Kathryn T. Hall

Catechol-O-Methyltransferase val158met Polymorphism Predicts Placebo Effect in Irritable Bowel Syndrome

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.

Effect of increased body mass index and anaesthetic duration on recovery of protective airway reflexes after sevoflurane vs desflurane

BACKGROUND Increased BMI may increase the bodys capacity to store potent inhaled anaesthetics, more so with more soluble agents. Accordingly, we asked whether increased BMI and longer anaesthesia prolonged airway reflex recovery. METHODS We measured time from anaesthetic discontinuation until first response to command (T1); from response to command until ability to swallow (T2); and from anaesthetic discontinuation to recovery of ability to swallow (T3) in 120 patients within three BMI ranges (18-24, 25-29, and >or=30 kg m(-2)). All received sevoflurane or desflurane, delivered via an LMA. RESULTS T1 and T3 after sevoflurane exceeded T1 and T3 after desflurane: 6.6 (sd 4.2) vs 4.0 (1.9) min (P<0.001), and 14.1 (sd 8.3) vs 6.1 (2.0) min (P<0.0001). T3 correlated more strongly with BMI after sevoflurane (28 s per kg m(-2), P=0.02) than desflurane (7 s per kg m(-2), P=0.03). Regarding T2, patients receiving sevoflurane with BMI >or=30 kg m(-2) were less often able to swallow 2 min after response to command than were those with BMI 18-24 or 25-29 kg m(-2) (3/20 vs 10/20 or 9/20, P<0.05). Each sevoflurane MAC-hour delayed T3 by 4.5 min (268 s) (R=0.46, P<0.001) whereas each desflurane MAC-hour delayed T3 by 0.2 min (16 s) (R=0.10, P=0.44). CONCLUSIONS Prolonged sevoflurane administration and greater BMI delay airway reflex recovery. The contribution of BMI to this delay is more pronounced after sevoflurane than desflurane.

Complementation of V(D)J recombination defect and X-ray sensitivity of scid mouse cells by human chromosome 8

Cells derived from mice homozygous for the severe combined immune deficiency (scid) mutation exhibit hypersensitivity to ionizing radiation, and defects in DNA double-strand break repair and V(D)J recombination. Using the technique of microcell-mediated chromosome transfer, we have introduced a number of dominantly marked human chromosomes into scid cells to localize the human homolog of the murine scid gene. Analysis of human-scid hybrid clones revealed that the presence of human chromosome 8 partially restored accurate V(D)J recombination and radioresistance to scid cells. Subsequent loss of the human chromosome 8 from human-scid hybrid clones rendered these cells sensitive to gamma-radiation and impaired their ability to catalyse V(D)J recombination. Introduction of chromosomes 2, 14, 16 and 19 that encode other repair genes did not result in the correction of these two scid defects. These observations demonstrate that the human homolog of the mouse scid gene resides on human chromosome 8.

Polymorphisms in Catechol-O-Methyltransferase Modify Treatment Effects of Aspirin on Risk of Cardiovascular Disease

Objective— Catechol-O-methyltransferase (COMT), a key enzyme in catecholamine metabolism, is implicated in cardiovascular, sympathetic, and endocrine pathways. This study aimed to confirm preliminary association of COMT genetic variation with incident cardiovascular disease (CVD). It further aimed to evaluate whether aspirin, a commonly used CVD prevention agent, modified the potential association of COMT with incident CVD. Approach and Results— We examined COMT polymorphism rs4680 (MAF [minor allele frequency], 0.47), encoding a nonsynonymous methionine-to-valine substitution, in the Women’s Genome Health Study (WGHS), a large population-based cohort of women with randomized allocation to aspirin or vitamin E when compared with placebo and 10-year follow-up. Rs4680 effects were confirmed with COMT polymorphism rs4818 and also examined in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis/The Coronary Artery Disease Genetics Consortium, consortia for genome-wide association studies of coronary artery disease. Among WGHS women allocated to placebo (135 events/n=5811), the rs4680 valine allele was protective against incident CVD relative to the methionine (hazard ratio [HR; 95% confidence interval {CI}], 0.66 [0.51–0.84]; P=0.0007); an association also observed in Coronary ARtery DIsease Genome-wide Replication and Meta-analysis and The Coronary Artery Disease Genetics Consortium (combined P=2.4×10−5). In the WGHS, the rs4680 association was abolished by randomized allocation to aspirin, such that valine/valine women experienced higher CVD rates with aspirin allocation when compared with placebo (HR [95% CI], 1.85 [1.05–3.25]; P=0.033), whereas methionine/methionine women experienced lower rates (HR [95% CI], 0.60 [0.39–0.93]; P=0.023). Allocation to vitamin E also conferred higher but nonsignificant CVD rates on valine/valine (HR [95% CI], 1.50 [0.83–2.70]; P=0.180) when compared with significantly lower rates on methionine/methionine (HR [95% CI], 0.53 [0.34–0.84]; P=0.006) women. Rs4818 results were similar. Conclusions— Common COMT polymorphisms were associated with incident CVD, and this association was modified by randomized allocation to aspirin or vitamin E. Replication of these findings is required.

Placebo, nocebo, and neuropathic pain.

Abstract Over the last decade, the apparent increase in placebo responses in randomized controlled trials (RCTs) of neuropathic pain have complicated and potentially limited development and availability of new effective pain medication. Placebo analgesia and nocebo hyperalgesia effects are well described in nociceptive and idiopathic pain conditions, but less is known about the magnitude and mechanisms of placebo and nocebo effects in neuropathic pain. In neuropathic pain, placebo treatments have primarily been used as control conditions for active agents under investigation in RCTs and these placebo responses are typically not controlled for the natural history of pain and other confounding factors. Recently, mechanistic studies that control for the natural history of pain have investigated placebo and nocebo effects in neuropathic pain in their own right. Large placebo analgesia but no nocebo hyperalgesic effects have been found, and the underlying mechanisms are beginning to be elucidated. Here we review placebo and nocebo effects and the underlying mechanisms in neuropathic pain and compare them with those of nociceptive and idiopathic pain. This allows for a novel discussion on how knowledge of psychological, neurobiological, and genetic factors underlying well-controlled placebo effects may help improve the information that can be obtained from and potentially restore the utility of RCTs.

STAAR: improving the reliability of care coordination and reducing hospital readmissions in an academic medical centre.

Setting Massachusetts General Hospital embarked on a 4-year project to reduce readmissions in a high volume general medicine unit (November 2009 to September 2013). Objective To reduce 30-day readmissions to 10% through improved care coordination. Design As a before–after study, a total of 7586 patients admitted to the medicine unit during the intervention period included 2620 inpatients meeting high risk for readmission criteria. Of those, 2620 patients received nursing interventions and 539 patients received pharmacy interventions. Intervention The introduction of a Discharge Nurse (D/C RN) for patient/family coaching and a Transitional Care Pharmacist (TC PharmD) for predischarge medication reconciliation and postdischarge patient phone calls. Other interventions included modifications to multidisciplinary care rounds and electronic medication reconciliation. Main outcome measure All-cause 30-day readmission rates. Results Readmission rates decreased by 30% (21% preintervention to 14.5% postintervention) (p<0.05). From July 2010 to December 2011, rates of readmission among high-risk patients who received the D/C RN intervention with or without the TC PharmD medication reconciliation/education intervention decreased to 15.9% (p=0.59). From January to June 2010, rates of readmission among high-risk patients who received the TC PharmD postdischarge calls decreased to 12.9% (p=0.55). From June 2010 to December 2011, readmission rates for patients on the medical unit that did not receive the designated D/C RN or TC PharmD interventions decreased to 15.8% (p=0.61) and 16.2% (0.31), respectively. Conclusions A multidisciplinary approach to improving care coordination reduced avoidable readmissions both among those who received interventions and those who did not. This further demonstrated the importance of multidisciplinary collaboration.

Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial

BackgroundPlacebo 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 designThis 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.DiscussionOLP 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 registrationClinicalTrials.gov, identifier: NCT02802241. Registered on 14 June 2016.

Genetic variation in catechol-O-methyltransferase modifies effects of clonidine treatment in chronic fatigue syndrome

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 2500 fewer steps compared with placebo (Pinteraction=0.04). There were no differences between clonidine and placebo among patients with COMT low-activity alleles. Similar gene–drug interactions were observed for sleep (Pinteraction=0.003) and quality of life (Pinteraction=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.

Conscientiousness is modified by genetic variation in catechol‐O‐methyltransferase to reduce symptom complaints in IBS patients

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.

Catechol-O-methyltransferase association with hemoglobin A1c.

AIMS Catecholamines have metabolic effects on blood pressure, insulin sensitivity and blood glucose. Genetic variation in catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines, is associated with cardiometabolic risk factors and incident cardiovascular disease (CVD). Here we examined COMT effects on glycemic function and type 2 diabetes. METHODS We tested whether COMT polymorphisms were associated with baseline HbA1c in the Womens Genome Health Study (WGHS), and Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC), and with susceptibility to type 2 diabetes in WGHS, DIAbetes Genetics Replication And Meta-analysis consortium (DIAGRAM), and the Diabetes Prevention Program (DPP). Given evidence that COMT modifies some drug responses, we examined association with type 2 diabetes and randomized metformin and aspirin treatment. RESULTS COMT rs4680 high-activity G-allele was associated with lower HbA1c in WGHS (β=-0.032% [0.012], p=0.008) and borderline significant in MAGIC (β=-0.006% [0.003], p=0.07). Combined COMT per val allele effects on type 2 diabetes were significant (OR=0.98 [0.96-0.998], p=0.03) in fixed-effects analyses across WGHS, DIAGRAM, and DPP. Similar results were obtained for 2 other COMT SNPs rs4818 and rs4633. In the DPP, the rs4680 val allele was borderline associated with lower diabetes incidence among participants randomized to metformin (HR=0.81 [0.65-1.00], p=0.05). CONCLUSIONS COMT rs4680 high-activity G-allele was associated with lower HbA1c and modest protection from type 2 diabetes. The directionality of COMT associations was concordant with those previously observed for cardiometabolic risk factors and CVD.