Volume 1292, Issue 1 p. 21-31
Original Article

New paradigms for treatment-resistant depression

Carlos Zarate

Carlos Zarate

Experimental Therapeutics & Pathophysiology Branch, Division of Intramural Research Program, National Institute of Mental Health, National Institutes of Health, and Department of Health and Human Services, Bethesda, Maryland

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Ronald S. Duman

Ronald S. Duman

Department of Psychiatry and Neurobiology, Yale University School of Medicine, New Haven, Connecticut

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Guosong Liu

Guosong Liu

Tsinghua-Peking Center for Life Sciences, School of Medicine, Tsinghua University, Beijing, China

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Simone Sartori

Simone Sartori

Department of Pharmacology and Toxicology, University of Innsbruck, Innsbruck, Austria

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Jorge Quiroz

Jorge Quiroz

Child and Adult Psychiatry, Neuroscience Translational Medicine, Roche, Nutley, New Jersey

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Harald Murck

Corresponding Author

Harald Murck

Covance, Princeton, New Jersey

Psychiatric Clinic of the Philipps-University of Marburg, Marburg, Germany

Address for correspondence: Harald Murck, MD PhD, Senior Medical Director, Neuroscience Medical and Scientific Services, Covance, 206 Carnegie Center, Princeton, NJ 08540. [email protected]Search for more papers by this author
First published: 22 July 2013
Citations: 77

Abstract

Clinical depression is a serious mental disorder characterized by low mood, anhedonia, loss of interest in daily activities, and other symptoms, and is associated with severe consequences including suicide and increased risk of cardiovascular events. Depression affects nearly 15% of the population. The standard of care for the last 50 years has focused on monoamine neurotransmitters, including such treatments as selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs). However, these treatments have significant limitations: they can take weeks before showing mood-altering effects, and only one to two out of ten patients shows clinical effects beyond those associated with placebo. A major paradigm shift in research into the treatment of depression is underway, based on promising results with the glutamatergic NMDA receptor antagonist ketamine. Further research has demonstrated the significance of glutamatergic pathways in depression and the association of this system with the stress pathway and magnesium homeostasis. Treatment with NMDA receptor antagonists and magnesium have shown the ability to sprout new synaptic connections and reverse stress-induced neural changes, opening up promising new territory for the development of drugs to meet the unmet need in patients with clinical depression.