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Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?

ABSTRACT: The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes.A Caucasian sample of 70 patients was recruited in 1996-1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months prior to assessment. All patients were genotyped for CYP2D6 alleles*3-5, *41, and for amplifications of the gene.There were 13 patients with TD. The mean (standard deviation (SD)) years of duration of antipsychotic treatment in TD-positive was 15.8 (7.9) vs TD-negative 11.1 (7.4) (p=0.04). Increased odds of experiencing TD were associated with increased ability to metabolize CYP2D6, as measured by genotypic category (odds ratio (OR)=4.2), increasing duration in treatment (OR=1.0), and having drug-induced Parkinsonism (OR=9.7).We found a significant association between CYP2D6 genotypic category and TD with the direction of effect being an increase in the number of functional CYP2D6 genes being associated with an increased risk of TD. This is the first study to examine the association between TD and CYP2D6 in Caucasians with this number of genotypic categories. In the future, metabolomics may be utilized in the discovery of biomarkers and novel drug targets.

SUBMITTER: Koola MM

PROVIDER: S-EPMC5950711 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?

Koola Maju M MM Tsapakis Evangelia M EM Wright Padraig P Smith Shubulade S Kerwin Rip Robert W RW Nugent Katie L KL Aitchison Katherine J KJ

Journal of psychopharmacology (Oxford, England) 20140304 7

<h4>Background</h4>The aim of this study was to examine whether there was an association between tardive dyskinesia (TD) and number of functional CYP2D6 genes.<h4>Methods</h4>A Caucasian sample of 70 patients was recruited in 1996-1997 from South London and Maudsley National Health Service (NHS) Foundation Trust, UK. Subjects had a DSM-IIIR diagnosis of schizophrenia and were treated with typical antipsychotics at doses equivalent to at least 100 mg chlorpromazine daily for at least 12 months pr ...[more]

PMID: 24595968

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Project description:Tardive dyskinesia (TD), a movement disorder associated with antipsychotics, most frequently affects the lower face and jaw muscles, but can also affect walking, breathing and use of the hands and limbs. Knowledge of TD among physicians may be limited, and the pathophysiology of TD is poorly understood. We conducted this review to summarise the current knowledge surrounding the pathophysiology of TD and present recommendations for prevention and treatment based on a literature search and roundtable discussion attended by psychiatrists in Japan. It has been suggested that dopamine hypersensitivity, damaged gamma-aminobutyric acidergic neurons and/or increased production of reactive oxygen species may contribute to development of TD. Symptoms can profoundly affect everyday life; patients who develop TD have poorer prognoses, worse health-related quality of life, greater social withdrawal and higher mortality than patients without TD. Traditional treatment options include dietary supplements, although evidence for their effectiveness is low. Among pharmaceutical interventions, there is moderate evidence that switching to the second-generation antipsychotic clozapine, which has a lower affinity for dopamine D2 receptors than other antipsychotics, may improve symptoms. Vesicular monoamine transporter 2 (VMAT-2) inhibitors, which oppose the increased dopaminergic activity associated with prolonged antipsychotic use by interfering with dopamine uptake and storage, have the strongest evidence for efficacy. VMAT-2 inhibitors are approved in the United States for the treatment of TD, and the first VMAT-2 inhibitor was approved in Japan for this indication in March 2022. Most guidelines recommend treating TD by first reducing the dose of antipsychotics or switching to clozapine or other second-generation antipsychotics, which have a lower association with TD than first-generation antipsychotics. We recommend focusing on prevention and monitoring for TD when prescribing antipsychotics, given that TD is often irreversible. Physicians should treat with antipsychotics only when necessary and at the lowest effective dose, and frequently monitor for TD symptoms.Plain language summaryPlain Language Summary (In Japanese).Visual summaryVisual Summary (In Japanese).

Dataset Information

Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?

Publications

Association of tardive dyskinesia with variation in CYP2D6: Is there a role for active metabolites?

Similar Datasets

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