Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

Sponsor

Centre for Addiction and Mental Health (Other)

Overall Status

Completed

CT.gov ID

NCT02640300

Collaborator

The Ian Douglas Bebensee Foundation (Other)

Enrollment

Location

Arms

Duration (Months)

0.5

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Schizophrenia Schizoaffective Disorder	Drug: Clozapine	Phase 4

Detailed Description

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 Design

Study Type:

Interventional

Actual Enrollment :

33 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

Study Start Date :

May 1, 1999

Actual Primary Completion Date :

Jul 1, 2004

Actual Study Completion Date :

Jul 1, 2004

Arms and Interventions

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

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

Outcome Measures

Primary Outcome Measures

Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks [0 and 8 weeks]

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Centre for Addiction and Mental Health	Toronto	Ontario	Canada	M5T 1R8

Sponsors and Collaborators

Centre for Addiction and Mental Health
The Ian Douglas Bebensee Foundation

Investigators

Principal Investigator: Gary Remington, MD, PhD, Centre for Addiction and Mental Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

The Centre for Addiction and Mental Health (CAMH) is the leading mental health and addictions research facility in Canada, and one of the largest in the world.

Publications

Responsible Party:

Gary Remington, Professor, Centre for Addiction and Mental Health

ClinicalTrials.gov Identifier:

NCT02640300

Other Study ID Numbers:

4962

First Posted:

Dec 28, 2015

Last Update Posted:

Jan 7, 2016

Last Verified:

Jan 1, 2016

Individual Participant Data (IPD) Sharing Statement:

Plan to Share IPD:

Keywords provided by Gary Remington, Professor, Centre for Addiction and Mental Health

antipsychotics, clozapine, schizophrenia, switching strategy

Additional relevant MeSH terms:

Schizophrenia

Psychotic Disorders

Clozapine

Study Results

No Results Posted as of Jan 7, 2016