Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

January 5, 2016 updated by: Gary Remington, Centre for Addiction and Mental Health
Clozapine has been demonstrated to be clinically superior to other antipsychotics in treatment-resistant schizophrenia (TRS), and is positioned as such in treatment guidelines. Because it is relegated to use in TRS, guidelines require that it only be used after other antipsychotics have failed; accordingly, clinicians routinely contend with stopping the previous antipsychotic in making the switch to clozapine. Perhaps because of its numerous and potentially severe side effects, the issue of clozapine titration has frequently been addressed, although to our knowledge no study has, as of yet, assessed the comparability of gradual vs. immediate antipsychotic discontinuation in switching to clozapine. To address the gap in knowledge specific to clozapine, the investigators conducted a pilot, 8-week, double-blind, randomized controlled trial examining immediate vs. gradual antipsychotic discontinuation in patients with schizophrenia undergoing a switch to clozapine.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Clozapine has been demonstrated to be clinically superior to other antipsychotics in treatment-resistant schizophrenia (TRS), and is positioned as such in treatment guidelines. Because it is relegated to use in TRS, guidelines require that it only be used after other antipsychotics have failed; accordingly, clinicians routinely contend with stopping the previous antipsychotic in making the switch to clozapine. Perhaps because of its numerous and potentially severe side effects, the issue of clozapine titration has frequently been addressed, although to our knowledge no study has, as of yet, assessed the comparability of gradual vs. immediate antipsychotic discontinuation in switching to clozapine.

While the question has not been asked vis-à-vis clozapine, there have been several studies examining gradual vs. immediate antipsychotic discontinuation in switching antipsychotics. Immediate antipsychotic discontinuation is associated with the following risks: (1) withdrawal/discontinuation symptoms or rebound syndromes related to cholinergic, histaminergic, and serotonergic activity; (2) supersensitivity syndromes (e.g., withdrawal dyskinesia, supersensitivity psychosis); and (3) exacerbation/re-emergence of symptoms secondary to diminished response with newly introduced antipsychotic. On the other hand, gradual antipsychotic discontinuation is associated with the risk of worsening/emergent side effects. This said, all of the studies, including one meta-analysis, report no differences in efficacy and safety between immediate and gradual discontinuation strategies in antipsychotic switching. However, it should be also noted that all of the studies were conducted under an open-label design or a single-blind design.

To address the gap in knowledge specific to clozapine, the investigators conducted a pilot, 8-week, double-blind, randomized controlled trial examining immediate vs. gradual antipsychotic discontinuation in patients with schizophrenia undergoing a switch to clozapine.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • Ontario
      • Toronto, Ontario, Canada, M5T 1R8
        • Centre for Addiction and Mental Health

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Child
  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Outpatients with a diagnosis of schizophrenia or schizoaffective disorder based on the Structured Clinical Interview for DSM-IV (SCID-I)
  • Candidacy for a trial of clozapine, defined as an inadequate clinical response to ≥ two antipsychotics (detailed in a pivotal clozapine study) and/or intolerable side effects

Exclusion Criteria:

  • Active substance use disorder; inability to undergo a trial of clozapine for medical reasons (e.g., myeloproliferative disorder or history of drug-induced granulocytopenia)
  • Evidence of significant nonadherence, defined as ≤75% adherence following patient interview, review of records, and discussion with treating physician and caregivers

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Immediate discontinuation group
The antipsychotic drugs that patients took at baseline were prepared in unmarked capsules, with the dose adjusted to provide a 25% reduction weekly over the next 3 weeks. The dose tapering schedule was as follows: 3 capsules at baseline, 2 capsules at week 1, 1 capsule at week 2, and 0 capsules at week 3. All capsules contained placebo (i.e., the antipsychotic drugs were abruptly discontinued). Clozapine was gradually increased to 300 mg/day according to the following schedule: 12.5 mg/day at day 0 and increased by 25 mg/day to 300 mg/day at day 12, with this dose maintained for three weeks and thereafter adjusted according to clinical judgment. Concomitant medications were kept constant throughout the study period.
Drug: Clozapine
Switching to clozapine with immediate or gradual antipsychotic discontinuation
Other Names:
  • Clozaril
Experimental: Gradual discontinuation group
The antipsychotic drugs that patients took at baseline were prepared in unmarked capsules, with the dose adjusted to provide a 25% reduction weekly over the next 3 weeks. The dose tapering schedule was as follows: 3 capsules at baseline, 2 capsules at week 1, 1 capsule at week 2, and 0 capsules (i.e., the antipsychotic drugs were discontinued) at week 3. Clozapine was gradually increased to 300 mg/day according to the following schedule: 12.5 mg/day at day 0 and increased by 25 mg/day to 300 mg/day at day 12, with this dose maintained for three weeks and thereafter adjusted according to clinical judgment. Concomitant medications were kept constant throughout the study period.
Drug: Clozapine
Switching to clozapine with immediate or gradual antipsychotic discontinuation
Other Names:
  • Clozaril

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
Change in the Simpson-Angus Scale (SAS) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Barnes Akathisia Rating Scale (BARS) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Abnormal Involuntary Movement Scale (AIMS) overall severity scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the UKU Side Effect Rating Scale (UKU) subscale average scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Clinical Global Impression - Severity scale (CGI-S) scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Calgary Depression Scale for Schizophrenia (CDSS) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Drug Attitude Inventory (DAI-10) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks
Change in the Schedule for the Assessment of Insight (SAI) total scores from baseline to 8 weeks
Time Frame: 0 and 8 weeks
0 and 8 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre for Addiction and Mental Health

Collaborators

The Ian Douglas Bebensee Foundation

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 1999

Primary Completion (Actual)

July 1, 2004

Study Completion (Actual)

July 1, 2004

Study Registration Dates

First Submitted

December 22, 2015

First Submitted That Met QC Criteria

December 22, 2015

First Posted (Estimate)

December 28, 2015

Study Record Updates

Last Update Posted (Estimate)

January 7, 2016

Last Update Submitted That Met QC Criteria

January 5, 2016

Last Verified

January 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 4962

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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