The placebo effect is an unexplained phenomenon wherein drugs, treatments, and therapies that aren’t supposed to have an effect — and are often fake — miraculously make people feel better. What’s going on?
Emma Bryce dives into the mystery of placebos’ bizarre benefits.
How difficult it is to get the truth about questionable drugs
The reanalysis of Study 329 illustrates the necessity of making primary trial data and protocols available to increase the rigour of the evidence base.
Access to primary data from trials has important implications for both clinical practice and research, including that published conclusions about efficacy and safety should not be read as authoritative.
Jon Jueridini and colleagues have reanalysed SmithKline Beecham’ infamous Study 329 (published by Keller and colleagues in 2001), the primary objective of which was to compare the efficacy and safety of paroxetine and imipramine with placebo in the treatment of adolescents with unipolar major depression.
The reanalysis under the restoring invisible and abandoned trials (RIAT) initiative was done to see whether access to and reanalysis of a full dataset from a randomised controlled trial would have clinically relevant implications for evidence based medicine.
Their analysis finds that neither paroxetine nor high dose imipramine showed efficacy for major depression in adolescents, and there was an increase in harms with both drugs.
The Fascinating Link Between Placebo and Antidepressants
2015 Study Abstract
High placebo responses have been observed across a wide range of pathologies, severely impacting drug development.
To examine neurochemical mechanisms underlying the formation of placebo effects in patients with major depressive disorder (MDD).
Design, Setting, and Participants
In this study involving 2 placebo lead-in phases followed by an open antidepressant administration, we performed a single-blinded 2-week crossover randomized clinical trial of 2 identical oral placebos (described as having either active or inactive fast-acting antidepressant-like effects) followed by a 10-week open-label treatment with a selective serotonin reuptake inhibitor or, in some cases, another agent as clinically indicated. The volunteers (35 medication-free patients with MDD at a university health system) were studied with positron emission tomography and the µ-opioid receptor–selective radiotracer [11C]carfentanil after each 1-week inactive and active oral placebo treatment. In addition, 1 mL of isotonic saline was administered intravenously within sight of the volunteer during positron emission tomographic scanning every 4 minutes over 20 minutes only after the 1-week active placebo treatment, with instructions that the compound may be associated with the activation of brain systems involved in mood improvement. This challenge stimulus was used to test the individual capacity to acutely activate endogenous opioid neurotransmision under expectations of antidepressant effect.
Main Outcomes and Measures
Changes in depressive symptoms in response to active placebo and antidepressant. Baseline and activation measures of µ-opioid receptor binding.
Higher baseline µ-opioid receptor binding in the nucleus accumbens was associated with better response to antidepressant treatment (r = 0.48; P = .02). Reductions in depressive symptoms after 1 week of active placebo treatment, compared with the inactive, were associated with increased placebo-induced µ-opioid neurotransmission in a network of regions implicated in emotion, stress regulation, and the pathophysiology of MDD, namely, the subgenual anterior cingulate cortex, nucleus accumbens, midline thalamus, and amygdala (nucleus accumbens: r = 0.6; P < .001). Placebo-induced endogenous opioid release in these regions was associated with better antidepressant treatment response, predicting 43% of the variance in symptom improvement at the end of the antidepressant trial.
Conclusions and Relevance
These data demonstrate that placebo-induced activation of the µ-opioid system is implicated in the formation of placebo antidepressant effects in patients with MDD and also participate in antidepressant responses, conferring illness resiliency, during open administration.
Sources and more information
Placebo power: Depressed people who respond to fake drugs get the most help from real ones, medicalxpress, September 30, 2015.
The Fascinating Link Between Placebo and Antidepressants, time, Sept. 30, 2015.
Placebo power: Depressed people who respond to fake drugs get the most help from real ones, U-M study finds, University of Michigan, SEPTEMBER 30, 2015
Association Between Placebo-Activated Neural Systems and Antidepressant ResponsesNeurochemistry of Placebo Effects in Major Depression, JAMA Psychiatry, doi:10.1001/jamapsychiatry.2015.1335, September 30, 2015.
A perspective from the NEJM on placebo effects in medicine
Medicine has used placebos as a methodologic tool to challenge, debunk, and discard ineffective and harmful treatments. But placebo effects are another story; they are not bogus. With proper controls for spontaneous remission and regression to the mean, placebo studies use placebos to elucidate and quantify the clinical, psychological, and biologic effects of immersion in a clinical environment. In other words, research on placebo effects can help explain mechanistically how clinicians can be therapeutic agents in the ways they relate to their patients in connection with, and separate from, providing effective treatment interventions. Of course, placebo effects are modest as compared with the impressive results achieved by lifesaving surgery and powerful, well-targeted medications. Yet we believe such effects are at the core of what makes medicine a healing profession.
Read Placebo Effects in Medicine, a Perspective from The New England Journal of Medicine, Ted J. Kaptchuk, and Franklin G. Miller, Ph.D., N Engl J Med 2015, DOI: 10.1056/NEJMp1504023, July 8, 2015.