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Medwave 2016;16(Suppl5):e6614 doi: 10.5867/medwave.2016.6614
¿Mejora la respuesta clínica al agregar un segundo antipsicótico a la clozapina en esquizofrenia resistente?
Does adding a second antipsychotic to clozapine improve clinical response in resistant schizophrenia?
Magdalena Jiménez-Cornejo, Gonzalo Munizaga, David Aceituno
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Resumen

La clozapina constituye el tratamiento de elección en los pacientes con esquizofrenia que no presentan remisión de los síntomas pese al manejo con antipsicóticos por periodos de tiempo y en dosis adecuados. Sin embargo, un porcentaje importante persiste sintomático pese al tratamiento con dosis óptimas de clozapina, por lo que se ha planteado que agregar un segundo antipsicótico podría mejorar la respuesta clínica. Utilizando la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en múltiples bases de datos, identificamos 17 revisiones sistemáticas que en conjunto incluyen 62 estudios, entre ellos 26 estudios aleatorizados pertinentes. Realizamos un metanálisis y tablas de resumen de los resultados utilizando el método GRADE. Concluimos que agregar un segundo antipsicótico a la clozapina en pacientes con esquizofrenia resistente probablemente resulta en poca o nula diferencia en la respuesta clínica, y aumenta los efectos adversos.


 
Problema

Existe entre un 20% a un 30% de los pacientes con esquizofrenia que se consideran resistentes al tratamiento, es decir, no presentan remisión de los síntomas pese al manejo con antipsicóticos por periodos de tiempo y en dosis adecuados [1]. Para este tipo de pacientes la clozapina es el tratamiento de elección [2], [3], [4]. Sin embargo, existe una proporción importante de los pacientes que persiste sintomático pese al tratamiento con dosis óptimas de clozapina [5]. Es por esto que se ha planteado que agregar un segundo antipsicótico podría mejorar la respuesta clínica, sin embargo, existe controversia sobre la real efectividad de esta medida. Por otra parte, se asocia a efectos adversos importantes, y a costos.

Métodos

Utilizamos la base de datos Epistemonikos, la cual es mantenida mediante búsquedas en 30 bases de datos, para identificar revisiones sistemáticas y sus estudios primarios incluidos. Con esta información generamos un resumen estructurado, siguiendo un formato preestablecido, que incluye mensajes clave, un resumen del conjunto de evidencia (presentado como matriz de evidencia en Epistemonikos), metanálisis del total de los estudios, tablas de resumen de resultados con el método GRADE, y tabla de otras consideraciones para la toma de decisión.

Mensajes clave

  • Agregar un segundo antipsicótico a la clozapina en pacientes con esquizofrenia resistente probablemente resulta en poca o nula diferencia en la respuesta clínica.
  • Los antipsicóticos son en general medicamentos de alto costo, cuyo uso en esquizofrenia es habitualmente por períodos prolongados y se asocian a una alta tasa de eventos adversos.
Acerca del conjunto de evidencia para esta pregunta

Cuál es la evidencia. 
Véase matriz de evidencia en Epistemonikos más abajo.

Encontramos 17 revisiones sistemáticas [5],[6],[7],
[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],
[18],[19],[20],[21] que incluyen 62 estudios
(reportados en 63 referencias) [22],[23],[24],[25],
[26],[27],[28],[29],[30],[31],[32],[33],[34],[35],
[36],[37],[38],[39],[40],[41],[42],[43],[44],[45],
[46],[47],[48],[49],[50],[51],[52],[53],[54],[55],
[56],[57],[58],[59],[60],[61],[62],[63],[64],[65],
[66],[67],[68],[69],[70],[71],[72][73],[74],[75],
[76],[77],[78],[79],[80],[81],[82],[83],[84], de
los cuales 26 corresponden a estudios controlados
aleatorizados [22],[23],[24],[25],[31],[34],[35],
[36],[37],[39],[40],[41],[43],[44],[48],[52],[58],
[62],[63],[64],[66],[67],[70],[75],[78],[79],[84].
Esta tabla y el resumen en general se basan en estos últimos.

Qué tipo de pacientes incluyeron los estudios

Todos los estudios incluyeron pacientes adultos, con diagnóstico de esquizofrenia (seis estudios según DSM IV o CIE 10 [31], [39], [44], [62], [63], [64]), con persistencia de síntomas psicóticos pese al tratamiento con clozapina, en dosis y duración adecuados.

Diecinueve estudios incluyeron también trastornos relacionados a esquizofrenia [22], [23], [24], [25], [31], [35], [39], [40], [41], [44], [48], [58], [62], [63], [64], [66], [70], [79], [84].

Los estudios incluyeron pacientes tanto ambulatorios como hospitalizados, sin comorbilidades mayores médicas o psiquiátricas.

Con respecto a la severidad del cuadro al inicio del estudio, 11 estudios reportaron PANSS >= a 60 [23], [24], [36], [41], [43], [44], [48], [52], [58], [64], [70], 11 estudios BPRS >= a 25 [22], [25], [31], [34], [35], [40], [63], [66], [78], [79], [84], dos estudios CGI >=4 [62], [75] y en el resto no se describió la severidad.

Qué tipo de intervenciones incluyeron los estudios

Todos los estudios compararon la adición de algún antipsicótico a clozapina contra clozapina sola o clozapina + placebo. Once estudios agregaron risperidona [23], [24], [39], [40], [43], [44], [48], [58], [62], [63],
 [64], cinco sulpiride [22], [25], [31], [70], [79], cuatro aripiprazol [34], [37], [66], [67], dos pimozida [35], [41], uno pipotiazina [84], uno haloperidol [52], uno ziprasidona [78], uno sertindol [36] y uno amisulpiride [75].

Qué tipo de desenlaces midieron

Los estudios midieron múltiples desenlaces, sin embargo, las diferentes revisiones sistemáticas los agruparon de la siguiente manera:

  • Respuesta clínica evaluada por una disminución de un 20% o más del puntaje en la escala PANSS o BPRS.
  • Falla en respuesta al tratamiento, recaídas, persistencia de síntomas psicóticos negativos y positivos, discontinuación de tratamiento,
  • Efectos adversos relacionados al sistema nervioso central: síntomas extrapiramidales, mareo, discinesia tardía, sedación
  • Efectos adversos relacionados al sistema cardiovascular: taquicardia, arritmias, bloqueos de rama.
  • Efectos adversos endocrinos: galactorrea, aumento de peso, aumento colesterol LDL.
  • Efectos adversos gastrointestinales: distensión abdominal, pérdida de apetito, constipación, salivación, náuseas.
  • Efectos adversos hematológicos: leucocitosis.
  • Otros efectos adversos: ansiedad, cefalea, insomnio, síntomas anímicos.
Resumen de los resultados

La información sobre los efectos de agregar un segundo antipsicótico a la clozapina está basada en 12 estudios aleatorizados [22], [25], [31], [39], [40], [44], [48], [58], [62], [63], [64], [79], los cuales incluyen a 771 pacientes. El resto de los estudios no midieron los desenlaces de interés o no entregaron datos que pudieran ser incorporados al metanálisis. El resumen de los resultados es el siguiente:

  • Agregar un segundo antipsicótico a la clozapina en pacientes con esquizofrenia refractaria probablemente resulta en poca o nula diferencia en la respuesta clínica. La certeza de la evidencia es moderada.
  • Agregar un segundo antipsicótico a la clozapina aumenta los efectos adversos. La certeza de la evidencia es alta.

Otras consideraciones para la toma de decisión

A quién se aplica y a quién no se aplica esta evidencia
  • Esta evidencia se aplica a pacientes adultos ambulatorios u hospitalizados, que cursan con esquizofrenia con persistencia de síntomas psicóticos pese al tratamiento con clozapina en dosis y por un periodo de tiempo adecuado.
  • No se aplica a pacientes cursando en forma intercurrente otros cuadros médicos o psiquiátricos graves como abuso de sustancias, depresión mayor o ideación suicida activa.
  • No se aplica a pacientes en los que se realiza aumento de la clozapina con fármacos distintos a antipsicóticos.
Sobre los desenlaces incluidos en este resumen
  • Se incluyeron los desenlaces críticos para la toma de decisión en este escenario clínico, de acuerdo a la opinión de los autores de este resumen. Estos coinciden con aquellos presentados en la mayoría de las revisiones identificadas, y las principales guías.
Balance riesgo/beneficio y certeza de la evidencia
  • Existe evidencia de moderada certeza para afirmar que agregar un segundo antipsicótico a la clozapina no mejora la respuesta clínica en esquizofrenia refractaria. En vista de que los efectos adversos relacionados al uso de antipsicóticos son frecuentes y pueden llegar a ser graves, el balance riesgo/beneficio no favorece su utilización.
  • Dentro de los principales efectos adversos reportados por los estudios se encuentran: hipersalivación, aumento de la prolactina sérica, síndrome metabólico, discinesia tardía, sedación, aumento de peso, alteraciones cognitivas, resistencia a la insulina, acatisia, agranulocitosis, crisis oculogiras, convulsiones, otros síntomas extrapiramidales, síndrome neuroléptico maligno, prolongación del intervalo QT.
Qué piensan los pacientes y sus tratantes
  • Si bien la evidencia existente debería llevar a la mayoría de los pacientes y tratantes a inclinarse en contra de la utilización de esta intervención, considerando que escasean las medidas efectivas demostradas para el manejo de pacientes con esquizofrenia refractaria al tratamiento con clozapina, creemos que algunos tratantes tenderán a favorecer su uso a pesar de la información entregada en este resumen, en especial considerando lo recomendado en las principales guías.
Consideraciones de recursos
  • En términos generales los antipsicóticos son de alto costo, y requieren un uso prolongado en el tiempo, por lo que implican un alto gasto de recursos, además de no tener beneficios y asociarse a efectos adversos. 
Diferencias entre este resumen y otras fuentes
  • En general, los hallazgos de este resumen concuerdan con los de las revisiones sistemáticas incluidas, aunque algunas refieren que existe evidencia de que el aumento con ciertos antipsicóticos podría ser eficiente y seguro [8], [10], [14], [16]. Tanto la guía NICE de esquizofrenia 2014 [85] como la guía APA para el tratamiento de la esquizofrenia [86] consideran el uso de un segundo antipsicótico agregado a la clozapina en pacientes con esquizofrenia resistente como una alternativa terapéutica válida.
¿Puede que cambie esta información en el futuro?
  • La probabilidad de que las conclusiones de este resumen acerca de los beneficios de agregar un segundo antipsicótico a la clozapina en pacientes con esquizofrenia resistente cambien con futura evidencia es baja debido a la certeza de la evidencia.
  • Identificamos al menos dos estudios en curso [87], [88] que abordan la temática en la International Clinical Trials Registry Platform de la Organización Mundial de la Salud, los cuales podrían entregar información relevante.
  • Nuevas revisiones sistemáticas de alta calidad y que incluyan una mayor proporción de estudios relevantes podrían entregar información útil, dado que las que identificamos tienen limitaciones importantes.

Cómo realizamos este resumen

Mediante métodos automatizados y colaborativos recopilamos toda la evidencia relevante para la pregunta de interés y la presentamos en una matriz de evidencia.

Siga el enlace para acceder a la versión interactiva: Agregar un segundo antipsicótico a la clozapina en esquizofrenia resistente

Notas

Si con posterioridad a la publicación de este resumen se publican nuevas revisiones sistemáticas sobre este tema, en la parte superior de la matriz se mostrará un aviso de “nueva evidencia”.  Si bien el proyecto contempla la actualización periódica de estos resúmenes, los usuarios están invitados a comentar en Medwave o contactar a los autores mediante correo electrónico si creen que hay evidencia que motive una actualización más rápida.

Luego de crear una cuenta en Epistemonikos, al guardar las matrices recibirá notificaciones automáticas cada vez que exista nueva evidencia que potencialmente responda a esta pregunta. El detalle de los métodos para elaborar este resumen están descritos aquí: http://dx.doi.org/10.5867/medwave.2014.06.5997.

La Fundación Epistemonikos es una organización que busca acercar la información a quienes toman decisiones en salud, mediante el uso de tecnologías. Su principal desarrollo es la base de datos Epistemonikos (www.epistemonikos.org).

Los resúmenes de evidencia siguen un riguroso proceso de revisión por pares interno.

Declaración de conflictos de intereses
Los autores declaran no tener conflictos de intereses con la materia de este artículo.

Licencia Creative Commons Esta obra de Medwave está bajo una licencia Creative Commons Atribución-NoComercial 3.0 Unported. Esta licencia permite el uso, distribución y reproducción del artículo en cualquier medio, siempre y cuando se otorgue el crédito correspondiente al autor del artículo y al medio en que se publica, en este caso, Medwave.

 

Clozapine constitutes the treatment of choice in patients with schizophrenia with persisting symptoms despite antipsychotics at adequate dose and treatment duration. However, an important proportion does not respond to optimal doses of clozapine, so the addition of a second antipsychotic might increase clinical response.

Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 17 systematic reviews comprising 62 studies addressing the question of this article, including 26 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding a second antipsychotic to clozapine in patients with refractory schizophrenia probably leads to little or no difference in clinical response, and increases adverse effects.

Autores: Magdalena Jiménez-Cornejo[1,2], Gonzalo Munizaga[1,2], David Aceituno[2,3]

Filiación:
[1] Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
[2] Proyecto Epistemonikos, Santiago, Chile
[3] Departamento de Psiquiatría, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

E-mail: daceituno@med.puc.cl

Correspondencia a:
[1] Facultad de Medicina
Pontificia Universidad Católica de Chile
Diagonal Paraguay 476
Santiago Centro
Chile

Citación: Jiménez-Cornejo M, Munizaga G, Aceituno D. Does adding a second antipsychotic to clozapine improve clinical response in resistant schizophrenia?. Medwave 2016;16(Suppl5):e6614 doi: 10.5867/medwave.2016.6614

Fecha de publicación: 2/12/2016

Ficha PubMed

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de Groot IW, Heck AH, van Harten PN. Addition of risperidone to clozapine therapy in chronically psychotic inpatients. J Clin Psychiatry. 2001 Feb;62(2):129-30 | PubMed |

Beauchemin MA, Millaud F, Nguyen KA. A case of neuroleptic malignant syndrome with clozapine and risperidone. Can J Psychiatry. 2002 Nov;47(9):886 | PubMed |

Benedetti A, Di Paolo A, Lastella M, Casamassima F, Candiracci C, Litta A, et al. Augmentation of clozapine with aripiprazole in severe psychotic bipolar and schizoaffective disorders: a pilot study. Clin Pract Epidemiol Ment Health. 2010 Jun 4;6:30-5 | CrossRef | PubMed |

Mossaheb N, Sacher J, Wiesegger G, Klein N, CJ, Asenbaum S, Kasper S. Haloperidol in combination with clozapine in treatment-refractory patients with schizophrenia. European Neuropsychopharmacology, (2006).16, 416 | Link |

Munro J, Matthiasson P, Osborne S, Travis M, Purcell S, Cobb AM, et al. Amisulpride augmentation of clozapine: an open non-randomized study in patients with schizophrenia partially responsive to clozapine. Acta Psychiatr Scand. 2004 Oct;110(4):292-8 | PubMed |

Rhoads E. Polypharmacy of 2 atypical antipsychotics. J Clin Psychiatry. 2000 Sep;61(9):678-80 | PubMed |

Koreen AR, Lieberman JA, Kronig M, Cooper TB. Cross-tapering clozapine and risperidone. Am J Psychiatry. 1995 Nov;152(11):1690 | PubMed |

Kaye NS. Ziprasidone augmentation of clozapine in 11 patients. J Clin Psychiatry. 2003 Feb;64(2):215-6 | PubMed |

Friedman J, Ault K, Powchik P. Pimozide augmentation for the treatment of schizophrenic patients who are partial responders to clozapine. Biol Psychiatry. 1997 Sep 15;42(6):522-3 | PubMed |

Ni J, Jang L, & Hong X. Therapeutic effects of clozapine, risperidone and their combination in the treatment of schizophrenia. Health Psychol J,(2001). 3, 181–182. | Link |

Stubbs JH, Haw CM, Staley CJ, Mountjoy CQ. Augmentation with sulpiride for a schizophrenic patient partially responsive to clozapine. Acta Psychiatr Scand. 2000 Nov;102(5):390-3; discussion 393-4 | PubMed |

Rajarethinam R, Gilani S, Tancer M, DeQuardo J. Augmentation of clozapine partial responders with conventional antipsychotics. Schizophr Res. 2003 Mar 1;60(1):97-8 | PubMed |

Mitsonis CI, Dimopoulos NP, Mitropoulos PA, Kararizou EG, Katsa AN, Tsakiris FE, et al. Aripiprazole augmentation in the management of residual symptoms in clozapine-treated outpatients with chronic schizophrenia: An open-label pilot study. Prog Neuropsychopharmacol Biol Psychiatry. 2007 Mar 30;31(2):373-7 | PubMed |

Weiner E, Conley RR, Ball MP, Feldman S, Gold JM, Kelly DL, et al. Adjunctive risperidone for partially responsive people with schizophrenia treated with clozapine. Neuropsychopharmacology. 2010 Oct;35(11):2274-83 | CrossRef | PubMed |

Josiassen RC, Joseph A, Kohegyi E, Stokes S, Dadvand M, Paing WW, et al. Clozapine augmented with risperidone in the treatment of schizophrenia: a randomized, double-blind, placebo-controlled trial. Am J Psychiatry. 2005 Jan;162(1):130-6 | PubMed |

Freudenreich O, Henderson DC, Walsh JP, Culhane MA, Goff DC. Risperidone augmentation for schizophrenia partially responsive to clozapine: a double-blind, placebo-controlled trial. Schizophr Res. 2007 May;92(1-3):90-4 | PubMed |

McCarthy RH, Terkelsen KG. Risperidone augmentation of clozapine. Pharmacopsychiatry. 1995 Mar;28(2):61-3 | PubMed |

Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008 May;69(5):720-31 | PubMed |

Fleischhacker WW, Heikkinen ME, Olié JP, Landsberg W, Dewaele P, McQuade R, et al. Weight change on aripiprazole-clozapine combination in schizophrenic patients with weight gain and suboptimal response on clozapine: 16-week double-blind study. European Psychiatry, (2008). 23, S114–S115. | CrossRef |

Raskin S, Katz G, Zislin Z, Knobler HY, Durst R. Clozapine and risperidone: combination/augmentation treatment of refractory schizophrenia: a preliminary observation. Acta Psychiatr Scand. 2000 Apr;101(4):334-6 | PubMed |

Tyson SC, Devane CL, Risch SC. Pharmacokinetic interaction between risperidone and clozapine. Am J Psychiatry. 1995 Sep;152(9):1401-2 | PubMed |

Xao H. A double-blind comparative study of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Sichuan Ment Health, (1999).12, 250–251 | Link |

Kontaxakis VP, Havaki-Kontaxaki BJ, Stamouli SS, Christodoulou GN. Toxic interaction between risperidone and clozapine: a case report. Prog Neuropsychopharmacol Biol Psychiatry. 2002 Feb;26(2):407-9 | PubMed |

Mowerman S, Siris SG. Adjunctive loxapine in a clozapine-resistant cohort of schizophrenic patients. Ann Clin Psychiatry. 1996 Dec;8(4):193-7 | PubMed |

Lerner V, Bergman J, Borokhov A, Loewenthal U, Miodownik C. Augmentation with amisulpride for schizophrenic patients nonresponsive to antipsychotic monotherapy. Clin Neuropharmacol. 2005 Mar-Apr;28(2):66-71 | PubMed |

Morera AL, Barreiro P, Cano-Muñoz JL. Risperidone and clozapine combination for the treatment of refractory schizophrenia. Acta Psychiatr Scand. 1999 Apr;99(4):305-6; discussion 306-7 | PubMed |

Assion HJ, Reinbold H, Lemanski S, Basilowski M, Juckel G. Amisulpride augmentation in patients with schizophrenia partially responsive or unresponsive to clozapine. A randomized, double-blind, placebo-controlled trial. Pharmacopsychiatry. 2008 Jan;41(1):24-8. doi: 10.1055/s-2007-993209 | PubMed |

Henderson DC, Goff DC. Risperidone as an adjunct to clozapine therapy in chronic schizophrenics. J Clin Psychiatry. 1996 Sep;57(9):395-7 | PubMed |

Anil Yağcioğlu AE, Kivircik Akdede BB, Turgut TI, Tümüklü M, Yazici MK, Alptekin K, et al. A double-blind controlled study of adjunctive treatment with risperidone in schizophrenic patients partially responsive to clozapine: efficacy and safety. J Clin Psychiatry. 2005 Jan;66(1):63-72 | PubMed |

Muscatello MR, Pandolfo G, Micò U, Lamberti Castronuovo E, Abenavoli E, Scimeca G, et al. Augmentation of clozapine with ziprasidone in refractory schizophrenia: a double-blind, placebo-controlled study. J Clin Psychopharmacol. 2014 Feb;34(1):129-33. | CrossRef | PubMed |

Si S, Yuan C. A comparative trial of the effects of sulpiride combined with clozapine in the treatment of schizophrenia. Shandong Arch Psychiatry, (1999).12, 17–20 | Link |

Chong SA, Tan CH, Lee HS. Atrial ectopics with clozapine-risperidone combination. J Clin Psychopharmacol. 1997 Apr;17(2):130-1 | PubMed |

Taylor CG, Flynn SW, Altman S, Ehmann T, MacEwan GW, Honer WG. An open trial of risperidone augmentation of partial response to clozapine. Schizophr Res. 2001 Mar 1;48(1):155-8 | PubMed |

Gupta S, Sonnenberg SJ, Frank B. Olanzapine augmentation of clozapine. Ann Clin Psychiatry. 1998 Sep;10(3):113-5 | PubMed |

Zink M, Knopf U, Henn FA, Thome J. Combination of clozapine and amisulpride in treatment-resistant schizophrenia--case reports and review of the literature. Pharmacopsychiatry. 2004 Jan;37(1):26-31 | PubMed |

Haibing Z, Guohang Y, Deqing D. A study of clozapine combined with or without pipotiazine palmitate in refractory schizophrenia. Journal of Clinical Psychological Medicine, (2002). 12(1), 15–17 | Link |

National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management 2014. | Link |

American Psychiatric Association. Practice guideline for the Treatment of Patients With Schizophrenia Second Edition,2010. | Link |

Sheng-Chang Wang, MD ,M Sc, Amisulpride Augmentation Therapy for Clozapine-resistant Schizophrenic Patients: A 14-week Randomized, Double-blind and Placebo-controlled Trial | Link |

Aalborg Psychiatric Hospital, Research Unit. Augmenting clozapine with sertindole - A double-blinded randomized placebo study (SERCLOZ) - SERCLOZ | Link |

Edición Julio 2022
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ISSN 0717-6384