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Mechanisms of Antidepressant Non-Response in Late-Life Depression

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ClinicalTrials.gov Identifier: NCT01931202
Recruitment Status : Completed
First Posted : August 29, 2013
Results First Posted : April 8, 2020
Last Update Posted : July 2, 2020
Sponsor:
Information provided by (Responsible Party):
Bret Rutherford, New York State Psychiatric Institute

Tracking Information
First Submitted Date  ICMJE August 26, 2013
First Posted Date  ICMJE August 29, 2013
Results First Submitted Date  ICMJE March 7, 2020
Results First Posted Date  ICMJE April 8, 2020
Last Update Posted Date July 2, 2020
Actual Study Start Date  ICMJE February 19, 2014
Actual Primary Completion Date January 17, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 6, 2020)
Hamilton Rating Scale for Depression (HRSD) [ Time Frame: Baseline ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: August 26, 2013)
Hamilton Psychiatric Rating Scale for Depression [ Time Frame: 8 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: April 6, 2020)
  • Hamilton Rating Scale for Depression (HRSD) [ Time Frame: Week 8 ]
    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.
  • Quick Inventory of Depressive Symptoms (QIDS-SR) [ Time Frame: Baseline ]
    QIDS-SR is a 16 item scale self-report form that was used to measure depression outcomes. This self-report is valuable in this study, because it is less susceptible to clinician and rater bias. The QIDS-SR has been increasingly used in antidepressant studies due to its equivalent weightings for each symptom item, clearly understandable anchor points, and inclusion of all DSM criteria for depression. The scores range from 0-27 with 27 being worse depressive symptoms.
  • Quick Inventory of Depressive Symptoms (QIDS-SR) [ Time Frame: Week 8 ]
    QIDS-SR is a 16 item scale self-report form that was used to measure depression outcomes. This self-report is valuable in this study, because it is less susceptible to clinician and rater bias. The QIDS-SR has been increasingly used in antidepressant studies due to its equivalent weightings for each symptom item, clearly understandable anchor points, and inclusion of all DSM criteria for depression. The scores range from 0-27 with 27 being worse depressive symptoms.
  • Credibility and Expectancy Scale-Better (CES) [ Time Frame: Pre-Baseline ]
    CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. Question 2 ('Better') asks the patient the chances of their depression being completely better at the end of this study, from 1 = very poor to 7 = very good. The higher the number, the higher the expectancy that they will be better.
  • Credibility and Expectancy Scale-Better (CES) [ Time Frame: Week 0 ]
    CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. Question 2 ('Better') asks the patient the chances of their depression being completely better at the end of this study, from 1 = very poor to 7 = very good. The higher the number, the higher the expectancy that they will be better.
  • Credibility and Expectancy Scale-Depression [ Time Frame: Pre-baseline ]
    CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. CES question 3 ('Depression') asks how the patient's depression will be at the end of the study, compared with now, from 1 = much worse to 7= much better. The higher the number, the higher the expectancy that their depression will be much better.
  • Credibility and Expectancy Scale-Depression [ Time Frame: Week 0 ]
    CES is an 8 item scale in which subjects rate their impression of the credibility of the treatment and how they estimate their expectation of improvement. The CES is the most widely used measure of expectancy and has demonstrated good psychometric properties in multiple studies. CES question 3 ('Depression') asks how the patient's depression will be at the end of the study, compared with now, from 1 = much worse to 7= much better. The higher the number, the higher the expectancy that their depression will be much better.
  • Quick Inventory of Depression Scale (QIDS-SR): Expectancy [ Time Frame: Pre-Baseline ]
    This 16-items assessment is used to rate the 9 criterion symptom domains of a major depressive episode: 4 items are used to rate sleep disturbance (early, middle, and late insomnia plus hypersomnia); 2 items are used to rate psychomotor disturbance (agitation and retardation); 4 items are used to rate appetite/weight disturbance (appetite increase or decrease and weight increase or decrease). Only 1 item is used to rate the remaining 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, and suicidal ideation). Each item is rated 0-3. For symptom domains that require more than 1 item, the highest score of the item relevant for each domain is taken. The total score ranges from 0-27. A lower rating indicates higher expectancy of improvement and lower expectation of depressive symptomatology, and a higher rating indicates lower expectancy of improvement, higher expectation of depression.
  • Quick Inventory of Depression Scale (QIDS-SR): Expectancy [ Time Frame: Week 0 ]
    This 16-items assessment is used to rate the 9 criterion symptom domains of a major depressive episode: 4 items are used to rate sleep disturbance (early, middle, and late insomnia plus hypersomnia); 2 items are used to rate psychomotor disturbance (agitation and retardation); 4 items are used to rate appetite/weight disturbance (appetite increase or decrease and weight increase or decrease). Only 1 item is used to rate the remaining 6 domains (depressed mood, decreased interest, decreased energy, worthlessness/guilt, concentration/decision making, and suicidal ideation). Each item is rated 0-3. For symptom domains that require more than 1 item, the highest score of the item relevant for each domain is taken. The total score ranges from 0-27. A lower rating indicates higher expectancy of improvement and lower expectation of depressive symptomatology, and a higher rating indicates lower expectancy of improvement, higher expectation of depression.
  • Executive Dysfunction: Stroop Color Word [ Time Frame: Pre-Baseline ]
    Stroop Color Word test asks patients to name the color of a word rather than reading the word. Stroop Color Word is how many colors they can name in 45 sec (higher is better, e.g., less executive dysfunction).
  • Executive Dysfunction: Stroop Interference [ Time Frame: Pre-Baseline ]
    The Stroop is a measure of inhibition under distracting conditions that is sensitive to frontal lobe dysfunction. in Stroop Color Word test patients are to name the color of a word rather than reading the word. Stroop Color Word is how many colors they can name in 45 sec (higher is better, e.g., less executive dysfunction). Stroop Interference is this score adjusted for age and education.
  • White Matter Hyperintensity (WMH) Outcome- Total WMH [ Time Frame: Pre-Baseline ]
    Magnetic Resonance Imaging (MRI) of the Brain was acquired. We rated the severity of WMH on axial T2 FLAIR images using the Fazekas modified Coffey Rating Scale. Deep WMH are scored as 0 (absent), 1 (punctate foci), 2 (beginning confluence of foci), and 3 (large confluent areas); subcortical gray matter HIs (basal ganglia) are scored as 0 (absent), 1 (punctate), 2 (multipunctate), and 3 (diffuse); periventricular HIs are scored as 0 (absent), 1 (caps), 2 (smooth halo), and 3 (irregular and extending into the deep white matter). Our primary measure of WMH burden will be DWMH score, which has been used to establish the only empirically validated diagnostic criteria for vascular depression, where scores of 0-1 were normal, but 2-3 indicated WHM.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2013)
  • Clinical Global Impression [ Time Frame: 8 weeks ]
  • Hamilton Anxiety Rating Scale [ Time Frame: 8 Weeks ]
  • Credibility and Expectancy Scale [ Time Frame: 8 Weeks ]
  • Quick Inventory of Depression Scale Quick Inventory of Depression Scale Quick Inventory of Depression Scale [ Time Frame: 8 Weeks ]
  • 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).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Mechanisms of Antidepressant Non-Response in Late-Life Depression
Official Title  ICMJE Mechanisms of Antidepressant Non-Response in Late-Life Depression
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Major Depressive Disorder
Intervention  ICMJE
  • 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
  • Drug: Placebo oral tablet
    Inert substance or treatment which is designed to have no therapeutic value but resemble the active medication in this study
    Other Name: placebo
Study Arms  ICMJE
  • Placebo Comparator: Double Blind-Placebo
    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.
    Intervention: Drug: Placebo oral tablet
  • Active Comparator: Double Blind-Escitalopram
    Blinded treatment with either escitalopram 10mg, increased to escitalopram 20mg at week 4 if depression has not remitted.
    Intervention: Drug: Escitalopram
  • Active Comparator: Open Treatment with Escitalopram
    Open treatment with 10mg of escitalopram, increased to 20mg if depression has not remitted at week 4.
    Intervention: Drug: Escitalopram
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: April 6, 2020)
138
Original Estimated Enrollment  ICMJE
 (submitted: August 26, 2013)
130
Actual Study Completion Date  ICMJE January 17, 2020
Actual Primary Completion Date January 17, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years to 90 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01931202
Other Study ID Numbers  ICMJE 6836
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Bret Rutherford, New York State Psychiatric Institute
Study Sponsor  ICMJE New York State Psychiatric Institute
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Bret Rutherford, MD New York State Psychiatric Institute
PRS Account New York State Psychiatric Institute
Verification Date June 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP