Although a number of studies have shown that DRI predicts poor response to antidepressant medication (2
), this is the first report that we know of showing a significant difference in response between medication and placebo in depressed patients with DRI. Extending our previous report (5
), it is not simply that depressed older adults with DRI respond poorly to antidepressant medication, in fact these patients respond less well than they would if they had been treated with placebo.
We also found a significant difference between citalopram and placebo among depressed patients without DRI, which contradicts a previous report indicating no difference between treatment conditions based on the total sample (9
). Thus, this study suggests that DRI is a potential confound of treatment response in the analysis of antidepressant medication trials and should be considered when interpreting the results of clinical trials conducted in late-life depression that did not find a significant difference between medication and placebo (9
). Future studies involving late-life depressed patients should report moderator analyses using a measure of DRI.
Although the mechanism of action of the placebo effect is unknown, the findings from this study indicate that it is different from SSRIs. Brain responses to antidepressant medications have been described as “placebo plus.” In a well known comparison of regional brain glucose metabolism between placebo and SSRI responders, Mayberg et al. (23
) found that both placebo and drug response were associated with increased metabolism in the prefrontal cortex, premotor cortex, inferior parietal cortex, posterior insula, and posterior cingulate and decreased metabolism in the subgenual cingulate, hypothalamus, thalamus, and parahippocampus. However, drug response was also associated with metabolism changes in other areas, such as the striatum, which were not associated with placebo response. These data may help explain why drug response should be preferentially reduced compared to placebo response in the current study. Patients with DRI have white matter lesions that may interrupt fronto-striatal pathways, possibly disrupting the connectivity of brain regions known to be associated with drug response over and above the placebo response.
The topic of this report raises the critical issue as to what is meant by the use of the term executive dysfunction in geriatric psychiatry and what aspects of it interact negatively with antidepressant medication. The term executive dysfunction is “vague and ill defined” (27
). The executive functions refer to a theorized cognitive system that involves the monitoring and allocation of attentional resources and subsumes a broad class of functions including planning, organization, problem solving, cognitive flexibility such as set shifting and switching, updating and monitoring of working memory representations, error monitoring, and response inhibition (1
). Typically, the term executive dysfunction is used despite the fact that only one or two components of the executive functions were assessed in the study or a single composite score is used based on an executive functions screening tool. In the latter case, although a broad array of functions is assessed, it is not clear from the composite score which aspect of executive functioning is affected. Therefore, we recommend when reporting results of studies using tests tapping the executive functions that researchers are specific to the test being used and do not generalize to the broader class of executive functions.
The second issue that is raised is what aspects of executive functioning interact negatively with antidepressant medication. Not all studies demonstrating interference with treatment response have measured the same components of the executive functions or used the same tests. For example, some studies have used the Stroop and the Attention Network Test (2
), which are response inhibition tasks, whereas other studies have used the initiation/perseveration subtest of the Dementia Rating Scale (3
), which incorporates a number of different components but may be most accurately described as a test of fluency (26
). It is not clear what the relationship is between response inhibition tasks and the initiation/perseveration subtest of the Dementia Rating Scale, and furthermore, why they are independently predictive of poor antidepressant treatment response. One possible explanation for the common effect is that both response inhibition and fluency tasks require cognitive flexibility and that deficits in cognitive flexibility predict poor treatment outcome.
As for the mechanism of executive dysfunction interference on antidepressant response, one possibility is disruption of frontostriatal tracts connecting the striatum to the prefrontal cortex, an important locus of central executive functioning as well as emotion regulation (27
). Consistent with this hypothesis, patients with late-onset depression and microvascular ischemic disease also tend to show deficits in executive functioning (29
). Although executive tasks activate a diffuse network of brain areas suggesting that the neuroanotomical basis for the executive functions is widely distributed (24
), the central locus of response inhibition appears to be the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) as seen on Positron Emission Tomography (PET) and functional magnetic resonance imaging (fMRI) studies (32
). Specifically, it has been suggested that the ACC is implicated in response-related processes such as conflict detection and monitoring, but that activity in this region decreases as the level of response conflict is reduced with practice and as attentional control is established in the DLPFC (36
). Thus, microvascular ischemic disease may interfere with the circuits necessary for both the therapeutic action of antidepressant medication and executive functioning in general and response inhibition in particular. It is interesting to note that Sneed et al. (5
) examined the relationship between response inhibition and qualitative ratings of microvascular ischemia using data from the Old-Old Study and found no relationship.
The Stroop Color-Word Test is a complex neuropsychological task that focuses on the slowing of reaction time in the color-word conflict condition relative the color-only condition. As opposed to a specific deficit in response inhibition, it is possible that a generalized slowing of reaction time or a slowing that occurs with greater cognitive demand accounted for the relationship between baseline Stroop performance and antidepressant response. However, we have shown in previous reports that the effect of DRI on antidepressant treatment response is independent of reaction time (Sneed, et al., 2007). We have also shown that poor antidepressant response is not associated with performance on any other neuropsychological task including mental status, psychomotor speed, reaction time, spatial judgment, or memory (7
This study should be interpreted in the context of several limitations, which are balanced by using data from the only randomized, placebo-controlled clinical trial of antidepressant treatment among depressed patients age 75 or older. One possibility is that these findings do not hold in younger samples. However, the effect of response inhibition on treatment response has been shown in both young-old (2
) and old-old samples (5
). This study represents the first report of its kind and awaits replication in both young-old and old-old samples. Another possibility is that task novelty in the elderly might limit the validity of the computerized Stroop task used in this study. However, these novelty issues are more likely in less educated subjects, and if education predicted treatment response equally as well as Stroop performance, one could make an argument that there is some general novelty or testing familiarity effect. However, we included education as a covariate to test for this possibility and it did not substantively change the findings. Finally, response inhibition was the only component of the executive functions used in this study. The executive functions represent a multifaceted class of functions and, therefore, these findings may not generalize to other tests of executive functioning.
The findings from this study are clinically significant and have important implications for the treatment of late-life depression. We extended our previous report by showing that patients with depression and DRI respond worse than they would have had they been assigned to treatment with placebo. The observed effects were moderate to large in size indicating not only statistical significance but also that the findings are meaningful and detectable in small samples. These findings also imply that the mechanism of SSRI and placebo response is different, which may lead to important breakthroughs with regard to the treatment of depression with cognitive impairment in the elderly.