The Complex Interplay Of Genetics And The Placebo Response

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Why do some people respond to placebos while others don't?

One possible answer: genetics.

A provocative new paper introducing the concept of a "placebome" — that is, the complex interplay between genetics and an individual's response to placebos — raises questions that might ultimately lead to changes in how clinical studies of drugs are evaluated.

Indeed, researchers from Harvard Medical School suggest that genes, and genetic variation, might play a far bigger role in the placebo response than previously thought.

That the placebo effect is an actual physiological response is well established. But the new report, a research review, looks specifically at the placebo response in the context of drug studies, where some participants get the active medication while others get a placebo, or non-active version of the drug.

The new findings, "call into question whether or not the outcomes in a drug treatment arm of a clinical trial are limited to the effect of the drug on the condition," says Kathryn Hall, an integrative medicine fellow in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center, and one of the study authors.

Instant Vantage/flickr
Instant Vantage/flickr

Several neurotransmitters, such as dopamine, appear to be involved in the placebo response, Hall said, and variation in the genes in these pathways appears to change our response to placebo. So different people with different genotypes respond differently to placebos.

But Hall takes it one step further. "When you are in a trial you don't know if you are getting the drug or the placebo, so not just the people in the placebo arm can have placebo responses. We are curious about the drugs' effect on the placebo response."

It's all a bit tough to wrap your brain around, so I asked Hall to give me an example. Here's what she said:

In the literature we see several studies in which in the placebo arm one group of people with a certain genotype have a strong placebo response and the other group has a weak placebo response. And when we look at the drug treatment arm, we see the outcomes are reversed, the people who had the strong response in the placebo arm now have a low response and the people who didn't have a response in the placebo arm now have a strong response. The historical interpretation of these results has been that only one group of people responds to the drug and we're pointing out that it's more complicated than that. It's that one group responded to the placebo and that response is eliminated in the drug treatment arm.

What all this means in the real world is still hard to know. But in their paper published this week in the journal, Trends in Molecular Medicine, the researchers offer these three key takeaways in the abstract:

•The predisposition to respond to placebo treatment may be in part a stable heritable trait.

•Candidate placebo response pathways may interact with drugs to modify outcomes in the drug treatment arms of clinical trials.

•Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

Here's more from the Beth Israel news release:

The placebo effect occurs when patients show improvement from treatments that contain no active ingredients. Scientists initially used behavioral instruments, such as personality measures, to predict which patients would respond to placebos, but over the past decade, the development of sophisticated neuroimaging technologies illuminated the activation of the brain's neurotransmitter pathways in response to placebos.

"Because they are the chemical messengers that either excite or inhibit nerve function in the brain, many neurotransmitters play key roles in reward and pain," explains Hall. "We hypothesized that genetic variation in the genes that encode the proteins in these neurotransmitter pathways might also modify placebo responses."

In 2012, Hall identified the first placebo biomarker, the catechol-O-methyltransferase (COMT) gene, reporting that genetic variations in COMT - which influence the brain's levels of the neurotransmitter dopamine — also determined the extent of an individual's placebo response.

A review of the scientific literature over the last 10 years provided the authors with further confirmation that, beyond the COMT gene, there is evidence for genetic variation in other neurotransmitter pathways that modify placebo response. These include the opioid, endocannabinoid and serotonin pathways — suggesting the potential existence of a placebome or "network" of genes...

Knowing that neurotransmitter pathways are involved in placebo responses now raises a new consideration for both patient care and clinical research, say the authors: What if placebo responses and drug responses share the same brain pathways?

"We're discovering that the placebo is not the only component in the placebo effect," explains the paper's coauthor Ted Kaptchuk, Director of the PiPS at BIDMC and Professor of Medicine at Harvard Medical School. "These neurotransmitter pathways, which are modified by genetics, are pathways that both drugs and the placebo act on. This now suggests that a drug could change a placebo response and a placebo response could modify a drug response."

The authors add that the potential overlap between placebo, drug treatment and disease adds to the complexity of the placebome and underscores the importance of understanding how it fits into larger more complex networks...

"The possibility that there could be a placebo-drug interaction as a result of genetic variation in placebo pathway genes suggests that we need to refine and recalibrate the assumptions of placebo controls in randomized clinical trials," the authors write. "An important next step in describing the placebome would be to include a no-treatment control in placebo-controlled randomized clinical trials. This approach might be cost effective and allow for a broad view of placebo response genes and other molecules across varying conditions and treatments."

As the "gold standard" for pharmaceutical research, randomized clinical trials include a "placebo arm," which is designed to control for the non-specific, non-pharmacological effects that are part of the administration and receipt of clinical treatment (i.e. the way a doctor is dressed, the way he or she describes what to expect from a drug, even the physical appearance of the doctor's office). But in order to properly study the placebo response, the authors propose that a "no -treatment" control needs to be incorporated into the trials.

"The best control for a drug is a placebo, but if you want to study placebos you need a no-treatment control," says Hall. "This is one of the major limitations in the scientific literature, but we believe that this could be addressed prospectively by including such an arm in future clinical trials.

"Knowledge of the placebome has the potential to guide development of novel strategies for both identifying placebo responders and clinical trial design," she adds.

Rachel Zimmerman Twitter Health Reporter
Rachel Zimmerman previously reported on health and the intersection of health and business for Bostonomix.