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Alan S. Brown, MD; Teodoro Bottiglieri, PhD; Catherine A. Schaefer, PhD; Charles P. Quesenberry Jr, PhD; Liyan Liu, MD, MSc; Michaeline Bresnahan, PhD; Ezra S. Susser, MD, DrPH

Arch Gen Psychiatry. 2007;64(1):31-39.

Context  Elevated prenatal homocysteine level is a plausible risk factor for schizophrenia because of its partial antagonism of N-methyl-D-aspartate receptors under physiologic glycine concentrations and its association with abnormal placental function and pregnancy complications.

Objective  We examined whether elevated maternal levels of homocysteine during the third trimester were associated with adult schizophrenia risk.

Design  Nested case-control study of a large birth cohort, born from 1959 through 1967 and followed up for schizophrenia from 1981 through 1997.

Setting  Population-based birth cohort and health plan.

Participants  Cases (n = 63) were diagnosed with schizophrenia and other spectrum disorders (mostly schizophrenia and schizoaffective disorder). Controls (n = 122) belonged to the birth cohort; had not been diagnosed with a schizophrenia spectrum or major affective disorder; and were matched to cases on date of birth, sex, length of time in the cohort, and availability of maternal serum samples.

Main Measures  Archived maternal serum samples were assayed for homocysteine levels during pregnancies of cases and matched controls.

Results  In a model that tested for a threshold effect of third-trimester homocysteine levels, an elevated homocysteine level was associated with a greater than 2-fold statistically significant increase in schizophrenia risk (odds ratio, 2.39; 95% confidence interval, 1.18-4.81; P = .02).

Conclusions  These findings indicate that elevated third-trimester homocysteine levels may be a risk factor for schizophrenia. Elevated third-trimester homocysteine levels may elevate schizophrenia risk through developmental effects on brain structure and function and/or through subtle damage to the placental vasculature that compromises oxygen delivery to the fetus. If future studies both replicate this association and support a causal link, then the use of folic acid supplementation would merit evaluation as a strategy for prevention of schizophrenia in offspring.

Author Affiliations: College of Physicians and Surgeons of Columbia University and New York State Psychiatric Institute (Drs Brown and Susser), and Mailman School of Public Health of Columbia University (Drs Brown, Bresnahan, and Susser), New York, NY; Baylor University Medical Center, Baylor Institute of Metabolic Disease, Dallas, Tex (Dr Bottiglieri); and Kaiser Permanente Division of Research, Oakland, Calif (Drs Schaefer, Quesenberry, and Liu).

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