PROJECT SUMMARY This is an application for an NIMH Mentored Patient-Oriented Research Career Development Award (K23) entitled "Neural Biomarkers of Clozapine Response." In this application, Dr. Deepak K. Sarpal, proposes a comprehensive plan for transitioning into an independent translational researcher focused on understanding the neural mechanisms of treatment response in psychotic disorders and integrating functional neuroimaging with clinical algorithms. A large number of patients with chronic psychotic disorders continue to have symptoms following unsuccessful trials with first-line antipsychotic drugs. For these patients with refractory psychosis, clozapine has consistently demonstrated superior efficacy. Clozapine is often underutilized and administered late in a patient's course of treatment, which leads to increased morbidity, unnecessary medication trials, and increased health care expenditure. Meanwhile, the mechanism of action underlying clozapine's novel effects remains unknown and has not been studied with modern neuroimaging methods. Identifying the neural mechanisms by which clozapine exerts its effects may lead to biomarkers that will facilitate efficient utilization of the drug, and introduce novel treatment targets. In patients with refractory psychotic symptoms, the proposed study will use resting-state and task-based functional MRI (fMRI) to examine the neural circuitry of efficacious treatment with a trial of clozapine. Patients will undergo fMRI scanning both before and after 12 weeks of treatment, with the aims of determining: baseline patterns of resting-state functional connectivity and task-based activation that predict response to treatment; and changes in resting-state and task-based functional circuitry associated with efficacious treatment. Results of this proposal may lead to biomarkers that will optimize treatment algorithms for psychotic disorders and facilitate drug development for refractory psychosis. While pursuing this line of research under the guidance of mentors who are recognized experts in translational studies in schizophrenia (Anil K. Malhotra, M.D., Todd Lencz, Ph.D.), clinical trials (John M. Kane, M.D.) and neuroimaging (Katherine H. Karlsgodt, Ph.D., Michael P. Milham, M.D., Ph.D.), Dr. Sarpal will engage in a comprehensive training program in neuropsychopharmacology, translational neuroimaging, and task-based fMRI methodology. He will also gain experience in executing and managing studies involving psychiatrically ill patients. The completion of the proposed Mentored Career Award will support a comprehensive, novel program of patient-oriented research, while allowing Dr. Sarpal to acquire essential skills that will support his development into an independent translational researcher.

PROJECT NARRATIVE Psychotic symptoms that do not respond to first-line antipsychotic drugs result in a significant amount of morbidity and mortality worldwide. Clozapine has consistently shown to be a superior drug for psychosis in patients who do not respond to other treatments, but its mechanism of action remains unknown. The overall goal of this K23 proposal is to examine the functional neural circuitry that underlies successful treatment with clozapine, which may lead to the identification of biomarkers that will allow for more efficient use of clozapine, as well as additional treatment targets for patients with refractory illness. Simultaneously, this proposal will launch the career of the Principal Investigator, Deepak K. Sarpal, M.D., as an independent translational researcher.