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
Open Access
- 30 September 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Neuropsychopharmacology
- Vol. 45 (11), 1842-1850
- https://doi.org/10.1038/s41386-020-0706-z
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.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I), FAST-PS contract (HHSN271201200007I))
- Taisho Toyama Pharmaceutical Company (Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc, Taisho Pharmaceutical R&D Inc)
This publication has 71 references indexed in Scilit:
- Decreased striatal dopamine in group II metabotropic glutamate receptor (mGlu2/mGlu3) double knockout miceBMC Neuroscience, 2013
- Clinical development of pomaglumetad methionil: A non-dopaminergic treatment for schizophreniaNeuropharmacology, 2013
- 1H-[13C]-Nuclear Magnetic Resonance Spectroscopy Measures of Ketamine's Effect on Amino Acid Neurotransmitter MetabolismBiological Psychiatry, 2012
- Xanomeline Modulation of the Blood Oxygenation Level-Dependent Signal in Awake Rats: Development of Pharmacological Magnetic Resonance Imaging as a Translatable Pharmacodynamic Biomarker for Central Activity and Dose SelectionThe Journal of pharmacology and experimental therapeutics, 2012
- 13C MRS studies of neuroenergetics and neurotransmitter cycling in humansNMR in Biomedicine, 2011
- A Multicenter, Inpatient, Phase 2, Double-Blind, Placebo-Controlled Dose-Ranging Study of LY2140023 Monohydrate in Patients With DSM-IV SchizophreniaJournal of Clinical Psychopharmacology, 2011
- Selective potentiation of the metabotropic glutamate receptor subtype 2 blocks phencyclidine-induced hyperlocomotion and brain activationNeuroscience, 2010
- Influence of heart rate on the BOLD signal: The cardiac response functionNeuroImage, 2009
- Effectiveness of antipsychotic drugs in first-episode schizophrenia and schizophreniform disorder: an open randomised clinical trialThe Lancet, 2008
- Preservation of baroreflex control of vascular resistance under ketamine anesthesia in ratsJournal of Anesthesia, 1988