Switching Antipsychotics: Abrupt Discontinuation Versus Overlap
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 33
- 试验地点
- 1
- 主要终点
- Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 60 Years（Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
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.
干预措施: Clozapine (Drug)
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.
干预措施: Clozapine (Drug)
结局指标
主要结局
Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks
时间窗: 0 and 8 weeks
次要结局
- Change in the Barnes Akathisia Rating Scale (BARS) total scores from baseline to 8 weeks(0 and 8 weeks)
- Change in the Simpson-Angus Scale (SAS) total 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 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 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)
研究者
Gary Remington
Professor
Centre for Addiction and Mental Health