- Email: [email protected]
THE BUSINESS OF SCIENCE AS IT APPLIES TO SCHIZOPHRENIA DRUG DEVELOPMENT
8
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
more efficacious than NMDA-glycine site agonists for the treatment of schizophrenia. Acknowledgements: NARSAD Investigator Award References [1] Tsai G, Young PJ, Chung LJ, Tsai IC, Tsai CW, Coyle JT. Dserine added to clozapine for the treatment of schizophrenia. Am J Psychiat, 1999;156:1822-5. [2] Tsai G, Lane H, Young PJ, Lane N, Chong M. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry, 2004;55:452-6. [3] Lane HY, Chang YC, Chiu CC, Tsai G. Sarcosine (N-methylglycine) or D-serine treatment for acutely exacerbated schizophrenia: a double-blind, placebo-controlled study. Arch Gen Psychiatry, 2005;62:1196-1204. [4] Lane HY, Lin YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai G. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry, 2008;63:9-12. MOLECULAR STUDIES OF NMDA RECEPTOR MODULATORS IN SCHIZOPHRENIA
Paul Harrison, L. Verrall, P.W.J. Burnet Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK [email protected] Introduction: There is evidence that glutamatergic neurotransmission, particularly mediated via NMDA receptors, is aberrant in schizophrenia. One aspect of the ‘NMDA receptor hypofunction’ hypothesis is deficient modulation of the receptor by the co-agonists glycine and/or D-serine; this is supported by the reported genetic association of the D-serine metabolising enzyme,D-amino acid oxidase (DAO), with schizophrenia. In addition to DAO, the availability of these NMDA modulators is potentially influenced by their synthesis and transport into and out of the synapse. These molecules are potential therapeutic targets in psychosis, especially for cognition. Methods: We are therefore studying the expression and function of several of the genes involved. Results: We have found increased DAO expression in schizophrenia, as well as increased activity of DAO. This suggests that D-serine degradation is increased in schizophrenia, which may contribute to decreased D-serine availability and hence NMDA receptor functi oning. DAO expression and activity were not related to two schizophreniaassociated tag SNPs in the gene, nor to SNPs in the putative DAO activator gene, G72. Expression of the D-serine synthetic enzyme, serine racemase, was not altered in schizophre nia. D-serine is removed from the synapse primarily by the Asc-1 transporter; its abundance was decreased in schizophrenia, possibly as a homeostatic response to a lower synaptic D-serine concentration. Conclusions: Studies are ongoing to further characterise these and other molecules involved in regulation of NMDA receptor modulators in schizophrenia, complemented by experiments in model systems to investigate the consequences of their altered expression.
neurotransmission may play a role in negative symptoms and cognitive impairment in schizophrenia. Methods: Between 2004-7 we randomized 195 patients with chronic schizophrenia, stabilized on anti-psychotic medication, to receive addon d-serine 2 gm/d or placebo. Each patient received double-blind medication for 4 months. Results: The mean age of the patients was 39.3±12.1, mean level of education was 10.9±2.7 years, the mean age of onset of illness was 23.4±8.5, mean number of hospitalizations was 5.5±5.5. Mean total PANSS score at baseline was 75.5±13.9, mean PANSS negative score at baseline was 26.3±4.8, mean CGI at baseline score was 4.6±0.76. The main outcome measure was the SANS, for which inter-rater reliability is >0.9. Conclusion: Preliminary results of the trail will be presented.
SESSION VI
June 22nd, 2008
Drug Development in Schizophrenia THE BUSINESS OF SCIENCE AS IT APPLIES TO SCHIZOPHRENIA DRUG DEVELOPMENT
Gary Pisano Harvard Business School, Boston, Massachusetts, USA [email protected] Abstract not received. REWARDS AND CHALLENGES IN SCHIZOPHRENIA DRUG DEVELOPMENT
Anders Gersel Pedersen Lundbeck, Copenhagen, Denmark [email protected] Abstract not received.
INCREASING PLACEBO RESPONSE IN ANTI-PSYCHOTIC TRIALS: FACT OR MYTH
Anand Ravi Oberwit, Switzerland [email protected] Abstract not received. WHAT ARE THE RULES? COULD WE HAVE AVOIDED UNPLEASANT SURPRISES?
Susanna Del Signore EMEA, London, UK Abstract not received.
D-SERINE VS. PLACEBO IN THE TREATMENT OF NEGATIVE SYMPTOMS AND COGNITIVE IMPAIRMENT OF SCHIZOPHRENIA
Mark Weiser 1 , D.C. Javitt 2 , U. Heresco-Levy 3 , A. Abramovitch 4 , A. Teitlebaum 5 , A. Doron 6 , M. Davidson 7 1 Chaim Sheba Medical Center, Tel-Hashomer, Israel; 2 Nathan Klaine Institute, New York, USA; 3 Herzog Medical Center, Jerusalem; 4 Beer Yaakov Mental Health Center, Beer Yaakov; 5 Kfar Shaul Mental Health Center, Jerusalem; 6 Lev Hasharon Mental Health Center, Pardessiya; 7 Sheba Medical Center, Ramat-Gan, Israel [email protected] Introduction: Functional under-activity of NMDA receptor-mediated
IS COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA A REALISTIC TARGET FOR PHARMACOLOGICAL INTERVENTION?
Michael Davidson Tel Aviv University, Tel Aviv, Israel [email protected] Because of its impact on the general social and vocational functioning, cognitive impairment has been at the forefront of schizophrenia research for the last 2 decades. The cognitive impairment precedes the onset of psychosis, persists after psychosis remits and is occa-
Abstracts / Schizophrenia Research 102/1–3, Supplement 2 (2008) 1–279
more efficacious than NMDA-glycine site agonists for the treatment of schizophrenia. Acknowledgements: NARSAD Investigator Award References [1] Tsai G, Young PJ, Chung LJ, Tsai IC, Tsai CW, Coyle JT. Dserine added to clozapine for the treatment of schizophrenia. Am J Psychiat, 1999;156:1822-5. [2] Tsai G, Lane H, Young PJ, Lane N, Chong M. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to antipsychotics for the treatment of schizophrenia. Biol Psychiatry, 2004;55:452-6. [3] Lane HY, Chang YC, Chiu CC, Tsai G. Sarcosine (N-methylglycine) or D-serine treatment for acutely exacerbated schizophrenia: a double-blind, placebo-controlled study. Arch Gen Psychiatry, 2005;62:1196-1204. [4] Lane HY, Lin YC, Huang CL, Chang YC, Liau CH, Perng CH, Tsai G. Sarcosine (N-methylglycine) treatment for acute schizophrenia: a randomized, double-blind study. Biol Psychiatry, 2008;63:9-12. MOLECULAR STUDIES OF NMDA RECEPTOR MODULATORS IN SCHIZOPHRENIA
Paul Harrison, L. Verrall, P.W.J. Burnet Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK [email protected] Introduction: There is evidence that glutamatergic neurotransmission, particularly mediated via NMDA receptors, is aberrant in schizophrenia. One aspect of the ‘NMDA receptor hypofunction’ hypothesis is deficient modulation of the receptor by the co-agonists glycine and/or D-serine; this is supported by the reported genetic association of the D-serine metabolising enzyme,D-amino acid oxidase (DAO), with schizophrenia. In addition to DAO, the availability of these NMDA modulators is potentially influenced by their synthesis and transport into and out of the synapse. These molecules are potential therapeutic targets in psychosis, especially for cognition. Methods: We are therefore studying the expression and function of several of the genes involved. Results: We have found increased DAO expression in schizophrenia, as well as increased activity of DAO. This suggests that D-serine degradation is increased in schizophrenia, which may contribute to decreased D-serine availability and hence NMDA receptor functi oning. DAO expression and activity were not related to two schizophreniaassociated tag SNPs in the gene, nor to SNPs in the putative DAO activator gene, G72. Expression of the D-serine synthetic enzyme, serine racemase, was not altered in schizophre nia. D-serine is removed from the synapse primarily by the Asc-1 transporter; its abundance was decreased in schizophrenia, possibly as a homeostatic response to a lower synaptic D-serine concentration. Conclusions: Studies are ongoing to further characterise these and other molecules involved in regulation of NMDA receptor modulators in schizophrenia, complemented by experiments in model systems to investigate the consequences of their altered expression.
neurotransmission may play a role in negative symptoms and cognitive impairment in schizophrenia. Methods: Between 2004-7 we randomized 195 patients with chronic schizophrenia, stabilized on anti-psychotic medication, to receive addon d-serine 2 gm/d or placebo. Each patient received double-blind medication for 4 months. Results: The mean age of the patients was 39.3±12.1, mean level of education was 10.9±2.7 years, the mean age of onset of illness was 23.4±8.5, mean number of hospitalizations was 5.5±5.5. Mean total PANSS score at baseline was 75.5±13.9, mean PANSS negative score at baseline was 26.3±4.8, mean CGI at baseline score was 4.6±0.76. The main outcome measure was the SANS, for which inter-rater reliability is >0.9. Conclusion: Preliminary results of the trail will be presented.
SESSION VI
June 22nd, 2008
Drug Development in Schizophrenia THE BUSINESS OF SCIENCE AS IT APPLIES TO SCHIZOPHRENIA DRUG DEVELOPMENT
Gary Pisano Harvard Business School, Boston, Massachusetts, USA [email protected] Abstract not received. REWARDS AND CHALLENGES IN SCHIZOPHRENIA DRUG DEVELOPMENT
Anders Gersel Pedersen Lundbeck, Copenhagen, Denmark [email protected] Abstract not received.
INCREASING PLACEBO RESPONSE IN ANTI-PSYCHOTIC TRIALS: FACT OR MYTH
Anand Ravi Oberwit, Switzerland [email protected] Abstract not received. WHAT ARE THE RULES? COULD WE HAVE AVOIDED UNPLEASANT SURPRISES?
Susanna Del Signore EMEA, London, UK Abstract not received.
D-SERINE VS. PLACEBO IN THE TREATMENT OF NEGATIVE SYMPTOMS AND COGNITIVE IMPAIRMENT OF SCHIZOPHRENIA
Mark Weiser 1 , D.C. Javitt 2 , U. Heresco-Levy 3 , A. Abramovitch 4 , A. Teitlebaum 5 , A. Doron 6 , M. Davidson 7 1 Chaim Sheba Medical Center, Tel-Hashomer, Israel; 2 Nathan Klaine Institute, New York, USA; 3 Herzog Medical Center, Jerusalem; 4 Beer Yaakov Mental Health Center, Beer Yaakov; 5 Kfar Shaul Mental Health Center, Jerusalem; 6 Lev Hasharon Mental Health Center, Pardessiya; 7 Sheba Medical Center, Ramat-Gan, Israel [email protected] Introduction: Functional under-activity of NMDA receptor-mediated
IS COGNITIVE IMPAIRMENT IN SCHIZOPHRENIA A REALISTIC TARGET FOR PHARMACOLOGICAL INTERVENTION?
Michael Davidson Tel Aviv University, Tel Aviv, Israel [email protected] Because of its impact on the general social and vocational functioning, cognitive impairment has been at the forefront of schizophrenia research for the last 2 decades. The cognitive impairment precedes the onset of psychosis, persists after psychosis remits and is occa-