Results Summary

What was the research about?

Depression makes people feel sad, hopeless, or empty. Depression that doesn’t get better even after trying two or more medicines is called treatment-resistant depression. Older adults with treatment-resistant depression are at high risk for suicide, disability, or death.

In this study, the research team compared different approaches to treat treatment-resistant depression in older adults. The study had two steps; each step was about 10 weeks long.

In step 1, the research team compared three approaches:

  • Keeping current depression medicine and adding aripiprazole
  • Keeping current depression medicine and adding bupropion
  • Switching from current depression medicine to bupropion alone

Step 2 included patients who didn’t feel better after step 1, plus some new patients. In this step the research team compared two approaches:

  • Keeping current depression medicines and adding lithium
  • Switching current depression medicines to nortriptyline alone

The research team wanted to learn which medicines worked best to improve patients’ well-being, depression, and social and physical activity. The team also looked at the risk of adverse events such as falls, serious illness, or going to the hospital.

What were the results?

Step 1. Overall, at 10 weeks, adding aripiprazole or bupropion was more effective than switching to bupropion alone and just as safe. Compared with patients who switched to bupropion alone, patients who added aripiprazole or bupropion had:

  • More improved well-being and depression
  • A similar number of adverse events
  • Similar changes to social and physical activities

Patients who added bupropion had more falls than patients who added aripiprazole.

Step 2. The study found no differences between patients who added lithium and patients who switched to nortriptyline alone.

Who was in the study?

The study included 742 patients ages 60 and older with treatment-resistant depression. Of the 619 patients in step 1, 84 percent were White, 7 percent were Black, and 8 percent were another race; 8 percent were Hispanic. The average age was 69, and 67 percent were women. Among the 248 patients in step 2, 90 percent were White, and 70 percent were women.

What did the research team do?

The research team assigned patients by chance to one of the three treatment approaches in step 1 and one of the two approaches in step 2. Patients’ doctors decided how much medicine they took, if they should also take other medicines, and if they should stop the medicines at any time. The team surveyed patients every 2 weeks for 10 weeks.

Patients, family caregivers, and clinicians gave input throughout the project.

What were the limits of the study?

Because fewer than the planned 1,500 patients took part in the study, the research team may not have been able to detect all differences between groups. Most patients were White women. Results may differ for patients of other backgrounds.

Future studies could look at other medicines to treat depression in older adults.

How can people use the results?

Older patients and their doctors can use these results when considering ways to treat treatment-resistant depression.

How this project fits under PCORI’s Research Priorities
PCORI identified treatment-resistant depression as an important research topic. Patients, clinicians, and others wanted 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 an initiative in 2015 on Management Strategies for Treatment-Resistant Depression. The initiative funded this research project and others.

Final Research Report

This project's final research report is expected to be available by July 2024.

Peer-Review Summary

Peer review of PCORI-funded research helps make sure the report presents complete, balanced, and useful information about the research. It also assesses how the project addressed PCORI’s Methodology Standards. During peer review, experts read a draft report of the research and provide comments about the report. These experts may include a scientist focused on the research topic, a specialist in research methods, a patient or caregiver, and a healthcare professional. These reviewers cannot have conflicts of interest with the study.

The peer reviewers point out where the draft report may need revision. For example, they may suggest ways to improve descriptions of the conduct of the study or to clarify the connection between results and conclusions. Sometimes, awardees revise their draft reports twice or more to address all of the reviewers’ comments. 

Peer reviewers commented and the researchers made changes or provided responses. Those comments and responses included the following:

  • The reviewers expressed concerns about the interpretation of the results for step 1 and step 2 because recruitment fell short of the target, compromising statistical power. They suggested softening the study conclusions to better reflect this limitation. In response, the authors revised the study limitations and actionable findings sections of the report. They stated that even though the study had greater than 80 percent power based upon revised power calculations, tests of effectiveness and safety may have been underpowered as the trial did not reach its originally intended sample size. 
  • The reviewers suggested revisions to the report’s abstract. They asked the authors to provide one or two of the most important findings instead of general statements about the qualitative findings. They further asked the authors to provide sample characteristics and the effect estimates for psychological well-being. The authors revised the abstract, providing patient characteristics and effect estimates for psychological well-being. They also added some of the findings from their qualitative analyses to the abstract.
  • The reviewers pointed out that there are other viable treatments for treatment-resistant depression that were not tested in this study and asked the authors to address these alternative treatments. This would provide a more complete rationale for the specific pharmacological treatments tested in this study. The researchers added information to their background section about potential psychotherapeutic and psychiatric alternatives or augmentations, and why they chose to test the specific medications they did in this study.
  • The reviewers requested to provide the minimum clinically important difference (MCID) for each outcome with citations to support these numbers. The authors made revisions to the methods section of the report and added text and references for the MCIDs for the National Institutes of Health Toolbox and Patient-Reported Outcome Measurement Information Systems (PROMIS)measures.
  • The reviewers asked the researchers to address the limitation of blinding only outcome assessors to the treatment assignments in the discussion section. The authors updated the study limitations of the discussion section to state that participants were not blinded to their treatment assignment and therefore the results might be biased. 

Conflict of Interest Disclosures

Project Information

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

Key Dates

July 2016
December 2022

Study Registration Information


Has Results
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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
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Last updated: April 15, 2024