Abstract
Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP). Several genetic polymorphisms, including superoxide dismutase (SOD) and DRD3 9ser, have been suggested as explanations why some patients suffer from TD. Methods. A PubMed search was used to search relevant articles using the following keywords: “Tardive Dyskinesia and Superoxide Dismutase”. Fifty-eight articles were retrieved. Among them, 16 were included in this review. Results. Overall, 58 studies were retrieved from PubMed. Most studies investigated the association between TD and the SOD-related polymorphisms. In addition, previous studies reported an association between TD occurrence and other genetic polymorphisms. Conclusion. This study found that the risk of TD is associated with altered SOD levels and several genetic polymorphisms, including VAL 66 Met and DRD3 9ser.
Uludag, K., Wang, D. M., & Zhang, X. Y. (2022). Tardive dyskinesia development, superoxide dismutase levels, and relevant genetic polymorphisms. Oxidative Medicine and Cellular Longevity, 2022(1), 5748924.
https://onlinelibrary.wiley.com/doi/full/10.1155/2022/5748924
commentary:
Commentary: Genetic Information as a Predictive Tool for Tardive Dyskinesia – The Role of Superoxide Dismutase Polymorphisms
Tardive dyskinesia (TD) remains a debilitating, often irreversible movement disorder induced by chronic antipsychotic treatment. Despite decades of research, clinicians lack reliable biomarkers to predict which patients will develop TD before irreversible symptoms appear. The accumulating evidence linking TD to oxidative stress – and specifically to superoxide dismutase (SOD) activity and its genetic variants – offers a promising avenue for risk stratification.
The oxidative stress hypothesis of TD posits that antipsychotics, particularly first‑generation agents, increase free radical production in the basal ganglia. SOD is a critical first‑line antioxidant enzyme that converts superoxide radicals to hydrogen peroxide. Reduced SOD activity has been consistently observed in TD patients, suggesting that impaired antioxidant capacity leaves vulnerable neurons susceptible to oxidative damage.
Genetic polymorphisms in SOD genes (e.g., SOD1, SOD2, and SOD3) have been associated with altered enzyme activity and TD susceptibility. The most studied variant, SOD2 Val16Ala (rs4880), affects mitochondrial SOD activity: the Ala allele confers higher activity but may also increase hydrogen peroxide accumulation, a double‑edged sword. Meta‑analyses have reported significant, albeit modest, associations between the SOD2 Ala allele and TD risk in specific ethnic groups. Other variants, such as SOD1 rs2070424 and SOD3 rs2536512, have shown preliminary associations but require replication.
Why genetic prediction matters clinically:
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Pre‑emptive risk assessment – If a patient carries high‑risk SOD polymorphisms, clinicians could consider lower‑risk antipsychotics (e.g., second‑generation agents with lower TD liability), adjunctive antioxidants (e.g., vitamin E, N‑acetylcysteine), or more frequent TD monitoring.
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Personalising treatment duration – Genetic risk information might justify earlier antipsychotic rotation or use of clozapine (which has low TD risk) in genetically susceptible individuals.
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Mechanistic insights – SOD polymorphisms point to a specific pathological pathway. This encourages trials of targeted antioxidants or agents that modulate mitochondrial oxidative stress in high‑genetic‑risk subgroups.
Challenges and future directions:
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Small effect sizes – Current SNPs explain only a fraction of TD heritability. Polygenic risk scores combining multiple oxidative‑stress genes (e.g., SOD2, CAT, GPX1, NOS1) will likely outperform single variants.
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Ethnic heterogeneity – Allele frequencies and linkage disequilibrium patterns differ across populations; validated risk models must be population‑specific.
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Gene‑environment interactions – Smoking, iron status, and concomitant medications influence oxidative balance. Predictive algorithms must integrate both genetic and modifiable factors.
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Prospective validation – Most studies are cross‑sectional or case‑control. Longitudinal cohorts with baseline genotyping and serial TD assessments are urgently needed.
Conclusion: Genetic information, particularly SOD polymorphisms, is not yet ready for standalone clinical use in TD prediction. However, it provides a critical proof‑of‑concept that inherited antioxidant capacity contributes to TD risk. As part of a multi‑variant polygenic score combined with clinical and demographic predictors, SOD genotyping could become a valuable tool for personalised antipsychotic prescribing. Until then, it serves as a powerful research tool to identify patients for antioxidant prevention trials and to unravel the pathophysiology of this iatrogenic disorder.
