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.

1. Introduction

Tardive dyskinesia (TD) is a movement disorder that occurs due to an excessive exposure to antipsychotics (AP), an essential problem in schizophrenia (SCZ) patients since they need to use APs for an extended period [1]. However, it is unclear why some patients develop TD, while some do not, and therefore, genetic studies have been done to try to account for the susceptibility to TD [2]. The superoxide dismutase (SOD) polymorphism is one of the candidates reported to be related to TD occurrence. SODs are universal enzymes [3] that have an essential role in inflammatory diseases [4] and oxidative stress (OS) [5]. Therefore, due to their relation to these diseases, they are associated with cognitive functions such as memory and attention.

Many previous studies have found an association between serum SOD levels and TD occurrence [6, 7]. Additionally, SCZ patients with TD have lower copper-zinc couple SOD (CuZnSOD) activity than non-TD patients [8]. Similarly, a different study found a decrease in erythrocyte SOD activity in the TD group than the non-TD group [9].

Recently, genetic studies concerning TD susceptibility have gained importance, and the combination of the MnSOD-9val and DRD3 9ser alleles has been associated with TD (Z. J. [10]). Furthermore, a study found that the excess of the -697 variant in the promoter regulation of the HTR2C gene may be a risk factor for TD [10, 11]. However, a different study did not support the previous findings and reported that the MnSOD gene Ala-9Val polymorphism did not have a role in TD risk [12].

It is crucial to consider that the previous studies may have adopted different methods to investigate the association between SOD and TD, and taken together, systematically exploring the association between TD and SOD-related parameters is vital. Furthermore, we have investigated the association between TD and SOD-related parameters according to inflammation and OS concerning cognitive deficits.

2. Methods

A PubMed search was used to find articles relevant to tardive dyskinesia (TD) and superoxide dismutase (SOD) using the keywords “tardive dyskinesia and superoxide dismutase”. Overall, 58 articles were found. Animal studies were excluded from this study, as well as non-English articles, articles prior to 1997, and articles not relevant to this research question. All the included studies were written in English and published between 1997 and 10 June 2022 (total of 16 studies were included).

SOD activity is not simply observed directly due to the rapid substrate disappearance at physiological pH [13]. SOD levels can be measured in several ways, including in serum and erythrocytes. For most of the studies mentioned in this review, determination of plasma total SOD activities was executed using an assay involving spectrophotometric determination as in previous study [14]. In addition, genotyping was performed by polymerase chain reaction (PCR). For some studies, the genotypes were combined by their functional significance to investigate the interaction between polymorphisms.

There are no well-established and comprehensive methods for measuring OS in SCZ patients [15]. Overall, the techniques for measuring OS include reactive oxygen species (ROS) fingerprinting and ROS in body fluids [16]. In addition, OS can be investigated in the peripheral and central nervous systems. Moreover, regional variations in OS in human skin can be observed [17]. However, it is essential to note that antioxidant capacity markers are suggested to be associated with oxidative damage markers, although they are insufficient [18]. Several methods have been used to investigate oxidative base modifications, including gas and liquid chromatography [19]. Additionally, developing technology has helped to determine the location of oxidation-related DNA damage [19].

3. Results

A total of 16 articles were retrieved related to tardive dyskinesia (TD) and superoxide dismutase (SOD) and included in this study (Table 1). In addition, a few articles were also related to cognitive skills and TD.

3.1. Results of Studies Related to Superoxide Dismutase-Related Polymorphisms

The included studies investigated the association between TD and Ala-9Val, DRD3 9ser, NQO1 Pro187Ser, and HTR2C polymorphisms. Furthermore, the studies investigated the combination of genes, including the combination of the MnSOD -9val and CAT-262C>T, and DRD3 9ser alleles were associated with TD [10, 11]. The combined genotypes of T/T in NQO1 Pro187Ser and Val/Val in MnSOD Ala-9Val polymorphisms were associated with a higher TD risk [20]. In addition, the excess of the -697 variant in the promoter regulation of the HTR2C gene may be a risk factor for TD [10, 11]. Moreover, no critical roles of SOD2Val16Ala, CAT-262C>T, and GPX1Pro200Leu polymorphisms in TD occurrence were found [21].

3.2. Results of Studies Related to Serum Superoxide Dismutase Levels

Several studies investigated the relationship between SOD serum levels and TD occurrence.

One study showed lower CuZnSOD activity in patients with TD than those without TD [6, 7]. Furthermore, SCZ patients with TD had lower CuZnSOD activity than patients without TD [8].

Another study showed that MnSOD activity was lower in patients with TD than in non-TD patients [22]. In addition, a different study showed a decrease in erythrocyte SOD activity in the TD group compared with the non-TD group [9].

4. Discussion

This study found that superoxide dismutase (SOD) is vital in understanding the risk of TD occurrence and may be used as a biomarker to predict TD occurrence. Moreover, most of the studies related to genetics were focused on the SOD-related polymorphisms.

Despite the common literature, the papers were difficult to compare due to the differences in study samples, including age, study design, comorbid disorders, and hospitalization status; the aim of the studies; and the methodologies.

SOD regulates OS, inflammation, and oxidation [23]. Some environmental factors may also be associated with MnSOD, such as exercise [24]. In addition, some studies mentioned the link between SOD-related parameters and cognitive skills.

TD-related theories focused on postsynaptic D2 receptor supersensitivity and dopamine hyperactivity [25] while D2 receptor hypersensitivity and degenerative changes in the neurons due to exposure to oxidative stress (OS) can lead to impacts on the synaptic plasticity of glutamatergic synapses, leading to an imbalance between pathways of basal ganglia and creating aberrant output to the sensorimotor cortex [26, 27]. Therefore, OS-related parameters may be used to understand TD mechanisms.

4.1. The Relationship between Superoxide Dismutase (SOD) and Oxidative Stress

Superoxide is a prevalent ROS produced by the mitochondria [28]. SODs are essential in treating OS-related diseases [29], and elevated SOD was related to lower mortality in older females [30]. A balance in ROS is essential, and SOD, a normal metabolite in standard amounts, facilitates critical roles [5]. The structure and location of SODs are vital for a healthy balance of superoxides [31]. Therefore, therapeutics targeting oxidation and superoxides should be investigated for treating neurodegeneration [32].

4.2. The Relationship between Superoxide Dismutase (SOD) and Cognitive Skills

Previous studies have investigated the association between SOD and specific cognitive functions and have found that extracellular SOD played a vital role in various cognitive functions [33]. Another study demonstrated the role of reactive oxygen species (ROS) in learning deficit (R. [34]).

Studies with animal models that overexpressed superoxide scavengers demonstrated that some neuronal processes are changed during diminished superoxide-related signaling [35]. Furthermore, a different study suggested that participants with late-life SCZ had disturbances in their antioxidant system, which was related to cognitive problems [36]. Therefore, an antioxidant with mitochondrial activity may improve cognitive impairments [37]. One study investigated changes in SOD levels after antioxidant kaempferol use and demonstrated increased SOD and diminished memory problems in rats [38]. Moreover, it has also been found that low SOD was related to an increased risk of poststroke cognitive deficiency (M.-S. [39]).

Taken together, SOD may play an essential role in cognitive skills, and antioxidants may relieve TD symptoms.

4.3. Antioxidant Treatment on Relieving Tardive Dyskinesia Symptoms

Some antioxidants, including Ginkgo biloba, vitamin E, omega 3, piracetam, and curcumin, could reduce the severity of TD symptoms ([40]; X. Y. [41]). Elsewhere, it has been found that resveratrol enhanced the expression of antioxidant enzymes such as heme oxygenase 1 and SOD, which are responsible for redox balance [42]. Consequently, antioxidants have been commonly suggested to possibly alleviate the severity of TD symptoms through oxidative mechanisms.

5. Conclusion

In conclusion, SOD levels and several SOD polymorphisms (e.g., MnSOD -9val and DRD3 9ser) are vital in understanding the risk of TD. Also, some SOD polymorphisms may be related to the severity of TD symptoms.

6. Limitations

This study had some limitations. Firstly, our review does not include all the studies that were related to SOD. Additionally, the study did not apply meta-analysis methods in analyzing the data.

7. Suggestions for Further Studies

Future research should use a meta-analysis to further investigate the association between TD and SOD. Additional studies should demonstrate the treatment response of antioxidants using genetic methods.


TD:Tardive dyskinesia
SOD:Superoxide dismutase
CuZnSOD:Copper-zinc superoxide dismutase
ROS:Reactive oxygen species
BD:Bipolar disorder
OS:Oxidative stress
PCR:Polymerase chain reaction.

Additional Points

Key Points. Studies found an association between TD and various polymorphisms. TD-related genetic polymorphisms include MnSOD -9val and DRD3 9ser polymorphisms. TD risk is associated with altered SOD levels.

Conflicts of Interest

The authors have no conflict of interest to declare.


We thank Nathan Allen and Dave Mallpress for helping us improve the article’s quality. This work was supported by the CAS International Cooperation Research Program (153111KYSB20190004), the CAS Pioneer Hundred Talents Program, and the CAS Key Laboratory of Mental Health. Also, K.U. was supported by the Doctoral Scholarship, provided by Chinese government.