Trial reportNeuropsychopharmacology : official publication of the American College of Neuropsychopharmacology2020
Proof of mechanism and target engagement of glutamatergic drugs for the treatment of schizophrenia: RCTs of pomaglumetad and TS-134 on ketamine-induced psychotic symptoms and pharmacoBOLD in healthy volunteers.
Trial report in Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
35 citing papers in PubMed, 52 citations in OpenAlex.
- Dose-Dependent Augmentation of Neuroplasticity-Based Auditory Learning in Schizophrenia: A Double-Blind, Placebo-Controlled, Randomized, Target Engagement Clinical Trial of the NMDA Glutamate Receptor Agonist d-serine.Biological psychiatry · 2023Trial
- Effect of mGluR2 positive allosteric modulation on frontostriatal working memory activation in schizophrenia.Molecular psychiatry · 2022Trial
- Mismatch negativity as an index of target engagement for excitation/inhibition-based treatment development: a double-blind, placebo-controlled, randomized, single-dose cross-over study of the serotonin type-3 receptor antagonist CVN058.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2022Trial
- Towards precision psychiatry: initial foundations and future directions.Nature reviews. Drug discovery · 2026Review
- Review
- Psychiatric genome-wide association study enrichment shows promise for future psychopharmaceutical discoveries.Communications medicine · 2025Article
- Glutamate-Based Therapeutic Strategies for Schizophrenia: Emerging Approaches Beyond Dopamine.International journal of molecular sciences · 2025Review
- Negative Symptoms in Schizophrenia: An Update on Research Assessment and the Current and Upcoming Treatment Landscape.CNS drugs · 2025Review
- Corticolimbic circuitry as a druggable target in schizophrenia spectrum disorders: a narrative review.Translational psychiatry · 2025Review
- Finding the Right Dose: NMDA Receptor-Modulating Treatments for Cognitive and Plasticity Deficits in Schizophrenia and the Role of Pharmacodynamic Target Engagement.Biological psychiatry · 2025Review
- Harnessing brain-derived extracellular vesicles to support RDoC-based drug development.Neuroscience applied · 2025Review
- Overview of Novel Antipsychotic Drugs: State of the Art, New Mechanisms, and Clinical Aspects of Promising Compounds.Biomedicines · 2025Review
- The excitatory-inhibitory balance as a target for the development of novel drugs to treat schizophrenia.Biochemical pharmacology · 2024Review
- Synaptic fidelity for drug development: is it time to move beyond glutamate release and receptors?Expert opinion on therapeutic targets · 2024Article
- Glutamatergic basis of antipsychotic response in first-episode psychosis: a dual voxel study of the anterior cingulate cortex.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2024Article
- Biomarker Methodologies: A NIMH Perspective.Advances in neurobiology · 2024Review
- New Developments in the Treatment of Schizophrenia: An Expert Roundtable.The international journal of neuropsychopharmacology · 2023Article
- Effects of the mGlu2/3 receptor agonist LY379268 on two models of disturbed auditory evoked brain oscillations in mice.Translational psychiatry · 2023Article
- Opposite Modulation of the NMDA Receptor by Glycine and S-Ketamine and the Effects on Resting State EEG Gamma Activity: New Insights into the Glutamate Hypothesis of Schizophrenia.International journal of molecular sciences · 2023Article
- Experimental Medicine Approaches in Early-Phase CNS Drug Development.Advances in neurobiology · 2023Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 1 country.
Funding
Abstract
Glutamate neurotransmission is a prioritized target for antipsychotic drug development. Two metabotropic glutamate receptor 2/3 (mGluR2/3) agonists (pomaglumetad [POMA] and TS-134) were assessed in two Phase Ib proof of mechanism studies of comparable designs and using identical clinical assessments and pharmacoBOLD methodology. POMA was examined in a randomized controlled trial under double-blind conditions for 10-days at doses of 80 or 320 mg/d POMA versus placebo (1:1:1 ratio). The TS-134 trial was a randomized, single-blind, 6-day study of 20 or 60 mg/d TS-134 versus placebo (5:5:2 ratio). Primary outcomes were ketamine-induced changes in pharmacoBOLD in the dorsal anterior cingulate cortex (dACC) and symptoms reflected on the Brief Psychiatric Rating Scale (BPRS). Both trials were conducted contemporaneously. 95 healthy volunteers were randomized to POMA and 63 to TS-134. High-dose POMA significantly reduced ketamine-induced BPRS total symptoms within and between-groups (p < 0.01, d = -0.41; p = 0.04, d = -0.44, respectively), but neither POMA dose significantly suppressed ketamine-induced dACC pharmacoBOLD. In contrast, low-dose TS-134 led to moderate to large within and between group reductions in both BPRS positive symptoms (p = 0.02, d = -0.36; p = 0.008, d = -0.82, respectively) and dACC pharmacoBOLD (p = 0.004, d = -0.56; p = 0.079, d = -0.50, respectively) using pooled across-study placebo data. High-dose POMA exerted significant effects on clinical symptoms, but not on target engagement, suggesting a higher dose may yet be needed, while the low dose of TS-134 showed evidence of symptom reduction and target engagement. These results support further investigation of mGluR2/3 and other glutamate-targeted treatments for schizophrenia.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.