Genetic Factors Associated With Tardive Dyskinesia: From Pre-clinical Models to Clinical Studies

Abstract

Tardive dyskinesia is a severe motor adverse event of antipsychotic medication, characterized by involuntary athetoid movements of the trunk, limbs, and/or orofacial areas. It affects two to ten patients under long-term administration of antipsychotics that do not subside for years even after the drug is stopped. Dopamine, serotonin, cannabinoid receptors, oxidative stress, plasticity factors, signaling cascades, as well as CYP isoenzymes and transporters have been associated with tardive dyskinesia (TD) occurrence in terms of genetic variability and metabolic capacity. Besides the factors related to the drug and the dose and patients’ clinical characteristics, a very crucial variable of TD development is individual susceptibility and genetic predisposition. This review summarizes the studies in experimental animal models and clinical studies focusing on the impact of genetic variations on TD occurrence. We identified eight genes emerging from preclinical findings that also reached statistical significance in at least one clinical study. The results of clinical studies are often conflicting and non-conclusive enough to support implementation in clinical practice.

Early Onset of Tardive Dyskinesia in an Antipsychotic-Naive Patient Treated With Low-Dose Cariprazine

“…Although research results are often conflicting and inconclusive, the D 3 receptor rs6280 has demonstrated an increase in the binding affinity of the receptor and has been associated with a higher chance of TD development. 16 The most prominent risk factors for developing TD include advanced age, elevated dosages of antipsychotic drugs, early onset of extrapyramidal symptoms, and the usage of FGAs and antiparkinsonian agents. In addition, preexisting affective and substance misuse disorders, cognitive decline, brain damage, and physical illnesses such as diabetes and HIV further contribute to the heightened likelihood of TD emergence.…”

“…From a genetic view standpoint, polymorphisms of the dopamine D 3 receptor Ser9Gly in patients with schizophrenia have been associated with TD, 15 supporting a possible role of D 3 receptor gene polymorphisms in susceptibility to TD. Although research results are often conflicting and inconclusive, the D 3 receptor rs6280 has demonstrated an increase in the binding affinity of the receptor and has been associated with a higher chance of TD development 16 …”

Tardive dyskinesia in Asia— current clinical practice and the role of neurologists in the care pathway

“…Therefore, genetic differences between individuals and populations are important to consider ( 31 ). The concept of pharmacogenomics is now being investigated in relation to APD prescribing in order to inform the selection of the most suitable therapeutic agent based on the patient's genetic information ( 92 ) and the link between a range of different genetic factors and the risk of developing TD is the subject of considerable research ( 93 ). These include dopamine and enzymes that metabolize it (such as dopamine beta-hydroxylase), serotonin, and the cytochrome P450 (CYP) family of enzymes in the liver that metabolize APDs and also many antidepressant medications, in particular CYP1A2, CYP2D6, CYP3A4, with CYP2C19, each of which can exhibit various polymorphisms that result in different phenotypes…”

A new era in the diagnosis and treatment of tardive dyskinesia

“…Pharmacogenetic studies of TD are preliminary but offer promise of identifying risk for TD 65 . Association studies of TD have focused on polymorphisms of genes related to metabolism of antipsychotics, neurotransmitter receptors, transporter proteins, and genes involved in synaptic plasticity, oxidative stress, and inflammation.…”