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Genes Implicated in Placebo Response Mechanism Could Affect Clinical Trials


NEW YORK (GenomeWeb) – Genotype has a part to play in how much an individual responds to a placebo in a clinical trial, according to a new review published today in Trends in Molecular Medicine. The findings suggest that clinical trial designers could achieve better results by more carefully constructing the placebo arm, but also raise a litany of ethical questions about the disclosure of genetic information.

Scientists from Harvard Medical School and Beth Israel Deaconess Medical Center, led by Kathryn Hall and Ted Kaptchuk, performed a review of GWAS data from a variety of sources. The researchers had to account for the fact that almost all clinical trials, both in general and among the ones considered in the study, lack a no-treatment control arm. Such a group would have allowed the researchers to "disentangle genuine psychosocial and physiological placebo responses to the symbols, rituals, and behaviors of the clinical encounter," they said. Still they found several gene candidates to further investigate.

Three types of studies yielded biomarkers of interest: a small randomized controlled trial investigating placebo responses that included a no-treatment control arm as well as candidate gene analysis; a placebo-controlled trial in patients that included genetic analysis of genes coinciding with the placebo response mechanism; and several experimental studies in healthy subjects that also examined potential placebo response-related genes.

Looking at genes associated with biochemical pathways known to play a role in placebo response was particularly fruitful. "It's widely accepted that the opioid signaling pathways are involved" with placebo response, Hall told GenomeWeb, especially in pain relief studies. Along the same lines, dopamine is involved in the expectation of relief from placebo treatment, she said, and added that there is circumstantial but "compelling" evidence that serotonin and endocannabinoid pathways are also involved in placebo response.

In multiple ways, genes appeared to affect response to both placebo and drug treatment, with consequences for the final analysis of the trial. "In many instances, one genotype responded to placebo but didn't respond to drugs, and another genotype didn't respond to placebo but did respond to drugs. The conclusion of that study was there's no difference between drug and placebo," Hall said. "What we're calling for is a more nuanced and comprehensive look at these studies. We want to get a panel of genetic loci with which to interrogate the data."

The star biomarker candidate was the gene COMT, which encodes catechol-O-methyltransferase, an enzyme that metabolizes dopamine and other catecholamines. COMT was strongly associated with changing outcomes in both the drug and placebo arms of numerous clinical trials, the authors said. A single nucleotide polymorphism in the gene results in a threefold to fourfold reduction of enzyme activity and is associated with higher levels of dopamine in the prefrontal cortex, a region of the brain thought to play a part in placebo response.

Genetic variation in the mu opioid receptor gene OPRM1 has also affected placebo response in pain studies. A polymorphism in this gene was shown to reduce receptor function in several studies of healthy volunteers.

Just how much genotype contributed to the response to placebo, or lack thereof, wasn't immediately obvious from the data analyzed by the study. "You'd have to do a specific study to discern that," Hall told GenomeWeb.

She explained that there are many factors contributing to placebo response. "A needle is a stronger inducer of placebo response than a pill, [and] a blue pill induces more response than a red pill," she said. And expectation, which is related to dopamine signaling, also plays a role. "Someone who is desperate and sees a warm, caring practitioner, they're ready to have a placebo response," Hall said.

Though the authors noted that results from the placebo arm of a trial without a no-treatment control arm should be "approached with an abundance of caution," they said that several relationships between genotype, drug, and placebo emerged from the study.

Another recurring result was that trial participants with a particular genotype fared better in the placebo arm and actually worse in the treatment arm. "This is a theme we keep seeing over and over again," Hall said.

At the very least, the results obtained in the study support the addition of small, no-treatment controls to randomized, controlled trials, Hall said. Such a group would be necessary to rigorously determine the effects of genes on placebo response, but would cost money. "Any time you're asking to spend more money or more time, you need to justify it, you need to show data," she said.

However, the additional arm could be beneficial. "There's enough data there to support doing research on this," she said.

Hall outlined three ways in which the consideration of genes implicated in placebo response could factor into clinical trial design. The first is to exclude participants who are likely to have a greater placebo response. "That should enrich the study with people who are going to respond to your drug," Hall explained. But that's been attempted already, without much success, through the concept of a run in, where all participants begin the trial receiving the placebo for a short period. People who greatly respond are not included moving forward. "That doesn't seem to necessarily improve outcomes in terms of finding drugs that are effective," Hall said.

The flip side of that idea would be to enrich the placebo arm with non-responders, but there's no data yet to suggest that would work better than screening out placebo responders.

A third option would be to stratify the trial based on genotype. Of course, in a clinically valid trial, the researchers would have to hypothesize which genotypes to stratify the patients by before the data were collected and analyzed. "You have to get a sense of what genes are going to be important to placebo response and then stratify the outcomes and understand what happens," Hall said, adding that that can't be done without more research.

There could even be situations where a trial might intentionally use a drug to modify placebo response, the authors said. "Purposefully using a drug to inhibit the placebo response in clinical trials could minimize the placebo response and allow for a more accurate measurement of the drug effect. In this case, the placebo-modifying drug would be administered to both the drug treatment and placebo arm of the trial, and any potential drug–drug or gene–drug interactions would have to be well characterized."

While their findings suggest ways to improve results in clinical trials, the study raises a number of ethical questions, the authors said in the paper. "Can, and should, physicians test for genetic placebo response propensities? Can patients refuse permission to be tested? Should patients be told about their propensity? Can patients refuse to know or to have this designation in their medical records? Can and how should physicians ethically utilize this information if it appears incidentally in genetic testing?" Because placebo response has a psychological component, there's also the question of whether knowing that you're a placebo responder could affect that same response.

Any decision to account for placebo-response genotype in controlled clinical trials will ultimately fall to the US Food and Drug Administration, Hall said. But that point is far in the future. She suggested that, until then, the National Institutes of Health can play a bigger role in fostering development of the science. A database with the extracted details of gene-drug-placebo interaction from clinical trials is something that could be put in place fairly easily if the will were established, she said.

"The NIH has databases with clinical trial data. Already there's a place to house all of the data," she said. "From an academic scientist's perspective, funding a small group in your trial [to be part of a no-treatment control] could benefit a lot of people. NIH might consider adding a small no-treatment arm in omics studies to populate this database and get some info on what's going on."