Increased serum levels of cysteine in patients with schizophrenia: A potential marker of cognitive function preservation
Introduction
Schizophrenia is a serious mental disorder which affects approximate 1% of the global population (Chong et al., 2016, Owen et al., 2016). Patients with schizophrenia exhibit positive symptoms, negative symptoms, mood symptoms and a broad range of cognitive dysfunctions (Jaaskelainen et al., 2013). The underlying neurobiological etiology of schizophrenia may be multifactorial (Cannon, 2015, Koga et al., 2016). Currently, oxidative stress has been implicated in the pathophysiology of schizophrenia (Li et al., 2011, Pandya et al., 2013, Wu et al., 2013). Regulation of the reducing and oxidizing (redox) state is involved in cell viability, activation and proliferation (Birben et al., 2012). Dysfunction of antioxidant defense mechanisms could result in a free radical attack on neural cells, and is associated with abnormal neural growth, differentiation or neuro-degeneration (Uttara et al., 2009). Evidence has shown that an imbalance of reactive oxygen species (ROS) and the antioxidant system may be involved in the pathophysiology of schizophrenia (Wood et al., 2009).
As part of the antioxidant system, cysteine, a semi-essential amino acid, is an important structural and functional part of proteins (Yin et al., 2016). Cysteine is the limiting precursor of the major intracellular antioxidant glutathione (GSH) (Burgoyne and Morgan, 2015, Stipanuk et al., 2006). GSH is a redox regulator (Wu et al., 2004), and is essential for the cellular detoxification of ROS, and it has anti-inflammatory and neuroprotective properties in brain cells (Dringen and Hirrlinger, 2003). A decrease in cysteine is associated with dysfunction of the intracellular antioxidant GSH (Trivedi et al., 2014). Cystine, a rate-limiting substrate for GSH synthesis, is the oxidized form of cysteine stored in the extracellular space (serum). With oxidative stress, cystine is transported across plasma membranes to maintain intracellular GSH (McBean, 2002). A disturbance in cystine may therefore denote a compromised GSH system in the brain when there is additional oxidative stress in patients with neuropsychiatric disease (Gall et al., 2010).
N-acetyl-l-cysteine (NAC), an acetyl derivative of cysteine, is widely available as a nutritional supplement with antioxidant properties (Samuni et al., 2013). NAC is converted to cysteine, which is then converted to GSH (Berk et al., 2013). NAC has emerged as an effective augmentative strategy in the treatment of many neuropsychiatric disorders, including schizophrenia (Dean et al., 2011, Deepmala et al., 2015). Adjunctive NAC has been suggested as beneficial for the reduction of positive symptoms (Magalhaes et al., 2016, Rapado-Castro et al., 2015), as well as for alleviating negative symptoms in patients with schizophrenia (Berk et al., 2008, Carmeli et al., 2012, Farokhnia et al., 2013). NAC administration may result in EEG synchronization, which might serve as a biomarker for treatment efficacy in schizophrenic patients. Moreover, the gene for the key glutathione-synthesizing enzyme, the glutamate cysteine ligase modifier (GCLM) subunit, has been associated with schizophrenia in several Caucasian studies (Gysin et al., 2011, Gysin et al., 2007, Tosic et al., 2006); however, such a correlation was not replicated in the Japanese population (Hanzawa et al., 2011, Kishi et al., 2008) or in the Han Chinese population (Ma et al., 2010).
To the best of our knowledge, only one case-control study has investigated differential cystine levels between patients with schizophrenia and healthy controls (Yang et al., 2013). Compared to healthy controls, an elevated level of cystine was observed in the urine of patients with schizophrenia; however, an opposite trend appeared in the serum levels of cystine. Moreover, it has been suggested that oxidative stress plays a role in cognition dysfunction in schizophrenia (Gonzalez-Liencres et al., 2014, Wu et al., 2014). Nevertheless, it remains unclear whether cysteine is associated with the clinical characteristics or neurocognitive functions in schizophrenic patients. To fill this research gap, this study investigated the difference in serum levels of cysteine between patients with schizophrenia and healthy control subjects. Additionally, the relationships between levels of cysteine, psychopathology and cognitive function were explored. We hypothesized that cysteine was associated with the psychopathology of schizophrenia involving the antioxidant system.
Section snippets
Participants
This cross-sectional, case-control study was approved by the institutional review board (IRB) of the Chang Gung Memorial Hospital (IRB No: 102-3977A3). Written informed consent was obtained from all participants.
Eligible patients with schizophrenia in an out-patient department in the Kaohsiung Chang Gung Memorial Hospital were selected for this study if they (1) were 18–65 years of age; (2) were assessed with the Mini International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998) and
Results
We recruited a total of 65 patients with schizophrenia (36 males and 29 females, mean age: 42.2 ± 9.8 years) and 65 healthy control subjects (mean age: 40.1 ± 12.0 years) (Table 1). From the patients with schizophrenia, the age of onset was 24.8 ± 7.6 years. The duration of the illness was 17.3 ± 9.8 years. The DDD of antipsychotics was 0.9 ± 0.5 years. Compared to healthy controls, patients with schizophrenia had higher levels of body weight (P = 0.002), body mass index (BMI) (P < 0.001) and triglycerides (P <
Discussion
The main finding of this study was that patients with schizophrenia had higher serum levels of cysteine when compared with healthy controls. Serum levels of cysteine were significantly correlated with fasting glucose in both patients and controls; however, a positive correlation between cysteine levels and cognitive function was observed only in patients with schizophrenia.
Conclusions
Significantly higher serum levels of cysteine were observed in patients with schizophrenia when compared to age- and gender-matched healthy controls. The cysteine levels were positively correlated with neurocognitive performance in patients with schizophrenia. These findings imply that oxidative stress may be involved in the pathogenesis of schizophrenia, and compensatory elevated cysteine may serve as an indicator of the preservation of cognition. Further prospective studies are warranted to
Role of the funding source
This study was supported by the Chang Gung Memorial Hospital Research Project (CMRPG8C1051 and CMRPG8C1291).
Contributors
LJW participated in interpreting data, reviewing references, and drafting the manuscript. PYL, YL, YCH, STH, CCC, MYC and CHL assisted with the study design and patient recruitment. CCW participated in lab data analysis. CFH executed the statistical analysis and revised the manuscript. All authors read and approved the final manuscript and contributed to the drafting and revising of the paper.
Conflict of interest
The authors declare no conflicts of interest.
Acknowledgements
The authors express their deepest gratitude to Professor Richard S.E. Keefe for granting us the use of the Chinese version of the BACS, Miss. Yi-Hsuan Lee, Pei-Yi Lee and Joanne Lo for assisting in participant recruitment, and thank all of the individuals who participated in this study.
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