Mechanisms of Antidepressant Non-Response in Late-Life Depression
Condition: Major Depressive Disorder
MeSH terms: Depressive Disorder; Depressive Disorder, Major
Study type: Interventional

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.
    

Detailed description: 
      To determine whether decreased antidepressant medication response in LLD patients with ED and
      WMH is caused by a loss of expectancy effects, Investigators will evaluate 130 outpatients
      with LLD at baseline to determine their degree of ED (interference score on Stroop Color-Word
      Test), WMH burden (severity score on Fazekas modified Coffey Rating Scale derived from
      anatomical MRI), and white matter tract integrity (using diffusion tensor imaging [DTI]).
      Building on work from the investigators K23 Award, the investigator will manipulate
      participants' expectancy of improvement in an 8-week duration antidepressant trial by
      randomizing patients between open administration of escitalopram (i.e., high expectancy) and
      placebo-controlled administration of escitalopram (i.e., low expectancy). The difference in
      antidepressant response observed between open and placebo-controlled medication treatment is
      a measure of the expectancy contribution to outcome, which is substantial in younger
      depressed adults but investigators hypothesize this will be diminished in LLD patients with
      ED and WMH.
    

Intervention name(s): Escitalopram; Placebo oral tablet
Intervention type(s): Drug; Drug
Intervention description(s): Escitalopram is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is FDA approved for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in adults and children over 12 years of age.; Inert substance or treatment which is designed to have no therapeutic value but resemble the active medication in this study
Other intervention name(s): Lexapro; placebo
Intervention MeSH terms: Escitalopram
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment