Tardive dyskinesia: Who gets it and why

Area of Science:

• Neuroscience
• Pharmacology
• Genetics

Background:

• Tardive dyskinesia (TD) is a potentially irreversible movement disorder caused by chronic use of dopamine receptor blocking agents (DRBA).
• Risk factors include antipsychotic type (first-generation agents being higher risk), illness duration, cumulative DRBA dose, advanced age, female sex, and certain ethnicities.
• Genetic susceptibility is suggested by the fact that only a subset of DRBA users develop TD, implicating genes in DRBA metabolism, receptor targets, and cellular processes.

Purpose of the Study:

• To review the known risk factors for tardive dyskinesia (TD).
• To explore potential genetic candidates involved in TD development.
• To discuss proposed pathogenic mechanisms of TD, including dopamine receptor supersensitivity, oxidative stress, and synaptic plasticity.

Main Methods:

• Literature review of studies on tardive dyskinesia (TD) and its associated risk factors.
• Analysis of genetic studies investigating susceptibility genes for TD.
• Discussion of proposed pathophysiological theories for TD development.

Main Results:

• Identified risk factors for TD include specific antipsychotics, duration and dose of DRBA, advanced age, female sex, and ethnicity.
• Potential genetic candidates implicated in TD include CYP2D6, Dopamine D2/D3 receptors, serotonin receptors (2A/2C), VMAT 2, MnSOD, and HSPG 2, though data are conflicting.
• Three main theories for TD pathogenesis are proposed: dopamine receptor supersensitivity, oxidative stress, and maladaptive synaptic plasticity.

Conclusions:

• Tardive dyskinesia (TD) is a significant adverse effect of DRBA, with multifactorial causes including clinical and genetic factors.
• While several genes are candidates, their definitive role in TD development requires further investigation.
• Understanding the pathogenesis of TD is crucial for prevention and management strategies, as it can be permanent and disabling.