title: Pharmacological properties of glutamatergic drugs targeting NMDA receptors and their application in major depression.
abstract: BACKGROUND
  A growing body of evidence suggests that glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology of major depressive disorders. An imbalance in glutamatergic neurotransmission may contribute to increased levels of NMDA agonism, thereby enhancing excitatory activity in most brain circuits involved in major depression. Although NMDA receptor antagonists have been demonstrated to possess antidepressant-like activity, the molecular changes underlying abnormal glutamatergic signaling still remain poorly understood. Therefore, we aimed to review the current literature focusing on the main pharmacological properties and the impact of glutamatergic drugs targeting NMDA receptors in major depression.
  
  
  METHODS
  A detailed literature search in PubMed/Medline and ScienceDirect databases using the terms glutamate, depression and major depressive disorder has been performed.
  
  
  RESULTS
  Most drugs acting at glutamatergic receptors showed biochemical effects indicative of antidepressant activity in both clinical and preclinical studies. Recent neuroimaging and genetic contributions also confirm the antidepressant properties of these medications. However, human studies including NMDA receptor antagonists provided mixed results. In overall, glutamatergic receptor modulation may facilitate neuronal stem cell enhancement (neurogenesis) as well as the release of neurotransmitters associated with treatment response to depression in humans.
  
  
  CONCLUSIONS
  Cognitive side effects and psychotomimetic properties complicate the application and the development of clinically useful agents.
  
  
  CONCLUSIONS
  Glutamatergic system represents a target for effective intervention in major depression. Specifically, those glutamatergic medications targeting NMDA receptors by inhibiting the release of neurotransmitters or modulating its post-synaptic responses may serve as molecule modulators with specific antidepressant properties.
authors.affiliation: Department of Neurosciences, Mental Health and Sensory Organs-Suicide Prevention Center, Sant’Andrea Hospital, Rome, Italy. gianluca.serafini@uniroma1.it
authors.forename: Gianluca
authors.initials: G
authors.lastname: Serafini
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pompili
authors.forename: Marco
authors.initials: M
authors.lastname: Innamorati
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Dwivedi
authors.forename: Goutam
authors.initials: G
authors.lastname: Brahmachari
authors.forename: Paolo
authors.initials: P
authors.lastname: Girardi
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D005971:Glutamates / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D015398:Signal Transduction
chemical_list: D000928:Antidepressive Agents; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate