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 acomprehensive plan for transitioning into an independent translational researcher focused on understandingthe neural mechanisms of treatment response in psychotic disorders and integrating functional neuroimagingwith clinical algorithms. A large number of patients with chronic psychotic disorders continue to have symptomsfollowing unsuccessful trials with first-line antipsychotic drugs. For these patients with refractory psychosis,clozapine has consistently demonstrated superior efficacy. Clozapine is often underutilized and administeredlate in a patient's course of treatment, which leads to increased morbidity, unnecessary medication trials, andincreased health care expenditure. Meanwhile, the mechanism of action underlying clozapine's novel effectsremains unknown and has not been studied with modern neuroimaging methods. Identifying the neuralmechanisms by which clozapine exerts its effects may lead to biomarkers that will facilitate efficient utilizationof the drug, and introduce novel treatment targets. In patients with refractory psychotic symptoms, theproposed study will use resting-state and task-based functional MRI (fMRI) to examine the neural circuitry ofefficacious treatment with a trial of clozapine. Patients will undergo fMRI scanning both before and after 12weeks of treatment, with the aims of determining: baseline patterns of resting-state functional connectivity andtask-based activation that predict response to treatment; and changes in resting-state and task-basedfunctional circuitry associated with efficacious treatment. Results of this proposal may lead to biomarkers thatwill optimize treatment algorithms for psychotic disorders and facilitate drug development for refractorypsychosis. While pursuing this line of research under the guidance of mentors who are recognized experts intranslational 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 willengage in a comprehensive training program in neuropsychopharmacology, translational neuroimaging, andtask-based fMRI methodology. He will also gain experience in executing and managing studies involvingpsychiatrically ill patients. The completion of the proposed Mentored Career Award will support acomprehensive, novel program of patient-oriented research, while allowing Dr. Sarpal to acquire essential skillsthat will support his development into an independent translational researcher.
Psychotic symptoms that do not respond to first-line antipsychotic drugs result in a significant amount ofmorbidity and mortality worldwide. Clozapine has consistently shown to be a superior drug for psychosis inpatients who do not respond to other treatments; but its mechanism of action remains unknown. The overallgoal of this K23 proposal is to examine the functional neural circuitry that underlies successful treatment withclozapine; 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 willlaunch the career of the Principal Investigator; Deepak K. Sarpal; M.D.; as an independent translationalresearcher.
