Genomic analysis of randomized placebo and no-treatment controlled trials are needed to fully realize the potential of the placebome.

Candidate placebo response pathways may interact with drugs to modify outcomes in both the placebo and drug treatment arms of clinical trials.

Predisposition to respond to placebo treatment may be in part a stable heritable trait.

Placebos are indispensable controls in randomized clinical trials (RCTs), and placebo responses significantly contribute to routine clinical outcomes. Recent neurophysiological studies reveal neurotransmitter pathways that mediate placebo effects. Evidence that genetic variations in these pathways can modify placebo effects raises the possibility of using genetic screening to identify placebo responders and thereby increase RCT efficacy and improve therapeutic care. Furthermore, the possibility of interaction between placebo and drug molecular pathways warrants consideration in RCT design. The study of genomic effects on placebo response, ‘the placebome’, is in its infancy. Here, we review evidence from placebo studies and RCTs to identify putative genes in the placebome, examine evidence for placebo–drug interactions, and discuss implications for RCTs and clinical care.

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Glossary

an informal term referring to biological studies of molecules derived from or affecting the genome. These studies tend to be large in scale and the terms used to describe them end in ‘–omics’ (i.e., genomics, transcriptomics, proteomics, and metabolomics).

a catecholamine neurotransmitter or hormone that is important in signaling in the reward-motivation and motor control neural pathways. Dysfunction in the dopamine system is associated with several diseases and disorders, including schizophrenia, attention deficit hyperactivity disorder, addiction, and Parkinson's disease.

the ability of a drug to produce a clinically beneficial effect. In a RCT, drug efficacy is determined by subtracting the primary clinical outcome in the placebo arm from the outcome in the drug treatment arm.

a group of neuromodulatory lipids that have a role in modulating mood, appetite, memory, and pain sensation.

naturally occurring peptides that relieve pain and signal reward in the brain.

a study used to scan and compare variation in genes across large numbers of individuals to identify genetic associations with disease incidence, treatment, and prevention.

the term given to the entire set of molecular interactions within the cell. Therefore, the interactome seeks to define the physical and biochemical influences that gene, protein, small molecule drugs, miRNA, and other biomolecular networks exert on each other across normal or disease states.

used to describe how many people in a given population carry the least common allele. If in a given population, the MAF is 20%, then among population members, one in five chromosomes will carry the minor allele and four out of five chromosomes will carry the other genetic variant, or major allele.

an arm of a RCT in which randomly allocated subjects receive no treatments or interventions. This arm is sometimes called the wait list and the subjects are observed during the time of the trial. When studying placebo effects, the NTC can be an important control for the placebo arm of a RCT because it allows for an estimate of the genuine effects of a placebo intervention by controlling for spontaneous remission, regression to the mean, and normal waxing and waning of an illness in the placebo treatment arm.

considered the opposite of placebo effects. They are negative or adverse effects in response to an inert or placebo treatment.

caused by stimulation of pain receptors in response to pressure, temperature, or irritating substances that send pain signals to the brain in response to injury or the possibility of injury. Antinociceptive treatments are designed to reduce such pain.

the study of how variation in the genome modifies individual response to drug treatment. The goal of pharmacogenomics is to use -omics data to guide the development of safer and more effective and, therefore, more personalized medicines.

an inert treatment (e.g., dummy pills, fake injections, or sham surgery) designed to simulate a biomedical intervention within a RCT. Placebo response is the positive health benefits that patients receive in response the symbols, rituals, and behaviors embedded in a clinical encounter.

the hypothesized group of genome-related or derived molecules (i.e., genes, proteins, or miRNAs) that affect an individual's response to placebo treatment.

the gold standard for clinical studies in which participants are randomized to an active exposure or inert treatment arm of the trial. In placebo-controlled RCTs, participants are blinded to their treatment allocation and the results are used to test the efficacy or effectiveness of a drug or active intervention.

a monoamine neurotransmitter that is important in regulating mood, appetite, and cognitive functions, including memory and learning. SSRIs are antidepressants that are designed to increase serotonin levels.

sites in the genome that differ in the DNA nucleotide sequence and, thus, give rise to genetic variability.