Person:

Hall, Kathryn

Identifying patients who are potential placebo responders has major implications for clinical practice and trial design. Catechol-O-methyltransferase (COMT), an important enzyme in dopamine catabolism plays a key role in processes associated with the placebo effect such as reward, pain, memory and learning. We hypothesized that the COMT functional val158met polymorphism, was a predictor of placebo effects and tested our hypothesis in a subset of 104 patients from a previously reported randomized controlled trial in irritable bowel syndrome (IBS). The three treatment arms from this study were: no-treatment (“waitlist”), placebo treatment alone (“limited”) and, placebo treatment “augmented” with a supportive patient-health care provider interaction. The primary outcome measure was change from baseline in IBS-Symptom Severity Scale (IBS-SSS) after three weeks of treatment. In a regression model, the number of methionine alleles in COMT val158met was linearly related to placebo response as measured by changes in IBS-SSS (p = .035). The strongest placebo response occurred in met/met homozygotes treated in the augmented placebo arm. A smaller met/met associated effect was observed with limited placebo treatment and there was no effect in the waitlist control. These data support our hypothesis that the COMT val158met polymorphism is a potential biomarker of placebo response.

Clonidine, an α2-adrenergic receptor agonist, decreases circulating norepinephrine and epinephrine, attenuating sympathetic activity. Although catechol-O-methyltransferase (COMT) metabolizes catecholamines, main effectors of sympathetic function, COMT genetic variation effects on clonidine treatment are unknown. Chronic fatigue syndrome (CFS) is hypothesized to result in part from dysregulated sympathetic function. A candidate gene analysis of COMT rs4680 effects on clinical outcomes in the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial (NorCAPITAL), a randomized double-blinded clonidine versus placebo trial, was conducted (N=104). Patients homozygous for rs4680 high-activity allele randomized to clonidine took 2,500 fewer steps compared to placebo (pinteraction=0.04). There were no differences between clonidine and placebo amongst patients with COMT low-activity alleles. Similar gene-drug interactions were observed for sleep (pint=0.003) and quality of life (pint=0.018). Detrimental effects of clonidine in the subset of CFS patients homozygous for COMT high-activity allele warrant investigation of potential clonidine-COMT interaction effects in other conditions.

Background: Placebo medications, by definition, are composed of inactive ingredients that have no physiological effect on symptoms. Nonetheless, administration of placebo in randomized controlled trials (RCTs) and in clinical settings has been demonstrated to have significant impact on many physical and psychological complaints. Until recently, conventional wisdom has suggested that patients must believe that placebo pills actually contain (or, at least, might possibly contain) active medication in order to elicit a response to placebo. However, several recent RCTs, including patients with irritable bowel syndrome (IBS), chronic low back pain, and episodic migraine, have demonstrated that individuals receiving open-label placebo (OLP) can still experience symptomatic improvement and benefit from honestly described placebo treatment. Methods and design This paper describes an innovative multidisciplinary trial design (n = 280) that attempts to replicate and expand upon an earlier IBS OLP study. The current study will compare OLP to double-blind placebo (DBP) administration which is made possible by including a nested, double-blind RCT comparing DBP and peppermint oil. The study also examines possible genetic and psychological predictors of OLP and seeks to better understand participants’ experiences with OLP and DBP through a series of extensive interviews with a randomly selected subgroup. Discussion OLP treatment is a novel strategy for ethically harnessing placebo effects. It has potential to re-frame theories of placebo and to influence how physicians can optimize watch-and-wait strategies for common, subjective symptoms. The current study aims to dramatically expand what we know about OLP by comparing, for the first time, OLP and DBP administration. Adopting a unique, multidisciplinary approach, the study also explores genetic, psychological and experiential dimensions of OLP. The paper ends with an extensive discussion of the “culture” of the trial as well as potential mechanisms of OLP and ethical implications. Trial registration ClinicalTrials.gov, identifier: NCT02802241. Registered on 14 June 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-1964-x) contains supplementary material, which is available to authorized users.

Background: Attention to and perception of physical sensations and somatic states can significantly influence reporting of complaints and symptoms in the context of clinical care and randomized trials. Although anxiety and high neuroticism are known to increase the frequency and severity of complaints, it is not known if other personality dimensions or genes associated with cognitive function or sympathetic tone can influence complaints. Genetic variation in catechol-O-methyltransferase (COMT) is associated with anxiety, personality, pain, and response to placebo treatment. We hypothesized that the association of complaint reporting with personality might be modified by variation in the COMT val158met genotype. Methods: We administered a standard 25-item complaint survey weekly over 3-weeks to a convenience sample of 187 irritable bowel syndrome patients enrolled in a placebo intervention trial and conducted a repeated measures analysis. Results: We found that complaint severity rating, our primary outcome, was negatively associated with the personality measures of conscientiousness (β = −0.31 SE 0.11, P = 0.003) and agreeableness (β = −0.38 SE 0.12, P = 0.002) and was positively associated with neuroticism (β = 0.24 SE 0.09, P = 0.005) and anxiety (β = 0.48 SE 0.09, P < 0.0001). We also found a significant interaction effect of COMT met alleles (β = −32.5 SE 14.1, P = 0.021). in patients genotyped for COMT val158met (N = 87) specifically COMT × conscientiousness (β = 0.73 SE 0.26, P = 0.0042) and COMT × anxiety (β = −0.42 SE 0.16, P = 0.0078) interaction effects. Conclusion: These findings potentially broaden our understanding of the factors underlying clinical complaints to include the personality dimension of conscientiousness and its modification by COMT.