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Metabolomic mapping of atypical antipsychotic effects in schizophrenia

Abstract

Schizophrenia is associated with impairments in neurotransmitter systems and changes in neuronal membrane phospholipids. Several atypical antipsychotic drugs induce weight gain and hypertriglyceridemia. To date, there has not been a comprehensive evaluation and mapping of global lipid changes in schizophrenia, and upon treatment with antipsychotics. Such mapping could provide novel insights about disease mechanisms and metabolic side effects of therapies used for its treatment. We used a specialized metabolomics platform ‘lipidomics’ that quantifies over 300 polar and nonpolar lipid metabolites (across seven lipid classes) to evaluate global lipid changes in schizophrenia and upon treatment with three commonly used atypical antipsychotics. Lipid profiles were derived for 50 patients with schizophrenia before and after treatment for 2–3 weeks with olanzapine (n=20), risperidone (n=14) or aripiprazole (n=16). Patients were recruited in two cohorts (study I, n=27 and study II, n=23) to permit an internal replication analyses. The change from baseline to post-treatment was then compared among the three drugs. Olanzapine and risperidone affected a much broader range of lipid classes than aripiprazole. Approximately 50 lipids tended to be increased with both risperidone and olanzapine and concentrations of triacylglycerols increased and free fatty acids decreased with both drugs but not with aripiprazole. Phosphatidylethanolamine concentrations that were suppressed in patients with schizophrenia were raised by all three drugs. Drug specific differences were also detected. A principal component analysis (PCA) identified baseline lipid alterations, which correlated with acute treatment response. A more definitive long-term randomized study of these drugs correlating global lipid changes with clinical outcomes could yield biomarkers that define drug-response phenotypes.

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References

  1. Jablensky A, Sartorius N, Ernberg G, Anker M, Korten A, Cooper JE et al. Schizophrenia: manifestations, incidence and course in different cultures. A World Health Organization ten-country study. Psychol Med Monogr Suppl 1992; 20: 1–97.

    Article  CAS  PubMed  Google Scholar 

  2. Javitt DC, Laruelle M . Neurochemical theories. In: Lieberman JA, Stroup TS and Perkins DO (eds). Textbook of Schizophrenia. American Psychiatric Publishing: Washington DC, 2006, pp 85–116.

    Google Scholar 

  3. Meltzer HY . Biological studies in schizophrenia. Schizophr Bull 1987; 13: 77–111.

    Article  CAS  PubMed  Google Scholar 

  4. Scolnick EM . Mechanisms of action of medicines for Schizophrenia and Bipolar Illness: status and limitations. Biol Psychiatry 2006; 59: 1039–1045.

    Article  CAS  PubMed  Google Scholar 

  5. Strauss JS, Carpenter Jr WT . Prediction of outcome in schizophrenia. III. Five-year outcome and its predictors. Arch Gen Psychiatry 1977; 34: 159–163.

    Article  CAS  PubMed  Google Scholar 

  6. Kane JM, Marder SR . Psychopharmacologic treatment of schizophrenia. Schizophr Bull 1993; 19: 287–302.

    Article  CAS  PubMed  Google Scholar 

  7. Carpenter Jr WT, Buchanan RW . Schizophrenia. N Engl J Med 1994; 330: 681–690.

    Article  PubMed  Google Scholar 

  8. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  PubMed  Google Scholar 

  9. Horrobin DF . The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998; 30: 193–208.

    Article  CAS  PubMed  Google Scholar 

  10. Mahadik SP, Yao JK . Phospholipids in schizophrenia. In: Lieberman JA, Stroup TS, Perkins DO (eds). Textbook of Schizophrenia. American Psychiatric Publishing: Washington, DC, 2006, pp 117–135.

    Google Scholar 

  11. American Diabetes Association, A.P.A. American Association of Clinical Endocrinologists, North American Association for the Study of Obesity, Consensus Development Conference on Antipsychotic Drugs and Obesity and Diabetes. J Clin Psychiatry 2004; 65: 267–272.

    Article  Google Scholar 

  12. McQuade RD, Stock E, Marcus R, Jody D, Gharbia NA, Vanveggel S et al. A comparison of weight change during treatment with olanzapine or aripiprazole: results from a randomized, double-blind study. J Clin Psychiatry 2004; 65 (Suppl 18): 47–56.

    CAS  PubMed  Google Scholar 

  13. Odunsi K, Wollman RM, Ambrosone CB, Hutson A, McCann SE, Tammela J et al. Detection of epithelial ovarian cancer using 1H-NMR-based metabonomics. Int J Cancer 2005; 113: 782–788.

    Article  CAS  PubMed  Google Scholar 

  14. Brindle JT, Antti H, Holmes E, Tranter G, Nicholson JK, Bethell HW et al. Rapid and noninvasive diagnosis of the presence and severity of coronary heart disease using 1H-NMR-based metabonomics. Nat Med 2002; 8: 1439–1444.

    Article  CAS  PubMed  Google Scholar 

  15. Brindle JT, Nicholson JK, Schofield PM, Grainger DJ, Holmes E . Application of chemometrics to 1H NMR spectroscopic data to investigate a relationship between human serum metabolic profiles and hypertension. Analyst 2003; 128: 32–36.

    Article  CAS  PubMed  Google Scholar 

  16. Rozen S, Cudkowicz ME, Bogdanov M, Matson WR, Kristal BS, Beecher C et al. Metabolomic analysis and signatures in motor neuron disease. Metabolomics 2005; 1: 101–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dunne VG, Bhattachayya S, Besser M, Rae C, Griffin JL . Metabolites from cerebrospinal fluid in aneurysmal subarachnoid haemorrhage correlate with vasospasm and clinical outcome: a pattern-recognition (1)H NMR study. NMR Biomed 2005; 18: 24–33.

    Article  CAS  PubMed  Google Scholar 

  18. Kenny LC, Dunn WB, Ellis DI, Myers J, Baker PN et al. Novel biomarkers for pre-eclampsia detected using metabolomics and machine learning. Metabolomics 2005; 1: 277–284.

    Article  Google Scholar 

  19. Yao JK, Reddy RD . Metabolic investigation in psychiatric disorders. Mol Neurobiol 2005; 31: 193–203.

    Article  CAS  PubMed  Google Scholar 

  20. Wang C, Kong H, Guan Y, Yang J, Gu J, Yang S et al. Plasma phospholipid metabolic profiling and biomarkers of type 2 diabetes mellitus based on high-performance liquid chromatography/electrospray mass spectrometry and multivariate statistical analysis. Anal Chem 2005; 77: 4108–4116.

    Article  CAS  PubMed  Google Scholar 

  21. Watkins SM . Lipomic profiling in drug discovery, development and clinical trial evaluation. Curr Opin Drug Discov Devel 2004; 7: 112–117.

    CAS  PubMed  Google Scholar 

  22. Watkins SM, Reifsnyder PR, Pan JH, German JB, Leiter EH . Lipid metabolome-wide effects of the PPARgamma agonist rosiglitazone. J Lipid Res 2002; 43: 1809–1817.

    Article  CAS  PubMed  Google Scholar 

  23. Watson AD . Lipidomics: a global approach to lipid analysis in biological systems. J Lipid Res 2006; 47: 2101–2111.

    Article  CAS  PubMed  Google Scholar 

  24. Guy W . ECDEU Assessment Manual for Psychopharmacology. US Department of Health, Education, and Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, National Institute of Mental Health, Psychopharmacology Research Branch, Division of Extramural Research Programs: Rockville, MD, 1976.

    Google Scholar 

  25. Folch J, Lees M, Stanley GH . A simple method for the isolation and purification of total lipids from animal tissues. J Biol Chem 1957; 226: 497–509.

    CAS  PubMed  Google Scholar 

  26. Watkins SM, Lin TY, Davis RM, Ching JR, DePeters EJ, Halpern GM et al. Unique phospholipid metabolism in mouse heart in response to dietary docosahexaenoic or alpha-linolenic acids. Lipids 2001; 36: 247–254.

    Article  CAS  PubMed  Google Scholar 

  27. Lutzke BS, Braughler JM . An improved method for the identification and quantitation of biological lipids by HPLC using laser light-scattering detection. J Lipid Res 1990; 11: 2127–2130.

    Google Scholar 

  28. Warensjo E, Ohrvall M, Vessby B . Fatty acid composition and estimated desaturase activities are associated with obesity and lifestyle variables in men and women. Nutr Metab Cardiovasc Dis 2006; 16: 128–136.

    Article  PubMed  Google Scholar 

  29. Riserus U, Tan GD, Fielding BA, Neville JM, Currie J, Savage DB et al. Rosiglitazone increases indexes of stearoyl-CoA desaturase activity in humans: link to insulin sensitization and the role of dominant-negative mutation in peroxisome proliferator-activated receptor-gamma. Diabetes 2005; 54: 1379–1384.

    Article  CAS  PubMed  Google Scholar 

  30. Shiwaku K, Hashimoto M, Kitajima K, Nogi A, Anuurad E, Enkhmaa B et al. Triglyceride levels are ethnic-specifically associated with an index of stearoyl-CoA desaturase activity and n-3 PUFA levels in Asians. J Lipid Res 2004; 45: 914–922.

    Article  CAS  PubMed  Google Scholar 

  31. R Development Core Team (2006). R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria. ISBN 3-900051-07-0, URL: http://www.R-project.org/.

  32. Golub TR, Slonim DK, Tamayo P, Huard C, Gaasenbeek M, Mesirov JP et al. Molecular classification of cancer: class discovery and class prediction by gene expression monitoring. Science 1999; 286: 531–537.

    Article  CAS  PubMed  Google Scholar 

  33. Kaddurah-Daouk R . Metabolic profiling of patients with schizophrenia (Letter). PLoS Med 2006; 3: 1222–1223.

    Article  Google Scholar 

  34. Harrigan G, Goodacre R . Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis. Kluwer Academic Publishers: Boston, 2003.

    Book  Google Scholar 

  35. Lindon JC, Holmes E, Bollard ME, Stanley EG, Nicholson JK . Metabonomics technologies and their applications in physiological monitoring, drug safety assessment and disease diagnosis. Biomarkers 2004; 9: 1–31.

    Article  CAS  PubMed  Google Scholar 

  36. Holmes E, Tsang TM, Huang JT, Leweke FM, Koethe D, Gerth CW et al. Metabolic profiling of CSF: evidence that early intervention may impact on disease progression and outcome in schizophrenia. PLoS Med 2006; 3: 1420–1428.

    CAS  Google Scholar 

  37. Rotrosen J, Wolkin A . Phospholipid and prostaglandin hypotheses of schizophrenia. In: Meltzer NY (ed). Psychopharmacology, The Third Generation on Progress. Raven Press: New York, 1987, pp 759–764.

    Google Scholar 

  38. Keshavan MS, Mallinger AG, Pettegrew JW, Dippold C . Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res 1993; 49: 89–95.

    Article  CAS  PubMed  Google Scholar 

  39. Mahadik SP, Mukherjee S, Correnti EE, Kelkar HS, Wakade CG, Costa RM 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.

    Article  CAS  PubMed  Google Scholar 

  40. Schmitt A, Maras A, Petroianu G, Braus DF, Scheuer L, Gattaz WF et al. Effects of antipsychotic treatment on membrane phospholipid metabolism in schizophrenia. J Neural Transm 2001; 108: 1081–1091.

    Article  CAS  PubMed  Google Scholar 

  41. Horrobin DF, Manku MS, Hillman H, Iain A, Glen M . Fatty acid levels in the brains of schizophrenics and normal controls. Biol Psychiatry 1991; 30: 795–805.

    Article  CAS  PubMed  Google Scholar 

  42. Yao JK, Leonard S, Reddy RD . Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schizophr Res 2000; 42: 7–17.

    Article  CAS  PubMed  Google Scholar 

  43. Pettegrew JW, Keshavan MS, Panchalingam K, Strychor S, Kaplan DB, Tretta MG 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.

    Article  CAS  PubMed  Google Scholar 

  44. Richardson AJ, Allen SJ, Hajnal JV, Cox IJ, Easton T, Puri BK . Associations between central and peripheral measures of phospholipid breakdown revealed by cerebral 31-phosphorus magnetic resonance spectroscopy and fatty acid composition of erythrocyte membranes. Prog Neuropsychopharmacol Biol Psychiatry 2001; 2: 1513–1521.

    Article  Google Scholar 

  45. Yao JK, Stanley JA, Reddy RD, Keshavan MS, Pettegrew JW . Correlations between peripheral polyunsaturated fatty acid content and in vivo membrane phospholipid metabolites. Biol Psychiatry 2002; 52: 823–830.

    Article  CAS  PubMed  Google Scholar 

  46. Horrobin DF . Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot Essent Fatty Acids 1996; 55: 3–7.

    Article  CAS  PubMed  Google Scholar 

  47. Holman RT . Essential fatty acid deficiency in humans. In: Galli C, Jacini G, Pecile A (eds). Dietary Lipids and Postnatal Development. Raven Press: New York, 1973, pp 127–143.

    Google Scholar 

  48. Horrobin DF, Manku MS, Morse-Fisher NM . Essential fatty acids in plasma phospholipids in schizophrenics. Biol Psychiatry 1989; 25: 562–568.

    Article  CAS  PubMed  Google Scholar 

  49. Kaiya H, Horrobin DF, Manku MS, Fisher NM . Essential and other fatty acids in plasma in schizophrenics and normal individuals from Japan. Biol Psychiatry 1991; 30: 357–362.

    Article  CAS  PubMed  Google Scholar 

  50. Yao JK, van Kammen DP, Gurklis J . Red blood cell membrane dynamics in schizophrenia. III. Correlation of fatty acid abnormalities with clinical measures. Schizophr Res 1994; 13: 227–232.

    Article  CAS  PubMed  Google Scholar 

  51. Ferno J, Raeder MB, Vik-Mo AO, Skrede S, Glambek M, Tronstad KJ et al. Antipsychotic drugs activate SREBP-regulated expression of lipid biosynthetic genes in cultured human glioma cells: a novel mechanism of action? Pharmacogenomics J 2005; 5: 298–304.

    Article  CAS  PubMed  Google Scholar 

  52. Raeder MB, Ferno J, Glambek M, Stansberg C, Steen VM . Antidepressant drugs activate SREBP and up-regulate cholesterol and fatty acid biosynthesis in human glial cells. Neurosci Lett 2006; 395: 185–190.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Funding for this was provided by NARSAD and Stanley Foundation. RAB is an employee of Lipomics and owns options. Dr KD is a stockholder in Metabolon. JM, PMD and KRRK have received honoraria, grants and consulting fees from pharmaceutical companies including the manufactures of the three antipsychotics discussed here. Some of the authors are also applicants with their employers on patents for mapping lipids in various CNS disorders including schizophrenia.

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Correspondence to R Kaddurah-Daouk.

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Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)

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Kaddurah-Daouk, R., McEvoy, J., Baillie, R. et al. Metabolomic mapping of atypical antipsychotic effects in schizophrenia. Mol Psychiatry 12, 934–945 (2007). https://doi.org/10.1038/sj.mp.4002000

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