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.
Highlights
All current FDA-approved drug treatments for schizophrenia act by antagonizing dopamine at the D2 receptors
We previously reported the results of biomarker validation studies using ketamine-induced changes in resting BOLD fMRI response and 1H-MRS glutamate+glutamine peak for their utility as biomarkers for subsequent target engagement studies [13]
In a post hoc analysis, we examined POMA and TS-134 effects on dorsal anterior cingulate cortex (dACC) pharmacoBOLD response to ketamine controlling for heart rate and found that low-dose TS-134 exerted a moderate effect on dACC pharmacoBOLD within (d = −0.41) and between-groups (d = −0.47)
Summary
All current FDA-approved drug treatments for schizophrenia act by antagonizing dopamine at the D2 receptors. While they often reduce psychotic symptoms and prevent their recurrence [1, 2], they have significant limitations in their efficacy and cause extensive side effects [3,4,5,6]. While PET remains the gold-standard technology by which to measure target engagement [12], there are very few radioligands that have been developed for glutamate receptors. Other biomarkers, such as EEG or fMRI, are informative, but provide less direct, functional measures of target engagement
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