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

RCT of Neurocognitive and Neuroimaging Biomarkers: Predicting Progression Towards Dementia in Patients With Treatment-resistant Late-life Depression (OPTIMUM-Neuro RCT)

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Depression; Dementia; Mild Cognitive Impairment; Major Depressive Disorder; Treatment Resistant Depression; Treatment-Refractory Depression; Late Life Depression; Geriatric Depression
• Intervention / Treatment: Drug: Aripiprazole Augmentation; Drug: Bupropion Augmentation; Drug: Switch to bupropion; Drug: Lithium Augmentation; Drug: Switch to nortriptyline

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.

• Study Type: Interventional
• Enrollment (Estimated): 600
• Phase: Phase 4

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M6J 1H4
      • Centre for Addiction and Mental Health
• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Late-Life Mood, Stress, and Wellness Research Program
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Healthy Mind Lab
  • New York
    • New York, New York, United States, 10032
      • Columbia University Adult and Late Life Depression Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Aripiprazole Augmentation; Augment current antidepressant treatment with aripiprazole (tablets), titrated from 2-15 mg daily based on symptom severity and side effects.	Drug: Aripiprazole Augmentation; 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.; Other Names: Abilify
Experimental: Bupropion Augmentation; Augment current antidepressant treatment with bupropion once-daily extended release, titrated from 150-300 mg daily based on symptom severity and side effects.	Drug: Bupropion Augmentation; 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.; Other Names: Wellbutrin
Experimental: Switch to Bupropion; Taper from current antidepressant therapy. Start bupropion once-daily extended, titrated from 150-300 mg daily based on symptom severity and side effects.	Drug: Switch to bupropion; 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.; Other Names: Wellbutrin
Experimental: Lithium Augmentation; 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).	Drug: Lithium Augmentation; Augment current antidepressant treatment with lithium carbonate tablets starting at 300 mg daily, titrated per blood level to 0.4-0.6 meQ/L.; Other Names: Lithium carbonate; Eskalith
Experimental: Switch to Nortriptyline; 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.	Drug: Switch to nortriptyline; 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; Other Names: Pamelor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
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.	Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
Safety Outcomes Assessment for Serious Adverse Events	Assessing; Life threatening illness, hospitalization, or need of medical care over the duration of the study	Step 1 (10 weeks), Step 2 (10 weeks), a period of up to 20 weeks
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).	Baseline, 6-months, 24-months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma biomarkers will be analyzed using a customized multiplex protein array platform for the Senescence-Associated Secretory Phenotype (SASP).	The SASP index will be used to look at circulating proteins related to immune-inflammatory control	Baseline, 6-months, 24-months

Collaborators and Investigators

• Sponsor: Centre for Addiction and Mental Health
• Collaborators: National Institute of Mental Health (NIMH)
• Investigators: Principal Investigator: Aristotle Voineskos, MD, Centre for Addiction and Mental Health

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Estimated): April 30, 2024
• Study Completion (Estimated): February 28, 2025

Study Registration Dates

• First Submitted: August 19, 2022
• First Submitted That Met QC Criteria: September 2, 2022
• First Posted (Actual): September 8, 2022

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: RCT; Comparative Effectiveness Research; Pragmatic Clinical Trials; Patient-Centered Outcomes Research; Research Clinical Trial
• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mood Disorders; Neurocognitive Disorders; Cognition Disorders; Depression; Depressive Disorder; Dementia; Cognitive Dysfunction; Depressive Disorder, Major; Depressive Disorder, Treatment-Resistant; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Serotonin Agents; Antidepressive Agents; Dopamine Agonists; Dopamine Agents; Serotonin 5-HT1 Receptor Agonists; Serotonin Receptor Agonists; Serotonin 5-HT2 Receptor Antagonists; Serotonin Antagonists; Dopamine D2 Receptor Antagonists; Dopamine Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Antidepressive Agents, Tricyclic; Antimanic Agents; Cytochrome P-450 CYP2D6 Inhibitors; Dopamine Uptake Inhibitors; Adrenergic Uptake Inhibitors; Aripiprazole; Bupropion; Lithium Carbonate; Nortriptyline
• Other Study ID Numbers: 080-2017, 086-2016 RCT; R01MH114970 (U.S. NIH Grant/Contract); R01MH114980 (U.S. NIH Grant/Contract); R01MH114981 (U.S. NIH Grant/Contract); R01MH114966-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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.

Drug and device information, study documents

• 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