The main results of this study are as follows: (i) First-episode schizophrenic patients are characterized by higher plasma Hcy and lower levels of folate and vitamin B12 compared with healthy control participants. These findings cannot be attributed to differences in age, BMI, or cigarette smoking in age as associated or causal factors. (ii) Patients with baseline high Hcy showed more severe psychopathological manifestations, more depressive symptoms, and a more deteriorating social cognitive performance than patients with normal Hcy levels. (iii) High Hcy levels at index hospitalization may predict a less favorable outcome over a 1-year follow-up period.
Our findings are in agreement with previous studies showing higher levels of Hcy and lower levels of folate or vitamin B12 in first-episode psychosis patients 10–12.
Studies measuring serum folate levels in patients with schizophrenia have consistently found significantly lower levels in those with the disorder compared with control participants 34–36. In addition, our results showed an association between a positive family history of schizophrenia and elevated plasma Hcy levels in first-episode schizophrenic patients. This is consistent with several studies that reported an association between a family history of schizophrenia and higher plasma Hcy levels 37–41. We also found that the first-episode schizophrenia patient group with high plasma Hcy levels had more severe psychopathological manifestations at index hospitalization as indicated by higher scores on PANSS scoring, more severe depressive symptoms, and poor social cognitive performance in comparison with those with normal plasma Hcy levels. These results are in line with previous studies showing that higher Hcy and lower folate levels are associated with higher severity of negative symptoms 18–20. In a randomized, double-blind, placebo-controlled, crossover design, patients with elevated Hcy levels were administered oral folic acid, B12, and pyridoxine for three adjunct treatments, and B vitamin appeared to be potentially useful in those with high Hcy levels 42. However, there are also studies that have failed to confirm this relationship 11,42–44. Inconsistent results might be because of recruitment of various subgroups of patients including first-episode schizophrenia-spectrum patients, acutely relapsed inpatients, or chronic patients.
We also found that during a 1-year period following index hospitalization, patients with baseline high Hcy levels showed little improvement in psychopathology than those with baseline normal Hcy.
Notably, we have also found that higher Hcy at index hospitalization may predict more severe psychopathology symptoms as assessed with the PANSS, higher depressive symptoms (using Montgomery–Asberg Depression Rating Scale), worse social cognition performance (using GEOPTE), longer duration of index hospital stay, more frequent admissions, antipsychotic polypharmacy and frequent switching strategies, and more deleterious impact over a 1-year follow-up period. These findings may indicate that baseline Hcy levels may be a marker for tailoring a treatment plan including nutritional intervention as an adjunctive treatment in first-episode patients. Some studies found that folate supplementation reduced Hcy levels in individuals with schizophrenia 42. This may help to avoid prescribing antipsychotic drugs at higher dosages and minimizing antipsychotic polypharmacy or multiple switching with hazardous consequences and unnecessary concomitant medications.
The present study has several limitations that require further discussion and therefore our results should be interpreted with caution. First, it should be noted that our sample size was limited.
Furthermore, we did not measure methylmalonic acid levels, which would have enabled differentiation between impaired folate and vitamin B12 status; we also did not genotype the MTHFR polymorphisms that may alter the levels.
We found an association between elevated Hcy levels and clinical characteristics in first-episode schizophrenic patients, adding further support to the ‘chicken–egg dilemma’ in terms of the heterogeneity of schizophrenia.
Despite the limitations of this study, our results contribute toward the importance of one-carbon metabolism alterations in first-episode schizophrenia. Nevertheless, our results indicate the need for further studies to clarify the role of Hcy in the etiology and prognosis of first-episode schizophrenic patients.
Future research should attempt to robustly evaluate such a personalized approach as it appears that schizophrenia may be a spectrum of disorders, rather than a discrete disorder. Furthermore, additional research aimed at identifying genetic variants associated with disturbances of biological pathways should be carried out to increase our understanding of this complex disorder and guide individualized treatment programs including nutritional strategies.
There are no conflicts of interest.
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