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Homocysteine and schizophrenia: From prenatal to adult life
Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 1175 – 1180 www.elsevier.com/locate/pnpbp
Review article
Homocysteine and schizophrenia: From prenatal to adult life Alan S. Brown *, Ezra S. Susser College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, United States Mailman School of Public Health of Columbia University, New York, NY, United States Accepted 17 June 2005 Available online 6 September 2005
Abstract Homocysteine is becoming increasingly recognized as an important substance in the pathogenesis and pathophysiology of schizophrenia. In this review, we first present background information supporting a role for homocysteine in schizophrenia. We then discuss our work on the role of hyperhomocystinemia during adulthood and risk of schizophrenia, and present preliminary evidence on a potential relationship between prenatal homocysteine and schizophrenia. Finally, we discuss the implications of these findings for future work on nutritional etiologies of schizophrenia. D 2005 Elsevier Inc. All rights reserved. Keywords: Homocysteine; Schizophrenia
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dutch famine study . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia and impaired homocysteine metabolism. . . . . . . 3.1. Case-control study of homocysteine and adult schizophrenia 4. Prenatal homocysteine and risk of schizophrenia in adulthood . . . 5. Preliminary results . . . . . . . . . . . . . . . . . . . . . . . . . 6. Future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Abbreviations: CNS, central nervous system; HPLC, high performance liquid chromatography; ICD, International Classification of Diseases; KPMCP, Kaiser Permanente Medical Care Plan; MTHFR, methylenetetrahydrofolate reductase; NMDA, N-methyl-d-aspartate; NTD, neural tube defects; PDS, Prenatal Determinants of Schizophrenia Study. * Corresponding author. New York State Psychiatric Institute, 1051 Riverside Drive, Unit 23, New York, NY 10032, United States. Tel.: +1 212 543 5629. E-mail address: [email protected] (A.S. Brown). 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.06.028
Increasing evidence supports a role for an elevation of homocysteine in schizophrenia. In this paper, we shall review our work on studies of homocysteine abnormalities in adult patients with schizophrenia, and our preliminary research findings on elevated homocysteine during pregnancy and risk of schizophrenia in the offspring. This work has the potential to increase our understanding of the biochemical mechanisms that underlie the pathophysiology of schizophrenia and yield new approaches to prevention of this disorder.
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2. Dutch famine study Our interest in homocysteine originated from our studies of schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944 –1945 (Susser et al., 1996; Susser and Lin, 1992). This tragic event in human history also presented a unique opportunity: to examine the role of prenatal nutrition in the etiology of schizophrenia. The famine was precipitated by a Nazi blockade in the last year of World War II. The famine commenced in October 1944 and gradually worsened over the subsequent months, until liberation in early May, 1945. The famine reached its peak between February and April, 1945. High mortality, low fertility, and increased adverse birth outcomes were observed (Stein et al., 1975). The cities of the western Netherlands were most affected. Several features of the famine and the situation in Holland contributed to the research design advantages of the study. The famine was brief and well-circumscribed, food rations were well-documented, and the Netherlands maintained a comprehensive database on psychiatric outcomes. Using these data, we found that individuals who were exposed to the famine during the periconceptional period, but not at other times in pregnancy, had a twofold and significantly increased risk of adult schizophrenia. An increased risk of congenital central nervous system (CNS) defects, mostly neural tube defects (NTDs), were also observed in individuals who were exposed to the famine during this period of gestation. We considered several nutritional, and non-nutritional, factors that might explain this finding. These are discussed in previous publications (Brown et al., 1996; Susser et al., 1996). One potential candidate nutrient is folic acid, given that folic acid supplementation during the periconceptional period has been well-documented to prevent neural tube defects (MRC Vitamin Study Research Group, 1991). Additional studies have shown diminished red blood cell (Kirke et al., 1993; Smithells et al., 1976; Yates et al., 1987) and serum folate levels (Kirke et al., 1993) in pregnant mothers who later gave birth to offspring with neural tube defects.
3. Schizophrenia and impaired homocysteine metabolism It has been demonstrated in previous studies that neural tube defects are related to a genetic defect in homocysteine metabolism (Van der Put et al., 1995; Whitehead et al., 1995). Sufficient intake of folic acid is believed to reduce this risk by enhancing methylation of homocysteine and its conversion to methionine, thereby compensating for this genetic defect. It has been shown that plasma homocysteine levels are elevated when folate levels were in the lower half of the normal range (Jacques et al., 1996). These studies, and our previous work on the Dutch famine study, led us to consider the hypothesis that patients with schizophrenia
might have a genetic defect in homocysteine metabolism which would be overcome by high folate intake. This hypothesis would predict that schizophrenia cases with low folate would have increased homocysteine levels, compared to controls, since dietary folate would be insufficient to compensate for the genetic defect. Although previous investigations of schizophrenia have demonstrated increased homocysteine levels compared to controls, it has not yet been documented whether these increases were specific to a subgroup with low folate levels. 3.1. Case-control study of homocysteine and adult schizophrenia We therefore conducted a case-control study that aimed to compare homocysteine levels between cases and controls, stratified by serum folate level (Susser et al., 1998). The patients consisted of 30 subjects with schizophrenia or schizoaffective disorder (DSM-III-R) (American Psychiatric Association, 1987), who resided on our Schizophrenia Research Unit of Columbia University; the controls were 33 volunteers who were recruited from the community, and in whom psychiatric disorders had been ruled out by a standardized diagnostic interview. The assay for homocysteine was by capillary gas chromatography – mass spectrometry (Allen et al., 1993). We quantified folate and cobalamin (vitamin B12), the latter of which is a co-factor in the conversion of homocysteine to methionine, by standard radioimmunoassays. We divided the subjects into two groups: those with low folate, defined as the bottom tertile for controls, and all others. The low-folate group consisted of 6 cases and 8 controls; the non-low-folate group consisted of 11 cases and 16 controls. We found that the mean homocysteine level in cases among the low folate group was 10.7 AM (S.D. = 3.2) and the mean homocysteine level in the controls among the low folate group was 7.7 AM (S.D. = 1.4) (t = 2.4, df = 12, p = 0.03). We also examined the data using a dichotomous measure of homocysteine (defined as > 90th percentile for controls). Under this definition, 4 cases among the low folate group, and no controls among the low folate group had elevated homocysteine (Fisher’s p = 0.01, two-tailed). Cobalamin levels were similar between cases and controls. In contrast, there were no differences in mean homocysteine levels among the low folate group. These data support the hypothesis that a subtle genetic defect in homocysteine metabolism may play an etiologic role in schizophrenia. Consistent with our finding, several studies have demonstrated that a polymorphism in the gene for methylenetetrahydrofolate reductase (MTHFR) is associated with schizophrenia (Arinami et al., 1997; Joober et al., 2000). MTHFR catalyzes the conversion of methylenetetrahydrofolate to methyl tetrahydrofolate. This process yields a methyl group which is donated to homocysteine in its conversion to methionine. Thus, a deficiency of MTHFR is associated with elevated homo-
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cysteine. Previous studies have demonstrated that this same MTHFR mutation is associated with neural tube defects (Van der Put et al., 1995; Whitehead et al., 1995), supporting the link between our finding in adult schizophrenia cases and our results from the Dutch famine study. In addition, this same MTHFR mutation has been linked to risk of cardiovascular disease in adults. This work is consistent with findings from other investigators. Regland et al. (1995) demonstrated abnormally elevated homocysteine levels in 45% of schizophrenia patients. Applebaum et al. (2004) and Levine et al. (2002) have also reported that homocysteine levels are elevated in both chronic and newly admitted schizophrenic patients. Not all authors, however, have demonstrated this relationship (Virgos et al., 1999). These studies, however, did not stratify the sample by low and high folate, in order to assess the potential role of a metabolic defect. The findings of our study might be explained, at least in part, by several potential confounders. Sedentary lifestyle, smoking, obesity, hypertension, and hypercholesterolemia have all been associated with elevated homocysteine (Nygard et al., 1995), and many of these behaviors and risk factors are more common in schizophrenia than in controls (McCreadie, 2003). Low folate, however, cannot account for the findings, since we stratified by folate level, and vitamin B12 levels, which can also affect serum homocysteine, were similar between the cases and controls in our study. Thus, while this work is consistent with a metabolic defect in the homocysteine pathways in adult patients with schizophrenia, replication is required with larger numbers of subjects and adjustment for confounding variables is necessary. Nonetheless, it is conceivable that these findings could provide an important clue toward understanding the etiopathogenesis of schizophrenia following the Dutch famine. If a deficiency of prenatal folate was responsible for the increase in risk of schizophrenia in this cohort, then the effects of this deficiency may have been more pronounced in subjects who were lacking the requisite enzymes necessary to metabolize homocysteine. The resulting elevation in maternal homocysteine levels may have acted as an embryotoxin, as demonstrated in a recent study in which chicken embryos exposed to homocysteine developed neural tube defects. The NTDs were prevented by N-methyl-d-aspartate (NMDA) receptor agonists, indicating that homocysteine was exerting an NMDA antagonist effect (Kamudhamas et al., 2004). Several lines of evidence support NMDA receptor hypofunction in the pathophysiology of schizophrenia (Coyle and Tsai, 2004). In summary, the authors demonstrated an elevation in homocysteine in patients with schizophrenia who were hospitalized on an inpatient unit. This elevation was observed only for subjects with low folate levels measured concurrently. The results suggest that a metabolic abnormality in enzymes responsible for metabolizing homocysteine may be present in schizophrenia. The C677 MTHFR polymorphism
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may explain our association, as this mutation has been linked to risk of schizophrenia in some studies. It is also worth considering the possibility that such a metabolic defect may link the increase in neural tube defects in the cohort of the Dutch famine with schizophrenia in these subjects.
4. Prenatal homocysteine and risk of schizophrenia in adulthood In a study in progress from our group, we are examining the relationship between prenatal homocysteine and risk of schizophrenia in adulthood (Brown et al., 2004). We have focused on two periods of gestation in these studies. The first period is the third trimester. It is known that hyperhomocystinemia is associated with subtle vascular defects, which may damage the placental vasculature (Nelen et al., 2000). Such anomalies may induce disturbances in the delivery of nutrients and oxygen from the mother to the fetus. This is of particular relevance to schizophrenia, since nutritional deficiencies (Susser et al., 1996) and fetal hypoxia (Dalman et al., 2001) have been implicated in its etiopathogenesis. We therefore sought to investigate the relationship between elevated homocysteine in the third trimester of development and risk of adult schizophrenia. We selected the third trimester for this analysis given that most of the growth of the placenta and fetus occurs during this period. We also conducted a pilot analysis on the relationship between first trimester homocysteine and adult schizophrenia. This analysis was based largely on the findings of the Dutch Hunger Winter, described above. If deficient folate during the periconceptional period contributed to the elevated risk of schizophrenia, then one would expect that elevated levels of homocysteine, a marker of folate deficiency, during this gestational period would be associated with an increased risk of schizophrenia. For these analyses, we utilized the birth cohort of the Child Health and Development study. This cohort consisted of over 19,000 livebirths from the Kaiser Permanente Medical Care Plan, Northern California Region (KPMCP) in Alameda County, California, and who were born from 1959 to 1967. This cohort study had many advantages, including systematic assessment of pregnancy, perinatal, and neonatal conditions, thorough interviews and comprehensive obstetric and medical records. In addition, the cohort featured prenatal serum specimens that were drawn from virtually all mothers in the study, and that were frozen and archived since the time that they were drawn. In 1999, our group completed the Prenatal Determinants of Schizophrenia (PDS) study, a follow-up investigation of schizophrenia in this birth cohort (Susser et al., 2000). The purpose of the PDS study was to investigate potential prenatal, perinatal, and neonatal factors in the etiopathogenesis of schizophrenia. For this purpose, we collaborated with Dr. Catherine Schaefer and her colleagues at the Kaiser
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Foundation Research Institute to access the records of KPMCP, which maintains a comprehensive and ongoing database on all psychiatric and medical hospitalizations, outpatient visits, and treatment with medications. Since the dates of KPMCP membership and drop-out dates were known, this permitted us to conduct a continuous follow-up study of schizophrenia in this birth cohort, an excellent design to adjust for bias due to loss to follow-up. There were approximately 12,000 livebirths followed in the PDS study because computerized registries necessary for ascertainment of schizophrenia cases did not become available until 1981, and about 7000 cohort members had left KPMCP between birth and that date. Using KPMCP records on inpatient hospitalization, outpatient visits, and pharmacy records, we ascertained cases of potential schizophrenia based on International Classification of Diseases (ICD) diagnoses and review of medical records. Face-to-face diagnostic interviews were administered and 71 cases of schizophrenia or schizophrenia spectrum disorders were diagnosed following consensus interviews and medical record reviews for those who could not be directly interviewed. The matched control group was drawn from cohort members without schizophrenia or major affective disorders. Controls were matched to cases on several variables including date of birth, gender, and availability of maternal sera. The sera were analyzed, blind to case and control status, in the laboratory of Dr. Teodoro Bottiglieri for total homocysteine using high performance liquid chromatography (HPLC) with coulometric electrochemical detection. This is a standard assay with excellent validity and reliability (Martin et al., 1999).
5. Preliminary results Thus far, we have completed a preliminary analysis of our data (Brown et al., 2004), which were presented at the Collegium Internationale Neuropsychopharmacology meeting in Paris in June, 2004. Homocysteine levels were divided into tertiles for analysis. Based on previous studies of folate and homocysteine, we examined whether homocysteine levels above a pre-defined threshold (the highest tertile) would be associated with an elevated risk of schizophrenia. As noted above, our main analysis was between third trimester homocysteine and risk of schizophrenia. We demonstrated a marked increase in the proportion of schizophrenia cases (N = 59) compared to matched controls (N = 112) in the highest tertile of the homocysteine distribution for controls. The risk of schizophrenia following prenatal exposure to elevated third trimester homocysteine was increased over twofold. We are presently examining these data further to adjust for potential confounders, and are considering alternative definitions of elevated homocysteine.
These findings are consistent with our a priori hypothesis, in which we postulated that increased third trimester homocysteine would be a risk factor for adult schizophrenia. We consider several pathogenic mechanisms that might explain this association. First, homocysteine is known to induce subtle damage to the placental vasculature (Nelen et al., 2000). This is consistent with a well-documented effect of homocysteine on risk of vascular disease (Parnetti et al., 1997). Although one would not expect serious vascular pathology in the vascular endothelium of the placenta, as in cardiovascular and cerebrovascular disease, it is conceivable that even modest alterations could disturb the exchange of oxygen to the fetus in a manner that increases schizophrenia risk. Many studies have documented that fetal hypoxia is a likely risk factor for schizophrenia (Dalman et al., 2001), possibly by disturbing the development of critical brain regions, such as the hippocampus, which are especially dependent on efficient oxygen delivery. Hyperhomocystinemia is also associated with pre-eclampsia (Ray and Laskin, 1999), which has also been related to schizophrenia in previous studies (Dalman et al., 1999). Although the mechanism for the relation between elevated homocysteine and pre-eclampsia has not been elaborated, investigators have demonstrated that preeclampsia is associated with reduced nutrient delivery to the fetus (Cnattingius et al., 1990). In addition, a disruption in fetal blood flow has been related to increased minor neurological dysfunction and neurologic impairment in childhood (Ley, 1997). We should also consider the role of the N-methyl-daspartate (NMDA) receptor in these findings. Numerous studies have demonstrated that hypofunction of the NMDA receptor may be involved in the pathophysiology of schizophrenia (Coyle and Tsai, 2004). As noted above, there is evidence that homocysteine disrupts neurodevelopment by acting as an antagonist of the NMDA receptor glycine co-agonist site (Rosenquist et al., 1999). As a result, hyperhomocystinemia may have predisposed to schizophrenia by disturbing development of NMDA receptors during fetal life. For the first trimester, we also demonstrated an increase in the proportion of schizophrenia cases compared to matched controls in the highest tertile of the homocysteine distribution for controls. This finding, however, fell well short of statistical significance, possibly a result of reduced power to detect an association. Thus, this finding should be interpreted with caution.
6. Future studies These findings have several implications for our ongoing and future work. With regard to our study of homocysteine in adulthood, our sample size was too small to permit definitive conclusions. Replication of these findings with
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larger and different populations is critical. Adjustment of several potential confounders, including hypertension, hypercholesterolemia, and sex was also not possible because of the small number of cases. Finally, the controls in our study were not representative of the source population that gave rise to the cases, and thus further studies would benefit from samples drawn from epidemiologic samples. With regard to our preliminary findings from our study of prenatal homocysteine and schizophrenia, we are taking several additional steps to clarify and further elucidate these findings. First, we are presently investigating whether the findings persist following adjustment for several potential confounders that have been associated with both schizophrenia and elevated homocysteine. These include race/ethnicity, socioeconomic status, and various medical conditions. Second, we aim to conduct further studies to follow up on this work. One key question is whether the elevated homocysteine observed in our study was due to deficiencies of other nutrients which are known to cause increases in serum homocysteine. As noted above, folic acid deficiency is the best known and among the most common in pregnancy. Unfortunately, folic acid is not stable in stored sera; in preliminary work from our cohort, the levels were not detectable on most subjects tested. In future work, we hope to identify markers of folate that are stable in stored sera. Vitamin B12 deficiency is another common nutritional cause of elevated homocysteine. Vitamin B12 is a co-factor in the transformation of homocysteine to methionine. Thus, when vitamin B12 levels decline, homocysteine levels increase. This nutrient is quantifiable in prenatal sera, and is stable in samples that have been stored over long intervals. Thus, in future work, we shall examine the relationship between prenatal levels of vitamin B12 and schizophrenia, as well as the role of hyperhomocystinemia as a mediator of the relationship (Graham, 1997). As noted above, several genetic polymorphisms are associated with increased homocysteine. The most commonly cited is the C677T polymorphism in the gene for MTHFR, which has been associated with schizophrenia in some, although not all, studies. One reason for these inconsistent findings may be that prenatal hyperhomocystinemia or an associated nutritional deficiency is required for the effect of the genetic mutation to become manifest. Thus, the investigation of interaction between this polymorphism and elevated homocysteine or associated nutritional deficiencies may elucidate an important geneenvironment interaction that plays a role in the etiology of schizophrenia.
7. Conclusions We have presented compelling evidence for potential roles for adult and prenatal hyperhomocystinemia in
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schizophrenia. These studies may have important implications for discovery of both the etiopathogenesis and pathophysiology of schizophrenia. With the use of unique resources, including well-characterized birth cohorts, and archived serum specimens drawn during the prenatal period, we hope to further assess potential abnormalities of homocysteine and related nutritional factors in schizophrenia. This work may also have important implications for unraveling genetic causes of schizophrenia, and their interplay with prenatal nutrition, as risk factors for schizophrenia.
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Review article
Homocysteine and schizophrenia: From prenatal to adult life Alan S. Brown *, Ezra S. Susser College of Physicians and Surgeons of Columbia University, New York State Psychiatric Institute, New York, NY, United States Mailman School of Public Health of Columbia University, New York, NY, United States Accepted 17 June 2005 Available online 6 September 2005
Abstract Homocysteine is becoming increasingly recognized as an important substance in the pathogenesis and pathophysiology of schizophrenia. In this review, we first present background information supporting a role for homocysteine in schizophrenia. We then discuss our work on the role of hyperhomocystinemia during adulthood and risk of schizophrenia, and present preliminary evidence on a potential relationship between prenatal homocysteine and schizophrenia. Finally, we discuss the implications of these findings for future work on nutritional etiologies of schizophrenia. D 2005 Elsevier Inc. All rights reserved. Keywords: Homocysteine; Schizophrenia
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dutch famine study . . . . . . . . . . . . . . . . . . . . . . . . . Schizophrenia and impaired homocysteine metabolism. . . . . . . 3.1. Case-control study of homocysteine and adult schizophrenia 4. Prenatal homocysteine and risk of schizophrenia in adulthood . . . 5. Preliminary results . . . . . . . . . . . . . . . . . . . . . . . . . 6. Future studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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1. Introduction
Abbreviations: CNS, central nervous system; HPLC, high performance liquid chromatography; ICD, International Classification of Diseases; KPMCP, Kaiser Permanente Medical Care Plan; MTHFR, methylenetetrahydrofolate reductase; NMDA, N-methyl-d-aspartate; NTD, neural tube defects; PDS, Prenatal Determinants of Schizophrenia Study. * Corresponding author. New York State Psychiatric Institute, 1051 Riverside Drive, Unit 23, New York, NY 10032, United States. Tel.: +1 212 543 5629. E-mail address: [email protected] (A.S. Brown). 0278-5846/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2005.06.028
Increasing evidence supports a role for an elevation of homocysteine in schizophrenia. In this paper, we shall review our work on studies of homocysteine abnormalities in adult patients with schizophrenia, and our preliminary research findings on elevated homocysteine during pregnancy and risk of schizophrenia in the offspring. This work has the potential to increase our understanding of the biochemical mechanisms that underlie the pathophysiology of schizophrenia and yield new approaches to prevention of this disorder.
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2. Dutch famine study Our interest in homocysteine originated from our studies of schizophrenia after prenatal exposure to the Dutch Hunger Winter of 1944 –1945 (Susser et al., 1996; Susser and Lin, 1992). This tragic event in human history also presented a unique opportunity: to examine the role of prenatal nutrition in the etiology of schizophrenia. The famine was precipitated by a Nazi blockade in the last year of World War II. The famine commenced in October 1944 and gradually worsened over the subsequent months, until liberation in early May, 1945. The famine reached its peak between February and April, 1945. High mortality, low fertility, and increased adverse birth outcomes were observed (Stein et al., 1975). The cities of the western Netherlands were most affected. Several features of the famine and the situation in Holland contributed to the research design advantages of the study. The famine was brief and well-circumscribed, food rations were well-documented, and the Netherlands maintained a comprehensive database on psychiatric outcomes. Using these data, we found that individuals who were exposed to the famine during the periconceptional period, but not at other times in pregnancy, had a twofold and significantly increased risk of adult schizophrenia. An increased risk of congenital central nervous system (CNS) defects, mostly neural tube defects (NTDs), were also observed in individuals who were exposed to the famine during this period of gestation. We considered several nutritional, and non-nutritional, factors that might explain this finding. These are discussed in previous publications (Brown et al., 1996; Susser et al., 1996). One potential candidate nutrient is folic acid, given that folic acid supplementation during the periconceptional period has been well-documented to prevent neural tube defects (MRC Vitamin Study Research Group, 1991). Additional studies have shown diminished red blood cell (Kirke et al., 1993; Smithells et al., 1976; Yates et al., 1987) and serum folate levels (Kirke et al., 1993) in pregnant mothers who later gave birth to offspring with neural tube defects.
3. Schizophrenia and impaired homocysteine metabolism It has been demonstrated in previous studies that neural tube defects are related to a genetic defect in homocysteine metabolism (Van der Put et al., 1995; Whitehead et al., 1995). Sufficient intake of folic acid is believed to reduce this risk by enhancing methylation of homocysteine and its conversion to methionine, thereby compensating for this genetic defect. It has been shown that plasma homocysteine levels are elevated when folate levels were in the lower half of the normal range (Jacques et al., 1996). These studies, and our previous work on the Dutch famine study, led us to consider the hypothesis that patients with schizophrenia
might have a genetic defect in homocysteine metabolism which would be overcome by high folate intake. This hypothesis would predict that schizophrenia cases with low folate would have increased homocysteine levels, compared to controls, since dietary folate would be insufficient to compensate for the genetic defect. Although previous investigations of schizophrenia have demonstrated increased homocysteine levels compared to controls, it has not yet been documented whether these increases were specific to a subgroup with low folate levels. 3.1. Case-control study of homocysteine and adult schizophrenia We therefore conducted a case-control study that aimed to compare homocysteine levels between cases and controls, stratified by serum folate level (Susser et al., 1998). The patients consisted of 30 subjects with schizophrenia or schizoaffective disorder (DSM-III-R) (American Psychiatric Association, 1987), who resided on our Schizophrenia Research Unit of Columbia University; the controls were 33 volunteers who were recruited from the community, and in whom psychiatric disorders had been ruled out by a standardized diagnostic interview. The assay for homocysteine was by capillary gas chromatography – mass spectrometry (Allen et al., 1993). We quantified folate and cobalamin (vitamin B12), the latter of which is a co-factor in the conversion of homocysteine to methionine, by standard radioimmunoassays. We divided the subjects into two groups: those with low folate, defined as the bottom tertile for controls, and all others. The low-folate group consisted of 6 cases and 8 controls; the non-low-folate group consisted of 11 cases and 16 controls. We found that the mean homocysteine level in cases among the low folate group was 10.7 AM (S.D. = 3.2) and the mean homocysteine level in the controls among the low folate group was 7.7 AM (S.D. = 1.4) (t = 2.4, df = 12, p = 0.03). We also examined the data using a dichotomous measure of homocysteine (defined as > 90th percentile for controls). Under this definition, 4 cases among the low folate group, and no controls among the low folate group had elevated homocysteine (Fisher’s p = 0.01, two-tailed). Cobalamin levels were similar between cases and controls. In contrast, there were no differences in mean homocysteine levels among the low folate group. These data support the hypothesis that a subtle genetic defect in homocysteine metabolism may play an etiologic role in schizophrenia. Consistent with our finding, several studies have demonstrated that a polymorphism in the gene for methylenetetrahydrofolate reductase (MTHFR) is associated with schizophrenia (Arinami et al., 1997; Joober et al., 2000). MTHFR catalyzes the conversion of methylenetetrahydrofolate to methyl tetrahydrofolate. This process yields a methyl group which is donated to homocysteine in its conversion to methionine. Thus, a deficiency of MTHFR is associated with elevated homo-
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cysteine. Previous studies have demonstrated that this same MTHFR mutation is associated with neural tube defects (Van der Put et al., 1995; Whitehead et al., 1995), supporting the link between our finding in adult schizophrenia cases and our results from the Dutch famine study. In addition, this same MTHFR mutation has been linked to risk of cardiovascular disease in adults. This work is consistent with findings from other investigators. Regland et al. (1995) demonstrated abnormally elevated homocysteine levels in 45% of schizophrenia patients. Applebaum et al. (2004) and Levine et al. (2002) have also reported that homocysteine levels are elevated in both chronic and newly admitted schizophrenic patients. Not all authors, however, have demonstrated this relationship (Virgos et al., 1999). These studies, however, did not stratify the sample by low and high folate, in order to assess the potential role of a metabolic defect. The findings of our study might be explained, at least in part, by several potential confounders. Sedentary lifestyle, smoking, obesity, hypertension, and hypercholesterolemia have all been associated with elevated homocysteine (Nygard et al., 1995), and many of these behaviors and risk factors are more common in schizophrenia than in controls (McCreadie, 2003). Low folate, however, cannot account for the findings, since we stratified by folate level, and vitamin B12 levels, which can also affect serum homocysteine, were similar between the cases and controls in our study. Thus, while this work is consistent with a metabolic defect in the homocysteine pathways in adult patients with schizophrenia, replication is required with larger numbers of subjects and adjustment for confounding variables is necessary. Nonetheless, it is conceivable that these findings could provide an important clue toward understanding the etiopathogenesis of schizophrenia following the Dutch famine. If a deficiency of prenatal folate was responsible for the increase in risk of schizophrenia in this cohort, then the effects of this deficiency may have been more pronounced in subjects who were lacking the requisite enzymes necessary to metabolize homocysteine. The resulting elevation in maternal homocysteine levels may have acted as an embryotoxin, as demonstrated in a recent study in which chicken embryos exposed to homocysteine developed neural tube defects. The NTDs were prevented by N-methyl-d-aspartate (NMDA) receptor agonists, indicating that homocysteine was exerting an NMDA antagonist effect (Kamudhamas et al., 2004). Several lines of evidence support NMDA receptor hypofunction in the pathophysiology of schizophrenia (Coyle and Tsai, 2004). In summary, the authors demonstrated an elevation in homocysteine in patients with schizophrenia who were hospitalized on an inpatient unit. This elevation was observed only for subjects with low folate levels measured concurrently. The results suggest that a metabolic abnormality in enzymes responsible for metabolizing homocysteine may be present in schizophrenia. The C677 MTHFR polymorphism
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may explain our association, as this mutation has been linked to risk of schizophrenia in some studies. It is also worth considering the possibility that such a metabolic defect may link the increase in neural tube defects in the cohort of the Dutch famine with schizophrenia in these subjects.
4. Prenatal homocysteine and risk of schizophrenia in adulthood In a study in progress from our group, we are examining the relationship between prenatal homocysteine and risk of schizophrenia in adulthood (Brown et al., 2004). We have focused on two periods of gestation in these studies. The first period is the third trimester. It is known that hyperhomocystinemia is associated with subtle vascular defects, which may damage the placental vasculature (Nelen et al., 2000). Such anomalies may induce disturbances in the delivery of nutrients and oxygen from the mother to the fetus. This is of particular relevance to schizophrenia, since nutritional deficiencies (Susser et al., 1996) and fetal hypoxia (Dalman et al., 2001) have been implicated in its etiopathogenesis. We therefore sought to investigate the relationship between elevated homocysteine in the third trimester of development and risk of adult schizophrenia. We selected the third trimester for this analysis given that most of the growth of the placenta and fetus occurs during this period. We also conducted a pilot analysis on the relationship between first trimester homocysteine and adult schizophrenia. This analysis was based largely on the findings of the Dutch Hunger Winter, described above. If deficient folate during the periconceptional period contributed to the elevated risk of schizophrenia, then one would expect that elevated levels of homocysteine, a marker of folate deficiency, during this gestational period would be associated with an increased risk of schizophrenia. For these analyses, we utilized the birth cohort of the Child Health and Development study. This cohort consisted of over 19,000 livebirths from the Kaiser Permanente Medical Care Plan, Northern California Region (KPMCP) in Alameda County, California, and who were born from 1959 to 1967. This cohort study had many advantages, including systematic assessment of pregnancy, perinatal, and neonatal conditions, thorough interviews and comprehensive obstetric and medical records. In addition, the cohort featured prenatal serum specimens that were drawn from virtually all mothers in the study, and that were frozen and archived since the time that they were drawn. In 1999, our group completed the Prenatal Determinants of Schizophrenia (PDS) study, a follow-up investigation of schizophrenia in this birth cohort (Susser et al., 2000). The purpose of the PDS study was to investigate potential prenatal, perinatal, and neonatal factors in the etiopathogenesis of schizophrenia. For this purpose, we collaborated with Dr. Catherine Schaefer and her colleagues at the Kaiser
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Foundation Research Institute to access the records of KPMCP, which maintains a comprehensive and ongoing database on all psychiatric and medical hospitalizations, outpatient visits, and treatment with medications. Since the dates of KPMCP membership and drop-out dates were known, this permitted us to conduct a continuous follow-up study of schizophrenia in this birth cohort, an excellent design to adjust for bias due to loss to follow-up. There were approximately 12,000 livebirths followed in the PDS study because computerized registries necessary for ascertainment of schizophrenia cases did not become available until 1981, and about 7000 cohort members had left KPMCP between birth and that date. Using KPMCP records on inpatient hospitalization, outpatient visits, and pharmacy records, we ascertained cases of potential schizophrenia based on International Classification of Diseases (ICD) diagnoses and review of medical records. Face-to-face diagnostic interviews were administered and 71 cases of schizophrenia or schizophrenia spectrum disorders were diagnosed following consensus interviews and medical record reviews for those who could not be directly interviewed. The matched control group was drawn from cohort members without schizophrenia or major affective disorders. Controls were matched to cases on several variables including date of birth, gender, and availability of maternal sera. The sera were analyzed, blind to case and control status, in the laboratory of Dr. Teodoro Bottiglieri for total homocysteine using high performance liquid chromatography (HPLC) with coulometric electrochemical detection. This is a standard assay with excellent validity and reliability (Martin et al., 1999).
5. Preliminary results Thus far, we have completed a preliminary analysis of our data (Brown et al., 2004), which were presented at the Collegium Internationale Neuropsychopharmacology meeting in Paris in June, 2004. Homocysteine levels were divided into tertiles for analysis. Based on previous studies of folate and homocysteine, we examined whether homocysteine levels above a pre-defined threshold (the highest tertile) would be associated with an elevated risk of schizophrenia. As noted above, our main analysis was between third trimester homocysteine and risk of schizophrenia. We demonstrated a marked increase in the proportion of schizophrenia cases (N = 59) compared to matched controls (N = 112) in the highest tertile of the homocysteine distribution for controls. The risk of schizophrenia following prenatal exposure to elevated third trimester homocysteine was increased over twofold. We are presently examining these data further to adjust for potential confounders, and are considering alternative definitions of elevated homocysteine.
These findings are consistent with our a priori hypothesis, in which we postulated that increased third trimester homocysteine would be a risk factor for adult schizophrenia. We consider several pathogenic mechanisms that might explain this association. First, homocysteine is known to induce subtle damage to the placental vasculature (Nelen et al., 2000). This is consistent with a well-documented effect of homocysteine on risk of vascular disease (Parnetti et al., 1997). Although one would not expect serious vascular pathology in the vascular endothelium of the placenta, as in cardiovascular and cerebrovascular disease, it is conceivable that even modest alterations could disturb the exchange of oxygen to the fetus in a manner that increases schizophrenia risk. Many studies have documented that fetal hypoxia is a likely risk factor for schizophrenia (Dalman et al., 2001), possibly by disturbing the development of critical brain regions, such as the hippocampus, which are especially dependent on efficient oxygen delivery. Hyperhomocystinemia is also associated with pre-eclampsia (Ray and Laskin, 1999), which has also been related to schizophrenia in previous studies (Dalman et al., 1999). Although the mechanism for the relation between elevated homocysteine and pre-eclampsia has not been elaborated, investigators have demonstrated that preeclampsia is associated with reduced nutrient delivery to the fetus (Cnattingius et al., 1990). In addition, a disruption in fetal blood flow has been related to increased minor neurological dysfunction and neurologic impairment in childhood (Ley, 1997). We should also consider the role of the N-methyl-daspartate (NMDA) receptor in these findings. Numerous studies have demonstrated that hypofunction of the NMDA receptor may be involved in the pathophysiology of schizophrenia (Coyle and Tsai, 2004). As noted above, there is evidence that homocysteine disrupts neurodevelopment by acting as an antagonist of the NMDA receptor glycine co-agonist site (Rosenquist et al., 1999). As a result, hyperhomocystinemia may have predisposed to schizophrenia by disturbing development of NMDA receptors during fetal life. For the first trimester, we also demonstrated an increase in the proportion of schizophrenia cases compared to matched controls in the highest tertile of the homocysteine distribution for controls. This finding, however, fell well short of statistical significance, possibly a result of reduced power to detect an association. Thus, this finding should be interpreted with caution.
6. Future studies These findings have several implications for our ongoing and future work. With regard to our study of homocysteine in adulthood, our sample size was too small to permit definitive conclusions. Replication of these findings with
A.S. Brown, E.S. Susser / Progress in Neuro-Psychopharmacology & Biological Psychiatry 29 (2005) 1175 – 1180
larger and different populations is critical. Adjustment of several potential confounders, including hypertension, hypercholesterolemia, and sex was also not possible because of the small number of cases. Finally, the controls in our study were not representative of the source population that gave rise to the cases, and thus further studies would benefit from samples drawn from epidemiologic samples. With regard to our preliminary findings from our study of prenatal homocysteine and schizophrenia, we are taking several additional steps to clarify and further elucidate these findings. First, we are presently investigating whether the findings persist following adjustment for several potential confounders that have been associated with both schizophrenia and elevated homocysteine. These include race/ethnicity, socioeconomic status, and various medical conditions. Second, we aim to conduct further studies to follow up on this work. One key question is whether the elevated homocysteine observed in our study was due to deficiencies of other nutrients which are known to cause increases in serum homocysteine. As noted above, folic acid deficiency is the best known and among the most common in pregnancy. Unfortunately, folic acid is not stable in stored sera; in preliminary work from our cohort, the levels were not detectable on most subjects tested. In future work, we hope to identify markers of folate that are stable in stored sera. Vitamin B12 deficiency is another common nutritional cause of elevated homocysteine. Vitamin B12 is a co-factor in the transformation of homocysteine to methionine. Thus, when vitamin B12 levels decline, homocysteine levels increase. This nutrient is quantifiable in prenatal sera, and is stable in samples that have been stored over long intervals. Thus, in future work, we shall examine the relationship between prenatal levels of vitamin B12 and schizophrenia, as well as the role of hyperhomocystinemia as a mediator of the relationship (Graham, 1997). As noted above, several genetic polymorphisms are associated with increased homocysteine. The most commonly cited is the C677T polymorphism in the gene for MTHFR, which has been associated with schizophrenia in some, although not all, studies. One reason for these inconsistent findings may be that prenatal hyperhomocystinemia or an associated nutritional deficiency is required for the effect of the genetic mutation to become manifest. Thus, the investigation of interaction between this polymorphism and elevated homocysteine or associated nutritional deficiencies may elucidate an important geneenvironment interaction that plays a role in the etiology of schizophrenia.
7. Conclusions We have presented compelling evidence for potential roles for adult and prenatal hyperhomocystinemia in
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schizophrenia. These studies may have important implications for discovery of both the etiopathogenesis and pathophysiology of schizophrenia. With the use of unique resources, including well-characterized birth cohorts, and archived serum specimens drawn during the prenatal period, we hope to further assess potential abnormalities of homocysteine and related nutritional factors in schizophrenia. This work may also have important implications for unraveling genetic causes of schizophrenia, and their interplay with prenatal nutrition, as risk factors for schizophrenia.
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