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RCT of Brain Longitudinal Biomarker Study (OPT-Neuro RCT) (ONR)

Primary Purpose

Depression, Dementia, Mild Cognitive Impairment

Status
Active
Phase
Phase 4
Locations
International
Study Type
Interventional
Intervention
Aripiprazole Augmentation
Bupropion Augmentation
Switch to bupropion
Lithium Augmentation
Switch to nortriptyline
Sponsored by
Centre for Addiction and Mental Health
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Depression focused on measuring Comparative Effectiveness Research, Pragmatic Clinical Trials, Patient-Centered Outcomes Research, Research Clinical Trial, RCT

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Men and women aged 60 and older, with approximately equal proportions aged 60-70 and 70+.
  • Current Major Depressive Disorder (MDD), single or recurrent, as diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria.
  • Failure to respond adequately to two or more antidepressant treatment trials of recommended dose and length (approximately 12 weeks).
  • PHQ-9 score of 10 or higher.

Exclusion Criteria:

  • Dementia; patients screened out due to possible dementia will be referred to a local Memory Clinic or back to their clinician for evaluation to clarify the presence or absence of dementia.
  • Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms.
  • High risk for suicide (e.g. active Suicidal ideations (SI) and or current/recent intent or plan)). Urgent psychiatric referral will be made in these cases.
  • Non-correctable, clinically significant sensory impairment (e.g., cannot hear well enough to cooperate with interview).
  • Unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management.
  • Moderate to severe substance or alcohol use disorder, as determined by study physician.
  • Seizure disorder.
  • Parkinson's Disease

Sites / Locations

  • UCLA Late-Life Mood, Stress, and Wellness Research Program
  • Washington University School of Medicine Healthy Mind Lab
  • Columbia University Adult and Late Life Depression Clinic
  • Centre for Addiction and Mental Health

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Aripiprazole Augmentation

Bupropion Augmentation

Switch to Bupropion

Lithium Augmentation

Switch to Nortriptyline

Arm Description

Augment current antidepressant treatment with aripiprazole (tablets), titrated from 2-15 mg daily based on symptom severity and side effects.

Augment current antidepressant treatment with bupropion once-daily extended release, titrated from 150-300 mg daily based on symptom severity and side effects.

Taper from current antidepressant therapy. Start bupropion once-daily extended, titrated from 150-300 mg daily based on symptom severity and side effects.

Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 mEq/L (milliequivalents/liter).

Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml.

Outcomes

Primary Outcome Measures

Change in Psychological Well-Being
Psychological well-being was assessed using the NIH Toolbox Psychological Wellbeing subscales of Positive Affect and General Life Satisfaction, with a T score calculated as the average of these two subscales. Higher scores indicate greater positive affect and life satisfaction. Reference T-score (mean=50, Standard Deviation (SD)=10.
Assessing the change in the Number of Participants With Remission From Depression
Remission defined as Montgomery Asberg Depression Rating Scale score ≤10. Scale ranges from 0-60 with higher scores indicating higher depressive symptoms.
Safety Outcomes Assessment for Serious Adverse Events
Assessing; Life threatening illness, hospitalization, or need of medical care over the duration of the study
To observe whether persistent (non-remitting) depression leads to greater cognitive decline (focusing on executive and episodic memory (EEM)-related cognitive domains
Using baseline differences to compare if non-remitters demonstrate greater decline in EEM than remitters leading to greater cognitive decline using . Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).

Secondary Outcome Measures

Full Information

First Posted
August 19, 2022
Last Updated
October 16, 2023
Sponsor
Centre for Addiction and Mental Health
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT05531591
Brief Title
RCT of Brain Longitudinal Biomarker Study (OPT-Neuro RCT)
Acronym
ONR
Official Title
RCT of Neurocognitive and Neuroimaging Biomarkers: Predicting Progression Towards Dementia in Patients With Treatment-resistant Late-life Depression (OPTIMUM-Neuro RCT)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
August 1, 2019 (Actual)
Primary Completion Date
April 30, 2024 (Anticipated)
Study Completion Date
February 28, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre for Addiction and Mental Health
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
The purpose of this study is to assess which antidepressants work the best in older adults who have treatment-resistant depression (TRD), and to test whether treatment-resistant late life depression is associated with declines in memory and attention and brain structure and function.
Detailed Description
Older adult participants with treatment-resistant depression will be randomly assigned to a Step 1 medication strategy. Adding aripiprazole to current antidepressant medication Adding bupropion to current antideprssant medication Replacing current antidepressant medication with bupropion If depression is not relieved at the end of 10 weeks, or if participants do not qualify for Step 1, participants will be randomly assigned to a Step 2 medication strategy: Adding lithium to current antidepressant medication Replacing current antidepressant medication with nortriptyline All medication strategies will be offered in collaboration with participants' own physicians with the the research team providing support and guidance. After treatment in Step 1 and/or Step 2, participants will enter the Continuation Phase to assess long term follow-up outcomes for 12 months. Participants in the Optimizing Outcomes of Treatment-Resistant Depression in Older Adults (OPTIMUM) (NCT02960763) study, will also be asked to participate in this clinical trial to gather imaging and biomarker data. The study will test if changes in brain structure and function are associated with decreases in memory. In this study, investigators will conduct a series of assessments/tests, mainly brain imaging and assessments of participant's memory and attention, to better understand how depression is linked to memory and thinking in older persons. Investigators will be collecting blood biomarkers as part of their study procedures. These samples will be used to look at other factors that may relate to depression or memory and attention processes. Mechanisms of Late life depression (LLD)-dementia through functional Magnetic Resonance Imaging (fMRI): Analyzing mechanisms of the LLD-dementia relationship through fMRI acquisitions and analyses, to capture the specific brain networks implicated in executive function and episodic memory decline. Neuropsychological Data: Including Montreal Cognitive Assessment (MoCA), Wide Range Achievement Test-4 (WRAT-4) Reading subtest, Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Delis-Kaplan Executive Function System (D-KEFS) (Color Word Interference, Trail Making and Verbal Fluency). Clinical Scales: Including the Everyday Cognition Scale (E-Cog), Global Clinical Dementia Rating (CDR), Performance Assessment of Selfcare Skills (PASS)-Cognitive Instrumental Activities of Daily Living(CIADL) Short version, Patient Health Questionnaire (PHQ-9), and Suicide Risk Assessments (Suicide Questions, Baseline Suicidal Ideation, Suicide Intent Scale, Beck Lethality Scale, Decision Outcome Inventory, Columbia-Suicide Severity Rating Scale, and High Suicide Risk Protocol). Investigators hope that this study will help the scientific community to understand why some people with depressive symptoms that are resistant to treatment in late-life experience declines in their memory and attention and whether effective treatment of such depression reduces that risk. Finally, investigators hope that this study will eventually lead to the development of better treatment options.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depression, Dementia, Mild Cognitive Impairment, Treatment Resistant Depression, Major Depressive Disorder, Treatment-Refractory Depression, Late Life Depression, Geriatric Depression
Keywords
Comparative Effectiveness Research, Pragmatic Clinical Trials, Patient-Centered Outcomes Research, Research Clinical Trial, RCT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
Outcomes Assessor
Allocation
Randomized
Enrollment
600 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Aripiprazole Augmentation
Arm Type
Experimental
Arm Description
Augment current antidepressant treatment with aripiprazole (tablets), titrated from 2-15 mg daily based on symptom severity and side effects.
Arm Title
Bupropion Augmentation
Arm Type
Experimental
Arm Description
Augment current antidepressant treatment with bupropion once-daily extended release, titrated from 150-300 mg daily based on symptom severity and side effects.
Arm Title
Switch to Bupropion
Arm Type
Experimental
Arm Description
Taper from current antidepressant therapy. Start bupropion once-daily extended, titrated from 150-300 mg daily based on symptom severity and side effects.
Arm Title
Lithium Augmentation
Arm Type
Experimental
Arm Description
Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 mEq/L (milliequivalents/liter).
Arm Title
Switch to Nortriptyline
Arm Type
Experimental
Arm Description
Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml.
Intervention Type
Drug
Intervention Name(s)
Aripiprazole Augmentation
Other Intervention Name(s)
Abilify
Intervention Description
Augment current antidepressant treatment with aripiprazole (tablets). Start at 2 mg daily; increase every two weeks (i.e., to 5, 7, 10 mg) to a maximum of 15 mg daily based on symptom severity and side effects.
Intervention Type
Drug
Intervention Name(s)
Bupropion Augmentation
Other Intervention Name(s)
Wellbutrin
Intervention Description
Augment current antidepressant treatment with bupropion once-daily extended release, starting at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects.
Intervention Type
Drug
Intervention Name(s)
Switch to bupropion
Other Intervention Name(s)
Wellbutrin
Intervention Description
Taper from current antidepressant therapy. Start bupropion once-daily extended release at 150 mg daily; titrated after four weeks to 300 mg daily based on symptom severity and side effects.
Intervention Type
Drug
Intervention Name(s)
Lithium Augmentation
Other Intervention Name(s)
Lithium carbonate, Eskalith
Intervention Description
Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L.
Intervention Type
Drug
Intervention Name(s)
Switch to nortriptyline
Other Intervention Name(s)
Pamelor
Intervention Description
Taper from current antidepressant therapy. Start on nortriptyline tablets starting at 1 mg per kg of body weight daily, titrated per blood level to 80-120 ng/ml
Primary Outcome Measure Information:
Title
Change in Psychological Well-Being
Description
Psychological well-being was assessed using the NIH Toolbox Psychological Wellbeing subscales of Positive Affect and General Life Satisfaction, with a T score calculated as the average of these two subscales. Higher scores indicate greater positive affect and life satisfaction. Reference T-score (mean=50, Standard Deviation (SD)=10.
Time Frame
Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
Title
Assessing the change in the Number of Participants With Remission From Depression
Description
Remission defined as Montgomery Asberg Depression Rating Scale score ≤10. Scale ranges from 0-60 with higher scores indicating higher depressive symptoms.
Time Frame
Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
Title
Safety Outcomes Assessment for Serious Adverse Events
Description
Assessing; Life threatening illness, hospitalization, or need of medical care over the duration of the study
Time Frame
Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
Title
To observe whether persistent (non-remitting) depression leads to greater cognitive decline (focusing on executive and episodic memory (EEM)-related cognitive domains
Description
Using baseline differences to compare if non-remitters demonstrate greater decline in EEM than remitters leading to greater cognitive decline using . Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).
Time Frame
Baseline, 6-months, 24-months
Other Pre-specified Outcome Measures:
Title
Plasma biomarkers will be analyzed using a customized multiplex protein array platform for the Senescence-Associated Secretory Phenotype (SASP).
Description
The SASP index will be used to look at circulating proteins related to immune-inflammatory control
Time Frame
Baseline, 6-months, 24-months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Men and women aged 60 and older, with approximately equal proportions aged 60-70 and 70+. Current Major Depressive Disorder (MDD), single or recurrent, as diagnosed by Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. Failure to respond adequately to two or more antidepressant treatment trials of recommended dose and length (approximately 12 weeks). PHQ-9 score of 10 or higher. Exclusion Criteria: Dementia; patients screened out due to possible dementia will be referred to a local Memory Clinic or back to their clinician for evaluation to clarify the presence or absence of dementia. Lifetime diagnosis of bipolar I or II disorder, schizophrenia, schizoaffective disorder, schizophreniform disorder, delusional disorder, or current psychotic symptoms. High risk for suicide (e.g. active Suicidal ideations (SI) and or current/recent intent or plan)). Urgent psychiatric referral will be made in these cases. Non-correctable, clinically significant sensory impairment (e.g., cannot hear well enough to cooperate with interview). Unstable medical illness, including delirium, uncontrolled diabetes mellitus, hypertension, hyperlipidemia, or cerebrovascular or cardiovascular risk factors that are not under medical management. Moderate to severe substance or alcohol use disorder, as determined by study physician. Seizure disorder. Parkinson's Disease
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Aristotle Voineskos, MD
Organizational Affiliation
Centre for Addiction and Mental Health
Official's Role
Principal Investigator
Facility Information:
Facility Name
UCLA Late-Life Mood, Stress, and Wellness Research Program
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Washington University School of Medicine Healthy Mind Lab
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Columbia University Adult and Late Life Depression Clinic
City
New York
State/Province
New York
ZIP/Postal Code
10032
Country
United States
Facility Name
Centre for Addiction and Mental Health
City
Toronto
State/Province
Ontario
ZIP/Postal Code
M6J 1H4
Country
Canada

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
A cleaned, complete, and de-identified copy of the final data set including administrative and technical metadata records will be made available on the National Institute of Mental Health (NIMH) Data Archive and registered at clinicaltrials.gov.
IPD Sharing Time Frame
Data will become available after all analyses and initial publication is complete.
IPD Sharing Access Criteria
The data will be accessible through the NIMH Data Archive (Collection ID: 2851). Please contact the principal investigators if you have further queries about access criteria.

Learn more about this trial

RCT of Brain Longitudinal Biomarker Study (OPT-Neuro RCT)

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