Working out for mental health

Researchers identify proteins that may predict effectiveness of exercise on depression


By Russell Rian

Could a simple blood test eventually determine whether exercise would help reduce symptoms of depression better than antidepressant medications? 

Dr. Madhukar Trivedi’s research identified proteins that may predict whether a depressive person is responding to workouts or medication.
Dr. Madhukar Trivedi’s research identified proteins that may predict whether a depressive person is responding to workouts or medication.

That’s the hope of UT Southwestern Medical Center psychiatrists who have identified specific signaling proteins found in blood cells that may predict whether a depressive person will respond better to workouts or medications.

UTSW psychiatrists tracked specific cytokines – messenger proteins in blood cells that tell the cell what to do and generally boost the body’s immune response. The researchers found that people with higher levels of these cytokines had greater decreases in depression symptoms after exercising, while other cytokines predicted a poor response to antidepressant medications.

Their TREAD (Treatment with Exercise Augmentation for Depression) investigation is available in Molecular Psychiatry, a journal of Nature.

“These initial findings showed that higher levels of pro-inflammatory cytokines may predict better outcomes with exercise therapy for depression for people with a poor response to anti-depressant medications,” said Dr. Madhukar Trivedi, Professor of Psychiatry and Director of the Depression Center at UT Southwestern. “It is an important step in identifying the biological responses that could eventually help us predict how to guide depression treatments and personalize treatments.”

In 2005, Dr. Trivedi and his team conducted the first study to look at exercise alone in treating mild to moderate depression. That study showed that depressive symptoms were reduced almost 50 percent in individuals who participated in 30-minute aerobic exercise sessions three to five times a week.  In that trial, researchers also noted that the effect of aerobic exercise alone in treating clinical depression is similar to that found with antidepressant medications.

Dr. Trivedi, who leads the Mood Disorders Research Program and Clinic at UT Southwestern, also is a principal investigator of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study – the largest investigation on the treatment of major depressive disorder and considered a benchmark in the field of depression research – and the National Drug Abuse Treatment Clinical Trials Network for Texas.

Dr. Trivedi and his lab team are now hunting for biomarkers, such as cytokines, that reveal the biological foundations of those reactions to different therapy. Their ongoing work in the EMBARC (Establishing Moderators and Biosignatures of Antidepressant Response for Clinical Care) investigation eventually could help psychiatrists offer each person a custom-tailored treatment plan to which he or she is likely to respond best.

UT Southwestern researchers plan to enroll about 100 of the 400 people needed for the EMBARC study, which is funded by the National Institute of Mental Health and includes researchers at Columbia University in New York, Massachusetts General Hospital in Boston, and the University of Michigan in Ann Arbor.

“We are aggressively seeking the biological indicators that can help us guide patients to the best treatment for their depression, and these latest findings give us further hope that we’re on the right track,” said Dr. Trivedi, a principal investigator for EMBARC.

The published TREAD study results followed patients before and after 12-week exercise regimes. Specifically, researchers found that:

  • Higher baseline levels of tumor necrosis factor alpha (TNF-a) showed a greater decrease in depression symptoms after a 12-week exercise regime. 
  • High TNF-a levels have been linked to poor response to antidepressant medications. 
  • Decreased levels of Interleukin-1 Beta (IL-1ß) from antidepressant medications were associated with better depression outcomes.

Other researchers involved in the study were Dr. Chad Rethorst, Assistant Professor of Psychiatry and lead author; Dr. Tracy Greer, Assistant Professor of Psychiatry; Dr. Marisa Toups, postdoctoral trainee in Psychiatry; Dr. Thomas Carmody, Associate Professor of Psychiatry and Clinical Sciences; Bruce Grannemann, Faculty Associate in Psychiatry; Dr. Ryan Huebinger, Instructor of Surgery; and Dr. Robert Barber, Associate Professor of Pharmacology and Neuroscience at the University of North Texas Health Science Center.

More information on the EMBARC trial can be found at


Dr. Trivedi holds the Betty Jo Hay Distinguished Chair in Mental Health.