The Role of Abnormalities Related to the One Carbon Cycle in Depression and Schizophrenia
John Smythies
Center for Brain and Cognition, UCSD.
DOI: 10.4236/nm.2012.31015   PDF    HTML   XML   6,069 Downloads   8,980 Views   Citations


This paper reviews our present knowledge of the role of the one-carbon cycle in mood disorder and schizophrenia with particular attention to S-adenosyl methionine (SAM). After an historical introduction the clinical data is first reviewed of the anti-depressant action of SAM, in particular a survey of double blind placebo-controlled trials. Then follows an account of the biochemical parameters of the action of SAM, in particular the role of folic acid and 5-methyltetrahydrofolate (vitamin B9), polyamines, homocysteine, together with epigenetic studies. In schizophrenia the effect of oral l-methionine on worsening the symptoms of some chronic schizophrenics has been known since 1961. Recent epigenetic research covered has addressed the mechanism of this reaction. This includes the role of SAM in modulating DNA methyltransferase-1 mRNA activity, cytosine 5-methylation, spine numbers and the expression of mRNAs encoding for reelin and GAD67 in GABAergic neurons in the frontal cortex in schizophrenia. There is also evidence that marker D8S542 located within the methionine sulfoxide reductase (MSRA) gene may be involved in schizophrenia as well as 677C > T polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene. The possible roles of homocysteine and methionine S-adenosyl transferase kinetics are also discussed.

Share and Cite:

J. Smythies, "The Role of Abnormalities Related to the One Carbon Cycle in Depression and Schizophrenia," Neuroscience and Medicine, Vol. 3 No. 1, 2012, pp. 101-106. doi: 10.4236/nm.2012.31015.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] H. Osmond and J. Smythies, “Schizophrenia: A New Approach,” Journal of Mental Science, Vol. 98, No. 411, 1953, pp. 309-315.
[2] B. T. Folate, “Vitamin B12, and Neuropsychiatric Disorders,” Nutrition Reviews, Vol. 54, No. 12, 1996, pp. 382-390.
[3] P. Salmaggi, G. M. Bressa, G. Nicchia, M. Coniglio, P. La Greca and C. Le Grazie “Double-Blind, Placebo-Controlled Study of S-Adenosyl-L-Methionine in Depressed Postmenopausal Women,” Psychotherapy and Psycho- somatics, Vol. 59, No. 1, 1993, pp. 34-40. doi:10.1159/000288642
[4] K. M. Bell, L. Plon, W. E. Bun-ney Jr. and S. G. Potkin, “S-Adeno-Sylmethionine Treatment of Depression: A Controlled Clinical Trial,” American Journal of Psychiatry, Vol. 145, No. 9, 1988, pp. 1110-1114.
[5] K. M. Bell, S. G. Potkin, D. Carreon and L. Plon, “S- Adenosylmethionine Blood Levels in Major Depression: Changes with Drug Treatment,” Acta Neurologica Scandinavica, Vol. 89, No. S154, 1994, pp. 15-18. doi:10.1111/j.1600-0404.1994.tb05404.x
[6] P. Pancheri, P. Scapicchio and R. D. Chiaie, “A Double-Blind, Randomized Parallel-Group, Efficacy and Safety Study of Intramuscular S-Adenosyl-L-Methionine 1,4- Butanedisul-Phonate (SAMe) versus Imipramine in Patients with Major Depressive Disorder,” International Journal of Neuropsychopharmacology, Vol. 5, 2002, pp. 287-294.
[7] R. Delle Chiaie, P. Pancheri and P. Scapicchio, “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, Vol. 76, 1996, pp. 1172-1176S.
[8] C. Berlanga, H. A. Ortega-Soto, M. Ontiveros and H. Senties, “Efficacy of S-Adenosyl-L-Methionine in Speeding the Onset of Action of Imipramine,” Psychiat Research, Vol. 44, No. 3, 1992, pp. 257-262. doi:10.1016/0165-1781(92)90029-3
[9] T. Bottiglieri, P. Godfrey, T. Flynn, M. W. Carney, B. K. Toone, E. H. Reynolds, “Cerebrospinal Fluid S-Adenosylme-Thionine in Depression and Dementia: Effects of Treatment with Parenteral and Oral S-Adenosylmethionine,” Journal of Neurology, Neurosurgery & Psychiatry, Vol. 53, 1990, pp. 1096-1098. doi:10.1136/jnnp.53.12.1096
[10] B. L. Kagan, D. L. Sultzer, N. Rosenlicht and R. H. Gerner, “Oral S-Adenosylmethionine in Depression: A Randomized, Double-Blind, Placebo-Controlled Trial,” Ame- rican Journal of Psychiatry, Vol. 147, No. 5, 1990, pp. 591-595.
[11] J. F. Lipinski, B. M. Cohen, F. Frankenburg, M. Tohen, C. Waternaux, R. Altesman, B. Jones and P. Harris, “Open Trial of S-Adenosylmethionine for Treatment of Depres-sion,” American Journal of Psychiatry, Vol. 141, No. 3, 1984, pp. 448-450.
[12] X. Ye, C. Q. Lai, J. W. Crott, A. M. Troen, J. M. Ordovas and K. L. Tucker, “The Folate Hydrolase 1561C>T Polymorphism Is Associated with Depressive Symptoms in Puerto Rican adults,” Psychosomatic Medicine, Vol. 73, No. 5, 2011, pp. 385-392. doi:10.1097/PSY.0b013e31821a1ab4
[13] T. Bottiglieri, M. Laundy, R. Crellin, B. K. Toone, M. W. Carney and E. H. Reynolds, “Homocysteine, Folate, Methylation, and Monoamine Metabolism in Depression,” Journal of Neurology, Neu-rosurgery & Psychiatry, Vol. 54, No. 2, 2000, pp. 382-390.
[14] M. T. Abou-Saleh and A. Coppen, “The Biology of Folate in Depression: Implications for Nutritional Hypotheses of the Psychoses,” Journal of Psychiatric Research, Vol. 20, No. 2, 1986, pp. 91-101. doi:10.1016/0022-3956(86)90009-9
[15] G. P. Guaraldi, M. Fava, F. Mazzi and P. la Greca, “An Open Trial of Methylte-trahydrofolate in Elderly Depressed Patients,” Annals of Clinical Psychiatry, Vol. 55, No. 5, 1993, pp. 101-105. doi:10.3109/10401239309148970
[16] C. A. Cooney, C. K. Wise, L. A. Poirier and S. F. Ali, “Methamphetamine Treatment Affects Blood and Liver S-Adenosylmethionine (SAM) in Mice, Correlation with Dopamine Depletion in the Striatum,” Annals of the New York Academy of Sciences, Vol. 844, 1998, pp. 191-200. doi:10.1111/j.1749-6632.1998.tb08234.x
[17] S. Genedani, S. Saltini, A. Benelli, M. Filaferro and A. Bertolini, “Influence of SAMe on the Modifications of Brain Polyamine Levels in an Animal Model of Depression,” NeuroReport, Vol. 12, No. 18, 2001, pp. 3939- 3942. doi:10.1097/00001756-200112210-00017
[18] W. Pollin, P. V. Cardon, S. S. Kety, “Effects of Amino Acid Feedings in Schi-zophrenic Patients Treated with Iproniazid,” Science, Vol. 133, No. 3346, 1961, pp. 104- 105. doi:10.1126/science.133.3446.104
[19] C. Walss-Bass, M. C. Soto-Bernardini, T. Johnson-Pais, et al., “Methionine Sulfoxide Reductase: A Novel Schizophrenia Candidate Gene,” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Vol. 150B, No. 2, 2009, pp. 219-225.
[20] J. W. Muntjewerff, R. S. Kahn, H. J. Blom, M. den Heller, “Homocysteine, Methy-lenetetrahydrofolate Reductase and Risk of Schizophrenia: A Meta-Analysis,” Molecular Psychiatry, Vol. 11, 2006, pp. 143-149. doi:10.1038/
[21] C. L. Smith, A. Bolton and G. Nguyen, “Genomic and Epigenomic Instability, Fragile Sites, Schizophrenia and Autism,” Current Genomics, Vol. 11, No. 6, 2010, pp. 447-469. doi:10.2174/138920210793176001
[22] A. Guidotti, W. Ruzicka, D. R. Grayson, M. Veldic, G. Pinna, J. M. Davis and E. Costa, “S-Adenosyl Methionine and DNA Methyltransferase-1 mRNA Overexpression in Psychosis,” NeuroReport, Vol. 18, 2007, pp. 57-60. doi:10.1097/WNR.0b013e32800fefd7
[23] P. Tueting, J. M. Davis, M. Veldic, F. Pibiri, B. Kadriu, A. Guidotti and E. Costa, “L-Methionine Decreases Dendritic Spine Density in Mouse Frontal Cortex,” NeuroReport, Vol. 21, 2010, pp. 543-548. doi:10.1097/WNR.0b013e3283373126
[24] M. O. Krebs, A. Bellon, G. Mainguy, T. M. Jay and H. Frieling, “One-Carbon Metabolism and Schizophrenia: Current Challenges and Future Directions,” Trends in Molecular Medicine, Vol. 15, No. 12, 2009, pp. 562-570. doi:10.1016/j.molmed.2009.10.001
[25] B. Regland, “Schi-zophrenia and Single-Carbon Metabolism,” Progress in Neu-ro-Psychopharmacology and Biological Psychiatry, Vol. 29, No. 7, 2005, pp. 1124-1132. doi:10.1016/j.pnpbp.2005.06.023
[26] B. Regland, B. V. Jo-hansson and C. G. Gottfries, “Homocysteinemia and Schizoph-renia as a Case of Methylation Deficiency,” Journal of Neural Transmission, Vol. 98, No. 2, 1994, pp. 143-152. doi:10.1007/BF01277017
[27] A. Kale, N. Naphade, S. Sapkale, M. Kamaraju, A. Pillai, S. Joshi and S. Mahadik, “Reduced Folic Acid, Vitamin B(12) and Docosahexaenoic Acid and Increased Homocysteine and Cortisol in Never-Medicated Schizophrenia Patients: Implications for Altered One-Carbon Metabolism,” Psychiatry Research, Vol. 175, No. 1, 2010, pp. 47-53. doi:10.1016/j.psychres.2009.01.013
[28] J. M. Freeman, J. D. Finkelstein and S H. Mudd, “Fo- late-responsive Homocystinuria and “Schizophrenia’. A Defect in Methylation Due to Deficient 5,10-methylene-tetrahydro-Folate Reductase Activity,” New England Jour- nal of Medicine, Vol. 292, 1975, pp. 491-496. doi:10.1056/NEJM197503062921001
[29] C. Miodownik, V. Lerner, T. Vishne, B. A. Sela and J. Levine, “High-Dose Vita-min B6 Decreases Homocysteine Serum Levels in Patients with Schizophrenia and Schizoaffective Disorders: A Preliminary Study,” Clinical Neuropharmacology, Vol. 30, No. 1, 2007, pp. 13-17. doi:10.1097/01.WNF.0000236770.38903.AF
[30] R. D. Strous, M. S. Ritsner, S. Adler, et al., “Improvement of Aggressive Behavior and Quality of Life Impair- ment Following S-Adenosyl-Methionine (SAM) Aug- mentation in Schizophre-nia,” European Neuropsycho- pharmacology, Vol. 19, No. 1, 2009, pp. 14-22. doi:10.1016/j.euroneuro.2008.08.004
[31] J. R. Smythies, R. D. Alarcon, D. Morere, et al., “Abnormalities of One-Carbon Metabolism in Psychiatric Disorders: Study of Methionine Ade-nosyltransferase Kinetics and Lipid Composition of Erythrocyte Membranes,” Biological Psychiatry, Vol. 21, No. 14, 1986, pp. 1301-1308. doi:10.1016/0006-3223(86)90330-6
[32] E. H. Reynolds, M. W. Carney and B. K. Toone, “Methylation and Mood,” Lancet, Vol. 2, No. 8396, 1984, pp. 196-198. doi:10.1016/S0140-6736(84)90482-3
[33] C. S. Thomas, T. Bottiglieri, J. Edeh, et al., “The Influence of S-Adenosylmethionine (SAM) on Prolactin in Depressed Patients,” International Clinical Psychopharmacology, Vol. 2, No. 2, 1987, pp. 97-102. doi:10.1097/00004850-198704000-00001
[34] D. A. Morere, R. D. Alarcon, J. A. Monti, et al., “Medication Effects on One-Carbon Metabolism in Schizophrenia, Mania, and Major Depression,” J Clin Psychopharmacology, Vol. 6, 1986, pp. 155-161.
[35] M. A. Sherer, G. L. Cantoni, R. N. Golden, et al., “Effects of S-Adenosyl-Methionine on Plasma Norepinephrine, Blood Pressure, and Heart Rate in Healthy Volunteers,” Psy-chiatry Research, Vol. 17, No. 2, 1986, pp. 111-118. doi:10.1016/0165-1781(86)90066-1
[36] T. Bottiglieri and K. Hyland, “S-Adenosylmethionine Levels in Psychiatric and Neurological Disorders: A Review,” Acta Neurologica Scandi-navica, Vol. 89, No. S154, 1994, pp. 19-26. doi:10.1111/j.1600-0404.1994.tb05405.x
[37] G. E. Lobley, A. Connell and D. Revell, “The Importance of Transmethylation Reactions to Methionine Metabolism in Sheep: Effects of Sup-plementation with Creatine and Choline,” British Journal of Nutrition, Vol. 75, No. 1, 1996, pp. 47-56. doi:10.1079/BJN19960109
[38] R. J. Baldessarini, “Neuro-pharmacology of S-Adenosyl- L-Methionine,” American Jour-nal of Medicine, Vol. 83, No. 5A, 1987, pp. 95-103. doi:10.1016/0002-9343(87)90860-6
[39] T. Doi, T. Kawata, N. Tadano, T. Iijima and A. Maekawa, “Effect of Vitamin B12 Deficiency on S-Adenosylme- thionine Metabolism in Rats,” Journal of Nutritional Science and Vitaminology, Vol. 35, No. 1, 1989, pp. 1-9. doi:10.3177/jnsv.35.1
[40] D. R. Grayson, Y. Chen, E. Dong, et al., “From trans- Methylation to Cytosine Methylation: Evo-lution of the Methylation Hypothesis of Schizophrenia,” Epi-genetics, Vol. 4, No. 3, 2009, pp. 144-149. doi:10.4161/epi.4.3.8534

Copyright © 2023 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.