Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status

The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction...

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Vydáno v:	CNS drugs Ročník 35; číslo 5; s. 527 - 543
Hlavní autoři:	Henter, Ioline D., Park, Lawrence T., Zarate, Carlos A.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Cham Springer International Publishing 01.05.2021 Springer Nature B.V
Témata:	Alzheimer's disease Animals Antidepressants Antidepressive Agents - pharmacology Antidepressive Agents - therapeutic use Bipolar disorder Bipolar Disorder - drug therapy Bipolar Disorder - physiopathology Brain-derived neurotrophic factor Cycloserine Depressive Disorder, Major - drug therapy Depressive Disorder, Major - physiopathology Developmental stages Dextromethorphan Emotional disorders Excitatory Amino Acid Agents - pharmacology Excitatory Amino Acid Agents - therapeutic use Glutamatergic transmission Glutamic Acid - metabolism Glutamic acid receptors Glutamic acid receptors (ionotropic) Glutamic acid receptors (metabotropic) Glycine Humans Ketamine Kinases Medicine Medicine & Public Health Mental depression Mental disorders Mood Mood disorders Mood Disorders - drug therapy Mood Disorders - physiopathology N-Methyl-D-aspartic acid receptors Neurology Neurosciences Nitrous oxide Pathophysiology Pharmacotherapy Psychiatry Psychopharmacology Quinidine Rapamycin Receptors, Glutamate - drug effects Receptors, Glutamate - metabolism Review Article Sarcosine TOR protein United States > US
ISSN:	1172-7047, 1179-1934, 1179-1934
On-line přístup:	Získat plný text
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Shrnutí:	The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic ( R,S )-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators (( R,S )-ketamine, esketamine, ( R )-ketamine, (2 R ,6 R )-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators ( d -cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N -methyl- d -aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with ( R,S )-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 ObjectType-Review-3 content type line 23 Authors’ contributions All authors contributed equally to the literature search, generation of the table and figure, writing, and revision of this manuscript. All authors approved the final version of the paper.
ISSN:	1172-7047 1179-1934 1179-1934
DOI:	10.1007/s40263-021-00816-x