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The Significance of Homocysteine Levels in Schizophrenia

To the Editor: We noted with interest the findings of Donald C. Goff, M.D., et al. (1) but question whether the comparison group they used was representative of homocysteine measurement. Differences in age and homocysteine measurement and an absence of dietary history and genotyping for methylenetetrahydrofolate reductase, which are important confounding variables, may have biased the homocysteine analysis.

The study group’s mean age was 20 years younger than the comparison group’s (the sixth Framingham Offspring cohort subgroup). Homocysteine levels rise progressively with age, approximately doubling from childhood to old age. There is a bias toward higher comparison homocysteine levels as a result (2, 3).

The accuracy of homocysteine differs among methods and laboratories. This effect had not been controlled. The Framingham Offspring comparison group’s homocysteine level was measured with high-performance liquid chromatography with fluorescent detection, whereas the study group used fluorescence polarization immunoassay. The use of a local comparison group with the same method and laboratory is recommended (3).

The Framingham Offspring Study shows that mandatory fortification policy has reduced the prevalence of low folate status (i.e., <3.0 ng/ml) by more than 90% and the prevalence of mild fasting hyperhomocysteinemia (homocysteine concentrations >130 mmol/liter) by about 50% among its population-based cohort of middle-age to elderly U.S. citizens (4).

We recommend that the assessment of homocysteine requires the measurement of known confounding variables, especially in smaller group sizes, from folic-acid-fortified regions. Contrary to larger previous studies with local comparison groups showing increased homocysteine levels in schizophrenia, these results should be treated with caution (5, 6).

References

1. Goff DC, Bottiglieri T, Arning E, Shih V, Freudenreich O, Evins AE, Henderson DC, Baer L, Coyle J: Folate, homocysteine, and negative symptoms in schizophrenia. Am J Psychiatry 2004; 161:1705–1708[Abstract/Free Full Text]
2. Jacques PF, Selhub J, Bostom AG, Wilson PWF, Rosenberg IH: The effect of folic acid fortification on plasma folate and total homocysteine concentrations. N Engl J Med 1999; 340:1449–1454[Abstract/Free Full Text]
3. Refsum H, Smith AD, Ueland PM, Nexo E, Clarke R, McPartlin J, Johnston C, Engbaek F, Schneede J, McPartlin C, Scott JM: Facts and recommendations about total homocysteine determinations: an expert opinion. Clin Chem 2004; 50:3–32[Abstract/Free Full Text]
4. Bostom AG, Selhub J, Jacques PF, Rosenberg IH: Power shortage: clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Ann Intern Med 2001; 135:133–137[Abstract/Free Full Text]
5. Applebaum J, Shimon H, Sela BA, Belmaker RH, Levine J: Homocysteine levels in newly admitted schizophrenic patients. J Psychiatr Res 2004; 38:413–416[CrossRef][Medline]
6. Levine J, Stahl Z, Ami B, Slava S, Ruderman GV, Belmaker RH: Elevated homocysteine levels in young male patients with schizophrenia. Am J Psychiatry 2002; 159:1790–1792[Abstract/Free Full Text]

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