New paradigms for treatment-resistant depression

Ann N Y Acad Sci. 2013 Jul;1292:21-31. doi: 10.1111/nyas.12223.

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.

Keywords: CP-AMPA; NMDA; SNRI; SSRI; depression; glutamate antagonist; glutamine; ketamine; magnesium; scopolamine.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Depression* / drug therapy
  • Depression* / metabolism
  • Depression* / physiopathology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Humans
  • Ketamine / therapeutic use*
  • Magnesium / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Serotonin Uptake Inhibitors / therapeutic use
  • Synapses / metabolism

Substances

  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Serotonin Uptake Inhibitors
  • Ketamine
  • Magnesium