Cognition impairment in schizophrenia patients with tardive dyskinesia: Association with plasma superoxide dismutase activity
Introduction
Long-term antipsychotic medication for schizophrenia is associated with the emergence of tardive dyskinesia (TD) (Lohr et al., 2003). While the pathophysiology of TD is not well understood, a number of risk factors including age, gender, length of antipsychotic treatment, prominent negative symptoms and thought disorder, more severe cognitive impairment, early onset extrapyramidal side effects, and diagnosis of diabetes mellitus have been identified (Sachdev, 2000). Among these factors, cognitive impairment was not only found to be more severe in schizophrenia patients with TD (Wegner et al., 1985b, Waddington and Youssef, 1986), but also specifically linked to orofacial dyskinesia (Waddington et al., 1987, Byne et al., 1998). Longitudinal perspective studies have found that cognitive deficits preceded the onset of TD and may be a risk factor (Struve and Willner, 1983, Wegner et al., 1985a), whereas others found that TD was predictive of impaired cognitive function in association with the development of orofacial dyskinesia (Waddington and Youssef, 1996). Our recent study in a larger cohort replicated these earlier findings, showing that TD was associated with greater cognitive impairment in patients with schizophrenia compared to those without TD (Wu et al., 2013).
Previous studies have evidenced that oxidative stress is associated with cognitive impairment in schizophrenia (Bitanihirwe and Woo, 2011, Yao and Keshavan, 2011) and with pathophysiology of TD (Lohr et al., 1990, Peet et al., 1993, Yamada et al., 1997, Tsai et al., 1998, Bitanihirwe and Woo, 2011, Yao and Keshavan, 2011). Preclinical and clinical studies implicated that oxidative stress-induced damage may contribute to cognitive impairment such as learning and memory (Fukui et al., 2001, Nicolle et al., 2001, Hu et al., 2006, Kapogiannis and Mattson, 2011). A recent preclinical study has found that in the DN-DISC1 mice model, the significant oxidative stress in the prefrontal cortex could elicit the activation of the nuclear GAPDH signaling cascade (Johnson et al., 2013). Augmentation of the oxidative stress-associated cascade can affect epigenetic and transcriptional machinery, which points to a mediating condition that could contribute to both cognitive and motivational impairments. In humans, it was reported that working memory ability was negatively correlated with protein carbonyl content (PCC), the most widely used marker of oxidative modification of proteins in schizophrenia (Asevedo et al., 2013) and serum protein oxidative stress was also elevated in siblings of patients with schizophrenia (Massuda et al., 2013). Our recent study has detected that total antioxidant status is significantly associated with attention index and RBANS total scores in schizophrenia patients, suggesting that progressive cognitive impairments in schizophrenia may be causally related to impaired antioxidant capacity resulting in increased oxidative stress (Zhang et al., 2012b). At the molecular level, the mechanism underlying the 6p25–p24 region linked to schizophrenia in families with high composite cognitive deficit scores has been pinned down to two adjacent promoter SNPs (rs7752203–rs4141761), which affected expressions of mitochondrial protein LYRM4 (Jablensky et al., 2012). LYRM4 down-regulation has been suggested as one of the mechanisms involved in inefficient oxidative phosphorylation and oxidative stress, increasingly recognized as contributors to schizophrenia pathogenesis. In relation to TD, previous studies have found lower levels of antioxidant markers superoxide dismutase (SOD) and thiobarbituric acid reactive substances (TBARS) in cerebrospinal fluid and peripheral tissues of schizophrenia patients with TD (Lohr et al., 1990, Peet et al., 1993, Yamada et al., 1997, Tsai et al., 1998). Also, our studies have found lower levels of plasma SOD, glutathione peroxidase, catalase, total antioxidant status, and higher malondialdehyde (MDA) levels in schizophrenia patients with TD compared to those without TD (Zhang et al., 2003, Zhang et al., 2007, Chen da et al., 2010).
In view of cognitive deficits and the marked alterations in oxidative stress existed in TD patients, and the important implication of oxidative stress in cognition, it would be of interest to explore the association between cognitive impairments and oxidative stress in TD. However, to our best knowledge, no previous studies have examined this association in TD. In the current study, we compared both the cognitive performance assessed by RBANS and the activity of the key antioxidant enzyme MnSOD in blood from schizophrenia patients with TD to those without TD, as well as healthy controls in a Chinese population. Given the fact that gender differences exist in cognitive domains and oxidative stress parameters in both schizophrenia patients and controls (Halari et al., 2006, Wisner et al., 2011, Han et al., 2012, Zhang et al., 2012a), we only included male subjects in this study.
Section snippets
Ethics statement
The research protocol was approved by the Institutional Review Board, Beijing Hui-Long-Guan hospital. A psychiatrist explained the research protocol and procedures to the potential subject. The description of the study was tailored to maximize the understanding of the subject using language appropriate to the subject's level of comprehension, and emotional readiness. If the subject was willing to consent to participate in the study the researcher provided an in depth description to the subject
Results
Clinical and demographic characteristics for the schizophrenia patients with and without TD along with healthy controls are presented in Table 1. Patients with TD, without TD, and normal controls showed no differences in age, education, body mass index (BMI), and smoking status (all p > 0.05). Age, education, BMI, and smoking status were not associated with MnSOD activity in the combined group, or when the associations were examined in TD, non-TD, and control groups respectively (all p > 0.05).
Discussion
Results from the present study revealed that 1) plasma MnSOD activity was significantly decreased in schizophrenia patients with TD than those without TD, and for each patient group (TD versus controls, non-TD versus controls), MnSOD activity was lower than the controls (Table 1); 2) the TD patients had significantly lower RBANS total score and Visuospatial/Constructional index score than the non-TD patients, and each patient group scored lower than the controls on all subscales of RBANS except
Role of funding source
This work was funded by the grant from the Beijing Municipal Natural Science Foundation (#7132063 and#7072035), National Natural Science Foundation of China (#81371477), NARSAD Independent Investigator Grant (#20314), and the Stanley Medical Research Institute (03T-459 and 05T-726). Jing Qin Wu received an NHMRC postdoctoral training fellowship (GNT1016870). These sources had no further role in study design, data collection and analysis, decision to publish, or preparation of the article.
Contributors
Jing Qin Wu and Xiang Yang Zhang were responsible for study design, statistical analysis, and manuscript preparation. Da Chun Chen, Yun Long Tan, Shu ping Tan, Zhi Ren Wang, Mei Hong Xiu and Fu De Yang were responsible for recruiting the patients, performing the clinical rating and collecting the samples. Xiang Yang Zhang was involved in writing the protocol, providing the funding for the study and editing the manuscript. All authors have contributed to and have approved the final manuscript.
Conflict of interest
The authors reported no biomedical financial interests or potential conflicts of interest.
Acknowledgments
The authors would like to thank Wu Fang Zhang, Song Chen, Zhi Ren Wang, Ling Yan Qi, Bao Hua Zhang, and Gui Gang Yang for all of their hard work and significant contributions toward the study.
References (66)
- et al.
Impact of peripheral levels of chemokines, BDNF and oxidative markers on cognition in individuals with schizophrenia
J. Psychiatr. Res.
(2013) - et al.
Oxidative stress in schizophrenia: an integrated approach
Neurosci. Biobehav. Rev.
(2011) - et al.
Glutathione peroxidase and CT scan abnormalities in schizophrenia
Biol. Psychiatry
(1987) - et al.
Platelet glutathione peroxidase and monoamine oxidase activity in schizophrenics with CT scan abnormalities: relation to psychosocial variables
Psychiatry Res.
(1990) - et al.
Cognitive functioning in schizophrenia and bipolar disorder: comparison of performance on the Repeatable Battery for the Assessment of Neuropsychological Status
Psychiatry Res.
(2004) - et al.
Elevated serum superoxide dismutase and thiobarbituric acid reactive substances in schizophrenia: a study of patients treated with haloperidol or clozapine
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2006) - et al.
Tardive dyskinesia: neuropsychological, computerized tomographic, and psychiatric symptom findings
Biol. Psychiatry
(1991) - et al.
Cognitive impairment but preservation of sexual dimorphism in cognitive abilities in chronic schizophrenia
Psychiatry Res.
(2006) - et al.
Gender differences in cognitive function of patients with chronic schizophrenia
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2012) - et al.
Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease
Lancet Neurol.
(2011)