Lipidomics Reveals Early Metabolic Changes in Subjects with Schizophrenia: Effects of Atypical Antipsychotics
Open accessAbstract
There is a critical need for mapping early metabolic changes in schizophrenia to capture failures in regulation of biochemical pathways and networks. This information could provide valuable insights about disease mechanisms, trajectory of disease progression, and diagnostic biomarkers. We used a lipidomics platform to measure individual lipid species in 20 drug-naïve patients with a first episode of schizophrenia (FE group), 20 patients with chronic schizophrenia that had not adhered to prescribed medications (RE group), and 29 race-matched control subjects without schizophrenia. Lipid metabolic profiles were evaluated and compared between study groups and within groups before and after treatment with atypical antipsychotics, risperidone and aripiprazole. Finally, we mapped lipid profiles to n3 and n6 fatty acid synthesis pathways to elucidate which enzymes might be affected by disease and treatment. Compared to controls, the FE group showed significant down-regulation of several n3 polyunsaturated fatty acids (PUFAs), including 20:5n3, 22:5n3, and 22:6n3 within the phosphatidylcholine and phosphatidylethanolamine lipid classes. Differences between FE and controls were only observed in the n3 class PUFAs; no differences where noted in n6 class PUFAs. The RE group was not significantly different from controls, although some compositional differences within PUFAs were noted. Drug treatment was able to correct the aberrant PUFA levels noted in FE patients, but changes in re patients were not corrective. Treatment caused increases in both n3 and n6 class lipids. These results supported the hypothesis that phospholipid n3 fatty acid deficits are present early in the course of schizophrenia and tend not to persist throughout its course. These changes in lipid metabolism could indicate a metabolic vulnerability in patients with schizophrenia that occurs early in development of the disease.
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The levels of PC and PE did not differ significantly in FEP patients and medicated patients.
“The levels of PC and PE did not differ significantly in FEP patients and medicated patients [53,54].”
From Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers (2024) · cites this paper as [53]
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
Applied Multivariate Statistical Analysis.
Johnson, A., & Wichern, D. W. (1988) · Biometrics · doi:10.2307/2531616 · Cited by 11,374 · see citing works
The control of the false discovery rate in multiple testing under dependency
Benjamini, Y., & Yekutieli, D. (2001) · The Annals of Statistics · doi:10.1214/aos/1013699998 · Cited by 10,490 · see citing works
Principles of bioactive lipid signalling: lessons from sphingolipids
Hannun, Y. A., & Obeid, L. M. (2008) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2329 · Cited by 3,331 · see citing works
Applied Multivariate Statistical Analysis
Ziegel, E. R., Johnson, R. A., & Wichern, D. W. (1999) · Technometrics · doi:10.2307/1271011 · Cited by 1,564 · see citing works
Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes
Boehm, G., Racoosin, J. A., LAUGHREN, T. P., & Katz, R. G. (2004) · Diabetes Care · doi:10.2337/diacare.27.8.2088-a · Cited by 1,204 · see citing works
Amminger, G. P., Schäfer, M. R., Papageorgiou, K., Klier, C. M., Cotton, S. M., Harrigan, S. M., Mackinnon, A., McGorry, P. D., & Berger, G. E. (2010) · Archives of General Psychiatry · doi:10.1001/archgenpsychiatry.2009.192 · Cited by 896 · see citing works
The Neurodevelopmental Hypothesis of Schizophrenia, Revisited
Fatemi, S. H., & Folsom, T. D. (2009) · Schizophrenia Bulletin · doi:10.1093/schbul/sbn187 · Cited by 860 · see citing works
Keshavan, M. S., Anderson, S., & Pettergrew, J. W. (1994) · Journal of Psychiatric Research · doi:10.1016/0022-3956(94)90009-4 · Cited by 525 · see citing works
Self-citationModulation of inflammation in brain: A matter of fat
Farooqui, A. A., Horrocks, L. A., & Farooqui, T. (2007) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04371.x · Cited by 460 · see citing works
Horrobin, D. F. (1998) · Schizophrenia Research · doi:10.1016/s0920-9964(97)00151-5 · Cited by 456 · see citing works
(2004) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.v65n0219 · Cited by 383 · see citing works
Diabetes mellitus in schizophrenic patients
Mukherjee, S., Decina, P., Bocola, V., Saraceni, F., & Scapicchio, P. L. (1996) · Comprehensive Psychiatry · doi:10.1016/s0010-440x(96)90054-1 · Cited by 368 · see citing works
Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients
Yao, J. K., Leonard, S. S., & Reddy, R. D. (2000) · Schizophrenia Research · doi:10.1016/s0920-9964(99)00095-x · Cited by 290 · see citing works
Self-citationLipid metabolome-wide effects of the PPARγ agonist rosiglitazone
Watkins, S. M., Reifsnyder, P. C., Pan, H.-J., German, J. B., & Leiter, E. H. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200169-jlr200 · Cited by 274 · see citing works
Metabolomic Mapping of Atypical Antipsychotic Effects in Schizophrenia
Kaddurah-Daouk, R., McEvoy, J., Baillie, R. A., Lee, D., Yao, J. K., Doraiswamy, P. M., & Krishnan, K. R. R. (2007) · Molecular Psychiatry · doi:10.1038/sj.mp.4002000 · Cited by 262 · see citing works
McQuade, R. D., Stock, E. G., Marcus, R. N., Jody, D. N., Abou-Gharbia, N., Vanveggel, S., Archibald, D., & Carson, W. H. (2004) · PubMed · Cited by 244 · see citing works
Arvindakshan, M., Sitasawad, S. L., Debsikdar, V. B., Ghate, M. R., Evans, D. R., Horrobin, D. F., Bennett, C. N., Ranjekar, P. K., & Mahadik, S. P. (2002) · Biological Psychiatry · doi:10.1016/s0006-3223(02)01443-9 · Cited by 232 · see citing works
Elongase reactions as control points in long-chain polyunsaturated fatty acid synthesis
Gregory, M. K., Gibson, R. A., Cook-Johnson, R. J., Cleland, L. G., & James, M. J. (2011) · PLoS ONE · doi:10.1371/journal.pone.0029662 · Cited by 192 · see citing works
The economic impact of schizophrenia.
Rice, D. P. (1999) · PubMed · Cited by 183 · see citing works
Hibbeln, J. R., Umhau, J. C., Linnoila, M., George, D. T., Ragan, P. W., Shoaf, S. E., Vaughan, M. R., Rawlings, R. R., & Salem, N. (1998) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00143-7 · Cited by 151 · see citing works
Depleted red cell membrane essential fatty acids in drug-treated schizophrenic patients
Peet, M., Laugharne, J., Rangarajan, N., Horrobin, D. F., & Reynolds, G. P. (1995) · Journal of Psychiatric Research · doi:10.1016/0022-3956(95)00001-l · Cited by 146 · see citing works
The semistructured BPRS interview and rating guide.
Rhoades, H. M., & Overall, J. E. (1988) · PubMed · Cited by 142 · see citing works
The metabolic syndrome in schizophrenia: is inflammation a contributing cause?
Leonard, B. E., Schwarz, M., & Myint, A.-M. (2012) · Journal of Psychopharmacology · doi:10.1177/0269881111431622 · Cited by 134 · see citing works
Hoen, W. P., Lijmer, J. G., Durán, M., Wanders, R. J. A., van Beveren, N. J. M., & de Haan, L. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.09.041 · Cited by 132 · see citing works
McEvoy, J. P. (2007) · PubMed · Cited by 122 · see citing works
Self-citationvan der Kemp, W. J. M., Klomp, D. W. J., Kahn, R. S., Luijten, P. R., & Pol, H. E. H. (2012) · Schizophrenia Research · doi:10.1016/j.schres.2012.08.014 · Cited by 119 · see citing works
Sengupta, S. M., Parrilla-Escobar, M. A., Klink, R., Fathalli, F., Ng, Y. K., Stip, É., Baptista, T., MALLA, A. K., & Joober, R. (2008) · Schizophrenia Research · doi:10.1016/j.schres.2008.02.013 · Cited by 108 · see citing works
Membrane fatty acids, niacin flushing and clinical parameters
Glen, A. I. M., Cooper, S. J., RYBAKOWSKI, J. K., Vaddadi, K. S., Brayshaw, N., & Horrobin, D. F. (1996) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/s0952-3278(96)90139-8 · Cited by 95 · see citing works
Erythrocyte membrane phospholipids in psychotic patients
Keshavan, M. S., Mallinger, A. G., Pettegrew, J. W., & Dippold, C. S. (1993) · Psychiatry Research · doi:10.1016/0165-1781(93)90032-c · Cited by 95 · see citing works
Self-citationImpaired Plasmalogens in Patients with Schizophrenia
Kaddurah-Daouk, R., McEvoy, J., Baillie, R., Zhu, H., K. Yao, J., Nimgaonkar, V. L., Buckley, P. F., Keshavan, M. S., Georgiades, A., & Nasrallah, H. A. (2012) · Psychiatry Research · doi:10.1016/j.psychres.2012.02.019 · Cited by 89 · see citing works
Self-citationSaddichha, S., Manjunatha, N., Ameen, S., & Akhtar, S. (2008) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.2008.01158.x · Cited by 87 · see citing works
Fatty acids differentially affect serotonin receptor and transporter binding in the rat brain
du Bois, T. M., Deng, C., Bell, W., et al. (2006) · Neuroscience · doi:10.1016/j.neuroscience.2006.02.068 · Cited by 76 · see citing works
Keshavan, M. S., Stanley, J. A., Montrose, D. M., Minshew, N. J., & Pettegrew, J. W. (2003) · Molecular Psychiatry · doi:10.1038/sj.mp.4001325 · Cited by 76 · see citing works
Self-citationLuo, C., Wang, K., Liu, D., Li, Y., & Zhao, Q.-S. (2008) · Cellular and Molecular Immunology · doi:10.1038/cmi.2008.1 · Cited by 70 · see citing works
Watkins, S. M., Lin, T. Y., Davis, R. M., Ching, J. R., DePeters, E. J., HALPERN, G. M., Walzem, R. L., & German, J. B. (2001) · Lipids · doi:10.1007/s11745-001-0714-8 · Cited by 69 · see citing works
The n-3 polyunsaturated fatty acid/dopamine hypothesis of schizophrenia
Ohara, K. (2006) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2006.11.013 · Cited by 63 · see citing works
Mahadik, S. P., & Evans, D. R. (2003) · Psychiatric Clinics of North America · doi:10.1016/s0193-953x(02)00033-3 · Cited by 62 · see citing works
Potwarka, J. J., Drost, D. J., Williamson, P., et al. (1999) · Biological Psychiatry · doi:10.1016/s0006-3223(98)00136-x · Cited by 59 · see citing works
Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia
YAO, J. K., Magan, S., Sonel, A. F., et al. (2004) · Prostaglandins Leukotrienes and Essential Fatty Acids · doi:10.1016/j.plefa.2004.03.011 · Cited by 55 · see citing works
Self-citationStrassnig, M., Brar, J. S., & Ganguli, R. (2005) · Schizophrenia Research · doi:10.1016/j.schres.2005.03.002 · Cited by 54 · see citing works
Cohen, D., Dekker, J., Peen, J., & Wied, C. C. G. (2005) · European Neuropsychopharmacology · doi:10.1016/j.euroneuro.2005.09.003 · Cited by 49 · see citing works
Kane, J. M., Potkin, S. G., Daniel, D. G., & Buckley, P. F. (2010) · The Journal of Clinical Psychiatry · doi:10.4088/jcp.07m03733yel · Cited by 42 · see citing works
Self-citationDervola, K.-S. N., Roberg, B., Wøien, G., Bogen, I. L., Sandvik, T., Sagvolden, T., Drevon, C. A., Johansen, E. B., & Walaas, S. I. (2012) · Behavioral and Brain Functions · doi:10.1186/1744-9081-8-56 · Cited by 42 · see citing works
Membrane fatty acid levels as a predictor of treatment response in chronic schizophrenia
Sumiyoshi, T., Higuchi, Y., Matsui, M., Itoh, H., Uehara, T., Itoh, T., Arai, H., Takamiya, C., Suzuki, M., & Kurachi, M. (2010) · Psychiatry Research · doi:10.1016/j.psychres.2010.07.049 · Cited by 31 · see citing works
Schizophrenia: The role of abnormal essential fatty acid and prostaglandin metabolism
Horrobin, D. F., & Huang, Y.-S. (1983) · Medical Hypotheses · doi:10.1016/0306-9877(83)90119-6 · Cited by 31 · see citing works
Wood, S. J., Cocchi, L., Proffitt, T., McConchie, M., Jackson, G. D., Takahashi, T., Pantelis, C., McGorry, P. D., & Berger, G. E. (2010) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2009.12.003 · Cited by 30 · see citing works
Computations using analysis of covariance
Barrett, T. J. (2011) · Wiley Interdisciplinary Reviews Computational Statistics · doi:10.1002/wics.165 · Cited by 28 · see citing works
N-3 polyunsaturated fatty acids in psychiatric diseases: mechanisms and clinical data.
Zeman, M., Jirák, R., Vecka, M., Raboch, J., & Žák, A. (2012) · PubMed · Cited by 15 · see citing works
Carson, W., McQuade, R. D., Abou-Gharbia, N., et al. (2004) · European Neuropsychopharmacology · doi:10.1016/s0924-977x(04)80281-5 · Cited by 2 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- [44]Horrobin DF (1999) The effects of antipsychotic drugs on membrane phospholipids: a possible novel mechanism of action of clozapine. In: Peet M Glen I Horrobin DF Phospholipid spectrum disorder in psychiatry. Carnforth: Marius Press pp. 113- 117.
Cited by
Sorted by citations
MahmoudianDehkordi, S., Ahmed, A. T., Bhattacharyya, S., Han, X., Baillie, R. A., Arnold, M., Skime, M. K., John-Williams, L. S., Moseley, M. A., Thompson, J. W., et al. (2021) · Translational Psychiatry · doi:10.1038/s41398-020-01097-6 · Cited by 95 · see citing works
Self-citationMetabolic Profiling Identifies Phospholipids as Potential Serum Biomarkers for Schizophrenia
Wang, D., Cheng, S. L., Fei, Q., Gu, H., Raftery, D., Cao, B., Sun, X., Yan, J., Zhang, C., & Wang, J. (2019) · Psychiatry Research · doi:10.1016/j.psychres.2018.12.008 · Cited by 73 · see citing works
de Almeida, V., Alexandrino, G. L., Aquino, A., Gomes, A. F., Murgu, M., Dobrowolny, H., Guest, P. C., Steiner, J., & Martins-de-Souza, D. (2020) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.109945 · Cited by 39 · see citing works
Lipids in Psychiatric Disorders: Functional and Potential Diagnostic Role as Blood Biomarkers
Zorkina, Y., Ushakova, V., Ochneva, A., Tsurina, A., Abramova, O., Savenkova, V., Goncharova, A., Alekseenko, I., Morozova, I., Riabinina, D., et al. (2024) · Metabolites · doi:10.3390/metabo14020080 · Cited by 36 · see citing works
Yan, L., Zhou, J., Wang, D., Si, D., Liu, Y., Zhong, L., & Yin, Y. (2018) · Metabolomics · doi:10.1007/s11306-018-1375-3 · Cited by 36 · see citing works
Wang, D., Sun, X., Maziade, M., Mao, W., Zhang, C., Wang, J., & Cao, B. (2021) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2020.1769188 · Cited by 26 · see citing works
Costa, A., Riça, L., van de Bilt, M., Zandonadi, F., Gattaz, W., Talib, L., & Sussulini, A. (2023) · Metabolites · doi:10.3390/metabo13050600 · Cited by 25 · see citing works
Wang, F., Guo, L., Zhang, T., Cui, Z., Wang, J., Zhang, C., Xue, F., Zhou, C., Li, B., Tan, Q., et al. (2022) · Medicina · doi:10.3390/medicina58111509 · Cited by 18 · see citing works
- Authors
- McEvoy, J., Baillie, R. A., Zhu, H., Buckley, P., Keshavan, M. S., Nasrallah, H. A., Dougherty, G. G., Yao, J. K., & Kaddurah-Daouk, R.
- Affiliations
- Duke Medical Center (US)
- Rosa (United States) (US)
- Augusta University (US)
- Beth Israel Deaconess Medical Center (US)
- University of Cincinnati (US)
- University of Pittsburgh (US)
- Corresponding author
- Kaddurah-Daouk, Rima
- ORCID
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2013-07-24
- Volume
- 8
- Issue
- 7
- Pages
- e68717
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3722141
- OpenAlex
- W2130012034
- Cited by
- 127
- References
- 50
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 14 · 2022: 10 · 2021: 9 · 2020: 13 · 2019: 8 · 2018: 10 · 2017: 11 · 2016: 11 · 2015: 12 · 2014: 8 · 2013: 1
- FWCI
- 7.56
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- D-Scholarship@Pitt (University of Pittsburgh) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- U.S. Department of Veterans Affairs
- National Institute of Mental Health (R01MH084941)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- schizophrenia, lipidomics, atypical antipsychotics, risperidone, aripiprazole, first-episode schizophrenia, chronic schizophrenia, medication non-adherence, omega-3 fatty acids, omega-6 fatty acids, phospholipid fatty acid composition, phosphatidylcholine, phosphatidylethanolamine, fatty acid synthesis pathway, metabolic biomarkers
- MeSH terms
- Adult, Fatty Acids, Unsaturated, Female, Glycerylphosphorylcholine, Humans, Male, Middle Aged, Phosphatidylethanolamines, Phospholipids, Schizophrenia, Antipsychotic Agents, Fatty Acids, Omega-3, Fatty Acids, Omega-6, Lipid Metabolism
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