Clinical trial NCT02640300: Switching Antipsychotics: Abrupt Discontinuation Versus Overlap
Official title: Switching Antipsychotics: Abrupt Discontinuation Versus Overlap
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Schizophrenia
Schizoaffective Disorder
Keywords: antipsychotics, clozapine, schizophrenia, switching strategy
Lead sponsor: Centre for Addiction and Mental Health
Sponsor class: OTHER
Collaborators: name: The Ian Douglas Bebensee Foundation
First posted: 2015-12-28
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
Secondary outcomes:
measure: Change in the Simpson-Angus Scale (SAS) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Barnes Akathisia Rating Scale (BARS) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Abnormal Involuntary Movement Scale (AIMS) overall severity scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the UKU Side Effect Rating Scale (UKU) subscale average scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Clinical Global Impression - Severity scale (CGI-S) scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Calgary Depression Scale for Schizophrenia (CDSS) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Drug Attitude Inventory (DAI-10) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
measure: Change in the Schedule for the Assessment of Insight (SAI) total scores from baseline to 8 weeks
timeFrame: 0 and 8 weeks
Other outcomes:
Locations:
city: Toronto
country: Canada
facility: Centre for Addiction and Mental Health
state: Ontario
Study officials:
affiliation: Centre for Addiction and Mental Health
name: Gary Remington, MD, PhD
role: PRINCIPAL_INVESTIGATOR
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