Mechanisms of Antidepressant Non-Response in Late-Life Depression
Status:
Completed
Trial end date:
2020-01-17
Target enrollment:
Participant gender:
Summary
This project seeks to elucidate the mechanisms by which antidepressant medications have
limited efficacy in Late Life Depression (LLD) in order to develop new treatment
interventions for this prevalent and disabling illness. Investigators hypothesize that the
presence of executive dysfunction (ED),which is common in depressed adults over 60, impairs
the ability to form appropriate expectancies of improvement with antidepressant treatment.
Greater expectancy has been shown to improve antidepressant treatment outcome and is
hypothesized to be a primary mechanism of placebo effects. Moreover, white matter
hyperintensities (WMH) on magnetic resonance imaging (MRI) are more prevalent in patients
with LLD compared to healthy controls. It has been argued that WMH contribute to the
pathogenesis of LLD with ED and decrease the efficacy of antidepressant medications by
disrupting connections between prefrontal cortical (PFC) and subcortical structures. Vascular
lesions to white matter tracts may also compromise the pathway by which expectancy-based
placebo effects influence depressive symptoms. Expectancies reflect activation in PFC areas
that may improve depressive symptoms by modulating the activity of subcortical regions
subserving negative affective systems (i.e., amygdala) as well as those important in reward
and hedonic capacity (nucleus accumbens and ventral striatum). Thus, LLD patients with ED and
WMH may sustain a "double-hit" to their ability to experience placebo effects in
antidepressant treatments: ED diminishes the ability to generate appropriate treatment
expectancies, while WMH disrupt the physiologic pathways by which expectancies lead to
improvement in depressive symptoms.