Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

Schizophrenia Clinical Trial

Official title:

Switching Antipsychotics: Abrupt Discontinuation Versus Overlap

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02640300
• Other study ID #: 4962
• Status: Completed
• Phase: Phase 4
• First received: December 22, 2015
• Last updated: January 5, 2016
• Start date: May 1999
• Est. completion date: July 2004

Study information

• Verified date: January 2016
• Source: Centre for Addiction and Mental Health
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: July 2004
• Est. primary completion date: July 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A and older

Eligibility

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 Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Psychotic Disorders
• Schizoaffective Disorder
• Schizophrenia

Intervention

Drug:
• Clozapine
Switching to clozapine with immediate or gradual antipsychotic discontinuation

Locations

Country	Name	City	State
Canada	Centre for Addiction and Mental Health	Toronto	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Centre for Addiction and Mental Health	The Ian Douglas Bebensee Foundation

Country where clinical trial is conducted

Canada, 

References & Publications (22)

Azorin JM, Spiegel R, Remington G, Vanelle JM, Péré JJ, Giguere M, Bourdeix I. A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia. Am J Psychiatry. 2001 Aug;158(8):1305-13. — View Citation

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. Epub 2003 Feb 28. — View Citation

Cerovecki A, Musil R, Klimke A, Seemüller F, Haen E, Schennach R, Kühn 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. Review. — View Citation

Chakos M, Lieberman J, Hoffman E, Bradford D, Sheitman B. Effectiveness of second-generation antipsychotics in patients with treatment-resistant schizophrenia: a review and meta-analysis of randomized trials. Am J Psychiatry. 2001 Apr;158(4):518-26. — View Citation

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. English, French. — View Citation

Devinsky O, Honigfeld G, Patin J. Clozapine-related seizures. Neurology. 1991 Mar;41(3):369-71. — View Citation

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. — View Citation

Ifteni P, Nielsen J, Burtea V, Correll CU, Kane JM, Manu P. Effectiveness and safety of rapid clozapine titration in schizophrenia. Acta Psychiatr Scand. 2014 Jul;130(1):25-9. doi: 10.1111/acps.12241. Epub 2013 Dec 20. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Lewis SW, Barnes TR, Davies L, Murray RM, Dunn G, Hayhurst KP, Markwick A, Lloyd H, Jones PB. Randomized controlled trial of effect of prescription of clozapine versus other second-generation antipsychotic drugs in resistant schizophrenia. Schizophr Bull. 2006 Oct;32(4):715-23. Epub 2006 Mar 15. — View Citation

McEvoy JP, Lieberman JA, Stroup TS, Davis SM, Meltzer HY, Rosenheck RA, Swartz MS, Perkins DO, Keefe RS, Davis CE, Severe J, Hsiao JK; CATIE Investigators. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006 Apr;163(4):600-10. — View Citation

Pacia SV, Devinsky O. Clozapine-related seizures: experience with 5,629 patients. Neurology. 1994 Dec;44(12):2247-9. — View Citation

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. — View Citation

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. Review. — View Citation

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. — View Citation

Souza JS, Kayo M, Tassell I, Martins CB, Elkis H. Efficacy of olanzapine in comparison with clozapine for treatment-resistant schizophrenia: evidence from a systematic review and meta-analyses. CNS Spectr. 2013 Apr;18(2):82-9. doi: 10.1017/S1092852912000806. Epub 2012 Dec 20. Review. — View Citation

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. — View Citation

Warnez S, Alessi-Severini S. Clozapine: a review of clinical practice guidelines and prescribing trends. BMC Psychiatry. 2014 Apr 7;14:102. doi: 10.1186/1471-244X-14-102. Review. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 22 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in the Brief Psychiatric Rating Scale (BPRS) total scores from baseline to 8 weeks		0 and 8 weeks	No
Secondary	Change in the Simpson-Angus Scale (SAS) total scores from baseline to 8 weeks		0 and 8 weeks	Yes
Secondary	Change in the Barnes Akathisia Rating Scale (BARS) total scores from baseline to 8 weeks		0 and 8 weeks	Yes
Secondary	Change in the Abnormal Involuntary Movement Scale (AIMS) overall severity scores from baseline to 8 weeks		0 and 8 weeks	Yes
Secondary	Change in the UKU Side Effect Rating Scale (UKU) subscale average scores from baseline to 8 weeks		0 and 8 weeks	Yes
Secondary	Change in the Clinical Global Impression - Severity scale (CGI-S) scores from baseline to 8 weeks		0 and 8 weeks	No
Secondary	Change in the Calgary Depression Scale for Schizophrenia (CDSS) total scores from baseline to 8 weeks		0 and 8 weeks	No
Secondary	Change in the Drug Attitude Inventory (DAI-10) total scores from baseline to 8 weeks		0 and 8 weeks	No
Secondary	Change in the Schedule for the Assessment of Insight (SAI) total scores from baseline to 8 weeks		0 and 8 weeks	No

External Links

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