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
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.
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.
Meltzer HY . Biological studies in schizophrenia. Schizophr Bull 1987; 13: 77–111.
Scolnick EM . Mechanisms of action of medicines for Schizophrenia and Bipolar Illness: status and limitations. Biol Psychiatry 2006; 59: 1039–1045.
Strauss JS, Carpenter Jr WT . Prediction of outcome in schizophrenia. III. Five-year outcome and its predictors. Arch Gen Psychiatry 1977; 34: 159–163.
Kane JM, Marder SR . Psychopharmacologic treatment of schizophrenia. Schizophr Bull 1993; 19: 287–302.
Carpenter Jr WT, Buchanan RW . Schizophrenia. N Engl J Med 1994; 330: 681–690.
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.
Horrobin DF . The membrane phospholipid hypothesis as a biochemical basis for the neurodevelopmental concept of schizophrenia. Schizophr Res 1998; 30: 193–208.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Yao JK, Reddy RD . Metabolic investigation in psychiatric disorders. Mol Neurobiol 2005; 31: 193–203.
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.
Watkins SM . Lipomic profiling in drug discovery, development and clinical trial evaluation. Curr Opin Drug Discov Devel 2004; 7: 112–117.
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.
Watson AD . Lipidomics: a global approach to lipid analysis in biological systems. J Lipid Res 2006; 47: 2101–2111.
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.
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.
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.
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.
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.
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.
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.
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/.
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.
Kaddurah-Daouk R . Metabolic profiling of patients with schizophrenia (Letter). PLoS Med 2006; 3: 1222–1223.
Harrigan G, Goodacre R . Metabolic Profiling: Its Role in Biomarker Discovery and Gene Function Analysis. Kluwer Academic Publishers: Boston, 2003.
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.
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.
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.
Keshavan MS, Mallinger AG, Pettegrew JW, Dippold C . Erythrocyte membrane phospholipids in psychotic patients. Psychiatry Res 1993; 49: 89–95.
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.
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.
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.
Yao JK, Leonard S, Reddy RD . Membrane phospholipid abnormalities in postmortem brains from schizophrenic patients. Schizophr Res 2000; 42: 7–17.
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.
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.
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.
Horrobin DF . Schizophrenia as a membrane lipid disorder which is expressed throughout the body. Prostaglandins Leukot Essent Fatty Acids 1996; 55: 3–7.
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.
Horrobin DF, Manku MS, Morse-Fisher NM . Essential fatty acids in plasma phospholipids in schizophrenics. Biol Psychiatry 1989; 25: 562–568.
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.
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.
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.
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.
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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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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DOI: https://doi.org/10.1038/sj.mp.4002000
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