Long term anti-psychotic treatment in schizophrenia: 30 years of data and experience

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. 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. 1970’s Placebo Controlled Relapse Prevention TrialStudy 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. 1970’s Placebo Controlled Relapse Prevention TrialTime to Relapse Cumulative % Relapse Treatment Month From Hogarty et al 1974

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. 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

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

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. 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. 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