Placebos may predict if antidepressants will work

"If 40 percent of people recover from a chronic illness without a medication, I want to know why," says Marta Zubieta. "And if you respond to a medication and half your response is due to a placebo effect, we need to know what makes you different from those who don't respond as well." (Credit: iStockphoto)

When it comes to treating depression, how well a person responds to a placebo may determine how well they’ll respond to a real medication, new research finds.

People who can muster their brain’s own chemical forces against depression may have a head start in overcoming its symptoms with help from medicine. On the contrary, those whose brain chemistry doesn’t react as much to a placebo will usually struggle even after getting an active drug.

The findings help explain the variation in treatment response and resiliency that confounds depression patients and their care teams. It also opens up the door to research on how to amplify the brain’s natural response in new ways to improve  treatment for the estimated 350 million people worldwide who suffer from depression at any given time.

The findings could also help those developing and testing new drugs to correct for the placebo effect that gets in the way of measuring a drug’s true effect.

In previous research, scientists showed that the brain’s natural “painkiller” system—called the mu-opioid system—responded to pain when patients got a placebo. They’ve also studied the genetic variation that makes certain people more likely to respond to sham painkillers.

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For the new study, published in JAMA Psychiatry, they studied the brain chemistry of 35 people with untreated major depression, who agreed to try what they thought was a new depression drug, before receiving actual drugs already approved to treat depression.

Participants who reported improvement of depression symptoms after getting the placebo also had the strongest mu-opioid response in brain regions involved in emotion and depression. And these individuals were also more likely to experience even fewer symptoms once they got a real drug.

In fact, response to placebo predicted nearly half of the variation between individuals in total response to the entire study, including actual drug treatment.

Biomarker for treatment

“This is the first objective evidence that the brain’s own opioid system is involved in response to both antidepressants and placebos, and that variation in this response is associated with variation in symptom relief,” says first author Marta Pecina, a research assistant professor of psychiatry at the University of Michigan.

“This finding gives us a biomarker for treatment response in depression—an objective way to measure neurochemical compounds involved in response. We can envision that by enhancing placebo effects, we might be able to develop faster-acting or better antidepressants.”

The placebo effect in the study came not only from participants’ belief that they were receiving a real drug, but also from the sheer impact of being in a treatment environment, says study leader Jon-Kar Zubieta, formerly at the University of Michigan and now chair of the department of psychiatry at the University of Utah.

Even as scientists work to understand this effect further, clinicians who treat people with depression may want to take heed of the findings, he says.

“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. We need to find out how to enhance the natural resiliency that some people appear to have.”

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Studies testing antidepressants against placebos suggest that 40 percent of response is due to the placebo effect. To drug developers, this is a nuisance. But to placebo researchers, it’s like catnip.

“If 40 percent of people recover from a chronic illness without a medication, I want to know why,” says Zubieta. “And if you respond to a medication and half your response is due to a placebo effect, we need to know what makes you different from those who don’t respond as well.” This could include genetic effects that are still to be discovered.

The findings were made using position emission tomography, or PET, scanning, and a substance that attaches to the receptors on brain cells that mu-opioid molecules bind to. In the single-blind randomized crossover design, the participants went in knowing that they wouldn’t be told full details about the purpose of the study until the end.

They then received two weeks of placebo pill treatment—but during one of those weeks, each was told they were taking a substance that is believed to activate internal mechanisms and may have antidepressant properties. At the end of this week, they also had a brain scan and received an injection of harmless salt water that they were told might have fast-acting antidepressant properties. After these two weeks and scan, they were prescribed a real antidepressant. They reported their depression symptoms using standard measurement scales throughout the study period.

The National Institutes of Health, the Phil F. Jenkins Foundation, and the Michigan Institute for Clinical Health research funded the work.

Source: University of Michigan