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


CONCLUSIONS
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.
Nosè
Michela
M
Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy. michela.nose@univr.it
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
D014150:Antipsychotic Agents / Q000627:therapeutic use*; D000068180:Aripiprazole; D002985:Clinical Protocols; D003024:Clozapine / Q000627:therapeutic use*; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D033161:Government Regulation; D006220:Haloperidol / Q000627:therapeutic use*; D006801:Humans; D007558:Italy; D010879:Piperazines / Q000627:therapeutic use*; D011446:Prospective Studies; D015363:Quinolones / Q000627:therapeutic use*; D012107:Research Design / Q000331:legislation & jurisprudence; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D010879:Piperazines; D015363:Quinolones; D000068180:Aripiprazole; D003024:Clozapine; D006220:Haloperidol