Cognitive impairment, including working memory (WM) deficit, is a core feature of schizophrenia which remains stable throughout the course of the illness, causes significant impairment and is highly correlated to long term disability (Green 1996a). Multiple lines of evidence including clinical and preclinical data, have emphasized a major role for the D1 receptor in this cognitive deficit. Recently a panel of experts gathered by the National Institute of Mental Health (NIMH)-sponsored MATRICS (Measurement and Treatment Research to Improve Cognition in Schizophrenia) meeting concluded that D1 agonists represent a promising approach to the treatment of cognitive impairment in schizophrenia. This proposal is a joint collaboration between an academic institution, Columbia University, and a pharmaceutical company, DarPharma Inc., as well as many outstanding scientists from the community at large, to conduct a proof of concept study assessing the use of a selective D1 agonist, DAR-0100, in the treatment of cognitive deficit in schizophrenia. In the proposed study, two doses (10 and 30 mg, s.c.) of a DAR-0100 or placebo will be given to three different groups (N=20 each) of clinically stable inpatients with schizophrenia treated with risperidone. Resting blood flow and neural activity in regions involved in working memory function will be used as biological markers to evaluate the potential efficacy of DAR-0100 acutely (2 days) and after subchronic treatment (7 days) in improving cognitive deficits in schizophrenia, (SA1). PET and [11C]NNC 112 will be used to establish the level of D1 receptor occupancy achieved acutely (day 1), to assess the level of occupancy associated with maximal WM improvement in patients with schizophrenia (SA2), and to test the hypothesis that, subacute D1 agonists administration can induce downregulation of DLPFC D1 receptors predictive of improvement in WM performance (SA2). In addition the impact on general cognition will be assessed after 7 days and 3 months (SA3). In keeping with the spirit of this PAR, we believe our proposal will lead to a conclusive body of work focused on the treatment of the most challenging clinical aspect of one of the most severe mental illnesses, which taxes as much the individual it affects as the society as a whole.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZMH1-ERB-S (10))
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Hillefors, MI
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New York State Psychiatric Institute
New York
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Girgis, Ragy R; Van Snellenberg, Jared X; Glass, Andrew et al. (2016) A proof-of-concept, randomized controlled trial of DAR-0100A, a dopamine-1 receptor agonist, for cognitive enhancement in schizophrenia. J Psychopharmacol 30:428-35
Horga, Guillermo; Cassidy, Clifford M; Xu, Xiaoyan et al. (2016) Dopamine-Related Disruption of Functional Topography of Striatal Connections in Unmedicated Patients With Schizophrenia. JAMA Psychiatry 73:862-70
Van Snellenberg, Jared X; Girgis, Ragy R; Horga, Guillermo et al. (2016) Mechanisms of Working Memory Impairment in Schizophrenia. Biol Psychiatry 80:617-26
Slifstein, Mark; Suckow, Raymond F; Javitch, Jonathan A et al. (2011) Characterization of in vivo pharmacokinetic properties of the dopamine D1 receptor agonist DAR-0100A in nonhuman primates using PET with [11C] NNC112 and [11C] raclopride. J Cereb Blood Flow Metab 31:293-304