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The development of second-generation (atypical) antipsychotics (SGAs) has markedly increased the hopes of psychiatrists, patients and their relatives for a better pharmacological treatment of schizophrenia, and thereby for a better prognosis for this serious psychiatric illness. For a long time, clozapine was the only SGA available; in the 1990s, the new SGAs amisulpride, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine followed. Most of these drugs do not fulfil the original, although mostly informal, definition of atypicality (antipsychotic efficacy without the typical motor adverse effects); at higher doses they induce, to different degrees, extrapyramidal symptoms (EPS). Atypicality was found to be dimensional, not categorical, and that was one of the reasons why this term was replaced by 'SGA'.[1] However, this distinction is also pseudo-categorical and the difficulty of defining SGAs versus first-generation antipsychotics (FGAs) should be kept in mind in the discussion about potential differences between these two classes of drugs.
With these new antipsychotics, success criteria became more ambitious and included a more thorough consideration of negative and cognitive symptoms, both of which are of major relevance for long-term prognosis. The most important change since the early 1990s is the long overdue consideration of the patients' perspective. The (subjective) well-being/quality of life under antipsychotic treatment had been largely neglected or was of very limited scientific relevance, respectively. It might not be a coincidence that scientific interest in the subjective effects of antipsychotic drugs started with the availability of the SGAs, perhaps induced by the clinical experience that, in addition to the reduced motor symptoms, many patients reported less dysphoria or anhedonia, which might be the reason why most patients prefer the SGAs over the FGAs.[2,3]
Numerous double-blind, controlled studies have compared SGAs with FGAs, most often favouring SGAs, i.e. greater symptom reduction (particularly for negative, cognitive and affective symptoms) and better tolerability (notably regarding motor adverse effects). In reaction to these positive studies, most international evidence-based guidelines advocate first-line use of SGAs,[4-8] supported by several meta-analyses showing advantages of some, but not all, SGAs.[9-13] However, meta-analyses were not consistent, and the rather high dosage of haloperidol, which was most often used as the comparator drug, was, according to Geddes et al.,[14] the major reason for the misleading positive trials, although the later review by Davis...