Adverse effects of antipsychotic agents. Do newer agents offer advantages?

Although antipsychotic drugs are effective in treating the so-called positive features of schizophrenia, between one-quarter and one-third of patients respond poorly. Furthermore, the incidence of adverse effects is high, especially those reflecting disruption of extrapyramidal function, and is a major source of non-compliance. There is a clear need for new compounds that are more efficacious and/or better tolerated. Until recently, the classical dopamine hypothesis, with its emphasis on D2 blockade as the key mechanism of antipsychotic action, dominated drug development, though the emphasis is now shifting. Three 'new' antipsychotics have reached the international market in the past 5 years-the newly rehabilitated clozapine and the genuinely new remoxipride and risperidone. Claims of enhanced tolerability have been made for each of these, but as none is free from adverse effects, their place in treatment can only be meaningfully established in relation to the efficacy of each in different clinical situations. Clozapine has an extensive profile of general, nonhaematological adverse effects which is slightly different in emphasis from, but comparable in incidence to, that of chlorpromazine. There is a 0.8% risk of agranulocytosis in the first year of exposure, which can be fatal, though the boundary separating it from other (especially phenothiazine) antipsychotics in this regard is becoming increasingly blurred. It has a clearly diminished liability to cause extrapyramidal adverse effects. Its proven efficacy in operationally defined treatment-resistant schizophrenia and in patients intolerant to the extrapyramidal adverse effects of standard drugs establishes its credentials for advantage in these groups. There is on present evidence, however, only a hint of enhanced efficacy in acute schizophrenia: this requires further investigation. Open maintenance studies provide impressive data on long term outcome, especially in terms of quality-of-life parameters, but this issue requires to be addressed in blind, randomised trials. Until such additional information is forthcoming the risks and consequent costs would not justify extension of its use. The evidence to date is that reported benefits in so-called negative features probably reflect its favourable neurological profile. While the advantages of clozapine are undoubted, they remain as yet restricted to selected patient groups. Remoxipride has a good general tolerability profile, its special strength being its low sedative effect. However, its reported association with aplastic anaemia has severely restricted its use, and regular haematological monitoring is required. Although remoxipride appears to have a lower liability to produce extrapyramidal adverse effects than the high potency haloperidol, its benefits relative to other low potency compounds in this regard remain unproven. The only obvious situation in which its risks and consequent costs would be justified would seem to be patients with established compliance problems as a result of intrusive sedation with standard drugs. The position of other benzamides such as raclopride and amisulpride remains to be established. Risperidone, perhaps from its antiadrenergic actions, has more in the way of cardiovascular adverse effects than haloperidol, though these can be obviated by graded early exposure. It may also be associated with greater weight gain. Otherwise it appears to be well tolerated. In comparison with haloperidol, it appears to be associated with a lower prevalence of acute extrapyramidal adverse effects in dosages < or = 10 mg/day, the most potentially important component of which is its reportedly insignificant likelihood of promoting akathisia. These conclusions emerge from comparisons with haloperidol in doses many might consider somewhat high. The question of the advantage of risperidone over low or milligram-equivalent haloperidol regimens remains open. (ABSTRACT TRUNCATED)