Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

NCT02640300 | Completed Phase 4

• 1 other identifier: 4962
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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.

Conditions

Schizophrenia; Schizoaffective Disorder

Keywords

antipsychotics, clozapine, schizophrenia, switching strategy

Outcome Measures

Primary Outcomes (1)

• Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks

  0 and 8 weeks

Secondary Outcomes (8)

• 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

Study Arms (2)

Immediate discontinuation group

EXPERIMENTAL

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

Gradual discontinuation group

EXPERIMENTAL

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

Interventions

Clozapine DRUG

Switching to clozapine with immediate or gradual antipsychotic discontinuation

Also known as: Clozaril

Gradual discontinuation group; Immediate discontinuation group

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre for Addiction and Mental Health: lead
• The Ian Douglas Bebensee Foundation: collaborator

Study Sites (1)

Centre for Addiction and Mental Health

Toronto, Ontario, M5T 1R8, Canada

Location

Related Publications (23)

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  PMID: 24708834 BACKGROUND

• Collins EJ, Lalonde P, Jones BD, Addington D, MacCrimmon DJ, MacEwan GW, Teehan MD. Clozapine in the treatment of refractory schizophrenia: Canadian policies and clinical guidelines. Can J Psychiatry. 1992 Sep;37(7):482-96. doi: 10.1177/070674379203700704. English, French.

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  PMID: 7991106 BACKGROUND

• Ronaldson KJ, Fitzgerald PB, Taylor AJ, Topliss DJ, Wolfe R, McNeil JJ. Rapid clozapine dose titration and concomitant sodium valproate increase the risk of myocarditis with clozapine: a case-control study. Schizophr Res. 2012 Nov;141(2-3):173-8. doi: 10.1016/j.schres.2012.08.018. Epub 2012 Sep 23.

  PMID: 23010488 BACKGROUND

• Kinon BJ, Basson BR, Gilmore JA, Malcolm S, Stauffer VL. Strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine. J Clin Psychiatry. 2000 Nov;61(11):833-40. doi: 10.4088/jcp.v61n1105.

  PMID: 11105736 BACKGROUND

• Lee CT, Conde BJ, Mazlan M, Visanuyothin T, Wang A, Wong MM, Walker DJ, Roychowdhury SM, Wang H, Tran PV. Switching to olanzapine from previous antipsychotics: a regional collaborative multicenter trial assessing 2 switching techniques in Asia Pacific. J Clin Psychiatry. 2002 Jul;63(7):569-76. doi: 10.4088/jcp.v63n0706.

  PMID: 12143912 BACKGROUND

• Casey DE, Carson WH, Saha AR, Liebeskind A, Ali MW, Jody D, Ingenito GG; Aripiprazole Study Group. Switching patients to aripiprazole from other antipsychotic agents: a multicenter randomized study. Psychopharmacology (Berl). 2003 Apr;166(4):391-9. doi: 10.1007/s00213-002-1344-3. Epub 2003 Feb 28.

  PMID: 12610718 BACKGROUND

• Weiden PJ, Simpson GM, Potkin SG, O'Sullivan RL. Effectiveness of switching to ziprasidone for stable but symptomatic outpatients with schizophrenia. J Clin Psychiatry. 2003 May;64(5):580-8. doi: 10.4088/jcp.v64n0514.

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• Ganguli R, Brar JS, Mahmoud R, Berry SA, Pandina GJ. Assessment of strategies for switching patients from olanzapine to risperidone: a randomized, open-label, rater-blinded study. BMC Med. 2008 Jun 30;6:17. doi: 10.1186/1741-7015-6-17.

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• Pae CU, Serretti A, Chiesa A, Mandelli L, Lee C, Lee C, Kim J, De Ronchi D, Paik IH. Immediate versus gradual suspension of previous treatments during switch to aripiprazole: results of a randomized, open label study. Eur Neuropsychopharmacol. 2009 Aug;19(8):562-70. doi: 10.1016/j.euroneuro.2009.04.002. Epub 2009 May 12.

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• Stip E, Zhornitsky S, Potvin S, Tourjman V. Switching from conventional antipsychotics to ziprasidone: a randomized, open-label comparison of regimen strategies. Prog Neuropsychopharmacol Biol Psychiatry. 2010 Aug 16;34(6):997-1000. doi: 10.1016/j.pnpbp.2010.05.010. Epub 2010 May 12.

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• Weiden PJ, Citrome L, Alva G, Brams M, Glick ID, Jackson R, Mattingly G, Kianifard F, Meng X, Pestreich L, Hochfeld M, Winseck A. A trial evaluating gradual- or immediate-switch strategies from risperidone, olanzapine, or aripiprazole to iloperidone in patients with schizophrenia. Schizophr Res. 2014 Mar;153(1-3):160-8. doi: 10.1016/j.schres.2013.11.042. Epub 2014 Feb 12.

  PMID: 24529610 BACKGROUND

• Cerovecki A, Musil R, Klimke A, Seemuller F, Haen E, Schennach R, Kuhn KU, Volz HP, Riedel M. Withdrawal symptoms and rebound syndromes associated with switching and discontinuing atypical antipsychotics: theoretical background and practical recommendations. CNS Drugs. 2013 Jul;27(7):545-72. doi: 10.1007/s40263-013-0079-5.

  PMID: 23821039 BACKGROUND

• Remington G, Chue P, Stip E, Kopala L, Girard T, Christensen B. The crossover approach to switching antipsychotics: what is the evidence? Schizophr Res. 2005 Jul 15;76(2-3):267-72. doi: 10.1016/j.schres.2005.01.009.

  PMID: 15949658 BACKGROUND

• Kane J, Honigfeld G, Singer J, Meltzer H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry. 1988 Sep;45(9):789-96. doi: 10.1001/archpsyc.1988.01800330013001.

  PMID: 3046553 BACKGROUND

• Takeuchi H, Lee J, Fervaha G, Foussias G, Agid O, Remington G. Switching to Clozapine Using Immediate Versus Gradual Antipsychotic Discontinuation: A Pilot, Double-Blind, Randomized Controlled Trial. J Clin Psychiatry. 2017 Feb;78(2):223-228. doi: 10.4088/JCP.15m10286.

  PMID: 28234436 DERIVED

Related Links

• 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.

MeSH Terms

Conditions

Schizophrenia; Psychotic Disorders

Interventions

Clozapine

Condition Hierarchy (Ancestors)

Schizophrenia Spectrum and Other Psychotic Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Dibenzazepines; Heterocyclic Compounds, 3-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Gary Remington, MD, PhD

  Centre for Addiction and Mental Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 22, 2015
• First Posted: December 28, 2015
• Study Start: May 1, 1999
• Primary Completion: July 1, 2004
• Study Completion: July 1, 2004
• Last Updated: August 21, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)