ADVERSE-EFFECTS OF ANTIPSYCHOTIC AGENTS - DO NEWER AGENTS OFFER ADVANTAGES

Although antipsychotic drugs are effective in treating the so-called p ositive features of schizophrenia, between one-quarter and one-third o f patients respond poorly. Furthermore, the incidence of adverse effec ts is high, especially those reflecting disruption of extrapyramidal f unction, and is a major source of noncompliance. 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 o n D-2 blockade as the key mechanism of antipsychotic action, dominated drug development, though the emphasis is now shifting. Three 'new' an tipsychotics 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 e ach of these, but as none is free from adverse effects, their place in treatment can only be meaningfully established in relation to the eff icacy of each in different clinical situations. Clozapine has an exten sive profile of general, nonhaematological adverse effects which is sl ightly different in emphasis from, but comparable in incidence to, tha t of chlorpromazine, There is a 0.8% risk of agranulocytosis in the fi rst year of exposure, which can be fatal, though the boundary separati ng it from other (especially phenothiazine) antipsychotics in this reg ard is becoming increasingly blurred. It has a clearly diminished liab ility to cause extrapyramidal adverse effects. Its proven efficacy in operationally defined treatment-resistant schizophrenia and in patient s intolerant to the extrapyramidal adverse effects of standard drugs e stablishes its credentials for advantage in these groups. There is on present evidence, however, only a hint of enhanced efficacy in acute s chizophrenia: this requires further investigation. Open maintenance st udies provide impressive data on long term outcome, especially in term s of quality-of-life parameters, but this issue requires to be address ed in blind, randomised trials. Until such additional information is f orthcoming the risks and consequent costs would not justify extension of its use. The evidence to date is that reported benefits in so-calle d negative features probably reflect its favourable neurological profi le. While the advantages of clozapine are undoubted, they remain as ye t restricted to selected patient groups. Remoxipride has a good genera l tolerability profile, its special strength being its low sedative ef fect. However, its reported association with aplastic anaemia has seve rely restricted its use, and regular haematological monitoring is requ ired, Although remoxipride appears to have a lower liability to produc e extrapyramidal adverse effects than the high potency haloperidol, it s benefits relative to other tow potency compounds in this regard rema in unproven. The only obvious situation in which its risks and consequ ent costs would be justified would seem to be patients with establishe d compliance problems as a result of intrusive sedation with standard drugs. The position of other benzamides such as raclopride and amisulp ride remains to be established.