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Mechanisms of Antidepressant Non-Response in Late-Life Depression

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT01931202
Recruitment Status : Recruiting
First Posted : August 29, 2013
Last Update Posted : August 20, 2019
Information provided by (Responsible Party):
Bret Rutherford, New York State Psychiatric Institute

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. 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.

Condition or disease Intervention/treatment Phase
Major Depressive Disorder Drug: Escitalopram Not Applicable

Detailed Description:
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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Mechanisms of Antidepressant Non-Response in Late-Life Depression
Actual Study Start Date : August 2013
Actual Primary Completion Date : February 2019
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Antidepressants

Arm Intervention/treatment
Placebo Comparator: Placebo Controlled Group
Blinded treatment with either escitalopram 10mg or placebo, increased to escitalopram 20mg or placebo at week 4 if depression has not remitted.
Drug: Escitalopram
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.
Other Name: Lexapro

Active Comparator: Open Group
Open treatment with 10mg of escitalopram, increased to 20mg if depression has not remitted at week 4.
Drug: Escitalopram
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.
Other Name: Lexapro

Primary Outcome Measures :
  1. Hamilton Psychiatric Rating Scale for Depression [ Time Frame: 8 weeks ]

Secondary Outcome Measures :
  1. Clinical Global Impression [ Time Frame: 8 weeks ]
  2. Hamilton Anxiety Rating Scale [ Time Frame: 8 Weeks ]
  3. Credibility and Expectancy Scale [ Time Frame: 8 Weeks ]
  4. Quick Inventory of Depression Scale Quick Inventory of Depression Scale Quick Inventory of Depression Scale [ Time Frame: 8 Weeks ]
  5. fMRI Scan [ Time Frame: 1 Day ]
    Images are obtained using a GE Signa 3 Tesla whole body scanner, and scans include: T1-weighted 3D SPGR (Spoiled Gradient Echo), T2 FLAIR, Dual FSE (Fast Spin Echo), and DTI (Diffusion Tensor Image).

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Ages Eligible for Study:   60 Years to 90 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01931202

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Contact: Kiley Cappetta 646-774-8652

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United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Kiley Cappetta    646-774-8652   
Principal Investigator: Bret R Rutherford, MD         
Sponsors and Collaborators
New York State Psychiatric Institute
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Principal Investigator: Bret Rutherford, MD New York State Psychiatric Institute

Additional Information:
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Responsible Party: Bret Rutherford, Assistant Professor of Clinical Psychiatry, New York State Psychiatric Institute Identifier: NCT01931202     History of Changes
Other Study ID Numbers: 6836
First Posted: August 29, 2013    Key Record Dates
Last Update Posted: August 20, 2019
Last Verified: August 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Additional relevant MeSH terms:
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Depressive Disorder
Depressive Disorder, Major
Mood Disorders
Mental Disorders
Antidepressive Agents
Psychotropic Drugs
Neurotransmitter Agents
Serotonin Agents
Physiological Effects of Drugs
Antidepressive Agents, Second-Generation
Antiparkinson Agents
Anti-Dyskinesia Agents
Autonomic Agents
Peripheral Nervous System Agents
Cholinergic Agents
Behavioral Symptoms
Serotonin Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Muscarinic Antagonists
Cholinergic Antagonists