title: New paradigms for treatment-resistant depression.
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.
authors.affiliation: 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, USA.
authors.forename: Carlos
authors.initials: C
authors.lastname: Zarate
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.forename: Guosong
authors.initials: G
authors.lastname: Liu
authors.forename: Simone
authors.initials: S
authors.lastname: Sartori
authors.forename: Jorge
authors.initials: J
authors.lastname: Quiroz
authors.forename: Harald
authors.initials: H
authors.lastname: Murck
mesh_terms: D000818:Animals; D003863:Depression / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D008274:Magnesium / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013569:Synapses / Q000378:metabolism
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007649:Ketamine; D008274:Magnesium; D016194:Receptors, N-Methyl-D-Aspartate; D017367:Selective Serotonin Reuptake Inhibitors
keywords: CP-AMPA; NMDA; SNRI; SSRI; depression; glutamate antagonist; glutamine; ketamine; magnesium; scopolamine