Evaluations on New Drugs

Drugs 12: 1-40 (1976)© ADIS Press 1976

Pimozide: A Review of Its Pharmacological Propertiesand Therapeutic Uses in Psychiatry

R.M. Pinder, R.N. Brogden, Phyllis R. Sawyer, T.M. Speight,Rosalind Spencer and G.S. A very

Australasian Drug Information Services. Auckland

Manuscript reviewed by: G.N. Bianchi, Department of Psychological Medicine, Christ­church Clinical School, Christchurch, New Zealand; D.P. Bobon, Clinique Psychiatrique,Universlte de Uege, Liege, Belgium; M.L. Clark, Central State Griffin Memorial Hospital,Norman, Oklahoma, USA; S. Gershon, Department of Psychiatry, New York UniversityMedical Centre, New York, USA; L.E. Hollister, Veterans Administration Hospital, PaloAlto, California, USA; D.A.W. Johnson, Department of Psychiatry, Withington Hospital,Manchester, England; I.H. Jones, Department of Psychiatry, University of Melbourne,Melbourne , Australia ; R.J. Naylor, Postgraduate School of Studies in Pharmacology,University of Bradford , Bradford , England; C. Perris, Department of Psychiatry, UmesUniversity, Umes, Sweden; B. Shopsin, Department of Psychiatry and Neuropsycho­pharmacology Research Unit, New York University Medical Centre, New York, USA;J.S. Werry, Department of Psychiatry, University of Auckland, Auckland, New Zealand .

Table ofContents

Summary. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21. Introduction .. . . . .... . . .. .. .. . . .. •.. . ... . . .. . .. ... .. 52. Pharmacodynamic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

2.1 Animal Studies 52.1.1 Design of Animal Tests . . . . . . . . . . . .• . . • . .. . . . . . . . . . . 62.1.2 Palpebral Ptosis and Catalepsy . .. .. . . . .. . ...• .. . ... . . . . 62.1.3 Effect on Avoidance Reactions .. . .... .. • ...... ... . ... . . 72.1.4 Antiamphetamine and Antiapomorphine Activities . . . . . . . . . . . . . . 72.1.5 Effect on Noradrenergic Systems . . . . . . . . . . . . . . . . . . . . . . . . 82.1.6 Effect on Dopaminergic Systems 92.1.7 Cardiovascular Effects 102.1.8 Antispasmodic Activity 102.1.9 Effects on Food Consumption 102.1.1 0 Endocrine Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102.1.11 Acute Toxicity 112.1.12 Chronic Toxicity .. . . . .. . . • . ... .. .... .. .. . . . ... . . 112.1.13 Dysmorphology and Reproduction Studies 11

2.2 Human Studies 122.2.1 Effects on the Central Nervous System 12

Pimozide: A Review

2.2.2 Amphetamine Responses2.2.3 Effect on EEG .2.2.4 Effect on Body Weight2.2.5 Onset and Duration of Action2.2.6 Autonomic Effects .2.2.7 Cardiovascular Effects .2.2.8 Psychometric Performance

3. Pharmacokinetic Studies .3.1 Animal Studies .

3.1.1 Absorption and Distribution3.L2 Metabolism and Excretion

3.2 Human Studies .3.2.1 Absorption .3.2.2 Metabolism and Excretion .

4. Therapeutic Trials .4.1 Design of Trials . .4.2 Chronic Schizophrenia . .

4.2.1 Comparison with Other Antipsychotic Drugs4.2.2 Comparison with Placebo .4.2.3 Which Symptoms Respond? .4.2.4 Other Determinants of Patient Response4.2.5 Use of Antiparkinsonian Drugs .4.2.6 Dosage and Duration of Action

4.3 Acute Schizophrenia ...4.4 Other Psychotic States . .4.5 Studies in Children . .4.6 Anxiety States .4.7 Dyskinesias .

4.7.1 Huntington's Chorea4.7.2 Tardive Dyskinesia . . .

4.8 Generalised Lipodystrophy5. Side-Effects .

5.1 Extrapyramidal Effects5.2 Epileptic Seizures . . .5.3 Cardiovascular Effects .5.4 Ocular Effects . . . . . . .

6. Drug Interactions . .7. Overdosage .8. Contra-Indications . . . . . .9. Precautions . .

10. Dosage . .

2

1212131314141414141415151516171718182525272727282829303232323333333334343434353535

Summary Synopsis : Pimozide' 1-(1-f4,4.bis(4·fluorophenyl)butyl}-a-piperidinyli-Zsbenzimidazo­lone, is the first of a new series of psychotropic drugs, the diphenylbutylpiperidines. It isadvocated for once-daily use as maintenance therapy in chronic schizophrenia and for thetreatment ofpsychic 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,

1 'Orap' (Janssen; McNeil)

Pimozide: A Review 3

perphenazine, or thioridazine. Patient groups have usually been too small to allow statis­tically significant differences to be apparent, but in some trials pimozide IWS significantlysuperior to trifluoperazine and to haloperidol. On present evidence, pimozide has no placein the hyperactive, aggressivetype ofpatient or in treating the acute phase ofschizophrenia,probably because of its relative lack of sedative properties compared with many anti­psychotic drugs. The incidence and severity of extrapyramidal reactions with pimozide arelow, but suitably designed controlled studies are needed to determine whether its use leadsto a reduction in the requirement for antiparkinsonian medication. In anxious patients,pimozide seems to offer no advantages over currently available anxiolytic agents, either interms of efficacy or incidence of side-effects. Claims for a specific effect against anxietyassociated with psychosis or disturbed personality traits remain unproven .

Pharmacodynamic studies have demonstrated significant and prolonged central nervoussystem activity following oral and subcutaneous administration to animals in a variety oflaboratory tests. Pimozide was found to possess typical neuroleptic properties with a profilemore akin to that of haloperidol than chlorpromazine. It was typically slower in onset butlonger in duration of action than either comparison drug in tests which included productionof catalepsy or palpebral ptosis, and inhibition of shock avoidance or intracranial self­stimulation reactions. like other neuroleptics, pimozide antagonises many of the actions ofamphetamine and apomorphine, such as stereotyped behaviour and emesis, but it is not soeffective as haloperidol or chlorpromazine in protecting animals against lethal doses ofnoradrenaline. It seems to be a specific blocker of central dopamine receptors, increasingturnover of brain dopamine but not noradrenaline. Pimozide causes a gradual decrease infood consumption and corresponding inhibition of weight gain in young animals. Nodysmorphogenic or ernbryotoxic 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 incardiovascular haemodynamics have been observed after pimozide, and the drug has minimalactivity on the autonomic nervous system.

In man, the pharmacological effects of pimozide are essentially those affecting thecentral nervous system. High oral doses of 20mg daily were not well accepted by normalprison volunteers, requests for removal from the study coming from days 16 to 20 becauseof nervousness, restlessness, insomnia, drowsiness, listlessness, and fatigue. Maintenancedoses in psychotic patients have failed to produce a similar incidence. In chronic schizo­phrenic patients, desynchronisation of the EEG is decreased, together with enhanceda-index (cortical activation), in those patients showing positive clinical response . There isstill some dispute, however, as to whether the EEG effects of pimozide differ or are similarto those of the antipsychotic phenothiazines; a double-blind trial detected no differencebetween pimozide and trifluoperazine, both marginally increasing amplitude variability.Single oral doses of pimozide, 5 to 20mg, reduced the subjective euphoric response tosubsequent intravenous injections of amphetamine in abusers of the drug. Cardiovascularchanges have been insignificant in most therapeutic trials with occasional incidences of bothmild 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 ofpimozide 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 liverfollowing subcutaneous administration showed that the compound remained at constantmaximal levels during the 8-hour period after dosing. The liver always contained about 11times more unchanged pimozide than the blood and 36 times more than the brain . Thedistribution pattern was identical whether the drug was given orally or subcutaneously.

Pimozide: A Review 4

Examination of the brain of dogs showed the highest concentration of drug to be in thepituitary and caudate nucleus. Study of the subcellular distribution suggested that the siteof action for pimozide is the submicroscopic nerve endings of the caudate nucleus , an areaof 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 oxidativeN-dealkylation. Excretion studies in rats indicated that about two-thirds of administeredpimozide 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, peakplasma levels of about 5/lg/100ml were achieved after about 8 hours followed by a declineover several days. Half-peak levels were maintained for 24 to 48 hours, and radioactivity wasstill detectable in the plasma after 14 days. Similar results were observed in studies inhealthy female prison inmates, who received a single dose of 2mg tritiated pimozide . Thepattern of absorption, which was identical for tablets or liquid concentrate, was similar tothat in the psychotic patients, except that peak levels of 18 to 20/lg/100ml were reached inabout 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 6hours after oral administration of 2mg tritiated pimozide, with approximately 45% of thedose 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 unchangedpimozide and two-thirds was 4-bis-(4-fluorophenyl)butyric acid. Faecal excretion inschizophrenic patients consisted mainly of unchanged pimozide, with about 5% beingexcreted as the butyric acid derivative.

Therapeutic trials: In most controlled trials of pimozide as maintenance therapy inchronic schizophrenia, no significant difference has generally been found between pimozideand other antipsychotic drugs, possibly because of the small patient groups involved.Pimozide was significantly superior to placebo in most controlled studies. There appears tobe no relationship between patient response and diagnostic category, sex, age, duration ofillness, or previous antipsychotic therapy. The only positive correlation has been betweenresponse 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 pimozidereduces the requirement for antiparkinsonian drugs have yet to be substantiated in suitablydesigned controlled trials.

Variations in the criteria for patient selection and evaluation, and the wide dose rangesused in some studies , make inter-trial comparison very difficult. However, double-blind trialscomparing pimozide with other antipsychotic drugs as daily maintenance therapy, and usingboth matched group and crossover analysis, have failed to find a significant differencebetween: pimozide (2.5 to 21mg) and chlorpromazine (75 to 450mg) in 51 patients over 24weeks; pimozide (7.5mg) and perphenazine (28mg) in 42 patients over 6 weeks; pimozide (2to 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) andfluphenazine (2.5 to 21mg) in a total of 144 patients in 5 separate trials lasting 8 to 30weeks. Pimozide (3 to 6mg) was significantly superior to haloperidol (7 to 14mg) in a trialin 20 patients over .12 weeks. The general consensus of opinion in controlled trials is thatmaintenance doses of pimozide are indistinguishable from those of trifluoperazine, thoughthey may be superior in improving psychomotor retardation and emotional withdrawal andsome trials have indicated a significant overall advantage for pimozide .

There is no evidence that pimozide is effective in acute schizophrenia or in the control ofhyperactive and aggressive patients. Some investigators, however, feel that the doses usedhave been too low and that therapeutic effects may not be apparent until dose levels of upto 60mg are reached. limited studies in children and adolescents suggest that the drug maybe effective in treating behavioural disorders and schizophrenic-like symptomatology.

Pimozide: A Review 5

Though significantly superior to placebo in patients with anxiety neurosis, pimozide hasno advantages over currently available anxiolytic drugs, either in terms of efficacy orincidence of side-effects. Addition of pimozide to a therapeutic regimen of chlordiazepoxidedid 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 effectagainst anxiety associated with psychosis or disturbed personality traits remain unproven .

Pilot trials suggest that pimozide may be of value in treating Huntington's chorea andother dyskinesias which involve excessive dopaminergic stimulation in the brain, includingthe tardive oral dyskinesias associated with long-term use of antipsychotic drugs. Pimozidemay be useful in generalised lipodystrophy.

Side-effects: Extrapyramidal reactions such as akathisia and Parkinsonian symptoms arethe most frequently observed side-effects of pimozide therapy, occurring in about 10 to15% of patients. They are readily reversed by reduction in dosage or administration ofantiparkinsonian drugs. Sedation is uncommon. Other effects such as insomnia, anorexia ,weight loss and autonomic effects have been reported less frequently, and there have beenrare instances of rashes, hypotension and glycosuria . Laboratory tests have failed to showany drug-related abnormality, and slit-lamp examinations have shown no changes in ocularpigmentation. Pimozide may lower the seizure threshold in both epileptic and non-epilepticpatients.

Overdosage has been rarely reported, but both adults and infants who have ingested thedrug have recovered uneventfully in the absence of excessive extrapyramidal reactionsfollowing ingestion of 60 to 100mg of pimozide.

Dosage: Pirnozide is given orally in initial single daily doses of 2 to 4mg, which may beincreased until the maintenance level is reached, usually about 6mg. The recommendedmaximum daily dosage is l Orng, Previous antipsychotic medication should be withdrawngradually as patients are transferred to pimozide, particularly in those with signs ofpsychomotor agitation. The dosage in psychic and functional disorders is 2mg daily.

1. Introduction

Pimozide is the first of a series of orally effec­tive long-acting antipsychotic drugs, the diphenyl­butylpiperidines. It is claimed to be structurallyunrelated to the classical tricyclic or butyro­phenone psychotropics, but a careful inspectionsuggests that there is some topographical similaritybetween them (Janssen, 1971) [fig. 1] .

2. Pharmacodynamic Studies

2.1 Animal Studies

Pimozide was found to possess typical neuro­leptic properties according to standard animal

experiments, and its activity was more similar tothat of haloperidol than to that of chlor­promazine. It was equally effective in mostlaboratory animal tests by either subcutaneous ororal administration. In most tests, pimozide wassignificantly slower in onset with a longer durationof action than haloperidol, whereas chlor­promazine was both shorter in onset and actionthan haloperidol.

Pimozide antagonises many of the actions ofamphetamine and apomorphine, such as hyper­activity, hyperthermia, and emesis. The drug wasnot so effective as haloperidol or chlorpromazinein protecting animals against lethal doses ofnoradrenaline and it had little effect on levels ofendogenous noradrenaline. Turnover of braindopamine was, however, significantly increased

Pimozide: A Review 6

F

Fig. 1. Structural formula of pimoz ide (I) and itsrelationship to the generalised formulae of the thioxan­thenes Oil. phenothiazines (1111 and butyrophenones(IV).

~~N(:::J

IV 0

2.1.1 Design ofAnimal TestsHollister (1972) has pointed out that anti­

psychotic drugs were first discovered as a result ofclinical observation, and pharmacological evalu­ation has subsequently taken place in laboratoryanimals. The resultant test procedures have thenbeen used to screen new compounds for similaractivity, in a closed circle of events. As yet , thereis no specific animal test which will unequivocallyidentify an experimental drug as antipsychotic incharacter, though there are a number of testswhich correlate the activities of clinically-useddrugs reasonably well with their antipsychoticactivity (see sections 2.1.2 to 2.1.6).

2.1.2 Palpebral Ptosis and CatalepsyResults of palpebral ptosis tests in rats (Janssen

et al. , 1968a) suggest that pimozide , orallyadministered, possesses weight for weight, activity4 times that of chlorpromazine and about half thatof haloperidol, as ptosis-inducing drugs. Pimozidewas significantly slower in onset with a longerduration of action than haloperidol, whereaschlorpromazine was both shorter in duration andfaster-acting than haloperidol. The lowest dose ofpimozide producing 40% or more ptosis was2.5mg/kg, either subcutaneously or orally.

In the production of catalepsy in rats, pimozideor haloperidol were equipotent orally, and about30 times as potent as chlorpromazine (Janssen etal., 1968a). Ptosis during handling was much lesscommonly associated with pimozide-inducedcatalepsy than it was with catalepsy induced bythe other two drugs, particularly chlorpromazine.Furthermore, pimozide, compared with halo­peridol or fluphenazine , produced only a relativelylow intensity of catalepsy (Costall and Naylor,1975).

In monkeys, pimozide (0.08mg/kg, sc), halo­peridol (0.08mg/kg, sc) and chlorpromazine(2.5mg/kg, sc) suppressed conditioned responsesand other behaviour possibly as a result ofcatalepsy. The ranking order of potency andduration of action was again haloperidol,

~YN~N;;::::!s~

III V

F

after pimozide, which seems to block central'dopaminergic receptors.

No significant alterations in cardiovascularhaemodynamics have been observed during animalexperiments with pimozide, and the drug hasminimal autonomic activity.

Pimozide: A Review

pimozide, chlorpromazine (Janssen et aI., 1968a) .In baboons; pimozide (0.5 to 2.5mg/kg, iv)produced mild sedation and some slowing in theEEG (Meldrum et aI., 1975) .

Subsedative dose (O.1mg/kg, im) of pimozideantagonised ketamine anaesthesia in dogs butpotentiated ketamine catalepsy (Hatch, 1974).

2.1.3 Effect on A voidance ReactionsIn tests designed to assess the inhibitory effects

of drugs on the avoidance reaction of rats tounpleasant stimuli, including noise or electricshock in either the jumping box or lever-pressing(Sidman apparatus) situations, pimozide had agenerally slower onset and a more prolonged effectthan either haloperidol or chlorpromazine (Janssenet aI., 1968a) . In these tests it was found to bemany times more active than chlorpromazinewhen given subcutaneously or orally, but theweight for weight potency was very similar to thatof haloperidol , that is an EDso of approximately0.1 to 0.2mg/kg. Similar effects were apparent indogs trained to avoid electric shock in a jumping­box. Pimozide, EDso O.1mg/kg (sc) or 0.2mg/kg(po), was about a half to two-thirds as potent ashaloperidol and about 23 times more potent thanchlorpromazine.

A similar trend in activity was apparent in ratscarrying monopolar electrodes in the medial fore­brain at the level of the lateral hypothalamus.Intracranial self-stimulation responses wereinhibited in a dose-related manner by anti­psychotic drugs; EDso values (sc) for pimozide,haloperidol and pipamperone were respectively0.22, 0.055 and 19.8mg/kg (Wauquier andNiemegeers, 1972). The centrally acting anti­cholinergic dexetimide completely abolishedpimozide-induced inhibition of self-stimulation inrats (Wauquier and Niemegeers, 1975) . Inhibitionby pimozide of self-stimulation in other brainareas, such as the nucleus accumbens and mesen­cephalon, appears to be mediated through bothdopaminergic and noradrenergic mechanisms(Liebman and Butcher, 1974; Phillips et al., 1975).

7

However, self-injection of apomorphine (Baxter etaI., 1974) or amphetamine (Yokel and Wise, 1975)was disrupted or enhanced by pimozide but not bynoradrenergic antagonists .

2.1.4 Antiamphetamine and AntiapomorphineActivitiesIn amphetamine and apomorphine antagonism

studies, tests which are supposed to be the mostsensitive animal procedures for predicting anti­psychotic activity (M¢ller-Nielsen et al., 1973),pimozide effectively inhibited the stimulation by,or the toxicity of, these compounds at dosesbelow that of chlorpromazine but greater thanthat of haloperidol (table I).

In animals, tolerance can develop rapidly to theantagonistic action of pimozide againstamphetamine- or apomorphine-induced stereo­typies but tolerance to the effects of pimozide inclinical practice has rarely been reported. Re­peated daily oral administration of 2.5mg/kg for12 days produced a 6-fold increase in the EDs 0 ofpimozide in antagonising apomorphine, 7 daysafter withdrawal of drug (M¢ller-Nielsen et al.,1974) .

In tests which were used to assess the ability ofdrugs to antagonise the stereotyped chewing move­ments and agitation in rats due to amphetamine orapomorphine, both pimozide and haloperidol wereactive against the chewing movements at doseswhich did little to affect the agitation, while thereverse was true for chlorpromazine (Janssen et al.,1968a). Again pimozide had a slower onset ofaction and longer duration of action than theother two drugs. Hill and Horita (1972) also notedinhibition of apomorphine-induced gnawing bypimozide in rabbits . Similarly, in monkeys, singledoses of pimozide were able to abolish ampheta­mine-induced stereotyped behaviour but did notaffect the reduced social behaviour.

Janssen et a1. (1968a) give the respectivesubcutaneous EDso values for pimozide and halo­peridol in the antiamphetamine and antiapo­morphine tests in rats as 0.11 and 0.032mg/kg,

Pimozide: A Review 8

Table 1. Comparative pharmacological activities inrats of pimozide, haloperidol, and chlorpromazineexpressed in terms of ED50 (data from Janssen et al.,1968a)

Rats, pretreated subcutaneously with one of thedrugs, received at varying times thereafter intravenousinjections of 10mg/kg amphetamine, or 1.25mg/kgeither apomorphine or noradrenal ine . The figures referrespectively to the lowest active dose, the lowest ED50(both in mg/kgl, the t ime to onset, and the durationof action (both in hours).

Chlorpromazine 0.160.631.252.8

Drug

Pimozide

Haloperidol

Antiam­phetamineact ivity 1

0.080.1129

0.020 .032<11.7

Antiapo­morphineactivity

0.160.1736.5

0.040.17<11

1.2510

< 11

Antinor­adrenalineactivity

10>40

1.253<16

0.310.60

< 11.7

(ED so, 4.2mg/kg), and apomorphine- or ampheta­mine-induced turning behaviour in mice withunilateral lesions of the striatal dopaminergic nerveterminals (EDso, 0.19mg/kg) [Dolphin et aI.,1975] .

Pimozide also inhibits such apomorphine­induced effects as hyperthermia in rabbits, hypo­thermia in rats and mice, and emesis and stereo­typy in dogs (Janssen et aI., 1968a; Hill andHorita, 1972; Rotrosen et aI., 1972; Grabowska etaI., 1973). Similarly, in laboratory animalsamphetamine-induced hyperthermia and hyper­kinesia are blocked by pimozide (Hill and Horita,1972; Matsumoto and Griffm, 1971; Schlechterand Butcher, 1972) as is levodopa-induced hyper­kinesia (Maj et aI., 1972) and the characteristicjumping response of mice to amphetamine­levodopa (La1 et aI., 1975). Pimozide is alsoeffective in antagonising the hypodipsia producedin rats by injection of amphetamine or apomor­phine (Nielsen and Lyon, 1973), and of a series of20 antipsychotic drugs pimozide was second onlyto fluphenazine in its ability to block compulsivegnawing induced in mice by methylphenidate(Pedersen and Christensen, 1972).

with pimozide being effective for 6.5 to 9 hours.In a comparison of pimozide with thioridazine asantagonists of amphetamine-induced stereotypedbehaviour in dogs, Klingenstein et a1. (1973) notedthat pimozide (OAmg/kg, im) was more effectivethan thioridazine (6mg/kg, im) at 1.5 hours afteradministration. At 20 hours, however, thioridazinewas as effective as pimozide had been at 1.5 hours.Janssen et a1. (1968a) give the ED so in blockingemesis in dogs as 0.012mg/kg (sc) and 0.018mg/kg(po) , and it is about 1.5 times as potent as halo­peridol by either route. Pimozide antagonisedapomorphine-induced stereotype in rats (ED so0.26mg/kg, ip), the apomorphine reversal ofreserpine-induced locomotor suppression in mice

2.1.5 Effect on Noradrenergic SystemsVarious antipsychotic drugs increase the

cerebral turnover of noradrenaline, causinga slightto moderate increase in the levels of endogenoustransmitter. However, with pimozide this effect isminimal (Anden et aI., 1970; Janssen et aI., 1968a;Keller et aI., 1973; Nyback et aI., 1970) [table I].The absence of alteration by pimozide of themetabolism of noradrenaline is consistent with thenegligible sedative properties of the drug in schizo­phrenic patients.

Pimozide resembles other antipsychotics inblocking the cyclic AMPresponse to noradrenalinein the limbic forebrain of the rat (Blumberg et aI.,1975). That this action may be involved in themode of action of antipsychotic drugs in man isindicated by the role of the limbic forebrain inintegrating sensory input from all the sensory

Pimozide: A Review

systems and relaying information to the hypo­thalamic and reticular areas.

2.1.6 Effect on Dopaminergic SystemsPimozide is a selective blocker of dopaminergic

receptors, and the turnover of brain dopamine isincreased following its administration to animals.Mathysse (1973) has noted that only the anti­psychotic diphenylbutylpiperidines, as well asphenothiazines or butyrophenones, have thischaracteristic effect . The drug is selectivelyretained in the nerve endings of the caudatenucleus in animals, a brain area almost exclusivelycomposed of dopaminergic neurons.

Soudijn and Van Wijngaarden (1972) notedthat pimozide does not influence either penetra­tion of (+).14 C-labelled amphetamine into thebrain, or its metabolism, and they concluded thatthe antiamphetamine action could not be due todecreased access of amphetamine to its sites ofaction, though an effect on its subcellular distri­bution was possible. However, the antiarnpheta­mine activity of pimozide correlated well with theshift of drug to the submicroscopic nerve endingsof the caudate, suggesting an involvement of theassociated dopamine receptors. Nyback et al.(1970) observed that the synthesis and disap­pearance of dopamine in mouse brain increasedduring pimozide treatment, in a manner similar tothat of other neuroleptics especially haloperidol.In a larger study, Anden et al. (1970) investigated15 antipsychotic drugs of phenothiazine , thiox­anthene, dibenzazepine, butyrophenone, anddiphenylbutylpiperidine types in rats. The drugsall blocked dopamine receptors in the striatum,pimozide being among the most effective incausing asymmetrical turning behaviour in animalswith unilateral striatal lesions (a dopaminergically­mediated effect). Pimozide was also among themost potent drugs in increasing turnover ofdopamine, and higher doses usually reduced thelevels of endogenous transmitter. However,pimozide was ineffective in blocking the levodopa­induced increase in the flexor reflex activity of

9

spinal rats (a noradrenergically-mediated effect) ,and had no effect on noradrenaline turnover.

Pimozide was more effective by a factor of 20in blocking apomorphine-induced emesis or stereo­typy in dogs than it was against the effects ofamphetamine (Rotrosen et al., 1971). Apo­morphine, in contrast to amphetamine whichprobably releases endogenous dopamine, has aclose structural resemblance to dopamine (pinder,1973). Indeed, studies of the structural require­ments for central dopamine-like activity, involvingstimulation of adenyl cyclase activity in vitro(Miller et al., 1974a) or a stereotyped behaviourfollowing intrastriatal injection (Costall et al.,1974) , suggest that antiapomorphine activity issynonymous with dopaminergic receptorantagonism. Certainly, antipsychotic diphenyl­butylpiperidines and other antipsychotic drugs,including pimozide, are among the most potent ofdrugs which inhibit dopamine-sensitive productionof cyclic-AMP in rat striatal homogenates in vitro(Miller et al., 1974b). The indications are thatpimozide is a specific antagonist at central ,probably striatal, dopaminergic receptors. Milleretal. (1974b) have suggested that the probableconformation of dopamine at its receptor sitescorresponds closely to those of the antipsychotics,at least as far as the important physicochemicalfeatures are concerned.

A recent in vitro study has established a directcorrelation between the clinical potency of anti­psychotic drugs and their effect in inhibiting theelectrically-stimulated release of dopamine fromrat striatal slices (Seeman and Lee, 1975).Pimozide was very effective in both respects.

Functional links probably exist between thedopaminergic and cholinergic systems in the brain(see Pinder, 1972) , and pimozide markedlydecreases striatal acetylcholine levels when givenalone to rats in doses of 0.5 mg/kg (Ladinsky etal., 1975). Furthermore, the centrally actinganticholinergic dexetimide abolishes bothpimozide-induced inhibition of self-stimulation inrats (Wauquier and Niegemeers, 1975) and the

Pimoz ide : A Review

pimozide-induced inhibition of mouse-jumpingdue to amphetamine-levodopa (Colpaert et al.,1975). Any role for acetylcholine in the mode ofaction of pimozide, however, is probablyexpressed through dopamine receptor blockade bythe neuroleptic drug, and its anticholinergicpotency is very low compared with other drugs ofthis type.

2.1. 7 Cardiovascular EffectsPimozide caused no significant alterations in

cardiovascular haemodynarnics in experiments inrats, dogs, and dwarf pigs (Janssen et al., 1968a).At the doses tested it exhibited only weaka-adrenergic receptor blocking activity and insig­nificant hypotensive action, even after relativelymassive doses of 2.5mg/kg (iv). In dwarf pigs,blood pressure, haematological values, and ECG'sremained normal after oral doses of Img/kg orintraperitoneal administration of 2.5mg/kg.Pimozide had no adverse haematological orelectrocardiographic effects during a l-year safetystudy (Janssen Pharmaceutica, unpublished data).

No vasoconstriction was observed in the in vitrorabbit ear vein preparation for assessing peripheralblood flow, with doses up to lOOJ..lg of eitherpimozide or haloperidol. Chlorpromazine, on theother hand , induced marked vasoconstriction atthis dose level. Janssen et al. (I 968a) also reportedthat pimozide did not significantly alter thedepressor effects seen during control experimentswith cat papillary muscle in vitro: chlorpromazineand haloperidol both produced significant negativeinotropic effects .

2.1.8 Antispasmodic ActivityPimozide, haloperidol, and chlorpromazine

have been compared for their abilities toantagonise the in vitro action of certain spas­mogens on guinea-pig ileum, rabbit duodenum,rabbit spleen, and rat stomach fundus (Janssen etal., 1968a) . All three drugs antagonised thespasmogenic effects of all the agents tested , that ishistamine, angiotensin , bradykinin, barium

10

chloride, nicotine, acetylcholine, adrenaline,noradrenaline, and 5-hydroxytryptamine, exceptfor the action of the latter on rat fundus. Pimozidewas more active against bradykinin-induced spasmsthan against any other type of contraction, thougheven here its EDso was only a modest 8 .96 x 10-8

g/ml.

2.1.9 Effects on Food ConsumptionGradual decreases in food consumption and

corresponding inhibition of body-weight gain inrats were observed with pimozide as well ashaloperidol and chlorpromazine . Pimozide wasagain much longer acting than the other twoantipsychotics. In dogs, only the highest doselevels (5mg/kg sc) of pimozide caused slight tomoderate suppression of food consumption, andtypical cataleptic effects were apparent at the dose(Janssen et al., 1968a). In one of the chronictoxicity tests carried out over I year, weight gainin beagles was inhibited only at the highest oraldose of 3mg/kg (Janssen Pharmaceutica, unpub­lished data) .

2.1.10 Endocrine EffectsIn a one-year safety evaluation of pimozide,

administered orally to dogs, histopathologicalfmdings suggested mammary gland stimulation atO.3Img/kg, prolonged anoestrus at 1.25mg/kg, andfollicular atresia at 2.5mg/kg, together with stimu­lation of the erythrosinophilic cells in the hypo­physis of femals receiving the higher doses. Beaglesalso received pimozide tablets for one year, whenmammary hyperplasia, not related to dose, wasfound among females; the condition regressed bythe third month (Janssen Pharmaceutica,unpublished data) .

Givant et al. (1973) studied the distribution,uptake, and effects of pimozide in ovariectornisedrats. High concentrations of drug were found inthe plasma and lung, but only moderate binding in

. the adrenals, kidneys and liver, with very lowuptake in the uterus and mammary glands. Uptakeinto lung, adrenals and brain was reduced on

Pimozide : A Review

oestradiol-primed rats . Pimozide markedlyinhibited milk yield in the rat , as reflected in lowerlitter weight , high pup mortality, and decreasedfood and water intake of the mothers; this effectwas in direct contrast to the advanced mammarydevelopment and elevated prolactin levels of theanimals.

Pimozide, 0.018 to 0.30mg daily for three days,reduced ovarian weight in immature rats treatedwith human chorionic gonadotrophin (Choudhuryet al., 1973). Apomorphine, on the other hand,stimulated ovarian development possibly becauseof its acute depleting action on pituitary follicle­stimulating hormone (FSH) levels. It is not clearwhether pimozide, or indeed apomorphine, exerttheir effects on FSH through inhibition orstimulation respectively of dopaminergic recep­tors.

2.1.11 Acute ToxicityOral LDso values for pimozide have been

determined in several species; mouse, 228mgJkg;rat, 10920mg/kg;guinea-pig, 188.8mg/kg;and dog,40mg/kg. The limiting toxicity of pimozide wasseen as tremor, ataxia, sedation and catalepsy , andclonic convulsions. Severe hypothermia, which is atypical feature of chlorpromazine-treated animals,was not observed with pimozide.

In the rat, the therapeutic ratio , that is theLDso to the EDso, after 7 days was 120,000(Janssen et al., 1968a).

2.1.12 Chronic ToxicityAn 18-month oral safety evaluation with daily

doses of pimozide of 0, 0.02, 1.7 or 13.3mg/kgwas conducted in rats (Janssen Pharmaceutica,upublished data) . There was no significantdifference in mortality between the control andexperimental groups of animals. Sedation wasinitially observed at all dose levels, but thisdecreased in the lower dose groups. Food con­sumption, and consequently body weight gain, waslower in animals of the two high-dose groups thanin controls. There were no significant changes in

11

haematological values or urinalyses . Mammaryenlargement was observed in females at all dosesand in two males at the highest dose level. Suchchanges are not uncommon following admini­stration of other potent antipsychotic drugs(Givant et al. , 1973). In a 3-week toxicity study inrats, Givant et al. (1973) observed that 20mg/kg(sc) of pimozide stunted growth while 5mg/kgcaused hypertrophy of the uterus and the ovaries.Pimozide was more active than either haloperidolor trifluoperidol in suppressing body organdevelopment , especially of the reproductivesystem.

In another study (McNeil Laboratories,unpublished data) beagles received pimozide astablets in daily doses of 0 , 0.5, 1.5, or 3.0mg/kgfor one year. Mammary hyperplasia, not dose­related, was found among female animals receivingthe drug but the condition regressed by the thirdmonth. Gingival hyperplasia was observed later inthe high dose-groups, being dose-related anddisappearing upon drug withdrawal. Weight gainwas inhibited in the high dose group. Pimozide hadno adverse haematological or electrocardiographiceffect or significant effect on renal or ocularfunctions.

2.1.13 Dysmorphology and ReproductionStudiesPimozide was evaluated for possible dys­

morphogenic effects in rats in a number of tests(Janssen Pharmaceutica, unpublished data). Oraldoses of 0, 0.04,0.31, or 2.5mg/kg were admini­stered to female rats during the following periods:from day 1 to 21 of pregnancy, from day 6 to 15of pregnancy, and from day 16 through 3 weeks oflactation. Utter data for the controls and the lowdose experimental animals were identical. Thesame doses administered to female or male rats for60 or 14 days before mating had little or no effecton fertility. From a total of 3,583 offspring fromthe controls there were 8 abnormal fetuses ,whereas 2,955 offspring from treated animalsyielded the same number of abnormalities.

Pimozide: A Review

Female rabbits received pimozide orally at doselevels of 0,0.16,0.63 or 2.5mg/kg from days 6 to18 after artificial insemination. Results fromcontrol and treated animals were similar except forincreased mortality of dams and increasedincidence of fetal resorption in the highest dosegroup.

2.2 Human Studies

2.2.1 Effects on the Central Nervous SystemThe pharmacological effects of pimozide in

man are essentially those affecting the centralnervous system. In studying tolerance in normalprison volunteers, Clark et al. (1971) reported thatoral doses of pimozide up to a maximum of20mg/day were not well accepted. Requests forremoval from the study generally occurred fromthe 16th to the 24th day, the principal complaintsbeing nervousness, restlessness, insomnia, drowsi­ness, listlessness, and fatigue. It should be noted ,however, that these subjects were normal healthyindividuals, who are likely to both complain morereadily of side-effects and be less motivatedtowards continuing with the drug.

Clinical trials using pimozide in schizophrenicpatients have reported little drowsiness orsedation. This absence concurs with the EEGevidence of Marjerrison et al. (1971) and Brasseur(1970) of increased cortical activation anda-rhythm in patients who responded to pimozideas opposed to the slowing-down of a-rhythminduced by most antipsychotic drugs. Recentevidence, however, suggests that pimozide andother antipsychotic drugs have similar effects onthe central nervous system (section 2.2.3; D'Elia etal.,1974).

Extrapyramidal effects have been observed insome patients, especially on higher doses ofpimozide, but the incidence due to pimozide maybe less than with many antipsychotic drugs (seesection 5).

12

2.2.2 Amphetamine ResponsesSingle doses of pimozide have been shown to

reduce the subjective euphoric response afterintravenous injections of amphetamine. Jonsson(1972) tested various compounds for theiramphetamine-blocking effects in abusers ofamphetamine. Compounds such as the o-adreno­receptor blocking agent phenoxybenzamine or the{j-adrenoreceptor blocking drug propranolol hadno significant effects in moderate to high doses.Chlorpromazine had to be givenat a dose of 50mg3 times daily for 4 days in order to obtain a signifi­cant effect, whereas single doses of 25 and 50mgdid not change the response to amphetamine.Single doses of thioridazine, 25 or 50mg given 4hours before amphetamine, were similarly inef­fective. However, pimozide was found to cause asignificant depression of the euphoric response tointravenous amphetamine (100 or 20Omg) afteroral doses of 5, 10, or 2Omg, though there was nodose-response relationship. Thus, pimozide at allthe doses studied reduced the maximal ampheta­mine-induced euphoria by about 50%.

Repeated administration of 5mg pimozide dailyfor 7 and 13 days respectively gave a similar degreeof reduction as the various single doses. During thefirst two days of administration (5mg daily),transient slight glossospasm and paraesthesia werenoted in 3 of 5 subjects. Pimozide also reduced theblood-pressure response to amphetamine, particu­larly its effect on the diastolic pressure. The bloodpressure after 13 days of pimozide, 5mg daily, wasabout the same as after a single dose, while thepulse rate was unaffected by the drug.

2.2.3 Effect on EEGMarjerrison et al. (1971) studied the effect of

pimozide on the EEG and the relationship toclinical response, using the technique of elec­tronically integrated EEG measurements todetermine EEG amplitude and its variability overtime. Comparisons were made of the changes inthe integrated EEG measures for those patientsshowing distinct clinical improvement as compared

Pimozide: A Review

with those who did not. It was apparent that thoseclinically improved patients (4) demonstrated asignificant decrease in signal variability (CV scores)over 4 weeks of treatment, while those who failedto respond (15) showed no change in EEG.Increased variability is characteristic of the anti­psychotic phenothiazines.

In his clinical trial, Singh (1971), from periodicEEG recordings on his patients, similarly reportedsignificant decreases in CV scores in those whoimproved on pimozide (21 patients) and generalincreases in mean integrated amplitudes. This againcompared with 10 patients who did not improveon the drug who showd no significant change inthese parameters. Results of frequency analysis inthis trial showed an increase of 1 to 3 Hz inpatients responding to treatment. This improve­ment occurred in all cases by the tenth week oftherapy, and, in the majority of cases, during thefirst four weeks. Brasseur (1969) reported aspeeding-up of the a-frequency by up to 1.5HZ inthose subjects who responded to treatment.

The results of these EEG studies suggest acortical activating effect on the patients whorespond to pimozide. Phenothiazines are usuallyassociated more with cortical deactivation, andabsence of sedation reported in most schizo­phrenic patients during pimozide treatmentconcurs with EEG evidence of increased a-rhythmin patients who respond, as opposed to the slowingdown of the rhythm in patients treated withphenothiazines. There is, however evidence that nosignificant difference exists between pimozide andtrifluoperazine in chronic schizophrenics in termsof their effects on the EEG (D'Elia et al., 1974).Objective EEG measurements in 20 femalepatients receiving either 3 to 5mg daily ofpimozide or 3 to 7.5mg trifluoperazine , taken at 1,3 and 5 weeks after starting treatment underdouble-blind conditions , showed no difference inintegrated amplitude. Moreover, in comparisonwth previous maintenance therapy, both drugsproduced a slight increase in amplitude variabilityduring the early phases of treatment followed by a

13

return to pretreatment levelswithin 5 weeks. Sinceboth drugs lack general sedative effects, it wouldbe interesting to compare the EEG effects inschizophrenic patients of pimozide directly with asedative phenothiazine.

Pimozide, given immediately prior to sleep indoses of 1 or 4mg, had no significant effect ontotal sleep, REM sleep, number of episodes ofREM, or total eye movements in 6 healthyvolunteers (Sagales and Erill, 1975). There were nodifferences between sleep patterns recorded pre- orpost-trial or during drug or placebo treatment.

2.2.4 Effect on Body WeightTherapeutic trials have produced conflicting

evidence as to whether or not patients treated withpimozide actually lose weight. Andersen etal. (1971, 1974) noted that an advantage ofpimozide over other antipsychotic drugs was thatpatients tended to lose weight rather than gain it ,an effect which occurs particularly with pheno­thiazines. However, the general consensus ofopinion seems.to be that there is no significant lossof weight during pimozide therapy .

2.2.5 Onset and Duration ofActionAnimal experiments have established that most

centrally-mediated actions of pimozide have aslower onset of action and a longer duration ofaction then either haloperidol or chlorpromazine(Janssen et al., 1968a). In man, the slow onset ofpimozide coupled with its weak antimanic activity,makes the drug unsuitable for control of theaggressive and hyperactive patient. QuantitativeEEG measurements in chronic schizophrenicssuggest that the attainment of full therapeuticbenefit with pimozide may be measured in termsof weeks rather than days (D'Elia et al., 1970). Itis claimed by some authors, for example Bobon etal. (1970) and La Roche (1968) to be effective for24 to 48 hours but most workers tend to favour aonce-daily dosage.

Pimozide has been extensively used as mainten­ance .therapy for chronic schizophrenia without

Pimozide : A Review

any sign of the development of tolerance to itsantipsychotic effects. It is interesting , therefore,that animal experiments suggest that tolerancedevelops rapidly to its antagonism of ampheta­mine- or apomorphine-induced stereotypies inrats, mice and dogs (see section 2.1.4).

2.2.6 Autonomic EffectsThe incidence of autonomic effects during

pimozide therapy is negligible, especially incomparison with many antipsychotics of thephenothiazine type which frequently lead toanticholinergic-type side-effects (Bobon et al.,1970). The only effect to be reported consistentlyhas been dryness of the mouth.

2.2.7 CardiovascularEffectsThe majority of investigations of ECG effects

during long-term pimozide therapy have failed toreveal any changes at either low or high doselevels. However, Clark et al. (1971), in a study ofhigh-dose pimozide (40mgjday) far above theusual therapeutic level, reported one patient whoshowed non-specific or primary T-wave changes onhis final ECG slightly over that present at the startof the study . These changes, as well as being non­specific, were readily influenced by other factors,and it seems unlikely that they were drug-related.Arfroidsson et al. (1971) reported similar effects,also in a single patient.

Pimozide does not generally have effects onblood pressure or pulse rate . No significantchanges were recorded from routine measurementsduring the therapeutic trials of Arfwidsson et al.(1971), Hellon (1971) Sugerman (1971), orGowardman et al. (1973). There have, howeverbeen occasional incidences of both mild increasesand decreases in blood pressure during pimozidetherapy but no true relationship to the drug hasyet been established (Chouinard et al., 1970;Claghorn, 1974).

2.2.8 Psychometric PerformanceJanke and Debus (1972) performed a double­

blind psychometric evaluation of pimozide versus

14

placebo in emotionally unstable volunteers undertwo different workload conditions, with specialconcern on performance and subjective experi­ence. Fifteen subjects were investigated using avariety of psychological tests.

Pimozide and haloperidol, at doses of 1 to 2mgorally, had effects which were dependent upon thesituation. Under low workload conditions (non­stress conditions) pimozide produced slight im­provement of performance in some areas, togetherwith emotional stabilisation and amelioration ofmood. Under high workload conditions, (stresssituations caused by performance of complexintellectual tasks), the effects of the drug werelittle changed whereas mental and motor perfor­mance deteriorated in subjects receiving halo­peridol. Most clinically effective anti-anxiety drugslike haloperidol have adverse effects on psycho­metric performance.

3. Pharmacokinetic Studies

The absorption , distribution, metabolism, andexcretion of pimozide have been extensivelyinvestigated in animals using trit ium- and carbon­labelled drug, but there is a relative paucity ofinformation regarding its pharmacokinetics inman. In general, it seems that pimozide reachespeak plasma levels within 2 to 6 hours of oral orsubcutaneous dosage, the portion that reaches thebrain is localised in certain areas particularly thedopaminergic nerve endings of areas such as thecaudate nucleus, and the pituitary. Its pharmaco­logical effects are probably due to unchanged drugand not to metabolites.

3.1 Animal Studies

3.1.1 Absorption and DistributionStudies in the rat clearly indicate that

pimozide is almost completely absorbed after oraladministration , and its distribution pattern is thesame whether it is given orally, subcutaneously, or

Pimozide: A Review

intravenously (Janssen and Allewijn, 1968; Givantet al., 1973). Measurement of the tritium-labelledpimozide content of rat blood, brain, and liverfollowing subcutaneous administration showedthat the compound and its metabolites remainedat constant maximal levels during the 8-hourperiod after dosing. During this period, 10% of thedose was stored in the liver, 0.7% in the blood, and0.1% in brain, though levels of unchangedpimozide were highest during the first hour; 3%inliver, 0.273% in blood, and 0.083% in brain. Theliver always contained about 11 times moreunchanged pimozide than the blood and 36 timesmore than the brain, the amount of drug in thecirculation thus exceeding the cerebral content bya constant factor greater than three. Biologicalhalf-life times for the three tissues are conse­quently identical, about 5.6 hours.

Pimozide metabolites could not be detected indog brain, in contrast to that of the rat, and all theradioactivity present following a subcutaneousdose of tritium-labelled pimozide was due tounchanged drug (Janssen et al., 1968b). Pimozidewas less effective by a factor of about 5 thanhaloperidol in localising in the brain after equiva­lent doses of the two drugs, the total cerebralcontent at time of sacrifice being 0.65% of thedose for haloperidol (after 3 hours) and 0.13% forpimozide (after 6 hours). The highest concen­tration of both drugs was found in the pituitarygland and the caudate nucleus, together with lesseramounts in the area postrema ; low doses ofhaloperidol but not of pimozide were also selec­tively retained by the cerebellum and parietalcortex, while the reverse applied to the lateralhypothalamus and the medula. Selective pimozideretention by the pituitary was very much higher(7.45 to 14.74 times the rest of the brain) at lowdoses (O.Olmg/kg), than it was (2.58 to 4.02times) at higher doses (0.63mg/kg). Studies of thesubcellular distribution of pimozide in the caudatenucleus of the dog, taken at the time of peakantiapomorphine actions of the drug, or in that ofthe rat, taken at the time of maximal anti-

15

amphetamine activity, showed that it localised atthe microscopic nerve ending (Janssen et al.,1968b; Soudijn and Van Wijngaarden, 1972).Though there was no correlation between caudateconcentrations of pimozide and its antiapo­morphine or antiamphetamine activities, a positivecorrelation was established between thesepharmacological effects and the subcellular distri­bution of the drug to the nerve endings.

3.1.2 Metabolism and ExcretionMetabolic studies suggest that the pharmaco­

logical effects of pimozide are due to unchangeddrug. Pharmacological effects occurred in dogs inthe absence of brain metabolites (Janssen et al.,1968b), while in the rat they correlated only withthe amount of unchanged pimozide and not withthe total pimozide plus metabolites in the brain(Soudijn and Van Wijngaarden, 1972). Pimozide isonly slowly metabolised in the rat with about halfof the subcutaneous dose being excreted in thefirst 48 hours, and the major metabolic pathway isoxidative N-deaIkyation (Soudijn and VanWijngaarden, 1969). About two-thirds of theadministered dose is excreted in the faeces, both asunchanged pimozide and as the three principalmetabolites, 4-bis{ 4-fluorophenyl) butyric acid,bis-(4-fluorophenyl) acetic acid, and N-4-piperi­dinylbenzimidazolin-2-one. The latter compoundis the major component of urinary excretion, butthere is no trace of carbonate which might havebeen formed by cleavage of the benzirnidazolinonering. None of these metabolites was active inpharmacological tests where pimozide was active.

3.2 Human Studies

3.2.1 AbsorptionIn studies in 3 patients with chronic schizo­

phrenia, who were already on a stable maintenancetherapy of 2 to 4mg pimozide daily, Baro et al.(1972) gave 0.86mg tritiated pimozide orally.Radioactivity was detected in the plasma soon

Pimozide : A Review

after drug administration and levels of tritiatedmaterial reached a peak of about 51lg/100rnlapproximately 8 hours after administration,followed by a decline over several days (fig. 2).Half-peak levels were maintained for about 24 to48 hours, and radioactivity was still detectableafter 14 days. The absorption pattern was notsignificantly different when the same experimentswere carried out in the same patients 70 days later.

Similar results were obtained in single-dosestudies in healthy female prison volunteers.(McNeil Laboratories, unpublished data). Onegroup of subjects received pimozide as a 2mgsoluble tablet and the other group received a liquidconcentrate containing 2mg pimozide. All subjectswere given the drug prior to breakfast following anovernight fast. The pattern of absorption , whichwas independent of formulation, was almostidentical to that in the chronic schizophrenicpatients, except that peak levels of 18 to20llg/100rnl were reached in about 3 to 6 hours.The plasma half-life of pimozide in healthy prisonvolunteers appears to be about 18 hours (JanssenPharmaceutica, unpublished data).

3.2.2 Metabolism and ExcretionMetabolism and excretion of pimozide in man

proceeds by much the same mechanism as inanimals. About 38% (23.5 to 59.5%) of the dose inchronic schizophrenic patients was excreted in theurine over 9 days, of which less than 1% wasunchanged pimozide and about two-thirds was4-bis-(4-fluorophenyl) butyric acid (fig.3) [Baro etal., 1972]. Faecal excretion over 4 to 7 daysconsisted mainly of unchanged pimozide, about5%being excreted as the butyric acid derivative. Inhuman volunteers, the peak of urinary excretionoccurred 2 to 6 hours after oral administration of2mg tritiated pimozide, with approximately 45%of the dose being recovered in the urine after 96hours (McNeil Laboratories, unpublished data).The principal urinary metabolite in volunteersappeared to be the benzimidazolinone derivative(Jenssen Pharmaceutica, unpublished data).

16

Hours lifter admin i'stntion

Fig. 2. Plasma levels of tr itiated pimozide (and/ormetabolites) following oral dosage of O.86mg in 3 patientswith chronic schizophrenia. Each value is the average of 6determinations, and the pat ients were already on a stablemaintenance therapy of 2 to 4mg pimozide daily (datafrom Baro et al., 1972).

50

37.5

~ 2.~·c

~<;"#. 12.5

Days after ildmin istration

Fig. 3. Cumulative urinary excretion of tritiated pimo­zide (and/or metabolites) following oral dosage of O.86mgin 3 patients with chronic schizophrenia. Each value is theaverage of 6 determinations and the patients were alreadyon a stable maintenance therapy of 2 to 4mg pimozidedaily (data from Baro et al., 1972).

Pimozide: A Review

Unchanged pimozide was not detectable in theplasma 72 hours after administration of O.86mg tochronic schizophrenic patients, but it is uncertainwhether the parent drug or any metabolites are thepharmacologically active species(Baro et al., 1972).

4. Therapeutic Trials

Pimozide has been studied in adult patientswith chronic schizophrenia (see section 4.2.),acute schizophrenia (see section 4.3), various otherpsychotic states (see section 4.4), anxiety (seesection 4.6) , and dyskinesias (see section 4.7). Ithas been given to children with a variety ofpsychiatric disorders (see section 4.5.) and in a fewcases of generalised lipodystrophy (see section4.8). In its major use as maintenance therapy inchronic schizophrenia, pimozide has beencompared in double-blind trials with placebo,chlorpromazine, fluphenazine, perphenazine ,trifluoperazine , thioridazine , carpipramine, halo­peridol, and flupenthixol (see section 4.2.1).

4.1 Designof Trials

Nowhere is the controlled therapeutic trial\

more necessary than in the evaluation of psycho-tropic drugs. It is made so by the very nature ofpsychiatric illness, in which not only are diagnosisand progress judgement inferential processes butalso the condition may often regress or deterioratespontaneously. Environmental factors play aconsiderable role in determining the course ofmany emotional disorders, particularly anxietyand depression, and the determination of drugeffects can be confounded by concurrent psycho­logical treatments designed to assist the patient.Nosological nomenclature tends to hide thegeneral ignorance of pathogenesis and the inabilityto identify diagnosis with pathological changes.Psychiatric rating scales, designed to minimise thesubjective nature of the judgement process have

17

the degree of validity and level of consensualagreement that characterises interpretation ofabnormal electrocardiograms or X-rays (Hollister,1972). However, they require careful training ofthe personnel using them, there is no one all­purpose scale, and no clinically meaningful normsexist.

Controlled therapeutic trials may eliminatemany of the vagaries due to extrinsic circum­stances. They are primarily based on adequatenumbers of patients with random allocation oftreatment, blind controls and investigators,objective recording, and statistical analysis ofresults. There are relatively few such studies withpimozide, either in comparison with anotherstandard antipsychotic drug or in comparison withplacebo. There is, on the other hand, a largenumber of uncontrolled trials in which pimozidehas merely been given to patients and theirresponse recorded. These latter studies will not beconsidered further except where valid conclusionscan be made or where controlled studies arelacking.

Many trials with pimozide have failed to useeither a drug-free period prior to the trial or acommon run-in drug. Drug-free periods have theadvantage that they may allow the patients 'condition to deteriorate often to the point whereeffects other than maintenance may be detected,and they may minimise any carry-over effect ofprevious medication. One of the more favouredprocedures in schizophrenic patients has been touse the same run-in drug as is being compared withpimozide. This is especially useful in comparisonsof effectiveness as maintenance therapy, butprecludes any conclusions being made about theefficacy of the drug as initial treatment and canoften lead to bias in favour of pimozide since anyimprovement with the standard drug may alreadyhave occurred prior to start of the actual trial.

The most commonly used method for ratingthe results of trials with pimozide is the BriefPsychiatric Rating Scale (BPRS) [table II] or anexpanded and up-dated modification such as the

Pimozide: A Review 18

Table II. The brief psychiatric rating scale (SPRS)

1 Each of the 18 symptoms is graded on a 7-pointscale, where a score of 1 indicates that the symptom isabsent and 7 signif ies the most severe grade of symptom(after Overall and Gorham. 1962).

Factor Construct Rating Scale. Other scales areavailable (Grayson , 1970) but they seem to offerlittle advantage over the BPRS and have been usedinfrequently in trials with pimozide. Some investi­gators have suggested that the BPRS is insuffici­ently sensitive to determine subtle differences indrug effects on the clinical aspects of chronicschizophrenics (Huber et aI., 1971; Pinard et al.,1972a,b), since the clinician's assessment ofschizophrenic behaviour puts prime emphasis onhis mental state with particular reference todelusions , hallucinations, thought disorder etc.Behavioural scales have been devised to measureother features , such as activity, social relationshipsand self-care (Honigfeld , 1965). However, evenwhen the medical and nursing assessments aremade there are yet other aspects of behaviourwhich are fequently overlooked. These are socialfunctioning in the widest sense - communityparticipation, family and group relationships,

Symptom cluster

Thinking disturbances

Withdrawal-retardation

Paranoidhostile-suspiciousness

Anxious-depression

Miscellaneous

Symptoms'

Conceptual d isorganisation,hallucinatory behaviour,unusual thought content

Emotional withdrawal, motorretardation. blunted affect

Hostility. suspiciousness. unco­operativeness

Anxiety, guilt feelings,depressive mood

Somatic concern. tension,mannerisms (posturing),grandiosity. excitement,d isorientation

decision making etc. Changes in this type of socialbehaviour are the most subtle indicators ofadequate functionining but they are measuredinfrequently in trials of pimozide or other drugs.

4.2 Chronic Schizophrenia

4.2.1 Comparison with other AntipsychoticDrugsMost controlled trials comparing pimozide with

other antipsychotic drugs as maintenance therapyin patients with chronic schizophrenia have failedto detect any significant difference overall,possibly because insufficient numbers of patientswere used (table III). Nevertheless, there aredefmite trends, in some cases statistically signifi­cant, towards pimozide in terms of its effects onfactors contributing to poor social adjustment ­emotional withdrawal, unusual thought content,hallucinations , delusions, blunted affect. Con­versely, it seems less effective than the anti­psychotic phenothiazines against excitement. Ingeneral , pimozide appears to be indistinguishablefrom other maintenance therapy, though it mayoffer some advantage in the apathetic, withdrawntype of patient. Variations in the criteria forpatient selection and evaluation, and the wide doseranges used in some studies, makes inter-trialcomparisons very difficult.

ChlorpromazinePimozide (mean dose 7mg) was not signifi­

cantly different from chlorpromazine (mean dose2l6mg) given once daily as a sustained-releaseformulation (Kolivakis et al., 1974). These authorscompared daily pimozide and sustained-releasechlorpromazine in 51 chronic schizophrenics whohad been stabilised on standard antipsychoticmedication (table III). The population included ahigh proportion of patients with emotionalwithdrawal, as well as blunted affect, and halluci­nations. Both pimozide and chlorpromazinesucessfully maintained control of symptoms in

Pimozide: A Review

patients who were previously stabilised on otherdrugs.

A significant reduction in total sympto­matology, as demonstrated by the mean totalBPRS score, was evident in both drug-treatedgroups, while the fmal measure of social per­formance showed that 87 to 90% of the patientswere maintained or improved by either therapy. Inthe 18 symptoms of the BPRS, both drugssignificantly reduced somatic concern, anxiety,tension, depressive mood, suspiciousness, motorretardation and blunted affect , but only pimozidesignificantly reduced emotional withdrawal ,conceptual disorganisation, hostility and unusualthought content. 90% of the pimozide patientsand all of the chlorpromazine group were eithermaintained or improved with therapy. Dropoutrates were similar, 7 from the pimozide group and9 from the chlorpromazine group; 4 patients ineach group withdrew because of intensifiedschizophrenic symptoms. This may indicate thatthe fmal analysis should be that about 75 to 80%improvement was obtained.

FluphenazineIn several controlled trials, the effects of

pimozide have been indistinguishable from thoseof fluphenazine. Chouinard et a1. (1970) studied20 chronic schizophrenics who had been hospital­ised for at least 2 years. Selection excluded thosewith physical illness or who had previouslyreceived fluphenazine. A 2-week drug-free periodprior to the trial led to a a significant deteriorationin both patient groups. Most patients receive lOmgdaily of pimozide or 15mg fluphenazine (in 2divided doses) for 12 weeks. The general improve­ment in the BPRS reached statistical significanceafter 1 week of drug administration but there wasno significant difference between the two drugsover 12 weeks. Both drugs improved emotionalwithdrawal, conceptual disorganisation, motorretardation, unusual though content, and bluntedaffect; fluphenazine additionally improvedanxiety, tension, mannerisms, and excitement

19

while pimozide improved hallucinatory behaviour.The effects of pimozide were statistically signifi­cant after 3 weeks of treatment whereas the effectof the phenothiazine derivative took 8 weeks toreach statistical significance, but this may havebeen due more to differences in the initial severityof symptoms than to any differences in speed ofaction .

Two other trials have been reported with thesedrugs under double-blind crossover conditions(Morris et al., 1970; Kenway and Masheter,1971a), and they have been summarised andcollated in a further report (Kenway et a1., 1971)[table III].

The first trial involved 30 male schizophrenics(14 paranoic, 2 catatonic, 14 with hebephrenicforms of the disease), with an average duration ofillness of 19.2 years. All had received previousantipsychotic medication. Patients were giveneither 3mg daily pimozide, increased to 9mg over2 weeks, or 5mg fluphenazine, increased likewiseto 15mg, each drug being given for 4 weeksfollowed by crossover to the alternate agent at theend of this period. Orphenadine l50mg daily wasgiven to all patients to prevent extrapyramidaleffects and thus preserve the double-blind natureof the trial. There was no significant differencebetween the treatments as measured by the BPRS,and in general the same patients responded orfailed to respond to each drug. Side-effects werepresent with both drugs but were more severe andfrequent with fluphenazine than with pimozide,particularly extrapyramidal reactions.

In the second trial , another group of 30patients included 20 who were younger and haddisease of shorter duration. No antiparkinsonianmedication was given; and the distribution oftypes of schizophrenia and the trial design weresimilar to the first trial. Average doses of 2.9mgpimozide gave overall similar results to 4.9mgfluphenazine, though pimozide was more effectivewhen given second than first. The only frequentside-effect was tremor, which occurred in half ofthe patients with both drugs. However, before the

Table III. Summary of double-bl ind t rials in wh ich p imoz ide has been compared with other ant ipsychotic drugs as maintenance therapy in pat ients "C

with chronic schizophrenia 3'0N

Author No. pts Duration Daily dose in Daily dose in Results1,2,3 c:co

trial (wks) rng of pimoz ide rng of other l-(mean) drug (mean) overall individual symptoms :xl

co<

Chlorpromazineiii'~

Kol ivak is et al. (1974) 51 24 2.5-21 .0 75-450 Pim = Cpz Pim > Cpz(7.0 ) (216) (emot ional w ithdrawal)

Fluphen azineCesareket al. (1974) 12 306 3-8 10- 20 Pim = Flu Flu> Pim

(6) (14) (anx iety, tension,manneri sms, excitement)

Chouinard et al. (1970 ) 20 12 10 15 Pim = Flu Pim > Flu(hallucinat ions, delusions)

Kenway and Masheter (1971a) 30 8 1.5-9.0 2.5-15 Pim = Flu(2.9) (4.9)

Lapierre and Lavallee (1975) 32 12 2-10 3-21 Pim = Flu Pim = Flu(6) (7.5)

Morris et al. (1970) 30 8 9 15 Pim = Flu

Sims and Burnside (1975) 20 16 2-10 2.5-12.5 Pim = Flu Pim = Flu(4.9) (6,15)

PerphenazineHellon (1971) 42 6 7.5 28 Pim = Per Pim> Per

(Paranoid hostility)

TrifluoperazineAndersen et al. (1971 , 1974) 40 8 3-14 3-12 Pim > Trif Pim > Trif

(retardation, emotionalw ithdrawal)

Oaghorn (1974) 87 24 2-8 5-20 Pim = Trif(5.16) (12.53)

Gross (1974) 41 16 2-12 5-30 Pim > Tr if Pim > Tr if(6.3) (17.5) (unusual thought content)

Kline et al. (1975) 44 16 6.5 15.7 Pim = Trif

Pinard et al. (1972) 80 10 3 or 6 15 (1 x 15) or Pim = Trif15 (3 x 5) (3 x 5)4

Pim (6) >Tr if (1 x 15)4 ""0

:Po3

Carpipramine 0N

Kudo (1972) 56 8 3-8 75-200 Pim = Carp - is:!'!

Thioridazinel>Jl

Oark et al. (1975) 30 24 2- 16 75 - 375 Pim = Thi - (l)

<(15 on each) (5.3) (188.8) CD's

HaloperidolGowardman et al. (1973) 20 12 3-6 7-14 Pim > Hal

FlupenthixolCesarek et al. (1974) 12 30 5 3-8 6-12 Pim = Flup

(6) (8)

1 Abbreviation s: Pim = Pimoz ide; Cpz = Chlorpromazine ; Flu = Fluphenazine ; Per = Perphenaz ine; Tr if = Tr ifluoperazine; Carp = Carp ipramine;Th i = Thior idazine; Hal = Haloperidol; Pen = Penfluridol; Flup = Flupenthixol2 All studies used SPRS evaluation except where otherwise stated3 = indicates no significant d ifference; > ind icat es significant advantage4 NOSIE evaluation5 Double-bl ind cro ssover st udy , with 5 weeks on fluphenazine, pimozide or flupenthixol , given either f irst or second

~

Pimozide: A Review

trial 12 patients had required benzhexol to controlthe extrapyramidal side-effects of other anti­psychotic medication. Furthermore, 12 patientswho continued on pimozide at a dosage of 2 to6mg daily for up to 6 months continued to showsatisfactory stabilisation of their schizophrenicsymptomatology and required no antiparkinsonianmedication. It is difficult to attribute this effect topimozide, however, since 90% of such patientstreated with antiparkinsonian medication for 3months with control of drug-induced symptoms candiscontinue the medication without furtherrecurrence of extrapyramidal signs (Coleman andHayes, 1975) (see section 4.2.5).

Two recent double-blind trials have failed todetect a significant difference between 4.9 to 6mgpimozide or 6.15 to 7.5mg fluphenazine , on eithergeneral symptomatology (Sims and Burnside,1975) or social behaviour (Lapierre and Lavalle,1975). Furthermore, Cesarek et al. (1974) foundno significant difference between pimozide (6mg)and fluphenazine (14mg) when given for 5 weeksduring a double -blind crossover study in 12schizophrenic patien ts who were selected forautism and lack of productive symptoms.

PerphenazineHellon (1971) could not detect any significant

difference between pimozide or perphenazine in adouble-blind trial lasting 6 weeks; 7.5mg daily ofpimozide were indistinguishable from 28mg dailyof perphenazine. The BPRS reductions were notsignificantly different, both drugs loweringanxiety, guilt feelings, depression and unusualthought content; pimozide also reduced somaticconcern, conceptual disorganisation, mannerisms,and posturing while the phenothiazines reducedtension and suspiciousness. Pimozide was signifi­cantly more effective than perphenazine againstthe paranoid hostility group of symptoms, that ishostility, suspiciousness, and unco-operativeness.The clinical global evaluation suggested thatpimozide improved or maintained 60% of patientscompared with the 71% of perphenazine . Patients

22

had been previously maintained on perphenazineand were selected for conceptual disorganisation,emotional withdrawal, blunted affect, bizarremannerisms, unusual thought content and halluci­nations, a group in which pimozide might havebeen expected to be superior.

TrifluoperazineThe general consensus of opinion in com­

parative trials is that pimozide is indistinguishablefrom trifluoperazine, though it may be superior inimproving psychomotor retardation and emotionalwithdrawal and some trials suggest a significantoverall advantage .(table III) . Andersen et al.(1971, 1974) have reported on a trial in 40chronic schizophrenics who were selected toexclude those hospitalised more than 10 years orwho had neurological disorders, a history ofalcoholism and drug addiction, depression ormanic behaviour . The trial was double-blind andlasted for 8 weeks, the doses being 3 to l4mgpimozide or 3 to 12mg trifluoperazine. Twopatients, 1 from each group, had to be withdrawnfrom the trial because of excessive psychomotorexcitation after 3 weeks. There was a significantimprovement in total rating scores after treatment,particularly in the pimozide group and despitepreviously adequate maintenance therapy withother antipsychotics. Pimozide was significantlysuperior to trifluoperazine in its effects onpscyhomotor retardation and paranoid features.Mean body weight in the pimozide group fell byover 2kg during the trial compared with the lessthan 1kg fall recorded in the trifluoperazine group.Side-effects were minimal in both groups and therewas no difference between them.

The efficacy of once-daily pimozide comparedwith twice- or thrice-daily trifluoperazine isconfirmed in a double-blind comparative trial ofvarious dosage regimens with each other and withplacebo (Pinard et al., 1972) . Eight chronicschizophrenic patients, hospitalised for at least 2years with no acute episode for 1 year, weredivided into 5 matched groups who all received

Pimozide: A Review

chlorpromazine maintenance therapy during a21-day run-in period. The groups received eitherplacebo or one of the drug regimens: 3mg or 6mgpimozide once daily, trifluoperazine 15mg oncedaily, or trifuluoperazine 5mg thrice daily. Sixpatients dropped out of the study, but only 1 ofthese was receiving pimozide and his withdrawalwas for reasons unconnected with psychosis.Analysis of the BPRS at the end of 70 daysshowed no significant differences between thegroups, though the NOSIE evaluation revealedmarked differences. Trifluoperazine once daily orlow-dose pimozide were not significantly betterthan placebo, all patients deteriorating to someextent. However, high-dose pimozide and thrice­daily trifluoperazine were significantly better thanplacebo all patients improving throughout the 70days of the study.

Gross (1974) has reported on pimozide asmaintenance therapy in 41 chronic schizophrenicswho were resident in a rehabilitative 'half-wayhouse'. The patients, who were schizophrenics ofat least 2 years duration or had experienced anacute episode within the previous 3 months , hadtheir previous maintenance therapy of chlor­promazine, thioridazine, trifluoperazine or flu­phenazine gradually replaced by the test drugsover a 4-week run-in period. Average doses were6.3mg pimozide (2 to 12mg) or 17.5mgtrifluoperazine (5 to 30mg) in two matched groupsunder double-blind conditions. Dropout rates werehigh; 24% of the pimozide group and 45% of thosereceiving trifluoperazine. However, lack of drugresponse accounted for almost 3 times as manytrifluoperazine dropouts as those withdrawingwhile on pimozide. Pimozide improved ormaintained 81% of patients compared with only50% for trifluoperazine, and it was significantlymore effective in reducing the BPRS. Both drugsreduced the severity of thinking disorders andtotal symptomatology, but while trifluoperazinewas better against excitement, pimozide wassignificantly better against depression, tension,unusual thought content, conceptual disorgan-

23

isation and anxiety. Emotional withdrawal withblunted affect responded to either drug, butsignificantly more rapidly with pimozide (week 2)than trifluoperazine (week 12).

Claghorn (1974) , however, could find nosignificant difference between the effects ofpimozide 2 to 8mg daily (mean 5.16mg) or trifluo­perazine 5 to 20mg daily (mean, 12.53mg) in 87chronic schizophrenic outpatients. The 24-weektrial, following a 2-week run-in on other anti­psychotic medication, revealed significant, butvirtually identical, improvement on both drugs.Pimozide was significantly more effective at week20 against somatic concern, depression and unco­operativeness but was less effective at week 2against guilt feelings; no other significant differ­ences were found at any stage of the trial. Incontrast to Andersen's (1974) findings, patientslost weight more readily on trifluoperazine thanon pimozide, while the former significantlyincreased diastolic blood pressure whereas

.pimozide decreased it in most patients. Pimozideproduced significantly fewer side-effects . 23patien ts reported 35 incidences with pimozidecompared with 67 incidences in 32 patients ontrifluoperazine . Similar results were reported byKline et al. (1975) in 44 chronic schizophrenicoutpatients, who received mean doses of 6.5mgpimozide or 15.7mg trifluoperazine for 16 weeks.There was no significant difference betweentreatments but drop-out rates were high - 10 inthe pimozide group and 12 of those on trifluo­perazine.

ThioridazineClark et al. (1975) could detect no significant

difference between thioridazine 75 to 375mg dailyand pimozide 2 to 6mg daily, though both weresignificantly superior to placebo. In the double­blind trial lasting 24 weeks, 15 patients receivedthioridazine , 15 pimozide , and 10 were onplacebo. Only 24 patients completed the study ,with 2 in the pimozide group and 2 in thethioridazine group being regarded as treatment

Pimozide: A Review

failures. There was no significant difference in theBPRS scores and several other behavioural ratingsnoted for the active drugs, but placebo patientsclearly deteriorated. Suspiciousness was the onlyBPRS item in which a difference was significant,pimozide being more effective. Pimozide producedless sedation but somewhat more extrapyramidal 'signs, but the difference was not significant.Heacache and restlessness occurred more oftenwith pimozide.

CarpipramineOne trial has found no Significant difference

between pimozide and carpipramine, a dibenza­zepine derivative which reportedly has a similarantipsychotic effect except for its shorter durationof action (Kudo, 1972). 56 chronic schizo­phrenics, with illness mainly of greater than 10years duration and including 32 paranoics and 39with emotional blunting, were divided intomatched pairs. They received either 3 to 8mgpirnozide or 75 to 200mg carpipramine, the dosebeing increased through the 8-week trial to matchthe patients' symptoms. Only 1 patient withdrewwhile receiving carpipramine. Pimozide producedimprovement or maintained control in 86% ofpatients compared with the 75% achieved bycarpipramine, but the difference was not statis­tically significant. No significant difference wasfound between the production of side-effects bythe two drugs, though over 78% of patientsexperienced them.

HaloperidolIn a small double-blind trial in 20 male chronic

schizophrenics, including 15 paranoics, 1catatonic, and 3 hebephrenics, Gowardman et at.(1973) found pirnozide to be superior to halo­peridol in activating chronic withdrawn patients.The drugs were given to 2 matched groups over a12-week period in doses of 3 to 6mg or 7 to 14mgrespectively, pimozide improving or maintaining 6of the group and haloperidol 4. Haloperidol wasbetter at controlling productive resocialisation.

24

Return of patients to their previous medicationsshowed that pirnozide produced better controlthan chlorpromazine, perphenazine, trifluo­perazine, haloperidol or fluphenazine decanoate in6 cases, but inferior to thioridazine, chlor­promazine, or haloperidol in 4 cases. Three of thelatter were schizophrenics of the hebephrenictype. Pimozide was significantly more effective onsome target symptoms, such as psychomotorretardation and conceptual disorganisation, butthe drugs were equally effective against emotionalwithdrawal, paranoid belligerence, agitateddepression, and delusion and hallucinations.Pimozide was better tolerated, in that only 1patient showed side-effects compared with 9 onhaloperidol; the latter drug also produced morefrequent extrapyramidal symptoms.

FlupenthixolCesarek et at. (1974) could find no significant

difference between the effects of pimozide (meandose 6mg) and flupenthixol (mean dose 8mg),during a double-blind trial in 12 schizophrenicswho received each drug for 5 weeks with cross­over. The patients were selected for autism andlack of productive symptoms, and each drug wasreplaced by the other during a l-week run-inperiod.

MiscellaneousHeinrich and Quaschning (1971) compared

pirnozide with basal therapy, the latter including21 drugs of various chemical classes; pheno­thiazines, thioxanthenes, butyrophenones,reserpine, and oxypertine but conclusions fromsuch a study are of dubious value. The populationof 116 patients were taken off these drugs for amonth, when there was exacerbation of theirpsychoses, and two groups then received eitherpirnozide or their previous basal medication for1 month followedby crossover.The mean daily dos­age of pimozide was 7.78mg, ranging from 4 to 14.

36 other patients, not included in the statis­tical evaluation, were withdrawn because of

Pimozide: A Review

psychomotor restlessness, excitement, insomnia,and emotional tension while receiving pimozide.Furthermore, in those 116 patients who com­pleted the trial pimozide was significantly lesseffective in ameliorating tension, which becamemore prominent during such therapy ; the drugfailed to show adequate sedative activity in hyper­active patients in contrast to many of the otherdrugs in the basal therapies. Pimozide was signifi­cantly superior in its effects on contact distur­bances and hallucinations. No significantdifference was apparen t in the incidence of side­effects , and extrapyramidal symptoms were ascommonly observed with pimozide as with theother antipsychotics. The variety of drugs used,often more than one per patient, makes interdrugcomparison difficult , but this study indicates thatpimozide is effective in providing maintenancetherapy for chronic schizophrenic patients.

4.2.2 Comparison with PlaceboThe results of double-blind placebo controlled

trials of pimozide in chronic schizophrenia showthat the drug is significantly superior to placebo inalmost all cases (table IV). Many chronic schizo­phrenic patients who have achieved maintenancestatus with other drugs will deteriorate while onplacebo, whereas others can apparently continueto be maintained satisfactorily by placebo for 3months or more. The use of a drug-free periodprior to the trial can assist in eliminating from thetrial the deterioration that can occur when drugsare withdrawn , thereby establishing a basalcondition for administration of placebo orpimozide. The results of such trials are discussed insections 4.2.3 to 4.2.9, together with those of thesignificant uncontrolled studies.

4.2.3 Which Symptoms Respond?Response to pimozide seems to be related more

to individual symptomatology than to the natureof previous drug therapy or the duration of illness.

Uncontrolled studies with pimozide suggestedthat it may be better in the autistic type of patient

25

with emotional withdrawal, delusions and halluci­nations, rather than in the agitated, aggressive type(see, for example, Janssen et al., 1972). Severalcontrolled trials have confirmed that pimozide issignificantly superior to some antipsychotic drugsor placebo against these features of chronicschizophrenia, but these differences are notapparent with all drugs in all trials (see tables IIIand IV). Kolivakis et al. (1974), for examplestudied a group which had a high proportion ofpatients with emotional withdrawal, blunted affectand hallucinations, against which pimozide wassuperior to chlorpromazine. Pimozide was signifi­cantly more effective than placebo or trifluo­perazine in assisting resocialisation in a group ofpatients undergoing rehabilitation (Gross, 1974).Per contra, Cesarek et al. (1974) found thatpimozide was indistinguishable from fluphenazineor flupenthixol in a group of 12 schizophrenicsselected for autistic and delusional tendencies.

Four uncontrolled trials are worth discussingin,more detail because of their selection of patientsor analysis of particular features of the schizo­phrenic personality. Singh (1971) found a meanoverall decrease in the BPRS of his 31 patientsfrom 46.00 to 27.20 during the IS-week trial. Thepatients had previously received a variety ofphenothiazines , thioxanthenes and butyro­phenones. Cluster analysis of the BPRS suggestedthat pimozide was particularly effective inreducing the severity of thinking disturbances (by42%), anxious-depression (by 45%), and with­drawal-retardation (by 52%). In a larger popu­lation, Kristjansen (1971) found that while overallBPRS scores were improved by 46%, the majorimprovements occurred in terms of autism (27 of52), paranoia (22 of 52), and hallucinations (15 of32). Rogeret al. (1972) specifically selected their48 patients for a high degree of delusions andhallucinations. Relatively high doses of pimozide(10 to 30mg) were well tolerated and eliminatedthe dominant symptomatology in 60% of patients.The drug was particularly effective againstauditory hallucinations, though paranoid delusions

Table IV. Summary of double-bl ind trials in which pimo zide has been compared with placebo as maintenance t herapy in patients with chronic "ll3'

schizophrenia 0Na

Author No. pts Durat ion Daily do se in Besults l Comments ~

trial (wk s) mg of pimozide l>::D

(mean) CD<iii':E

Betta et at. (1973) 30 12 8 Pim> Plac

Botter and Amery (1971) 20 8 3 Pim > Plac Pronounced ant i aut istic effect

Clark et al. (1971) 20 12 40 Pim> Plac High dose well tolerated

Clark et al. (1975) 25 24 2-16 Pim> Plac 60% of placebo group dropped out. only(15 on plmozide, (5.3) 25% of pimozide group did so10 on placebo)

Denijs and Vereecken (1973) 40 26 7.72 Pim> Plac 17 placebo patien ts needed halope ridol .only 3 of pimoz ide group did so

De Silva and Masheter (1971) 18 20 2-10 Pim > Plac 7 pat ients relapsed on pimozide.(6) Pimoz ide signif icantly better against

emotional w ithdrawal. delusions.hallucinat ions and conceptual dis-organisation

Gross (1974) 41 16 2-12 Pim > Plac(6.3)

Heinrich and Quaschning 58 4 3-12 Pim > Plac Pimozide best against hallucinations(1971 ) (6.19) and contact disturbances

Janssenet al. (1972) 141 20 6 Pim > Plac 26 patients relapsed on pimozide bu t84 did so when pimozide was withdrawn

Pinard et al, (1972) 45 20 3 or 6 Pim (3) = Plac Low dose pimozide not significantlyPim (6) > Plac d ifferent from placebo

Sugerman (1971) 5 12 12-30 Pim > Plac(24 )

1 Abbreviat ions: Pim =-Pimozide ; Plac = Placebo '"C»

Pimozide : A Review

also responded very well. Perenyi and Varkonyi(1974) found that hullucinations of the olfactory,optic , auditory and tactile types were improved oreliminated to much the same degree in 28 of 39patients. Depersonalisation, delusion, confusionand memory disturbances all improved signifi­cantly in IS of 22,39 of 51,27 of 36, and 13 of18 patients respectively. .

4.2.4 Other Determinants of Patient ResponseAlmost all types of chronic schizophrenic

patients seem to be equally responsive to pimozide.The only positive correlation in controlled studieshas been between symptomatology and response,that is pimozide tended to be more effective in thewithdrawn, autistic type of patient (Denijs andVereecken, 1973; Janssen et al., 1972; see section4.2.3) . . There appears to be no relationshipbetween response and diagnostic category, sex,age, or duration of illness (Brasseur, 1969; Denijsand Vereecken, 1973; Goldwurm et al., 1971;Singh, 1971; Janssen et al., 1972; Sharma andSukerkar, 1974). Suggestions have been madefrom uncontrolled studies that pimozide is moreeffective in the younger inactive schizophrenicoutpatient with disease of short duration(Brasseur, 1969; Kristjansen, 1971), but these havenot been confirmed in double-blind trials. Indeed,Denijs and Vereecken (1973) found the drug to beeffective in elderly female patients with disease ofan average 24 years duration. There appears to beno relationship between the nature of previousantipsychotic therapy and response to pimozide.Suggestions that patients taking high-dose drugslike chlorpromazine or thioridazine do betterwhen transferred to pimozide than do those onlow or medium-dose haloperidol or trifluoperazine(Marshall, 1971; Morris et al., 1971) have not beenconfirmed in trials which specifically analysed thistopic (Kristjansene, 1971; Munkvad et al., 1971).

4.2.5 UseofAntiparkinsonian DrugsOne of the claimed advantages of pimozide over

other antipsychotic drugs is its low propensity to

27

produce extrapyramidal effects with a consequentreduction in the need for antiparkinsonianmedication.

This feature of pimozide's action has not beenstudied adequately in controlled trials in patientsalready stabilised on optimum antipsychotic andantiparkinsonian therapy, and it remains un­proven. Antiparkinsonian drugs are overused inpatients receiving antipsychotic therapy , for theymay be safely withdrawn in all patients who havebeen treated for 3 months if the extrapyramidalsymptoms are under control (Coleman and Hayes,1975). About 90% of such patients can continuetreatment on the same antipsychotic regimen with­out exacerbation of extrapyramidal symptoms andwithout the need for further antiparkinsoniandrugs. Trials with pimozide have involved patientson various drug regimens for differing periods oftime, who might have been receiving unnecessaryantiparkinsonian medication. Controlled studies inwhich pimozide is substituted for existing mainte­nance therapy are needed in that 10% who needantiparkinsonian drugs reinstituted after unsuccess­ful withdrawal , before pimozide can be saidunequivocally to reduce the need for anti­parkinsonian drugs.

4.2.6 Dosage and Duration ofActionThe effective dose of pimozide as maintenance

therapy in chronic schizophrenic patients whohave been previously maintained on other anti­psychotic drugs appears to be about 6mg daily(tables III and IV). Neuhaus (1968) has claimed itto be as high as 11.4mg, and Sterkmans et al.(1968) as low as 2.8mg. Pinard et al. (1972),however, found that 3mg pimozide was indis­tinguishable from placebo in a controlled trial. Noadvantage seems to be gained by increasing thedose to very high levels, that is greater than 20mgdaily. The duration of action is between 24 and 48hours ; most workers have used daily dosage, butLa Roche (1968) suggested that 9.9mg every otherday was sufficient for maintenance therapy. Someworkers have felt that the doses of pimozide used

Pimozide : A Review

in many studies have been too low, and that moresatisfactory results might be forthcoming if higherdoses were employed. However, in double-blindstudies the response rate to low-dose pimozide inchronic schizophrenia does not differ from thatusing a high-dose regimen, which seems to offerlittle advantage in efficacy. A high-dose regimenfor pimozide was used by Clark et al. (1971) andHuber et al. (1971) in 20 male schizophrenics,who were previously maintained on thioridazine.­Over the 12-week trial period pimozide, 40mgdaily, successfully maintained the status achievedwith thioridazine , while there was a non-Significanttrend in the pacebo group towards deterioration.Improvement was evident in the drug group in theareas of social competence, social interest andirritability. Side-effects, even at this very highdosage, were not exceptional, consisting chiefly ofmild extrapyramidal signs, but one patient com­plained of bad dreams and increased auditoryhallucinations. In a further study in 25 patientsbut using a low-dose regimen (table IV), Clark etal. (1975) showed that 66% of the pimozide groupwere maintained or improved, compared with onlyII% of the placebo group. All patients hadpreviously been maintained on thioridazine.

4.3 Acute Schizophrenia

At the present time, there is no unequivocalevidence that pimozide is effective in acutepsychoses or in the control of the restless, hyper­active, aggressive schizophrenic. There is only onecontrolled trial, which found no significantdifference between pimozide and perphenazine,but some workers believe that the doses used inmost studies have been too low for acuteconditions (Shopsin, personal communication) .Controlled trials now in progress indicate thattherapeutic effects in acute schizophrenia may notbe apparent until doses of up to 60mg pimozideare given.

In a double-blind trial, Svesta and Nahurek(1972) compared daily doses of I to 30mg

28

pimozide with 8 to 192mg perphenazine, in3-week treatment periods involving 44' femaleacute schizophrenics, with up to 24 drug-free daysbetween crossover. Pimozide achieved full orpartial remission in 60% of these patientscompared with the 80% achieved by perphenazine ,but the difference was not statistically significant.The rating scores were lower before perphenazine,that is following 3 weeks of pimozide and a drug­free period, than they were prior to any treatment,suggesting a prolonged action of pimozide. Thepopulation of this trial involved a large proportionof restless hyperactive patients, in whom a sedativeantipsychotic like perphenazine is particularlyeffective.

Uncontrolled trials which have included acuteschizophrenics have usually concluded thatpimozide is less effective in the acute than thechronic phase (Goldwurm et al., 1971; Bastos andMoura, 1972). In a study in 20 acute schizo­phrenics, Fracassi and Delvecchio, (1971) reportedexcellent results after 3.5mg pimozide daily, butthe lack of a control placebo group makes theinterpretation open to doubt.

4.4 Other Psychotic States

Pimozide has been studied in a variety ofpsychotic patients, but the uncontrolled nature ofthe trials leaves the result open to doubt. The drugmay be effective in some paranoid and neuroticpsychoses, and in monosymptomatic psychosis(Riding and Munro, 197Sa,b).

Kenway and Masheter (l97Ib) studied 52'schizoid' patients, who were not schizophrenicbut exhibited paranoid symptomatology andemotional withdrawal as a result of social andenvironmental factors. They were mostly old andwidowed, and had no history of psychiatric illnessin the 10 years prior to the trial. Both chlor­promazine, 25mg given·thrice daily, and pimozide,3mg once daily with a twice daily placebo,produced a loss of hostility and relief of seclusion­seeking behaviour after 4 weeks of treatment

Pimozide: A Review

under double-blind conditions. Withdrawal ofdrugs resulted in a reversion towards the formerstatus, though never quite to the extent whichprevailed prior to drug treatment. Schizoidsymptoms, particularly suspiciousness, wereimproved in 14 of the chlorpromazine-treatedgroup, 11 of whom had relapsed by week 4 ofwithdrawal, and in 16 of those on pimozide, 8 ofwhom subsequently relapsed. The presence of aninterested . research group in such a group ofpatients may have played a role in the improve­ment, particularly since the dose of chlor­promazine used is well below the normallyaccepted therapeutic level.

In a multicentre pilot trial involving 120outpatients with a variety of personality disorders,Reyntjens (1972a) reported good to excellentimprovement in 69% of patients, with a poorresponse in only 8.5%. Virtually all the items of a39-item psychiatric scale were improved during 8weeks treatment with 1 to 8mg pimozide,including symptoms relating to schizoid orparanoid personalities, obsessive compulsion,hysteria, borderline schizoid or inadequatepersonalities, and sexual deviants. A variety ofpsychotropic drugs totalling 144 differentcompounds had failed to offer similar relief butthe lack of a placebo control seriously com­promises the validity of the results. Anotheruncontrolled trial in the same series (Amery et aI.,1972) selected patients with paranoid sympto­matology. There was a significant improvement inmost patients, particularly in 4 of 5 items on theparanoid rating scale (delusions, suspiciousness,obsession,and lack of insight).

4.5 Studies in Children

Many of the trials listed in tables III and IVhave included young patients, particularlyadolescents, in their patient populations. However,there has been little effort in general to delineatethe response of this group to pimozide from the

29

response of the population as a whole. There areonly two double-blind trials and three open studiesin young patients and these suggest that the effectsof pimozide on childhood behavioural disordersare similar to those in adults.

Pangalila-Ratulangi (1973) gave pirnozide to 10children, aged 9 to 14 years, who had behaviouraldisorders and schizophrenic-like symptomatology.The initial open phase established the effectivedose as 1mg in one patient and 2mg in the others,after which the drug was given for 4 weekswithout further change in dosage. In the single­blind evaluation, pimozide was replaced byplacebo for a period of 5 weeks or until relapse ofthe patient , and all patients continued to receiveintensive individually adapted behavioural treat ­ment. Seven children showed striking improve­ment in the initial open phase with amelioration ofthe 'immature' EEG pattern in 4 of them, that ismore regular and better formed a-waves anddisappearance of diminution of a-wave inter­ruptions. The remaining 3 patients improved to alimited extent. Replacement by placebo in thesingle-blind phase led to relapse within 2 weeks in3 of the 7 patients who had previously improved,with deterioration of EEG tracings to their formerimmature character in all subjects. A significantincrease was found for the items neuroticism andintroversion in 9 patients, with an increase incontact disturbances in 8 of them. The effectivedose of pimozide in children appeard to be about0.05mg/kg, and no side-effects were observed atthe doses used in this study.

Le Vann (1971) studied 16 adolescent patientsaged 13 to 20 years (median 14) suffering fromchildhood or juvenile schizophrenia of 19 to 93months (median 37.5) duration . The patientsrelapsed when antipsychotic maintenancemedication was withdrawn, and improved to theirprevious level when it was restored. Pimozide, 1 to3mg daily or placebo was given for 4 weeks underdouble-blind conditions.

15 patients successfully completed all stages ofthe study, relapsing within 2 to 3 weeks of

Pimozide: A Review

termination of baseline therapy and relapsingwhen switched from pimozide to placebo. Onepatient withdrew before the commencement ofthe double-blind stage because of uncontrollableand impulsive behaviour when on pimozide , andhe clearly benefited from the sedative andhypokinetic effects of his previous medication,chlorprothixene and haloperidol. All 16 symptomsof a modified BPRS were significantly bettercontrolled with pimozide compared with notreatment . and compared with the previousmedication; 8 of 15 patients were symptom-freeduring pimozide treatment. Social behaviourunderwent the same satisfactory changes aspsychotic symptoms, differences betweenpimozide or no treatment being significant for all9 items of the rating scale but only for less thanhalf of them when baseline treatment wascompared with no treatment. Side-effects wereinfrequent and mild, being significantly less duringpimozide treatment than during treatment withother antipsychotic drugs.

The second double-blind trial involved 30 maleadolescents aged 10 to 16 years (mean 13), whowere not psychotic but had learning disabilitiesand disturbances of their social and emotionalrelationships (Goldberg and Kurland, 1974).Target symptoms included anxiety, unco­operativeness, hyperactivity , inattentiveness andirritability. Patients received either placebo or 5 to8mg daily pimozide over a period of 12 weeks, thisperiod being preceded by a 2-week administrationof placebo only . No statistically significantdifference could be detected between treatmentgroups on 12 social and emotional behaviourfactors, but pimozide was significantly better inreducing paranoid thinking, improving self-controland lowering anxiety. Patients were as effectivelymaintained by the drug as by previous tranquil­lising medications, while a statistically significantnumber (6) of the placebo group worsenedcompared with none of the pimozide-treatedpatients. Despite the high doses, limiting side­effects were observed in only 2 patients, though

30

10 patients experienced the usual effects associ­ated with pimozide therapy.

Uncontrolled studies (Debray et al., 1972 ;Reyntjens, 1972b) have suggested a panacea-likerole for pimozide in childhood conditions rangingfrom behavioural disorders and schizoid-likesymptoms to enuresis and somnambulism. Theseclinical impressions in small numbers of patientshave yet to be conflrmed in placebo-controlledtrials involving adequate numbers of patients witheach disorder.

4.6 Aurrxiety States

The possible anxiolytic effects of pimozidewere first noted in psychotic patients. Double­blind evaluations in non-psychotic subjects withanxiety neurosis have shown that 2mg pimozidedaily is significantly more effective than placeboand indistinguishable from chlordiazepoxide,diazepam or haloperidol (table V). In some studieshowever , particularly with diazepam, the doses ofcomparison drug have been lower than are usuallyemployed therapeutically. Pimozide seems to offerno advantages over currently available anxiolyticagents, either in terms of efficacy or incidence ofside-effects.

In a double-blind trial in 58 anxious patients,there was no Significant difference between theeffects of mixtures of chlordiazepoxide (30 to60mg daily) with either pimozide (2mg daily) orplacebo, when given for 4 weeks (GeneralPractitioner Research Group, 1975). The additionof pimozide to chlordiazepoxide did not result in amore rapid anxiolytic effect, an enhanced effect, asparing of chlordiazepoxide dosage, or a reducedincidence of side-effects.

The results of uncontrolled trials have led toclaims that pimozide is particularly effective inpatients with stress-induced psychic and functionalsymptoms, the psychic fatigability syndrome(Acioli et al., 1974; Cohen Bentolila , 1974;Deberdt, 1972, 1974; Reyntjens, 1972a ; Van

Pimoz ide: A Review 31

Table V. Summary of therapeut ic trials in which pimoz ide has been used to treat patients with an xiety neu rosis

Authors No. pts Durat ion Daily dose Daily dose Results',2 Commentstr ial (wks) of pimo- of other

zide (mg) drug (mg) global Hamiltonevaluat ion scale

PlaceboCervera (1974) 21 4 Pim > Plac Low-close

pimozideeffective

Reyntjens and 50 4 2 Pim > Plac Pim> PlacVan Mierlo (1972)

Verhelst (19753 ) 15 8 2 Pim > Plac

ChlordiazepoxideGenera l Pract it ioner 72 4 2-4 40-60 Pim =Cdp Pim =Cdp4 Abou t 50% im-Clinical Trial (1972) provement in

both groups

DiazepamPoldinger (1975)5 50 2 2 15 Pim = Dzp Pim = Dzp Low dose of

diazepam

Fleynt jens and 49 4 2 10 Pim ;;' Dzp Pim ;;' Dzp Low dose ofVan Mier lo (1972 ) d iazepa m not

significantl yd iffe rentfrom placebo

"'aloperidolKenway (1973) 70 4 2 Pim = Hal Pim = Hal Abou t 60%

improvementin each group

1 Abbreviations; Pim = Pimozide; Plac = Placebo; Cdp = Chlord iazepoxide; Dzp = Diazepam; Hal = Haloperidol2 Results with the Hamilton Scale refer to both the psychic and somatic anxiety symptom clusters3 Jansen Pharmaceutica, unpublished data = Verhelst, R.G.J. 'Pimozide in reactive anxiety. A placebo-controlled

double-blind study'4 General Practitioner Research Group Rating Scale5 Janssen Pharmaceutica, unpublished data : Pold inger, W. 'The therapeutic effects of p imozide on psvchopatho-

logncal d isturbances and anx iety neuroses. A double-blind co mparison with diazepam'

Mierlo , 1972). This followed the double-blind trialof Janke and Debus (1972), in which 15 suchsubjects performed psychometric tasks under highstress conditions better when taking 1 to 2mgpirnozide daily than on similar doses of halo-

peridol. Furthe rmore, Deberdt (1975) could findno significant difference between the beneficialeffects of pimozide, 2mg daily, and chlor­imipramine, 25mg daily, in 26 patients withpsychic fatigability; chlorirnipramine has previ-

Pimozide: A Review

ously been the drug of choice. Further controlledtrials are required to establish the role ofpimozide, and to determine the efficacy ofcombinations of pimozide and anxiolytic drugs(Deberdt, 1974).

Some feeling exists that pimozide is not ananxiolytic drug like the benzodiazepines but ratherhas an effect on anxiety when this occurs inpsychotic patients or in subjects with disturbedpersonality traits (Janssen Pharmaceutica,unpublished data). There is little evidence incontrolled antipsychotic or anxiolytic trials tosupport this contention, and that for personalitytraits is, apart from psychic fatigability, derivedmainly from uncontrolled studies.

4.7 Dyskinesias

Huntington's chorea may involve a normal in­put of dopamine from almost unaffected nigralcells to a striatum which has undergone degenera­tion. It is possible that the symptoms of Hunting­ton's chorea are a result of abnormal sensitivity ofthe remaining striatal receptors to a normal inputof dopamine, and hypersensitivity has also beenimplicated in the lingual-facila-buccal dyskinesias(tardive dyskinesia) so common to long-termantipsychotic or levodopa administration (Klawans,1973). The use of dopaminergic antagonists istherefore a logical approach to therapy.

4.7.1 Huntington's ChoreaBoth haloperidol and chlorpromazine have been

used with some success to treat Huntington'schorea. Pimozide was given in doses of 1 to 6mgdaily for 3 to 4 weeks to 12 patients withHuntington's chorea, followed by combinationwith tetrabenzine (3 x 25mg daily) for 2 to 7months (Fog and Pakkenberg, 1970). A strikingamelioration of hyperkinetic symptoms wasobserved in 6 patients and a moderate decrease in4 others, with the combination regimen. The

32

therapeutic effect developed in 1 or 2 days anddisappeared rapidly on withdrawal of medication;either drug given alone produced successful resultsbut the symptoms tended to reappear within a fewweeks.

4.7.2 Tardive DyskinesiaTardive dyskinesia is common, with an

incidence of about 15% in patients who haverecieved antipsychotic drugs for several months. Itis a serious problem because some 250 millionpatients have received such treatment over the last20 years, and the withdrawal of treatmentfrequently precipitates or exacerbates thecondition.

Initial trials by Fog and Pakkenberg (1970) andKristjansen (1971) suggested that either pimozide.alone or a combination of pimozide and tetra­benazine was effective in 70 to 75% of patientswith tardive dyskinesia. In a further study in 1,6patients, Pakkenberg and Fog (1974) initially gavepimozide to 5 patients and tetrabenazine to 9patients, but most ultimately received thecombination. An average daily dose of 2 to 3rngpimozide with 50 to 75mg tetrabenazine w.asstrikingly effective in rapidly abolishing oraldyskinesias, which rarely recurred except wheneither drug was used alone.

In a double-blind study in 18 patients wi.thphenothiazine-induced oral dyskinesias, pimozidewas given in maximum tolerated doses (mean,18.8mg/day), for 6 weeks (Claveria et al., 1975).There was no deterioration in the therapeurticaction of the drug over the trial period, and it wassignificantly superior to placebo at all stages ofevaluation. Parkinsonian side-effects and sedat ionwere the main adverse effects, which v.'erecorrected by reduction of the dose, but they oftenrecurred and necessitated frequent dosage adj ust­ment.

Pimozide has no place in the treatment: oflevodopa-induced dyskinesias in Parkinsonianpatients because it tends to worsen the Par kin­sonian symptoms (Tarsy et al., 1975). In a

Pimozide: A Review

double-blind trial, 10 Parkinsonian patients onstable levodopa therapy but with levodopa­induced abnormal involuntary movements,received 1 to 4mg pimozide daily. Mean totaldisability scores after 4 weeks treatment weresignificantly increased, particularly for akinesiaand rigidity, whereas involuntary movements wereabolished in 5 patients and reduced in a sixth.These changes in Parkinsonism and levodopadyskinesias occurred simultaneously , and were notevident with placebo (Tarsy et al. 1975).

4.8 Generalised lipodystrophy

. Lipodystrophic diabetes or generalised lipo­dystrophy is a rare and previously untreatabledisease in which the peripheral blood contains highlevels of factors such as gonadotrophin-releasinghormone and corticotrophin-releasing factor,probably as a result of disturbed dopaminergicmechanisms in the hypothalamus (Corbin et al.,1974).

Corbin et al. (1974) have described the suc­cessful treatment of one patient, a 7-year-old girl,who received a daily oral dose of 8.0mg pimozidefor 10 months, after which plasma levels ofcorticotrophin-releasing factor were undetectableand luteinising hormone-releasing factor haddropped by 81%. Many of the clinical symptomsdisappeared and fat deposition was reinitiated ,while relapse was evident within 3 weeks ofdiscontinuation of pimozide.

5. Side-Effects

A distinguishing feature of pimozide in thegeneral context of antipsychotic drugs is its lowcapacity to cause side-effects. Infrequentlyreported effects include anorexia , nausea,abdominal pain, diarrhoea, constipation, hypo­tension, sedation , drowsiness, insomnia, anxiety,

33

agitation , excitement, hallucinatory experiences,dry mouth, amenorrhoea with galactorrhoea , facialswelling, oedema of the eyelids, and erythematousrashes. Most of these are dose-related and haveoccurred when the daily dose exceeded lOmg.Many of them disappeared with continued drugadministration while the remainder were easilymanaged by dosage reduction or temporarywithdrawal of pimozide. Analysis of data in over2,000 patients receiving therapeutic doses suggeststhat the occurrence of any of the aboveside-effects is unlikely in more than 5% ofpatients.

5.1 Extrapyramidal Effects

The most frequent side-effects of pimozidehave been extrapyramidal in nature - akathisiaand parkinsonian symptoms (tremor, rigidity,salivation and masked facies). It is not clearwhether akathisia is truly drug-induced or arisesbecause pimozide, which essentially lacks sedativeproperties, fails to prevent the restlessness associ­ated with pyschosis. The incidence of extra­pyramidal reactions in patients receiving pimozideappears to be of the order of 10 to 15%. They aregenerally dose-related, though an increasedincidence has not been recorded in some studiesemploying high doses, and can be readily reversedby reduction of dosage or concomitant admini­stration of an antiparkinsonian drug (see section4.2.5). They have rarely been recorded in patientsreceiving less than 6mg daily of pimozide. Othertypes of neuromuscular complications such asdystonia , oculogyric crises, or opisthotonos havenot been reported.

5.2 Epileptic Seizures

Early reports on pimozide suggested that it didnot cause convulsions even when prescribed invery high doses, and that it could be administered

Pimozide: A Review

to epileptics without any adverse effect. HoweverBurkitt and Faulkner (1972) reported on 3patients who had epileptiform seizures whilereceiving pimozide. They had not experiencedseizures before and none was receiving anti­convulsant medication. Seizures occurred duringreduction of dosage of pimozide, the intervalsbetween reduction and the first seizure being 13 to31 days. It is significant in this context thatexperiments in rats suggest that decreased centraldopamine activity enhances seizure intensity;administration of pimozide enhanced the intensityof electroshock seizures as well as blocking theseizure-antagonism normally produced byapomorphine or dopamine (Stull et al., 1973).Pimozide may play a part in inducing seizures innormal patients, and possibly in enhancing them inepileptic patients, and care should be taken in itsadministration to subjects receiving anticonvulsantdrugs.

5.3 Cardiovascular Effects

Therapeutic trials with pimozide have failed todetect any adverse cardiovascular effects due topimozide though changes in blood pressure, heartrate and ECG have been recorded in some studies(e.g, Arfaridsson et al., 1971). Nevertheless, theAustralian Adverse Drug Reactions AdvisoryCommittee Report for 1973 included three casesof fatal cardiac disorders in young patients (lessthan 37 years old) associated with the use ofpimozide. Extensive investigations revealed anumber of additional factors which may havecontributed to the fatalities - concurrent therapywith phenothiazines or chloral hydrate, and res­piratory infection.

5.4 Ocular Effects

Slit-lamp examinations of patients treated withpimozide, who had ocular pigmentation due to

34

previous treatment with phenothiazines, showedno increase in pigment deposition (Claghorn,1974; Huber et al., 1971).

Pupillary paralysis, attributed to pimozide in asingle patient (Crawford, 1971) was probably dueto the high dosage of benztropine that the patientwas also receiving(Pearson, 1971).

6. DrugInteractions

Pimozide has been prescribed without adverseeffects for patients with a variety of physicalailments besides the psychiatric disorder. It can,however, potentiate the action of drugs havingcentral nervous system depressant or sedativeactivities, such as barbiturates,narcotic analgesics,antihistamines, alcohol, and other antipsychoticdrugs. Pimozide has been administered safely whilepatients were receiving electroconvulsive therapy,but it may antagonise the actions of anticon­vulsant drugs (see section 5.2).

7. Overdosage

The manner in which pimozide is used, chieflyin psychiatric clinics or hospitals has led to ratherinfrequent opportunity of overdosage. Van Ussel(see Ayd, 1971) reported on a 17-year-old girl whoingested 100 tablets of 1mg in a suicide attempt.Gastric lavage was performed shortly thereafterbut no tablets were found in the gastric fluids.Physical and neurological examinations werenormal except for some slight tremor of theextremities, which subsided within a few hours.Laboratory studies were normal, including EEG.After 2 uneventful days observation in hospital,without other treatment, the patient was released.Debray et al. (1972) reported only mild andtransient extrapyramidal symptoms in a 2*-year­old child who ingested 60mg.

Pimozide : A Review

8. Contra-Indications

Pimozide is contra-indicated in patients who arehypersensitive to the drug and in those with pre­existing Parkinson's disease, endogenous depres­sion, or epilepsy. It should not be used to treataggressiveness, agitation, or psychomotor hyper­activity, where sedative control is required.

9. Precautions

As with any antipsychotic drug, patients mayexperience impairment of mental and physicalabilities necessary for driving a car or operatingmachinery. However, in contrast to most otherdrugs of its type, pirnozide does not seem toproduce sedation. Again like other antipsychoticsit may potentiate the primary effects of anaes­thetics and analgesics, as well as drugs havingcentral nervous system depressant effects such asbarbiturates, narcotic analgesics, antihistamines,and alcohol.

Pimozide has a central inhibitory action on thechemoreceptor trigger zone which controlsvomiting, and it may therefore mask the toxiceffects of other centrally acting drugs. It mayexacerbate or precipitate epileptiform seizures,and dosage of anticonvulsant drugs may requireadjustment during pimozide therapy.

Elderly or debilitated patients are known to beunduly sensitive to antipsychotic drugs and careshould be exercised during the initial stages oftherapy in such people. Pimozide carries the samehazards to the pregnant and nursing mother as anyother drug, though no dysmorphogenic effectshave been observed in animals. likewise careshould be exercised in patients with coronaryinsufficiency, hypertension, or cardiac rhythmdisorders, even though pimozide causes littledisturbance in general to the cardiovascularsystem.

35

10. Dosage

Pimozide is intended for oral administration asa single daily dose. The initial dosage of 2 to 4mgmay be increased until the maintenance level isreached, usually about 6mg. The recommendedmaximum daily dosage is IOrng. limited studies inchildren suggest that the optimum dose may beabout 1 to 3mg, though daily administration of 5to 8mg has been used in adolescents withoutexcessive untoward effects. Previous antipsychoticmedication should be withdrawn gradually whenpatients are transferred to pimozide, particularlyin those who have signs of psychomotor agitation.

The recommended dosage in patients withpsychic and functional disorders is 2mg daily.

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Pimozide: A Review

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Huber, W.; Serafetinides, E.A.; Coimore, l.P. and Clark,M.: Pimozide in chronic schizophrenic patients.Journal of Clinical Pharmacology 11: 304 (1971).

Janke, W. and Debus, G.: Double-blind psychometricevaluation of pimozide and haloperidol versus placeboin emotionally labile volunteers under two differentwork load conditions. Pharmakopsychiatrie Neuro­psychopharmakologie 5 : 34 (1972).

Janssen, P.A.1.: A new series of neuroleptic drugs. The 4,4-diphenylbutyl-piperidines and their relationship withother neuroleptics. Clinical Trials Journal 8 (Suppl.II) : 7 (1971).

Janssen, P.A.J. and Allewijn, F.T.N.: Pimozide, achemically novel, highly potent and orally long-actingneuroleptic drug. Part II. Kinetic study of the distri­bution of pimozide and metabolites in brain, liver, andblood of the Wistar rat. Arzneimittel-Forschung 18:279 (1968).

Janssen , P.A.J.; Brugmans, J. ; Dony, J. and Schuermans,V.: An international double-blind clinical evaluationof pimozide. Journal of Clinical Pharmacology 12: 26(1972).

Janssen, P.A.J.; Niemegeers, C.J.E. ; Schellekens, K.H.L.;Dresse, A.; Lenaerts, F.M.; Pinchard, A.; Schaper,W.K.A.; Van Nueten, J.M. and Vebruggen, F.J.:Pimozide, a chemically novel, highly potent and orallylong-acting neuroleptic drug. Part I. The comparativepharmacology. , of pimozide, haloperidol andchlorpromazine. Arzneimittel-Forschung 18: 261(1968a).

Janssen, P.A.J.; Soudijn, W.; Van Wijngaarden, I. andDresse, A.: Pimozide, a chemically novel, highlypotent and orally long-acting neuroleptic drug. PartIII. Regional distribution of pimozide and of halo­peridol in the dog brain. Arzneimittel-Forschung 18:282 (1968b).

Johnsson, L.E.: Pharmacological blockade of ampheta­mine effects in amphetamine-dependent subjects.European Journal of Clinical Pharmacology 4: 206(1972).

Pimozide: A Review

Keller, H.H.; Bartholini, G. and Pletscher , A.: Increase of3-metho xy-4-hydroxy-phenylethylene glycol in ratbrain by neuroleptics. European Journal of Pharma­cology 23: 183 (1973).

Kenway, A.K.: A double-blind comparison of pimozideand haloperidol in the treatment of recurrent anxietystates. Brit. J. clin. Pract. 27: 67 (1973).

Kenway, A.K. and Masheter, H.C.: Pimozide comparedwith fluphenazine in schizophrenia. British Journal ofClinical Practice 25: 69 (1971a).

Kenway, A.K. and Masheter, H.C.: A social and thera­peutic study of schizoid cases. A double-blind com­parison of pimozide (Crap) and chlorpromazine.Clinical Trials Journal 8 (Suppl. 11): 39 (1971 b).

Kenway, A.K.; Morris, P.A.; Masheter, H.C. andMacKenzie, D.H.: The treatment of chronic schizo­phrenia . A double-blind study comparing pimozide(Orap) with fluphenazine. Clinical Trials Journal 8(Suppl. 11): 33 (1971).

Klawans, H.L.: The pharmacology of extrapyramidalmovement disorders (Karger, Basel, 1973).

Kline, F.; Burgoyne, R.W. and Yamamoto, J.: Com­parison of pimozide and trifluoperazine as once dailythe rapy in chronic schizophrenic outpatients. Un­published data , Janssen Pharmaceutica (1975).

Klingenstein, R.J.; Wallach, M.B. and Gershon, S.: Acomparison of pimozide and thioridazine as antag­onists of amphetamine-induced stereotyped behaviourin dogs. Archives Internationales de Pharmacodynamieet de Therapie 203: 67 (1973).

Kolivakis, T.; Azim, H. and Kingstone, E.: A double-blindcomparison of pimozide and chlorpromazine in themaintenance care of chronic schizophrenic out­patients. Current Therapeutic Research 16: 998(1974) .

Kristjansen , P.: Social behaviour in schizophrenia . Theinfluence of pimozide (Orap) . Clinical Trials Journal 8(Suppl. 11): 61 (1971).

Kudo, Y.: A double-blind comparison of pimozide withcarpipramine in schizophrenic patients. Acta Psychi­atrica Belgica 72: 685 (1972).

Ladinsky, H.; Consolo, S.; Bianchi, S.; Samanin, R. andGhezzi, D.: Cholinergic-doparninergic interaction inthe striatum. Brain Research 84: 221 (1975).

Lal, H.; Colpaert, F .C. and Laduran , P.: Narcotic with­drawal-like mouse jumping produced by amphetamineand L-dopa. European Journal of Pharmacology 30:113 (1975).

Lapierre, Y.D. and Lavallee, J.: Pimozide and the socialbehaviour of schizophrenics. Current TherapeuticResearch 18: 181 (1975).

La Roche, J.: Clinical evaluation of a new neuroleptic,pimozide (R6238), in chronic schizophrenics. Disser-

38

tation, Psychiatric Clinic of the University and Rhine­land Provincial Hospital, Dusseldorf, 1968.

Le Vann, L.J. : Clinical evaluation of pimozide (Orap) inadolescents. Clinical Trials Journal 8 (Suppl. 11): 55(1971).

Liebman , J.M. and Butcher , L.L.: Comparative involve­ment of dopamine and noradrenaline in rate-free self­stimulation in substantia nigra, lateral hypothal­amus, and mesencephalic central gray. Naunyn­Schmiedeberg's Archives of Pharmacology 284: 167(1974).

Marjerrison, G.; Keogh, R.P. and Nair, N.P.V.: Pimozide:EEG effects related to clinical response. CanadianPsychiatric Association Journal 16: 437 (1971).

Marshall, W.K.: Pimozide (Orap): A multicentre study.Clinical Trials Journal 8 (Suppl. II): 49 (1971).

Matsumoto, C. and Griffin , W.: Antagonism of(+)-amphetamine-induced hyperthermia in rats bypimozide. Journal of Pharmacy and Pharmacology 23:710 (1971).

Matthysse , S.: Antipsychotic drug action: a clue to theneuropathology of schizophrenia. Federation Pro­ceedings 32: 200 (1973).

Meldrum, B.; Anlezark, G. and Trimble, M.: Drugsmodifying dopaminergic activity and behaviour, theEEG and epilepsy in Papio Papio. European Journal ofPharmacology 32: 203 (1975).

Miller, R.J.; Horn, A.S.; Iversen, L.L. and Pinder, R.M.:Effects of dopamine-like drugs on rat striatal adenylcyclase have implications for CNS dopamine receptortopography. Nature 250: 238 (1974a).

Miller, R.J. ; Horn, A.S. and Iversen, L.L.: The action ofneuroleptic drugs on dopamine-stimulated adenosinecyclic 3', 5' -monophosphate production in rat neostri­atum and limbic forebrain . Molecular Pharmacology10: 759 (1974b).

M¢ller-Nielsen, I. ; Fjalland , B.; Pedersen, V. and Nymark,M.: Pharmacology of neuroleptics upon repeatedadministration. Psychopharmacologia 34: 95 (1974).

M¢ller-Nielsen, I.; Pedersen , V.; Nymark , M.; Franck,K.F. ; Boeck, V.; Fjalland, B. and Christensen, A.V.:The comparative pharmacology of flupenthixol andsome reference neuroleptics. Acta Pharmacologica etToxicologica 33: 353 (1973).

Morris, P.A.; MacKenzie, D.H. and Masheter, H.C.: Acomparative double-blind trial of pimozide andfluphenazine in chronic schizophrenia. British Journalof Psychiatry 117: 683 (1970).

Morris, P.A.; Rosenber , H.; TOOl, I.J .S.; Marshall, W.K.;Micey, V.; Kahn, S.Y.; Millard, D.W.; Westfield , D.R.;Cranin, D.P.; Tadross, E.H.; Dodds, A.; Le Gassiche,J. ; Hughes, B.D.; Roberts, J.M.; Mahapatra , S.B.;Eastwood, P.R. and Andersen , K.H.: Pimozide as

Pimozide: A Review

maintenance treatment in chronic schizophrenia.British Journal of Clinical Practice 25: 417 (1971).

Munkvad, 1.; Hein, G. and Herskin, B.: The treatment ofchronic schizophrenics with pimozide (Orap). ClinicalTrials Journal 8 (Suppl. 11): 67 (1971).

Neuhaus, B.: The effect of the neuroleptic agent pimozide(R6238) in patients with chronic schizophrenia belowand above the neuroleptic threshold. Dissertation,Psychiatric Clinic of the University of RhinelandProvincial Hospital, Dusseldorf, 1968 .

Nielsen, E.B. and Lyon, M.: Drinking behaviour and braindopamine: antagonistic effect of two neurolepticdrugs (pimozide and spiramide) upon amphetamine- orapomorphine-induced hypodipsia. Psychopharrna­cologia 33: 299 (1973).

Nyback, H.; Schubert, J. and Sedvall, G.: Effect ofapomorphine and pimozide on synthesis and turnoverof labelled catecholamines in mouse brain . Journal ofPharmacy and Pharmacology 22: 622 (1970).

Overall, J.E . and Gorham, R.D.: The brief psychiatricrating scale. Psychological Reports 10: 799 (1962).

Pakkenberg, H. and Fog, R.: Spontaneous oral dyskinesia.Archives of Neurology 31: 352 (1974).

Pangalila-Ratulangi, E.A. : Pilot evaluation of Orap(pimozide, R6238) in child psychiatry. Psychiatria,Neurologia , Neurochirurgia 76: (1973).

Pearson, R.: Pupillary paralysis after tranquillizer. BritishMedical Journal 3: 639 (1971).

Pedersen , V. and Christensen, A.V.: Antagonism ofmethylphenidate-induced stereotyped gnawing inmice. Acta Pharmacologica et Toxicologica 31: 488(1972).

Perenyi , G. and Varkonyi, B.: Results obtained with Orapin the therapy of neuropsychiatric outpatients.Therapia Hungarica 22: 65 (1974).

Phillips, A.G.; Brooke, S.M. and Fibiger, H.C.: Effects ofamphetamine isomers and neuroleptics on self­stimulation from the nucleus accumbens and dorsalnoradrenergic bundle. Brain Research 85 : 13 (1975).

Pinard, G.; Prenoveau, Y.; Fliesen, W.; Elie, R.; Bielmann ,P.; Lamontagne, Y. and Tetrault, L.: Pimozide: Acomparative study in the treatment of chronicschizophrenic patients. International Journal ofClinical Pharmacology, Therapy and Toxicology 6: 22(1972a).

Pinder , R.M.: The pharmacotherapy of Parkinsonism.Progress in Medicinal Chemistry 9: 191 (1972).

Pinder, R.M.: The design of dopamine-like drugs.Advances in Neurology 3: 295 (1973).

Reyntjens, A.M.: A series of multicentric pilot trials withpimozide in psychiatric practice. 1. Pimozide in thetreatment of personality disorders . Acta PsychiatrieaBelgica 72: 653 (1972a).

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Reyntjens, A.M.: A series of multicentric pilot trials withpimozide in psychiatric practice. 11. Pimozide in thetreatment of behavioural disorders in childhood andadolescence. Acta Psychiatrica Belgica 72: 662(1972b).

Reyntjens, A.M. and Van Mierlo, F .P.: A comparativedouble-blind trial of pimozide in stress-inducedpsychic and functional disorders. Current MedicalResearch and Opinion 1: 116 (1972).

Riding, B.E.J. and Munro, A.: Pimozide in mono­symptomatic psychosis. Lancet 1: 400 (1975a).

Riding, T. and Munro, A.: Pimozide in the treatment ofmonosymptomatic hypochondria1 psychosis . ActaPsychiatrica Scandinavica 52 : 23 (1975b).

Roger, B.-B.; Guilloux, J. and Saillant , A.: Pimozide,delusions and hallucinations. Annales medico ­psychologiques 130: 419 (1972).

Rotrosen, J.; Wallach, M.B.; Angrist, B. and Gershon, S.:Antagonism of apomorphine-induced stereotypy andemesis in dogs by thioridazine, haloperidol andpimozide. Psychopharmacologia 26: 185 (1972).

Sagales, T. and Erill, S.: Effects of central dopaminergicblockade with pimozide upon the EEG stages of sleepin man. Psychopharmacologia 41: 53 (1975).

Schlechter, J.M. and Butcher, L.L.: Blockade by pimozideof (+)-amphetamine-induced hyperkinesia in mice.Journal of Pharmacy and Pharmacology 24: 408(1972).

Seeman , P. and Lee, T.: Antipsychotic drugs: Directcorrelation between clinical potency and presynapticaction on dopamine neurons. Science 188: 1217(1975).

Sharma, S.D. and Sukerkar, N.V.: Clinical impressions ofpimozide: An open study. Journal of InternationalMedical Research 2: 206 (1974).

Sims, A.C.P. and Burnside , I.G.: Activity in chronicschizophrenic patients: Comparison of pimozide withfluphenazine in a double-blind trial. PsychologicalMedicine 5: 161 (1975).

Singh, A.N.: Evaluation of clinical efficacy of pimozide asmaintenance therapy in chronic schizophrenicpatients. Current Therapeutic Research 13: 695(1971).

Soudijn, W. and Van Wijngaarden, 1.: The metabolism andexcretion of the neuroleptic drug pimozide (R6238)by the Wistar rat . Life Sciences (part I) 8: 291 (1969).

Soudijn, W. and Van Wijngaarden, 1.: Localisation of[' H] pimozide in the rat brain in relation to its anti­amphetamine potency. Journal of Pharmacy andPharmacology 24: 773 (1972) .

Sterkmans, P.; Brugmans, J. and Gevers, F.: The clinicalefficacy of pimozide in chronic psychotic patients.Clinical Trials Journal 5: 1107 (1968).

Pimozide: A Review

Stull, R.E.; Jobe , P.C.; Geiger, P.F . and Ferguson , G.G.:Effects of dopamine receptor stimulation andblockade on Ro 4-1284-induced enhancement ofelectroshock seizure. Journal of Pharmacy andPharmacology 25: 842 (1973).

Sugerman, A.A.: A pilot study of pimozide in chronicschizophrenic patients. Current Therapeutic Research13: 706 (1971).

Svestka, J. and Nahurek , K.: A comparison of pimozidewith perphenazine in the treatment of acute schizo­phrenic psychoses. Activitas Nervosa Superior 14: 93(1972).

Tarsy, D.; Parkes, J.D. and Marsden, C.D.: Meto­clopramide and pimozide in Parkinson's disease andlevodopa-induced dyskinesias. Journal of Neurology,Neurosurgery and Psychiatry 38: 331 (1975).

Van Mierlo, P.J.: Open pilot trial of pimozide in patientssuffering from psychic stress. Arzneimittel-Forschung22: 2147 (1972).

Wauquier, A. and Niemegeers, C.J.E .: Intracranial self­stimulation in rats as a function of various stimulus

40

parameters. II. Influence of haloperidol, pimozide andpipamperone on medial forebrain bundle stimulationwith monopolar electrodes. Psychopharmacologia 27:191 (1972).

Wauquier, A. and Niemegeers, C.LE. : The effects ofdexetimide on pimozide-haloperidol and pipamperone­induced inhibition of brain self-stimulation in rats.Archives Intemationales de Pharmacodynamie et deTherapie 217: 280 (1975).

Yokel, R.A. and Wise, R.A.: Increased lever pressing foramphetamine after pimozide in rats : Implications for adopamine therapy of reward. Science 187: 547(1975).

Authors' address: R.M Pinder, R.N. Brogden, PhyllisR. Sawyer, T.M Speight , Rosalind Spencer and G.S. A very,Australasian Drug Information Services, P.O. Box 34-030,Birkenhead , Auckland 10 (New Zealand).