How Frailty in Older Adults With Depression Hinders Antidepressant Response

January 18, 2021
Cornel N. Stanciu, MD, MRO

Research zeroes in on how frailty impacts depression treatment in elderly patients.


The number of Americans over the age of 65 grew by over one-third during the past decade and is expected to rise, with important implications for planning and delivery of health care.1 The most problematic expression of population aging is the clinical condition of frailty, defined as a state of vulnerability to poor resolution of homeostasis following stress; it is a consequence of cumulative decline in multiple physiological systems over a lifespan.2 The cumulative decline erodes homeostatic reserve until minor stressor events trigger disproportionately large and negative changes in health status. Up to half of those aged 85 years and older are frail, and this is associated with increased risk of disability and other physical and mental health outcomes.3

When depression, the leading cause of global disease burden,4 is also present in frail elderly patients, they tend to have higher mortality risk as they display lower physical activity levels, have a greater prevalence of fatigue and significant weight loss, have slower gait speeds, and have weaker grip strength than those without depression. Brown and colleagues5 evaluated whether frailty burden predicts who will or will not respond to antidepressant medication.

Structured Investigation

Question. Do frail elderly adults with a depressive disorder respond differently than non-frail elderly adults with depression when standard antidepressant treatments are implemented?

Type of study. Outpatient placebo-controlled 8-week clinical trial followed by 10-months of open treatment.

Population. 34 men and 66 women aged 60 years or older who received a diagnosis of major depressive disorder (MDD) or persistent depressive disorder and managed as outpatients at the Clinic for Aging, Anxiety and Mood Disorders at New York State Psychiatric Institute.

Method. Participants were treated with antidepressant medications (escitalopram or duloxetine) in a placebo-controlled trial for 8 weeks, following which participants could continue open-label treatment for 10 months. During these 10 months they were treated as clinically indicated with both antidepressant switching and augmentation strategies. Baseline and follow-up assessments were completed pretreatment, at 8 weeks, and at 6 and 12 months. The diagnoses of depression subtypes were made based on DSM-5 clinical interview, with severity assessments based on the Hamilton Depression Rating Scale (HAM-D).

Baseline characteristics. The 100 participants in the study were all 60 years or older and had a baseline score of 16 or higher on the 24-item HAM-D. They were all assessed for frailty at baseline (3 or more deficits on gait speed, grip strength, activity level, fatigue, and weight loss) and categorized into frail (n = 49) and non-frail (n = 51). There were no intergroup differences between medical comorbidities, socioeconomic status, demographics, cognitive, or depressive variables. Participants did not have any severe medical illnesses, substance use disorders, or cognitive impairments.

Results. After 8 weeks of acute placebo-controlled treatment, frail adults (n = 49) showed an average HAM-D score that is 2.82 points higher than the non-frail adults (t = 2.12, df89, p = 0.037) and this difference persisted over the entire study follow-up period of 10 months. Additional analysis revealed that weak grip strength and low physical activity levels were each associated with worse response to antidepressants and lower response and remission rates over the course of the study, while slow gait speed, exhaustion, and significant weight loss were not. Patients who are frail also received more antidepressant medication trials.

The Bottom Line

This study suggests that frailty identifies a high-risk subgroup of elderly patients with depressive disorders characterized by lower antidepressant response despite several antidepressant trials, some with augmentation trials.


Brown and colleagues5 assessed an interesting question: Do elderly patients with depressive disorders and comorbid frailty respond differently to antidepressants compared with non-frail elderly patients with MDD? The authors branched off a previous metanalysis6 that found no statistically valid difference in response or remission to antidepressants compared to placebo in elderly adults. They hypothesized that an extra complexity, frailty, would pose even more pronounced challenges.5 It might possibly tease out a sub-population of elderly patients that would respond differently.6 Indeed, the findings in this study support the pre-study hypothesis, as this predominantly female, elderly patient population have poor responses but also often require additional antidepressant trials and perhaps polypharmacy antidepressant augmentation.5

Frailty in the context of late-life depression may indicate antidepressant medications are not sufficient, and that adjunctive interventions in the form of physical therapy and exercise, behavioral therapy, case management, and other assistance may be needed. For psychiatrists who encounter elderly patients with depression in clinical practice, it is important to comprehensively assess them beyond the standard of psychiatric diagnosis and symptom severity ratings. Physical characteristics such as activity level, strength, and mobility can provide insight into the clinical trajectories of such patients.

The Figure outlines an approach to assessment and management of depression in elderly patients. It includes a careful frailty assessment to better understand the optimal treatment course of action.


There are several limitations to this study:

• Only escitalopram and duloxetine were used in the initial placebo-controlled treatment phase. Although the open label portion included additional interventions (antidepressant switch or augmentation), it is unclear whether different antidepressants or classes of antidepressants may have had different outcomes.

• In assessing depressive symptomatology, the Hamilton Depression Rating Scale was used. Although it is the most commonly used scale for reporting symptoms in research, this is not specific, or extensively validated, for the geriatric population.

• The study seems to have included a greater proportion of women than men, which may have skewed the baseline starting characteristics and outcomes.

• Additionally, the population comprises mostly Caucasian participants, with 16 years of education on average across the spectrum. Generalization to other races and ethnic backgrounds and to those with less or more education is questionable.

• Exclusion criteria eliminated those with extensive medical illnesses and acute needs as well as those with substance use in the past 12 months. From the perspective of real-life clinical practice this seems unrealistic.

• The sample was limited to 1 site, which happens to be a geriatric specialist site. The generalization outside this system to other communities and treatment settings is unknown.

Dr Stanciuis assistant professor of psychiatry at Dartmouth’s Geisel School of Medicine and Director of Addiction Services at New Hampshire Hospital, Concord, NH. He is Addiction Section Editor for Psychiatric TimesTM. The author reports no conflicts of interest concerning the subject matter of this article.


1. Population and Housing Unit Estimates. United States Census Bureau. Accessed January 13, 2021.

2. Clegg A, Young J, Iliffe S, et al. Frailty in elderly people. Lancet. 2013;381(9868):752-762.

3. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146–M156.

4. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet. 2017;390(10100):1211-1259.

5. Brown PJ, Ciarleglio A, Roose SP, et al. Frailty worsens antidepressant treatment outcomes in late life depression. Am J Geriatr Psychiatry. 2020:S1064-7481(20)30593-5.

6. Mallery L, MacLeod T, Allen M, et al. Systematic review and meta-analysis of second-generation antidepressants for the treatment of older adults with depression: questionable benefit and considerations for frailty. BMC Geriatr. 2019;19(1):306.