October 19, 2015

Placebo Effect in Depression Treatment

At a Glance

  • People with depression who benefited from a placebo showed signature changes in the brain and also responded better to subsequent medication.
  • Gaining a better understanding of how placebos work could lead to the development of more effective therapies for a variety of mental disorders.
Placebo gel capsules. Scientists are exploring how placebos can improve symptoms—even in people who know they’re taking something without real medicine.hanohiki/iStock/Thinkstock

A placebo is a substance, such as a pill or shot, that doesn’t contain any active medicine. Scientists typically use placebos as controls in research studies. This helps them understand how much of a medicine’s effects are due to the drug itself, versus how much are due to participants’ expectations or other factors.

People who are given a placebo may report improvements in symptoms, sometimes even when they know they’re taking something that doesn’t contain real medicine. To better understand the neurochemical mechanisms underlying the placebo effect, a team led by Dr. Jon-Kar Zubieta, formerly at the University of Michigan School of Medicine and now at the University of Utah, examined such effects in depression treatment. The study was funded in part by NIH’s National Institute of Mental Health (NIMH). Results appeared online on September 30, 2015, in JAMA Psychiatry.

The scientists enrolled 35 people with major depression who weren’t taking any medications. In the first phase of the study, the participants were randomly assigned to receive placebo pills that were described as a potentially fast-acting antidepressant (“active” placebo group) or identical pills described as a placebo with no antidepressant effects (“inactive” placebo group). Each group took the pills for a week, and then after a few days, the groups switched.

At the end of each week of treatment, the participants completed a questionnaire about their depression symptoms. They also underwent a PET brain scan to measure the activity of µ-opioid receptors, which are known to be involved in emotion, stress, social rewards, and depression. During the scan, the active placebo group received intravenous doses of saline with the understanding that it might activate brain systems involved in mood improvement. This was done to monitor the acute effects of an active placebo on brain function. The inactive placebo group received no infusions during the scan.

In the second phase of the study, all participants were treated for 10 weeks with antidepressants (usually selective serotonin reuptake inhibitors), and their depression symptoms were monitored. At the end of the study, each person was fully briefed on the study design and use of placebos.

The researchers found that the participants reported significant decreases in depression symptoms when they took the active placebo, compared to when they took the inactive placebo. These reductions were linked to increased µ-opioid receptor brain activity in regions of the brain associated with emotion and stress regulation. Notably, the increased µ-opioid activity induced by the active placebo was also associated with significantly better responses to the subsequent antidepressant treatment.

“These results suggest that some people are more responsive to the intention to treat their depression, and may do better if psychotherapies or cognitive therapies that enhance the clinician-patient relationship are incorporated into their care as well as antidepressant medications,” Zubieta says. “We need to find out how to enhance the natural resiliency that some people appear to have.”

—by Carol Torgan, Ph.D.

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Reference: Association Between Placebo-Activated Neural Systems and Antidepressant Responses: Neurochemistry of Placebo Effects in Major Depression. Peciña M, Bohnert AS, Sikora M, Avery ET, Langenecker SA, Mickey BJ, Zubieta JK. JAMA Psychiatry. 2015 Sep 30:1-8. doi: 10.1001/jamapsychiatry.2015.1335. [Epub ahead of print]. PMID: 26421634.

Funding: NIH'’s National Institute of Mental Health (NIMH), Phil F. Jenkins Foundation, and Michigan Institute for Clinical & Health Research.