Pimozide

Abstract
Synopsis: Pimozide1 1-(1-[4,4-bis(4fluorophenyl)butyl]-4-piperidinyl)-2-benzimidazolone, is the first of a new series of psychotropic drugs, the diphenylbutylpiperidines. It is advocated for once-daily use as maintenance therapy in chronic schizophrenia and for the treatment of psychic and functional disorders induced by personality traits. Published data suggest that in chronic schizophrenia, pimozide 4 to 6mg daily is indistinguishable from maintenance doses of chlorpromazine, fluphenazine, flupenthixol, perphenazine, or thioridazine. Patient groups have usually been too small to allow statistically significant differences to be apparent, but in some trials pimozide was significantly superior to trifluoperazine and to haloperidol. On present evidence, pimozide has no place in the hyperactive, aggressive type of patient or in treating the acute phase of schizophrenia, probably because of its relative lack of sedative properties compared with many anti-psychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide are low, but suitably designed controlled studies are needed to determine whether its use leads to a reduction in the requirement for antiparkinsonian medication. In anxious patients, pimozide seems to offer no advantages over currently available anxiolytic agents, either in terms of efficacy or incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven. Pharmacodynamic studies have demonstrated significant and prolonged central nervous system activity following oral and subcutaneous administration to animals in a variety of laboratory tests. Pimozide was found to possess typical neuroleptic properties with a profile more akin to that of haloperidol than chlorpromazine. It was typically slower in onset but longer in duration of action than either comparison drug in tests which included production of catalepsy or palpebral ptosis, and inhibition of shock avoidance or intracranial self-stimulation reactions. Like other neuroleptics, pimozide antagonises many of the actions of amphetamine and apomorphine, such as stereotyped behaviour and emesis, but it is not so effective as haloperidol or chlorpromazine in protecting animals against lethal doses of noradrenaline. It seems to be a specific blocker of central dopamine receptors, increasing turnover of brain dopamine but not noradrenaline. Pimozide causes a gradual decrease in food consumption and corresponding inhibition of weight gain in young animals. No dysmorphogenic or embryotoxic effects have been noted in long-term toxicity studies, though high-dose regimens have produced some incidences of mammary gland stimulation, prolonged anoestrus, follicular atresia and gingival hyperplasia. No significant alterations in cardiovascular haemodynamics have been observed after pimozide, and the drug has minimal activity on the autonomic nervous system. In man, the pharmacological effects of pimozide are essentially those affecting the central nervous system. High oral doses of 20mg daily were not well accepted by normal prison volunteers, requests for removal from the study coming from days 16 to 20 because of nervousness, restlessness, insomnia, drowsiness, listlessness, and fatigue. Maintenance doses in psychotic patients have failed to produce a similar incidence. In chronic schizophrenic patients, desynchronisation of the EEG is decreased, together with enhanced α-index (cortical activation), in those patients showing positive clinical response. There is still some dispute, however, as to whether the EEG effects of pimozide differ or are similar to those of the antipsychotic phenothiazines; a double-blind trial detected no difference between pimozide and trifluoperazine, both marginally increasing amplitude variability. Single oral doses of pimozide, 5 to 20mg, reduced the subjective euphoric response to subsequent intravenous injections of amphetamine in abusers of the drug. Cardiovascular changes have been insignificant in most therapeutic trials with occasional incidences of both mild hyper- and hypotension and non-specific T-wave changes in the EEG of a few subjects. There have been few reports of autonomic activity, except for occasional dryness of mouth. Pharmacokinetic studies: The absorption, distribution, metabolism, and excretion of pimozide have been well studied in animals but there are only limited data for man. Measurement of the tritium-labelled pimozide content of rat blood, brain, and liver following subcutaneous administration showed that the compound remained at constant maximal levels during the 8-hour period after dosing. The liver always contained about 11 times more unchanged pimozide than the blood and 36 times more than the brain. The distribution pattern was identical whether the drug was given orally or subcutaneously. Examination of the brain of dogs showed the highest concentration of drug to be in the pituitary and caudate nucleus. Study of the subcellular distribution suggested that the site of action for pimozide is the submicroscopic nerve endings of the caudate nucleus, an area of high dopaminergic activity. The pharmacological effects are due to unchanged pimozide, which is only slowly metabolised in the rat and the major metabolic pathway is oxidative N-dealkylation. Excretion studies in rats indicated that about two-thirds of administered pimozide is excreted in the faeces. Following oral dosage of 0.86mg tritiated pimozide to 3 patients with chronic schizophrenia, who were already on stable maintenance therapy of 2 to 4mg pimozide daily, peak plasma levels of about 5μg/100ml were achieved after about 8 hours followed by a decline over several days. Half-peak levels were maintained for 24 to 48 hours, and radioactivity was still detectable in the plasma after 14 days. Similar results were observed in studies in healthy female prison inmates, who received a single dose of 2mg tritiated pimozide. The pattern of absorption, which was identical for tablets or liquid concentrate, was similar to that in the psychotic patients, except that peak levels of 18 to 20μg/100ml were reached in about 3 to 6 hours. Plasma half-life in normal volunteers was about 18 hours. In human volunteers, the peak of urinary excretion of radioactivity occurred 2 to 6 hours after oral administration of 2mg tritiated pimozide, with approximately 45% of the dose being recovered in the urine over 96 hours. About 38% of the dose in chronic schizophrenic patients was excreted in the urine over 9 days, of which less than 1% was unchanged pimozide and two-thirds was 4-bis-(4-fluorophenyl)butyric acid. Faecal excretion in schizophrenic patients consisted mainly of unchanged pimozide, with about 5% being excreted as the butyric acid derivative. Therapeutic trials: In most controlled trials of pimozide as maintenance therapy in chronic schizophrenia, no significant difference has generally been found between pimozide and other antipsychotic drugs, possibly because of the small patient groups involved. Pimozide was significantly superior to placebo in most controlled studies. There appears to be no relationship between patient response and diagnostic category, sex, age, duration of illness, or previous antipsychotic therapy. The only positive correlation has been between response and symptomatology, that is pimozide is more effective in the apathetic, withdrawn type of patient than it is in the hyperactive, aggressive type. Claims that pimozide reduces the requirement for antiparkinsonian drugs have yet to be substantiated in suitably designed controlled trials. Variations in the criteria for patient selection and evaluation, and the wide dose ranges used in some studies, make inter-trial comparison very difficult. However, double-blind trials comparing pimozide with other antipsychotic drugs as daily maintenance therapy, and using both matched group and crossover analysis, have failed to find a significant difference between: pimozide (2.5 to 21 mg) and chlorpromazine (75 to 450mg) in 51 patients over 24 weeks; pimozide (7.5mg) and perphenazine (28mg) in 42 patients over 6 weeks; pimozide (2 to 16mg) and thioridazine (75 to 375mg) in 30 patients over 24 weeks; pimozide (3 to 8mg) and flupenthixol (6 to 12mg) in 12 patients over 30 weeks; and pimozide (1.5 to 10mg) and fluphenazine (2.5 to 21 mg) in a total of 144 patients in 5 separate trials lasting 8 to 30 weeks. Pimozide (3 to 6mg) was significantly superior to haloperidol (7 to 14mg) in a trial in 20 patients over 12 weeks. The general consensus of opinion in controlled trials is that maintenance doses of pimozide are indistinguishable from those of trifluoperazine, though they may be superior in improving psychomotor retardation and emotional withdrawal and some trials have indicated a significant overall advantage for pimozide. There is no evidence that pimozide is effective in acute schizophrenia or in the control of hyperactive and aggressive patients. Some investigators, however, feel that the doses used have been too low and that therapeutic effects may not be apparent until dose levels of up to 60mg are reached. Limited studies in children and adolescents suggest that the drug may be effective in treating behavioural disorders and schizophrenic-like symptomatology. Though significantly superior to placebo in patients with anxiety neurosis, pimozide has no advantages over currently available anxiolytic drugs, either in terms of efficacy or incidence of side-effects. Addition of pimozide to a therapeutic regimen of chlordiazepoxide did not result in a more rapid anxiolytic effect, an enhanced effect, a sparing of chlordiazepoxide dosage, or a reduced incidence of side-effects. Claims for a specific effect against anxiety associated with psychosis or disturbed personality traits remain unproven. Pilot trials suggest that pimozide may be of value in treating Huntington’s chorea and other dyskinesias which involve excessive dopaminergic stimulation in the brain, including the tardive oral dyskinesias associated with long-term use of antipsychotic drugs. Pimozide may be useful in generalised lipodystrophy. Side-effects: Extrapyramidal reactions such as akathisia and Parkinsonian symptoms are the most frequently observed side-effects of pimozide therapy, occurring in about 10 to 15% of patients. They are readily reversed by reduction in dosage or administration of antiparkinsonian drugs. Sedation is uncommon. Other effects such as insomnia, anorexia, weight loss and autonomic effects have been reported less frequently, and there have been rare instances of rashes, hypotension and glycosuria. Laboratory tests have failed to show any drug-related abnormality, and slit-lamp examinations have shown no changes in ocular pigmentation. Pimozide may lower the seizure threshold in both epileptic and non-epileptic patients. Overdosage has been rarely reported, but both adults and infants who have ingested the drug have recovered uneventfully in the absence of excessive extrapyramidal reactions following ingestion of 60 to 100mg of pimozide. Dosage: Pimozide is given orally in initial single daily doses of 2 to 4mg, which may be increased until the maintenance level is reached, usually about 6mg. The recommended maximum daily dosage is 10mg. Previous antipsychotic medication should be withdrawn gradually as patients are transferred to pimozide, particularly in those with signs of psychomotor agitation. The dosage in psychic and functional disorders is 2mg daily.
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