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One-carbon metabolism in psychiatric illness

Published online by Cambridge University Press:  14 December 2007

C Sugden
C Sugden*
Affiliation:
Centre for Nutrition and Food Safety, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
*
Corresponding author: C. Sugden, email [email protected]
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Abstract

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The cost of psychiatric illness to the UK economy was recently estimated at £77 billion annually. Despite years of research no firm aetiological explanation exists, and with no physiological or biochemical markers diagnosis is made entirely on a behavioural basis. All current pharmacological therapies are associated with serious long-term side effects. Substantial evidence supports the involvement of one-carbon cycle dysregulation in psychiatric illness, but this is not currently used as a basis for diagnosis or treatment. The present paper reviews the evidence for one-carbon cycle dysregulation in schizophrenic, bipolar, depressed and autistic patients. Also presented are novel findings from the field of epigenetics, which demonstrate how the one-carbon cycle-derived methyl donor S-adenosylmethionine influences the expression of key genes in the brain affecting memory, learning, cognition and behaviour, genes whose expression is reduced to varying degrees in these patient groups. Clinical evidence that nutritional supplements can rectify one-carbon cycle activity, and restore normal gene expression, suggests a novel approach to the development of biochemical tests and simple, non-harmful treatments for some psychiatric patients. Conversely, evidence from animal studies highlights the dangers of exposing the unborn fetus to very high dietary levels of folic acid, a one-carbon cycle cofactor. Fetal adaptations to a high-folate environment may interfere with folate metabolism postnatally, with serious consequences for the epigenetic regulation of gene expression. The public health implications of these diverse scenarios indicate an urgent need for further research in this field.

Keywords

MethylationEpigeneticsPsychiatric illnessAutismOne-carbon metabolismS-adenosylmethionine
Type
Research Article
Information
Nutrition Research Reviews , Volume 19 , Issue 1 , June 2006 , pp. 117 - 136
Copyright
Copyright © The Author 2006

References

Abdolmaleky, HM, Smith, CL, Faraone, SV, Shafa, R, Stone, W, Glatt, SJ & Tsuang, MT (2003) Methylomics in psychiatry: modulation of gene-environment interactions may be through DNA methylation. American Journal of Medical Genetics 127B, 51–59.Google Scholar
Ahokas, A, Aito, M & Turianen, S (2000) Association between oestradiol and puerperal psychosis. Acta Psychiatrica Scandinavica 101, 167–169.Google Scholar
Alpert, JE & Fava, M (1997) Nutrition and depression: the role of folate. Nutrition Reviews 55, 145–149.CrossRefGoogle ScholarPubMed
Andreoli, VM & Maffei, F (1975) Blood-levels of S-adenosylmethionine in schizophrenia. Lancet 306, 922.Google Scholar
Anonymous (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131–137.Google Scholar
Antun, FT, Burnett, GB, Cooper, AJ, Daly, RJ, Smythies, JR & Zealley, AK.(1971) The effects of L-methionine (without MAOI) in schizophrenia. Journal of Psychiatric Research 8, 63–71.CrossRefGoogle ScholarPubMed
Applebaum, J, Shimon, H, Sela, B-A, Belmaker, RH & Levaine, J (2004) Homocysteine levels in newly admitted schizophrenic patients. Journal of Psychiatric Research 38, 413–416.CrossRefGoogle ScholarPubMed
Arinami, T, Yamada, N, Yamakawa-Kobayashi, K, Hamaguchi, H & Toru, M (1997) Methylenetetrahydrofolate reductase variant and schizophrenia/depression. American Journal of Medical Genetics (Neuropsychiatric Genetics) 74, 526–528.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Arvindakshan, M, Sitasawad, S, Debsikdar, V, Ghate, M, Evans, D, Horrobin, DF, Bennett, C, Ranjekar, PK & Mahadik, SP (2003) Essential polyunsaturated fatty acid and lipid peroxide levels in never-medicated and medicated schizophrenic patients. Biological Psychiatry 53, 56–64.Google Scholar
Bennett, CN & Horrobin, DF (2003) Impaired niacin flushing in schizophrenia: possible biological mechanisms. Schizophrenia Research 60, Suppl. 1, 98.Google Scholar
Bentall, R (2003) Power to the patients. New Scientist, 40–43, 30 08 2003.Google Scholar
Bertolino, A, Caforio, G, Blasi, G, De Candia, M, Lattore, V, Petruzzella, V, Altamura, M, Nappi, G, Papa, S, Callicott, JH, et al. (2004) Interaction of COMT val 108/158 met genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. American Journal of Psychiatry 161, 1798–1805.Google Scholar
Borroni, B, Agosti, C, Archetti, S, Costanzi, C, Bonomi, S, Ghianda, D, Lenzi, GL & Caimi, L, Di Luca, M & Padovani, A (2004) Catechol-O-methyltransferase gene polymorphism is associated with risk of psychosis in Alzheimer disease. Neuroscience Letters 370, 127–129.Google Scholar
Botez, MI, Young, SN, Bachevalier, J & Gautier, S (1979) Folate deficiency and decreased 5-hydroxytryptamine synthesis in man. Nature 278, 182–183.Google Scholar
Bottiglieri, T (2002) S-adenosyl-L-methionine (SAMe): from the bench to the bedside–molecular basis of a pleiotrophic molecule. American Journal of Clinical Nutrition 76, Suppl.1151S–1157S.Google Scholar
Bottiglieri, T, Laundy, M, Crellin, R, Toone, BK, Carney, MWP & Reynolds, EH (2000) Homocysteine, folate, methylation, and monoamine metabolism in depression. Journal of Neurology, Neurosurgery and Psychiatry 69, 228–232.Google Scholar
Brockington, IF & Meakin, CJ (1994) Clinical clues to the aetiology of puerperal psychosis. Progress in Neuropsychopharmacology and Biological Psychiatry 18, 417–429.Google Scholar
Carboni, G, Tueting, P, Tremolizzo, I, Sugaya, I, Davis, J, Costa, E & Guidotti, A (2004) Enhanced dizocilpine efficacy in heterozygous reeler mice relates to GABA turnover downregulation. Neuropharmacology 46, 1070–1081.Google Scholar
Chagoya, de, Sanchez, VC, Hernandez-Munoz, R, Sanchez, L, Vidrio, S, Yanez, L & Suarez, J (1991) Twenty-four hour changes of S-adenosylmethionine, S-adenosylhomocysteine adenosine and their metabolising enzymes in rat liver; possible physiological significance in phospholipid methylation. International Journal of Biochemistry 23, 1439–1443.Google Scholar
Chen, Y, Sharma, RP, Costa, RH, Costa, E & Grayson, DR (2002) On the epigenetic regulation of the human reelin. Nucleic Acids Research 30, 2930–2939.Google Scholar
Chiaie, RD, Pancheri, P & Scapicchio, P (2002) Efficacy and tolerability of oral and intramuscular S-adenosyl-L-methionine 1,4-butanedisulfonate (SAMe) in the treatment of major depression: comparison with imipramine in 2 multicenter studies. American Journal of Clinical Nutrition 76, Suppl.1172S–1176S.Google Scholar
Christman, JK, Sheikhnejad, G, Dizik, M, Abileah, S & Wainfan, E (1993) Reversibility of changes in nucleic acid methylation and gene expression induced in rat liver by severe methyl deficiency. Carcinogenesis 14, 551–557.Google Scholar
Clarke, S & Banfield, K (2001) S-adenosylmethionine-dependent methyltransferases. In Homocysteine in Health and Disease, pp. 63–78 [Carmel, R, Jacobsen, DW, editors]. Cambridge, UK: Cambridge University Press.Google Scholar
Cohen, M, Dembling, B & Schorling, J (2002) The association between schizophrenia and cancer: a population-based mortality study. Schizophrenia Research 57, 139–146.Google Scholar
Cook, RJ (2001) Folate metabolism. In Homocysteine in Health and Disease, pp. 113–134 [Carmel, R, Jacobsen, DW, editors]. Cambridge, UK: Cambridge University Press.Google Scholar
Cooney, CA, Dave, AA & Wolff, GL (2002) Maternal methyl supplements in mice affect epigenetic variation and DNA methylation of offspring. Journal of Nutrition 132, 2393S–2400S.Google Scholar
da Costa, K-A, Badea, M, Fischer, LM & Zeisel, SH (2004) Elevated serum creatine phosphokinase in choline-deficient humans: mechanistic studies in C2C12 mouse myoblasts. American Journal of Clinical Nutrition 80, 163–170.Google Scholar
Davis, SR, Stacpoole, PW, Williamson, J, Kick, LS, Quinlivan, EP, Coats, BS, Shane, B, Bailey, LB & Gregory, JF III (2004) Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. American Journal of Physiology 286, E272–E279.Google ScholarPubMed
DeLong, CJ, Hicks, AM & Cui, Z (2002) Disruption of choline methyl group donation for phosphatidylethanolamine methylation in hepatocarcinoma cells. Journal of Biological Chemistry 19, 17217–17225.Google Scholar
DeLong, CJ, Shen, Y-J, Thomas, MJ & Ciu, Z (1999) Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway. Journal of Biological Chemistry 274, 29683–29688.Google Scholar
Deth, RC, DuRand, CJ, Sharma, A, Liu, D (1996) Lymphocyte phospholipid methylation is altered in schizophrenia. Biological Psychiatry 39, 504.Google Scholar
Detich, N, Bovenzi, V & Szyf, M (2003) Valproate induces replication-independent active DNA demethylation. Journal of Biological Chemistry 278, 27586–27592.Google Scholar
Ding, D & Greenberg, ML (2003) Lithium and valproate decrease the membrane phosphatidylinositol/phosphatidylcholine ratio. Molecular Microbiology 47, 373–381.Google Scholar
Do, KQ, Trabesinger, AH, Kirsten-Kruger, M, Lauer, CJ, Dydak, U, Hell, D, Holsboer, F, Boesiger, P & Cuenod, M (2000) Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. European Journal of Neuroscience 12, 3721–3728.Google Scholar
Doraiswamy, M, Martin, W, Metz, A & Deveaugh-Geiss, J (1995) Psychosis in Parkinson's disease: diagnosis and treatment. Progress in Neuro-Psychopharmacology and Biological Psychiatry 19, 835–846.Google Scholar
Drouva, SV, Rerat, E, Leblanc, P, Laplante, E & Kordon, C (1987) Variations of phospholipid methyltransferase(s) activity in the rat pituitary: estrous cycle and sex differences. Endocrinology 121, 569–574.Google Scholar
Durand, C, Mary, S, Brazo, P & Dollfus, S (2003) Psychiatric manifestations of vitamin B12 deficiency: a case report. Encephale 29, 560–565.Google Scholar
Durand, P, Prost, M & Blache, D (1995) Pro-thrombic effects of a folic acid deficient diet in rat platelets and macrophages related to elevated homocysteine and decreased n-3 polyunsaturated fatty acids. Atherosclerosis 121, 231–243.Google Scholar
Ende, G, Braus, DF, Walter, S, Weber-Fahr, W & Henn, FA (2000) The hippocampus in patients treated with electroconvulsive therapy. Archives of General Psychiatry 57, 937–943.Google Scholar
Fan, J-B, Zhang, C-S, Gu, N-F, Li, X-W, Sun, W-W, Wany, H-Y, Geny, G-Y, St Clair, D & Hee, L (2005) Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biological Psychiatry 57, 139–144.Google Scholar
Fatemi, SH, Stary, JM, Earle, JA, Araghi-Nikman, M & Eagan, E (2005) GABAergic dysfunction in schizophrenia and mood disorders as reflected by decreased levels of glutamic acid decarboxylase 65 and 67 kDa and reelin proteins in cerebellum. Schizophrenia Research 72, 109–122.Google Scholar
Fatemi, SH, Stary, JM, Halt, AR & Realmuto, GR (2001) Dysregulation of reelin and Bcl-2 proteins in autistic cerebellum. Journal of Autism and Developmental Disorders 31, 529–535.CrossRefGoogle ScholarPubMed
Finnell, RH, Spiegelstein, O, Wlodarczyk, B, Triplett, A, Pogribny, IP, Melnyk, S & James, JS (2002) DNA methylation in FolBP1 knockout mice supplemented with folic acid during gestation. Journal of Nutrition 132, 2457S–2461S.Google Scholar
Fournier, I, Ploye, F, Cottet-Emard, J-M, Brun, J & Claustrat, B (2002) Folate deficiency alters melatonin secretion in rats. Journal of Nutrition 132, 2781–2784.Google Scholar
Fraga, MF, Ballestar, E, Paz, MF, Ropero, S, Setien, F, Ballestar, ML, Heine-Suner, D, Cigudosa, JC, Urioste, M, Benitez, J, et al. (2005) Epigenetic differences arise during the lifetime of monozygotic twins. Proceedings of the National Academy of Sciences USA 102, 10604–10609.Google Scholar
Glatt, SJ, Faraone, SV & Tsuang, MT (2003) Association between a functional catechol-O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. American Journal of Psychiatry 160, 469–476.Google Scholar
Glen, ACA, MacDonald, DJ & Boyle, RM (2003 a) Cytosolic phospholipase A2 (IVAPLA2) in red cells in schizophrenia and other psychiatric disorders. In: Phospholipid Spectrum Disorders in Psychiatry, pp. 183–192 [Peet, M, Glen, I, Horrobin, DF, editors]. Carnforth, Lancs, UK: Marius Press.Google Scholar
Glen, I, McKenzie, I, Obajimi, K, Dodd, GH, Ward, PE & Ross, BM (2003 b) Markers of oxidative damage in exhalant and their use in schizophrenia and other disorders. In Phospholipid Spectrum Disorders in Psychiatry, pp. 357–364 [Peet, M, Glen, I and Horrobin, DF, editors]. Carnforth, Lancs, UK: Marius Press.Google Scholar
Gluckman, P & Hanson, M (2005) The Fetal Matrix. Evolution, Development and Disease. Cambridge, UK: Cambridge University Press.Google Scholar
Godfrey, PS, Toone, BK, Carney, MW, Flynn, TG, Bottiglieri, T, Laundy, M, Chanarin, I & Reynolds, EH (1990) Enhancement of recovery from psychiatric illness by methylfolate. Lancet 336, 392–395.Google Scholar
Goff, DC, Bottiglieri, T, Arning, E, Shih, V, Freundenreich, O, Evins, AE, Henderson, DC, Baer, L & Coyle, J (2004) Folate, homocysteine and negative symptoms in schizophrenia. American Journal of Psychiatry 161, 1705–1708.Google Scholar
Grima, G, Benz, B, Parpura, V, Cuenod, M & Do, KQ (2003) Dopamine-induced oxidative stress in neurons with glutathione deficit: implication for schizophrenia. Schizophrenia Research 62, 213–224.CrossRefGoogle ScholarPubMed
Grinshpoon, A, Barchana, M, Ponizovsky, A, Lipshitz, I, Nahon, D, Tal, O, Weizman, A & Levav, I (2005) Cancer in schizophrenia: is the risk higher or lower?. Schizophrenia Research 73, 333–341.Google Scholar
Guidotti, A, Auta, J, Davis, JM, Di-Giorgi-Gerevini, V, Dwivedi, Y, Grayson, DR, Impagnatiello, F, Pandey, G, Pesold, C, Sharma, R, et al. (2000) Decrease in reelin and glutamic acid decarboxylase67 (GAD67) expression in schizophrenia and bipolar disorder. Archives of General Psychiatry 57, 1061–1069.CrossRefGoogle ScholarPubMed
Gultepe, M, Ozcan, O, Avsar, K, Cetin, M, Ozdemir, AS & Gok, M (2003) Urine methylmalonic acid measurements for the assessment of cobalamin deficiency related to neuropsychiatric disorders. Clinical Biochemistry 36, 275–282.Google Scholar
Heresco-Levy, U, Javitt, DC, Ermilov, M, Mordel, C, Silipo, G & Lichtenstein, M (1999) Efficacy of high-dose glycine in the treatment of enduring negative symptoms of schizophrenia. Archives of General Psychiatry 56, 29–36.CrossRefGoogle ScholarPubMed
Hermesh, H, Manor, I, Shiloh, R, Weizman, R & Munitz, H (2001) Absence of myoglobinuria in acute psychotic patients with marked elevation in serum creatine phosphokinase level. European Neuropsychopharmacology 11, 111–115.Google Scholar
Hirata, F & Axelrod, J (1980) Phospholipid methylation and biological signal transmission. Science 209, 1082–1090.Google Scholar
Hoffer, A, Osmond, H & Smythies, JR (1954) Schizophrenia: a new approach. Part II. Journal of Mental Science 100, 29–45.Google Scholar
Hook, EB & Czeizel, AE (1997) Can terathanasia explain the protective effect of folic-acid supplementation on birth defects? Lancet 350, 513–515.Google Scholar
Horrobin, DF (1999) The phospholipid concept of psychiatric disorders and its relationship to the neurodevelopmental concept of schizophrenia. In Phospholipid Spectrum Disorder in Psychiatry, pp. 3–20 [Peet, M, Glen, I, Horrobin, DF, editors]. Carnforth, Lancs, UK: Marius Press.Google Scholar
Hunter, R, Barnes, J, Oakeley, HF & Matthews, DM (1970) Toxicity of folic acid given in pharmacological doses to healthy volunteers. Lancet i, 61–63.Google Scholar
Hustad, S, Ueland, PM, Vollset, SE, Zhang, Y, Bjorke-Monsen, AL & Schneede, J (2000) Riboflavin as a determinant of plasma total homocysteine: effect modification by the methylenetetrahydrofolate reductase C677T polymorphism. Clinical Chemistry 46, 1065–1071.Google Scholar
Impagnatiello, F, Guidotti, A, Pesold, C, Dwivedi, Y, Caruncho, H, Pisu, MG, Uzunov, DP, Smalheiser, NR, Davis, JM, Pandey, GN, et al. (1998) A decrease of reelin expression as a putative vulnerability factor in schizophrenia. Proceedings of the National Academy of Sciences USA 95, 15718–15723.Google Scholar
Ingrosso, D, Cimmino, A, Perna, AF, Masella, L, De, Santo, NG, De, Bonis, ML, Vacca, M, D'Esposito, M, D'Urso, M, Galletti, P, et al. (2003) Folate treatment and unbalanced methylation and changes of allelic expression induced by hyperhomocysteinaemia in patients with uraemia. Lancet 361, 1693–1699.Google Scholar
James, SJ, Cutler, P, Melnyk, S, Jernigan, S, Janak, L, Gaylor, DE & Neubrander, JA (2004) Metabolic biomarkers of increased oxidative stress and impaired methylation capacity in children with autism. American Journal of Clinical Nutrition 80, 1611–1617.Google Scholar
Joober, R, Benkelfat, C, Lal, S, Bloom, D, Labelle, A, Lalonde, P, Turecki, G, Rozen, R, Rouleau, GA (2000) Association between the methylenetetrahydrofolate reductase 677C-T missense mutation and schizophrenia. Molecular Psychiatry 5, 323–326.Google Scholar
Khan, M, Evans, D, Gunna, V, Scheffer, RE, Parikh, VV, Mahadik, SP (2002) Reduced erythrocyte membrane essential fatty acids and increased lipid peroxides in schizophrenia at the never-medicated first-episode of psychosis and after years of treatment with antipsychotics. Schizophrenia Research 58, 1–10.Google Scholar
Kim, YI (2000) Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutrition Reviews 58, 205–209.Google Scholar
Kingsbury, SJ & Garver, DL (1998) Lithium and psychosis revisited. Progress in Neuro-psychopharmacology and Biological Psychiatry 22, 249–263.Google Scholar
Levi, RN & Waxman, S (1975) Schizophrenia, epilepsy, cancer, methionine, and folate metabolism. Pathogenesis of schizophrenia. Lancet ii, 11–13.Google Scholar
Levine, J, Agam, G, Sela, BA, Garver, DL, Torrey, EF & Belmaker, RH (2005) CSF homocysteine is not elevated in schizophrenia. Journal of Neural Transmission 112, 297–302.Google Scholar
Levine, J, Stahl, Z, Sela, BA, Gavendo, S, Ruderman, V & Belmaker, RH (2002) Elevated homocysteine levels in young male patients with schizophrenia. American Journal of Psychiatry 159, 1790–1792.Google Scholar
Lewis, SJ, Zammit, S, Gunnell, D & Smith, GD (2005) A meta-analysis of the MTHFR C677T polymorphism and schizophrenia risk. American Journal of Medical Genetics (Neuropsychiatric Genetics 2005) 135B, 2–4.Google Scholar
Lindenbaum, J, Healton, EB & Savage, DG (1988) Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. New England Journal of Medicine 318, 1720–1728.CrossRefGoogle ScholarPubMed
Lipton, SA, Kim, W-K, Choi, Y-B, Kumar, S, D'Emilia, DM, Rayudu, PV, Arnelle, DR & Stamler, JS (1997) Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proceedings of the National Academy of Sciences USA 94, 5923–5928.Google Scholar
McGrath, M, Kawachi, I, Ascherio, A, Colditz, GA, Hunter, DJ & De Vivo, I (2004) Association between catechol-O-methyltransferase and phobic anxiety. American Journal of Psychiatry 161, 1703–1705.Google Scholar
Maclean, R, Ward, PE, Glen, I, Roberts, SJ & Ross, BM (2003) On the relationship between methylnicotinate-induced skin-flush and fatty acids levels in acute psychosis. Progress in Neuro-psychopharmacology and Biological Psychiatry 27, 927–933.Google Scholar
McNulty, H, McKinley, M, Wilson, B, McPartlin, J, Strain, JJ, Weir, DG & Scott, JM (2002) Impaired functioning of thermolabile methylenetetrahydrofolate reductase is dependent on riboflavin status: implications for riboflavin requirements. American Journal of Clinical Nutrition 76, 436–441.Google Scholar
Manor, I, Hermesh, H, Valevski, A, Benjamin, Y, Munitz, H & Weizman, A (1998) Recurrence pattern of serum creatine phosphokinase levels in repeated acute psychosis. Biological Psychiatry 43, 288–292.Google Scholar
Miller, JW, Selhub, J, Nadeau, MR, Thomas, CA, Feldman, RG & Wolf, PA (2003) Effect of l-dopa on plasma homocysteine in PD patients. Neurology 60, 1125–1129.Google Scholar
Mischoulon, D & Fava, M (2002) Role of S-adenosyl-methionine in the treatment of depression: a review of the evidence. American Journal of Clinical Nutrition 76, Suppl., 1158S–1161S.Google Scholar
Molloy, AM & Weir, DG (2001) Homocysteine and the nervous system. In: Homocysteine in Health and Disease, pp. 183–198 [Carmel, R and Jacobsen, DW, editors]. Cambridge, UK: Cambridge University Press.Google Scholar
Muller, T, Renger, K & Kuhn, W (2004) Levodopa-associated increase of homocysteine levels and sural axonal neurodegeneration. Archives of Neurology 61, 657–660.Google Scholar
Munoz-Moran, E, Dieguez-Lucena, JL, Fernandez-Arcas, N, Peran-Mesa, S & Reyes-Engel, A (1998) Genetic selection and folate intake during pregnancy. Lancet 352, 1120–1121.Google Scholar
Muntjewerff, J-W, van der Put, N, Eskes, T, Ellenbroek, B, Steegers, E, Blom, H & Zitman, F (2003) Homocysteine metabolism and B-vitamins in schizophrenic patients: low plasma folate as a possible independent risk factor for schizophrenia. Psychiatry Research 121, 1–9.Google Scholar
Na, C & Lee, YS (2004) Serum homocysteine, folate level and MTHFR 677, 1298 gene polymorphism in schizophrenia. European Neuropsychopharmacology 14, Suppl. 3, S232–S233.Google Scholar
Noh, JS, Sharma, RP, Veldic, M, Salvacion, AA, Jia, X, Chen, Y, Costa, E, Guidotti, A & Grayson, DR (2004) DNA methyltransferase 1 regulates reelin mRNA expression in mouse primary cortical cultures. Proceedings of the National Academy of Sciences USA 102, 1749–1754.Google Scholar
Noga, AA, Stead, LM, Zhao, Y, Brosnan, ME, Brosnan, JT & Vance, DE (2003) Plasma homocysteine is regulated by phospholipid methylation. Journal of Biological Chemistry 278, 5952–5955.Google Scholar
Noga, AA & Vance, DE (2003) A gender-specific role for phosphatidylethanolamine-N-methyltransferase-derived phosphatidylcholine in the regulation of plasma high density and very low density lipoproteins in mice. Journal of Biological Chemistry 278, 21851–21859.Google Scholar
Olney, JW, Newcomer, JW & Farber, NB (1999) NMDA receptor hypofunction model of schizophrenia. Journal of Psychiatric Research 33, 523–533.Google Scholar
Oltean, S & Banerjee, R (2003) Nutritional modulation of gene expression and homocysteine utilisation by vitamin B12. Journal of Biological Chemistry 278, 20778–20784.Google Scholar
Osher, Y, Sela, B-A, Levine, J & Belmaker, RH (2004) Elevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration. Bipolar Disorders 6, 82.Google Scholar
Peet, M & Bennett, CN (1999) Relationship between brain lipids, depression and suicide. In Phospholipid Spectrum Disorder in Psychiatry, pp. 403–408 [Peet, M, Glen, I, Horrobin, DF, editors]. Carnforth, Lancs, UK: Marius Press.Google Scholar
Peet, M, Brind, J, Ramchand, CN, Shah, S & Vankar, GK (2000) Two double-blind placebo-controlled pilot studies of eicosapentanoic acid in the treatment of schizophrenia. Schizophrenia Research 49, 243–251.Google Scholar
Persico, AM, D'Agruma, L, Maiorano, N, Totaro, A, Militerni, R, Bravaccio, C, Wassink, TH, Schneider, C, Melmed, R, Trillo, S, et al. (2001) Reelin gene alleles and haplotypes as a factor predisposing to autistic disorder. Molecular Psychiatry 6, 150–159.Google Scholar
Petronis, A, Gottesman, II, Kan, P, Kennedy, JL, Basile, VS, Paterson, AD & Popendikyte, V (2003) Monozygotic twins exhibit numerous epigenetic differences: clues to twin discordance?. Schizophrenia Bulletin 29, 169–178.Google Scholar
Petry, CJ, Ozanne, SE & Hales, CN (2001) Programming of intermediary metabolism. Molecular and Cellular Endocrinology 185, 81–91.Google Scholar
Quinlivan, EP & Gregory, JF III (2003) Effect of food fortification on folic acid intake in the United States. American Journal of Clinical Nutrition 77, 221–225.Google Scholar
Rees, WD, Hay, SM, Brown, DS, Antipatis, C & Palmer, RM (2000) Maternal protein deficiency causes hypermethylation of DNA in the livers of rat fetuses. Journal of Nutrition 130, 1821–1826.Google Scholar
Regland, B, Abrahamsson, L, Blennow, K, Grebfeldt, B & Gottfries, CG (2004) CSF-methionine is elevated in psychotic patients. Journal of Neural Transmission 111, 631–640.Google Scholar
Reichelt, KL, Hole, K, Hamberger, A, Saelid, G, Edminson, PD, Braestrup, CB, Lingjaerde, O, Ledaal, P & Orbeck, H (1981) Biologically active peptide-containing fractions in schizophrenia and childhood autism. Advances in Biochemical Psychopharmacology 28, 627–643.Google Scholar
Reynolds, EH (2002) Benefits and risks of folic acid to the nervous system. Journal of Neurology, Neurosurgery and Psychiatry 72, 567–571.Google Scholar
Rogers, JD, Sanchez-Saffron, A, Frol, AB & Diaz-Arrastia, R (2003) Elevated plasma homocysteine in patients treated with levodopa: association with vascular disease. Archives of Neurology 60, 59–64.CrossRefGoogle ScholarPubMed
Rosa, A, Peralta, V, Cuesta, MJ, Zarzuela, A, Serrano, F, Martinez-Larrea, A, & Fananas, L (2004) New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. American Journal of Psychiatry 161, 1110–1112.Google Scholar
Ross, BM, Hudson, C, Erlich, J, Warsh, JJ & Kish, SJ (1997) Increased phospholipid breakdown in schizophrenia. Evidence for the involvement of calcium-independent phospholipase A2. Archives of General Psychiatry 54, 487–494.Google Scholar
Rowling, MJ, McMullen, MH, Chipman, DC & Schalinske, KL (2002) Hepatic glycine N-methyltransferase is up-regulated by excess dietary methionine in rats. Journal of Nutrition 132, 2545–2550.Google Scholar
Sargent, T III, Kusubov, N, Taylor, SE & Budinger, TF (1992) Tracer kinetic evidence for abnormal methyl metabolism in schizophrenia. Biological Psychiatry 32, 1078–1090.Google Scholar
Sarmiento, IA, Stoll, AL & Cohen, B (1999) The role of essential lipids in the management of bipolar disorder. In Phospholipid Spectrum Disorder in Psychiatry, pp. 457–462 [Peet, M, Glen, I, Horrobin, DF, editors]. Carnforth, Lancs, UK: Marius Press.Google Scholar
Sartorius, A, Neumann-Haefelin, C, Vollmayr, B, Hoehn, M & Henn, FA (2003) Choline rise in the rat hippocampus induced by electroconvulsive shock treatment. Biological Psychiatry 53, 620–623.Google Scholar
Sazci, A, Ergul, E, Guzelhan, Y, Kaya, G & Kara, I (2003) Methylenetetrahydrofolate reductase gene polymorphisms in patients with schizophrenia. Molecular Brain Research 117, 104–107.Google Scholar
Shumeiko, O, Levine, J, Sela, BA & Belmaker, RH (2003) Homocysteine reducing strategies in chronic schizophrenic patients with hyperhomocysteinemia. European Journal of Neuropsychopharmacology 13, Suppl. 4, S280–S281.Google Scholar
Singh, U, Yokota, K, Gupta, C & Shinozuka, H (1990) Choline deficiency activates phospholipases A2 and C in rat liver without affecting the activity of protein kinase C. Journal of Nutritional Biochemistry 1, 434–439.Google Scholar
Slack, A, Cervoni, N, Pinard, M & Schizophrenicyf, M (1999) Feedback regulation of DNA methyltransferase gene expression by methylation. European Journal of Biochemistry 264, 191–199.Google Scholar
Stahl, Z, Belmaker, RH, Friger, M & Levine, J (2005) Nutritional and life style determinants of plasma homocysteine in schizophrenic patients. European Neuropsychopharmacology 15, 291–295.Google Scholar
Stead, LM, Jacobs, RL, Brosnan, ME & Brosnan, JT (2004) Methylation demand and homocysteine metabolism. Advances in Enzyme Regulation 44, 321–333.Google Scholar
Susser, E, Brown, AS, Klonowski, E, Allen, RH & Lindenbaum, J (1998) Schizophrenia and impaired homocysteine metabolism: a possible association. Biological Psychiatry 44, 141–143.Google Scholar
Tiemeier, H, Ruud van Tuijl, H, Hofman, A, Meijer, J, Kilian, AJ & Breteler, MMB (2002) Vitamin B12, folate, and homocysteine in depression: The Rotterdam Study. American Journal of Psychiatry 159, 2099–2101.Google Scholar
Tolbert, LC, Monti, JA, Walter-Ryan, W, Alarcon, RD, Bahar, B, Keriotis, JT, Allison, JG, Cates, A, Antun, F & Smythies, JR (1988) Clinical correlations of one-carbon metabolism abnormalities. Progress in Neuropsychopharmacology and Biological Psychiatry 12, 491–502.Google Scholar
Tolmunen, T, Hintikka, J, Ruusunen, A, Voutilainen, S, Tanskanen, A, Valkonen, VP, Viinamaki, H, Kaplan, GA & Salonen, JT (2004) Dietary folate and the risk of depression in Finnish middle-aged men. A prospective follow-up study. Psychotherapy and Psychosomatics 73, 334–339.Google Scholar
Tolmunen, T, Voutilainen, S, Hintikka, J, Rissanen, T, Tanskanen, A, Viinamaki, H, Kaplan, GA & Salonen, JT (2003) Dietary folate and depressive symptoms are associated in middle-aged Finnish men. Journal of Nutrition 133, 3233–3236.Google Scholar
Tremolizzo, L, Carboni, G, Ruzicka, WB, Mitchell, CP, Sugaya, I, Tueting, P, Sharma, R, Grayson, DR, Costa, E & Guidotti, A (2002) An epigenetic mouse model for molecular and behavioural neuropathologies related to schizophrenia vulnerability. Proceedings of the National Academy of Sciences USA 99, 17095–17100.Google Scholar
Tremolizzo, L, Doueiri, M-S, Dong, E, Grayson, DR, Davis, J, Pinna, G, Tueting, P, Rodriguez-Menendez, V, Costa, E & Guidotti, A (2005) Valproate corrects the schizophrenia-like epigenetic behavioural modifications induced by methionine in mice. Biological Psychiatry 57, 500–509.Google Scholar
Tsai, G, Lane, H-Y, Yang, P, Chong, M-Y & Lange, N (2004) Glycine transporter 1 inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry 55, 452–456.Google Scholar
Tsai, G, Tang, P, Chung, L-C, Lange, N & Coyle, JT (1998) D-serine added to antipsychotics for the treatment of schizophrenia. Biological Psychiatry 44, 1081–1089.Google Scholar
Tuominen, HJ, Tiihonen, J & Wahlbeck, K (2005) Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis. Schizophrenia Research 72, 225–234.Google Scholar
Ueland, PM, Hustad, S, Schneede, J, Refsum, H & Vollset, SE (2001) Biological and clinical implications of the MTHFR C677T polymorphism. Trends in Pharmacological Sciences 22, 195–201.Google Scholar
Vance, DE, Walkey, CJ & Cui, Z (1997) Phosphatidylethanolamine N-methyltransferase from liver. Biochimica et Biophysica Acta 1348, 142–150.Google Scholar
Veldic, M, Caruncho, HJ, Liu, WS, Davis, J, Satta, R, Grayson, DR, Guidotti, A & Costa, E (2004 a) DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proceedings of the National Academy of Sciences USA 101, 348–353.Google Scholar
Veldic, M, Guidotti, A, Maloku, E, Davis, JM & Costa, E (2004 b) In psychosis, cortical interneurons overexpress DNA-methyltransferase 1. Proceedings of the National Academy of Sciences USA 102, 2152–2157.Google Scholar
Virgos, C, Martorell, L, Simo, JM, Valero, J, Figureuera, L, Joven, J, Labad, A & Vilella, E (1999) Plasma homocysteine and the methylenetetrahydrofolate reductase C677T gene variant: lack of association with schizophrenia. Neuroreport 10, 2035–2038.Google Scholar
Waterland, RA & Jirtle, RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Molecular and Cellular Biology 23, 5293–5300.Google Scholar
Watkins, SM, Zhu, X & Zeisel, SH (2003) Phosphatidylethanolamine-N-methyltransferase activity and dietary choline regulate liver-plasma lipid flux and essential fatty acid metabolism in mice. Journal of Nutrition 133, 3386–3391.Google Scholar
Waziri, R, Baruah, S & Sherman, AD (1992) Abnormal serine-glycine metabolism in the brains of schizophrenics. Schizophrenia Research 8, 233–243.Google Scholar
Waziri, R & Mott, J (1986) Drug effects on serine metabolism in psychiatric patients. Psychiatry Research 18, 119–126.Google Scholar
Weaver, ICG, Champagne, FA, Brown, SE, Dymov, S, Sharma, S, Meaney, MJ & Szyf, M (2005) Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: altering epigenetic marking later in life. Journal of Neuroscience 25, 11045–11054.Google Scholar
Weickert, TW, Goldberg, TE, Mishara, A, Apud, JA, Kolachana, BS, Egan, MF & Weinberger, DR (2004) Catechol-O-methyltransferase Val108/158Met genotype predicts working memory response to antipsychotic medications. Biological Psychiatry 56, 677–682.Google Scholar
Weir, DG & Molloy, AM (2000) Microvascular disease and dementia in the elderly: are they related to hyperhomocysteinemia? American Journal of Clinical Nutrition 71, 859–860.Google Scholar
Weir, DG & Scott, JM (1995) The biochemical basis of the neuropathy in cobalamin deficiency. Bailliere's Clinical Haematology 8, 479–497.Google Scholar
Weisberg, I, Tran, P, Christensen, B, Sibani, S & Rozen, R (1998) A second genetic polymorphism in methylenetetrahydrofolate reductase (MTHFR) associated with decreased enzyme activity. Molecular Genetics and Metabolism 64, 169–172.Google Scholar
Wyatt, RJ, Termini, BA & Davis, J (1971) Biochemical and sleep studies of schizophrenia: a review of the literature–1960–1970. Schizophrenia Bulletin 4, 10–44.Google Scholar
Zeisel, SH, Mar, M-H, Howe, JC & Holden, JM (2003) Concentrations of choline-containing compounds and betaine in common foods. Journal of Nutrition 133, 1302–1307.Google Scholar
Zhao, R, Chen, Y, Tan, W, Waly, M, Sharma, A, Stover, P, Rosowsky, A, Malewicz, B & Deth, RC (2001) Relationship between dopamine-stimulated phospholipid methylation and the single-carbon folate pathway. Journal of Neurochemistry 78, 788–796.Google Scholar