HTR1A, HTR1B, HTR2A, HTR2C and HTR6 Gene Polymorphisms and Extrapyramidal Side Effects in Haloperidol-Treated Patients with Schizophrenia.

Mirko Grubor,Alma Mihaljevic-Peles,Matea Nikolac Perkovic,Dubravka Svob Strac,Maja Zivkovic,Marina Sagud,Dorotea Muck-Seler,Nela Pivac

doi:10.3390/ijms21072345

Abstract

Schizophrenia is a serious, chronic psychiatric disorder requiring lifelong treatment. Extrapyramidal side effects (EPS) are common adverse reactions to antipsychotic medications. In addition to the dopaminergic system, serotonergic mechanisms, including serotonin (5-HT) receptors, might be involved in EPS development. This study aimed to examine molecular associations of HTR1A, HTR1B, HTR2A, HTR2C and HTR6 gene polymorphisms with acute EPS in 229 male schizophrenia patients, following two weeks of haloperidol monotherapy. The Simpson–Angus Rating Scale for Extrapyramidal Side Effects (SAS), Barnes Akathisia Rating Scale (BARS) and Extrapyramidal Symptom Rating Scale (ESRS) were used to evaluate EPS severity. Genotyping was performed using real-time PCR, following extraction of blood DNA. Significant acute EPS appeared in 48.03% of schizophrenia patients. For the rs13212041 HTR1B gene polymorphism, affecting microRNA regulation of HTR1B gene expression, a higher frequency of TT carriers was found among haloperidol-treated patients with akathisia when compared to the group without akathisia symptoms. In comparison to C-allele carriers, patients carrying the TT genotype had higher akathisia severity, as determined by the SAS, BARS and ESRS scales. These molecular findings suggest potential involvement of 5-HT1B receptors in akathisia development following haloperidol treatment, as well as possible epigenetic mechanisms of serotonergic modulation associated with antipsychotic-induced EPS.

Highlights

Schizophrenia is a serious, chronic psychiatric disorder, requiring lifelong treatment [1]
A majority of the patients previously met the criteria for complete or partial disease remission, whereas 13.10% of them were considered to be treatment-resistant (Table 1). As demonstrated by their high baseline positive, negative, general psychopathology and total Positive and Negative Syndrome Scale (PANSS) scores, all subjects were admitted to the hospital due to acute exacerbation of schizophrenia and subsequently treated with haloperidol
A total of 66.81% of the schizophrenia patients reported some kind of EPS, and in those patients acute EPS usually developed on the 5th day of haloperidol monotherapy

Summary

Introduction

Schizophrenia is a serious, chronic psychiatric disorder, requiring lifelong treatment [1]. Due to its very strong antagonistic activity on dopamine D2 receptors of the mesolimbic dopamine pathway [3], haloperidol acts as a very potent antipsychotic agent, and it is included on the World Health Organization’s list of essential drugs [4]. Like other FGAs, it is associated with the development of both acute and long-term extrapyramidal side effects (EPS) [5], possibly due to blockade of the D2 receptor in the nigrostriatal pathway [6]. Other predictors of EPS include younger age, male gender, longer treatment durations, higher dosage, psychiatric diagnoses, such as mood disorder, and previous EPS history [8,9,10,11]. Genetic factors have been considered, including those related to the metabolism of antipsychotic drugs and free radical scavenging [12,13,14], as well as variants in genes coding for various components of the dopaminergic system [15,16,17]

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