Focus on clozapine: a new explanation for its atypical character.

Although atypical antipsychotics have become the treatment of choice for schizophrenia, there is no consensus on the mechanisms of action leading to the ‘atypical ’ character of these medications. Atypical antipsychotics are often referred to as ‘novel’, even though the prototypical antipsychotic of this series, clozapine, has been introduced into clinics for decades. Clozapine was found effective in some of the animal models predicting an antipsychotic action, for instance blockade of apomorphine-induced climbing, but not on models such as blockade of apomorphineinduced stereotypies. The dissociation between the effects of clozapine, which contrasts with those of the classical antipsychotics like haloperidol that is equally effective on both models, did not draw particular attention initially, was not recognized as an indication for a potential atypical clinical profile and is still incompletely understood. Psychiatrists using clozapine in psychotic patients at the time of its introduction in clinics were not particularly impressed by its therapeutic efficacy and were daunted by the serious side-effects that led to the discontinuation of the drug. The interest in clozapine was rejuvenated in 1988 after the publication of a double-blind clinical study showing the efficacy of clozapine in psychotic patients refractory to typical antipsychotics, such as chlorpromazine (Kane et al., 1988). Due to its potentially harmful side-effects, neutropenia and agranulocytosis, the use of clozapine is now restricted to patients who do not respond to other antipsychotic medications, under strict monitoring of peripheral neutrophil counts. There is no consensus on the definition of the term atypical antipsychotic. All psychiatrists agree that atypical antipsychotics elicit fewer extrapyramidal side-effects (EPS), which include Parkinson-like symptoms at the initiation of the treatment and tardive dyskinesia after long-term use, than typical antipsychotics. Indeed, lesser propensity to elicit EPS was noticed in all clinical trials with the more recent atypical antipsychotics olanzapine, risperidone or amisulpride. Importantly, the lower risk of side-effects attributed to atypical antipsychotics should be restricted to EPS, as weight gain and associated metabolic dysfunctions, such as diabetes and cardiovascular complications, are nowadays a serious concern with olanzapine, while amisulpride elicits hyperprolactinaemia. However, as far as efficacy is concerned, the data are more conflicting. The studies reporting on superior efficacy of atypical antipsychotics against positive symptoms of schizophrenia are confounded by the fact that comparator doses have often been excessive and controlling this factor eliminated such an advantage. Moreover, the advantage in efficacy is only seen in very large studies, suggesting that it is small, and is further compromised by a bias of recruitment of patients in these studies, which include a significant proportion of poorly responding patients. Regarding negative symptoms of schizophrenia, the alleged higher efficacy of atypical antipsychotics also seems modest, but has been documented in some studies. However, it is still not clear whether the superiority of clozapine on some dimensions represents a primary effect of the drug or an effect related to the absence of adverse effects Nevertheless, in recent meta-analyses, clozapine emerges above all antipsychotics in terms of effect size, followed by amisulpride and then olanzapine and Address for correspondence : Dr P. Sokoloff, INSERM U 573, Department of Neurobiology and Molecular Pharmacology, Centre Paul Broca, 7504 Paris, France. Tel. : +33 1 40 78 86 59 Fax : +33 1 45 80 72 93 E-mail : [email protected]