Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With TRD

NCT02977299 | Completed Phase 4 DMC FDA Drug FDA Device

• 1 other identifier: 2015P002430
• Study Type: interventional
• Target: 278
• Locations: 2 countries
• Sites: 13

Brief Summary

This is a multi-site, randomized, open-label, effectiveness trial comparing three treatment arms for Major Depressive Disorder (MDD) patients with TRD who are currently on ongoing, stable and adequate antidepressant therapy (ADT). Adequate ADT is defined as a therapeutically sufficient dose for a sufficient treatment period, which would be expected to be effective as listed in the MGH Antidepressant Treatment Response Questionnaire (ATRQ). Patients will be randomized in a 1:1:1 fashion to one of three open-label treatment arms: a) aripiprazole augmentation, b) rTMS augmentation, and c) switching to venlafaxine XR or Duloxetine.

Conditions

Treatment Resistant Major Depressive Disorder

Outcome Measures

Primary Outcomes (1)

• Montgomery-Asberg Depression Rating Scale (MADRS)

  Assessment of depression severity.

  8 weeks

Secondary Outcomes (1)

• Quality of Life, Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)

  8 weeks

Other Outcomes (1)

• Massachusetts General Hospital Cognitive and Physical Symptoms Questionnaire (MGH CPFQ)

  8 weeks

Study Arms (3)

Aripiprazole Augmentation

EXPERIMENTAL

Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial and initiate adjunctive aripiprazole. The starting dose will be 5mg daily. The dose may be reduced to as low as 2mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial). The dose may be adjusted in 2 or 5mg increments. The minimum time per increment will be 7 days. The maximum dose will be set at 15mg daily. For patients who are not on potent cytochrome 2D6 inhibitors (such as paroxetine, fluoxetine, duloxetine) or on potent cytochrome 3A4 inhibitors (such as fluvoxamine and nefazodone) and who are able to tolerate 15mg daily, the maximum dose can be raised to 20mg daily for efficacy.

Drug: Aripiprazole

rTMS Augmentation

EXPERIMENTAL

Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics at their current dose throughout the 8-week trial. We will use clinical TMS stimulators with focal figure-of-eight coils. We will start by measuring the patient´s motor threshold (MT), which is a measure of cortical excitability used to standardize the intensity of stimulation across subjects.

Device: Repetitive transcranial magnetic stimulation (rTMS)

Switching To Venlafaxine XR

EXPERIMENTAL

Patients randomized to this treatment arm will be instructed to continue all permitted psychotropics throughout the 8-week trial, except for their antidepressant(s). They will be instructed to discontinue all antidepressants and initiate venlafaxine that day, as direct switch to serotonergic antidepressants is well tolerated and avoids loss of precious therapeutic time (Montgomery et al., 2014), including to switching to venlafaxine in STAR\*D (Rush et al., 2006b). For patients who do not prefer a direct switch, or when clinically indicated otherwise in the opinion of the site investigator, a gradual tapering during the screening period will be permitted as long as a direct switch to venlafaxine is made on the baseline visit from the final antidepressant dose. The starting dose of venlafaxine will be 75mg daily. The dose may be reduced to as low as 37.5mg for tolerability issues (this will be the lowest dose permitted for continuation in the trial).

Drug: Venlafaxine XR

Interventions

Aripiprazole DRUG

Oral adjunctive therapy with aripiprazole, dose adjusted for effectiveness and tolerability.

Also known as: Abilify

Aripiprazole Augmentation

Repetitive transcranial magnetic stimulation (rTMS) DEVICE

Adjunctive therapy with transcranial magnetic stimulation, dose adjusted for effectiveness and tolerability.

rTMS Augmentation

Venlafaxine XR DRUG

Oral switch therapy with venlafaxine, dose adjusted for effectiveness and tolerability.

Also known as: Effexor XR

Switching To Venlafaxine XR

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• women and men ages 18-80,
• with MDD, of at least 12 weeks duration, according to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria confirmed by the Mini International Neuropsychiatric Interview (MINI; Sheehan et al, 1998),
• have a Montgomery-Asberg Depression Rating Scale (MADRS - Montgomery and Asberg, 1979) score of at least 20 at screen and baseline as assessed by site clinicians,
• meet criteria for TRD during the current major depressive episode documented in the MGH Antidepressant Treatment History Questionnaire (ATRQ) (Chandler et al., 2010), which will be defined as being non-responders (less than 50% of symptom improvement) to two or more depression treatment trials of adequate dose and duration as defined by the MGH ATRQ,
• are currently on an antidepressant of adequate dose (as defined by the MGH ATRQ) and duration (at least 8 weeks), with the antidepressant dose being stable over the past four weeks, and with documented (in the MGH ATRQ) non-response (less than 50% improvement) to the current antidepressant.
• Patients who have passed the MGH CTNI remote assessment, with documentation provided to sites by MGH CTNI.

You may not qualify if:

• pregnant or breastfeeding women, women of childbearing potential who are not using an accepted means of birth control, or women with a positive urine pregnancy test,
• patients who have received treatment with rTMS, aripiprazole, electroconvulsive therapy (ECT), or venlafaxine during the current episode,
• patients who express an objection to receiving treatment with at least one of the three treatment arms of our study,
• patients with any history of bipolar disorder or psychosis (diagnosed by MINI),
• patients with active alcohol or substance abuse disorders within the past 6 months (diagnosed by MINI),
• patients with suicidal ideation of the degree that, in the opinion of the evaluating clinician, participation in the study would place them at significantly increased risk of suicide,
• patients with unstable medical issues of such degree that, in the opinion of the evaluating clinician, participation in the study would place them at significant risk of a serious adverse event, or patients with a screening hemoglobin A1c level greater than 7.5%, or patients with epilepsy, dementia, Parkinson's disease, or Huntington's Disease,
• patients who have received treatment with vagus nerve stimulation (VNS),
• patients who have not responded to more than five FDA-approved antidepressant treatment trials of adequate dose and duration during the current episode, or who did not respond to ECT in previous episodes
• patients on excluded medications,
• patients with a positive urine screen drug test for a substance for which they do not have a valid prescription for a valid medical reason,
• patients with currently abnormal thyroid function tests,
• patients who have received at least one dose of a monoamine oxidase inhibitor (MAOI) four weeks or less prior, and
• for patients on concomitant psychotropic agents (anticonvulsants, benzodiazepines, hypnotics, opiates, triiodothyronine (T3), modafinil, psychostimulants, buspirone, melatonin, omega-3 fatty acids, folate, l-methylfolate, s-adenosyl methionine, lithium) not on the same dose for at least four weeks prior to study entry or who do not agree to continue at the same dose during the acute phase of the study.
• Patients who do not meet safety criteria for TMS: history of seizures, cardiac pacemaker, DBS or VNS, brain aneurism clips or other metallic implants in the intracranial space.

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• Patient-Centered Outcomes Research Institute: collaborator

Study Sites (13)

The University of Alabama School of Medicine

Birmingham, Alabama, 35294, United States

Location

Pacific Institute of Medical Research

Los Angeles, California, 90095, United States

Location

Stanford University

Stanford, California, 94305, United States

Location

University of South Florida

Tampa, Florida, 33613, United States

Location

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

New York University

New York, New York, 10003, United States

Location

University of Cincinnati

Cincinnati, Ohio, 45219, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104, United States

Location

Roper St. Francis Hospital

Charleston, South Carolina, 29425, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390, United States

Location

Baylor College of Medicine

Houston, Texas, 77030, United States

Location

University of British Columbia

Vancouver, British Columbia, Canada

Location

University of Manitoba St. Boniface Hospital

Winnipeg, Manitoba, R2H 2A6, Canada

Location

Related Publications (2)

• Guidetti C, Chaikali S, Trivedi MH, Shelton RC, Iosifescu DV, Thase ME, Jha MK, Mathew SH, DeBattista C, Dokucu ME, Brawman-Mintzer O, Hernandez Ortiz JM, Currier GW, McCall WV, Modirrousta M, Macaluso M, Bystritsky A, Vila-Rodriguez F, Nelson EB, Yeung AS, MacGregor LC, Carmody T, Fava M, Papakostas GI. Comparative Effectiveness Research Trial for Antidepressant Incomplete and Nonresponders With Treatment Resistant Depression (ASCERTAIN-TRD): Effect of Aripiprazole or Repetitive Transcranial Magnetic Stimulation Augmentation Versus Switching to the Antidepressant Venlafaxine on Quality of Life. J Clin Psychiatry. 2025 Aug 11;86(3):24m15614. doi: 10.4088/JCP.24m15614.

  PMID: 40801757 DERIVED

• Papakostas GI, Trivedi MH, Shelton RC, Iosifescu DV, Thase ME, Jha MK, Mathew SJ, DeBattista C, Dokucu ME, Brawman-Mintzer O, Currier GW, McCall WV, Modirrousta M, Macaluso M, Bystritsky A, Rodriguez FV, Nelson EB, Yeung AS, Feeney A, MacGregor LC, Carmody T, Fava M. Comparative effectiveness research trial for antidepressant incomplete and non-responders with treatment resistant depression (ASCERTAIN-TRD) a randomized clinical trial. Mol Psychiatry. 2024 Aug;29(8):2287-2295. doi: 10.1038/s41380-024-02468-x. Epub 2024 Mar 7.

  PMID: 38454079 DERIVED

MeSH Terms

Interventions

Aripiprazole; Transcranial Magnetic Stimulation; Venlafaxine Hydrochloride

Intervention Hierarchy (Ancestors)

Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolones; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Magnetic Field Therapy; Therapeutics; Cyclohexanols; Hexanols; Fatty Alcohols; Alcohols; Organic Chemicals; Phenethylamines; Ethylamines; Amines; Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Lipids

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Scientific Director, MGH Clinical Trial Network and Institute (CTNI)

Study Record Dates

• First Submitted: November 28, 2016
• First Posted: November 30, 2016
• Study Start: May 1, 2017
• Primary Completion: April 24, 2022
• Study Completion: April 24, 2022
• Last Updated: April 27, 2022

Record last verified: 2022-04

Data Sharing

• IPD Sharing: Will not share

Locations

CA (2); US (11)