1. Next-Generation Strategies for the Therapeutic Management of Schizophrenia Diana O. Perkins, MD, MPH Professor, Department of Psychiatry Medical Director OASIS Program (Outreach and Support Intervention Services) University of North Carolina at Chapel Hill Chapel Hill, North Carolina

2. Negative symptoms Relationship of Symptom Domains in Schizophrenia Mood symptoms Cognition Positive symptoms Antipsychotics

3. What Do We Know? Antipsychotics improve positive symptoms Antipsychotics have a modest impact on: –Negative symptoms –Cognition Residual symptoms remain in most patients Residual symptoms underlie disability in chronic schizophrenia

4. Antipsychotic Efficacy: Symptoms

5. Meta-analysis: Efficacy of Second-Generation Antipsychotics on Symptoms in Schizophrenia -0.6 -0.5 -0.4 -0.3 0.2 0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447. Favors AntipsychoticFavors Placebo Negative symptoms N = 36; n = 5403 Positive symptoms N = 30; n = 4941 SMD = change in symptoms on placebo (in “SD units”)—change in symptom on drug (in “SD units”) Total symptoms N = 35; n = 5568

6. Meta-analysis: Use of EPS Medications 2 - 2.5 -2 -1.5 -1.0 -.5 1 0.5 1.0 1.5 2.0 2.5 3.0 Favors Antipsychotic Favors Placebo Aripiprazole N = 6; n = 1310 Olanzapine N = 3; n = 481 Ziprasidone N = 4; n = 598 Haloperidol N = 11; n = 1608 Quetiapine N = 3; n = 509 Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447. Risperidone N = 4; n = 323

7. Meta-analysis: EPS Rating Scale Favors Antipsychotic Favors Placebo Aripiprazole N = 6; n = 1591 Olanzapine N = 3; n = 612 Risperidone N = 5; n = 642 Ziprasidone N = 1; n = 95 Haloperidol N = 7; n = 1004 Quetiapine N = 3; n = 529 Adapted from Leucht S, et al. Mol Psychiatry. 2009;14(4):429-447. 2 - 2.5 -2 -1.5 -1.0 -.5 1 0.5 1.0 1.5 2.0 2.5 3.0

8. Second-Generation vs First-Generation Antipsychotics Leucht S, et al. Lancet. 2009;373(9657):31-41. Copyright © 2009 Elsevier Ltd. N= n= N= n= N= n= N= n= N= n= N= n=

9. Symptomatic Remission: Remission in Schizophrenia Working Group PANSS symptoms and signs mild or less (severity ≤ 3) for 6 months Positive symptoms –Delusions –Unusual thought content –Hallucinatory behavior Disorganization –Conceptual disorganization –Mannerisms/posturing Negative symptoms –Blunted affect –Social withdrawal –Lack of spontaneity Andreasen NC, et al. Am J Psychiatry. 2005;162(3):441-449.

10. EPPIC Study Early Psychosis Prevention and Intervention Centre Henry LP, et al. J Clin Psychiatry. 2010;71(6):716-728. 723 first-episode psychosis patients* treated for up to the first 2 years of illness Median follow-up: 7.2 years; mean age at follow-up: 28.7 years *Includes schizophrenia, schizophreniform disorder, schizoaffective disorder, affective psychosis, and other psychosis Remission/Recovery Criteria Schizophrenia + Schizophreniform Disorder (%) Total Cohort (%) Symptom remission BPRS5059 BPRS + SANS2937 Social/vocational recovery2231 Social/vocational recovery + symptom remission BPRS1826 BPRS + SANS1524 BPRS = Brief psychotic rating scale SANS = Schedule for assessment of negative symptoms

11. Antipsychotic Efficacy: Cognition

12. Normative Data Compared With a Schizophrenia Sample on the RBANS Neuropsychological Test RBANS = Repeatable Battery for Assessment of Neuropsychological Status 0 5 10 15 20 25 30 35 < 50-5051-6061-7071-8081-9091-100101-110111-120121-130131-140140+ Total Scale Score % of Cases Schizophrenia (n = 575) Normal controls (n = 540) Data from Wilk CM, et al. Schizophr Res. 2004;70(2-3):175-186. 0.4% 0% 16.5% 7.2% 22.8% 20.6% 22.6% 7.9% 2.2% 0.4% 1.6% 7.0% 16.0% 25.0% 0% 16.0% 0.4% 1.6% 7.0% 25.0%

13. Effect Sizes* for Average Improvement in Cognition With Atypical Antipsychotics Healthy Control Mean (Theoretical) ∆ in Baseline (Standard Deviation) 0.0 -0.5 -1.5 *Values represent average improvement as measured by changes from baseline in standard deviations; figures are weighted for the study group size in each study and collapsed across all newer medications. Adapted from Harvey PD, Keefe RS. Am J Psychiatry. 2001;158:176-184. Immediate Memory Secondary Memory VigilanceExecutive Functions Visual Motor Skills Verbal Fluency Spatial Functions.13.39.18.27.43.20

14. Next-Generation Strategies

15. Prevention Psychotherapeutic interventions New pharmacological targets

16. Next-Generation Strategies: Public Education Program to Promote Early Intervention Impact on Symptoms Data from Melle I, et al. Arch Gen Psychiatry. 2008;65(6):634-640. Control group: n = 118, mean DUP = 16 weeks; Intervention group: n = 113, mean DUP = 4 weeks 25 Baseline3 month12 month24 month 20 15 10 5 0 PANSS Score Negative Sx (Control Group) Negative Sx (Early Detection Group) Positive Sx (Control Group) Positive Sx (Early Detection Group)

17. Next-Generation Strategies: Psychotherapy Data from Eack SM, et al. Psychiatr Serv. 2009;60(11):1468-1476. Percent Change at 2 Years 60 Total Symptoms (P = 0.008) 50 40 30 20 10 0 Cognitive Enhancement Therapy (n = 31) Enriched Supportive Therapy (n = 27) Negative Symptoms (P = 0.01) Neurocognition (P = 0.02) Social Cognition (P < 0.001)

18. Next-Generation Strategies: Pharmacological Next-generation drug development driven by theoretical relationship of negative and cognitive symptoms to frontal cortical dysfunction and glutamate circuits Hui C, Tsai GE. In: Brain Protection in Schizophrenia, Mood and Cognitive Disorders. New York, NY: Springer Science+Business Media; 2010.

19. Glutamate “Partners” at the NMDA Receptor

20. Meta-analysis: Efficacy of Glycine/Serine/Cycloserine Augmentation on Negative Symptoms -0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537. Favors DrugFavors Placebo Glycine N = 7; n = 261 D-serine N = 5; n = 208 D-cycloserine N = 8; n = 317

21. Meta-analysis: Efficacy of Glycine/Serine/Cycloserine Augmentation on Positive Symptoms Favors DrugFavors Placebo Glycine N = 6; n = 145 D-serine N = 5; n = 208 D-cycloserine N = 7; n = 212 Note: Consistent negative results for clozapine augmentation studies Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537. -0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2

22. Next-Generation Strategies: Pharmacological Next-generation drug development driven by theoretical relationship of negative and cognitive symptoms to frontal cortical dysfunction and glutamate circuits Hui C, Tsai GE. In: Brain Protection in Schizophrenia, Mood and Cognitive Disorders. New York, NY: Springer Science+Business Media; 2010.

23. Glycine Reuptake Inhibitors

24. Javitt DC, et al. Mol Psychiatry. 2005;10(3):275-287. Copyright © 2004 Nature Publishing Group. Inhibition of Glycine Transport by Clozapine % Control [ 3 H] Glycine Uptake 100 80 60 40 20 0 0.010.1110100 Clozapine Concentration (mcg/mL) plasma brain * * * ** *** *P < 0.05 vs control; **P < 0.01; ***P < 0.001.

25. -0.4 -0.3 -0.2 -0.1 00 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 Meta-analysis: Efficacy of Sarcosine Augmentation on Schizophrenia Symptoms Favors DrugFavors Placebo Positive N = 5; n = 162 Total Symptoms N = 5; n = 162 Negative N = 5; n = 162 Adapted from Tsai GE, et al. Curr Pharm Des. 2010;16(5):522-537.

26. Glycine Reuptake Inhibitors RG1678 Study Design Subjects: 323 clinically stable schizophrenia patients with predominantly negative symptoms, low severity of positive symptoms Design: 8-week, randomized, double-blind, placebo-controlled trial Treatment: 10 mg, 30 mg, and 60 mg of RG1678 added to ongoing treatment Outcomes: negative symptom severity, overall symptom severity, function Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

27. RESULTS: Negative Symptom (PANSS) Change Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49. 0 -2 -3 -4 -5 -6 -7 -8 BaselineWeek 1Week 2Week 4Week 6Week 8 Placebo RG1678 10 mg/day RG1678 30 mg/day RG1678 60 mg/day 10 mg vs placebo P < 0.1 10 mg vs placebo 30 mg vs placebo P < 0.1 10 mg vs placebo P < 0.1 10 mg vs placebo 30 mg vs placebo P < 0.05 ∆ NSFS score Mixed model repeated measures analysis

28. Results: CGI Negative Symptom Scale Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49. 50 40 30 20 10 0 Very much improved Much improved Minimally improved No change PlaceboRG1678 30 mg/day RG1678 10 mg/day RG1678 60 mg/day P < 0.05 P < 0.1 Patients (%)

29. Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49. Results: Negative Symptom (PANSS) Response Rates

30. Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49. Results: Functional Improvement 60 58 56 54 52 0 Baseline Week 4 Week 8 PlaceboRG1678 30 mg/day RG1678 10 mg/day RG1678 60 mg/day P < 0.1 Patients (%) 50 P value is vs placebo; analysis of covariance

31. Safety Data Data from Umbricht D, et al. Neuropsychopharmacology. 2010;35(suppl 1):49.

32. Summary and Clinical Implications Cognitive, negative, and residual positive symptoms occur in most patients with schizophrenia Residual symptoms lead to functional disability Early intervention and relapse prevention may lessen severity of residual symptoms Psychotherapeutic strategies may augment antipsychotic medications Glycine reuptake inhibitors are a promising approach to treat residual symptoms