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

/05/98-May Schizophrenia is heterogeneous and costly

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

/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

/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

/05/98-May % decrease from baseline in the symptom groupings of the PANSS score in chronic schizophrenic subjects over 2 years Lindstrom E (1995) weeks risperidone 8-9 mg year 2 years Cognitive symptoms Excitation Anxiodepressive symptoms Negative symptoms Positive symptoms

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

/05/98-May Incidence of Tardive Dyskinesia after 1 year in stabilized schizophrenics haloperidol 11.7 mg risperidone 4.9 mg Csernansky, 2000

/05/98-May TIME TO RELAPSE Csernansky, 2002 Risperidone Haloperidol Days Probability of Remaining Relapse-Free (%)

/05/98-May Change in quality of life after 1 year, measured by the mental health score SF-36 Merideth C (1998) * p=0.03 * 8 7 RisperidoneConventional neuroleptics

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

/05/98-May Subjective position on the DAI-30 scale of schizophrenics stabilized on treatment Classic NLPRisperidone 3.8 mg Voruganti L (2000) * * p < 0.05 vs Classic NLP

/05/98-May Mortality in psychogeriatric patients New APHaloperidol % Nasrallah HA (2000) * * p < vs haloperidol

/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

/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

/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 Number of days of hospitalization * p= compared to the previous period * *

/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)

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

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

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

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

/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 Days per patient

/05/98-May Two-year impact of risperidone on number of hospitalizations (n=146) After Albright, Total Hospital Admissions After risperidone Before risperidone Months of treatment

/05/98-May Two-year impact of risperidone on days in hospital (n=146) After Albright, Total Hospital Days After risperidone Before risperidone Months of treatment

/05/98-May Dosages After Procyshyn, 1998

/05/98-May Costs After Procyshyn, 1998 * p<

/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 * ** *

/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< compared to olanzapine *p<0.03 compared to olanzapine % rehospitalizations after 12 months risperidone 4.5 mg olanzapine 17.9 mg * ** *

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

/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) (1998) –Riverview Hospital, Canada Objective

/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 < days risperidone 5.3 mg olanzapine 14.5 mg * %

/05/98-May Daily cost of all inpatient medication Kasper S (2000) * p < * *

/05/98-May RODOS (Belgium-Luxemburg) VariableRisperidone (n=64) Olanzapine (n=88) p-Value Parients discharged before or on day (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) < Daily cost of all inpatient drugs (euros) < Data on file

/05/98-May General reflections & conclusion

/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 % Estimated % of patients treated only with SGA % 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

/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

/05/98-May Antipsychotic administration: dosing and costs Variable HaloperidolHaloperidol Decanoate ClozapineOlanzapineQuetiapineRisperidoneZiprasidone Relative potency * 2NA Initiation dose (mg) Typical dose range (mg/d) (mg/month) Maximum dose (mg/d) Average cost (per year U.S. $) 501,50011,0005,5003,4002,800NA * mg of drug equivalent to 100 mg chlorpromazine After Jibson-Tandon 2000

/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)