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.