Persistent negative and cognitive symptoms are a primary cause of chronic disability and poor long-term outcome in schizophrenia. Phencylidine (PCP) and other antagonists of N-methyl-D-aspartate (NMDA)-mediated neurotransmission induce symptoms and cognitive deficits that closely resemble those of schizophrenia, indicating a potentially critical role of NMDA receptors in the etiopathology of primary negative symptoms. NMDA receptors are modulated in vivo by glycine and D-serine, which bind to a modulatory site of the NMDA receptor complex. Clinical trials with NMDA/glycine site agonists have yielded highly encouraging clinical data. This CDDG application will focus on development of D-serine as an effective treatment for persistent negative symptoms and cognitive dysfunction in schizophrenia, in collaboration with Rexim Corporation, a major manufacturer of D-serine and other amino acids for the pharmaceutical industry. The application consists of two projects. Project 1 will consist of PK/PD, dose-finding and subsequent double-blind treatment studies at NKI involving patients, with chronic schizophrenia, and investigating D-serine effects on persistent negative symptoms and cognitive dysfunction. Project 2 will consist of a collaborative multicenter trial of D-serine treatment of the schizophrenia prodrome to be conducted at Yale University and Zucker Hillside Hospital. Together these projects will validate treatment targets for NMDA agonists in general and D-serine in particular and will encourage continued clinical development.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01MH074356-02
Application #
7126783
Study Section
Special Emphasis Panel (ZMH1-ERB-Y (01))
Program Officer
Hillefors, MI
Project Start
2005-09-30
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
2
Fiscal Year
2006
Total Cost
$707,558
Indirect Cost
Name
Nathan Kline Institute for Psychiatric Research
Department
Type
DUNS #
167204762
City
Orangeburg
State
NY
Country
United States
Zip Code
10962
Kantrowitz, Joshua T; Epstein, Michael L; Lee, Migyung et al. (2018) Improvement in mismatch negativity generation during d-serine treatment in schizophrenia: Correlation with symptoms. Schizophr Res 191:70-79
Kantrowitz, Joshua T; Woods, Scott W; Petkova, Eva et al. (2015) D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial. Lancet Psychiatry 2:403-412
Woods, Scott W; Walsh, Barbara C; Hawkins, Keith A et al. (2013) Glycine treatment of the risk syndrome for psychosis: report of two pilot studies. Eur Neuropsychopharmacol 23:931-40
Javitt, Daniel C (2012) Glycine transport inhibitors in the treatment of schizophrenia. Handb Exp Pharmacol :367-99
Cornblatt, Barbara A; CarriĆ³n, Ricardo E; Addington, Jean et al. (2012) Risk factors for psychosis: impaired social and role functioning. Schizophr Bull 38:1247-57
Seidman, Larry J; Giuliano, Anthony J; Meyer, Eric C et al. (2010) Neuropsychology of the prodrome to psychosis in the NAPLS consortium: relationship to family history and conversion to psychosis. Arch Gen Psychiatry 67:578-88
Kantrowitz, Joshua T; Malhotra, Anil K; Cornblatt, Barbara et al. (2010) High dose D-serine in the treatment of schizophrenia. Schizophr Res 121:125-30
Javitt, Daniel C (2009) Glycine transport inhibitors for the treatment of schizophrenia: symptom and disease modification. Curr Opin Drug Discov Devel 12:468-78