A randomized trial of a low-trapping nonselective N-methyl-D-aspartate channel blocker in major depression
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Background The high-affinity N-methyl-D-aspartate (NMDA) antagonist ketamine exerts rapid antidepressant effects but has psychotomimetic properties. AZD6765 is a low-trapping NMDA channel blocker with low rates of associated psychotomimetic effects. This study investigated whether AZD6765 could produce rapid antidepressant effects in subjects with treatment-resistant major depressive disorder (MDD).Methods In this double-blind, randomized, crossover, placebo-controlled study, 22 subjects with DSM-IV treatment-resistant MDD received a single infusion of either AZD6765 (150 mg) or placebo on 2 test days 1 week apart. The primary outcome measure was the Montgomery-Åsberg Depression Rating Scale, which was used to rate overall depressive symptoms at baseline and 60, 80, 110, and 230 min postinfusion and on Days 1, 2, 3, and 7 postinfusion. Several secondary outcome measures were also used, including the Hamilton Depression Rating Scale.Results Within 80 min, Montgomery-Åsberg Depression Rating Scale scores significantly improved in subjects receiving AZD6765 compared with placebo; this improvement remained significant only through 110 min (d = .40). On the Hamilton Depression Rating Scale, a drug difference was found at 80 and 110 min and at Day 2 (d = .49). Overall, 32% of subjects responded to AZD6765, and 15% responded to placebo at some point during the trial. No difference was observed between the groups with regard to psychotomimetic or dissociative adverse effects.Conclusions In patients with treatment-resistant MDD, a single intravenous dose of the low-trapping NMDA channel blocker AZD6765 was associated with rapid but short-lived antidepressant effects; no psychotomimetic effects were observed.
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Lanicemine 150 mg IV transiently improved MADRS scores at 80 and 110 minutes after treatment in unmedicated patients with major depression.
“However, another NMDAR channel blocker AZD6765 (lanicemine, 150 mg i.v.), transiently improved MADRS scores at 80- and 110-minutes post-treatment in patients with major depression that were otherwise unmedicated”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Zarate et al., 2013
Lanicemine initially demonstrated rapid-acting antidepressant effects in patients with TRD.
“Lanicemine (AZD6765) initially demonstrated rapid-acting antidepressant effects in patients with TRD [165, 166]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [165]
Other exploratory antidepressant compounds that exemplify NMDAR antagonism without ketamine's associated psychotomimetic and dissociative properties include memantine, lanicemine, and CERC 301.
“Other exploratory AD compounds that exemplify NMDAR antagonism without ketamine’s associated psychotomimetic and dissociative properties include memantine [131], lanicemine [142], and CERC 301 [143].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [142]
The NMDA receptor antagonist AZD6765, or lanicemine, exerts rapid but short-lived antidepressant effects in clinical trials without evidence of eliciting psychotomimetic effects.
“Similar to ketamine, the NMDA receptor antagonist AZD6765, or lanicemine (AstraZeneca), a blocking molecule that is trapped inside the NMDA channel pore, exerts rapid, but short-lived, antidepressant effects in clinical trials without evidence of eliciting psychotomimetic effects (Zarate Jr. et al., 2013).”
From Novel pharmacological targets in drug development for the treatment of anxiety and anxiety-related disorders (2019) · cites this paper as Zarate Jr. et al., 2013
A single intravenous administration of AZD6765 exerted transient (~110 min) antidepressant responses in major depressed patients, which were not maintained.
“In addition, a single intravenous administration of AZD6765 (i.e., lanicemine), a low-trapping non-selective NMADR channel blocker, exerted transient (~110 min) antidepressant responses in major depressed patients, which were not maintained 100.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [100]
Alternative NMDAR channel-blocking antagonists may exert clinical antidepressant actions, but such actions are not of the same time frame or magnitude as those exerted by ketamine.
“This literature leads to the conclusion that while alternative NMDAR channel-blocking antagonists may exert clinical antidepressant actions, such actions are not of the same time frame or magnitude as those exerted by ketamine.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [100]
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- Authors
- Zarate, C. A., Mathews, D., Ibrahim, L., Chaves, J. F., Marquardt, C., Ukoh, I., Jolkovsky, L., Brutsche, N. E., Smith, M. A., & Luckenbaugh, D. A.
- Affiliations
- National Institutes of Health (US)
- AstraZeneca (United States) (US)
- Corresponding author
- Zarate, Carlos A.
- Venue
- Biological Psychiatry
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 74
- Issue
- 4
- Pages
- 257-264
- ISSN
- 0006-3223 (ISSN-L)
- PMC
- PMC3594049
- OpenAlex
- W2121117021
- Cited by
- 255
- References
- 46
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 29 · 2023: 10 · 2022: 14 · 2021: 15 · 2020: 18 · 2019: 18 · 2018: 16 · 2017: 15 · 2016: 16 · 2015: 34 · 2014: 31 · 2013: 30
- FWCI
- 22.35
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Biological Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute of Mental Health (ZIAMH002857, ZIAMH002927)
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Health Sciences › Medicine › Psychiatry and Mental health › Electroconvulsive Therapy Studies
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- NMDA receptor antagonists, major depressive disorder, treatment-resistant depression, rapid antidepressant effects, psychotomimetic effects, antidepressant response
- MeSH terms
- Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Female, Humans, Male, Middle Aged, Phenethylamines, Pyridines, Receptors, N-Methyl-D-Aspartate, Excitatory Amino Acid Antagonists
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