Time to evaluate long-acting neuroleptics?

'The use of routine maintenance therapy is widespread—estimates of its frequency being 70%-90% in State Hospitals' (Gunderson et al, 1974). This comment on current practice in N. America can be matched by the chemotherapeutic treatment of schizophrenics in Great Britain and other European countries, where the majority of the patients have been receiving psychotropic drugs, mostly phenothiazines and butyrophenones, on a long-term basis for more than a decade. In the last five years the introduction of injected and oral long-acting drugs has given a marked impetus to this trend. Unfortunately, the formation of a satisfactory judgement on long-acting preparations has been hampered by lack of information on a number of questions. Of these the most fundamental are concerned with the pharmacodynamic action of these compounds. While they are known to cause widespread interference with enzymes and transmitters of the autonomic and central nervous system, the connexion between these effects and the aetiology of schizophrenia remains tentative and the subject of much speculation (Hornykiewicz, 1966; Kety, 1967; Mattock, et al., 1967; Vartanyan, 1969; Laduron, 1971; Stein and Wise, 1971; Matthyse, 1973, 1974; Fyro et al., 1974; Miller and Hiley, 1974; Pope, 1974; Rackensperger et al., 1974; Taylor, 1974; Trabucchi et ah, 1974; Vogt, 1974). It is also unclear whether the drugs or their metabolites are the active agents and whether their effect is specific or merely symptomatic. Since the relationship of drug concentrations in plasma and cerebrospinal fluid to their effects has not been established, the therapeutic dosage remains inevitably empirical. In practice, there appear to be enormous variations, which, of course, have a profound bearing on the important question of side-effects. Disquiet on this score has been increased by the use of long-term medication and is reflected in the current cataract of publications (De Alarcon and Carney, 1969; Simpson, 1970; Orlov et al., 1971; Allan and White, 1972; Grove and Crammer, 1972; Kazamatsuri et al., 1972; Mindham et al, 1972; Prien and Klett, 1972; Andrews, 1973; Ayd, 1973, 1974; Martin, 1973; Carney, 1974; Chien et ah, 1974; McClelland et al., 1974). In addition to the startling disparity in the reported incidence of side-effects (Simpson, 1970), it is surprising to find from controlled trials of maintenance treatment for schizophrenia, oral or injected, that anti-Parkinsonian medication is prescribed or increased as much for the patients on placebo as for those on active medication (Leff and Wing, 1971; Hirsch et al., 1973). This strongly suggests that something is lacking in the clinical identification and assessment of extrapyramidal symptoms, a conclusion reinforced by the findings of a blind trial of the efficacy of standard anti-Parkinsonian medication which failed to show a significant difference from a placebo in its effect on Parkinsonian symptoms (Mindham et al, 1972). The authors suggest that this 'calls into question the widespread practice of prescribing anticholinergic drugs in drug-induced Parkinsonism'. Comparing their own study with several others, they note that 'the evidence for the efficacy of anticholinergic drugs in Parkinson's disease itself is very limited' and conclude that 'All in all, the efficacy of anticholinergic drugs in drug-induced Parkinsonism is not well founded'. On the other hand, severe reactions were noted in some subjects on neuroleptics from whom anti-Parkinsonian medication was withdrawn, which were relieved by a resumption of the drug (Orlov et al, 1971; Grove and Crammer, 1972), though other workers have withdrawn antiParkinsonian drugs from patients on neuroleptics and have not reported such reactions (Ekdawi and Fowke, 1966; McClelland et al, 1974). Simpson (1970) has indicated a probable source of part of the difficulty in demonstrating that the elements of the drug-induced extrapyramidal syndrome vary in incidence, dose dependence, time of appearance, persistence, and response to specific medication.