Results Summary

What was the research about?

Posttraumatic stress disorder, or PTSD, is a mental health problem that can occur after a traumatic event. To manage PTSD symptoms, patients may take a serotonin reuptake inhibitor, or SRI. SRIs are a type of medicine often used to treat depression. If patients continue to have symptoms, doctors may add other types of medicine. It’s unclear how much these medicines help PTSD symptoms. They may cause other problems, such as weight gain or heart disease.

In this study, the research team compared health records of patients with PTSD who were taking an SRI and received a prescription for one of four types of additional medicine:

  • An atypical antipsychotic, usually used to treat schizophrenia and other psychotic disorders
  • Prazosin, usually used to treat high blood pressure
  • Mirtazapine, usually used to treat depression
  • A tricyclic antidepressant, usually used to treat depression

The research team compared the mental and physical health of patients before and after they received prescriptions for these medicines.

What were the results?

Mental health. Patients receiving prescriptions for each of the medicines showed improved mental health. They had

  • Very small decreases in PTSD symptoms
  • Fewer hospital stays or emergency room visits for a mental health problem
  • Fewer thoughts of suicide

Most patients received prescriptions for the new medicine after their mental health problems got worse. Three to four months after receiving a prescription, mental health problems usually went back to earlier levels but didn’t continue to improve.

Physical health. Some health problems increased after patients received one of the four types of medicine. Health problems were more common for mirtazapine and least common for prazosin. For example,

  • Weight gain and new cases of high cholesterol, high blood pressure, and high blood sugar were more common for patients prescribed mirtazapine and antipsychotics and less common for patients prescribed prazosin.
  • Patients prescribed prazosin were less likely to get heart disease, have a heart attack or stroke, or die compared with patients prescribed the other types of medicine.

What did the research team do?

The research team looked at health records for 169,982 patients with PTSD. Of these, 74 percent were White, 19 percent were Black, 7 percent were another race, and 7 percent were Hispanic. The average age was 52, and 90 percent were men. All received care from the US Department of Veterans Affairs, or VA.

The research team compared patient health in the year before versus the year after adding a medicine. The team looked at patient traits, such as age or gender, which could affect the results.

Patients, clinicians, veterans’ groups, and other groups gave input throughout the study.

What were the limits of the study?

Because the study didn’t assign patients by chance to add the different types of medicine, other factors may have affected the study results. Most patients in the study were men. All received care at the VA. Results may differ for patients from other backgrounds.

Future research could assign patients by chance to add one of the types of medicine.

How can people use the results?

Patients with PTSD and their doctors can use the results when considering treatment for PTSD.

Final Research Report

View this project's final research report.

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 noted that the report presented a large number of subgroup analyses, which could increase the risk of identifying a false positive result. The researchers agreed and indicated that most of these analyses were exploratory. Therefore, the researchers focused their subgroup analyses on the primary outcomes only, removing some of the results and discussion related to the subgroup analyses on secondary outcomes.
  • The reviewers noted that an individual patient might be prescribed additional medication more than once, so they asked whether one patient could contribute multiple times to the study, which lasted eight years. The researchers said individual patients could contribute more than one augmenting medication episode because polypharmacy is common in patients with posttraumatic stress disorder so patients might receive augmenting medication in more than one medication category. To make sure that including multiple episodes from the same patient would not bias their analyses, the researchers explained that they conducted sensitivity analyses that showed that restricting patients to contributing an episode to a single medication class did not lead to substantial differences in results.
  • The reviewers suggested that a weakness of the study was the analysis of just three antipsychotic medications despite the large number of medications available in this category, and in particular the increasing use of medications that do not promote weight gain. The researchers agreed that it would be helpful to examine additional medications in future studies, but said they were asked to focus on a relatively small number of agents when they designed the study so they could better examine comparative effectiveness. The researchers said they chose to analyze the antipsychotic medications that were most widely used within the Veterans Health Administration during the study period and had the most clinical trial evidence for potential benefit for posttraumatic stress disorder.
  • The reviewers noted that the researchers only counted episodes of adjunctive medication when the medication was taken for at least 60 days and would therefore, miss trials of medication that ended early due to side effects. The researchers acknowledged in the limitations section that their data collection missed these early discontinuation cases, but that this was because the researchers felt they needed at least 60 days of medication use to evaluate the impact of these medications on mental health and metabolic outcomes. 

Conflict of Interest Disclosures

Project Information

Beth Cohen, MD, MAS
University of California San Francisco
Improving Care for Veterans with PTSD: Comparative Effectiveness of Medications to Augment First-line Pharmacotherapy

Key Dates

April 2016
March 2021

Study Registration Information


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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: December 16, 2022