The underlying neurobiological basis of major depressive disorder remains elusive due to the severity, complexity, and heterogeneity of the disorder. While the traditional monoaminergic hypothesis has largely fallen short in its ability to provide a complete picture of major depressive disorder, emerging preclinical and clinical findings suggest that dysfunctional glutamatergic neurotransmission may underlie the pathophysiology of both major depressive disorder and bipolar depression. In particular, recent studies showing that a single intravenous infusion of the glutamatergic modulator ketamine elicits fast acting, robust, and relatively sustained antidepressant, antisuicidal, and antianhedonic effects in individuals with treatment resistant depression have prompted tremendous interest in understanding the mechanisms responsible for ketamine's clinical efficacy. These results, coupled with new evidence of the mechanistic processes underlying ketamine's effects, have led to inventive ways of investigating, repurposing, and expanding research into novel glutamate-based therapeutic targets with superior antidepressant effects but devoid of dissociative side effects. Ketamine's targets include noncompetitive N-methyl-D-aspartate receptor inhibition, alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid throughput potentiation coupled with downstream signaling changes, and N-methyl-D-aspartate receptor targets localized on gamma-aminobutyric acid-ergic interneurons. Here, we review ketamine and other potentially novel glutamate-based treatments for treatment resistant depression, including N-methyl-D-aspartate receptor antagonists, glycine binding site ligands, metabotropic glutamate receptor modulators, and other glutamatergic modulators. Both the putative mechanisms of action of these agents and clinically relevant studies are described.
Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments / B. Kadriu, L. Musazzi, I. Henter, M. Graves, M. Popoli, J. Zarate CA. - In: INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY. - ISSN 1461-1457. - 22:2(2019 Feb), pp. 119-135.
|Titolo:||Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments|
MUSAZZI, LAURA (Secondo)
POPOLI, MAURIZIO (Penultimo)
|Parole Chiave:||antidepressants; glutamate receptors; ketamine; treatment-resistant depression|
|Settore Scientifico Disciplinare:||Settore BIO/14 - Farmacologia|
Settore BIO/13 - Biologia Applicata
|Progetto:||Risposte maladattative dello stress: studio dei meccanismi che le regolano per identificare nuovi bersagli terapeutici nelle malattie neuropsichiatriche.|
microRNA regulation of synaptic BDNF in the effects of ketamine on dendritic arborization and depressive-like behaviour
|Data di pubblicazione:||feb-2019|
|Data ahead of print / Data di stampa:||18-nov-2018|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.1093/ijnp/pyy094|
|Appare nelle tipologie:||01 - Articolo su periodico|