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

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.

Relationship of Brain Glutamate Response to D-Cycloserine and Lurasidone to Antidepressant Response in Bipolar Depression: A Pilot Study

“…A reduced stress response is consistent with preclinical studies, indicating that NMDAR antagonist related antidepressant response may produce a resilience effect (49). Similarly, putative glutamatergic treatments in schizophrenia also appear to reduce NMDAR antagonist induced glutamate increases (50). Thus, we have previous proposed that elevated Glu or Glx may be a marker of depressive illness severity (51), and a reduction is an indicator of antidepressant response to NMDAR antagonists.…”

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

“…Further dose escalation studies may also be desirable as no signi cant safety concerns emerged even at the highest dose tested. In the FAST-FAIL approach [9][10][11][12][13][14][15], demonstration of target engagement, as in the present study, validates the compound, although it remains to be determined whether or not treatment through this mechanism (5-HT 3 R antagonism) will ultimately lead to clinical bene t.…”

“…Antipsychotics are the primary treatment for schizophrenia, but in addition to signi cant side effects [6,7], marketed antipsychotics have limited e cacy for neurocognitive de cits [8], indicating the need for alternative approaches. A key challenge in the development of novel treatments for schizophrenia is the need for target engagement biomarkers, which facilitate dose selection and initial proof-of-mechanism assessment [9][10][11][12][13][14][15]. Here, we evaluate the utility of auditory mismatch negativity (MMN) as a target engagement biomarker for development of serotonin type-3 receptor (5-HT 3 R) antagonists in the treatment of persistent neurocognitive impairments in schizophrenia.…”

Neuroimaging as a Window Into the Pathophysiological Mechanisms of Schizophrenia

“…Taken together, our findings from ketamine challenge studies lend empirical support to the putative link between NMDA receptor hypofunction, disruption in brain function and glutamate excess and provide a theoretical framework for the interpretation of abnormal brain signatures in schizophrenia in the context of NMDA receptor hypofunction. It is important to note that this type of framework can also be leveraged to test target engagement for putative novel pharmacological agents as recently demonstrated a multi-center proof of mechanism study of pomaglumetad ( 102 ), which will ideally translate into accelerated development of novel drugs.…”