Homocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses

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Abstract

In the recent years, elevated homocysteine plasma levels have been reported to represent a risk factor not only for atherosclerosis, but also to be associated with dementia, depression and–in a gender-specific manner–schizophrenia. Here, we explored a possible association between homocysteinemia and psychiatric disorders. Fasting homocysteine, vitamin B12 and folate were determined in an ethnically homogeneous female population with different psychiatric disorders. Homocysteine was not elevated in females suffering from schizophrenia (mean, 11.6 ± 5.8 μmol/l). As shown previously, increased homocysteine concentrations were associated not only with dementia of different aetiology (mean, 17.2 ± 6.7 μmol/l; χ2 = 23.39, p < 0.001, compared to the schizophrenia group), but also with depressive disorders (mean, 12.9 ± 3.8 μmol/l; χ2 = 6.88, p = 0.009). B12 and folate levels did not differ between different diagnostic groups. To further explore the connection between homocysteinemia and affective psychoses, a case–control study examining the C677T and the A1298C variants of methylenetetrahydrofolate reductase was conducted. The latter polymorphism not only was associated with affective psychoses in general, but also when divided in unipolar depression and bipolar affective disorder. In conclusion, we suggest that in females homocysteinemia is an unspecific risk factor for organic brain disorders like dementia, and possibly depression, but not for schizophrenia.

Introduction

The non-protein amino acid homocysteine (HCY) occurs in humans by the demethylation of nutritional methionine, catalyzed by methyltransferases. Its major catabolic pathways involve the enzymes cystathionine B synthase and methionine synthase; the latter depending on tetrahydrofolate and vitamin B12, so that homocysteine degradation is closely linked to the nutritional status regarding those vitamins. In severe cases of homocysteinemia, which are relatively rare, mutations in key enzymes of homocysteine metabolism can be found. In contrast, most cases of mild homocysteinemia are due to nutritional folate and vitamin B deficiency, and/or reduced glomerular filtration rate. Furthermore, common genetic polymorphisms in the methylenetetrahydrofolate reductase gene explain some of the variance in HCY levels, with C677T being the most extensively investigated SNP. Another variant, acting synergistically with 677T, is the A1298C transition, which was also shown to be associated with higher HCY levels (Weisberg et al., 1998, Weisberg et al., 2001). Furthermore, considerable gene × environment interactions do exist: for example, 677T seems to impact with greater effect on vegetarians, compared to controls (Geisel et al., 2003).

HCY is a potent cytotoxin and shows an association with atherosclerosis (Christen et al., 2000, Mangoni and Jackson, 2002) and cerebrovascular disease (Li et al., 2003, Faraci and Lentz, 2004). Besides other mechanisms, it increases oxidative stress and reduces NO functioning by generation of superoxide and the consecutive reaction of this radical with NO to peroxynitrite, a deleterious reactive nitrogen species (Zhang et al., 1998, Zhang et al., 2000, Stanger and Weger, 2003). Interestingly, HCY further impairs the NO pathway by increasing asymmetrical dimethylarginine (Stuhlinger et al., 2001, Boger, 2003), an endogenous NO synthase inhibitor which is also a strong risk factor for cardiovascular disease, by inhibiting the catabolic enzyme DDAH, or increased methylation.

Following initial reports on HCY as a potential atherosclerotic factor, several studies aimed to investigate the role of HCY metabolism in neuropsychiatric disorders by determination of HCY, folate, B12, and sometimes MTHFR genotyping. Alzheimer's (AD) and vascular dementia (VD) were among the first disorders to be investigated. Several independent studies provided substantial evidence for homocysteinemia being a risk factor for those disorders as well as for mild cognitive impairment (MCI). The largest study derived from the seminal Framingham study data set and included a cross-sectional sample of 1092 subjects: when plasma HCY was elevated above 14 μmol/l, the risk for AD was almost doubled (Seshadri et al., 2002).

In contrast to dementia, the picture is less clear in depression. Several studies targeted a possible role of homocysteinemia or B12 deficiency, respectively, in depression, with ambiguous results. Even more vague is the connection between schizophrenic psychoses and homocysteinemia. Previous studies on the HCY pathway in psychiatric disorders, however, are hard to compare because of different methods of HCY determination, ethnical admixture, diagnostic assessment and apparent intervening variables. We have thus attempted to investigate parameters of HCY metabolism (HCY itself, folate, B12) in an ethnically homogeneous female population with different psychiatric disorders in a naturalistic approach. Furthermore, as schizophrenia is widely thought to constitute a heterogeneous disorder, we have applied two diagnostic systems: ICD-10 (World Health Organisation, 1992), and Leonhard and Beckmann's (1995) differentiated nosology of endogenous psychoses. Our hypothesis was that HCY elevation can be found frequently in dementia, but not endogenous psychoses. In a second step, two MTHFR polymorphisms, which result in elevated HCY, were examined in affective psychoses.

Section snippets

Subjects

To determine HCY, folate and B12 levels, 133 female subjects were enrolled in this study according to a “sample-of-convenience”-strategy. The women were recruited consecutively from an admission ward for female inpatients with acute psychiatric disorders. The age ranged from 18 to 92 years. Patients who abused substances or who were substituted with vitamins were excluded from subsequent data analysis (13 subjects). None of the subjects received phenytoine, primidone and phenobarbital, as well

Homocysteine, vitamin B12 and folate levels in psychiatric disorders

A total of 120 subjects were enrolled in the first part study of this study, which was to determine HCY, vitamin B12 and folate in psychiatric disorders. According to ICD-10 criteria, 64 suffered from schizophrenia or schizoaffective disorder, 24 from affective psychoses and 32 from dementia or MCI. Mean HCY was 13.4 ± 6.0 μmol/l, mean folate 7.3 ± 3.8 ng/ml and mean B12 512 ± 340 pg/ml. Seventy-six of the 120 patients were smokers. HCY tended to be higher in smokers, which however was not

Discussion

In order to test for an association of HCY metabolism with psychiatric disorders, we first screened female inpatients stemming from a small catchment area for HCY, folate and vitamin B12 levels in an observational trial. In this sample, we found increased HCY levels in dementia as well as affective psychoses, so that we chose to examine MTHFR polymorphisms in the second step of the study. Regarding confounding factors, age–but not smoking or medication–was shown to have an effect: older age in

Conclusion

The authors suggest that homocysteinemia and MTHFR genotype is a risk factor for, or associated with, affective disorders. For future studies, it is justified to investigate whether it has a special role in the proposed disease entity “vascular depression” and whether it interacts with other genes shown to play a role both for vascular and affective disorders, like NOS-III (Reif et al., in press). In women, however, HCY elevation however does not seem to play a role in the pathophysiology of

Acknowledgement

We are indebted to Alex Strobel, Institute of Psychology II, Dresden University of Technology, Dresden, Germany, for performing the statistical tests for the case–control association study. We gratefully acknowledge T. Töpner for excellent technical assistance and the Central Laboratory of the University of Würzburg (Chair: Prof. Dr. U. Walter) for the determination of homocysteine, folate and vitamin B12. This study was supported by the Deutsche Forschungsgemeinschaft (Grant RE1632/1-1 to

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