This UO1 application is a response to the NIMH Program Announcement intended to accelerate the development of a high priority therapeutic agent by establishing its dose-related pharmacodynamic effects on biomarkers designed to inform subse- quent clinical development. Dopamine D1 receptor (D1R) agonism is among the most highly prioritized adjunctive treatment mechanisms for schizophrenia. Currently, all D1R agonists are also D5R agonists. D1R/D5R agonists have pro-cognitive and antipsychotic-like effects in preclinical studies, reflecting their ability to stabilize prefrontal cortical network activity in the face of distractors, and to enhance the precision of spatial working memory (sWM) by enhancing inhibitory tuning of prefrontal cortical (PFC) functional connectivity (FC). Yet, dose-related benefits of D1R/D5R agonism in patients could not be demonstrated in prior pilot studies. This application proposes that the testing of D1R/D5R agonists requires both a more direct translational/computational neuroscience framework (i.e., the most appropriate biomarkers) and a precision medicine strategy (i.e., the appropriate subpopulation of patients). To accelerate the selection of an optimal dose, we propose a multi- center study that densely maps the dose-related effects of the D1R/D5R partial agonist, PF-06412562 immediate release (IR), on three informative translational functional neuroimaging (fMRI) biomarkers as primary outcome measures: i) sWM-related activation; ii) task-based FC; and iii) resting-state FC in early course schizophrenia patients. Primary Aim 1 will apply a mul- tivariate analytic strategy to these three outcome measures (sWM-related activation, task-based FC and resting-state FC) to test if PF-06412562 produces a dose-related effect. This multivariate translational neural marker is designed and powered to inform a clear Go/No-Go decision with regards to proceeding to a full-scale clinical trial. A Go decision will be indicated if there is a significant dose-related drug effect on the neural signal measured via the multivariate combination of task-evoked activation and FC during the sWM task and FC during rest. Conversely, a No-Go decision will be reached if there is an absence of a dose-related effect on the multivariate index. Secondary Aim 2 will quantify dose-related drug effects on sWM precision based on behavioral data collected during fMRI. Exploratory Aim 3 will model the biophysical properties of PF- 06412562 in a cortical circuit model capable of sWM simulations, which will simulate hypothesized molecular mechanisms governing pro-cognitive PF-06412562 effects on sWM. In turn, we will will test if the dose-related pattern of PF-06412562 effects on resting FC in patients maps onto D1R and D5R receptor transcriptomic profiles in humans derived from from Allen Human Brain Atlas. Finally, Exploratory Aim 4 will study potential clinical predictors and moderators of PF-06412562 ef- fects on neuroimaging biomarkers. Collectively, this translational biomarker study informs the highest priority experimental treatment mechanism identified by the NIMH MATRICS Initiative using a precision medicine strategy that targets a specific subpopulation of early course schizophrenia patients who may pro-cognitively respond to D1R/D5R agonism.
D1 receptor (D1R) agonism is the highest priority experimental treatment mechanism identified by the NIMH MATRICS Initiative remaining to be rigorously tested. Here, we propose the first test in schizophrenia patients of the dose-related effects of a D1R/D5R partial agonist, PF-06412562, on neuroimaging biomarkers selected on the basis of a translational and computational neuroscience understanding of the role of D1R/D5Rs in cortical systems. Furthermore, we are testing this drug using a precision medicine strategy that targets a subpopulation of early course schizophrenia patients with spatial working memory deficits that might respond to D1R/D5R agonism.
