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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