Identification of genetic marker for placebo response could influence trial design
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 trials
- Date : 06 Feb 2013
- Topic : Basic science
Although placebos have played a critical role in medicine and clinical research for more than 70 years, it has been a mystery why these inactive treatments help to alleviate symptoms in some patients and not others. Now researchers have for the first time identified genetic differences between placebo responders and non-responders, providing an important new clue to the placebo effect.
Led by investigators at Beth Israel Deaconess Medical Center (BIDMC) and Harvard Medical School, the new findings demonstrate that genetic differences that account for variations in the brain's dopamine levels help to determine the extent of a person's placebo response. The discovery not only has important implications for patient care, but could also prove to be of significant benefit to researchers in designing and conducting clinical trials to help determine a drug's effectiveness. 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 trials.
The findings appeared in the October 23, 2012 issue of PLOS ONE.
There has been increasing evidence that the neurotransmitter dopamine is activated when people anticipate and respond to placebos, according to the study's first author, Kathryn Hall, PhD, a research fellow in the Division of General Medicine and Primary Care and member of the Program in Placebo Studies (PiPs) and Therapeutic Encounter at BIDMC.
Because dopamine is known to be important to both reward and pain, the investigators began their search for a genetic placebo marker in the dopamine pathway. Their focus soon turned to the catechol-O-methyltransferase (COMT) gene. COMT is an excellent candidate, because it is implicated in the cause and treatment of many conditions, including pain and Parkinson's disease. It has also been found in behavioural genetic models of reward responsiveness and confirmation bias.
Polymorphisms are gene variations and, in the case of the COMT val158met polymorphism, 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 have three to four times more dopamine available in their prefrontal cortex (the brain area associated with cognition, personality expression, decision making, and social behaviour) than the people with two copies of val.
The scientists hypothesized that if dopamine was indeed involved in the placebo response, they would see a difference between how met/met, val/val, and met/val genotypes responded to placebo treatments, with the met/met individuals showing a higher response.
To test this hypothesis, the researchers took advantage of a unique opportunity, revisiting a 2008 clinical trial led by PiPS Director Ted Kaptchuk that was designed to study the placebo effect in patients with irritable bowel syndrome (IBS).
The patients were assigned to one of three treatment arms, and the researchers explored the placebo response in relation to the patient-provider experience and the clinical environment in which the placebo is administered.
The treatment conditions included either being "waitlisted' and receiving no treatment, receiving placebo acupuncture in a business-like clinical manner, or receiving placebo acupuncture treatment from a warm, supportive healthcare provider.
Armed with this original data, the scientists 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 and the type of treatment received.
The regression analysis found that as the copies of met increased, placebo responses increased in a linear fashion, presumably because more dopamine was available.
The findings showed that, among the IBS patients who had been in the waitlist treatment arm, there was 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. Among those in the group that received a placebo administered in a business-like manner, the met/met genotypes showed a small improvement over their val/val and met/val counterparts.
However, among the individuals who had received placebo treatment from the warm, supportive healthcare providers, there was a striking difference: the met/mets demonstrated a six-fold greater improvement in their IBS symptoms relative to the val/vals.
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. In addition, the study findings underscore differences in placebo response based on the patient's experience of the clinical environment. In the case of the met/met individuals, one can really see the advantage of a positive doctor-patient relationship. Conversely, the findings suggest that the val/val patients are less influenced by placebo treatment, and this sheds light on a clinical challenge faced by many healthcare providers whose empathic care helps some people, but makes no difference to others.
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