Plasma homocysteine in schizophrenia: Determinants and clinical correlations in Tunisian patients free from antipsychotics

Abstract

The existence of association between hyperhomocysteinaemia (HHC) and schizophrenia has been suggested by several recent studies. This study aimed to determine the prevalence of HHC and its main determinants, and sought a correlation with clinical features in Tunisian patients with schizophrenia. Plasma homocysteine (Hcy), folate, and vitamin B12, as well as the C677T methylene tetrahydrofolate reductase (MTHFR) polymorphism, were studied in 33 patients with schizophrenia, all free from antipsychotic treatment, and 35 age- and smoking-habit-matched healthy subjects as controls. Biochemical determinations and psychometric evaluations were carried out in patients before the administration of antipsychotics. The prevalence of HHC was higher and plasma B12 vitamin was significantly lower in patients. There was no significant difference in genotypic distribution and allelic frequency of the C677T MTHFR polymorphism between groups. Hcy was significantly correlated to the ‘anhedonia-asociality’ subscales of the Scale for the Assessment of Negative Symptoms (SANS). This study showed an association between HHC and schizophrenia, especially with the negative symptoms of the disease. In the Tunisian population, HHC in schizophrenia seems to be linked to vitamin B12 deficiency, likely caused by a lack of dietary animal proteins.

Introduction

Schizophrenia is a severe and complex mental disease. Although its pathogenesis is still unknown, there is a likely involvement of genetic, neurodevelopmental, neurodegenerative and environmental factors (Morrison and Murray, 2005).

Homocysteine (Hcy) is a sulphur-containing amino acid formed by the demethylation of methionine. Homocysteine is remethylated to methionine by the vitamin-B12-dependent enzyme methionine synthase. This reaction also requires the participation of a folate-dependent enzyme, methylenetetrahydrofolate reductase (MTHFR). Through the trans-sulphuration pathway, homocysteine forms cysteine, in a reaction catalyzed by a vitamin B6-dependent enzyme, cystathionine β-synthase (Fig. 1).

Any genetic deficiency in this enzymatic or vitamin arsenal could induce severe hyperhomocysteinaemia (Bolander-Gouaille and Bottigglieri, 2003, Mattson and Shea, 2003, Troen, 2005).

Mild-to-moderate hyperhomocysteinaemia (HHC) can be the consequence of dietary B vitamins' deficiency, renal insufficiency, excessive consumption of tobacco, alcohol or coffee, use of some medications and polymorphisms in the enzymes of Hcy metabolism, especially the C677T polymorphism of the MTHFR gene (Jacques et al., 2001, Bolander-Gouaille and Bottigglieri, 2003).

HHC is recognised as a risk factor for cardiovascular diseases. Further, it is suspected to be involved in several neuropsychiatric disorders such as neural tube defect, cerebrovascular conditions, Alzheimer disease and depression (Troen, 2005). A number of authors have proposed that HHC be considered as a risk factor for schizophrenia (Regland et al., 1995, Regland, 2005, Susser et al., 1998, Levine et al., 2002Applebaum et al., 2004, Brown and Susser, 2005, Muntjewerff et al., 2005, Muntjewerff et al., 2006, Neeman et al., 2005, Lee et al., 2006, Adler Nevo et al., 2006, Haidemenos et al., 2007, Akanji et al., 2007). A recent meta-analysis demonstrated that a 5 μmol l^–1 increase of plasma Hcy concentration is associated with 70% higher risk of schizophrenia (Muntjewerff et al., 2006).

HHC in patients with schizophrenia was related to the presence of the 677CNTMTHFR polymorphism and folate deficiency (Muntjewerff et al., 2006, Lee et al., 2006). HHC in schizophrenia was also associated with young and male patients (Levine et al., 2002, Applebaum et al., 2004). For some authors, HHC predicts Parkinsonism and abnormal movements induced by antipsychotics (Goff et al., 2004, Lerner et al., 2005). Finally, some authors suggested that HHC could induce a clinical expression dominated by negative symptoms of schizophrenia (Levine et al., 2002, Levine et al., 2006).

However, the association between HHC and schizophrenia is still controversial due to the existence of several negative results (Virgos et al., 1999, Muntjewerff et al., 2003, Reif et al., 2003).

The present study aimed to determine the prevalence of HHC and its main determinants in patients with schizophrenia and to seek correlation between Hcy and clinical features of the disease.