Glutamatergic mechanisms of psychosis and target engagement

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PROJECT SUMMARY/ABSTRACT: Schizophrenia (Sz) is associated with psychotic symptoms that remain partially or fully refractory to standard antipsychotic medications for most patients. All marketed antipsychotics primarily work through blocking dopamine D2 receptors. Despite robust effectiveness in preclinical models, alternative, glutamatergic approaches for treatment development have not yet led to FDA approved medications. A major barrier to effective glutamatergic treatment development is the absence of validated measures for functional target engagement that can identify effective compounds and guide dose selection. The present project seeks to refine ketamine-induced pharmacoBOLD (phBOLD) as target engagement biomarker for development of metabotropic glutamate (mGluR2/3) agonists. The combination of aims will permit future studies using phBOLD to identify potential candidates for glutamate-based interventions, permit target engagement studies within Sz and explore the mechanisms of dopamine and glutamate in psychosis. As part of the recently completed NIMH multicenter FAST-PS initiative, we have evaluated ketamine-induced phBOLD in healthy volunteers (HV). In an initial HV study, we demonstrated that ketamine induces a robust, highly significant increase in phBOLD response. More recently, using this assay we have demonstrated that the dose of an mGluR2/3 agonist (POMA) used in the prior clinical studies (80 mg) did not lead to significant inhibition of ketamine-induced phBOLD or symptomatic response in HV, suggesting that prior negative clinical results may have resulted from inadequate dosing. By contrast, at doses ~4x higher than those used in the negative clinical trials, evidence of behavioral target engagement was observed, underscoring the need for in vivo clinical biomarkers. In parallel studies of of a more recently developed mGluR2/3 agonist (TS-134), we demonstrated showed evidence of both behavioral ( and phBOLD pre-post target engagement. In addition, TS- 134 suppressed ketamine induced phBOLD known to be integral for dopaminergic function. Aims of the present project are as follows. Under Aim 1, we will titrate the ketamine dose downward in HV in order to identify doses that produce reduced psychotomimetic effects, but nevertheless sufficiently robust (d=1.5) phBOLD effects to permit detection of mGluR2/3 agonist effect. We will then evaluate the degree to which still-lower doses of ketamine nevertheless produce sufficient phBOLD response (d=1.5) to enable target engagement testing in Sz patients. Finally, we will evaluate the relative sensitivity of different doses of ketamine to TS-134 in HV in order to determine optimal target effect sizes for future target engagement studies in Sz. In parallel, we evaluate the sensitivity of the dopamine system to NMDAR antagonism, along with the relationship of ketamine phBOLD, 1H MRS and a proxy measure of dopamine synthesis capacity using neuromelanin.