Long term anti-psychotic treatment in schizophrenia:

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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

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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

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1970s 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
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1970s Placebo Controlled Relapse Prevention
TrialTime to Relapse
Cumulative Relapse
Treatment Month
From Hogarty et al 1974
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1970s 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
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1990s Placebo Controlled Relapse Prevention
TrialStudy 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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1990s 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
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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

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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

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

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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