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Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia.

ABSTRACT: BACKGROUND: One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. METHODS/DESIGN: The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. DISCUSSION: The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia.

SUBMITTER: Nose M

PROVIDER: S-EPMC2689216 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia.

Nosè Michela M Accordini Simone S Artioli Paola P Barale Francesco F Barbui Corrado C Beneduce Rossella R Berardi Domenico D Bertolazzi Gerardo G Biancosino Bruno B Bisogno Alfredo A Bivi Raffaella R Bogetto Filippo F Boso Marianna M Bozzani Alberto A Bucolo Piera P Casale Marcello M Cascone Liliana L Ciammella Luisa L Cicolini Alessia A Cipresso Gabriele G Cipriani Andrea A Colombo Paola P Dal Santo Barbara B De Francesco Michele M Di Lorenzo Giorgio G Di Munzio Walter W Ducci Giuseppe G Erlicher Arcadio A Esposito Eleonora E Ferrannini Luigi L Ferrato Farida F Ferro Antonio A Fragomeno Nicoletta N Parise Vincenzo Fricchione VF Frova Maria M Gardellin Francesco F Garzotto Nicola N Giambartolomei Andrea A Giupponi Giancarlo G Grassi Luigi L Grazian Natalia N Grecu Lorella L Guerrini Gualtiero G Laddomada Francesco F Lazzarin Ermanna E Lintas Camilla C Malchiodi Francesca F Malvini Lara L Marchiaro Livio L Marsilio Alessandra A Mauri Massimo Carlo MC Mautone Antonio A Menchetti Marco M Migliorini Giuseppe G Mollica Marco M Moretti Daniele D Mulè Serena S Nicholau Stylianos S Nosè Flavio F Occhionero Guglielmo G Pacilli Anna Maria AM Pecchioli Stefania S Percudani Mauro M Piantato Ennio E Piazza Carlo C Pontarollo Francesco F Pycha Roger R Quartesan Roberto R Rillosi Luciana L Risso Francesco F Rizzo Raffella R Rocca Paola P Roma Stefania S Rossattini Matteo M Rossi Giuseppe G Rossi Giovanni G Sala Alessandra A Santilli Claudio C Saraò Giuseppe G Sarnicola Antonio A Sartore Francesca F Scarone Silvio S Sciarma Tiziana T Siracusano Alberto A Strizzolo Stefania S Tansella Michele M Targa Gino G Tasser Annamarie A Tomasi Rodolfo R Travaglini Rossana R Veronese Antonio A Ziero Simona S

Trials 20090515

<h4>Background</h4>One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers ha ...[more]

PMID: 19445659

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Project description:BackgroundAlthough clozapine is the treatment of choice for treatment-refractory schizophrenia, 30-40% of patients have an insufficient response, and others are unable to tolerate it. Evidence for any augmentation strategies is scarce. We aimed to determine whether cognitive behavioural therapy (CBT) is an effective treatment for clozapine-resistant schizophrenia.MethodsWe did a pragmatic, parallel group, assessor-blinded, randomised controlled trial in community-based and inpatient mental health services in five sites in the UK. Patients with schizophrenia who were unable to tolerate clozapine, or whose symptoms did not respond to the drug, were randomly assigned 1:1 by use of randomised-permuted blocks of size four or six, stratified by centre, to either CBT plus treatment as usual or treatment as usual alone. Research assistants were masked to allocation to protect against rater bias and allegiance bias. The primary outcome was the Positive and Negative Syndrome Scale (PANSS) total score at 21 months, which provides a continuous measure of symptoms of schizophrenia; PANSS total was also assessed at the end of treatment (9 months). The primary analysis was by randomised treatment based on intention to treat, for all patients for whom data were available. This study was prospectively registered, number ISRCTN99672552. The trial is closed to accrual.FindingsFrom Jan 1, 2013, to May 31, 2015, we randomly assigned 487 participants to either CBT and treatment as usual (n=242) or treatment as usual alone (n=245). Analysis included 209 in the CBT group and 216 in the treatment as usual group. No difference occurred in the primary outcome (PANSS total at 21 months, mean difference -0·89, 95% CI -3·32 to 1·55; p=0·48), although the CBT group improved at the end of treatment (PANSS total at 9 months, mean difference -2·40, -4·79 to -0·02; p=0·049). During the trial, 107 (44%) of 242 participants in the CBT arm and 104 (42%) of 245 in the treatment as usual arm had at least one adverse event (odds ratio 1·09, 95% CI 0·81 to 1·46; p=0·58). Only two (1%) of 242 participants in the CBT arm and one (<1%) of 245 in the treatment as usual arm had a trial-related serious adverse event.InterpretationAt 21-month follow-up, CBT did not have a lasting effect on total symptoms of schizophrenia compared with treatment as usual; however, CBT produced statistically, though not clinically, significant improvements on total symptoms by the end of treatment. There was no indication that the addition of CBT to treatment as usual caused adverse effects. The results of this trial do not support a recommendation to routinely offer CBT to all people who meet criteria for clozapine-resistant schizophrenia; however, a pragmatic individual trial might be indicated for some.FundingNational Institute for Health Research Technology Assessment programme.

Dataset Information

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia.

Publications

Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia.

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