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Catechol-O-methyl transferase

About: Catechol-O-methyl transferase is a research topic. Over the lifetime, 1646 publications have been published within this topic receiving 87360 citations.


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TL;DR: The analyses indicate that there is an association between COMT Val108/158Met and schizophrenia in the general population and in Caucasian populations, this risk could be increased.
Abstract: An association between a catechol-O-methyltransferase (COMT) Val156Met (rs4680) polymorphism and schizophrenia has been reported in the literature, although no conclusive outcomes have been attained. The aim of this study was to evaluate the association of the COMT Val108/158Met polymorphism with schizophrenia in a systematic review and meta-analysis. We performed a keyword search on PubMed and EBSCO databases. All English language case-control studies published up to April 2015 were selected. A total of 67 studies were selected for inclusion. The genotype distribution of subjects with schizophrenia was compared with healthy control subjects, using allelic, additive, dominant and recessive models. The pooled results from the meta-analysis (15,565 cases and 17,251 healthy subjects) after the elimination of heterogeneity showed an association between COMT Val108/158Met and schizophrenia [recessive model: OR 1.08 CI 95 % (1.01-1.15)]. We conducted subgroup analyses according to ethnicity. An association was observed in our Caucasian population in the additive model [OR 1.21 CI 95 % (1.06-1.37)] and in the recessive model [OR 1.21 CI 95 % (1.11-1.32)], but not in the allelic or dominant models. However, when we analysed our Asian population after the elimination of heterogeneity, no evidence of a significant association was found in any of the genetic models. Our analyses indicate that there is an association between COMT Val108/158Met and schizophrenia in the general population. Furthermore, in Caucasian populations, this risk could be increased.

74 citations

Journal ArticleDOI
TL;DR: Opicapone was well-tolerated and presented dose-proportional kinetics, and sustained inhibition of erythrocyte soluble COMT activity was demonstrated, providing a basis for further clinical development of opicapone.
Abstract: Opicapone is a novel catechol-O-methyltransferase (COMT) inhibitor. The purpose of this study was to evaluate the tolerability, pharmacokinetics (including the effect of food) and pharmacodynamics (effect on COMT activity) following single oral doses of opicapone in young healthy male volunteers. Single rising oral doses of opicapone (10, 25, 50, 100, 200, 400, 800 and 1,200 mg) were administered to eight groups of eight subjects per group (two subjects randomized to placebo and six subjects to opicapone), under a double-blind, randomized, placebo-controlled design. In an additional group of 12 subjects, a 50 mg single dose of opicapone was administered on two occasions, once having fasted overnight and once with a high-fat high-calorie meal. Opicapone was well tolerated at all doses tested. The extent of systemic exposure (area under the plasma concentration–time curve and maximum plasma concentration) to opicapone and metabolites increased in an approximately dose-proportional manner and showed a decrease following concomitant ingestion of a high-fat high-calorie meal. The apparent terminal elimination half-life of opicapone was 0.8–3.2 h. Sulphation appeared to be the main metabolic pathway for opicapone, and both opicapone and the main sulphated metabolite are likely excreted by the biliary route. Maximum COMT inhibition by opicapone was dose dependent, ranged from 36.1 % (10 mg) to 100 % (200 mg and above), and reached statistical significance at all doses tested. The long duration of COMT inhibition by opicapone, however, tended to be independent from the dose taken. The observed half-life of opicapone-induced COMT inhibition in human erythrocytes was 61.6 h (standard deviation [SD] = 37.6 h), which reflects an underlying dissociative process with a kinetic rate constant of 3.1 × 10−6 s−1 (SD = 1.9 × 10−6 s−1). Such a process compares well to the estimated dissociation rate constant (koff) of the COMT–opicapone molecular complex (koff = 1.9 × 10−6 s−1). Opicapone was well-tolerated and presented dose-proportional kinetics. Opicapone demonstrated marked and sustained inhibition of erythrocyte soluble COMT activity. Based on the observation that the half-life of COMT inhibition is independent of the dose and that it reflects an underlying kinetic process that is consistent with the koff value of the COMT–opicapone complex, we propose that the sustained COMT inhibition, far beyond the observable point of clearance of circulating drug, is due to the long residence time of the reversible complex formed between COMT and opicapone. Globally, these promising results provide a basis for further clinical development of opicapone.

74 citations

Journal ArticleDOI
TL;DR: While for PD patients, val homozygotes showed heightened DLPFC activation and increased set-like behavior, for healthy older adults, the opposite pattern of results was observed and supports the hypothesis that there is an inverted-U shaped functional relationship between PFC DA levels and attentional set formation.
Abstract: A key mechanism by which the prefrontal cortex (PFC) supports goal-oriented behaviors is attentional set formation: the formation and maintenance of an attentional bias toward relevant features It has previously been proposed that a common single nucleotide polymorphism (val158met) in the gene that codes for the catechol O-methyltransferase (COMT) enzyme may affect an individual's ability to form and maintain an attentional set by modulating PFC dopamine (DA) levels Here, we present data from a functional magnetic resonance imaging study that investigated the effect of this polymorphism on the tendency for older adults to display set-like behavior, and we compare these results to preexisting data from Parkinson's Disease (PD) patients Our results demonstrate that putatively different levels of PFC DA predict both attentional set formation and right dorsolateral PFC (DLPFC) activation More specifically, while for PD patients, val homozygotes showed heightened DLPFC activation and increased set-like behavior, for healthy older adults, the opposite pattern of results was observed This interaction between COMT genotype and PD accords well with previous studies that have shown an excess of DA in the PFC in early PD patients and, furthermore, supports the hypothesis that there is an inverted-U shaped functional relationship between PFC DA levels and attentional set formation

74 citations

Journal ArticleDOI
TL;DR: These findings support a model in which exploration is hypothesized to have a dopaminergic basis, and in keeping with findings in other behavioral and cognitive domains, the response to an increase in presumptively frontal dopamine is dependent upon baseline dopamine tone.

74 citations

Journal ArticleDOI
TL;DR: Erythrocyte catechol-O-methyl transferase activity was studied in patients with primary affective disorders and controls and in selected relatives, suggesting that COMT activity identifies genetic vulnerability to affective order.
Abstract: • Erythrocyte catechol-O-methyl transferase (COMT) activity was studied in 53 patients with primary affective disorders and 38 controls and in selected relatives. Patients with affective disorders tended to have higher activity levels than normals, after correcting for sex differences. The COMT activity was positively correlated between relatives and is heritable. Within families, elevation of COMT activity distinguished healthy relatives from probands and ill relatives. This suggests that COMT activity elevation and affective illness do not show independent assortment and implies that COMT activity identifies genetic vulnerability to affective disorder.

73 citations


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Performance
Metrics
No. of papers in the topic in previous years
YearPapers
202338
202265
202129
202032
201931
201834