Despite the wide differences in the potency of the neuroleptics in current use, and the differences in specificity regarding their effects on various neurotransmitter systems in the mammalian brain, there is little evidence to suggest that their overall efficacy in treating the symptoms of schizophrenia, mania and other psychoses markedly differs. Thus the ''classical'' neuroleptics appear to be effective in attenuating the positive symptoms of schizophrenia (e.g. hallucinations and delusions) without affecting appreciably the negative symptoms of the illness (lethargy and social withdrawal), although a critical analysis of the actions of neuroleptics on the positive and negative symptoms suggests that both types of symptoms, which may coexist in the patient simultaneously or occur at different times during the course of the illness, may be favourably influenced by those drugs. Whether these effects on the positive and negative symptoms can be explained in terms of changes in the functional activity of different subtypes of dopamine and other neurotransmitter receptors is presently uncertain.
Dopamine receptor adaptation occurs in response to chronic neuroleptic treatment, and this may be important in understanding both the efficacy and side effects of the drugs. Thus while the blockade of dopamine receptor functions is quite rapid, the clinical response does not occur for several days. Further, the extrapyramidal side effects which occur as a consequence of dopamine receptor blockade in the basal ganglia cause a sequence of changes beginning with dystonia and followed by akathisia and parkinsonism-like movements after several weeks or months of treatment. Tardive dyskinesia, should it occur, may take months or even years to be manifest. While attempts have been made to explain the complexity of these adverse neurological effects in terms of changes in dopamine receptor sensitivity arising as a consequence of prolonged dopamine receptor blockade in the basal ganglia, knowledge that the commonly used neuroleptics also interact with many other neurotransmitter systems in that region of the brain makes such an explanation implausible. Furthermore, orofacial dyskinesias occur to a significant extent in untreated schizophrenic patients and it is now well established that neuroleptics combined with the ageing process increase the prevalence of such disorders. Nevertheless, there is clear evidence from clinical studies on schizophrenic patients being treated with neuroleptics that changes in central dopaminergic function are related to the clinical response to treatment. Thus it has been shown that the free plasma concentration of homovanillic acid (HVA), the main metabolite of dopamine, correlates significantly with the antipsychotic effect of the phenothiazines. Undoubtedly the increased use of PET techniques to study neurotransmitter receptors in schizophrenic patients during neuroleptic treatment will provide invaluable information regarding the precise sites of action of these drugs in the patient's brain.
The serum concentrations of ''classical'' neuroleptics and their metabolites vary considerably in patients, even when the dose of drug administered has been standardized. Such interindividual variation may account for the differences in the therapeutic and side effects. High interindividual variations in the steady-state plasma levels have been reported for pimozide, fluphenazine, flupenthixol and haloperidol, some of these differences being attributed to differences in absorption and metabolism between patients.
Various factors may account for the variability in response to neuroleptics. These include differences in the diagnostic criteria, concurrent administration of drugs which may affect the absorption and metabolism of the neuroleptics (e.g. tricyclic antidepressants), different times of blood sampling, and variations due to the different type of assay method used. In some cases, the failure to obtain consistent relationships between the plasma neuroleptic concentration and the clinical response may be explained by the contribution of active metabolites to the therapeutic effects. Thus chlorpromazine, thioridazine, levomepromazine (methotrime-prazine) and loxapine have active metabolites which reach peak plasma concentrations within the same range as those of the parent compounds. As these metabolites often have pharmacodynamic and pharmacokinetic activities which differ from those of the parent compound, it is essential to determine the plasma concentrations of both the parent compound and its metabolites in order to establish whether or not a relationship exists between the plasma concentration and the therapeutic outcome.
Even in the case of drugs like haloperidol which do not have active metabolites, an unequivocal relationship cannot be found between the clinical effects and the plasma concentrations.
Fluphenazine enanthate, fluphenazine decanoate and haloperidol decanoate were developed as depot preparations to overcome many of the problems of oral neuroleptic administration, particularly lack of compliance, which has been estimated to be as high as 60% in outpatients. Depot neuroleptics produce a fairly predictable and constant plasma level and have the advantage of not being metabolized in the gastrointestinal tract or liver before reaching the brain. Despite the clear advantages of depot over oral preparations, the relapse rate among schizophrenic patients on such preparations over a 2-year period approaches 30%. The incidence of extrapyramidal side effects would also appear to be similar, but the longer half-life of the depot neuroleptic means that there is a longer delay before such symptoms may be controlled.
The relationship between plasma levels, drug doses and clinical response gives no clear guidelines for clinical practice. There is no convincing evidence that a ''therapeutic window'' exists for neuroleptics. Furthermore, there is little evidence to show that very high doses of neuroleptics improve the overall level of response or speed of resolution of an acute psychosis. High doses of neuroleptics may benefit those patients who fail to achieve optimal plasma concentrations on standard doses. Regarding the depot preparations, in a study in which patients treated with a low dose of fluphenazine decanoate (range 1.25-5.0 mg every 2 weeks) were compared with a group on a standard dose (range 12.5-50.0 mg every 2 weeks) over a 12-month period, the relapse rates were significantly higher in the low dose group (56% versus 7%). Furthermore, there was no clear advantage in the lower dose regarding the frequency of side effects or improved social functioning. It would seem that depot neuroleptics may be the appropriate method of drug administration for short-term treatment, just as orally administered neuroleptics have a place in long-term maintenance treatment.
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