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Long term anti-psychotic Long term anti-psychotic treatment in schizophrenia:treatment in schizophrenia:
30 years of data and experience 30 years of data and experience Nina R. Schooler, Ph.D.
Georgetown University School of MedicineVISN 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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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
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1970’s Placebo Controlled Relapse Prevention TrialTime to Relapse
From Hogarty et al 1974
0
10
20
30
40
50
60
70
80
90
2 4 6 8 10 12 14 16 18 20 22 24
PBO
PBO+MRT
Drug
Drug+MRT
Treatment Month
Cum
ulat
ive
% R
elap
se
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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
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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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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
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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 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 NIMHSchooler et al 1997
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A 1980s – 1990s Placebo Controlled Trial Using an Early Intervention Strategy
Time to Relapse
Schooler et al 1997Months
Cu
mu
lativ
e P
rop
ort
ion
in T
rea
tme
nt
0
20
40
60
80
100
120
0 3 6 9 12 15 18 21 24
Moderate/Applied
Moderate/Supportive
Low/Applied
Low/Supported
Targeted/Applied
Targeted/Supportive
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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
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