# Presentation: 918835

## 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

## 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

## 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*

## 1970’s Placebo Controlled Relapse Prevention TrialTime to Relapse

*From Hogarty et al 1974*

- Treatment Month

- Cumulative % Relapse

## 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*

## 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*

## Slide 7

## 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*

## 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

## 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

## 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*

## A 1980s – 1990s Placebo Controlled Trial Using an Early Intervention StrategyTime to Relapse

*Schooler et al 1997*

- Months

- Cumulative Proportion in Treatment

## 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*

## 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

## 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