Glutamatergic Mechanisms of Psychosis and Target Engagement (SA1)

Schizophrenia (Sz) is associated with psychotic symptoms, such as hearing voices and paranoid beliefs that remain partially or fully refractory to standard antipsychotic medications for \~2/3 of patients. Alternative, glutamatergic approaches for treatment development have been proposed but have not yet led to FDA-approved medications. Moreover, several glutamate-targeted medications, such as pomaglumetad (POMA), have failed in pivotal clinical trials despite robust effectiveness in preclinical models. A major barrier to effective glutamatergic treatment development is the absence of validated measures for target engagement that can identify effective compounds and guide dose selection. Target" refers to a factor that an intervention is intended to modify, leading to improvement in symptoms, and target engagement biomarkers are a measure of the ability of the intervention to "engage" the target. As part of the recently completed NIMH multicenter FAST-PS initiative (IRB protocol 6925 and 7285), we evaluated ketamine-induced pharmacoBOLD (phBOLD) in healthy volunteers (HV) as a potential target engagement biomarker for development of metabotropic glutamate (mGluR2/3) agonists, as a prelude to planned studies in Sz. BOLD imaging indirectly measures brain energy, as a proxy for glutamate target engagement. The present study will (1) build on these initial positive results to develop phBOLD for use in Sz, (2) optimize ketamine dosing to further increase sensitivity of the phBOLD approach, and (3) explore mechanisms of psychosis. The present study will enable a personalized medicine approach to target engagement and dose evaluation in Sz, while, in parallel, evaluating mechanisms in Sz. The structure of this grant requires successful completion of Specific Aim (SA) 1 over the first 18 months prior to initiation of SA2 and SA3. We will amend the PSF and consent to include a full description of SA's 2 and 3 prior to its initiation. In FAST-PS, we selected a high dose of ketamine (0.23 mg/kg) in order to produce robust pharmacological effects. Under SA1, we will titrate this dose downward in HV in order to identify doses that produce reduced psychotomimetic effects, but nevertheless sufficiently robust phBOLD effects. 50 HV will participate in 2 identical phBOLD sessions at least 7 days apart. In total, MRI scans will last approximately 45 minutes, including pre and post ketamine scan. The design is based on our published study(Javitt, Carter et al. 2018). On both days, clinical assessments will be performed following removal of the subject from the scanner. HV will be discharged home after clearance by the study physician. Although we expect all HV to tolerate ketamine challenge, in the case that a subject does not tolerate it well, we have the capability of admitting a HV subject to an inpatient unit for monitoring and treatment if necessary. SA1 will assign ketamine doses in successive 10 subject cohorts. The ketamine dose for the 1st cohort will start at 0.08 mg/kg. For subsequent cohorts, the bolus will be successively reduced or increased by 0.02 mg/kg (n=10/dose) to determine the lowest dose of ketamine that still produces a robust phBOLD response. The study will be subject and rater blind, i.e. subjects and raters, will be blinded to the treatment (ketamine dose) group. The study physician will be aware of the ketamine dose, and ketamine dose will be the same for both sessions. Subjects will not be told what the exact ketamine dose they will receive, but it will be based on their weight and will be no higher than 0.08 mg/kg.