Mechanisms of Antidepressant Non-Response in Late-Life Depression

NCT01931202 | Completed Results

• 1 other identifier: 6836
• Study Type: interventional
• Target: 138
• Locations: 1 country
• Sites: 1

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.

Conditions

Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Hamilton Rating Scale for Depression (HRSD)

  Our target is depressive symptomatology as measured by the Hamilton Rating Scale for Depression (HRSD). The HRSD is a 24-item questionnaire used as an indication of depression and a guide to evaluate recovery. Total scores range from 0-74, not including atypical symptoms sub-scale. A score of 16 or above is typically considered to indicate the presence of depressive symptoms. Higher scores indicate greater severity.

  Baseline

Secondary Outcomes (12)

• Hamilton Rating Scale for Depression (HRSD)

  Week 8

• Quick Inventory of Depressive Symptoms (QIDS-SR)

  Baseline

• Quick Inventory of Depressive Symptoms (QIDS-SR)

  Week 8

• Credibility and Expectancy Scale-Better (CES)

  Pre-Baseline

• Credibility and Expectancy Scale-Better (CES)

  Week 0

Study Arms (3)

Double Blind-Placebo

PLACEBO COMPARATOR

Blinded treatment with placebo, one pill a day. If after the 4 weeks, the patient has not remitted, they will be increased to 2 pills a day.

Drug: Placebo oral tablet

Double Blind-Escitalopram

ACTIVE COMPARATOR

Blinded treatment with either escitalopram 10mg, increased to escitalopram 20mg at week 4 if depression has not remitted.

Drug: Escitalopram

Open Treatment with Escitalopram

ACTIVE COMPARATOR

Open treatment with 10mg of escitalopram, increased to 20mg if depression has not remitted at week 4.

Drug: Escitalopram

Interventions

Escitalopram DRUG

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.

Also known as: Lexapro

Double Blind-Escitalopram; Open Treatment with Escitalopram

Placebo oral tablet DRUG

Inert substance or treatment which is designed to have no therapeutic value but resemble the active medication in this study

Also known as: placebo

Double Blind-Placebo

Eligibility Criteria

• Age: 60 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Men and women aged 60-90 years
• Diagnosis with nonpsychotic Diagnostic and Statistical Manual (DSM) IV MDD
• item Hamilton Rating Scale for Depression (HRSD) score ≥ 16
• Willing to and capable of providing informed consent and complying with study procedures

You may not qualify if:

• 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

Sponsors & Collaborators

• New York State Psychiatric Institute: lead

Study Sites (1)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Related Publications (1)

• 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.

  PMID: 32919398 DERIVED

Related Links

• Rutherford BR, Roose SP. A Model of Placebo Response in Antidepressant Clinical Trials. Am J Psychiatry. 2013 Jan 15. doi: 10.1176/appi.ajp.2012.12040474. \[Epub ahead of print\] PubMed PMID: 23318413

MeSH Terms

Conditions

Depressive Disorder, Major

Interventions

Escitalopram

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Nitriles; Benzofurans; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Bret R. Rutherford
• Organization: New York State Psychiatric Institute

bret.rutherford@nyspi.columbia.edu

6467748660

Study Officials

• Bret Rutherford, MD

  New York State Psychiatric Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor of Clinical Psychiatry

Study Record Dates

• First Submitted: August 26, 2013
• First Posted: August 29, 2013
• Study Start: February 19, 2014
• Primary Completion: January 17, 2019
• Study Completion: January 17, 2020
• Last Updated: July 2, 2020
• Results First Posted: April 8, 2020

Record last verified: 2020-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)