October 24, 2012
Placebo Effect Research Finds Important Implications For Patient Care
Lee Rannals for redOrbit.com — Your Universe Online
For the first time, researchers have identified genetic differences between placebo responders and non-responders.
The new findings demonstrate that genetic differences that account for variations in the brain's dopamine levels help determine the extent of a person's placebo response.
This discovery has important implications for patient care, and could also prove to be a significant benefit to researchers in designing and conducting clinical trials to help determine a drug's effectiveness.
"There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos, " the study's first author Kathryn Hall, PhD, a research fellow in the Division of General Medicine and Primary Care at Beth Israel Deaconess Medical Center (BIDMC), said in a press release. "With this new research, we may now be able to use a person's genetic makeup to predict whether or not they will respond to a placebo."
The placebo effect takes place when patients show improvement from treatments that contain no active ingredients.
When scientists are conducting clinical trials of new drugs, placebo responses can pose a difficult challenge and require investigators to recruit additional patients in order to acquire statistically significant data.
Because dopamine is known to be important to both reward and pain, the team started their search for a genetic placebo marker in the dopamine portion of the genes, focusing on the catechol-O-methyltransferase (COMT) gene.
"COMT made for an excellent candidate because it's been implicated in the cause and treatment of many conditions, including pain and Parkinson's disease," Hall said in the release. "It's also been found in behavioral genetic models of reward responsiveness and confirmation bias, the tendency to confirm new information based on your beliefs."
The changes in the COMT gene result in people having either two copies of the methionine (met) allele, two copies of the valine (val) allele, or one copy of each.
"People with two copies of met, the "met/mets," have three to four times more dopamine available in their prefrontal cortex [the brain area associated with cognition, personality expression, decision making and social behavior] than the people with two copies of val," explains Hall.
The team believed that if dopamine was involved in the placebo response, they would see a difference between how met/met, val/val and met/val genotypes responded to placebo treatments.
To test their hypothesis, the scientists revisited a 2008 clinical trial designed to study the placebo effect in patients with irritable bowel syndrome (IBS).
"In our original work, IBS patients were assigned to one of three treatment arms and we explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered," PiPS Director Ted Kaptchuk, who led the IBS study, said in a press release.
The treatment conditions included either being "wait listed" and receiving no treatment, receiving placebo acupuncture in business manner, or receiving placebo acupuncture from a health care provider.
The scientists used this data and genotyped blood samples from patients from the earlier study, using a statistical method known as regression analysis to analyze the effects of a person's genotype.
"Our regression analysis found that as the copies of met increased, placebo responses increased in a linear fashion, presumably because more dopamine was available," Hall said in the release.
The findings showed that IBS patients who had been in the wait list treatment had no difference in treatment responses between met/met, val/val and met/val genotypes as determined by the IBS-Symptom Severity Scale and Adequate Relief.
Those who received a placebo administered in a businesslike fashion showed small improvements. Also, those individuals who received the acupuncture from health care providers had a striking difference, with a six-fold great improvement in their IBS Symptoms relative to the val/val genotypes.
"These findings suggest that it is possible that met/met is a genetic marker for the placebo response and val/val is a marker for non-response," says Hall. "In addition, our findings underscore differences in placebo response based on the patient's experience of the clinical environment."
She said their findings suggest that the val/val patients are less influenced by placebo treatment, and that this sheds light on a clinical challenge faced by health care providers.
The team said these findings will need to be replicated, but they do offer the first step in dealing with the placebo effect when conducting clinical trials.
"Currently, most drugs need to demonstrate superior efficacy performance against a placebo before they can receive approval from regulatory agencies, such as the U.S. Food and Drug Administration [FDA]," Gunther Winkler, PhD, Principal of ASPB Consulting, LLC, and consultant to the pharmaceutical industry, said in a press release. "Being able to predict a genetic predisposition for heightened placebo response could potentially have a major impact in reducing the size, cost and duration of clinical trials."
He said these findings are a step toward understanding, predicting and controlling the placebo effect.
"This study opens a new avenue of investigation into the biological basis of the placebo response," Kaptchuk said in the release. "Just as some people find attending church or synagogue to be transforming and others just fall asleep, there are people who are enticed and deeply influenced by the rituals and symbols of medicine, and now we recognize that there may be a genetic explanation for some of this response."
He said they hope as more research continues, the implications and expansion of these findings may contribute to improve clinical care, and the efficiency of conducting clinical trials.