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Research highlights role of neurotransmission system within placebo effects

Results from a crossover randomized clinical trial of two identical oral placebos among individuals with major depressive disorder show a placebo-induced activation of the μ-opioid system, suggesting that placebo effects may occur in clinical trials.

“High rates of placebo responses are consistently reported across medical conditions, notably mood disorders, Parkinson’s disease, and pain, but also schizophrenia, substance use disorders, and surgical procedures. Placebo response rates in antidepressant trials average 31% to 45% compared with approximately 50% responses to antidepressants, and they have increased over the last 30 years,” Marta Peciña, MD, PhD, University of Michigan, Ann Arbor, and colleagues wrote. “The failure of antidepressant responses to separate from placebo has contributed to the reduction or discontinuation of research on new treatments for depression and other neuropsychiatric illnesses, hindering the development of novel neuropsychiatric treatments.”

Marta Peciña

To assess neurochemical mechanisms underlying placebo effects among individuals with major depressive disorder (MDD), researchers conducted a single-blinded 2-week crossover trial of two placebos followed by a 10-week open-label treatment with an antidepressant. The study cohort included 35 medication-free patients with MDD. Researchers used positron emission tomography and carfentanil after each 1-week inactive and active oral placebo treatment.

Higher baseline μ-opioid receptor binding in the nucleus accumbens was associated with a better response to antidepressant treatment (P = .02).

Reductions in depressive symptoms after 1 week of active placebo treatment were associated with increased placebo-induced μ-opioid neurotransmission in the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus and amygdala (nucleus accumbens: P < .001).

Better antidepressant treatment response was associated with placebo-induced endogenous opioid release in these regions and predicted 43% of symptom improvement variance at the end of the antidepressant trial.

“The identification of a biological response, namely, a modulation of μ-opioid neurotransmission, to placebo exposure among patients with MDD is consistent with the view that placebo treatment can, in fact, induce robust neurobiological changes and that the brain responds to this type of intervention in a way that is quite robust and leads to changes in brain functioning,” Maurizio Fava, MD, of Massachusetts General Hospital, Harvard Medical School, Boston, wrote in an accompanying editorial. “These findings appear to provide an additional rationale for the use of open-label placebo as a possible first-line treatment for depression. Therefore, in addition to the traditional rationales — such as double-blind placebos being roughly 80% as effective as antidepressants in randomized clinical trials, classic conditioning being a possible mechanism for automatic self-healing, and positive expectations increasing placebo effects — the evidence of an actual biosignature of the effect of placebo in MDD may provide patients with MDD with the demonstration that placebos can be actually active treatments in their condition.” – by Amanda Oldt

Disclosure: Peciña reports no relevant financial disclosures. Please see the full study for a list of all authors’ relevant financial disclosures.