To the Editor: With great interest, we read the report on elevated homocysteine levels in young male patients with schizophrenia by Joseph Levine, M.D., et al. (1). We would like to point to a finding not mentioned by the authors that may be clinically significant. The authors reported that the significant difference in mean homocysteine levels was entirely in male patients younger than 50. However, it appears from Table 1 that female patients ages 50 to 59 had a significantly higher mean homocysteine level than the female comparison subjects of the same age (mean=16.1 μM, SD=1.5, versus mean=11.3 μM, SD=2.3) (t=3.65, df=59, p<0.001, two-tailed). This finding might be related to the postmenopausal status of these women. Menopause is associated with increased homocysteine levels (2), and hormone replacement therapy decreases homocysteine levels in postmenopausal women (3). Women with schizophrenia may have poor nutritional status, which may modulate homocysteine levels, and/or be less likely to take hormone replacement therapy, which may explain the difference between the women with schizophrenia and the comparison subjects. Therefore, women’s hormonal status should be taken into account in the design of future randomized controlled trials on the effect of folic acid, cobalamin, and pyridoxine supplementation.

In addition, the finding of no differences in homocysteine levels in the groups older than 60 (1, 4) is compatible with an association that has been found between a mutation in the methylenetetrahydrofolate reductase gene and good therapeutic response to conventional neuroleptics (5). Subjects with neuroleptic nonresponse may be overrepresented in older hospitalized patients with schizophrenia.