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Mol Neurobiol. 2016 Jul;53(5):2927-2935. doi: 10.1007/s12035-015-9183-5. Epub 2015 May 2.

Toward Omics-Based, Systems Biomedicine, and Path and Drug Discovery Methodologies for Depression-Inflammation Research.

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IMPACT Research Center, Deakin University, Geelong, Australia.
Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand.
Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil.
IMPACT Strategic Research Center, Barwon Health, Deakin University, Geelong, Vic, Australia.
Department of Pharmacobiology, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.
Department of Neurobiology, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland.
Department of Pharmacology, Faculty of Medicine, University Complutense, Centro de Investigación Biomédica en Salud Mental (CIBERSAM) & Instituto de Investigación Sanitaria Hospital 12 de Octubre, Madrid, Spain.
Department of Psychology and Neuroscience, Dalhousie University, Halifax, Canada.
Research Institute for Marine Nutrition and Drugs, Guangdong Ocean University, Zhanjiang, China.
Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Science, Krakow, Poland.
Department of Psychiatry, University of Groningen, Groningen, The Netherlands.
Department of Adult Psychiatry, Medial University of Łódź, Łódź, Poland.
Department of Psychiatry, Universidade Federal de São Paulo (UNIFESP), Sao Paulo, Brazil.
Luxembourg Centre for Systems Biomedicine, University of Luxemburg, Esch-sur-Alzette, Luxembourg.
IMPACT Research Center, Deakin University, Geelong, Australia.
Orygen, The National Centre of Excellence in Youth Mental Health, Department of Psychiatry and The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Australia.


Meta-analyses confirm that depression is accompanied by signs of inflammation including increased levels of acute phase proteins, e.g., C-reactive protein, and pro-inflammatory cytokines, e.g., interleukin-6. Supporting the translational significance of this, a meta-analysis showed that anti-inflammatory drugs may have antidepressant effects. Here, we argue that inflammation and depression research needs to get onto a new track. Firstly, the choice of inflammatory biomarkers in depression research was often too selective and did not consider the broader pathways. Secondly, although mild inflammatory responses are present in depression, other immune-related pathways cannot be disregarded as new drug targets, e.g., activation of cell-mediated immunity, oxidative and nitrosative stress (O&NS) pathways, autoimmune responses, bacterial translocation, and activation of the toll-like receptor and neuroprogressive pathways. Thirdly, anti-inflammatory treatments are sometimes used without full understanding of their effects on the broader pathways underpinning depression. Since many of the activated immune-inflammatory pathways in depression actually confer protection against an overzealous inflammatory response, targeting these pathways may result in unpredictable and unwanted results. Furthermore, this paper discusses the required improvements in research strategy, i.e., path and drug discovery processes, omics-based techniques, and systems biomedicine methodologies. Firstly, novel methods should be employed to examine the intracellular networks that control and modulate the immune, O&NS and neuroprogressive pathways using omics-based assays, including genomics, transcriptomics, proteomics, metabolomics, epigenomics, immunoproteomics and metagenomics. Secondly, systems biomedicine analyses are essential to unravel the complex interactions between these cellular networks, pathways, and the multifactorial trigger factors and to delineate new drug targets in the cellular networks or pathways. Drug discovery processes should delineate new drugs targeting the intracellular networks and immune-related pathways.


Depression; IDO; Immune; Inflammation; Leaky gut; Neuroprogression; Oxidative and nitrosative stress; TRYCATs

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