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. In the meantime, results have been published in peer-reviewed journals, as listed below.

What is the research about?

Major depression is a serious health problem that affects tens of millions of adults in the United States. Major depression affects the brain and causes severe symptoms that influence how people think, feel, and handle daily activities such as sleeping, eating, and working.

Major depression is common among older adults. More than half of older adults who are diagnosed with major depression don’t get better even after trying two or more antidepressant medicines. These adults have treatment-resistant depression. Older adults who have treatment-resistant depression are at higher risk for disability, suicide, or death.

Although there are several treatment options for patients with treatment-resistant depression, research hasn’t compared their benefits and risks for older adults. Knowing how benefits and risks may change as people get older can help lead to personalized treatment for older adults.

This research study compares how well different types and combinations of medicines work for adults aged 60 years and older who have treatment-resistant depression.

Who can this research help?

Information from this study can help older adults who have treatment-resistant depression and their doctors choose a treatment or combination of treatments.

What is the research team doing?

The research team is enrolling 1,500 older adults with major depression that has not gotten better after treatment with at least two antidepressant medicines. The study takes place at five medical centers across the United States and Canada.

The study has two phases; each phase is 10 weeks long. In the first phase, the research team is assigning patients by chance to one of three groups. Patients in two of the groups are each adding one of two medicines (aripiprazole or bupropion) to the one they currently take. Patients in a third group are replacing their current medicine with another medicine (buproprion). Patients who are still depressed after the first phase move to the second phase. In the second phase, the research team is assigning these patients by chance to either add another medicine (lithium carbonate) to the one they already take or switch to a different medicine (nortriptyline). Patients continue to take the medicine or combination that works for them.

The research team is following all patients for one year. The research team is looking at the medicines’ long-term effects on patients’ well-being, severity of depression, serious health problems, falls, and mental and physical functioning.

A group of patients, family members, and healthcare professionals is advising the research team throughout the project. Patients and healthcare professionals also are helping to recruit participants. The research team is interviewing patient advisors about their experiences with medicines throughout the study.

Research methods at a glance

Design Element Description
Study Design Randomized controlled trial
Population Adults aged 60 years and older who have major depression that hasn’t responded to at least 2 different antidepressant medicines

Phase 1:

  • Take current antidepressant and aripiprazole
  • Take current antidepressant and bupropion
  • Switch current antidepressant to bupropion

Phase 2: (Only for patients who remain depressed following Phase 1)

  • Take current antidepressant and lithium carbonate
  • Switch current antidepressant to nortriptyline

Primary: psychological well-being scores, depression scores, life-threatening illness, hospitalization, or need of medical care

Secondary: number of falls, injuries from falls, mental and physical functioning

Timeframe Timeframe Length of follow-up for collecting data on primary outcomes. View Glossary 12-month follow-up for primary outcomes

Project Information

Eric Juckeland Lenze, MD
Washington University School of Medicine
Optimizing Outcomes in Treatment-Resistant Depression in Older Adults

Key Dates

July 2016
September 2023

Study Registration Information


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 22, 2023