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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 by Joshua T. Kantrowitz; Jack Grinband; Donald C. Goff; Adrienne C. Lahti; Stephen R. Marder; Lawrence S. Kegeles; Ragy R. Girgis; Tarek Sobeih; Melanie M. Wall; Tse-Hwei Choo; Michael F. Green; Yvonne S. Yang; Junghee Lee; Guillermo Horga; John H. Krystal; William Z. Potter; Daniel C. Javitt; Jeffrey A. Lieberman is a Neuroscience article available to read on EtoBox.

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## 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 wit

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Author

Joshua T. Kantrowitz; Jack Grinband; Donald C. Goff; Adrienne C. Lahti; Stephen R. Marder; Lawrence S. Kegeles; Ragy R. Girgis; Tarek Sobeih; Melanie M. Wall; Tse-Hwei Choo; Michael F. Green; Yvonne S. Yang; Junghee Lee; Guillermo Horga; John H. Krystal; William Z. Potter; Daniel C. Javitt; Jeffrey A. Lieberman

Publisher

Springer Science and Business Media LLC

Published

2020

Language

EN

Field

Neuroscience (Life Sciences)