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Placebo has helped to ease symptoms of illness for centuries and have been a fundamental component of clinical research to test new drug therapies for more than 70 years. But why some people respond to placebos and others do not remains under debate. Genetic sequencing is revealing that the placebo response is, in fact, a complex phenotype with an unfolding physiology; the study of genomic effects on the placebo response, what some authors call “the placebome“, is in its infancy, but there is already ample evidence that genetic variations in the brain’s neurotransmitter pathways modify placebo effects. As a result, placebo responses are emerging as a legitimate series of molecular and biological reactions, most likely organized in complex (neurological) networks of interacting genes (and their respective coded for proteins) in the placebome (see the mind boggling 2017 article by Wang et al. in the Journal of Clinical Investigation for an overview).
The exciting question is now if there exist definitive genetic biomarlers which could be used to prospectively identify individuals who are perceptive for placebo responses? If so, how many of such genetic biomarkers exist? Can the medical field harness the placebo response to enhance personalized medical treatment? What might be the impact of placebo-drug interactions? And what will this new information mean for randomized clinical trials, which depend on
placebo controls to test the efficacy of new drug candidates? Should a “no-treatment” control be added to future trials?
In 2012, a first genetic placebo biomarker, the catechol-O-methyltransferase (COMT) gene, was identified in that a genetic variation (in particular the exonic SNP (rs4680, Val158Met)) in COMT, which influences the brain’s levels of the neurotransmitter dopamine, also determined the extent of an individual’s placebo response in irritable bowl syndrome (IBS).
The article by Wang et al. (see above) further explores the concept of the placebome and puts it into relation to similar gene networks thought to be active in drug action (drug modules) and in disease aetiologies and responses to treatment (disease modules). Within this framework, the researchers hope to further decipher the physiological basis of placebo and to find the raisons for differences of the strength of placebo in diseases where this effect is high (such as alcoholism, anxiety, asthma, Crohn’s disease, depression, diabetic neuropathies, duodenal ulcer, epilepsy, eating disorders, fibromyalgia, irritable bowel syndrome, Parkinson disease, migraine disorders, osteoarthritis, chronic pancreatitis, restless leg syndrome, schizophrenia, and ulcerative colitis) versus diseases where this effect is low or absent (such as bacterial infection, infertility, viremia, pneumothorax, uremia, hepatocellular carcinoma and renal cell carcinoma. There have been about 15 candidate genes identified which may be implicated at the origin of the placebo effect; further research will more clearly reveal their role, the involvement of particular mutations, and eventually allow to identify individuals, based on genetic tests, who are naturally carrying a strong placebo effect predispostion (giving rise to the field of placebomics).
Possibility of “Placebo-Drug Interactions” and “No-Treatment Arms” in Clinical Trials
Knowing that neurotransmitter pathways are involved in placebo responses now raises a new consideration for both patient care and clinical research. Since seemingly neurotransmitter pathways are modified by genetics and are pathways that both drugs and the placebo act on, drugs could change a placebo response and a placebo response could modify a drug response. This 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 one needs to refine and recalibrate the assumptions of placebo controls in randomized clinical trials. 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.
It may no longer be sufficient for pharmaceutical research to include in randomized clinical trials 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. In order to properly study the placebo response, a frank “no -treatment” control may have to be incorporated into well designed future clinical trials. This may help to provide the right treatment in the right place at the right time, not only for the responding patient, but also for the “placebo patient”.