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 trying two or more antidepressants, is adding another treatment better or worse than switching to a new one? To help answer this question, PCORI launched a funding initiative in 2015 called 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. In the meantime, results have been published in peer-reviewed journals, as listed below.

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 more than just feeling sad or blue for a few days.

People with depression can

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

One in three adults with major depression does not feel better even after treatment with antidepressant medicines. When antidepressants don’t help, people have a form of major depression called treatment-resistant depression. People with treatment-resistant depression are at risk of alcohol use, drug use, hospitalization, and suicide attempts.

This study compares electroconvulsive therapy (ECT) and the medication ketamine to see which works best for adults with treatment-resistant depression. ECT, sometimes called shock therapy, is an effective treatment for adults with treatment-resistant depression. But people may feel ashamed about getting ECT or may not like its side effects, such as memory problems. They may also dislike receiving anesthesia to become unconscious to get ECT or suffering memory loss from the treatment. Ketamine has no effects on memory and is given when a person is awake, but it may have other side effects and is not a standard treatment for depression.

Who can this research help?

This study can help people with major depression that does not get better after they take multiple antidepressants. The results may help these people and their doctors choose a new treatment.

What is the research team doing?

The research team is comparing two ways to treat adults with treatment-resistant depression. One treatment is ECT. During ECT, a person gets medicine to make them sleep, and a small amount of electrical current passes through the brain, causing a seizure. The seizure causes chemical changes in the brain that can help relieve depression.

The second treatment in this study is a medicine called ketamine. A doctor injects ketamine in small doses. People are awake while receiving ketamine, and it does not cause memory loss. However, ketamine is normally used to prevent and manage pain, not as a standard treatment for depression. So, its safety and effectiveness for treating severe depression are unknown. Ketamine can also cause some side effects, people can abuse it. Ketamine is not covered by insurance.

The research team is involving volunteers whose doctors have referred them for ECT treatment. Patients in the study agree to be assigned by chance to receive one of the two treatments—either ketamine twice a week or ECT three times a week—for three weeks. Patients report changes in their depression symptoms, memory, and quality of life. The research team is also asking patients’ doctors how they rate the patients’ depression. The team follows patients whose depression gets better after receiving ECT or ketamine for six months. The research team tracks how these patients feel after they return to their regular doctors.

The research team is designing and running the study with input from people with major depression, patient advocacy groups, healthcare professionals, and organizations that pay for health care. A committee of these individuals is advising the research team and monitoring the study’s progress.

Research methods at a glance

Design Element Description
Design Randomized controlled trial
Population Adults ages 21 to 75 years who have a diagnosis of depression and who have had at least 2 adequate trials of antidepressant treatment during their lifetime.
  • Electroconvulsive therapy
  • Ketamine

Primary: self-reported change in depressive symptoms, memory function, and quality of life

Secondary: scores on depression measurement scales

Timeframe Timeframe Length of follow-up for collecting data on primary outcomes. View Glossary 3 weeks or end of treatment period for primary outcomes

Project Information

Amit Anand, MD^
Cleveland Clinic Foundation
Electroconvulsive Therapy versus Ketamine for Treatment Resistant Depression

Key Dates

July 2016
March 2024

Study Registration Information

^Principal Investigator Amit Anand, MD—who is at Mass General Brigham/Harvard Medical School in Massachusetts as of May 2023—was at Cleveland Clinic in Ohio when the study was funded.


Has Results
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: March 14, 2024