Project Summary

PCORI has identified treatment-resistant depression as an important research topic. Patients, clinicians, and others want to learn: For patients whose depression has not gotten better after using two types of antidepressants, is it better to add another treatment or switch to a new one? To help answer this question, PCORI launched a funding initiative in 2015 on Management Strategies for Treatment-Resistant Depression. This research project is one of the studies PCORI awarded as part of this program.

This research project is in progress. PCORI will post the research findings on this page within 90 days after the results are final.

What is the research about?

Major depression is a serious medical illness that affects tens of millions of adults in the United States. Major depression is a disorder of the brain and is more than just feeling sad or blue for a few days. Adults with major depression can

  • Feel sad or empty
  • Lose interest in their favorite activities
  • Eat and sleep more or less than they usually do
  • Feel hopeless, irritable, anxious, or guilty
  • Have physical symptoms such as aches, pains, tiredness, headaches, cramps, or digestive problems
  • Think about death or suicide

One in three people with major depression don’t get better even after trying two or more antidepressant medicines. These people are considered to have a form of major depression called treatment-resistant depression. Although there are several treatment options for people with treatment-resistant depression, few research studies have directly compared their benefits and risks.

Who can this research help?

Information from this study can help adults with treatment-resistant depression and their doctors choose a treatment.

What is the research team doing?

The research team is recruiting patients from 10 university hospitals across the United States. Working with the hospitals in different parts of the country allows the research team to involve a mix of patients with different characteristics. Patients in the study have depression that has lasted at least 12 weeks and that has not gotten better after they took at least two different first-line antidepressant medicines. Patients must be on an antidepressant medicine that they have taken for at least eight weeks. The research team is assigning patients by chance to receive one of three treatments that the Food and Drug Administration has approved for treatment-resistant depression.

  • For one group of patients, doctors are adding a treatment called repetitive transcranial magnetic stimulation (rTMS) to the antidepressant medicine each patient currently takes. During rTMS, a magnet above a patient’s head painlessly stimulates brain cells to improve depression symptoms. Patients in this treatment group are receiving rTMS five times a week for the first five weeks and twice a week for the next three weeks.
  • For the second group of patients, doctors are adding a second medicine, aripiprazole, to each patient’s current medicine.
  • For the third group of patients, doctors are switching from their current antidepressant medicines to a different medicine, venlafaxine.

All patients visit a doctor once to start treatment and go to weekly visits for eight weeks. During that time, the research team calls patients each week to ask about their depression symptoms and quality of life. After the eight weeks, patients continue with their treatment and complete online surveys once per month for a year to report on their depression symptoms, ability to do daily tasks at work and home, and quality of life.

The research team is involving patients in designing the study, performing roles such as selecting outcomes and treatments. The team is interacting regularly with an advisory board of patients, family members, healthcare professionals, insurance companies, policy makers, and others who have personal or professional experience with depression.

Research methods at a glance

Design Element Description
Study Design Randomized controlled trial
Population Adults who are 18 to 80 years old, have depression that has lasted at least 12 weeks and has not responded to at least 2 different antidepressant medicines, and have a current antidepressant medicine that they have taken for at least 8 weeks
  • Current (ineffective) antidepressant plus repetitive transcranial magnetic stimulation (rTMS)
  • Current (ineffective) antidepressant plus aripiprazole
  • Venlafaxine instead of current (ineffective) antidepressant

Primary: self-reported depression symptoms

Secondary: functioning at work and home, quality of life

Timeframe 8-week follow-up for primary outcome

Project Information

George Papakostas, MD
Massachusetts General Hospital
Switching versus Augmentation in Treatment-Resistant Depression^

Key Dates

July 2016
May 2023

Study Registration Information

^This project was previously titled: Augmentation versus Switch: Comparative Effectiveness Research Trial for Antidepressant Incomplete and Non-responders with Treatment Resistant Depression (ASCERTAIN-TRD)


Award Type
Health Conditions Health Conditions These are the broad terms we use to categorize our funded research studies; specific diseases or conditions are included within the appropriate larger category. Note: not all of our funded projects focus on a single disease or condition; some touch on multiple diseases or conditions, research methods, or broader health system interventions. Such projects won’t be listed by a primary disease/condition and so won’t appear if you use this filter tool to find them. View Glossary
Populations Populations PCORI is interested in research that seeks to better understand how different clinical and health system options work for different people. These populations are frequently studied in our portfolio or identified as being of interest by our stakeholders. View Glossary
Intervention Strategy Intervention Strategies PCORI funds comparative clinical effectiveness research (CER) studies that compare two or more options or approaches to health care, or that compare different ways of delivering or receiving care. View Glossary
State State The state where the project originates, or where the primary institution or organization is located. View Glossary
Last updated: October 18, 2023