After evaluating the evidence for older adults, we considered how the evidence could apply to frailty.
Rationale for a focus on antidepressants
Frail older adults have high rates of depression. Two reviews [
1,
3] show that those who are frail are at increased risk of having depression, even after adjusting for potential confounders. In a landmark study, Fried [
2] reported that 31% of frail older adults had a “suggestive diagnosis of depression” compared to only 3% of non-frail elders. As well, medical conditions that are commonly associated with frailty have high rates of depression—approximately 31% with stroke, [
39] 22% with heart failure, [
40] 23% with Parkinson’s disease, [
41] and 32% with mild cognitive impairment [
42].
In the case of late-life depression, the prevailing opinion is that older adults are underdiagnosed and undertreated for depression [
43]. Yet, among frail older adults, the opposite may be true. In Canadian long-term care, where the majority of older adults are typically severely frail, roughly 44% have a diagnosis and/or symptoms of depression and nearly 60% use an antidepressant, although possibly for diverse indications [
4]. In U.S. nursing homes, 54% of residents were diagnosed with depression—33% at admission and a further 21% during the first year [
5]. The authors of that study conclude that “the high antidepressant use in nursing homes may reflect a spiraling trend of over-diagnosing [and treating] depression.”
As there is insufficient evidence specific to the frail, we considered how results from studies of older adults could be relevant to those who are frail using a frailty-informed framework that poses five questions [
35]. These questions focus on features of frailty that could affect the applicability of evidence, such as: 1) characteristics of the trial population; 2) outcomes; 3) timeline for benefit; 4) harms; and 5) other relevant evidence. This inquiry, used in earlier reviews, [
27,
34,
35] is conducted by an interdisciplinary team of evidence appraisal specialists, pharmacists, family physicians, and geriatricians.
Application of the framework questions resulted in the following analysis:
1.
How does the study population compare with those who are frail?
The subjects in our meta-analysis were generally younger and healthier than those who are frail. All studies excluded subjects with unstable medical conditions and other psychiatric syndromes (Table
2). However, one study enrolled subjects with stable heart failure [
15] and in another study, most subjects had one or more health problems [
14]. As individuals with heart failure and medical illness have a high prevalence of frailty, [
44] these two studies may more closely represent the frail population. Both showed that antidepressants were no more effective than placebo.
Table 2
Inclusion/exclusion criteria and characteristics of participants from included studies
Diagnosis of Major Depressive Disorder according to DSM and/or achieving a pre-specified rating on a depression scale | Treatment-resistant depression |
Moderate to severe depression based on standard clinical measures of depression (e.g., HDRS, MARS) | Complex depressive disorders, such as bipolar disorder, depression with psychotic features, dysthymic disorder, neurotic depression, or minor depression |
Age ≥ 65 years (only one study included patients ≥75 years old [ 21] ) | Comorbid alcohol disorders or substance abuse disorders |
• Subject were mostly outpatients, although this was not always specified • One study enrolled only inpatients admitted under the care of a geriatrician or family physician [ 14] | Unstable medical conditions, although two studies allowed inclusion of patients with concomitant medical conditions. Fraguas studied patients with stable heart failure [ 15] and Evans included patients with other medical conditions, including dementia [ 14]. |
Not at risk of suicide | Four of nine studies specifically excluded subjects with dementia [ 16‐ 18, 21]. The other five studies either did not explicitly state the exclusion of subjects with dementia or enrolled subjects with mild stage dementia [ 14, 15, 19, 20, 22]. |
Similar to this meta-analysis, a systematic review of randomized controlled trials of antidepressants for older adults with late-life depression [
45] found that “geriatric characteristics” were rarely taken into account or considered as co-variables and that the oldest adults were underrepresented in these clinical trials. The authors, thus, questioned whether evidence for treating major depression had sufficient external validity for the heterogenic population of older adults.
2.
Are study outcomes relevant to those who are frail?
Outcomes that are relevant for healthier adults may not be relevant with frailty. Therefore, we consider how an outcome might relate to overall health when individuals are frail.
In our meta-analysis, primary and secondary outcomes were response and remission based on Depression Rating Scales. However, it is not clear whether these rating scales can differentiate symptoms of depression from characteristics of frailty and whether measured change represents meaningful benefit. In particular, DSM-5 criteria for major depression and depressive symptoms overlap with common manifestations of both frailty and chronic health conditions (Table
3). When individuals are frail, conditions such as functional disability, cognitive decline, impaired mobility, and/or physical symptoms may give rise to features commonly attributed to depression, such as fatigue, limited activity, decreased interest, trouble sleeping, feelings of sadness, and/or thoughts of death. Medications, such as those used to treat pain, may impair concentration. In addition, old age commonly brings challenging circumstances, such as the loss of a spouse or financial insecurity, which can lead to despondency. Indeed, Lohman [
46] postulated that the strong correlation between frailty and depression could be related to the criteria used in their measurement and concluded that that available measures of frailty and depression are either poor at discriminating between the two constructs or identify the same underlying condition.
Table 3
Overlapping symptoms of depression and frailty
Depressed mood/irritability | Y | Y |
Loss of interest | Y | Y |
Weight change | Y | Y |
Reduced activity | Y | Y |
Fatigue/loss of energy | Y | Y |
Change in sleep | Y | Y |
Decreased concentration | Y | Y |
Guilt and feeling worthless | Y | Maybe |
Suicidality | Y | Thoughts of dying |
3.
Is the timeframe relevant for those who are frail?
Given the shortened life expectancy associated with frailty and the expected progression of frailty over time, treatment benefits that accrue over many years may not be applicable to the frail, while studies of short duration may underestimate risk.
In this meta-analysis, study duration ranged from 8 to 12 weeks, a reasonable timeframe to achieve benefit. However, none of the studies addressed the sustainability of response nor the likelihood of developing adverse effects as frailty increases over time. In one 12-week study that had a 12-week extension, [
20] falls were more frequent with duloxetine compared to placebo over 24-weeks that included the acute plus continuation phase (24% vs 14%,
p = 0.04) but not in the first 12 weeks (16% vs 10%,
p = 0.15).
4.
Have potential harms been sufficiently considered?
Since the frail are vulnerable, medication adverse effects may impact their quality of life and health status to a greater extent compared to healthier adults. Thus, both potential risks and benefits related to treatment need to be equally considered in the context of frailty.
The harms reported in this meta-analysis appear to be minor. However, nausea, fatigue, constipation, and dizziness were more frequent with antidepressants compared to placebo, which may be burdensome for frail older adults who are less able to tolerate perturbations in health due to decreased reserve. Notably, rates of withdrawal due to adverse events in subjects receiving antidepressants was twice the rate for those receiving placebo. In addition, frail older adults with multiple co-morbidities are at risk of polypharmacy. As the number of medications increase, so too does the potential for adverse medication events related to antidepressants.
5.
Is there further evidence pertaining to frail populations?
Although frail patients may not be specifically enrolled in randomized controlled trials, other categories of evidence can shed light on frailty response. Here, we consider two sources: (1) examination of medical conditions that are significantly associated with frailty; and (2) observational studies.
We deliberated on two medical conditions that are associated with high rates of frailty—heart failure and Parkinson’s disease.
With heart failure, a systematic review and meta-analysis showed that the overall estimated prevalence of frailty was 44.5% (95% CI: 36.2–52.8%, z = 10.54,
p < 0.001) [
44]. Similarly, a substantial number of individuals with Parkinson’s disease would be considered frail, as this illness typically affects mobility.
Two DBRCTs of adults with heart failure found that antidepressants did not improve depression compared to placebo. The Sertraline Against Depression and Heart Disease in Chronic Heart Failure (SADHART-CHF) [
47] included 469 subjects with a mean age of 62. At 12 weeks, there was no significant difference in depression scores for sertraline compared to placebo. Similarly, the Mortality, Morbidity, and Mood in Depressed Heart Failure Patients (MOOD-HF) trial, [
48] which included 372 adults with a mean age of 62 years, showed that there was no significant improvement in depression with escitalopram compared to placebo.
We examined five meta-analyses of antidepressants for depression in Parkinson’s disease [
49‐
53]. Three of the meta-analyses found insufficient evidence to support the use of antidepressants for the treatment of depression with Parkinson’s disease [
49‐
51]. Two meta-analyses reached a different conclusion and found that antidepressants significantly improved depression with Parkinson’s disease, [
52,
53] although one of these meta-analyses included trials without a placebo arm [
53] and the other included a study that enrolled subjects without depression [
52].
In our meta-analysis, the two studies that enrolled subjects with depression and concomitant medical conditions, likewise, showed no statistically significant benefit from antidepressants [
14,
15].
Although randomized trials are the best way to determine medication efficacy, observational studies may suggest potential associations. Three observational studies support the hypothesis that those who are frail may be less responsive to antidepressants compared to the non-frail. A multi-site naturalistic prospective cohort study from the Netherlands of 378 subjects over age 60 [
54] found that depression with comorbid frailty was less likely to resolve compared to depression unaccompanied by frailty. In that study, frail patients achieved 2-year remission significantly less often than their robust counterparts (55.4% versus 30.6%, χ
2 = 8.3, df = 2,
P = .016). Analogously, in a longitudinal study [
55] of 189 persons with depressed mood, remission was less likely with higher levels of physical frailty (hazard rate = 0.72, 95% confidence interval 0.58–0.91,
P = .005). Finally, using data from the Nordic Research on Ageing (NORA), [
56] Brown found that the combination of late-life depression and frailty was associated with increased likelihood of poor outcomes. In that study, depressed older women with frailty had higher death rates compared to those who were frail but not depressed.