Catechol-O-methyltransferase val158met polymorphism predicts placebo effect in irritable bowel syndrome

Abstract

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.

Figure 1. Effect of COMT genotype on change in IBS-SSS.

Number of val158met met alleles showed a significant linear effect on IBS-SSS (beta = 0.17; p = .032). IBS-SSS includes abdominal pain severity, abdominal pain frequency, abdominal distention severity, dissatisfaction with bowel habits, and disruption of quality of life. Change in IBS-SSS  =  (IBS-SSS at baseline – IBS-SSS at 3-weeks). Regression model included COMT genotype (number of met alleles) and baseline IBS-SSS. Error bars indicate the standard error of the mean. N = 104.

Figure 2. Interaction effect of COMT genotype and treatment arm on change in IBS-SSS.

The interaction between COMT genotype (number of met alleles) and treatment arm was statistically significant (beta = 0.17; p = .035). Regression model included the following parameters: COMT genotype (number of met alleles), treatment arm, baseline IBS-SSS and their interaction (COMT genotype x treatment arm). Error bars indicate the standard error of the mean. N = 104.

Figure 3. Interaction effect of COMT genotype and treatment arm on Adequate Relief.

The interaction (COMT genotype x treatment arm) was statistically significant (beta = 0.25; p = .009), but not COMT genotype (beta = 0.01; p = .954). Adequate Relief was assessed by a single dichotomous categorization at three weeks, which asked patients: “Over the past week have you had adequate relief of your IBS symptoms?” Regression model parameters included: COMT genotype (number of met alleles), treatment arm and their interaction (COMT genotype x treatment arm). Error bars are standard error of the mean. N = 102.