- 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 plasma total homocysteine levels of 193 schizophrenic patients vs. 762 controls for plasma homocysteine levels. The effect of schizophrenia was marked (p<0.0001) and mean homocysteine level was 16.3+/-12 (S.D.) microM in schizophrenic patients vs. 10.6+/-3.6 (S.D.) microM in healthy controls. The increase was almost entirely in young male schizophrenic patients. It seemed important to determine if this finding is already present in newly admitted schizophrenic patients. Serum homocysteine levels were studied in 184 consecutively admitted schizophrenic patients and 305 control subjects. Homocysteine levels were markedly increased in this population of newly admitted schizophrenic patients, especially in young males. However, no difference was found for CSF homocysteine levels between schizophrenia patients and controls. We also examined homocysteine levels in 41 euthymic outpatients with bipolar disorder. Functional deterioration in patients was rated as 'present' or 'absent' by consensus of two treating clinicians. Young male bipolar patients were found to have higher homocysteine levels than controls. Among the male subjects, bipolar patients showing deterioration had homocysteine levels which were significantly higher than other patients. We attempted to develop a model of homocysteine neurotoxicity in mice. Mice were fed homocysteine in water at a dose of 200 mg/kg per mouse per day. Independent samples of animals were studied at 2 to 6 months with behavioral tests including apomorphine-induced stereotypy and spatial learning and memory in the Morris Water Maze. Homocysteine levels were elevated up to 800% at months 5 and 6 by this procedure. No homocysteine-induced defects were found in any behavioral test until month 5 when mild but statistically significant abnormalities in the Morris Water Maze were detected.