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

June 12, 2026 updated by: George I. Papakostas, Massachusetts General Hospital

Augmentation Versus Switch: Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders With Treatment Resistant Depression (ASCERTAIN-TRD)

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

278

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada
        • University of British Columbia
    • Manitoba
      • Winnipeg, Manitoba, Canada, R2H 2A6
        • University of Manitoba St. Boniface Hospital
  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • The University of Alabama School of Medicine
    • California
      • Los Angeles, California, United States, 90095
        • Pacific Institute of Medical Research
      • Stanford, California, United States, 94305
        • Stanford University
    • Florida
      • Tampa, Florida, United States, 33613
        • University of South Florida
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University, Feinberg School of Medicine
    • New York
      • New York, New York, United States, 10003
        • New York University
    • Ohio
      • Cincinnati, Ohio, United States, 45219
        • University of Cincinnati
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • University of Pennsylvania
    • South Carolina
      • Charleston, South Carolina, United States, 29425
        • Roper St. Francis Hospital
    • Texas
      • Dallas, Texas, United States, 75390
        • University of Texas Southwestern Medical Center
      • Houston, Texas, United States, 77030
        • Baylor College of Medicine

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

14 years to 76 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  1. women and men ages 18-80,
  2. 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),
  3. 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,
  4. 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,
  5. 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.
  6. Patients who have passed the MGH CTNI remote assessment, with documentation provided to sites by MGH CTNI.

Exclusion Criteria:

  1. 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,
  2. patients who have received treatment with rTMS, aripiprazole, electroconvulsive therapy (ECT), or venlafaxine during the current episode,
  3. patients who express an objection to receiving treatment with at least one of the three treatment arms of our study,
  4. patients with any history of bipolar disorder or psychosis (diagnosed by MINI),
  5. patients with active alcohol or substance abuse disorders within the past 6 months (diagnosed by MINI),
  6. 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,
  7. 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,
  8. patients who have received treatment with vagus nerve stimulation (VNS),
  9. 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
  10. patients on excluded medications,
  11. 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,
  12. patients with currently abnormal thyroid function tests,
  13. patients who have received at least one dose of a monoamine oxidase inhibitor (MAOI) four weeks or less prior, and
  14. 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.
  15. 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.
  16. Also excluded is an individual who has received any administration of ketamine in the current episode for the treatment of depression.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Aripiprazole Augmentation
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
Oral adjunctive therapy with aripiprazole, dose adjusted for effectiveness and tolerability.
Other Names:
  • Abilify
Experimental: rTMS Augmentation
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)
Adjunctive therapy with transcranial magnetic stimulation, dose adjusted for effectiveness and tolerability.
Experimental: Switching To Venlafaxine XR
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
Oral switch therapy with venlafaxine, dose adjusted for effectiveness and tolerability.
Other Names:
  • Effexor XR

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Montgomery-Asberg Depression Rating Scale (MADRS)
Time Frame: 8 weeks
The Montgomery-Åsberg Depression Rating Scale (MADRS) is a clinician-rated scale that assesses the severity of depressive symptoms. The scale consists of 10 items evaluating apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts, and suicidal thoughts. Each item is scored from 0 to 6. Item scores are summed to calculate a total MADRS score ranging from 0 to 60, with higher scores indicating more severe depressive symptoms and a worse outcome.
8 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Quality of Life, Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF)
Time Frame: 8 weeks
The Quality of Life Enjoyment and Satisfaction Questionnaire - Short Form (Q-LES-Q-SF) is a self-reported assessment tool used to evaluate an individual's degree of enjoyment and satisfaction across various areas of daily functioning. The questionnaire assesses domains such as physical health, mood, work, household activities, social relationships, leisure activities, and overall well-being. The short form consists of 16 items, with respondents rating their level of satisfaction and functioning over the past week. The first 14 items are summed to generate a total raw score ranging from 14 to 70, with higher scores indicating greater life satisfaction and better quality of life. Raw scores may also be converted to a percentage of the maximum possible score, ranging from 0% to 100%, to facilitate interpretation and comparison across studies. The final two items assess overall medication satisfaction and overall life satisfaction and are typically analyzed separately rather than included
8 weeks

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Massachusetts General Hospital Cognitive and Physical Symptoms Questionnaire (MGH CPFQ)
Time Frame: 8 weeks
The Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (MGH CPFQ) is a self-reported assessment tool designed to evaluate cognitive and physical symptoms commonly associated with depression and its treatment. The questionnaire assesses areas such as motivation, wakefulness, energy, focus, memory, mental sharpness, and physical well-being. The instrument consists of 7 items, each rated on a 6-point scale from 1 (greater than normal functioning) to 6 (totally absent or severe impairment). Item scores are summed to generate a total score ranging from 7 to 42, with higher scores indicating greater impairment in cognitive and physical functioning. The MGH CPFQ is widely used in clinical research to assess functional deficits associated with depression and to monitor changes in cognitive and physical symptoms during treatment.
8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Massachusetts General Hospital

Collaborators

Patient-Centered Outcomes Research Institute

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 13, 2017

Primary Completion (Actual)

April 24, 2022

Study Completion (Actual)

April 24, 2022

Study Registration Dates

First Submitted

November 28, 2016

First Submitted That Met QC Criteria

November 29, 2016

First Posted (Estimated)

November 30, 2016

Study Record Updates

Last Update Posted (Actual)

July 9, 2026

Last Update Submitted That Met QC Criteria

June 12, 2026

Last Verified

June 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2015P002430

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Subscribe