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Study Finds Dopamine Gene Variant Predictive of Placebo Response in IBS Patients

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Researchers led by a group at Beth Israel Deaconess Medical Center have identified a genetic marker associated with the placebo effect in patients with irritable bowel syndrome.

According to the group, the finding is the first to show "genetic modulation of true placebo effects," and supports the possibility of using genomic information to better design placebo-controlled clinical trials.

The researchers described their results in PLOS One this week. The project used genotyping to measure whether a polymorphism in the dopamine pathway's COMT gene was associated with differences in placebo response among 104 IBS patients enrolled in a three-arm trial of different placebo treatments.

After studying the distribution of the val158met polymorphism among the trial's three arms — no treatment (a waitlist), treatment with placebo alone, and placebo treatment with an "augmented" physician-patient interaction involving more support — the group found that the strongest placebo response occurred in met/met homozygotes who received the augmented placebo treatment.

The researchers identified a weaker link between met/met and response in the placebo-only arm. And patients in the waitlist control arm showed no difference in response based on their genotype.

The study's first author, Kathryn Hall, told PGx Reporter this week that having a genetic predictor of placebo response could allow researchers to stratify future placebo-controlled drug trials by potential responders and non-responders.

IBS is known to have a high placebo response rate. Hall said it's likely that the use of genetic predictors for placebo response will be most relevant to trials of drugs for conditions that are similarly associated with high placebo response levels, such as depression, headache, allergies, and pain.

"In conditions where there tends to be a high placebo response, oftentimes a drug fails because it can't prove efficacy above the placebo response. In those cases, the pharmaceutical companies are basically losing quite a bit of money and time and resources," Hall said.

"So the question is – is this a possibility? Obviously, it hasn't been done before and probably will need a lot more validation before anyone actually wants to do it," she said. "But if it does hold true at least for some conditions and treatments, it would allow you to focus in on just the people who are [not going to respond to the placebo] – so it would build your power [and] reduce your cost, since you don't have this set of people that are inflating the placebo response."

Hall cited diseases like Parkinsons and schizophrenia, which involve dopamine metabolism, as examples where new treatments might see their efficacy estimation confounded by the placebo effect.

At a minimum, Hall suggested that drug developers might improve the success rates of their products by balancing the number of patients who are predisposed to respond and not respond to the placebo effect in both the treatment and placebo arms of a trial.

In the study, Hall and her colleagues evaluated a subset of patients from an earlier randomized controlled IBS trial.

In the previous trial, the group measured differences in response, based on patient-reported symptoms, after either placebo treatment alone, "augmented" placebo treatment in which patients were given extra physician interaction and support, or no treatment, and placement on a waiting list.

In the genetic follow-up, the researchers genotyped 104 patient samples to look for associations between val158met genotype and placebo-response, based on reported symptoms and quality of life.

The group coded each patient according to the presence of the COMT met allele and found that patients with the met/met genotype had the greatest level of improvement — based on their scores in a measure called the IBS-Symptom Severity Scale — while those with the val/val type had the least. Val/met patients fell in the middle.

While patients homozygous for the COMT val158met allele were the most responsive to placebo overall, the strongest signal was in the augmented treatment arm, with a smaller effect in the placebo-alone arm, and virtually no effect, or even a reverse effect, in the waitlist control arm.

Overall, the group concluded that the results "strongly suggest that COMT val158met, specifically the met/met genotype, is a potential marker for placebo response in IBS."

The fact that the genotype is associated with a positive outcome only in groups given a placebo, and not in the control group, indicates that it is a true predictor of placebo effect, not just improvement in general, the group wrote.

While previous studies have looked for a genetic link to placebo response, they have not included this control arm, according to the Beth Israel team. Additional studies that hypothesize a COMT involvement and include a no-treatment arm "will be critical to confirm our findings," the group added.

According to Hall, the field is likely still far away from using genomic information to influence the design of placebo-controlled trials. However, her group's results suggest a path forward, she said.

The results may also have implications for more personalized treatment strategies, she said.

"On one hand, you could hypothesize that there are situations where people are placebo responders and taking a drug with a lot of side effects … Obviously giving people placebo pills is a long way off, but [perhaps you could] minimize someone's drug intake if they are having more of a placebo response so they don’t have to have all the side effects," she said.

At the same time, she said, the trial highlighted the influence of the "warm, caring doctor relationship."

"Having a mechanistic understanding of what's going on there, I think, will reinforce the need and the importance of this part of medicine," she said, at least for some. The fact that val/val subjects, for example, showed the same lack of response in both the placebo-alone and augmented arms of the study may shed some light on why, "despite their best efforts, many a warm and caring physician has had patients that seemed to derive minimum benefit from their empathic attentions," the study authors wrote.

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