk of falls or fractures.4 Also, given their ability to raise acetylcholine levels, TCAs are generally not recommended for senior care.

This study provides a helpful reminder that, even among the medications that are considered to be “safer” for seniors, there are still concerns regarding the risk/benefit profiles for these drugs. In this light, naturopathic medicine may be able to serve this population well by creating a more comprehensive plan to address mental health.

Elderly patients may be at the greatest risk for failure to respond to the initial medication selected and appear to have a greater risk of re-emergent depression once remission is achieved.5

As naturopathic doctors, given this information on adverse events and the fact that elderly patients are at greater risk of re-emergent illness, we need to strive to offer our patients natural care recommendations that have clear benefits to heal the underlying pathology of depressive illness. For example, it is known that hippocampal atrophy is a signature of depression and cognitive decline. A study of 120 older adults with dementia showed that subjects who performed moderate-intensity aerobic exercise 3 days a week for 1 year showed increased hippocampal volume (by 2%) and this activity effectively reversed any age-related loss in brain volume. Expected brain loss was seen in control subjects who did not perform aerobic exercise, but instead performed only stretching and toning work.6

Even among the medications that are considered to be ‘safer’ for seniors, there are still concerns regarding the risk/benefit profiles for these drugs.

Simple lifestyle additions may also be of value. In a 10-year cohort study of more than 50,000 older women, investigators found that, compared with those who drank 1 cup or less of caffeinated coffee per week, those who drank 2 to 3 cups per day had a 15% decreased risk for depression, and those who drank 4 cups or more had a 20% decreased risk. For older people who are predisposed to depression, daily intake of caffeinated coffee may make good sense.7 Other studies have found that hormonal support8 was helpful in treatment-resistant depressed older women, and addressing lead exposure9 can improve cognitive function.

Non-pharmacologic supplementation may also help to avoid the need for drugs. MRI studies in depressed geriatric patients found that imbalances in the prefrontal cortex could be resolved using acetyl L-carnitine.10 Low-dose fish oil therapy in 66 senior patients (1,000 mg total, breaking down to about 300 mg of EPA and DHA) provided clinical benefit and had a much greater effect than placebo in another double-blind, randomized, placebo-controlled study, which showed clear differences in the Geriatric Depression scale after accounting for confounding factors such as body mass, thyroid dysfunction, and cholesterol.11


Overall, while this analysis was strong and helpful, some limitations are worth mentioning.

First, and most importantly, the doses of antidepressants studied reflected the lower limit (or lower half) of the recommended usual range for older adults. Second, none of the trials reviewed were actually designed to evaluate adverse events. Third, the evaluations on which these results were based excluded patients with multiple comorbidities or other neuropsychiatric conditions like dementia or a high suicide risk. These first 3 limitations collectively may have led to an underreporting of adverse effects.

Because only single randomized controlled trials were available for certain drugs, the authors explained they had a limited ability to detect adverse events for bupropion, mirtazapine, trazodone, or vortioxetine. Thus, these drugs may also be a concern.

Finally, since the authors did not have data to allow them to evaluate whether harms differed according to patient sex, we cannot tell whether this information applies disproportionately to men or women.

Categorized Under


  1. Gaboda D, Lucas J, Siegel M, Kalay E, Crystal S. No longer undertreated? Depression diagnosis and antidepressant therapy in elderly long-stay nursing home residents, 1999 to 2007. J Am Geriatr Soc. 2011;59(4):673-680.
  2. Moore DP, Jefferson, JW. Handbook of Medical Psychiatry. 2nd ed. Philadelphia: Elsevier Mosby; 2004.
  3. Gallo JJ, Rabins PV. Depression without sadness: Alternative presentations of depression in late life. Am Fam Physician. 1999;60(3):820-826.
  4. The 2019 American Geriatrics Society Beers Criteria® Update Expert Panel. American Geriatrics Society 2019 updated Beers Criteria® for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674-694.
  5. Hinrichsen GA. Recovery and relapse from major depressive disorder in the elderly. Am J Psychiatry. 1992;149:1575-1579.
  6. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011;108(7):3017-3022.
  7. Lucas M, Mirzaei F, Pan A, et al. Coffee, caffeine, and risk of depression among women. Arch Intern Med. 2011;171(17):1571-1578.
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  9. Shih RA, Glass TA, Bandeen-Roche K et al. Environmental lead exposure and cognitive function in community-dwelling older adults. Neurology. 2006;67:1556-1562.
  10. Pettegrew JW, Levine J, Gershon S, et al. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord. 2002;4(1):61-66.
  11. Tajalizadekhoob Y, Sharifi F, Fakhrzadeh H, et al. The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: a double-blind, randomized, placebo-controlled study. Eur Arch Psychiatry Clin Neurosci. 2011;261(8):539-549.