Immediate versus gradual suspension of previous treatments during switch to aripiprazole: Results of a randomized, open label study

Abstract

The aim of the present work was to investigate possible differences in terms of efficacy and tolerability between different switching options to aripiprazole. 77 subjects were randomly assigned to (1) administration of aripiprazole (10 mg) with simultaneous discontinuation of current antipsychotic; (2) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 4 weeks with half dose after the first 2 weeks; (3) administration of aripiprazole (10 mg) and tapering off current antipsychotic over 6 weeks with half dose after the first 2 weeks. Efficacy assessments included CGI-S, CGI-I, BPRS and SANS. Safety assessments included SAS, BAS and AIMS. Severity of symptoms significantly decreased from baseline over the 12 weeks of treatment. Patients switched to aripiprazole with immediate discontinuation of the previous antipsychotic showed an increase of symptoms' severity at week 1. However, severity of side effects did not overall change significantly during the 12-weeks follow-up. Previous treatment's tapering off strategy for switching patients to aripiprazole could be preferable as compared to abrupt discontinuation, in order to prevent early worsening of symptoms and premature discontinuation of treatment, though this results has to be considered with caution given the limitations of the study.

Introduction

Aripiprazole is a new antipsychotic, a prototype of ‘third generation’ of antipsychotics, so called dopamine-serotonin-system stabilisers (Rivas-Vasquez, 2003), which efficacy was proved in many randomized controlled studies. In particular, it was found to be significantly better than placebo in decreasing relapse rates and increasing compliance (El-Sayeh et al., 2006); it showed comparable efficacy to typical and atypical antipsychotics (Bhattacharjee and El-Sayeh, 2008, El-Sayeh et al., 2006) and provided a significant advantage over them in terms of fewer extra-pyramidal symptoms and less prolongation of the average QTc interval (Bhattacharjee and El-Sayeh, 2008, El-Sayeh et al., 2006). Furthermore, aripiprazole is reported to be useful in all phases of schizophrenia and to enhance cognitive function (Rivas-Vasquez, 2003). In 2002, the drug was approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia and it is now included in recent guidelines for the treatment of the same disorder (Wilf, 2004).

Because of lack of response and induced side effects of many antipsychotics, switch from one antipsychotic to another is a common practice (Kane, 1987). However, only recently, analysis of the best switching strategy between antipsychotics has received attention. Up to recent years, how to switch from one antipsychotic drug to another was scarcely investigated and available evidence was mainly based on case series and case reports. In particular no definitive consensus was achieved between abrupt withdrawal of the previous medication and the gradual reduction of previous medication while the new antipsychotic was given (Essock et al., 2006, Kirov et al., 1997, Weiden, 2006, Weiden et al., 1997, Weiden et al., 1998). A review focusing on the transition from previous antipsychotic medications to risperidone concluded that clinicians should consider with caution the patient's clinical history and current status (Borison, 1996). A following review (Viguera et al., 1997) revealed that after abrupt discontinuation of oral medication, the risk of relapse reached 50% within 30 weeks, with little additional risk thereafter to 3.7 years and suggested that, since the risk was lower after gradually discontinuing oral antipsychotic therapy or stopping depot injections, early relapse may be avoided by applying a slow discontinuation of the previous drug.

The first systematic study investigating strategies for switching from conventional antipsychotic drugs or risperidone to olanzapine reported that switching to olanzapine was most successful when a full therapeutic dose of olanzapine was immediately initiated while gradually discontinuing prior conventional antipsychotic drug or risperidone treatment (Kinon et al., 2000). However, actual evidence is not univocal, in particular for the new antipsychotic aripiprazole. Clinical experience suggested that immediate switch to aripiprazole may worsen the positive symptomatology possibly because of the relative increase in dopamine transmission mediated by its agonistic activity (Raja, 2007, Ramaswamy et al., 2004).

This important issue was faced by a multi-centred study where patients were randomly assigned to 30 mg/day aripiprazole with simultaneous discontinuation of current antipsychotic, to 30 mg/day aripiprazole while tapering off current antipsychotic over 2 weeks, or up-titrating aripiprazole to 30 mg/day over 2 weeks, while simultaneously tapering off the current antipsychotic treatment. Surprisingly, no significant difference was found among the three groups at any time (Casey et al., 2003). Furthermore, data indicated that patients taking an antipsychotic medication could be switched to aripiprazole from their current antipsychotic medication with a minimal risk of symptom exacerbation or relapse in each case. A following meta-analysis about switching strategies of anti-psychotics did not support the superiority of a particular switching strategy as well (Remington et al., 2005). Despite this evidence, being clinical experience quite sound in the direction outlined before, recent clinical guidelines suggest that the recommended option is that prior antipsychotic should remain stable for several weeks after aripiprazole is introduced (Cassano et al., 2007, Sullivan, 2007). Nevertheless, a small recent trial also evidenced no difference between simultaneous discontinuation and gradual tapering off of the current antipsychotic (Takeuchi et al., 2008).

The present work therefore tried to clarify this debated issue investigating possible differences in terms of efficacy and tolerability between different switching options to aripiprazole. In particular we tested the hypothesis that abrupt discontinuation of previous treatment during switch to aripiprazole was associated to a worsening of clinical symptoms in the first weeks after the switch.