Mechanisms of Antidepressant Non-Response in Late-Life Depression
| Status: | Recruiting |
|---|---|
| Conditions: | Depression, Depression, Major Depression Disorder (MDD) |
| Therapuetic Areas: | Psychiatry / Psychology, Pulmonary / Respiratory Diseases |
| Healthy: | No |
| Age Range: | 60 - 90 |
| Updated: | 8/19/2018 |
| Start Date: | August 2013 |
| End Date: | August 2019 |
| Contact: | Kiley Cappetta |
| Email: | kiley.cappetta@nyspi.columbia.edu |
| Phone: | 646-774-8652 |
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. We 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 withED 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.
limited efficacy in Late Life Depression (LLD) in order to develop new treatment
interventions for this prevalent and disabling illness. We 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 withED 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.
To determine whether decreased antidepressant medication response in LLD patients with ED and
WMH is caused by a loss of expectancy effects, we 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 my K23 Award, we will manipulate participants' expectancy of improvement in an 8-week
duration antidepressant trial by randomizing them 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 we hypothesize will be
diminished in LLD patients with ED and WMH.
WMH is caused by a loss of expectancy effects, we 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 my K23 Award, we will manipulate participants' expectancy of improvement in an 8-week
duration antidepressant trial by randomizing them 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 we hypothesize will be
diminished in LLD patients with ED and WMH.
Inclusion Criteria:
- Men and women aged 60-90 years
- Diagnosis with nonpsychotic Diagnostic and Statistical Manual (DSM) IV MDD
- 24-item Hamilton Rating Scale for Depression (HRSD) score ≥ 16
- Willing to and capable of providing informed consent and complying with study
procedures
Exclusion Criteria:
- Current comorbid Axis I DSM IV disorder other than Nicotine Dependence, Adjustment
Disorder, or Anxiety Disorder
- diagnosis of substance abuse or dependence (excluding Nicotine Dependence) within the
past 12 months
- History of psychosis, psychotic disorder, mania, or bipolar disorder
- Diagnosis of probable Alzheimer's Disease, Vascular Dementia, or Parkinson's Disease
- MMSE < 24
- HRSD suicide item > 2 or Clinical Global Impressions (CGI)-Severity score of 7 at
baseline
- history of allergic or adverse reaction to escitalopram, or non-response to adequate
trial of escitalopram (at least 4 weeks at dose of 20mg) during the current episode
- current treatment with psychotherapy, antidepressants, antipsychotics, or mood
stabilizers
- having contraindication to MRI scanning (such as metal in body) or unable to tolerate
the scanning procedures (i.e., severe obesity, claustrophobia)
- acute, severe, or unstable medical or neurological illness
We found this trial at
1
site
1051 Riverside Dr
New York, New York 10032
New York, New York 10032
646-774-5000
Principal Investigator: Bret R Rutherford, MD
Phone: 646-774-8652
New York State Psychiatric Institute The New York State Psychiatric Institute (NYSPI), established in 1895,...
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