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Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients

Abstract

Extensive research has been conducted on post-mortem brain tissue in schizophrenia (SCZ), particularly the dorsolateral prefrontal cortex (DLPFC). However, to what extent the reported changes are due to the disorder itself, and which are the cumulative effects of lifetime medication remains to be determined. In this study, we employed label-free liquid chromatography–mass spectrometry-based proteomic and proton nuclear magnetic resonance-based metabonomic profiling approaches to investigate DLPFC tissue from two cohorts of SCZ patients grouped according to their lifetime antipsychotic dose, together with tissue from bipolar disorder (BPD) subjects, and normal controls (n=10 per group). Both techniques showed profound changes in tissue from low-cumulative-medication SCZ subjects, but few changes in tissue from medium-cumulative-medication subjects. Protein expression changes were validated by Western blot and investigated further in a third group of subjects who were subjected to high-cumulative-medication over the course of their lifetime. Furthermore, key protein expression and metabolite level changes correlated significantly with lifetime antipsychotic dose. This suggests that the detected changes are present before antipsychotic therapy and, moreover, may be normalized with treatment. Overall, our analyses revealed novel protein and metabolite changes in low-cumulative-medication subjects associated with synaptogenesis, neuritic dynamics, presynaptic vesicle cycling, amino acid and glutamine metabolism, and energy buffering systems. Most of these markers were altered specifically in SCZ as determined by analysis of the same brain region from BPD patients.

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Acknowledgements

This research was supported by the Stanley Medical Research Institute and the donations of the Stanley brain collection courtesy of Drs Michael B Knable, E Fuller Torrey and Robert H Yolken. Special thanks to Dr Maree Webster for providing post-mortem brain samples. We thank Drs Dan Ma, Lan Wang and Xiaoping Yang for intellectual input. Many thanks to Drs Yishai Levin and Emanuel Schwarz for LC-MSE instrument tuning and statistical advice. We thank Miss Sandra Pietsch for sectioning the schizophrenia brain samples for 1H NMR analysis. Dr MK Chan was funded by Fundação para a Ciência e a Tecnologia, Portugal. Most of all, thanks to all patients and healthy volunteers for donating samples used in this study.

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Correspondence to S Bahn.

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SB is Chief Scientific Officer for Psynova Neurotech Ltd. PG acts as a consultant for Psynova Neurotech Ltd. MKC, TMT, LWH, EH declare no conflict of interest.

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Chan, M., Tsang, T., Harris, L. et al. Evidence for disease and antipsychotic medication effects in post-mortem brain from schizophrenia patients. Mol Psychiatry 16, 1189–1202 (2011). https://doi.org/10.1038/mp.2010.100

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  • DOI: https://doi.org/10.1038/mp.2010.100

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