No Association of a Set of Candidate Genes on Haloperidol Side Effects

Drago, Antonio; Giegling, Ina; Schäfer, Martin; Hartmann, Annette M.; Möller, Hans; Ronchi, Diana De; Stassen, Hans H.; Serretti, Alessandro; Rujescu, Dan

doi:10.1371/journal.pone.0044853

Cited by 7 publications

(3 citation statements)

References 30 publications

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“…3 , 6 , 7 There are also some findings regarding the absence of correlation between development of side effects during haloperidol medication and different gene polymorphisms. 8 An investigation on CYP3A4*22 polymorphism shows that presence of this heterozygote does not increase the serum levels of antipsychotics (including haloperidol) which are metabolized by CYP3A4 and CYP2D6. 9 The role of CYP3A5 should be investigated deeper as there is evidence that CYP3A5 catalyzes the alternative metabolic pathways which can lead to appearance of intermediate metabolites with yet unknown pharmacological properties, and it can also limit the biological availability of the drug which passes through the first metabolic pathway.…”

Section: Introductionmentioning

confidence: 99%

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

Застрожин

Grishina

Ryzhikova

et al. 2017

PGPM

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BackgroundIsoenzymes CYP2D6 and CYP3A4, the activity of which varies widely, are involved in metabolism of haloperidol and may influence its profile of efficacy and safety.ObjectiveThe primary aim of this study was to estimate the relationship between CYP3A5 gene polymorphism, activity of the CYP3A isoenzyme, and the risk of development of adverse drug reactions by haloperidol in patients with alcohol abuse.MethodsSixty-six male alcohol-addicted patients participated in the study. The safety of haloperidol was evaluated by Udvalg for Kliniske Undersogelser Side Effect Rating Scale (UKU) and Simpson–Angus Scale for extrapyramidal symptoms (SAS). The activity of CYP3A was evaluated by determining the concentrations of an endogenous substrate of this isoenzyme (cortisol) and its urinary metabolite (6-beta-hydroxycortisol, 6-B-HC). Genotyping of CYP3A5*3 was performed by real-time polymerase chain reaction with allele-specific hybridization.ResultsThe frequency of A-allele occurrence in Russian population was very poor (2.27%). CYP3A5*3 polymorphism had no influence on safety profile indicators of haloperidol (UKU scale: p=0.55, SAS scale: p=0.64). In addition, there was no statistical significant difference between the values of indexes of the metabolic ratio (6-B-HC/cortisol) in groups with different genotypes of CYP3A5*3: GG 5.00 (3.36; 6.39) vs AG 5.26 (2.10; 6.78) (p=0.902).ConclusionThe frequency of A-allele occurrence of CYP3A5*3 in Russian population is very poor, and it has no high influence on the safety of haloperidol treatment; therefore, there are no reasons to take this polymorphism into account in patients with alcohol addiction who receive haloperidol.

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Section: Introductionmentioning

confidence: 99%

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

Застрожин

Grishina

Ryzhikova

et al. 2017

PGPM

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“…Despite extensive efforts, we have a limited understanding of the heritability of motoric ADRs in humans (Zhang and Malhotra 2011;Drago et al 2012;Crowley et al 2014). As shown in Table 2, estimates of heritability for the phenotypes measured using the CC-RIX ranged from 0.21 (for change in body weight) to 0.4 (for both number of VCMs and change in distance traveled).…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

Giusti‐Rodríguez

Xenakis

Crowley

et al. 2020

G3 Genes|Genomes|Genetics

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Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors. Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychotic-induced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS). Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol. Understanding the genetic basis for the susceptibility to antipsychotic ADRs may be possible in mouse, and extrapolation to humans could lead to safer therapeutic approaches for schizophrenia.

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“…Despite extensive efforts, we have a limited understanding of the heritability of motoric ADRs in humans (Z hang and M alhotra 2011; D rago et al . 2012; C rowley et al .…”

Section: Discussionmentioning

confidence: 99%

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

Giusti‐Rodríguez

Xenakis

Crowley

et al. 2019

Preprint

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Schizophrenia is an idiopathic disorder that affects approximately 1% of the human population, and presents with persistent delusions, hallucinations, and disorganized behaviors.Antipsychotics are the standard pharmacological treatment for schizophrenia, but are frequently discontinued by patients due to inefficacy and/or side effects. Chronic treatment with the typical antipsychotic haloperidol causes tardive dyskinesia (TD), which manifests as involuntary and often irreversible orofacial movements in around 30% of patients. Mice treated with haloperidol develop many of the features of TD, including jaw tremors, tongue protrusions, and vacuous chewing movements (VCMs). In this study, we used genetically diverse Collaborative Cross (CC) recombinant inbred inter-cross (RIX) mice to elucidate the genetic basis of antipsychoticinduced adverse drug reactions (ADRs). We performed a battery of behavioral tests in 840 mice from 73 RIX lines (derived from 62 CC strains) treated with haloperidol or placebo in order to monitor the development of ADRs. We used linear mixed models to test for strain and treatment effects. We observed highly significant strain effects for almost all behavioral measurements investigated (p<0.001). Further, we observed strong strain-by-treatment interactions for most phenotypes, particularly for changes in distance traveled, vertical activity, and extrapyramidal symptoms (EPS). Estimates of overall heritability ranged from 0.21 (change in body weight) to 0.4 (VCMs and change in distance traveled) while the portion attributable to the interactions of treatment and strain ranged from 0.01 (for change in body weight) to 0.15 (for change in EPS).Interestingly, close to 30% of RIX mice exhibited VCMs, a sensitivity to haloperidol exposure, approximately similar to the rate of TD in humans chronically exposed to haloperidol.

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No Association of a Set of Candidate Genes on Haloperidol Side Effects

Cited by 7 publications

References 30 publications

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

The influence of CYP3A5 polymorphisms on haloperidol treatment in patients with alcohol addiction

Antipsychotic Behavioral Phenotypes in the Mouse Collaborative Cross Recombinant Inbred Inter-Crosses (RIX)

Antipsychotic behavioral phenotypes in the mouse Collaborative Cross recombinant inbred inter-crosses (RIX)

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