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

https://www.nature.com/articles/s41386-020-0706-z

This is a study on pomaglumetad and a new-to-me drug called TS-134. The authors suggest that the reason for the failure of POMA in large trials could be that the tested dose was too low. The dose tested which showed efficacy on symptoms in this study was 320 mg vs 80mg in the Lilly study.

Higher doses had to be titrated up though, due to nausea and vomiting.

This study was on healthy volunteers given ketamine and then given a brain scan to determine target engagement, and assessment of psychiatric symptoms (using BPRS).

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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