CoChat
Sign Up
Cited by 48Schizophrenia research and treatmentMetabolomics and Mass Spectrometry StudiesTryptophan and brain disorders

Impaired Metabolic Reactivity to Oxidative Stress in Early Psychosis Patients

Open access
Fournier, Margot, Ferrari, Carina, Baumann, Philipp S., Polari, Andrea, Monin, Aline, Bellier-Teichmann, Tanja, Wulff, Jacob, Pappan, Kirk L. +3 more·2014·Schizophrenia Bulletin
DOI 10.1093/schbul/sbu053PMC PMC4133680
Open this paper in CoChat — free account

Abstract

Because increasing evidence point to the convergence of environmental and genetic risk factors to drive redox dysregulation in schizophrenia, we aim to clarify whether the metabolic anomalies associated with early psychosis reflect an adaptation to oxidative stress. Metabolomic profiling was performed to characterize the response to oxidative stress in fibroblasts from control individuals (n = 20) and early psychosis patients (n = 30), and in all, 282 metabolites were identified. In addition to the expected redox/antioxidant response, oxidative stress induced a decrease of lysolipid levels in fibroblasts from healthy controls that were largely muted in fibroblasts from patients. Most notably, fibroblasts from patients showed disrupted extracellular matrix- and arginine-related metabolism after oxidative stress, indicating impairments beyond the redox system. Plasma membrane and extracellular matrix, 2 regulators of neuronal activity and plasticity, appeared as particularly susceptible to oxidative stress and thus provide novel mechanistic insights for pathophysiological understanding of early stages of psychosis. Statistically, antipsychotic medication at the time of biopsy was not accounting for these anomalies in the metabolism of patients' fibroblasts, indicating that they might be intrinsic to the disease. Although these results are preliminary and should be confirmed in a larger group of patients, they nevertheless indicate that the metabolic signature of reactivity to oxidative stress may provide reliable early markers of psychosis. Developing protective measures aimed at normalizing the disrupted pathways should prevent the pathological consequences of environmental stressors.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1093/schbul/sbu053

Cites

12 of 12 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 64

  1. [1]1. Do KQ, Cabungcal JH, Frank A, Steullet P, Cuenod M. Redox dysregulation, neurodevelopment, and schizophrenia. Curr Opin Neurobiol. 2009;19:220–230 [DOI] [PubMed] [Google Scholar]
  2. [2]2. Ben Othmen L, Mechri A, Fendri C, et al. Altered antioxidant defense system in clinically stable patients with schizophrenia and their unaffected siblings. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:155–159 [DOI] [PubMed] [Google Scholar]
  3. [3]3. Pedrini M, Massuda R, Fries GR, et al. Similarities in serum oxidative stress markers and inflammatory cytokines in patients with overt schizophrenia at early and late stages of chronicity. J Psychiatr Res. 2012;46:819–824 [DOI] [PubMed] [Google Scholar]
  4. [4]4. Yao JK, Reddy R, McElhinny LG, van Kammen DP. Reduced status of plasma total antioxidant capacity in schizophrenia. Schizophr Res. 1998;32:1–8 [DOI] [PubMed] [Google Scholar]
  5. [5]5. Zhang XY, Tan YL, Cao LY, et al. Antioxidant enzymes and lipid peroxidation in different forms of schizophrenia treated with typical and atypical antipsychotics. Schizophr Res. 2006;81:291–300 [DOI] [PubMed] [Google Scholar]
  6. [6]6. Do KQ, Trabesinger AH, Kirsten-Krüger M, et al. Schizophrenia: glutathione deficit in cerebrospinal fluid and prefrontal cortex in vivo. Eur J Neurosci. 2000;12:3721–3728 [DOI] [PubMed] [Google Scholar]
  7. [9]9. Prabakaran S, Swatton JE, Ryan MM, et al. Mitochondrial dysfunction in schizophrenia: evidence for compromised brain metabolism and oxidative stress. Mol Psychiatry. 2004;9:684–97, 643 [DOI] [PubMed] [Google Scholar]
  8. [10]10. Gysin R, Kraftsik R, Sandell J, et al. Impaired glutathione synthesis in schizophrenia: convergent genetic and functional evidence. Proc Natl Acad Sci U S A. 2007;104:16621–16626 [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. [12]12. Gysin R, Kraftsik R, Boulat O, et al. Genetic dysregulation of glutathione synthesis predicts alteration of plasma thiol redox status in schizophrenia. Antioxid Redox Signal. 2011;15:2003–2010 [DOI] [PubMed] [Google Scholar]
  10. [15]15. Lataster T, Valmaggia L, Lardinois M, van Os J, Myin-Germeys I. Increased stress reactivity: a mechanism specifically associated with the positive symptoms of psychotic disorder. Psychol med. 2013;43:1389–1400 [DOI] [PubMed] [Google Scholar]
  11. [16]16. Myin-Germeys I, Peeters F, Havermans R, et al. Emotional reactivity to daily life stress in psychosis and affective disorder: an experience sampling study. Acta Psychiatr Scand. 2003;107:124–131 [DOI] [PubMed] [Google Scholar]
  12. [17]17. Davis KL, Kahn RS, Ko G, Davidson M. Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry. 1991;148:1474–1486 [DOI] [PubMed] [Google Scholar]
  13. [18]18. Glenthøj BY. The brain dopaminergic system. Pharmacological, behavioural and electrophysiological studies. Dan Med Bull. 1995;42:1–21 [PubMed] [Google Scholar]
  14. [19]19. Laruelle M. The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies. Brain Res Brain Res Rev. 2000;31:371–384 [DOI] [PubMed] [Google Scholar]
  15. [20]20. Laruelle M, Abi-Dargham A. Dopamine as the wind of the psychotic fire: new evidence from brain imaging studies. J Psychopharmacol. 1999;13:358–371 [DOI] [PubMed] [Google Scholar]
  16. [22]22. Myin-Germeys I, Marcelis M, Krabbendam L, Delespaul P, van Os J. Subtle fluctuations in psychotic phenomena as functional states of abnormal dopamine reactivity in individuals at risk. Biol Psychiatry. 2005;58:105–110 [DOI] [PubMed] [Google Scholar]
  17. [23]23. Hastings TG. The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson’s disease. J Bioenerg Biomembr. 2009;41:469–472 [DOI] [PubMed] [Google Scholar]
  18. [27]27. Orešič M, Tang J, Seppänen-Laakso T, et al. Metabolome in schizophrenia and other psychotic disorders: a general population-based study. Genome Med. 2011;3:19. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. [28]28. He Y, Yu Z, Giegling I, et al. Schizophrenia shows a unique metabolomics signature in plasma. Transl Psychiatry. 2012;2:e149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. [29]29. Yang J, Chen T, Sun L, et al. Potential metabolite markers of schizophrenia. Mol Psychiatry. 2013;18:67–78 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. [30]30. Pinkus R, Weiner LM, Daniel V. Role of oxidants and antioxidants in the induction of AP-1, NF-kappaB, and glutathione S-transferase gene expression. J Biol Chem. 1996;271:13422–13429 [DOI] [PubMed] [Google Scholar]
  22. [31]31. Prestera T, Holtzclaw WD, Zhang Y, Talalay P. Chemical and molecular regulation of enzymes that detoxify carcinogens. Proc Natl Acad Sci U S A. 1993;90:2965–2969 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. [32]32. Schilderman PA, van Maanen JM, ten Vaarwerk FJ, et al. The role of prostaglandin H synthase-mediated metabolism in the induction of oxidative DNA damage by BHA metabolites. Carcinogenesis. 1993;14:1297–1302 [DOI] [PubMed] [Google Scholar]
  24. [33]33. Auburger G, Klinkenberg M, Drost J, et al. Primary skin fibroblasts as a model of Parkinson’s disease. Mol Neurobiol. 2012;46:20–27 [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. [34]34. Mytilineou C, Werner P, Molinari S, Di Rocco A, Cohen G, Yahr MD. Impaired oxidative decarboxylation of pyruvate in fibroblasts from patients with Parkinson’s disease. J Neural Transm Park Dis Dement Sect. 1994;8:223–228 [DOI] [PubMed] [Google Scholar]
  26. [35]35. Wiedemann FR, Winkler K, Lins H, Wallesch CW, Kunz WS. Detection of respiratory chain defects in cultivated skin fibroblasts and skeletal muscle of patients with Parkinson’s disease. Ann N Y Acad Sci. 1999;893:426–429 [DOI] [PubMed] [Google Scholar]
  27. [36]36. Yung AR, Yuen HP, McGorry PD, et al. Mapping the onset of psychosis: the Comprehensive Assessment of At-Risk Mental States. Aust N Z J Psychiatry. 2005;39:964–971 [DOI] [PubMed] [Google Scholar]
  28. [37]37. Baumann PS, Crespi S, Marion-Veyron R, et al. Treatment and early intervention in psychosis program (TIPP-Lausanne): implementation of an early intervention programme for psychosis in Switzerland. Early Interv Psychiatry. 2013;7:322–328 [DOI] [PubMed] [Google Scholar]
  29. [38]38. Preisig M, Fenton BT, Matthey ML, Berney A, Ferrero F. Diagnostic interview for genetic studies (DIGS): inter-rater and test-retest reliability of the French version. Eur Arch Psychiatry Clin Neurosci. 1999;249:174–179 [DOI] [PubMed] [Google Scholar]
  30. [39]39. Evans AM, DeHaven CD, Barrett T, Mitchell M, Milgram E. Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal Chem. 2009;81:6656–6667 [DOI] [PubMed] [Google Scholar]
  31. [41]41. Lu C, King RD. An investigation into the population abundance distribution of mRNAs, proteins, and metabolites in biological systems. Bioinformatics. 2009;25:2020–2027 [DOI] [PubMed] [Google Scholar]
  32. [42]42. Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci U S A. 2003;100:9440–9445 [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. [43]43. Andreasen NC, Pressler M, Nopoulos P, Miller D, Ho BC. Antipsychotic dose equivalents and dose-years: a standardized method for comparing exposure to different drugs. Biol Psychiatry. 2010;67:255–262 [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. [44]44. Davis JM, Chen N. Dose response and dose equivalence of antipsychotics. J Clin Psychopharmacol. 2004;24:192–208 [DOI] [PubMed] [Google Scholar]
  35. [45]45. Horrobin DF. Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot Essent Fatty Acids. 1996;55:3–7 [DOI] [PubMed] [Google Scholar]
  36. [46]46. Keshavan MS, Mallinger AG, Pettegrew JW, Dippold C. Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res. 1993;49:89–95 [DOI] [PubMed] [Google Scholar]
  37. [47]47. Mahadik SP, Mukherjee S, Correnti EE, et al. Plasma membrane phospholipid and cholesterol distribution of skin fibroblasts from drug-naive patients at the onset of psychosis. Schizophr Res. 1994;13:239–247 [DOI] [PubMed] [Google Scholar]
  38. [48]48. Yao JK, Leonard S, Reddy RD. Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schizophr Res. 2000;42:7–17 [DOI] [PubMed] [Google Scholar]
  39. [49]49. Kato T, Shioiri T, Murashita J, Hamakawa H, Inubushi T, Takahashi S. Lateralized abnormality of high-energy phosphate and bilateral reduction of phosphomonoester measured by phosphorus-31 magnetic resonance spectroscopy of the frontal lobes in schizophrenia. Psychiatry Res. 1995;61:151–160 [DOI] [PubMed] [Google Scholar]
  40. [50]50. Pettegrew JW, Keshavan MS, Panchalingam K, et al. Alterations in brain high-energy phosphate and membrane phospholipid metabolism in first-episode, drug-naive schizophrenics. A pilot study of the dorsal prefrontal cortex by in vivo phosphorus 31 nuclear magnetic resonance spectroscopy. Arch Gen Psychiatry. 1991;48:563–568 [DOI] [PubMed] [Google Scholar]
  41. [51]51. Potwarka JJ, Drost DJ, Williamson PC, et al. A 1H-decoupled 31P chemical shift imaging study of medicated schizophrenic patients and healthy controls. Biol Psychiatry. 1999;45:687–693 [DOI] [PubMed] [Google Scholar]
  42. [52]52. Shioiri T, Someya T, Murashita J, et al. Multiple regression analysis of relationship between frontal lobe phosphorus metabolism and clinical symptoms in patients with schizophrenia. Psychiatry Res. 1997;76:113–122 [DOI] [PubMed] [Google Scholar]
  43. [53]53. Stanley JA, Williamson PC, Drost DJ, et al. Membrane phospholipid metabolism and schizophrenia: an in vivo 31P-MR spectroscopy study. Schizophr Res. 1994;13:209–215 [DOI] [PubMed] [Google Scholar]
  44. [54]54. Williamson PC, Brauer M, Leonard S, Thompson T, Drost D. 31P magnetic resonance spectroscopy studies in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 1996;55:115–118 [DOI] [PubMed] [Google Scholar]
  45. [55]55. Stanley JA, Williamson PC, Drost DJ, et al. An in vivo study of the prefrontal cortex of schizophrenic patients at different stages of illness via phosphorus magnetic resonance spectroscopy. Arch Gen Psychiatry. 1995;52:399–406 [DOI] [PubMed] [Google Scholar]
  46. [56]56. Arvindakshan M, Ghate M, Ranjekar PK, Evans DR, Mahadik SP. Supplementation with a combination of omega-3 fatty acids and antioxidants (vitamins E and C) improves the outcome of schizophrenia. Schizophr Res. 2003;62:195–204 [DOI] [PubMed] [Google Scholar]
  47. [57]57. Bentsen H, Solberg DK, Refsum H, et al. Bimodal distribution of polyunsaturated fatty acids in schizophrenia suggests two endophenotypes of the disorder. Biol Psychiatry. 2011;70:97–105 [DOI] [PubMed] [Google Scholar]
  48. [58]58. Glen AI, Glen EM, Horrobin DF, et al. A red cell membrane abnormality in a subgroup of schizophrenic patients: evidence for two diseases. Schizophr Res. 1994;12:53–61 [DOI] [PubMed] [Google Scholar]
  49. [59]59. Hoen WP, Lijmer JG, Duran M, Wanders RJ, van Beveren NJ, de Haan L. Red blood cell polyunsaturated fatty acids measured in red blood cells and schizophrenia: a meta-analysis. Psychiatry Res. 2013;207:1–12 [DOI] [PubMed] [Google Scholar]
  50. [60]60. Khan MM, Evans DR, Gunna V, Scheffer RE, Parikh VV, Mahadik SP. 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. Schizophr Res. 2002;58:1–10 [DOI] [PubMed] [Google Scholar]
  51. [61]61. Peet M, Laugharne J, Rangarajan N, Horrobin D, Reynolds G. Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients. J Psychiatr Res. 1995;29:227–232 [DOI] [PubMed] [Google Scholar]
  52. [62]62. van der Kemp WJ, Klomp DW, Kahn RS, Luijten PR, Hulshoff Pol HE. A meta-analysis of the polyunsaturated fatty acid composition of erythrocyte membranes in schizophrenia. Schizophr Res. 2012;141:153–161 [DOI] [PubMed] [Google Scholar]
  53. [63]63. Grignon S, Chianetta JM. Assessment of malondialdehyde levels in schizophrenia: a meta-analysis and some methodological considerations. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:365–369 [DOI] [PubMed] [Google Scholar]
  54. [64]64. Zhang M, Zhao Z, He L, Wan C. A meta-analysis of oxidative stress markers in schizophrenia. Sci China Life Sci. 2010;53:112–124 [DOI] [PubMed] [Google Scholar]
  55. [65]65. Kano S, Colantuoni C, Han F, et al. Genome-wide profiling of multiple histone methylations in olfactory cells: further implications for cellular susceptibility to oxidative stress in schizophrenia. Mol Psychiatry. 2013;18:740–742 [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. [66]66. Mahadik SP, Mukherjee S, Wakade CG, Laev H, Reddy RR, Schnur DB. Decreased adhesiveness and altered cellular distribution of fibronectin in fibroblasts from schizophrenic patients. Psychiatry Res. 1994;53:87–97 [DOI] [PubMed] [Google Scholar]
  57. [68]68. Benedikt J, Inyushin M, Kucheryavykh YV, et al. Intracellular polyamines enhance astrocytic coupling. Neuroreport. 2012;23:1021–1025 [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. [69]69. Aricioglu F, Altunbas H. Is agmatine an endogenous anxiolytic/antidepressant agent? Ann N Y Acad Sci. 2003;1009:136–140 [DOI] [PubMed] [Google Scholar]
  59. [70]70. Williams K. Modulation and block of ion channels: a new biology of polyamines. Cell Signal. 1997;9:1–13 [DOI] [PubMed] [Google Scholar]
  60. [71]71. Zeidan MP, Zomkowski AD, Rosa AO, Rodrigues AL, Gabilan NH. Evidence for imidazoline receptors involvement in the agmatine antidepressant-like effect in the forced swimming test. Eur J Pharmacol. 2007;565:125–131 [DOI] [PubMed] [Google Scholar]
  61. [72]72. Zomkowski AD, Santos AR, Rodrigues AL. Putrescine produces antidepressant-like effects in the forced swimming test and in the tail suspension test in mice. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:1419–1425 [DOI] [PubMed] [Google Scholar]
  62. [73]73. MacAllister RJ, Parry H, Kimoto M, et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol. 1996;119:1533–1540 [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. [74]74. Shahani N, Sawa A. Nitric oxide signaling and nitrosative stress in neurons: role for S-nitrosylation. Antioxid Redox Signal. 2011;14:1493–1504 [DOI] [PubMed] [Google Scholar]
  64. [75]75. Yao JK, Leonard S, Reddy RD. Increased nitric oxide radicals in postmortem brain from patients with schizophrenia. Schizophr Bull. 2004;30:923–934 [DOI] [PubMed] [Google Scholar]

Cited by

Sorted by citations

Authors
Fournier, M., Ferrari, C., Baumann, P. S., Polari, A., Monin, A., Bellier-Teichmann, T., Wulff, J., Pappan, K. L., Cuenod, M., Conus, P., & Do, K. Q.
Affiliations
  • Centre Hospitalier Universitaire Vaudois (CH)
  • Metabolon (United States) (US)
ORCID
Venue
Schizophrenia Bulletin
Publisher
Oxford University Press (OUP)
Published
2014-04-01
Volume
40
Issue
5
Pages
973-983
ISSN
  • 0586-7614 (ISSN-L)
  • 1745-1701
DOI
10.1093/schbul/sbu053
PMC
PMC4133680
OpenAlex
W2114109396
Cited by
48
References
12
Citations by year
2026: 2 · 2025: 1 · 2024: 2 · 2023: 7 · 2021: 1 · 2020: 3 · 2019: 1 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 10 · 2014: 5
FWCI
7.38
Type
journal article
Language
en
Open access
Locations
  • Schizophrenia Bulletin (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • IRIS (submittedVersion)
  • SERVAL (Université de Lausanne) (submittedVersion)
Funders
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (125759, 122419, 320030)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Keywords
early psychosis, oxidative stress
MeSH terms
Adaptation, Physiological, Adult, Cell Membrane, Extracellular Matrix, Female, Fibroblasts, Humans, Male, Psychotic Disorders, Oxidative Stress, Genetic Predisposition to Disease, Metabolomics, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review