Bénéfices comparés des anti-psychotiques atypiques versus neuroleptiques classiques

Abstract

La clozapine est indiquée dans la schizophrénie résistante. La survenue d’une neutropénie constitue un effet indésirable rare de ce traitement, qui dans les recommandations internationales, justifie son arrêt et sa contre-indication ultérieure en raison de sa gravité. Néanmoins, devant l’inefficacité des antipsychotiques introduits après l’arrêt de la clozapine, la question de sa réintroduction se pose malgré la survenue d’une neutropénie.Cet article est une revue de la littérature concernant les protocoles mis en place lors de la réintroduction de la clozapine après neutropénie chez des patients schizophrènes résistants.Ces dernières années, sous couvert d’une surveillance accrue ou de molécules permettant d’augmenter le taux de polynucléaires neutrophiles circulants, la clozapine a pu être réintroduite durablement sans nouvelle complication. Les réintroductions rapportées dans la littérature sont de trois sortes : réintroduction simple, réintroduction avec association de lithium et/ou avec association de Granulocyte - colony stimulating factor (G-CSF).Les publications retrouvées, bien que d’un faible niveau de preuve, tendent à montrer qu’une réintroduction encadrée de précautions suffisantes peut se dérouler sans récidive de neutropénie et permettre une amélioration clinique du patient. Le choix de réintroduire cette molécule doit s’effectuer après une analyse bénéfice–risque scrupuleuse pratiquée au cas par cas. Il doit tenir compte en particulier des potentiels effets secondaires inhérents au lithium et au G-CSF et, de ce fait, conduire à privilégier autant que possible une réintroduction simple assortie d’une surveillance soigneuse.Dans l’ensemble, la réintroduction de la clozapine après neutropénie chez des patients schizophrènes résistants est une alternative à considérer au cas par cas après échec des autres stratégies thérapeutiques. Les données existantes demanderaient à être confrontées à la réalisation d’études comparatives.Clozapine is an atypical antipsychotic known for its efficacy in refractory schizophrenia. One of the adverse effects is neutropenia. This dysplasia is a rare but major side effect which leads to a discontinuation and constitutes further contraindication. Thereafter, therapeutic options decrease dramatically. Mechanisms involved are not well known at this time and can be combined. A toxic hypothesis may be more likely than an immune-allergic one.We have reviewed publications on Medline describing procedures that allowed clozapine rechallenge after blood dyscrasia in refractory schizophrenia. Three different procedures were found: simple rechallenge, rechallenge with lithium and rechallenge with Granulocyte - colony stimulating factor (G-CSF). Rechallenge could be simple or multiple.These past years, clozapine have been rechallenged successfully after neutropenia thanks to different procedures, the different options being simple rechallenge, rechallenge with lithium and/or rechallenge with G-CSF. Lithium as G-CSF are used to increase neutrophil blood rate and prevent neutropenia recurrence after clozapine rechallenge. G-CSF was first used within the context of chemotherapy and extends now to clozapine-induced neutropenia. Both for lithium and G-CSF, numerous procedures are reviewed and cannot be compared.Publications are limited but increasing, and they point out that a careful rechallenge can be successful. However, interesting data can be extracted. First, clozapine is more likely to be incriminated in neutropenia when patients receive many drugs, but a careful study could prevent some discontinuation. Indeed, other drugs or a hematologic disease could be involved. Moreover, several contributing factors have been found such as HLA group and drug interaction. Ethnic origin also affects neutrophil rate. That is why, in Great Britain, a subgroup of patients “benign ethnic neutropenia” has been introduced to enlarge threshold and allow these patients to access clozapine despite lower blood counts. Then, rechallenge choice has to be done on a case-by-case basis and only after considering the benefits and risks of such a treatment. Most of the time, clinical advice of rechallenge arises from the inefficiency of other antipsychotics and even sismotherapy failure. Patients and sometimes families have to be informed and give their consent. Preventive measures have been found such as taking a hematologic recommendation and doing twice-a-week blood sample monitoring. With regards lithium and G-CSF, some efficient doses are assumed (lithium: 0,4–1,1 mEq/L and G-CSF > 0,3 mg/week). Lithium as G-CSF may have other adverse effects which need to be considered. There is no successful rechallenge reported after agranulocytosis. Some publications highlight that if neutropenia occurs on rechallenge, it will do so more quickly and more severe than at the time of initial trial of clozapine.There is emerging evidence of successful clozapine rechallenging. However, further investigations are required as randomized controlled trials to reassess guidelines and establish the safety and effectiveness of the different procedures. Because of the practical and ethical difficulties of designing such studies, referral hospitals could be elected, and common background writing proposed in order to ease data comparison.