In the present study, we found that (1) FEDN patients with schizophrenia had higher serum Hcy levels than healthy controls, (2) serum concentrations of Hcy were positively correlated with the PANSS general psychopathology subscale and PANSS total scores for patients, and (3) male patients had significantly higher Hcy levels than female patients. To the best of our knowledge, few studies have reported the sex difference in serum Hcy levels in FEDN patients with schizophrenia of Chinese ethnicity.
The present study showed that serum levels of Hcy were significantly increased in FEDN schizophrenia patients, when compared to healthy controls, which is consistent with other reports [24, 29]. A cross-sectional study reported that Hcy levels were increased in schizophrenia, when compared with bipolar disorder patients [30]. Another study reported that common polygenic variants, such as methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, correlated with plasma total Hcy levels, which had a cumulative effect on schizophrenia and may be a risk factor for this disorder [31]. There is also increasing evidence that Hcy is directly or indirectly involved in multiple pathways in pathophysiological mechanisms of schizophrenia. Methylation pathway defects (including catecholamine methylation) due to folate and cobalamin deficiencies, and impaired re-methylation of methionine by Hcy, can cause hyperhomocysteinemia [32]. Another impaired pathway is transsulfuration pathway, which is a metabolic pathway from Hcy to L-cysteine to glutathione (GSH), resulting in reduced GSH levels and oxidative phosphorylation [33]. In addition, Hcy induces immune responses, and in a mouse model, elevated Hcy activates nuclear translocation of transcription factor NF-κB and increased expressions of interleukins-1β and tumor necrosis factor-α [11]. However, the exact etiology and pathways of Hcy in schizophrenia remain ambiguous and warrant further study.
Another finding of the study was that serum Hcy levels were positively correlated with psychopathological symptoms of FEDN schizophrenia patients. Similar results have been reported in several previous studies. Trześniowska-Drukała et al. [34] reported that increased Hcy concentrations resulted in worse cognitive functions and higher PANSS scores in patients with schizophrenia, suggesting that Hcy blood levels were related to the severity of schizophrenia. Song et al. [35] reported that increased serum Hcy levels positively correlated with PANSS total scores in FEDN schizophrenia patients after controlling for influencing factors. Petronijević et al. [36] reported that plasma Hcy levels were positively correlated with PANSS negative subscores both in the exacerbation and remission phases of young male schizophrenia patients. Gao et al. [37] reported that MTHFR C677T polymorphism was correlated with PANSS negative symptoms and cognitive deficits in chronic schizophrenia patients. Furthermore, models models fed Hcy were found to have significantly impaired cognitive functions during the reversal phase of the Morris water maze test [38]. Together, these results suggest that Hcy plays an essential role in the disease process of schizophrenia, including an increase of psychotic symptoms.
Previous studies have proposed there are several factors influencing Hcy levels such as age, sex, BMI, smoking, coffee drinking, poor nutrition, vitamin intake, folate, and ultraviolet radiation [39, 40]. Previous studies have reported differences in Hcy levels between male and female schizophrenia patients, although the results have been inconsistent. Meta-analyses suggested that plasma total Hcy levels were higher in both male and female schizophrenia patients [41]. A cross sectional study also reported no significant disparity in hyperhomocysteinemia between male and female schizophrenia patients [30]. In the present study, we found that the serum Hcy levels were higher in male patients with FEDN schizophrenia, when compared with female patients, which was consistent with the findings of an earlier study [38]. Another study reported that male sex and older age were risk factors for developing hyperhomocysteinemia in schizophrenia patients [42]. These inconsistencies in the results may be due to different antipsychotic medications, methods of Hcy measurement, different phases of the disease, nutrient status, and ethnicity. Notably, sex differences in Hcy levels were found in patients with schizophrenia, and also in patients with bipolar disorders [43], and Alzheimer’s dementia [44]. However, the exact etiological mechanism underlying the discrepancy in Hcy levels between males and females remains unclear. A review stated that high dose testosterone administration increased total Hcy levels in female-to-male transsexuals [45]. Two other studies reported that hormone treatment, oral ethinyl estradiol and transdermal 17beta estradiol treatments for male-to-female transsexuals reduced Hcy levels [46, 47]. Moreover, one study reported a significant sex disparity in Hcy levels for MTHFR C677T polymorphism [41]. Consequently, we postulate that hormone levels and genetics may be causative factors contributing to sex differences in Hcy levels.
In the present study, we found that severities of clinical symptoms were significantly different between male and female FEDN patients with schizophrenia, which were consistent with the results of other studies [48, 49]. However, some discrepant results were reported due to different stages of illness, duration of illness, representation of research subjects, and administration of medications. In addition, there was no significant relationship of Hcy concentrations for BMI in our study. Although the results are the same as previously reported [50], there are nevertheless many reports of varying results, suggesting that Hcy concentrations correlated with BMI in patients with schizophrenia [24, 51]. The Hcy levels were closely associated with elderly males, obesity, uric acid content, glycolipid metabolism, and metabolic syndromes [42, 44, 52], whereas our study subjects were on average young and unmedicated, mitigating the effects of confounding factors on Hcy levels, so the results may be more accurate.
There were several limitations in this study. First, based on a cross-sectional study, a causal interaction between Hcy and clinical profile could not be determined. Second, the study subjects were recruited from only one region, and it is possible that different dietary habits and nutrition may have had an impact on the results, so future studies will need to be conducted in a more general area. Third, we did not collect markers related to B vitamins, folate, and glycolipid metabolism, which previous studies suggested may have had an effect on Hcy levels.
In summary, our findings confirmed that serum Hcy levels were higher in FEDN patients with schizophrenia, when compared with healthy controls, and that higher Hcy levels were correlated with severe clinical symptoms. Importantly, male FEDN schizophrenia patients had higher Hcy levels than female patients. Considering the limitations, the present study preliminarily suggested that Hcy played an important role in the pathophysiology of schizophrenia, which requires further validation in a longitudinal study.