Clinical trial NCT01931202: Mechanisms of Antidepressant Non-Response in Late-Life Depression
Official title: Mechanisms of Antidepressant Non-Response in Late-Life Depression
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Major Depressive Disorder
Lead sponsor: New York State Psychiatric Institute
Sponsor class: OTHER
First posted: 2013-08-29
Enrollment: 138
Sex: ALL
Minimum age (years): 60
Maximum age (years): 90
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Hamilton Rating Scale for Depression (HRSD)
timeFrame: Baseline
Secondary outcomes:
measure: Hamilton Rating Scale for Depression (HRSD)
timeFrame: Week 8
measure: Quick Inventory of Depressive Symptoms (QIDS-SR)
timeFrame: Baseline
measure: Quick Inventory of Depressive Symptoms (QIDS-SR)
timeFrame: Week 8
measure: Credibility and Expectancy Scale-Better (CES)
timeFrame: Pre-Baseline
measure: Credibility and Expectancy Scale-Better (CES)
timeFrame: Week 0
measure: Credibility and Expectancy Scale-Depression
timeFrame: Pre-baseline
measure: Credibility and Expectancy Scale-Depression
timeFrame: Week 0
measure: Quick Inventory of Depression Scale (QIDS-SR): Expectancy
timeFrame: Pre-Baseline
measure: Quick Inventory of Depression Scale (QIDS-SR): Expectancy
timeFrame: Week 0
measure: Executive Dysfunction: Stroop Color Word
timeFrame: Pre-Baseline
measure: Executive Dysfunction: Stroop Interference
timeFrame: Pre-Baseline
measure: White Matter Hyperintensity (WMH) Outcome- Total WMH
timeFrame: Pre-Baseline
Other outcomes:
Locations:
city: New York
country: United States
facility: New York State Psychiatric Institute
state: New York
Study officials:
affiliation: New York State Psychiatric Institute
name: Bret Rutherford, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Wengler K, Ashinoff BK, Pueraro E, Cassidy CM, Horga G, Rutherford BR. Association between neuromelanin-sensitive MRI signal and psychomotor slowing in late-life depression. Neuropsychopharmacology. 2021 Jun;46(7):1233-1239. doi: 10.1038/s41386-020-00860-z. Epub 2020 Sep 12.