The DOI matches its Crossref record; 186 of the 187 references it cites were found in a registry or an index.
Glutamatergic Neurotransmission: Pathway to Developing Novel Rapid-Acting Antidepressant Treatments
Open accessAbstract
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, α-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.
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“Broadly, these agents demonstrated no significant antidepressant efficacy and an adverse events profile that led to the early terminations of some clinical trials in indications such as MDD, TRD, and Parkinson's disease [169,170]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [170]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“NR2B-specific subunit antagonists such as traxoprodil (CP-101,606), MK-0657 (CERC-301), and eliprodil (EVT-101) were developed but suffered similar failures.”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [170]
Experimental — accuracy not yet measuredIn the citing paper
“Nuedexta is FDA-approved for pseudobulbar affect treatment, and alternative formulations designed to increase DM’s bioavailability without the risk of quinidine toxicity are under investigation [144].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
In the citing paper
“In all reports, initial efficacy was either transient or inconsistent in larger studies [97,103,144,145,146].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
In the citing paper
“In TRD, AD efficacy was seen in early open-label studies but not replicated by more rigorous clinical trials [144,179], (see Table 1).”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
In the citing paper
“Riluzole promotes post-synaptic GABAA receptor allosteric modulation and reduces glutamatergic activity via direct NMDA and kainate receptor inhibition, blockade of tetrodotoxin (TTX)-sensitive sodium channels, and simultaneous reuptake acceleration and inhibition of release [144].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
In the citing paper
“Riluzole also increases glutamate–glutamine cycling, a potential explanation for in vitro observations of enhanced neuroplasticity and amelioration of excitotoxicity [176,177], as well as in vivo reductions in depressive behaviors [144,178].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
In the citing paper
“According to meta-analysis findings, riluzole augmentation and monotherapy both demonstrate sustained antidepressant and anxiolytic efficacy for depressive disorders [144,179].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [144]
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Citations
Cites
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Self-citationTHE CATECHOLAMINE HYPOTHESIS OF AFFECTIVE DISORDERS: A REVIEW OF SUPPORTING EVIDENCE
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mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists
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Flagged first, then by citations
1 of the 187 references couldn’t be matched to a known paper.
Research works printed but not linked: 3
- Insel TR, 2014, Director’s Blog: Ketamine
- Paterson, 2015, A randomized, double- blind, placebo-controlled, sequential parallel study of CERC-301 in the adjunctive treatment of subjects with severe depression and recent active suicidal ideation despite antidepressant treatment
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Cited by
Sorted by citations
Prognosis and improved outcomes in major depression: a review
Kraus, C., Kadriu, B., Lanzenberger, R., Zarate, C. A., & Kasper, S. (2019) · Translational Psychiatry · doi:10.1038/s41398-019-0460-3 · Cited by 482
Self-citationBahji, A., Vazquez, G. H., & Zarate, C. A. (2021) · Journal of Affective Disorders · doi:10.1016/j.jad.2020.09.071 · Cited by 408
Self-citationMajor Depressive Disorder: Advances in Neuroscience Research and Translational Applications
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Self-citation
Metadata
- Authors
- Kadriu, B., Musazzi, L., Henter, I. D., Graves, M., Popoli, M., & Zarate, C. A.
- Affiliations
- National Institutes of Health (US)
- University of Milan (IT)
- Corresponding author
- Kadriu, Bashkim
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2018-11-16
- Volume
- 22
- Issue
- 2
- Pages
- 119-135
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- PMC
- PMC6368372
- OpenAlex
- W2900937351
- Cited by
- 165
- References
- 187
- Citations by year
- 2026: 10 · 2025: 14 · 2024: 16 · 2023: 21 · 2022: 31 · 2021: 24 · 2020: 29 · 2019: 19 · 2018: 1
- FWCI
- 2.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion, public-domain)
- Europe PMC (PubMed Central) (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
- BOA (University of Milano-Bicocca) (submittedVersion)
- Funders
- National Institute of Mental Health
- National Institutes of Health (IRP-NIMH-NIH, ZIA MH002857)
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- glutamatergic neurotransmission, ketamine, treatment-resistant depression, major depressive disorder, bipolar depression, NMDA receptor antagonists, AMPA receptor potentiation, GABAergic interneurons, rapid-acting antidepressants, antidepressant mechanism
- MeSH terms
- Antidepressive Agents, Humans, Ketamine, Receptors, N-Methyl-D-Aspartate, Excitatory Amino Acid Antagonists, Depressive Disorder, Treatment-Resistant
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