Our data support a strong association between depression and incident frailty in older adult women. We also found, in those free from frailty at baseline, any amount of antidepressant use is associated with frailty development at three years follow-up. All comparison groups had an increased risk for incident frailty, even when controlling for confounders, including chronic medical co-morbidities. However, antidepressant users also exhibiting depressive symptoms appeared to have the highest risk of becoming frail. The reasons for these findings warrant exploration.
To our knowledge, this is the first study examining antidepressant medication as treatment for depression in relation to frailty development. Prior studies have linked depressive symptoms, as opposed to treatment for depression, to current (prevalent) frailty, as well as to new onset (incident) frailty.(2
) In their landmark study using data from the Cardiovascular Health Study, Fried and colleagues reported that 31% of frail older adults had a CES-D score of at least 10, suggestive of depression, compared with 14% of intermediate frail older adults, and only 3% of nonfrail elders (trend p-value <0.001).(2
) Using data from the Women’s Health Initiative, Woods and colleagues reported that nonfrail older adults experiencing depressive symptoms were 2.2 times as likely to become frail over 3 years than older adults without depressive symptoms (p-value <0.001).(3
) Older adults taking antidepressants were excluded from both the Fried and the Woods study, so results cannot be generalized to individuals not receiving pharmacologic treatment for depression.
The strong association between frailty and depression is not surprising given the overlap of frailty characteristics with depressive symptoms. Both frailty and depression are associated with inactivity, weight loss, reduced physical activity, and exhaustion, in addition to negative long-term health consequences, such as physical disability, hospitalization, and mortality. (2
) The role of antidepressants is less clear. Amongst the women taking antidepressants who had few depressive symptoms, it is reasonable to postulate a similar risk for frailty as for non-users with few depressive symptoms. Similarly, it is reasonable to postulate that all depressed older adults might have a similar risk of frailty regardless of antidepressant use. Instead, we found that, even in the absence of depressive symptoms, antidepressant users had an increased risk for developing frailty.
We offer the following possible explanations for our seemingly incongruent findings. First, antidepressant adverse effects may have contributed to frailty risk. Second, individuals receiving medication treatment for depressive symptoms may differ from those who do not receive pharmacotherapy in ways we did not measure. Third, and most likely, antidepressant users, especially those still experiencing depressive symptoms, may suffer from a more severe, recurrent, or chronic form of depression.
All antidepressants are associated with adverse effects. For example, antidepressants are associated with increase risk for falls and fractures, which are in turn associated with frailty development.(19
) Adverse effects and tolerability vary by antidepressant class due to class specific pharmacologic actions. Despite this variability, our results indicate that all antidepressant classes are associated with an increased risk for frailty. We were limited in our ability to meaningfully compare frailty risk between individual classes, however. Instead, we compared SSRI, TCA, and other or multiple antidepressant use to no use and found that users of other or multiple antidepressants appeared to have the highest risk of becoming frail. Direct antidepressant class comparisons warrant future exploration.
Antidepressant users experiencing depressive symptoms scored higher on the Burnam scale, on average, than the other groups in our study, suggesting more severe depression. Additionally, we found that women with greater depressive symptoms had the highest risk of becoming frail. In a sensitivity analysis, we excluded users of other psychoactive medications in an attempt to exclude those with worse mental health or with co-occurring mental health diagnoses. Results did not change. Users with depressive symptoms also suffered from significantly poorer health – they were more likely to rate their health as fair or poor and to suffer from chronic co-morbidities. Co-morbid illness is a predictor of both depression and inadequate response to antidepressant treatment. (38
) Our results suggest the overlap of depressive symptoms with disease burden may promote frailty development, despite antidepressant treatment.
We did not have access to information about length of the current depressive episode or history of depression. However, recurrent and treatment resistant depression would be expected to result in longer durations of antidepressant use. We examined the association between duration of antidepressant use as a proxy for length of depressive symptoms and incident frailty. Risk did not seem to vary with duration of antidepressant use, suggesting no differences in short-term and long-term treatment. These findings must be interpreted with caution, however, and future studies should explore how depression severity and treatment resistance relates to frailty.
Strengths of our study include its prospective design, the inclusion of more than 1300 antidepressant users, the objective collection of antidepressant use, and the availability of information on health behaviors, health status, and co-morbidities. We were able to control for a large number of covariates related to frailty. Additionally, unlike many other frailty studies, our frailty definition was distinct from our measure of depressive symptoms.
Limitations include the lack of information on antidepressant indication, dose, and treatment adherence. Antidepressants are commonly used for conditions other than depression, including anxiety, sleep, and pain.(42
) While we were able to determine that an antidepressant had been prescribed, we did not have access to clinician diagnoses, nor did we have dosing information to help elucidate treatment adequacy or indication. Further, we could not determine that an antidepressant medication was actually taken, though misclassification of antidepressant use could be expected to bias our results toward the null. During the 3-year follow-up period, we were not able to ascertain antidepressant initiation or discontinuation in relation to frailty development. The prevalence of depression in our sample is lower than that reported in other WHI studies, which could be due to our exclusion of women who were frail at baseline. Also, we were not able to directly examine whether the effect of antidepressant use on incident frailty differs between women who did and did not experience depressive symptoms at baseline. Finally, despite attempts to control for potential confounding, our results are subject to confounding by indication biases.
Confounding by indication threatens the validity of all pharmacologic observational studies. In general terms, confounding by indication occurs when the indication for a medication being studied is associated with the outcome of interest. Depression is a known strong predictor of frailty development, and the primary indication for antidepressant use. Confounding by indication bias could conceal any beneficial effects of antidepressant treatment on incident frailty. We attempted to control for this source of bias by creating four mutually exclusive groups based on antidepressant use and depressive symptoms, by controlling for potential confounders in our multivariate adjustment, and by using multinomial logistic regression models. However, we cannot exclude the possibility that we were unable to completely account for baseline differences between antidepressant users and nonusers. Only a randomized controlled trial can completely control for this potential bias.
In conclusion, in this large, prospective observational study of more than 27,000 women, depressive symptoms and antidepressant use were strongly related to increased risks for incident frailty over three years. Even in the absence of depressive symptoms, antidepressant use was associated with becoming frail. While we cannot exclude the possibility of residual confounding due to inadequate measurement of depressive symptoms, our results highlight the importance of depression screening in older adults and suggest that pharmacotherapy alone for treatment of depression does not reduce an older depressed woman’s risk for becoming frail. Depression treatment trials in older adults should include frailty as an outcome measure. Further research is needed to elucidate the possible role of antidepressants in the depression-frailty relationship.