Switching antipsychotics. Antipsychotic tolerance, withdrawal and relapse: unresolved issues and research implications

Sir, Having shown that clozapine induces a discontinuation syndrome in rats (Goudie et al., 1999), some years ago we reviewed the clinical significance of this syndrome (Goudie, 2000). We suggested that withdrawal-induced stress facilitates relapse to psychosis, and that it is therefore important to study the interrelated topics of antipsychotic drug (APD) tolerance, withdrawal and relapse. We revisit this topic for various reasons: (i) recent studies suggest that APD withdrawal-induced relapse is of clinical significance; (ii) switching between APDs is increasing – this may well cause clinically important withdrawal effects, although there are often not clear switching guidelines (Chue et al., 2004; Weiden, 2006) and (iii) the issues involved suggest that important aspects of the psychopharmacology of APDs related to chronic administration have been largely ignored. The hypothesis that discontinuation syndromes may facilitate relapse derives historically from the work of Baldessarini et al. with lithium and APDs. They suggested that neuroadaptations to chronically administered drugs induce signs of such adaptations (i.e., discontinuation syndromes) that cause ‘stress’ on drug withdrawal. This can facilitate relapse (Baldessarini et al., 1999a, 1999b). In a major review of studies in patients withdrawn from APDs, Viguera et al. (1997) reported that rapid and gradual (over 3 weeks) withdrawal induced different relapse rates, rapid withdrawal inducing greater relapse. Persistent differences between gradual and rapid withdrawal were apparent six months after withdrawal initiation, suggesting, most importantly, that APD withdrawal can have longterm effects. A major recent study indirectly supports this basic idea. Essock et al. (2006) analysed data from the CATIE study (Lieberman et al., 2005) in a novel way. In this trial, patients on different types of baseline drug treatment were randomly allocated to various APDs. The trial measure was time to ceasing treatment. Essock et al. (2006) analysed the extent to which APD actions were affected by switching. Patients staying with their baseline APD remained in the trial for longer than those switched to another APD. There are various explanations for these important data. Switching may have been clinically detrimental because patients had stabilized on optimal baseline medication regimes and thus responded poorly to switching. Alternatively, dosing regimes may not have been equivalent for all drugs (Davis et al., 2006). However, the data may also be explicable in terms of discontinuation effects. APDs are an heterogeneous group of drugs, thus switching would have induced various different ‘between drug’ discontinuation syndromes, although this possible explanation of the findings was not considered by Essock et al. (2006). A major conclusion from this study is thus that, although we know that switching APDs is detrimental, we do not know the consequences of switching in terms of discontinuation effects, which will have varied as a result of both the drug switched from and that switched to. Our current understanding of ‘between drug’ discontinuation syndromes is very limited indeed. Other recent studies related to the issues under consideration are summarized in Table 1. Taken together, these findings suggest that both tolerance to and withdrawal from various different APDs can induce important, clinically relevant effects. Clozapine withdrawal clearly induces rapid relapse in a large proportion of patients, although such relapse can be ameliorated by medication with drugs that are not APDs. Clozapine withdrawal can also interfere with the subsequent clinical response to clozapine (Grassi et al., 1999) and other APDs (Gerlach et al., 1974; Meltzer et al., 1996; Tollefson et al., 1999). It seems highly likely that all APD treatments induce clinically important neuroadaptations during chronic drug administration, although the nature of such neuroadaptations remains unclear. The National Collaborating Centre for Mental Health (2003), commissioned by NICE, noted, as a major research recommendation, that APD discontinuation and its relation to relapse should be a research priority, although there seems to be very little systematic work in this area. We suggest that the issues involved actually reveal major gaps in the psychopharmacology of APDs. Most