A randomized add-on trial of high-dose d-cycloserine for treatment-resistant depression
Open accessAbstract
Antagonism of N-methyl-d-aspartate glutamatergic receptors (NMDAR) may represent an effective antidepressant mechanism. d-cycloserine (DCS) is a partial agonist at the NMDAR-associated glycine modulatory site that at high doses acts as a functional NMDAR antagonist. Twenty-six treatment-resistant major depressive disorder patients participated in a double blind, placebo-controlled, 6-wk parallel group trial with a gradually titrated high dose (1000 mg/d) of DCS added to their antidepressant medication. DCS treatment was well tolerated, had no psychotomimetic effects and led to improvement in depression symptoms as measured by Hamilton Depression Rating Scale (HAMD; p = 0.005) and Beck Depression Inventory (p = 0.046). Of the 13 subjects treated with DCS, 54% had a ⩾50% HAMD score reduction vs. 15% of the 13 patients randomized to placebo (p = 0.039). A significant (p = 0.043) treatment× pre-treatment glycine serum levels interaction was registered. These findings indicate that NMDAR glycine site antagonism may be a cost-effective target for development of mechanistically novel antidepressants. Larger-sized DCS trials are warranted.
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In a larger (n = 26) RCT, high-dose DCS augmentation showed superior AD efficacy to placebo.
“The same group of researchers later conducted a larger (n = 26) RCT, in which high-dose DCS augmentation showed superior AD efficacy to placebo [171].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [171]
Partial agonists at the NMDAR glycineB binding site, including GLYX-13 and D-cycloserine, manifest antidepressant effects in clinical trials and animal tests without sharing ketamine's NMDAR inhibition-mediated side effects.
“Another finding challenging the NMDAR inhibition hypothesis of ketamine’s antidepressant mechanism of action is the fact that partial agonists at the NMDAR glycineB binding site, including GLYX-13 (i.e., rapastinel) and D-cycloserine manifest antidepressant effects in clinical trials 104, 105 and in animal tests 106–109, without sharing ketamine’s NMDAR inhibition-mediated side effects 109.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [104]
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“The same group of researchers later conducted a larger ( n = 26) RCT, in which high-dose DCS augmentation showed superior AD efficacy to placebo [171].”
BackgroundCarter, B., Strawbridge, R., Husain, M. I., Jones, B. D. M., Short, R., Cleare, A. J., Tsapekos, D., Patrick, F., Marwood, L., Taylor, R. W., et al. (2020) · International Review of Psychiatry · doi:10.1080/09540261.2020.1765748 · Cited by 47 · see citing works
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“A double-blind RCT showed the antagonist of glutamatergic NMDA receptor D-cycloserine effective against depressive symptoms in patients with treatment-resistant MDD, reinforcing a role of the glutamatergic system as an important target for depression treatment [107].”
BackgroundIntrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review
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All roads lead to glutamate: NMDA and AMPA receptors as targets for rapid-acting antidepressants
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- Authors
- Heresco-Levy, U., Gelfin, G., Bloch, B., Levin, R., Edelman, S., Javitt, D. C., & Kremer, I.
- Affiliations
- Psychiatry Department, Ezrath-Nashim Herzog Memorial Hospital, Jerusalem, Israel
- Hebrew University of Jerusalem (IL)
- Technion – Israel Institute of Technology (IL)
- Herzog Hospital (IL)
- Columbia University (US)
- Venue
- International Journal of Neuropsychopharmacology
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04-01
- Volume
- 16
- Issue
- 3
- Pages
- 501-506
- ISSN
- 1461-1457 (ISSN-L)
- 1469-5111
- OpenAlex
- W2146645762
- Cited by
- 177
- References
- 4
- Citations by year
- 2026: 5 · 2025: 16 · 2024: 8 · 2023: 12 · 2022: 10 · 2021: 12 · 2020: 12 · 2019: 17 · 2018: 12 · 2017: 14 · 2016: 11 · 2015: 23 · 2014: 14 · 2013: 11
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The International Journal of Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Alliance for Research on Schizophrenia and Depression
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- D-cycloserine, treatment-resistant depression, major depressive disorder, NMDA receptor antagonism, antidepressant mechanism, newer antidepressants
- MeSH terms
- Adult, Aged, Antidepressive Agents, Cycloserine, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Drug Resistance, Drug Therapy, Combination, Humans, Male, Middle Aged, Treatment Outcome
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