Homocysteine as a risk factor in Schizophrenia

Homocysteine (Hcy) is an amino acid generated via methionine metabolism suggested to be rapidly taken up by neurons via a specific membrane transporter. Several enzymes, including methylenetetrahydrofolate reductase, methionine synthase and cystathionine beta-synthase, are involved in homocysteine metabolism and vitamins B12 and B6 and folate serve as co-factors for these and other enzymes involved in homocysteine metabolism. Homocysteine is suggested to be a neurotoxic amino acid via its effects on the NMDA receptors and/or the cell redox status. Elevated plasma homocysteine has been found to be a risk factor for Alzheimer's disease as well as cerebral vascular disease, suggesting that some risk factors can accelerate or increase the severity of several CNS disease processes. We screened 193 chronic schizophrenic patients from our region for plasma homocysteine levels and compared them with 762 controls (evaluated in a screening program for employee health). Mean homocysteine level was 16.3 ± 11.8 (SD) μM in schizophrenic patients vs. 10.6 ± 3.6 (SD) μM in healthy controls. The elevation in homocysteine was statistically significant and was evident almost entirely in young male schizophrenic patients. A second study in 184 consecutively admitted schizophrenic patients and 305 control subjects showed similar results. Homocysteine can be lowered by providing oral folic acid, vitamin B12 and pyridoxine. Forty-two schizophrenic patients with plasma homocysteine levels above 15 μM were treated either with these vitamins for three months or placebo for three months in a randomized double-blind placebo controlled crossover design. Homocysteine levels significantly declined on vitamin therapy compared to placebo in all patients except for one non-compliant subject. Clinical symptoms of schizophrenia as measured by the Positive and Negative Syndrome Scale (PANSS) declined significantly more in those on active treatment compared with placebo. Of the neuropsychological test results, the Wisconsin Card Sort (Categories Completed) results were significantly better after vitamin treatment than after placebo. A subgroup of schizophrenic patients with hyperhomocysteinemia may thus benefit from the addition of B vitamins, a fairly simple therapeutic strategy.