How the placebo effect can help develop new treatments for depression


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Depression is among the least understood medical conditions and, as a result, one of the hardest to treat effectively. Now, a new study at the University of Michigan Medical School hints that the degree to which a person responds to a fake medicine may actually determine how well they'll respond to a real one.


Natural resistance


According to the researchers, there is a direct positive correlation between the brain's inherent ability to fight depression and the way it responds to treatment. The study suggests those whose own natural chemical forces can fight symptoms of depression effectively when a placebo is taken already have an in-built advantage in overcoming symptoms with help from an active medication. Those whose brain chemistry doesn't react as well to a placebo, on the other hand, may not do as well with the real thing.

The discovery could open doors to new research on how to amplify the brain's natural response and so improve treatment for the estimated 350 million people worldwide who suffer with depression. The findings — published in the journal JAMA Psychiatry — could help those developing and testing new drugs, helping them correct for the placebo effect that often distorts the way a drug's true effect is measured and could also help explain the variation in treatment response and resiliency that affects depression patients and their care teams.


A history of pain


The scientists at Michigan, who have studied the so-called "placebo effect" for more than a decade, use sophisticated brain scanning techniques in healthy people. They previously pioneered research into the brain's natural "painkiller" system — called the mu-opioid system — showing how it responds to pain when patients are given a placebo as well as the genetic variation that makes certain people more likely to respond to sham painkillers.

For the new study, the scientists looked at the brain chemistry of 35 people with untreated major depression. First, the participants received a placebo that they had been told was a new depression drug — they were then given actual drugs approved for treatment of depression. As the researchers might have expected, participants who reported improvement of their depression symptoms after taking the placebo also had the strongest mu-opioid response. The results showed they were also more likely to experience reduced symptoms once they got the real drug.




"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 lead author Dr. Marta Pecina, research assistant professor in the U-M Department of Psychiatry. "This finding gives us…an objective way to measure neurochemical compounds involved in response," she says. "We can envision that by enhancing placebo effects, we might be able to develop faster-acting or better antidepressants."

The research team was led by Pecina's colleague, Dr. Jon-Kar Zubieta. He says the placebo effect they observed was not just because of participants' belief that they were receiving a real drug — it was also the response to simply knowing they were in a treatment environment. This "self-help," he says, could benefit future treatment methods. "These results," says Zubieta, "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."


Positive response


Clinicians who treat people with depression may find the continuing research useful, says Zubieta. "We need to find out how to enhance the natural resiliency that some people appear to have." Studies testing antidepressants against placebos suggest that 40 percent of recorded response is due to the placebo effect. "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."

In addition to aiding the search for better depression drugs to help those who do not respond as well to placebos, the new study could help identify which patients might benefit from non-drug strategies known to help people who aren't helped by antidepressant drugs. These include electroconvulsive therapy or ECT, deep-brain stimulation or DBS and transcranial magnetic stimulation or TMS. The researchers say they are recruiting people for further brain-scanning studies — if you think you're a good fit, you can click here for more information.