To the best of our knowledge, this is the first study to examine Hcy levels in inpatients with SZ, ATPD, ME, and MDD in a Chinese population. Prior to this study, insights into the neural similarities and differences in SZ, ME, and MD primarily stemmed from individual comparisons to HC or direct comparisons between two of the three disorders (SZ and ME, ME and MD, and MD and SZ)[5–7, 17, 19]. Hcy is influenced by various biological factors, such as age, medication, and the presence of psychiatric symptoms [6, 19, 20]. Petronijevic and co-workers found that Hcy levels decreased after antipsychotic therapy, and the severity of psychotic symptoms was associated with higher Hcy levels [21]. In addition, Levine and colleagues found that mean Hcy levels were elevated only in age groups over 50 y old[22]. Other studies have also reported that Hcy is associated with age[6]. Therefore, we ensured that the study sample consisted of first-episodic, drug-naïve, younger individuals (18–45 y), during the relatively early stages of their psychiatric illnesses (illness duration < 5 y), and all with psychotic symptoms. Thus, the confounding effects of age, medication, and illness chronicity were minimized.
In this study, significant differences in Hcy levels were found between the psychiatric-disorder groups and the HC group. Interestingly, the SZ, ATPD, ME, and MD groups did not show significant intergroup differences in Hcy levels in the omnibus analysis, suggesting that the psychopathophysiologies of these disorders share common neural substrates. Our results showed significantly higher serum Hcy levels in patients with SZ, ATPD, ME, and MD, in overall agreement with previous studies [5, 6, 19, 23, 24], but prior evidence for the involvement of Hcy in acute and transient psychotic disorders is poor. However, the majority of previous studies [6, 19, 23, 25] have shown that Hcy levels are elevated in patients with SZ. Yang and co-workers and Zhou and co-workers found that Hcy concentrations were elevated in SZ in Han Chinese people [19, 23]. Kevere and co-workers observed that mean Hcy levels were elevated in patients with SZ, and patients in the acute phase had higher levels than did those in the remission phase [26]. Liu and Zhong reported that Hcy levels were elevated in patients with first-episode SZ[27, 28].
Similarly, previous studies have also found elevated Hcy in participants with disorders featuring ME. Zhou and co-workers identified a possible relationship between Hcy and bipolar disorder (BD) in a Han Chinese population [17]. Ozdogan and colleagues reported finding statistically higher Hcy levels in participants with BD [5]. Most recently, in a large sample of 195 participants with BD matched to 85 controls, a positive association was found between higher BMI and significantly higher Hcy levels and Hcy-related impairments [29].
Because Hcy levels tend to be elevated in patients with SZ and BD, Hcy might plausibly contribute to disease severity in patients with MDD as well [14, 30, 31]. Tao and co-workers found that Hcy levels are elevated in patients with first-episode depression [31]. Zhou and co-workers also observed that mean Hcy levels were elevated in patients with late-life depression and were negatively associated with cognitive performance [14]. A positive association of Hcy dysregulation with depression was subsequently found in young patients. In the same study, lower vitamin B12 levels were associated with elevated Hcy in this group [16, 30].
Other studies have compared Hcy levels between two or three psychiatric disorders. For example, the Fe'li study included 100 patients with SZ or BD. Similar to the results of our study, they did not find a difference in Hcy levels between the two disorders[6]. However, in male patients with bipolar disorder, the proportion of Hhcy was higher than that in female patients. Narayan et al. included some patients aged 18–45 y who were diagnosed with MD/SZ and also failed to find a significant difference in Hcy levels between the two disorders[7]. The proportion of Hhcy was higher in patients with SZ, however. This may be related to the fact that more male patients with schizophrenia were included (MD: 12 [30%] vs. SZ: 27 [67.5%]). Hcy levels were found to be higher in male than in female patients in almost all psychiatric disorders, including SZ, BD, and depressive disorders [5, 6, 17]. It is interesting to note that similar findings were obtained in the present study. Our results showed that male sex was a significant risk factor for Hhcy in cases of SZ, ATPD, and MD.
Male patients have significantly higher Hcy levels than do female patients [5, 9, 17]. Moreover, the proportion of Hhcy was also greater in male patients, which is consistent with previously reported results [17]. However, the reasons for the preponderance of male patients remain unclear. Some studies have suggested that higher Hcy levels in male patients may be related to hormone levels, metabolic characteristics, and genetic polymorphisms [32–34]. HCY levels were decreased in pregnant women or pre- and post-menopausal women who had received hormone replacement therapy [35]. In addition, Nilsson and co-workers demonstrated a significant influence of estrogen on the biosynthesis of Hcy[34] .That study also found a relationship between Hcy levels and BMI. Hcy levels are higher in obese individuals, and high Hcy levels promote the development of abnormal lipid metabolism. Male patients are more likely to develop metabolic syndrome [32]. Moreover, the effect of MTHFR gene polymorphisms on Hcy showed significant gender differences [36]. Taken together, these results show that the higher Hhcy frequencies observed in male patients and the sex differences in Hcy metabolism are complex issues that deserves further research.
Elevated Hcy levels can also be attributed to advanced age, genetics, low intake of folic acid and vitamin B12 in the diet, alcohol abuse or dependence, obesity, and certain medications[23, 37–39]. Age is an important risk factor for high Hcy levels. A positive correlation has been found between age and Hcy levels in the general population [40]. Hcy levels are also correlated with age among patients with depression [14]. In addition, elder patients with SZ have a relatively high risk of Hhcy [19]. Our study did not find a correlation between age and Hcy levels, which may be related to the narrow age range of our participants, 18–45; the mean ages in the diagnostic groups studied here were 26.7, 27.4, 27.2, 27.3, and 24.3, respectively.
In addition, changes in gene polymorphisms are important for the development of Hhcy in psychiatric patients. Several studies have shown an association between changes in MTHFR gene polymorphisms and elevated HCY levels, with two common polymorphisms of the MTHFR gene mutations being C677T and A1298C [41, 42]. These two polymorphisms may lower the activity of MTHFR and lead to increased Hcy levels [42]. However, elevated Hcy levels and MTHFR gene polymorphisms are associated with risks of SZ, BD, and MDD [42, 43].
It has been suggested that a defect in the methylation processes due to deficiencies in vitamins B6, B12, or folate is central to neuropsychiatric manifestations. Hcy is remethylated to methionine via the 5-methyltetrahydrofolate pathway, with vitamin B12 acting as a cofactor and folic acid providing the methyl group transferred in the reaction. Alternatively, Hcys can be condensed with serine to form cystathionine in a reaction VB6 acts as a coenzyme. Some studies have found that folic acid and B vitamins are reduced in patients with schizophrenia as well as affective psychosis [37, 44, 45]. Consistent with this, Hill et al. showed that folic acid and vitamin B12 can reduce Hcy levels and improve symptoms [44]. A more convincing randomized controlled double-blind study used B vitamins as a combination treatment for patients with depressive disorders, taking into account MTHFR genetic polymorphisms. The results found a mean reduction in Hcy concentrations of 2.4 mmol/l after 8 weeks of treatment and contributed to clinical symptom improvement [45].
Limitations
There were several limitations in this study: First, the sample size was modest, although statistically robust. Second, our research is a cross-sectional study that can prove only an association between Hcy and psychiatric disease and cannot determine causation. Third, only the Chinese population was enrolled in this study, limiting its generality with respect to ethnic groups. Fourth, we did not study the serum/plasma levels of vitamin B12, vitamin B6, folate, or MTHFR genotypes, which would have provided further insight into this interesting association, since these variables are known to affect both Hcy levels and mental-health status. Fifth, our study did not assess the clinical symptoms of the patients, nor did it assess the relationship between clinical symptoms and Hcy. Therefore, further clarification will be required in future studies.