Hostname: page-component-586b7cd67f-vdxz6 Total loading time: 0 Render date: 2024-11-24T02:44:49.915Z Has data issue: false hasContentIssue false
  • English
  • Français

Homocysteine as a peripheral biomarker in bipolar disorder: A meta-analysis

Published online by Cambridge University Press:  23 March 2020

E. Salagre ,
A.F. Vizuete ,
M. Leite ,
D.J. Brownstein ,
A. McGuinness ,
F. Jacka ,
S. Dodd ,
B. Stubbs ,
C.A. Köhler  and
E. Vieta
...Show all authors
E. Salagre*
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia Bipolar Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
A.F. Vizuete
Affiliation:
Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
M. Leite
Affiliation:
Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
D.J. Brownstein
Affiliation:
Monash University, Faculty of Medicine, Nursing and Health Sciences, Melbourne, Australia
A. McGuinness
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia
F. Jacka
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia
S. Dodd
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia Department of Psychiatry, University of Melbourne, Parkville, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia
B. Stubbs
Affiliation:
Health, Social Care and Education, Anglia Ruskin University, Chelmsford, UK Geriatrics Division, Department of Medicine-DIMED, University of Padova, Padova, Italy Institute of clinical Research and Education in Medicine (IREM), Padova, Italy Physiotherapy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, SE5 8AZLondon, UK
C.A. Köhler
Affiliation:
Translational Psychiatry Research Group and Department of Clinical Medicine, Faculty of Medicine, Federal University of Ceará, Fortaleza, CE, Brazil
E. Vieta
Affiliation:
Bipolar Unit, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain
A.F. Carvalho
Affiliation:
Physiotherapy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, SE5 8AZLondon, UK
M. Berk
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia Department of Psychiatry, University of Melbourne, Parkville, Australia Florey Institute for Neuroscience and Mental Health, University of Melbourne, Parkville, Australia Orygen, The National Centre of Excellence in Youth Mental Health, University of Melbourne, Parkville, Australia
B.S. Fernandes*
Affiliation:
Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
*
*Corresponding author. Deakin University, School of Medicine, Barwon Health, Geelong, Victoria, Australia.
*Corresponding author. Deakin University, School of Medicine, Barwon Health, Geelong, Victoria, Australia.
Get access

Abstract

Background:

Bipolar disorder (BD) is a psychiatric disorder with an uncertain aetiology. Recently, special attention has been given to homocysteine (Hcy), as it has been suggested that alterations in 1-carbon metabolism might be implicated in diverse psychiatric disorders. However, there is uncertainty regarding possible alterations in peripheral Hcy levels in BD.

Methods:

This study comprises a meta-analysis comparing serum and plasma Hcy levels in persons with BD and healthy controls. We conducted a systematic search for all eligible English and non-English peer-reviewed articles.

Results:

Nine cross-sectional studies were included in the meta-analyses, providing data on 1547 participants. Random-effects meta-analysis showed that serum and plasma levels of Hcy were increased in subjects with BD in either mania or euthymia when compared to healthy controls, with a large effect size in the mania group (g = 0.98, 95% CI: 0.8–1.17, P < 0.001, n = 495) and a small effect in the euthymia group (g = 0.3, 95% CI: 0.11–0.48, P = 0.002, n = 1052).

Conclusions:

Our meta-analysis provides evidence that Hcy levels are elevated in persons with BD during mania and euthymia. Peripheral Hcy could be considered as a potential biomarker in BD, both of trait (since it is increased in euthymia), and also of state (since its increase is more accentuated in mania). Longitudinal studies are needed to clarify the relationship between bipolar disorder and Hcy, as well as the usefulness of peripheral Hcy as both a trait and state biomarker in BD.

Keywords

Precision psychiatryBiomarkerHomocysteineBipolar disorderSystematic reviewMeta-analysis
Type
Review
Information
European Psychiatry , Volume 43 , June 2017 , pp. 81 - 91
Copyright
Copyright © European Psychiatric Association 2017

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alawieh, AZaraket, FALi, JLMondello, SNokkari, ARazafsha, Met al.Systems biology, bioinformatics, and biomarkers in neuropsychiatry. Front Neurosci 2012;6:187.CrossRefGoogle ScholarPubMed
Domenici, EWille, DRTozzi, FProkopenko, IMiller, SMcKeown, Aet al.Plasma protein biomarkers for depression and schizophrenia by multi analyte profiling of case-control collections. PLoS One 2010;5:e9166.CrossRefGoogle ScholarPubMed
Frey, BNAndreazza, ACHouenou, JJamain, SGoldstein, BIFrye, MAet al.Biomarkers in bipolar disorder: a positional paper from the International Society for Bipolar Disorders Biomarkers Task Force. Aust N Z J Psychiatry 2013;47: 321–332.CrossRefGoogle ScholarPubMed
Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane Collaboration; 2011.Google Scholar
Fernandes, BSGama, CSCereser, KMYatham, LNFries, GRColpo, Get al.Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis. J Psychiatr Res 2011;45: 995–1004.CrossRefGoogle ScholarPubMed
Fernandes, BSBerk, MTurck, CWSteiner, JGoncalves, CADecreased peripheral brain-derived neurotrophic factor levels are a biomarker of disease activity in major psychiatric disorders: a comparative meta-analysis. Mol Psychiatry 2014;19: 750–751.CrossRefGoogle ScholarPubMed
Fernandes, BSMolendijk, MLKohler, CASoares, JCLeite, CMMachado-Vieira, Ret al.Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies. BMC Med 2015;13:289.CrossRefGoogle ScholarPubMed
Fernandes, BSSteiner, JBerk, MMolendijk, MLGonzalez-Pinto, ATurck, CWet al.Peripheral brain-derived neurotrophic factor in schizophrenia and the role of antipsychotics: meta-analysis and implications. Mol Psychiatry 2015;20: 1108–1119.CrossRefGoogle ScholarPubMed
Molendijk, MLSpinhoven, PPolak, MBus, BAPenninx, BWElzinga, BMet al.concentrations as peripheral manifestations of depression: evidence from a systematic review and meta-analyses on 179 associations (N = 9484). Mol Psychiatry 2014;19: 791–800.CrossRefGoogle Scholar
Fernandes, BSSteiner, JBernstein, HGDodd, SPasco, JADean, OMet al.C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Mol Psychiatry 2016;21: 554–564.CrossRefGoogle Scholar
Howren, MBLamkin, DMSuls, JAssociations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009;71: 171–186.CrossRefGoogle ScholarPubMed
Fernandes, BSSteiner, JMolendijk, MLDodd, SNardin, PGoncalves, CAet al.C-reactive protein concentrations across the mood spectrum in bipolar disorder: a systematic review and meta-analysis. Lancet Psychiatry 2016;3(12):1147–1156.CrossRefGoogle ScholarPubMed
Ghanizadeh, ASingh, ABBerk, MTorabi-Nami, MHomocysteine as a potential biomarker in bipolar disorders: a critical review and suggestions for improved studies. Expert Opin Ther Targets 2015;19: 927–939.CrossRefGoogle ScholarPubMed
Cosar, AIpcioglu, OMOzcan, OGultepe, MFolate and homocysteine metabolisms and their roles in the biochemical basis of neuropsychiatry. Turk J Med Sci 2014;44: 1–9.CrossRefGoogle ScholarPubMed
Yadav, UKumar, PGupta, SRai, VRole of MTHFR C677T gene polymorphism in the susceptibility of schizophrenia: an updated meta-analysis. Asian J Psychiatr 2016;20: 41–51.CrossRefGoogle ScholarPubMed
Numata, SKinoshita, MTajima, ANishi, AImoto, IOhmori, TEvaluation of an association between plasma total homocysteine and schizophrenia by a Mendelian randomization analysis. BMC Med Genet 2015;16:54.CrossRefGoogle ScholarPubMed
Muntjewerff, JWKahn, RSBlom, HJden Heijer, MHomocysteine, methylenetetrahydrofolate reductase and risk of schizophrenia: a meta-analysis. Mol Psychiatry 2006;11: 143–149.CrossRefGoogle ScholarPubMed
Assies, JMocking, RJLok, ARuhe, HGPouwer, FSchene, AHEffects of oxidative stress on fatty acid- and one-carbon-metabolism in psychiatric and cardiovascular disease comorbidity. Acta Psychiatr Scand 2014;130: 163–180.CrossRefGoogle ScholarPubMed
Moustafa, AAHewedi, DHEissa, AMFrydecka, DMisiak, BHomocysteine levels in schizophrenia and affective disorders-focus on cognition. Front Behav Neurosci 2014;8:343.CrossRefGoogle ScholarPubMed
Baek, JHBernstein, EENierenberg, AAOne-carbon metabolism and bipolar disorder. Z J Psychiatry 2013;47: 1013–1018.Google ScholarPubMed
Hooshmand, BMangialasche, FKalpouzos, GSolomon, AKareholt, ISmith, ADet al.Association of vitamin B12, folate, and sulfur amino acids with brain magnetic resonance imaging measures in older adults: a longitudinal population-based study. JAMA Psychiatry 2016;73: 606–613.CrossRefGoogle ScholarPubMed
Kolling, JScherer, EBSiebert, CLongoni, ALoureiro, SWeis, Set al.Severe hyperhomocysteinemia decreases respiratory enzyme and Na(+)-K(+) ATPase activities, and leads to mitochondrial alterations in rat amygdala. Neurotox Res 2016;29: 408–418.CrossRefGoogle ScholarPubMed
Das, UNFolic acid and polyunsaturated fatty acids improve cognitive function and prevent depression dementia, and Alzheimer's disease – but how and why?. Prostaglandins Leukot Essent Fatty Acids 2008;78: 11–19.CrossRefGoogle ScholarPubMed
Hu, HWang, CJin, YMeng, QLiu, QLiu, Ket al.Alpha-lipoic acid defends homocysteine-induced endoplasmic reticulum and oxidative stress in HAECs. Biomed Pharmacother 2016;80: 63–72.CrossRefGoogle ScholarPubMed
Wang, GSiow, YLKarmin, OHomocysteine stimulates nuclear factor kappaB activity and monocyte chemoattractant protein-1 expression in vascular smooth-muscle cells: a possible role for protein kinase C. Biochem J 2000;352(Pt 3):817–826.CrossRefGoogle ScholarPubMed
Boldyrev, ABryushkova, EMashkina, AVladychenskaya, EWhy is homocysteine toxic for the nervous and immune systems?. Curr Aging Sci 2013;6: 29–36.CrossRefGoogle ScholarPubMed
Skovierova, HMahmood, SBlahovcova, EHatok, JLehotsky, JMurin, REffect of homocysteine on survival of human glial cells. Physiol Res 2015;64: 747–754.Google ScholarPubMed
Kim, BJSeo, MHuh, JKKwon, CHKim, JTSung, KCet al.Associations of plasma homocysteine levels with arterial stiffness in prehypertensive individuals. Clin Exp Hypertens 2011;33: 411–417.CrossRefGoogle ScholarPubMed
Kinoshita, MNumata, STajima, AShimodera, SImoto, IOhmori, TPlasma total homocysteine is associated with DNA methylation in patients with schizophrenia. Epigenetics 2013;8: 584–590.CrossRefGoogle ScholarPubMed
Kok, DEDhonukshe-Rutten, RALute, CHeil, SGUitterlinden, AGvan der Velde, Net al.The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenetics 2015;7:121.CrossRefGoogle ScholarPubMed
Pana, AHomocysteine and neuropsychiatric disease. Psychiatr Ann 2015;45: 463–468.CrossRefGoogle Scholar
Berk, MKapczinski, FAndreazza, ACDean, OMGiorlando, FMaes, Met al.Pathways underlying neuroprogression in bipolar disorder: focus on inflammation, oxidative stress and neurotrophic factors. Neurosci Biobehav Rev 2011;35: 804–817.CrossRefGoogle ScholarPubMed
Sharma, ANBauer, IESanches, MGalvez, JFZunta-Soares, GBQuevedo, Jet al.Common biological mechanisms between bipolar disorder and type 2 diabetes: focus on inflammation. Prog Neuropsychopharmacol Biol Psychiatry 2014;54: 289–298.CrossRefGoogle ScholarPubMed
Peng, HYMan, CFXu, JFan, YElevated homocysteine levels and risk of cardiovascular and all-cause mortality: a meta-analysis of prospective studies. J Zhejiang Univ Sci B 2015;16: 78–86.CrossRefGoogle ScholarPubMed
Nazef, KKhelil, MChelouti, HKacimi, GBendini, MTazir, Met al.Hyperhomocysteinemia is a risk factor for Alzheimer's disease in an Algerian population. Arch Med Res 2014;45: 247–250.CrossRefGoogle Scholar
Beydoun, MABeydoun, HAGamaldo, AATeel, AZonderman, ABWang, YEpidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health 2014;14:643.CrossRefGoogle ScholarPubMed
Nabi, HBochud, MGlaus, JLasserre, AMWaeber, GVollenweider, Pet al.Association of serum homocysteine with major depressive disorder: results from a large population-based study. Psychoneuroendocrinology 2013;38: 2309–2318.CrossRefGoogle ScholarPubMed
Reif, APfuhlmann, BLesch, KPHomocysteinemia as well as methylenetetrahydrofolate reductase polymorphism are associated with affective psychoses. Prog Neuropsychopharmacol Biol Psychiatry 2005;29: 1162–1168.CrossRefGoogle ScholarPubMed
Bjelland, ITell, GSVollset, SERefsum, HUeland, PMFolate, vitamin B12, homocysteine, and the MTHFR 677C->T polymorphism in anxiety and depression: the Hordaland Homocysteine Study. Arch Gen Psychiatry 2003;60: 618–626.CrossRefGoogle ScholarPubMed
Gu, PDeFina, LFLeonard, DJohn, SWeiner, MFBrown, ESRelationship between serum homocysteine levels and depressive symptoms: the Cooper Center Longitudinal Study. J Clin Psychiatry 2012;73: 691–695.CrossRefGoogle ScholarPubMed
Delport, DSchoeman, Rvan der Merwe, Nvan der Merwe, LFisher, LRGeiger, Det al.Significance of dietary folate intake, homocysteine levels and MTHFR 677 C>T genotyping in South African patients diagnosed with depression: test development for clinical application. Metab Brain Dis 2014;29: 377–384.CrossRefGoogle Scholar
Bala, KADogan, MMutluer, TKaba, SAslan, OBalahoroglu, Ret al.Plasma amino acid profile in autism spectrum disorder (ASD). Eur Rev Med Pharmacol Sci 2016;20: 923–929.Google Scholar
Nishi, ANumata, STajima, AKinoshita, MKikuchi, KShimodera, Set al.Meta-analyses of blood homocysteine levels for gender and genetic association studies of the MTHFR C677T polymorphism in schizophrenia. Schizophr Bull 2014;40: 1154–1163.CrossRefGoogle Scholar
Dias, VVBrissos, SCardoso, CAndreazza, ACKapczinski, FSerum homocysteine levels and cognitive functioning in euthymic bipolar patients. J Affect Disord 2009;113: 285–290.CrossRefGoogle ScholarPubMed
Bortolato, BMiskowiak, KWKohler, CAMaes, MFernandes, BSBerk, Met al.Cognitive remission: a novel objective for the treatment of major depression?. BMC Med 2016;14:9.CrossRefGoogle ScholarPubMed
Vuksan-Cusa, BJakovljevic, MSagud, MMihaljevic Peles, AMarcinko, DTopic, Ret al.Metabolic syndrome and serum homocysteine in patients with bipolar disorder and schizophrenia treated with second generation antipsychotics. Psychiatry Res 2011;189: 21–25.CrossRefGoogle ScholarPubMed
Ghanizadeh, AIncreased glutamate and homocysteine and decreased glutamine levels in autism: a review and strategies for future studies of amino acids in autism. Dis Markers 2013;35: 281–286.CrossRefGoogle ScholarPubMed
Higgins, JPThompson, SGDeeks, JJAltman, DGMeasuring inconsistency in meta-analyses. BMJ 2003;327: 557–560.CrossRefGoogle ScholarPubMed
Stang, ACritical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010;25: 603–605.CrossRefGoogle ScholarPubMed
Handbook for Systematic reviews of Interventions Version 5.1.0. Higgins, JPTGreen, S (Editors). The Cochrane Collaboration 2011. Available from www.cochrane-handbook.org. [updated March 2011].Google Scholar
Sistrom, CLMergo, PJA simple method for obtaining original data from published graphs and plots. AJR Am J Roentgenol 2000;174: 1241–1244.CrossRefGoogle ScholarPubMed
Hamilton, MA rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23: 56–62.CrossRefGoogle ScholarPubMed
Young, RCBiggs, JTZiegler, VEMeyer, DAA rating scale for mania: reliability, validity and sensitivity. Br J Psychiatry 1978;133: 429–435.CrossRefGoogle ScholarPubMed
Carvalho, AFKohler, CABrunoni, ARMiskowiak, KWHerrmann, NLanctot, KLet al.Bias in peripheral depression biomarkers. Psychother Psychosom 2016;85: 81–90.CrossRefGoogle ScholarPubMed
Carvalho, AFKohler, CAFernandes, BSQuevedo, JMiskowiak, KWBrunoni, ARet al.Bias in emerging biomarkers for bipolar disorder. Psychol Med 2016;46: 2287–2297.CrossRefGoogle ScholarPubMed
Egger, MDavey Smith, GSchneider, MMinder, CBias in meta-analysis detected by a simple, graphical test. BMJ 1997;315: 629–634.CrossRefGoogle ScholarPubMed
Duval, STweedie, RTrim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics 2000;56: 455–463.CrossRefGoogle ScholarPubMed
Cohen, JStatistical power analysis for the behavioral sciences, 2nd ed., NJ: Lawrence Erlbaum Associates, Inc.; 1988.Google Scholar
Lau, JIoannidis, JPSchmid, CHQuantitative synthesis in systematic reviews. Ann Intern Med 1997;127: 820–826.CrossRefGoogle ScholarPubMed
Vargas, HONunes, SOBarbosa, DSVargas, MMCestari, ADodd, Set al.Castelli risk indexes 1 and 2 are higher in major depression but other characteristics of the metabolic syndrome are not specific to mood disorders. Life Sci 2014;102: 65–71.CrossRefGoogle Scholar
Dittmann, SSeemuller, FSchwarz, MJKleindienst, NStampfer, RZach, Jet al.Association of cognitive deficits with elevated homocysteine levels in euthymic bipolar patients and its impact on psychosocial functioning: preliminary results. Bipolar Disord 2007;9: 63–70.CrossRefGoogle ScholarPubMed
Levine, JSela, BAOsher, YBelmaker, RHHigh homocysteine serum levels in young male schizophrenia and bipolar patients and in an animal model. Prog Neuropsychopharmacol Biol Psychiatry 2005;29: 1181–1191.CrossRefGoogle ScholarPubMed
Bell, IRMorrow, FDRead, MBerkes, SPerrone, GLow thyroxine levels in female psychiatric inpatients with riboflavin deficiency: implications for folate-dependent methylation. Acta Psychiatr Scand 1992;85: 360–363.CrossRefGoogle ScholarPubMed
Carney, MWChary, TKLaundy, MBottiglieri, TChanarin, IReynolds, EHet al.Red cell folate concentrations in psychiatric patients. J Affect Disord 1990;19: 207–213.CrossRefGoogle ScholarPubMed
Carney, MWSheffield, BFSerum folic acid and B12 in 272 psychiatric in-patients. Psychol Med 1978;8: 139–144.CrossRefGoogle ScholarPubMed
Coppen, AAbou-Saleh, MTPlasma folate and affective morbidity during long-term lithium therapy. Br J Psychiatry 1982;141: 87–89.CrossRefGoogle ScholarPubMed
Davison, KMKaplan, BJVitamin and mineral intakes in adults with mood disorders: comparisons to nutrition standards and associations with sociodemographic and clinical variables. J Am Coll Nutr 2011;30: 547–558.CrossRefGoogle ScholarPubMed
Ellingrod, VLTaylor, SFDalack, GGrove, TBBly, MJBrook, RDet al.Risk factors associated with metabolic syndrome in bipolar and schizophrenia subjects treated with antipsychotics: the role of folate pharmacogenetics. J Clin Psychopharmacol 2012;32: 261–265.CrossRefGoogle ScholarPubMed
Issac, TGSoundarya, SChristopher, RChandra, SRVitamin B12 deficiency: an important reversible co-morbidity in neuropsychiatric manifestations. Indian J Psychol Med 2015;37: 26–29.Google ScholarPubMed
Lee, SChow, CCShek, CCWing, YKChen, CNFolate concentration in Chinese psychiatric outpatients on long-term lithium treatment. J Affect Disord 1992;24: 265–270.CrossRefGoogle ScholarPubMed
Lundin, NBNiciu, MJLuckenbaugh, DAIonescu, DFRichards, EMVande Voort, JLet al.Baseline vitamin B12 and folate levels do not predict improvement in depression after a single infusion of ketamine. Pharmacopsychiatry 2014;47: 141–144.Google Scholar
McKeon, PShelley, RO’Regan, SO’Broin, JSerum and red cell folate and affective morbidity in lithium prophylaxis. Acta Psychiatr Scand 1991;83: 199–201.CrossRefGoogle ScholarPubMed
McLaughlin, BMcMahon, AFolate and depression. Br J Psychiatry 1993;162:572.CrossRefGoogle ScholarPubMed
Permoda-Osip, ADorszewska, JBartkowska-Sniatkowska, AChlopocka-Wozniak, MRybakowski, JKVitamin B12 level may be related to the efficacy of single ketamine infusion in bipolar depression. Pharmacopsychiatry 2013;46: 227–228.Google ScholarPubMed
Permoda-Osip, ADorszewska, JSkibinska, MChlopocka-Wozniak, MRybakowski, JKHyperhomocysteinemia in bipolar depression: clinical and biochemical correlates. Neuropsychobiology 2013;68: 193–196.CrossRefGoogle ScholarPubMed
Silver, HVitamin B12 levels are low in hospitalized psychiatric patients. Isr J Psychiatry Relat Sci 2000;37: 41–45.Google ScholarPubMed
Snaith, RPMehta, SRaby, AHSerum folate and vitamin B12 in epileptics with and without mental illness. Br J Psychiatry 1970;116: 179–183.CrossRefGoogle ScholarPubMed
Stern, SLBrandt, JTHurley, RSStagno, SJStern, MGSmeltzer, DJSerum and red cell folate concentrations in outpatients receiving lithium carbonate. Int Clin Psychopharmacol 1988;3: 49–52.CrossRefGoogle ScholarPubMed
Alexopoulos, PTopalidis, SIrmisch, GPrehn, KJung, SUPoppe, Ket al.Homocysteine and cognitive function in geriatric depression. Neuropsychobiology 2010;61: 97–104.CrossRefGoogle ScholarPubMed
Gultepe, MOzcan, OAvsar, KCetin, MOzdemir, ASGok, MUrine methylmalonic acid measurements for the assessment of cobalamin deficiency related to neuropsychiatric disorders. Clin Biochem 2003;36: 275–282.CrossRefGoogle ScholarPubMed
Henderson, JGDawson, AASerum vitamin-B12 levels in psychiatric patients on long-term psychotropic drug therapy. Br J Psychiatry 1970;116: 439–442.CrossRefGoogle ScholarPubMed
Iosifescu, DVPapakostas, GILyoo, IKLee, HKRenshaw, PFAlpert, JEet al.Brain MRI white matter hyperintensities and one-carbon cycle metabolism in non-geriatric outpatients with major depressive disorder (Part I). Psychiatry Res 2005;140: 291–299.CrossRefGoogle Scholar
Ipcioglu, OMOzcan, OGultepe, MAtes, ABasoglu, CCakir, EReduced urinary excretion of homocysteine could be the reason of elevated plasma homocysteine in patients with psychiatric illnesses. Clin Biochem 2008;41: 831–835.CrossRefGoogle ScholarPubMed
Kaner, GSoylu, MYuksel, NInanc, NOngan, DBasmisirli, EEvaluation of nutritional status of patients with depression. Biomed Res Int 2015;2015:521481.CrossRefGoogle ScholarPubMed
Lok, AMocking, RJAssies, JKoeter, MWBockting, CLde Vries, GJet al.The one-carbon-cycle and methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism in recurrent major depressive disorder; influence of antidepressant use and depressive state?. J Affect Disord 2014;166: 115–123.CrossRefGoogle ScholarPubMed
Mischoulon, DLamon-Fava, SSelhub, JKatz, JPapakostas, GIIosifescu, DVet al.Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment. CNS Spectr 2012;17: 76–86.CrossRefGoogle ScholarPubMed
Narayan, SKVerman, AKattimani, SAnanthanarayanan, PHAdithan, CPlasma homocysteine levels in depression and schizophrenia in South Indian Tamilian population. Indian J Psychiatry 2014;56: 46–53.CrossRefGoogle ScholarPubMed
Scott, TMTucker, KLBhadelia, ABenjamin, BPatz, SBhadelia, Ret al.Homocysteine and B vitamins relate to brain volume and white-matter changes in geriatric patients with psychiatric disorders. Am J Geriatr Psychiatry 2004;12: 631–638.CrossRefGoogle Scholar
Wolfersdorf, MMaier, VFroscher, WLaage, MStraub, R[Folic acid deficiency in patients hospitalized with depression? A pilot study of clinical relevance]. Nervenarzt 1993;64: 269–272.Google Scholar
Hasanah, CIKhan, UAMusalmah, MRazali, SMReduced red-cell folate in mania. J Affect Disord 1997;46: 95–99.CrossRefGoogle ScholarPubMed
Chen, ZLiu, YZhang, DLiu, ZWang, PZhou, Det al.C677T methylenetetrahydrofolate reductase gene polymorphisms in bipolar disorder: an association study in the Chinese population and a meta-analysis of genetic association studies. Neurosci Lett 2009;449: 48–51.CrossRefGoogle Scholar
Jonsson, EGLarsson, KVares, MHansen, TWang, AGDjurovic, Set al.Two methylenetetrahydrofolate reductase gene (MTHFR) polymorphisms, schizophrenia and bipolar disorder: an association study. Am J Med Genet B Neuropsychiatr Genet 2008;147B:976–982.CrossRefGoogle ScholarPubMed
Kempisty, BBober, ALuczak, MCzerski, PSzczepankiewicz, AHauser, Jet al.Distribution of 1298A>C polymorphism of methylenetetrahydrofolate reductase gene in patients with bipolar disorder and schizophrenia. Eur Psychiatry 2007;22: 39–43.CrossRefGoogle Scholar
Kempisty, BMostowska, AGorska, ILuczak, MCzerski, PSzczepankiewicz, Aet al.Association of 677C>T polymorphism of methylenetetrahydrofolate reductase (MTHFR) gene with bipolar disorder and schizophrenia. Neurosci Lett 2006;400: 267–271.CrossRefGoogle Scholar
Kempisty, BSikora, JLianeri, MSzczepankiewicz, ACzerski, PHauser, Jet al.MTHFD 1958G>A and MTR 2756A>G polymorphisms are associated with bipolar disorder and schizophrenia. Psychiatr Genet 2007;17: 177–181.CrossRefGoogle Scholar
Malhotra, NKulhara, PChakrabarti, SGrover, SA prospective, longitudinal study of metabolic syndrome in patients with bipolar disorder and schizophrenia. J Affect Disord 2013;150: 653–658.CrossRefGoogle Scholar
Arinami, TYamada, NYamakawa-Kobayashi, KHamaguchi, HToru, MMethylenetetrahydrofolate reductase variant schizophrenia/depression. Am J Med Genet 1997;74: 526–528.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Davison, KMKaplan, BJNutrient intakes are correlated with overall psychiatric functioning in adults with mood disorders. Can J Psychiatry 2012;57: 85–92.CrossRefGoogle ScholarPubMed
Hickie, IScott, ENaismith, SWard, PBTurner, KParker, Get al.Late-onset depression: genetic, vascular and clinical contributions. Psychol Med 2001;31: 1403–1412.CrossRefGoogle ScholarPubMed
Kunugi, HFukuda, RHattori, MKato, TTatsumi, MSakai, Tet al.C677T polymorphism in methylenetetrahydrofolate reductase gene and psychoses. Mol Psychiatry 1998;3: 435–437.CrossRefGoogle ScholarPubMed
Tan, ECChong, SALim, LCChan, AOTeo, YYTan, CHet al.Genetic analysis of the thermolabile methylenetetrahydrofolate reductase variant in schizophrenia and mood disorders. Psychiatr Genet 2004;14: 227–231.CrossRefGoogle ScholarPubMed
Callaghan, NMitchell, RCotter, PThe relationship of serum folic acid and vitamin B 12 levels to psychosis in epilepsy. Ir J Med Sci 1969;8: 497–505.CrossRefGoogle ScholarPubMed
Coppen, ASwade, CJones, SAArmstrong, RABlair, JALeeming, RJDepression and tetrahydrobiopterin: the folate connection. J Affect Disord 1989;16: 103–107.CrossRefGoogle ScholarPubMed
Ezzaher, AMouhamed, DHMechri, AOmezzine, ANeffati, FDouki, Wet al.Hyperhomocysteinemia in Tunisian bipolar I patients. Psychiatry Clin Neurosci 2011;65: 664–671.CrossRefGoogle ScholarPubMed
Ozbek, ZKucukali, CIOzkok, EOrhan, NAydin, MKilic, Get al.Effect of the methylenetetrahydrofolate reductase gene polymorphisms on homocysteine, folate and vitamin B12 in patients with bipolar disorder and relatives. Prog Neuropsychopharmacol Biol Psychiatry 2008;32: 1331–1337.CrossRefGoogle ScholarPubMed
Chiarani, FTramontina, JFCereser, KMKunz, MPaim, LVargas, CRet al.Homocysteine and other markers of cardiovascular risk during a manic episode in patients with bipolar disorder. Rev Bras Psiquiatr 2013;35: 157–160.CrossRefGoogle ScholarPubMed
Bromberg, ABersudsky, YLevine, JAgam, GGlobal leukocyte DNA methylation is not altered in euthymic bipolar patients. J Affect Disord 2009;118: 234–239.CrossRefGoogle Scholar
Vuksan-Cusa, BSagud, MJakovljevic, MPeles, AMJaksic, NMihaljevic, Set al.Association between C-reactive protein and homocysteine with the subcomponents of metabolic syndrome in stable patients with bipolar disorder and schizophrenia. Nord J Psychiatry 2013;67: 320–325.CrossRefGoogle Scholar
Osher, YBersudsky, YSilver, HSela, BABelmaker, RHNeuropsychological correlates of homocysteine levels in euthymic bipolar patients. J Affect Disord 2008;105: 229–233.CrossRefGoogle ScholarPubMed
Osher, YSela, BALevine, JBelmaker, RHElevated homocysteine levels in euthymic bipolar disorder patients showing functional deterioration. Bipolar Disord 2004;6: 82–86.CrossRefGoogle ScholarPubMed
Doganavsargil Baysal, GOGokmen, ZAkbas, HCinemre, BMetin, OKaraman, T[Association of serum homocysteine and methionine levels with cognition and functioning in bipolar disorder]. Turk Psikiyatri Derg 2013;24: 7–16.Google Scholar
Dittmann, SSeemuller, FGrunze, HCSchwarz, MJZach, JFast, Ket al.The impact of homocysteine levels on cognition in euthymic bipolar patients: a cross-sectional study. J Clin Psychiatry 2008;69: 899–906.CrossRefGoogle ScholarPubMed
Puig-Alcaraz, CFuentes-Albero, MCalderon, JGarrote, DCauli, OIncreased homocysteine levels correlate with the communication deficit in children with autism spectrum disorder. Psychiatry Res 2015;229: 1031–1037.CrossRefGoogle ScholarPubMed
Ganguly, PAlam, SFRole of homocysteine in the development of cardiovascular disease. Nutr J 2015;14:6.CrossRefGoogle ScholarPubMed
Jadavji, NMWieske, FDirnagl, UWinter, CMethylenetetrahydrofolate reductase deficiency alters levels of glutamate and gamma-aminobutyric acid in brain tissue. Mol Genet Metab Rep 2015;3: 1–4.CrossRefGoogle ScholarPubMed
Yang, ZWang, LZhang, WWang, XZhou, SPlasma homocysteine involved in methylation and expression of thrombomodulin in cerebral infarction. Biochem Biophys Res Commun 2016;473: 1218–1222.CrossRefGoogle ScholarPubMed
Fernandes, BSDash, SJacka, FDodd, SCarvalho, AFKohler, CAet al.Leptin in bipolar disorder: a systematic review and meta-analysis. Eur Psychiatry 2016;35: 1–7.CrossRefGoogle ScholarPubMed
Ludwig, BDwivedi, YDissecting bipolar disorder complexity through epigenomic approach. Mol Psychiatry 2016;21: 1490–1498.CrossRefGoogle ScholarPubMed
Mitchell, ESConus, NKaput, JB vitamin polymorphisms and behavior: evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci Biobehav Rev 2014;47: 307–320.CrossRefGoogle ScholarPubMed
Durga, Jvan Boxtel, MPSchouten, EGBots, MLKok, FJVerhoef, PFolate and the methylenetetrahydrofolate reductase 677C-->T mutation correlate with cognitive performance. Neurobiol Aging 2006;27: 334–343.CrossRefGoogle ScholarPubMed
Schiepers, OJvan Boxtel, MPde Groot, RHJolles, JBekers, OKok, FJet al.Genetic variation in folate metabolism is not associated with cognitive functioning or mood in healthy adults. Prog Neuropsychopharmacol Biol Psychiatry 2011;35: 1682–1688.CrossRefGoogle ScholarPubMed
Yeh, TKHu, CYYeh, TCLin, PJWu, CHLee, PLet al.Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population. Brain Cogn 2012;80: 282–289.CrossRefGoogle Scholar
Eszlari, NKovacs, DPetschner, PPap, DGonda, XElliott, Ret al.Distinct effects of folate pathway genes MTHFR and MTHFD1L on ruminative response style: a potential risk mechanism for depression. Transl Psychiatry 2016;6:e745.CrossRefGoogle ScholarPubMed
Pirchl, MUllrich, CHumpel, CDifferential effects of short- and long-term hyperhomocysteinaemia on cholinergic neurons, spatial memory and microbleedings in vivo in rats. Eur J Neurosci 2010;32: 1516–1527.CrossRefGoogle Scholar
Martinez-Aran, AVieta, ECognition as a target in schizophrenia, bipolar disorder and depression. Eur Neuropsychopharmacol 2015;25: 151–157.CrossRefGoogle ScholarPubMed
Miskowiak, KWCarvalho, AFVieta, EKessing, LVCognitive enhancement treatments for bipolar disorder: a systematic review and methodological recommendations. Eur Neuropsychopharmacol 2016;26: 1541–1561.CrossRefGoogle ScholarPubMed
Vieta, ETorrent, CFunctional remediation: the pathway from remission to recovery in bipolar disorder. World Psychiatry 2016;15: 288–289.CrossRefGoogle ScholarPubMed
Sharpley, ALHockney, RMcPeake, LGeddes, JRCowen, PJFolic acid supplementation for prevention of mood disorders in young people at familial risk: a randomised, double blind, placebo controlled trial. J Affect Disord 2014;167: 306–311.CrossRefGoogle ScholarPubMed
Bedson, EBell, DCarr, DCarter, BHughes, DJorgensen, Aet al.Folate Augmentation of Treatment – Evaluation for Depression (FolATED): randomised trial and economic evaluation. Health Technol Assess 2014;18:vii–viii [1–159].Google ScholarPubMed
Almeida, OPFord, AHFlicker, LSystematic review and meta-analysis of randomized placebo-controlled trials of folate and vitamin B12 for depression. Int Psychogeriatr 2015;27: 727–737.CrossRefGoogle ScholarPubMed
Wu, DPardridge, WMBlood-brain barrier transport of reduced folic acid. Pharm Res 1999;16: 415–419.CrossRefGoogle ScholarPubMed
Pietrzik, KBailey, LShane, BFolic acid and L-5-methyltetrahydrofolate: comparison of clinical pharmacokinetics and pharmacodynamics. Clin Pharmacokinet 2010;49: 535–548.CrossRefGoogle ScholarPubMed
Geddes, JRGardiner, ARendell, JVoysey, MTunbridge, EHinds, Cet al.Comparative evaluation of quetiapine plus lamotrigine combination versus quetiapine monotherapy (and folic acid versus placebo) in bipolar depression (CEQUEL): a 2 × 2 factorial randomised trial. Lancet Psychiatry 2016;3: 31–39.CrossRefGoogle ScholarPubMed
Dankner, RChetrit, ADror, GKSela, BAPhysical activity is inversely associated with total homocysteine levels, independent of C677T MTHFR genotype and plasma B vitamins. Age 2007;29: 219–227.CrossRefGoogle ScholarPubMed
Vancampfort, DFirth, JSchuch, FRosenbaum, SDe Hert, MMugisha, Jet al.Physical activity and sedentary behavior in people with bipolar disorder: a systematic review and meta-analysis. J Affect Disord 2016;201: 145–152.CrossRefGoogle ScholarPubMed
Deminice, RRibeiro, DFFrajacomo, FTTThe effects of acute exercise and exercise training on plasma homocysteine: a meta-analysis. PLoS ONE 2016;11(3):e0151653. http://dx.doi.org/10.1371/journal.pone.0151653.CrossRefGoogle ScholarPubMed
Vancampfort, DStubbs, BPhysical activity and metabolic disease among people with affective disorders: prevention, management and implementation. J Affect Disord 2016;201: 145–152.CrossRefGoogle Scholar
Maron, BALoscalzo, JThe treatment of hyperhomocysteinemia. Annu Rev Med 2009;60: 39–54.CrossRefGoogle ScholarPubMed
Misiak, BFrydecka, DSlezak, RPiotrowski, PKiejna, AElevated homocysteine level in first-episode schizophrenia patients – the relevance of family history of schizophrenia and lifetime diagnosis of cannabis abuse. Metab Brain Dis 2014;29: 661–670.CrossRefGoogle ScholarPubMed
Gaikwad, NWMass spectrometry evidence for formation of estrogen-homocysteine conjugates: estrogens can regulate homocysteine levels. Free Radic Biol Med 2013;65: 1447–1454.CrossRefGoogle ScholarPubMed
Slyepchenko, AMaes, MJacka, FNKohler, CABarichello, TMcIntyre, RSet al.Gut microbiota, bacterial translocation, and interactions with diet: pathophysiological links between major depressive disorder and non-communicable medical comorbidities. Psychother Psychosom 2016;86: 31–46.CrossRefGoogle ScholarPubMed
LeBlanc, JGLaino, JEdel Valle, MJVannini, Vvan Sinderen, DTaranto, MPet al.B-group vitamin production by lactic acid bacteria – current knowledge and potential applications. J Appl Microbiol 2011;111: 1297–1309.CrossRefGoogle ScholarPubMed
Rogers, GBKeating, DJYoung, RLWong, MLLicinio, JWesselingh, SFrom gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatry 2016;21: 738–748.CrossRefGoogle ScholarPubMed
Dinan, TGCryan, JFMelancholic microbes: a link between gut microbiota and depression?. Neurogastroenterol Motil 2013;25: 713–719.CrossRefGoogle ScholarPubMed
Selhub, JHomocysteine metabolism. Annu Rev Nutr 1999;19: 217–246.CrossRefGoogle ScholarPubMed
Obeid, RHerrmann, WMechanisms of homocysteine neurotoxicity in neurodegenerative diseases with special reference to dementia. FEBS Lett 2006;580: 2994–3000.CrossRefGoogle Scholar
Young, JJSilber, TBruno, DGalatzer-Levy, IRPomara, NMarmar, CRIs there progress? An overview of selecting biomarker candidates for major depressive disorder. Front Psychiatry 2016;7:72.CrossRefGoogle ScholarPubMed
Fernandes, BSGama, CSKauer-Sant’Anna, MLobato, MIBelmonte-de-Abreu, PKapczinski, FSerum brain-derived neurotrophic factor in bipolar and unipolar depression: a potential adjunctive tool for differential diagnosis. J Psychiatr Res 2009;43: 1200–1204.CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.