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PIIVIOZiDE: PHARMACOLOGY AND CLINICAL USE

Pharmacodynamics
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 corning
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, desynchronisa-
tion of the EEG is decreased, together with enhanced a-index (cortical activation), in those patients showing positive
clinicalresponse. 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 triflu-
operazine, both marginally increasing amplitude variability. Single oral doses of pimozide, 5 to 20mg, reduced the
subjective euphoric response to subsequent intravenousjnjections of amphetamine in abusers of the drug. Cardio-
vascular 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.

Pharmacokinetics
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 5JJ.g/1 OOml 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
20}J.g/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 2lmg) 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 lOmg) and fluphenazine (2.5 to 2lmg) 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.

INPHARMA 21st August, 1976 p17


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. Umited studies in children aild 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 chlordiaze-
poxide 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 triais suggest thal pimozidc may be of value in treating Huntington's chorea and other dyskinesias which involve
excessive dopaminergic stimulation in the brain, including the tardive oral dyskii1esias associated with long-leon 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 anti parkinsonian 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 l OOmg of pimozide.

Pinder, R.M. et al.: Drugs 12: 1-40 (No 1, 1976) [130 references]

INPHARMA 21st August, 1976 p18