Glutamate modulators as potential therapeutic drugs in schizophrenia and affective disorders.

Abstract

Severe psychiatric disorders such as schizophrenia are related to cognitive and negative symptoms, which often are resistant to current treatment approaches. The glutamatergic system has been implicated in the pathophysiology of schizophrenia and affective disorders. A key component is the dysfunction of the glutamatergic N-methyl-D-aspartate (NMDA) receptor. Substances regulating activation/inhibition of the NMDA receptor have been investigated in schizophrenia and major depression and are promising in therapeutic approaches of negative symptoms, cognition, and mood. In schizophrenia, add-on treatments with glycine, D-serine, D-alanine, D-cycloserine, D-amino acid oxidase inhibitors, glycine transporter-1 (GlyT-1) inhibitors (e.g., sarcosine, bitopertin) and agonists (e.g., LY2140023) or positive allosteric modulator (e.g., ADX71149) of group II metabotropic glutamate receptors (mGluRs) have been studied. In major depression, the NMDA receptor antagonists (e.g., ketamine, AZD6765), GluN2B subtype antagonists (e.g., traxoprodil, MK-0657), and partial agonists (e.g., D-cycloserine, GLYX-13) at the glycine site of the NMDA receptor have been proven to be effective in animal studies and first clinical trials. In addition, clinical studies of mGluR2/3 antagonist BCI-838 (a prodrug of BCI-632 (MGS0039)), mGluR2/3-negative allosteric modulators (NMAs) (e.g., RO499819, RO4432717), and mGluR5 NAMs (e.g., AZD2066, RO4917523) are in progress. Future investigations should include effects on brain structure and activation to elucidate neural mechanisms underlying efficacy of these drugs.

• Authors: Kenji Hashimoto, Berend Malchow, Peter Falkai, Andrea Schmitt
• Journal: European archives of psychiatry and clinical neuroscience (Eur Arch Psychiatry Clin Neurosci) Vol. 263 Issue 5 Pg. 367-77 (Aug 2013) ISSN: 1433-8491 [Electronic] Germany
• PMID: 23455590 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Excitatory Amino Acid Agents
• Glutamic Acid

Topics

• Excitatory Amino Acid Agents (therapeutic use)
• Glutamic Acid (metabolism)
• Humans
• Mood Disorders (drug therapy)
• Schizophrenia (drug therapy)