Homocysteine in Schizophrenia: Independent Pathogenetic Factor with Prooxidant Activity or Integral Marker of Other Biochemical Disturbances?

Abstract

A wide range of studies have demonstrated that hyperhomocysteinemia is associated with the risk of schizophrenia, but currently available assumptions about the direct involvement of homocysteine (Hcy) in the pathogenesis of schizophrenia are hypothetical. It is possible that in vivo Hcy is only a marker of folate metabolism disturbances (which are involved in methylation processes) and is not a pathogenetic factor per se. Only one study has been conducted in which associations of hyperhomocysteinemia with oxidative stress in schizophrenia (oxidative damage to protein and lipids) have been found, and it has been suggested that the oxidative stress may be induced by the elevated Hcy in schizophrenic patients. But the authors did not study the level of reduced glutathione (GSH), as well as possible causes of hyperhomocysteinemia—disturbances of folate metabolism. The aim of this work is to analyze the association of Hcy levels with the following: (1) redox markers in schizophrenia GSH, markers of oxidative damage of proteins and lipids, and the activity of antioxidant enzymes in blood serum; (2) with the level of folate and cobalamin (В12); and (3) with clinical features of schizophrenia measured using the Positive and Negative Syndrome Scale (PANSS). 50 patients with schizophrenia and 36 healthy volunteers, matched by sex and age, were examined. Hcy in patients is higher than in healthy subjects ( p = 0.0041 ), and this may be due to the lower folate level in patients ( p = 0.0072 ). In patients, negative correlation was found between the level of Hcy both with the level of folate ( ρ = − 0.38 , p = 0.0063 ) and with the level of B12 ( ρ = − 0.36 , p = 0.0082 ). At the same time, patients showed higher levels of oxidative modification of serum proteins ( p = 0.00046 ) and lower catalase (CAT) activity ( p = 0.014 ). However, Hcy is not associated with the studied markers of oxidative stress in patients. In the group of patients with an increased level of Hcy (>10 μmol/l, n = 42 ) compared with other patients ( n = 8 ), some negative symptoms (PANSS) were statistically significantly more pronounced: difficulty in abstract thinking (N5, p = 0.019 ), lack of spontaneity and flow in conversation (N6, p = 0.022 ), stereotyped thinking (N7, p = 0.013 ), and motor retardation (G7, p = 0.050 ). Thus, in patients with schizophrenia, hyperhomocysteinemia caused by deficiency of folate and B12 is confirmed and can be considered a marker of disturbances of vitamin metabolism. The redox imbalance is probably not directly related to hyperhomocysteinemia and is hypothetically caused by other pathological processes or by an indirect effect of Hcy, for example, on the enzymatic antioxidant defence system (CAT activity), which requires further exploration. Further study of the role of Hcy in the pathogenesis of schizophrenia is relevant, since the proportion of patients with hyperhomocysteinemia is high and correlations of its level with negative symptoms of schizophrenia are noted.

Is Vitamin B12 Level a Reliable Predictor of Psychosis Severity in Male Patients with Megaloblastic Anemia at a Single Tertiary Hospital?

“…32 Impaired folic acid and vitamin B12 levels are the main contributors to OCM changes. 33 The present study findings show significantly elevated CRP level within the schizophrenia inpatient group consistent with a published study by Dickerson et al among schizophrenic patients. In Dickerson et al's study, schizophrenia patients received the following medications: atypical antipsychotics (clozapine, risperidone, olanzapine), antidepressant medication, anti-cholinergic, and lithium.…”

Increased serum homocysteine in first episode and drug-naïve individuals with schizophrenia: sex differences and correlations with clinical symptoms

“…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 [ 36 ]. 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 [ 37 ].…”

Correlation of Serum High-Sensitivity C-Reactive Protein, Homocysteine, and Macrophage Migration Inhibitory Factor Levels With Symptom Severity and Cognitive Function in Patients With Schizophrenia

“…23 Zhilyaeva et al have observed that PANSS negative symptom scores, including difficulty with abstract thinking, lack of spontaneity and fluency in conversation, stereotyped thinking, and motor retardation, were more pronounced in SP patients with elevated Hcy levels, supporting the positive association between PANSS and high Hcy levels that we observed. 24,25 It has been also evaluated that patients with SP perform worse on cognitive assessments, and high levels of Hcy are associated with this. [26][27][28] Some articles have shown an association between elevated Hcy levels and cognitive dysfunction in patients with SP.…”