1. 1 Long term anti-psychotic treatment in schizophrenia: 30 years of data and experience Nina R. Schooler, Ph.D. Georgetown University School of Medicine VISN 5 MIRECC Department of Veterans Affairs

2. 2 Overview Prevention of relapse –Need long term trials targeting symptomatically stable patients Placebo produces: –High relapse and rehospitalization for patients in the community –High symptom exacerbation for hospitalized patients Can placebo controlled trials be conducted without these consequences? –Rescue medications are ineffective

3. 3 1970’s Placebo Controlled Relapse Prevention Trial Study Design Schizophrenia diagnosis Community dwelling stabilized patients 2 year treatment period 2 X 2 Design –Chlorpromazine v PBO –Psychosocial treatment v treatment as usual Definition of relapse required return of psychotic symptoms Multi center US –sponsored by NIMH Hogarty et al 1974

4. 4 1970’s Placebo Controlled Relapse Prevention Trial Time to Relapse From Hogarty et al 1974 Treatment Month Cumulative % Relapse

5. 5 1970’s Placebo Controlled Relapse Prevention Trial Placebo relapse rate significantly higher than active medication 75 percent of relapses led to hospitalization Placebo relapse rate consistent over time –Approximately 3% per month Psychosocial treatment may reduce relapse in second year in medicated patients Hogarty et al 1974

6. 6 1990’s Placebo Controlled Relapse Prevention Trial: Study Design Schizophrenia diagnosis Hospitalized stabilized patients One year treatment period Three doses of ziprasidone v PBO Definition of “impending” relapse depended upon observation over three day period Multi-center European –sponsored by Pfizer, Inc. Arato et al 2002

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8. 8 1990’s Placebo Controlled Relapse Prevention Trial Placebo relapse rate significantly higher than active medication In hospitalized patients risk of hospitalization is controlled Medication - placebo differences increase over time Arato et al 2002

9. 9 Summary from Placebo Controlled Trials Anti-psychotic medications are effective in delaying relapse Relapse is not prevented by medication –All studies show relapse on medication albeit at reduced rates Among patients who are stable on medication – placebo differences may be difficult to detect in the first weeks of placebo substitution

10. 10 Can Long-Term, Placebo-Controlled Studies be Designed to Prevent Undue Harm to Patients? Prodromal signs and symptoms often precede relapse Monitoring of early signs could allow early intervention before a full relapse occurs Strategy has several names –Early intervention –Targeted treatment –Intermittent treatment

11. 11 A 1980s – 1990s Placebo Controlled Trial Using an Early Intervention Strategy Study Design Schizophrenia diagnoses Community dwelling stabilized patients with families 2 year treatment period – pts seen at least every two weeks 3 X 2 design Fluphenazine decanoate Moderate dose Low dose Placebo High v low intensity family intervention – education about prodromal signs in both groups Early intervention with oral fluphenazine at prodromal signs in ALL groups Definition of relapse required 140 days of open label medication Multi center US sponsored by NIMH Schooler et al 1997

12. 12 A 1980s – 1990s Placebo Controlled Trial Using an Early Intervention Strategy Time to Relapse Schooler et al 1997 Months Cumulative Proportion in Treatment

13. 13 A 1980s – 1990s Placebo Controlled Trial Using an Early Intervention Strategy Early intervention condition looks like placebo Relapse rates were lowest in moderate dose, intermediate in low dose and highest in early intervention Rehospitalization –Moderate and low dose – 24% –Early intervention – 48% Schooler et al. 1997

14. 14 Conclusions Regarding Early Intervention Early intervention does not effectively prevent relapse Relapse rates look like those with placebo Use of “impending” relapse as an endpoint does not prevent rehospitalization of patients who are not receiving anti-psychotic medication Withdrawal of medication in stable patients may have substantial socioeconomic effects even if patients are monitored closely

15. 15 Summary Placebo produces increased relapse compared to active medication in long-term trials –75% rehospitalization in community sample –48% rehospitalization with early intervention Early intervention strategies for rescue of placebo treated patients do not prevent relapse or rehospitalization Use of placebo leads to unacceptable risks