Role of COMT V158M Polymorphism in the Development of Dystonia after Administration of Antipsychotic Drugs.

Antonio Gennaro Nicotera,Maria Cristina Costanzo,Sebastiano Antonino Musumeci,Laura Turriziani,Antonino Musumeci,Rosanna Galati Rando,Emanuela Stracuzzi,Girolamo Aurelio Vitello,Francesco Calì,Gabriella Di Rosa,Mirella Vinci

doi:10.3390/brainsci11101293

Abstract

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia; however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient’s genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.

Highlights

Dopamine is a neurotransmitter that belongs to the catecholamine and phenethylamine families
These results showed a significant deviation from the Hardy-Weinberg equilibrium for V158M variation in APDR patients (p = 0.0003), while, as we expected, the control group was in the Hardy-Weinberg equilibrium for the same variant
94.11% of patients included in the APDR group (n = 16/17) did not experience any adverse effect since they were carrying A/A and G/G polymorphisms. These data suggest that G/G and A/A genotype polymorphisms of catechol O-methyltransferase (COMT) gene are associated with a protective effect for developing collateral extrapyramidal symptoms in patients treated with antipsychotics drugs (APDs); on the other hand, the G/A genotype, almost exclusively present in APDS patients, could be considered as a risk factor for developing dystonia after administration of APDs

Summary

Introduction

Dopamine is a neurotransmitter that belongs to the catecholamine and phenethylamine families. It is released by neurons and plays a critical role in the motivational component, release of various hormones, and motor control. Dopamine exerts its functions by binding to different dopamine receptors located throughout the peripheral and central nervous systems [1]. Dopamine receptors are a class of G protein-coupled receptors. There are five subtypes of dopamine receptors, which include: D1, D2, D3, D4, and D5. Based on their biochemical and structural properties, these receptors are divided into two different groups: D1-like group (including D1 and D5) and D2-like group (including D2, D3, and D4). D1 receptors are post-synaptically expressed and increase the probability of neuronal firing [2], while D2 receptors are expressed both pre-synaptically and post-synaptically

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