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Effective Health Care Program

Harms of First-Line Depression Treatment in Older Adults

Key Questions Draft

Draft Key Questions

Key Question 1: For older adults (>65 years) with major depressive disorder (MDD), what are the harms and comparative harms of different first-line treatment options?

Key Question 2: For different subgroups of older adults with major depressive disorder, what are the harms of different first-line treatment options?

Draft Contextual Question

For older adults (>65 years) with major depressive disorder, what is the effectiveness and comparative effectiveness of first-line antidepressant medications? Are there any differences in effectiveness for certain subgroups of patients?

Note: Contextual questions are not systematically reviewed, and use a “best evidence” approach. Information about the contextual question may be included as part of the introduction or discussion sections, and related as appropriate to the systematic review.

Draft Analytic Framework

Figure 1 depicts the key questions (KQs) within the context of the populations, interventions, comparators, outcomes, timings, and settings (PICOTS) considered in this review. The figure illustrates how older adults (>65 years) with Major Depressive Disorder may be treated for depression, and how these treatment options are associated with a range of potential adverse effects and outcomes. KQ address the harms of the first line pharmacologic treatments (KQ 1) for depression and the risk of adverse events associated certain patient subpopulations (KQ 2). The patient population of interest for KQ1 is older adults who have Major Depressive Disorder. The patient population of interest for KQ2 is subgroups of older adults such as patients with high risk of falls, history of fracture, taking other medications with central nerve system activity, nursing home residents, patient with dementia and multiple co-morbidities.  The first line pharmacologic treatments are Selective Serotonin Reuptake Inhibitors (SSRIs), Serotonin and Norepinephrine Reuptake Inhibitor (SNRIs), Bupropion and Mirtazapine. Outcomes of interest for KQ1 and KQ2 are measures of adverse clinical outcomes such as falls, fractures, hyponatremia, bleeding and mortality.


Depression is a common psychiatric disease in older adults. Approximately 15–20 percent of adults older than age 65 in the United States have experienced depression1.

Multiple systematic reviews have shown that antidepressant medications are better than placebo for treating depression in older patients2. However, effects are modest and side effects are common. Depression treatment in older patients may be complicated by their other comorbid conditions, age-related physiologic changes, and potential interactions with other medications. As a result, certain treatment options may be contraindicated, inadequately dosed, or poorly tolerated. In addition clinicians must consider the balance of the risks and benefits of antidepressant medications, especially in comparison to other treatment options. While the effectiveness of interventions for treatment of depression in the elderly has been previously reviewed2 the harms of commonly used treatments of depression have not been well quantified specifically in older adults.

The American Geriatric Society (AGS) regularly compiles a list of medications that should be used with caution in older individuals called the Beers Criteria. Medications on the list are best avoided, avoided by those with specific conditions, or used with caution, at lower doses, or with careful monitoring. In 2015, this list recommended that clinicians avoid prescribing selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) in older adults with a history of falls or fractures3. However they noted that there may be situations when use of these medications may be appropriate and clinicians and patients must carefully weigh both benefits and potential harms4.

This review seeks to systematically review the harms and comparative harms of first-line depression treatment in adults over 65 years old, and will focus on those commonly prescribed in the US. This will assist clinicians and patients balance the benefits and harms of treatment and more fully inform decision-making about treatment options.



Older adults >65 years old with Major Depressive Disorder


  • Sex
  • Patients with risk of falls or history of fracture
  • Patients with taking more than one other medication with central nervous system activity
  • Patients with dementia or cognitive decline
  • Patients living in a nursing home
  • Patients with multiple comorbidities
  • Exclude: patients with seizures


First-line pharmacologic treatment of MDD

  • Selective Serotonin Reuptake Inhibitors (SSRIs)
  • Serotonin and Norepinephrine Reuptake Inhibitor (SNRIs)
  • Bupropion
  • Mirtazapine

Proposed exclusions

  • Vagus Nerve Stimulation (VNS)
  • Repetitive Transcranial Magnetic Stimulation (rTMS)
  • Electroconvulsive Therapy (ECT)
  • Complementary and Alternative Medicine (CAM)
  • Exercise
  • Tricyclic Anti-depressants (TCAs)
  • Other 2nd generation antidepressants except Bupropion and Mirtazapine
Proposed Interventions
Drug Class Drug
  • Paroxetine
  • Sertraline
  • Citalopram
  • Escitalopram
  • Fluoxetine
  • Fluvoxamine
  • Venlafaxine
  • Desvenlafaxine
  • Duloxetine
Other 2nd generation antidepressant
  • Bupropion
  • Mirtazapine


Other active treatment or placebo


Harms and comparative harms of treatment, including
  • Falls
  • Fractures
  • SIADH (Syndrome of Inappropriate Antidiuretic Hormone Secretion)/hyponatremia
  • Bleeding
  • Mortality


  • Setting (primary, specialty, hospital)

Definition of Terms

  • AD: Antidepressant
  • AGS: American Geriatric Society
  • CAM: Complementary and Alternative Medicine
  • ECT: Electroconvulsive Therapy
  • MDD: Major Depressive Disorder
  • rTMS: Repetitive Transcranial Magnetic Stimulation
  • SIADH: Syndrome of Inappropriate Antidiuretic Hormone Secretion
  • SRNI: Serotonin and Norepinephrine Reuptake Inhibitor
  • SSRI: Selective Serotonin Reuptake Inhibitor
  • TCA: Tricyclic Anti-depressant
  • VNS: Vagus Nerve Stimulation


  1. CDC Promotes Public Health Approach to Address Depression among Older Adults
  2. Kok RM, Reynolds CF III, Management of Depression in Older Adults A Review. JAMA. 2017;317(20):2114-2122. doi:10.1001/jama.2017.5706. Available at:
  3. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults by the American Geriatrics Society 2015 Beers Criteria Update Expert Panel (2015)
  4. How to Use the AGS 2015 Beers Criteria – A Guide for Patients, Clinicians, Health Systems, and Payors

Other Resources

  1. Gartlehner G, Gaynes BN, Amick HR, Asher G, Morgan LC, Coker-Schwimmer E, Forneris C, Boland E, Lux LJ, Gaylord S, Bann C, Pierl CB, Lohr KN. Nonpharmacological Versus Pharmacological Treatments for Adult Patients With Major Depressive Disorder. Comparative Effectiveness Review No. 161. (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center under Contract No. 290-2012-00008-I.) AHRQ Publication No. 15(16)-EHC031-EF. Rockville, MD: Agency for Healthcare Research and Quality; December 2015. Available at:
  2. Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux LJ, Van Noord M, Mager U, Gaynes BN, Thieda P, Strobelberger M, Lloyd S, Reichenpfader U, Lohr KN. Second-Generation Antidepressants in the Pharmacologic Treatment of Adult Depression: An Update of the 2007 Comparative Effectiveness Review. (Prepared by the RTI International–University of North Carolina Evidence-based Practice Center, Contract No. 290-2007-10056-I.) AHRQ Publication No. 12-EHC012-EF. Rockville, MD: Agency for Healthcare Research and Quality. December 2011.
  3. Gaynes BN, Lux L, Lloyd S, Hansen RA, Gartlehner G, Thieda P, Brode S, Swinson Evans T, Jonas D, Crotty K, Viswanathan M, Lohr KN. Nonpharmacologic Interventions for Treatment-Resistant Depression in Adults. Comparative Effectiveness Review No. 33. (Prepared by RTI International-University of North Carolina (RTI-UNC) Evidencebased Practice Center under Contract No. 290-02-0016I.) AHRQ Publication No. 11-EHC056- EF. Rockville, MD: Agency for Healthcare Research and Quality. September 2011.
  4. Santaguida P, MacQueen G, Keshavarz H, Levine M, Beyene J, Raina P. Treatment for Depression After Unsatisfactory Response to SSRIs. Comparative Effectiveness Review No. 62. (Prepared by McMaster University Evidence-based Practice Center under Contract No. HHSA 290 2007 10060 I.) AHRQ Publication No.12-EHC050-EF. Rockville, MD: Agency for Healthcare Research and Quality; April 2012.
  5. Beers list (2015)