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Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine’s Antidepressant Effect

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Abstract

Depression is a worldwide illness with a significant impact on both family and society. Conventional antidepressants are ineffective for more than 30% of patients. In such patients, who have what is called treatment-resistant depression (TRD), inflammatory biomarkers are expressed excessively in both the central nervous system (CNS) and the peripheral blood. Ketamine, a glutamate receptor antagonist, exerts a rapid and sustained therapeutic effect in patients with TRD. Thus, the investigation of the relations between inflammation and glutamate underlying depression has drawn great attention. Inflammation influences glutamate release, transmission, and metabolism, resulting in accumulated extracellular glutamate in the CNS. Downstream of the glutamate receptors, the mammalian target of rapamycin (mTOR) signaling pathway plays a key role in mediating ketamine’s antidepressant effect by improving neurogenesis and plasticity. Based on the mechanism and clinical evidence of the inflammatory contribution to the pathogenesis of depression, extensive research has been devoted to inflammatory biomarkers of the clinical response of depression to ketamine. The inconsistent findings from the biomarker investigations are at least partially attributable to the heterogeneity of depression, limited sample size, and complex gene–environment interactions. Deep exploration of the clinical observations and the underlying mechanism of ketamine’s antidepressant response can provide new insights into the selection of specific groups of depressed patients for ketamine treatment and to aid in monitoring the therapeutic effect during antidepressant medication. Further, targeting persistent inflammation in patients with TRD and the key molecules mediating ketamine’s antidepressant effect may encourage the development of novel therapeutic strategies.

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Acknowledgments

This study was supported in part by the China Precision Medicine Initiative (2016YFC0906300) and Research Center for Air Pollution and Health of Zhejiang University. We thank Dr. David L. Bronson for excellent editing of this manuscript.

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Authors and Affiliations

  1. State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University School of Medicine, Hangzhou, China

    Wenyan Cui & Ming D. Li

  2. The Affiliated Brain Hospital of Guangzhou Medical University, Guangzhou, China

    Yuping Ning

  3. Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Wu Hong

  4. School of Biomedical Engineering, Tianjin Medical University, Tianjin, China

    Ju Wang

  5. The Second Xiangya Hospital of Central South University, Changsha, China

    Zhening Liu

  6. Research Center for Air Pollution and Health, Zhejiang University, Hangzhou, China

    Ming D. Li

  7. Institute of NeuroImmune Pharmacology, Seton Hall University, South Orange, NJ, USA

    Ming D. Li

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Cui, W., Ning, Y., Hong, W. et al. Crosstalk Between Inflammation and Glutamate System in Depression: Signaling Pathway and Molecular Biomarkers for Ketamine’s Antidepressant Effect. Mol Neurobiol 56, 3484–3500 (2019). https://doi.org/10.1007/s12035-018-1306-3

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