To the Editor: We appreciate the letter from Dr. O’Donnell and Mr. Stephens and agree that our study did not clarify the question of whether homocysteine levels are elevated in schizophrenia patients. This was not the intention of our study. Our hypothesis, that serum folate concentrations would correlate inversely with the severity of negative symptoms, was based on the dual roles of glutamate carboxypeptidase II as a modulator of brain N-methyl-d-aspartic acid activity and as a facilitator of folate absorption in the intestines. This primary hypothesis was supported by our results. Although a comparison of serum concentrations with a nonpsychiatric study group was not an objective of our original study, we provided a comparison with the Framingham Offspring Study cohort as a frame of reference for our findings. Dr. O’Donnell and Mr. Stephens are correct in stating that this comparison group was not matched for age (the mean age of our group was 43 years versus 56 years for the Framingham group), nor were the same assay methods used. An ideal comparison group would be matched by age, smoking status, gender, exercise level, and diet—a daunting task. We chose the Framingham Offspring Study sample because the subjects lived in the same geographical region, were sampled after folate supplementation of grain products had been implemented, and were not taking vitamins with folate. The substantially lower folate concentrations both in our total sample and in schizophrenia nonsmokers compared to this nonpsychiatric group support the hypothesis that low folate concentrations might result from the low activity of glutamate carboxypeptidase II. As we emphasized in our discussion, there are several alternative explanations for our findings.

We did not design our study to test the hypothesis that homocysteine concentrations are elevated in schizophrenia patients compared to a healthy population, and our results should not be interpreted as such. We failed to find hypothesized clinical correlations with homocysteine serum concentrations except for a positive correlation with extrapyramidal symptoms. Age did not predict homocysteine concentrations in our group, whereas gender was a very strong predictor that should be controlled in future comparison studies. Homocysteine levels have varied widely among schizophrenia groups, having been found to be dramatically elevated primarily in young men in two groups from Israel (Applebaum et al., 2004, and Levine et al., 2002) and not elevated in groups of schizophrenia patients from the Netherlands (1) and Spain (2) and in female schizophrenia patients from Germany (3). We agree that careful examination of environmental and dietary factors will be important in understanding these findings. Clarification of the possible neuropathological role of elevated homocysteine, as found by Levine and colleagues (2002), will be of great interest to the field.