Summary. A significant proportion of patients with schizophrenia have increased homocysteine levels that are unrelated to psychopharmacological medication or nutrient deficiency in folate or cobalamin. This supports the hypothesis that inherent methylation deficiency is involved in the pathogenesis of schizophrenia.

The gene for methylenetetrahydrofolate reductase (MTHFR) has shown polymorphism in the general human population. In its homozygous form, a C677T mutation occurs in more than 5% of the grown-up population and produces a thermolabile variant which reduces the overall enzyme activity to less than 30% of normal. We investigated patients with schizophrenia-like psychosis. If hyperhomocysteinemic, their DNA-genotype for thermolabile C677T mutation was determined. Seven of 11 patients, six males and one female, were homozygous for thermolabile MTHFR. One male patient was heterozygous and all three normal homozygotes were females. In the patients who were homozygous for the C677T mutation, the homocysteine concentrations did not respond to vitamin B12 but were normalized by folate supplementation. In the normal homozygotes, however, the homocysteine concentrations were reduced by vitamin B12 alone. Our results suggest that homozygosity for thermolabile MTHFR is a risk factor for schizophrenia-like psychosis. Possibly, this risk may be reduced by folate supplementation.

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Cerebrospinal fluid levels of methionine (MET), homocysteine (HCY) and cystathionine were studied in patients with psychotic disorders (n=36) and in healthy controls (n=25). Patients had significantly higher MET than controls (p<0.00001), and ten of the patients had MET levels above anyone of the controls. Moreover, three young male patients had HCY levels highly above any of the controls. There were no significant gender differences in any of the parameters. Neither ageing nor neuroleptic treatment offered an explanation for the increase of MET, because also young and drug-naive patients had significantly higher MET than the controls. We conclude that patients with psychotic disorders, at least in a phase of acute exacerbation, are often in a state of disturbed one-carbon metabolism.

Although the psychotic symptoms in schizophrenia can be alleviated by treatment with dopaminergic receptor antagonists, the etiology and underlying neurochemical pathology remains obscure. Both neuropathological and magnetic resonance imaging studies have found evidence for neuronal loss and atrophy in the thalamus in schizophrenia, implicating this key structure for gating information to cortical areas in the pathophysiology. Recent studies have also found evidence of synaptic loss in the thalamus in schizophrenia. To further examine possible synaptic disturbances, we studied the synaptic related protein rab3a as a marker for synaptic density, using both quantitative Western blotting and immunohistochemistry. The material consisted of brains from 22 schizophrenic patients (mean age 79.3 years), and 24 control subjects (74.8 years). Reduced rab3a protein levels were found in the left thalamus in schizophrenia (0.47 +/- 0.17 vs. 1.00 +/- 0.18; p < 0.0001), while a less marked decrease was found also in the right thalamus (0.75 +/- 0.13 vs. 1.00 +/- 0.09; p < 0.0001). Immunohistochemistry, performed on two schizophrenic and two control brains, revealed that rab3a immunoreactivity was most reduced in the left anterior and mediodorsal thalamic nuclei. Therefore, we extended the study to brain regions connected these thalamic nuclei. Reduced rab3a protein levels were found schizophrenia also in the frontal cortex, hippocampus, gyrus cinguli, and parietal cortex, while no significant differences were found in the temporal cortex, or in cerebellum. The reduction in rab3a was not found to be secondary to confounding factors such as age-differences, post-mortem delay time, generalized brain atrophy, or antipsychotic medication. Therefore, the reduction of rab3a probably reflects synaptic disturbances, possibly synaptic loss, in the limbic system and neocortical areas, in schizophrenia. This part of the brain is known to be involved in behavioral and emotional control, and thus to be crucial for higher mental functions, suggesting that synaptic disturbances in the limbic system may be of importance in the development of psychotic symptoms in schizophrenia.