Treating Depression in Older Adults with Dementia

Dementia management is a growth industry, as the number of cases in the US is expected to skyrocket from 5 million now to as many as 16 million by 20501. Behavioral problems in dementia are extremely common and include agitation, psychosis, anxiety, and depression2. Behavioral problems are a leading cause of health care expenditures3, nursing home placement4, and caregiver burden5 in dementia. Thus, depression and other behavioral problems in dementia are a big problem that is getting bigger; effective means of controlling them are of great importance for clinicians and for the community. In this issue of the Journal of the American Geriatrics Society, Drs. Nelson and Devanand ask a simple question: do antidepressant medications help depressive symptoms in dementia? To answer this question, they performed a scholarly review and meta-analysis of seven studies that randomized elderly demented persons with depression to antidepressant or placebo (total N=330). They found only marginal evidence of efficacy of antidepressants to bring about response or remission from depression, or to bring about a greater reduction in depressive symptoms than placebo. The studies in the meta-analysis were of good quality but were generally underpowered (only one study randomized more than 50 subjects). Moreover, the studies were heterogeneous in terms of classes of antidepressants tested, depressive symptom measures, levels of severity of depression, and definitions of “depression in dementia.” Among the individual studies, only two of seven found a statistically significant benefit of antidepressant over placebo. What do these findings mean for clinicians and for researchers? Before addressing these questions, it is important to mention some limitations to the use of meta-analyses in examining mental health treatments. First, a meta-analysis cannot overcome methodological limitations of the studies included in the analysis. Two limitations underlying almost all behavioral treatment research, including antidepressant treatments, are (a) the examination of a “complex phenotype” (a euphemism for “we don’t know what ‘clinical depression’ is on a molecular or systems level”), and (b) the use of crude outcome measures based largely on self-report, which are little-changed since the 1950s. These two limitations are exacerbated in geriatric studies, because of heterogeneity due to medical and cerebrovascular changes6 and because of problems with insight and recall which undermine researchers’ ability to accurately measure outcomes. In fact, a meta-analysis may exaggerate methodological limitations, as the weighting favors studies with larger sample sizes, possibly at the expense of smaller but more methodologically sound studies. Finally, the gold standard for validity of a scientific finding is independent confirmation, not meta-analysis; and, the efficacy of antidepressants for depression in dementia has been shown in two independent studies – although, on the other hand, the largest study to date, a multi-center study specifically meant to confirm this efficacy finding, failed to do so7. To their credit, Drs. Nelson and Devanand clearly outline the various methodological problems of the underlying research as well as the limitations of a meta-analytic approach in this instance. Clinicians frequently look to meta-analyses for treatment recommendations, but the main finding here is that the question “How do I treat depressive symptoms in my demented patients?” remains incompletely answered. The authors suggest that the marginal findings in this meta-analysis are due to modest efficacy of antidepressants for older adults in general (whether demented or not)8. Yet clinicians can achieve excellent outcomes with antidepressant treatment in our older adults. Based on research findings and my own experience as a geriatric psychiatrist who sees such patients and has participated in numerous clinical trials of antidepressant treatment, I would have three points of advice: First, decide whether initiating antidepressant treatment is appropriate (vs. watchful waiting). To make this decision, ask the following questions: is depression causing the patient, and/or the caregiver, suffering? Is it recalcitrant to environmental changes (such as increasing physical activity or social and pleasurable events)? Is it frequent? Is it clearly “depression” (including sadness or inability to experience pleasure, excess somatization, core symptoms such as pessimism, guilt, worthlessness and wish to die) or something more non-specific such as apathy or fatigue? Are non-medication options (such as pain relief, medical rehabilitation, or a change in living situation) likely to relieve the depressive symptoms? Second, follow the patient closely to optimize treatment. If the treatment is poorly-tolerated, or there is clearly no benefit at an adequate dose, the decision is simple: stop it and try something else. If the treatment is beneficial but incompletely so, try augmentation (if dose is optimized already); the use of dose optimization and medication augmentation and switching approaches will get most depressed older adults to remission.9 Also continue to reinforce non-pharmacological approaches10 which may become more feasible and effective when combined with antidepressants. Close follow-up will also improve adherence and provide a clearer ascertainment of benefits and risks,11 which will mitigate acute risks of antidepressants such as hyponatremia leading to confusion12 or increased suicidality.13 Third, determine a maintenance strategy. Here, “the dose that gets you well, keeps you well” has been clearly demonstrated for both cognitively impaired and intact elderly.14 If an antidepressant medication has been demonstrated to work and is well-tolerated, it should be maintained. In summary, by limiting treatment only to those who are likely to benefit, by discarding treatments that do not work and optimizing those that do, and by using maintenance treatment, astute clinicians usually will get our patients well from depression and keep them well. This meta-analysis has important implications for researchers. Drs. Nelson and Devanand suggest that additional research is needed to establish the efficacy of antidepressants in depressed patients with dementia, focusing on patients most likely to be drug-responsive; i.e., those with more severe levels of depressive symptoms, and those with a more chronic or recurrent illness. Additionally, the authors point out the challenges in accurately assessing outcomes of depression using standard rating scales. Taking this point further, it is unlikely that we will be able to clarify the benefits of antidepressants (or any behavioral treatment) in older adults, or to personalize treatment based on clinical trial findings, until we greatly improve assay sensitivity of our outcome measures. Experience sampling15 and objective measures of physical and social functioning16 are well known and validated methods to overcome insight and recall biases and might greatly increase the precision of depression outcome measurement. Finally, observational studies have recently raised a host of potential long-term risks of antidepressants in older adults, including suicide17, gastrointestinal bleed18, and falls and bone loss leading to increased fracture risk19. The suicide risk seems unlikely in the aggregate, as a large FDA meta-analysis specifically examining suicide in antidepressant clinical trials found a protective effect of antidepressants versus placebo in those aged 65+.20 Likewise gastrointestinal bleed is a rare event, so its potential risk would not preclude antidepressant use in most older adults. But the growing concern of falls, bone loss, and fractures with serotonergic antidepressants could and should be determined definitively by an appropriate randomized clinical trial; until then, the causality of these risks will remain unclear. It would be helpful to know whether in treating depression we are contributing to the $19 billion-plus annual US cost of treating fall-related injuries in older adults.21 In conclusion, Nelson and Devanand show us not only what we have learned in treating depression in dementia, but how much we still need to learn. Improved methods to measure outcomes, and a greater focus on risks as well as benefits of treatment should be the focus of future clinical trials in this field. Until then, clinicians should continue to use a trial-and-error approach, often frustrating but (with adequate skill and time) still producing good clinical outcomes in the treatment of late-life depression.