Glutamate modulators as novel interventions for mood disorders.
Recent evidence suggests that critical molecules in neurotrophic signaling cascades are long-term targets for currently available monoaminergic antidepressants. As chronic and severe mood disorders are characterized by impairments in neuronal resilience, pharmacological strategies that subserve a neuroprotective function might alter disorder pathophysiology and modify disease progression. Several promising approaches involve modulation of the glutamate neurotransmitter system, via post-synaptic receptor blockade or potentiation and presynaptic vesicular release inhibition. A focused review of the extant scientific literature was conducted, with a discussion of 3 compounds or classes of drugs currently undergoing clinical investigation: ketamine, riluzole, and AMPA receptor potentiators. Recent investigations in mood disordered patients suggest that the NMDA receptor antagonist ketamine might demonstrate rapid antidepressant properties. Riluzole has been shown to reverse glutamate-mediated impairments in neuronal plasticity and to stimulate the synthesis of brain derived neurotrophic factor. Open-label trials in treatment-resistant depression have yielded promising results. Likewise, AMPA receptor potentiators favorably impact neurotrophic factors as well as enhance cognition.


CONCLUSIONS
Pharmacological approaches that modulate components of the glutamate system offer novel targets for severe, recurrent mood disorders. Controlled studies are necessary.
Mathew
Sanjay J
SJ
Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. sanjay.mathew@mssm.edu
Keegan
Kathryn
K
Smith
Lisa
L
D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D006801:Humans; D007649:Ketamine / Q000627:therapeutic use*; D019964:Mood Disorders / Q000188:drug therapy*; D009434:Neural Pathways / Q000187:drug effects; D009473:Neuronal Plasticity / Q000187:drug effects; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D019782:Riluzole / Q000627:therapeutic use*; D009435:Synaptic Transmission / Q000187:drug effects
D000928:Antidepressive Agents; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D007649:Ketamine; D019782:Riluzole