1. 980640-114/05/98-May Outcomes and risk-benefit ratio of second-generation antipsychotics versus classic neuroleptics M. FLORIS M.D. NOTRE-DAME CLINIC TOURNAI - BELGIUM

2. 980640-214/05/98-May Schizophrenia is heterogeneous and costly

3. 980640-314/05/98-May Efficacy & Outcomes of Second-Generation Antipsychotics (SGA) Data on risperidone

4. 980644-415/05/98-May SYMPTOM GROUPINGCLASSIC NEUROLEPTICS SECOND-GENERATION ANTIPSYCHOTICS PSYCHOTIC + + ++ + DISORGANIZED + + + + + + + NEGATIVE +/-+ + + QUALITY OF LIFE ++ + + COGNITIVE DEFICITS :  Memory +/-+  Attention +/-+  Executive Function +/-+ After Csernansky 1998 Symptom groupings in schizophrenia and responses to drugs

5. 980644-515/05/98-May Course of positive, negative and cognitive symptoms in schizophrenia After Jibson-Tandon 2000 Time Positive Symptoms Negative Symptoms Cognitive Impairment First Episode Premorbid Severity of Symptoms

6. 980644-615/05/98-May % decrease from baseline in the symptom groupings of the PANSS score in chronic schizophrenic subjects over 2 years Lindstrom E (1995) -25 -30 -40 -35 8 weeks -10 -20 0 risperidone 8-9 mg 0 -15 1 year 2 years Cognitive symptoms Excitation Anxiodepressive symptoms Negative symptoms Positive symptoms

7. 980644-715/05/98-May Implications of EPS After Jibson-Tandon 2000 EPS Tardive Dyskinesia Aggression Noncompliance Motor Side Effects Dysphoria Cognitive Dysfunction Negative Symptoms

8. 980644-815/05/98-May Incidence of Tardive Dyskinesia after 1 year in stabilized schizophrenics 2 0 0.5 3 haloperidol 11.7 mg 2.5 1. 5 1 risperidone 4.9 mg Csernansky, 2000

9. 980644-915/05/98-May TIME TO RELAPSE Csernansky, 2002 Risperidone Haloperidol Days Probability of Remaining Relapse-Free (%) 0100200300400500600700800 90 100 0 70 80 50 60 30 40 10 20

10. 980644-1015/05/98-May Change in quality of life after 1 year, measured by the mental health score SF-36 Merideth C (1998) 4 0 1 6 5 3 2 * p=0.03 * 8 7 RisperidoneConventional neuroleptics

11. 980644-1115/05/98-May Change in quality of life after 8 months on the SF-36 subscores Bobés J. (1998) * p<0.0001 compared to the basseline * risperidone 5.5 mg 051015202530 Mental health Emotional role limitation Social functioning Vitality General health Bodily pain Physical role limitation Physical functioning * * * * * * * *

12. 980644-1215/05/98-May Subjective position on the DAI-30 scale of schizophrenics stabilized on treatment 0 5 10 15 20 25 Classic NLPRisperidone 3.8 mg Voruganti L (2000) * * p < 0.05 vs Classic NLP

13. 980644-1315/05/98-May Mortality in psychogeriatric patients 0 5 10 15 20 25 New APHaloperidol % Nasrallah HA (2000) * * p <0.00001 vs haloperidol

14. 980644-1415/05/98-May Efficacy of Risperidone, Haloperidol and Placebo on Affective Symptomatology in Schizophrenia Mean change in BPRS « Anxiety-Depression » score from baseline After Burrows 1996 Placebo (n=86)Risperidone 6 mg (n=85)Haloperidol 20 mg (n=85) *** * p<0.05 vs placebo** p<0.01 vs haloperidol 0 -0.2 -0.4 -0.6 -0.8 -1.2 -1.4 -1.6 -1.8

15. 980644-1515/05/98-May Comorbidity of schizophrenia and mood disorders (National Comorbidity Study n=8,098) Schizophrenia without comorbidity of mood disorders19% Schizophrenia with comorbidity of mood disorders81% with unipolar mood disorders59% MDD27% MDD + Dysthymia22% Dysthymia10% with bipolar I and II mood disorders22% Mania + Depression21% Hypomania + Depression1% After Floris 1997

16. 980644-1615/05/98-May % decrease in hospitalizations during treatment with risperidone in 120 schizophrenics in a natural environment for more than 22 months Keegan (1999) Number of (re)hospitalizations 47.5 49.5 49 46.5 47 48 48.5 Number of days of hospitalization * p=0.0001 compared to the previous period * 45.5 46 *

17. 980644-1715/05/98-May % of schizophrenics with a preference for risperidone compared to the previous depot neuroleptic Desai NM (1999) Much betterBetter risperidone 6 mg A little better The sameLess good (a little to much) 20 10 0 40 30

18. 980644-1815/05/98-May Ten most debilitating side effects from the standpoint of the schizophrenic patient After Angermeyer & Matschinger, 1999

19. 980644-1915/05/98-May Mean weight gain with novel antipsychotics after 10 weeks of treatment After Allison et al., 1999

20. 980640-2014/05/98-May Pharmaco-Economic Aspects of Second-Generation Antipsychotics (SGA) Data on risperidone

21. 980644-2115/05/98-May Summary Of Incremental Cost/Patient/Year By Type Of Service After Albright, 1996

22. 980644-2215/05/98-May After Lindstrom, 1998 Two-year impact of risperidone on hospital stay (n=18) Total stay Treatment home stay Hospital stay Year-2BaselineYear+1Year+2 50 0 150 100 250 200 Days per patient

23. 980644-2315/05/98-May Two-year impact of risperidone on number of hospitalizations (n=146) After Albright, 1998 6121824 50 0 200 100 350 300 Total Hospital Admissions 150 250 After risperidone Before risperidone Months of treatment

24. 980644-2415/05/98-May Two-year impact of risperidone on days in hospital (n=146) After Albright, 1998 6121824 1000 0 4000 2000 7000 6000 Total Hospital Days 3000 5000 After risperidone Before risperidone Months of treatment

25. 980644-2515/05/98-May Dosages After Procyshyn, 1998

26. 980644-2615/05/98-May Costs After Procyshyn, 1998 * p< 0.0001

27. 980644-2715/05/98-May % of hospitalized chronic schizophrenics meeting specified clinical criteria after a maximum of 120 days Procyshyn R (1998) 0 Responding to treatment instituted Discharge from hospital with initial medical treatment *p=0.02 compared to olanzapine **p=0.006 compared to olanzapine risperidone 4.9 mg olanzapine 17.2 mg * ** 20 40 60 30 50 10 *

28. 980644-2815/05/98-May Naturalistic differences in clinical efficacy over 1 year in schizophrenics Snaterse S (2000) Time to initial response (days) Time to discharge from hospital (days) ** p<0.0001 compared to olanzapine *p<0.03 compared to olanzapine % rehospitalizations after 12 months risperidone 4.5 mg olanzapine 17.9 mg * ** * 10 30 60 70 20 40 50 0

29. 980640-2914/05/98-May R O D O S R isperidone O lanzapine D rug O utcomes studies in S chizophrenia

30. 980644-3015/05/98-May To compare the drug usage pattern and the costs and outcomes associated with the treatment of schizophrenia with either risperidone or olanzapine within a single hospital setting Protocol based on published study : –Procyshyn RM, Zerjav S ; Clinical Therapeutics 20 (6) 1203-1217 (1998) –Riverview Hospital, Canada Objective

31. 980644-3115/05/98-May % of patients in whom the physician rated the treatment as effective, over the course of time, in a naturalistic multinational study (RODOS) Kasper S (2001) p < 0.0001 0120 days306090 risperidone 5.3 mg olanzapine 14.5 mg * 0 40 100 20 60 80 %

32. 980644-3215/05/98-May Daily cost of all inpatient medication Kasper S (2000) * p < 0.0001 * *

33. 980644-3315/05/98-May RODOS (Belgium-Luxemburg) VariableRisperidone (n=64) Olanzapine (n=88) p-Value Parients discharged before or on day 120 43 (67 %)47 (53 %)0.21 Days before efficacy was established 14 (4-110)26 (2-120)0.003 Dropouts for lack of efficacy5 (8 %)7 (8 %)0.97 Average daily dose (mg/d)4.8 (+/- 1.7)13.7 ( +/- 4.6) Daily cost of treatment drug (euros) 2.875.67<0.0001 Daily cost of all inpatient drugs (euros) 3.736.39<0.0001 2002 Data on file

34. 980640-3414/05/98-May General reflections & conclusion

35. 980644-3515/05/98-May Utilisation of the SGA in Europe Nine countries (D – DK – E – F - UK – I – NL – S – CH) Estimated % of patients treated only with classic neuroleptics 50.58 % Estimated % of patients treated only with SGA 39.75 % Estimated % of patients treated with both SGA and classic neuroleptics µ 9.66 % Estimated % of GP’s who should prescribe a SGA for a relative 73 % After Sarfati 1999

36. 980644-3615/05/98-May Medication Guideline/Algorithm recommendations Variable ECST 1996 TMAP 1996 VA 1997 APA 1997 CPA 1998 ECST 1999 TMAP 1999 First line Atypicals YYYYYYY First line Typicals YYYYNNN Second choice A,T A,T,CA, TAA Third choice CACCCCA Fourth choice --C C+C+ C Combinations -- CF ECST = Expert Consensus Schizophrenia Treatment TMAP = Texas Medication Algorithm Project VA = Veterans Affairs APA = American Psychiatric Association CPA = Canadian Psychiatric Association Y = Yes C = Clozapine N = No C + = Clozapine augmentation A = Atypicals CF = Clozapine failure T = Typicals After Miller 2001

37. 980644-3715/05/98-May Antipsychotic administration: dosing and costs Variable HaloperidolHaloperidol Decanoate ClozapineOlanzapineQuetiapineRisperidoneZiprasidone Relative potency * 2NA50480120 Initiation dose (mg) 5-10100251050280 Typical dose range (mg/d) 10-20100-300 (mg/month) 200-600 15-30300-8002-680-160 Maximum dose (mg/d) 20400900408008160 Average cost (per year U.S. $) 501,50011,0005,5003,4002,800NA * mg of drug equivalent to 100 mg chlorpromazine After Jibson-Tandon 2000

38. 980644-3815/05/98-May After Floris 1997 Overall impact ↑Efficacy ↓Negative symptoms ↓Positive symptoms ↓Affective symptoms More rapid effect ↓Side effects Direct costsIndirect costs ↓ Treatment duration ↑ Treatment compliance ↓ Long-term relapses ↑ Quality of life ↓ Hospitalization ↓ Direct costs ↑ Fitness for work ↑ Social functioning ↓ Indirect costs (patients) ↓ Indirect costs (carers)