Randomized, Double-Blind, Placebo-Controlled Trial of the mGlu2/3 Negative Allosteric Modulator Decoglurant in Partially Refractory Major Depressive Disorder
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OBJECTIVE: To assess putative antidepressant and procognitive effects of decoglurant, a selective metabotropic glutamate receptor type 2/3 (mGlu2/3) negative allosteric modulator, as adjunctive treatment to selective serotonin reuptake inhibitors and/or serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs) in patients with partially refractory major depressive disorder (MDD), diagnosed using DSM-IV-TR criteria. METHODS: This randomized, placebo-controlled, double-blind, multicenter phase 2 trial consisted of 4 weeks' screening, 6 weeks' treatment, and 8 weeks' follow-up between September 2011 and June 2014. Individuals with Montgomery-Åsberg Depression Rating Scale (MADRS) score ≥ 25 and Clinical Global Impressions-Severity of Illness scale score ≥ 4, despite up to 2 adequate trials of an SSRI/SNRI and compliance confirmed by positive SSRI/SNRI blood levels, were randomized to decoglurant 5 mg (n = 101), 15 mg (n = 102), or 30 mg (n = 55) daily or placebo (n = 99) as adjunct to ongoing treatment with 1 SSRI/SNRI. An adaptive design was used with an interim analysis after 30 patients in each group had received 6 weeks' treatment. The primary outcome variable was change in MADRS total score from baseline to end of treatment. Primary assessments were performed by fully blinded centralized raters. RESULTS: Of 357 participants, 310 completed 6 weeks' treatment. At 6 weeks, no significant differences between any active treatment arm and placebo in reducing MADRS total score or response or remission rates were observed. Decoglurant exerted no significant effects on Cambridge Neuropsychological Test Automated Battery cognitive accuracy and cognitive speed composite scores or on secondary measures of mood and functioning. A relatively high placebo response was observed, which may have constrained the ability to detect treatment effects. No deaths occurred; few patients reported serious adverse events. CONCLUSIONS: Decoglurant was well tolerated overall but did not exert any antidepressant or procognitive effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01457677.
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RO4995819 (decoglurant), an mGluR2/3 NAM, completed Phase 1 and a Phase 2 trial in partially refractory MDD, but no significant differences were observed between decoglurant and placebo.
“RO4995819 (decoglurant), an mGluR2/3 NAM, has also completed Phase 1 clinical trials and a Phase 2 trial in partially refractory MDD, but no significant differences were observed between decoglurant and placebo [195]”
From Ketamine in neuropsychiatric disorders: an update (2024) · cites this paper as [195]
At 6 weeks, decreases in MADRS scores were noted from baseline with decoglurant but without reaching statistical significance when compared to the placebo group, failing the primary endpoint, and for the secondary endpoints, mood and functioning and cognitive impairment, it also failed to separate from the placebo group.
“At 6 weeks, decreases in MADRS scores were noted from baseline, but without reaching statistical significance when compared to the placebo group, failing the primary endpoint, and, for the secondary endpoints, mood and functioning and cognitive impairment, it has also failed in separate from the placebo group.”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [140]
Decoglurant (Roche), an mGlu2/3 antagonist receptor, was tested in a large clinical trial (n = 370) where the primary objective was to access antidepressive and procognitive effects of the compound versus placebo as an adjunctive therapy to SSRI/SNRI therapy in individuals with TRD.
“Decoglurant (Roche), an mGlu2/3 antagonist receptor, was tested in a large clinical trial (n = 370), where the primary objective was to access antidepressive and procongnitive of the compound versus placebo as an adjunctive therapy to SSRI/SNRI therapy in individuals with TRD [140].”
From Pharmacotherapies Targeting GABA-Glutamate Neurotransmission for Treatment-Resistant Depression (2023) · cites this paper as [140]
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- Authors
- Umbricht, D., Niggli, M., Sanwald-Ducray, P., Deptula, D., Moore, R., Grünbauer, W., Boak, L., & Fontoura, P.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Umbricht, Daniel
- Venue
- The Journal of Clinical Psychiatry
- Publisher
- Physicians Postgraduate Press, Inc
- Published
- 2020-07-14
- Volume
- 81
- Issue
- 4
- ISSN
- 0160-6689 (ISSN-L)
- 1555-2101
- OpenAlex
- W3043046802
- Cited by
- 39
- References
- 0
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 3 · 2023: 9 · 2022: 12 · 2021: 6 · 2020: 3
- FWCI
- 4.50
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Funders
- F. Hoffmann-La Roche
- Topics
- Health Sciences › Medicine › Pharmacology › 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
- mGluR2/3, negative allosteric modulators, major depressive disorder, treatment-resistant depression, adjunctive antidepressant therapy, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, procognitive effects, cognitive speed, placebo response, antidepressant efficacy
- MeSH terms
- Adult, Allosteric Regulation, Antidepressive Agents, Depressive Disorder, Major, Major Depressive Disorder, Double-Blind Method, Drug Therapy, Combination, Female, Humans, Male, Middle Aged, Treatment Outcome, Excitatory Amino Acid Antagonists, Depressive Disorder, Treatment-Resistant
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