Psychopharmacology (1982) 76:13 - 19 Psychopharmacology �9 Springer-Verlag 1982

Pimozide in the Treatment of Newly Admitted Schizophrenic Patients

G. Chouinardl' 2 and L. Annable 1

1 Allan Memorial Institute Pharmacology Research Unit, Department of Psychiatry, McGill University, and 2 Research Department, H6pital Louis-H. Laf~ntaine, Montreal, Quebec, Canada H1N 3M5

Abstract. Pimozide, a specific dopamine blocking agent, was compared with chlorpromazine in a 4-week double-blind study of the treatment of 40 schizophrenic patients newly admitted to hospital through the emergency room. Dosage was adjusted according to therapeutic effect and during the final week ranged from 10-70 rag/day (median 30 rag/day) for pimozide and 600-1,500rag/day (median 900mg/day) for chlorpromazine. Pimozide was found to exert somewhat less of an overall therapeutic effect than chlorpromazine, particularly in highly agitated patients. Women responded better to either treatment than men. A weighted mean of the doses given to male and female patients during the final week suggests that in the treatment of acutely ill patients the mg dose equivalency of pimozide in terms of chlorpromazine is approximately 1:25, considerably lower than estimates from maintenance studies. Pimozide induced significantly more parkinsonian symptoms but less autonomic side effects than chlorpromazine. It is suggested that the weaker presynaptic dopamine blocking effect of pimozide might be responsible for its reduced potency in the treatment of acute schizo- phrenic symptoms.

Key words: Pimozide - Neuroleptics - Schizophrenia - Parkinsonism - Tardive dyskinesia - Chlorpromazine - Supersensitivity

The diphenylbutylpiperidines are a new class of antipsychotic drugs that are chemically related to haloperidol. Pimozide, a member of this class, is considered to be a relatively specific dopamine receptor blocker (Janssen et al. 1968; And~n et al. 1970) and, unlike haloperidol and chlorpromazine, does not block noradrenergic receptors (Wauquier 1979). In contrast to the standard neuroleptics which have the ability to block both pre- and post-synaptic dopamine receptors, pimozide has been shown to have a weaker effect on presynaptic than postsynaptic receptors (Waiters and Roth 1976). In this respect, pimozide seems to be similar to clozapine which has been reported to have no presynaptic dopaminergic blocking effect (Walters and Roth 1976) and no tolerance to its induced homovanillic acid increments after repeated administration (Honma and Hirose 1979). Both substances have been

Presented at the 132nd Annual Meeting of the American Psychiatric Association, Chicago, Illinois, May 12-15, 1979 Offprint requests to: Guy Chouinard, M.D., McGill University, Department of Psychiatry, AMI Pharmacology Research Unit, 1033 Pine Ave. West, Montreal, Quebec, Canada H3A IAI

claimed to have the potential to induce less tardive dyskinesia than other neuroleptics (Gibson 1978; Ayd 1974). Thus the effect of pimozide in schizophrenia is of both practical and theoretical interest. Several double-blind controlled studies have shown pimozide to be efficacious in the long-term treatment of schizophrenia (Chouinard et al. 1970; Clark et al. 1975; Falloon et al. 1978). However, its effect in the treatment of acute schizophrenia has been studied mainly in uncontrolled trials (Shopsin and Selzer 1977; Piyakulmala et al. 1977). The present paper reports a double-blind controlled trial of pimozide in newly admitted male and female schizo- phrenic patients and compares its effect with that of chlorpromazine.

Materials and Methods

Study Design. Forty newly admitted schizophrenic patients, satisfying the study criteria given below, were selected for inclusion in the trial immediately after being admitted through the emergency room of H6pital Louis-H. Lafon- taine. Patients entered the study as they became available, and for each patient the trial was of 4 weeks' duration. All patients needed admission, and none had received long-acting neuro- leptic drugs for at least 2 weeks prior to the study. Twenty patients were randomly assigned to each of the two drug treatments : pimozide or chlorpromazine. Patients were start- ed on the experimental treatment as soon as their evaluations and laboratory tests were completed (1 or 2 days after admission). Before the trial commenced, acutely agitated patients were given chlorpromazine on a PRN basis whenever their behavior was uncontrollable. After treatment with the research drug had begun, no other medications (including hypnotics) were administered during the trial, except for an antiparkinsonian.

Selection Criteria. Selection criteria required that: (1) patients be aged between 18 and 65years; (2) a primary hospital diagnosis of schizophrenia be confirmed by the research psychiatrist on the basis of the Research Diagnostic Criteria (Spitzer et al. 1978); (3) two or more of the target symptoms listed in the NIMH-Psychopharmacology Service Center collaborative study of acute schizophrenia (NIMH- Psychopharmacology Study Group, 1964) be present; (4) patients with physical illness, childhood schizophrenia, chronic or acute brain syndrome, mental deficiency (IQ below 70), alcoholism, epilepsy, or drug addiction be excluded from the study. All the patients and, where judged necessary, a relative or guardian were required to give written informed

0033-3158/82/0076/0013/$ 01.40

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consent after the purpose of the study and the possible side effects were explained to them.

Patient Characteristics. Table I shows details of the sex, age, previous hospitalization, and paranoid status according to the criteria of Tsuang and Winokur (1974), for patients in each treatment group. There were no significant (P < 0.05) differences between the two treatment groups for any of these

Table l. Patient characteristics

Pimozide Chlorpromazine (n=20) (n=20)

Men/Women 13/7 13/7 Age (range; median) 23-64; 36 20-54; 33 No. previously hospitalized 20 17 Total duration of previous 0.1-22,3; 0.9 0-13.6; 0.8

hospitalization in years (range; median)

Paranoid/nonparanoid a 14/6 10/10

" According to Tsuang and Winokur (1974) criteria

characteristics (Fisher's exact probability test or t-test, as appropriate).

Drug Schedule. Pimozide and chlorpromazine were adminis- tered in identical capsules under double-blind conditions. Because of its reportedly prolonged duration of action (Pinder et al. 1976), pimozide was given as a single dose in the morning, and chlorpromazine was given on an equally divided BID (AM and HS) regimen. Pimozide-treated pa- tients received pimozide placebo at night. Pimozide was administered in 10 mg capsules and chlorpromazine in 150 mg capsules. To ensure compliance the capsules were taken with water in the presence of a nurse. The initial doses were chosen on the basis of an equivalency of 10mg of pimozide for 300 mg chlorpromazine. Dosages were subsequently adjusted according to therapeutic effect. Table 2 shows details of the dosages given at the end of each week of the trial for both treatment groups. There was no substantial difference be- tween pimozide- and chlorpromazine-treated patients with respect to the number of capsules taken daily. Men did not differ significantly from women as regards the mean dosage of pimozide 018 = 0.79, P > 0 . 1 0 ) or chlorpromazine (tls = 0.52, P > 0.10) given during the trial. The weighted

Table 2. Dosage of pimozide and chlorpromazine given at end of each treatment week (mg/day) ~

Week Pimozide Chlorpromazine

Range Median Mean Range Median Mean

Men Women Men Women

1 10--60 20 23 20 300- 900 600 554 643 2 10-70 25 29 29 600-1200 900 831 857 3 10-70 30 37 30 600--1500 900 900 943 4 10-70 30 42 30 600--1500 900 946 986

a PRN medication not included

Table 3. Pimozide or chlorpromazine PRNs and antiparkinsonian (procyclidine) medication required during each week of study

Week

I 2 3 4

No, of patients requiring PRNs: Pimozide group 8 Chlorpromazine group 6

Minimum, maximum and median dose of PRNs (mg/week):

Pimozide group Chlorpromazine group

No. of patients requiring antiparkinsonian:

Pimozide group 9 a Chlorpromazine group 4

Mean dose of antiparkinsonian _+ SEM (mg/day) for those who needed it:

Pimozide group Chlorpromazine group

7 6 6 b 5 2 1

5 - 70; 15 5-320; 25 5--475; 17.5 5-490; 97.5 150-300; 200 150--450; 300 150--300 150

16 r 16 ~ 17 ~ 6 8 8

8.4 • i .7 12.6 __+ 1.7 14.9 • 1.7 18. I • 2.1 9.6 __+ 1.0 15.7 • 0.9 15.t +__ 1.2 I7.5 • 1.7

,.b,o Significantly (P < 0.10, P < 0.05 and P < 0.0t, respectively) greater than for chlorpromazine group (Fisher's exact probability test)

mean of the doses given to men and women during the final week would suggest that the mg potency ratio of pimozide to chlorpromazine was approximately 1:25.

Supplementary Medication. For ethical reasons, P R N medi- cat ion was permitted for acute agitation. Subjects requiring P R N medicat ion received, under double-bl ind conditions, supplementary doses of the drug they were receiving in the trial. Thirteen pimozide-treated patients needed at least one dose of pimozide P R N and 11 chlorpromazine-treated pa- tients needed at least one dose of chlorpromazine P R N during the trial. The number of patients requiring P R N medication, the minimum, maximmn and median dosages per week are shown in Table3. During the final week, significantly (P < 0.05) more pimozide-treated patients required P R N medicat ion than chlorpromazine-treated patients (Fisher 's exact probabi l i ty test). Two pimozide-lxeated patients who were not adequately control led by the pimozide PRNs were also given P R N doses of chlorpromazine (one received a total of 450 mg in six separate doses and the other 925 mg in eight doses).

Antiparkinsonian Medication. Procyclidine HC1 was the only ant iparkinsonian medicat ion administered during the trial

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and was given as needed if at least one significant parkin- sonian symptom (tremor, akinesia, rigidity or akathisia) was present. The number of patients needing procyclidine and their mean daily dose during each week of the trial is shown in Table 3, F rom week 2 onwards, significantly (P < 0.01) more pimozide-treated patients needed ant iparkinsonian medi- cation than chlorpromazine-treated patients (Fisher 's exact probabi l i ty test).

Assessment Procedure. Assessment of symptoms was based on clinical interviews conducted by the psychiatrist. The mental status of patients was scored on days 0, 7, 14, 21 and 28 on the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham 1962) and a 7-point Clinical Global Impression (CGI) of severity of illness, Fac tor scores for thinking disturbance, hostile suspiciousness, withdrawal re tardat ion and anxious depression were formed from the items of the BPRS (Overall and Klet t 1972). Side effects were recorded weekly on the Treatment-Emergent Symptoms form and on the Extrapyramidal Symptom Rating Scale of Chouinard and Ross-Chouinard (Chouinard et al. 1979a, 1980). The blood pressure and pulse rate were recorded at weekly intervals both in the standing and supine posit ions following the A M A procedure. Labora tory tests (biochemistry, hematology, and

Table 4. Initial (X) and adjusted final mean (Ya) scores for BPRS and CGI after 4 weeks of treatment with either pimozide or chlorpromazine

Pimozide Chlorpromazine Statistical Statistical significance significance of difference of difference between adjusted between sexes treatment means

BPRS Total 56.3 36.8 54.9 30.3 Somatic concern 3.0 1.8 2.6 1.4 Anxiety 4.0 2.4 3.4 2.0 Emotional withdrawal 3.8 3.0 4.2 2.4 Conceptual disorganization 4.8 2.9 5.1 2.3 Guilt feelings - men" 1.9 1.7 2.4 1.2 Guilt feelings - women ~ 2.1 1.0 2.0 1.7 Tension 3.4 2.3 3.3 t.6 Mannerisms and posturing 2.8 2.4 3.2 1.7 Grandiosity 3.3 2.6 u 3.0 1.4 b Depressed mood 3.3 1.6 3.1 t.7 Hostility 2.6 1.5 i .7 1.2 Suspiciousness 4.5 2.4 3.6 2.0 Hallucinatory behaviour 4.7 2.6 4.9 2.2 Motor retardation 1.5 1.0 2.0 1.5 Uncooperativeness 1.9 1.5 1.7 1.2 Unusual thought content 4.3 2.7 4.1 2.0 Blunted affect 3.0 2.3 3.4 2.0 Excitement 2.3 1.4 2.0 1.1 Disorientation 1,5 l.lU 1.7 1.2 b

Factors Thinking disturbance 4.6 2.7 4.7 2.1 Hostile suspiciousness 3.0 1.8 2.3 1.4 Withdrawal retardation 2.8 2.1 3.2 1.9 Anxious depression --men ~ 3.1 2.1 2.9 1.5 Anxious depression - women ~ 3.1 1.5 2.9 1.9

CGI 5.5 3.6 5.2 3.0

P < 0.10 P < 0.10

P < 0.10 P < 0.I0

P < 0.05 P < 0.10

P < 0.10 P < 0.05

P=0.10

P < 0.10 P < 0.10

P < 0.05 P < 0.10

P = 0.10 P < 0.10

Statistically significant (P < 0.05) sex X treatment interaction: means shown for each sex separately b Statistically significant (P < 0.05) heterogeneity of covariance: unadjusted final mean scores shown

16

Table 5. Initial (X) and adjusted final mean (Ya) scores for the Extrapyramidal Symptom Rating Scale (ESRS) after 4 weeks of treatment with either pimozide or chlorpromazine

Pimozide Chlorpromazine Statistical Statistical significance significance of difference of difference between adjusted between sexes

7~ Ya X ~a treatment means

Parkinsonism Questionnaire: Total score 0.2 Physician's examination: Total score" 2.0 Items

Expressive automatic movements 0,1 Bradykinesia 0.0 Rigidity 0,4 Gait and postnre 0.4 Tremors 0.9 Akathisia 0.3 Sialorrhea 0.0 Dystonia 0.2

Factors Hypokinesia 0.9 Hyperkinesia 1.1

Tardive dyskinesia CGI 1,9 Total score 1.4 Items

Lingual movements 0.7 Jaw 0.3 Bucco-labial 0.4 Truncal 0.0 Upper extremities 0.0 Lower extremities 0.0 Other 0.0

Factors Bucco-lingual masticatory 1.4 Extremities 0.0

2.2 0.2 1.5

7.8 2.0 6.2

1.0 0.1 0.5 0.3 0.2 0.3 1.2 0,2 2.7 1.0 0.2 0.6 2.9 1.2 1.6 1.1 0.2 0.6 0:2 0.0 0.0 0.3 0.1 0.3

3.7 0.7 4.0 4.0 1.4 2.2

2.1 1.9 2.0 2.1 1,5 2.1

1.0 0.8 0.8 0.5 0.2 0.5 0.3 0.1 0.4 0.0 0.1 0.0 0.2 0.3 0.1 0.1 0.1 0,2 0.1 0.0 0.1

1.7 1.0 1.7 0.4 0.4 0.2

P < 0.I0

P < 0.10

P < 0.10 P < 0.I0

P < 0.10

a Non-acute dystonia excluded

urinalysis), electrocardiograms and physical examinations were carried out on day 0 and 28. Temperatures were taken daily. Plasma prolact in levels were determined by homo- logous radioimmunoassay using a double ant ibody method (Sinha et al. 1973). The intra-assay variabili ty of the method was 10 %. Blood samples were taken in the morning after an overnight fast (24 h after the last dose of pimozide and il I h after the last dose of chtorpromazine) and were immediately centrifuged. The plasmas were frozen and stored at - 2 0 ~ until assayed.

Results

All patients completed the 4-week trial. The weekly rat ing scale scores were submitted to separate factorial analyses of covariance with drug treatment and sex as factors and initial scores as covariate. These were carried out using a computer program for multiple linear regression (Overall and Klet t 1972). In each analysis the homogeneity of the within- treatment covariance regression coefficients was tested.

Clinical Change. Table 4 lists the initial and adjusted final (day28) mean scores for the BPRS and CGI of patients

treated with pimozide or chlorpromazine. Chlorpromazine was significantly (P < 0.05) superior to pimozide for tension, and tended (P < 0.10) to be superior to pimozide for the CGI severity of illness, the BPRS total, mannerisms and postur- ing, and excitement. Motor retardat ion was absent from the pimozide group at the end of the trial and pimozide tended (P = 0.10) to be superior to chlorpromazine for this item. Women responded significantly (P < 0.05) better to treat- merit with either drug than men as regards hallucinatory behaviour and the thinking disturbance factor, and tended (P < 0.t0) to respond better than men as regards the BPRS total, emotional withdrawal, conceptual disorganization, suspiciousness, blunted affect, the hostile suspiciousness

f a c t o r and the CGI. In addition, there was significant ( P < 0.05) treatment x sex interaction for guilt feelings and the anxious depression factor; in both cases women re- sponded better to pimozide than men, whereas the reverse tended to be true for chlorpromazine.

Extrapyramidal Symptoms. The initial and adjusted final (day28) mean scores for the Extrapyramidal Symptom Rating Scale are shown in Table 5, At day 28, pimozide- treated patients tended ( P < 0.10) to have a significantly

17

Porkinsonism meon IoIQ1 score

(n:20)

@

0 OI 71 ...... 141 211 [ IsII DAYS

Fig. 1. Course of parkinsonism during trial for patients treated with pimozide (PMZ) or chlorpromazine (CPZ) as measured by weekly mean total scores for physician's examination. (P-value refers to statistical significance of difference between adjusted mean scores as obtained from analysis of covariance)

higher adjusted mean score for hyperkinetic parkinsonian symptoms but a lower adjusted mean score for rigidity than those treated withchlorpromazine. Also male patients tended (P < 0.10) to have more hyperkinesia than female patients, irrespective of the treatment they were receiving. Figure 1 illustrates the course of the total score for parkinsonism during the trial. At day 7 pimozide-treated patients had significantly (P<0.05) more parkinsonism than chlor- promazine-treated patients, but this difference was not present at subsequent evaluations, presumably as a result of the greater antiparkinsonian administration among patients treated with pimozide. Tardive dyskinesia was assessed on the Extrapyramidal Symptom Rating Scale and was present in six patients in each treatment group (30 %) on entry to the trial (borderline cases excluded). At day 28 there were eight cases of tardive dyskinesia in the pimozide-treated group and six in the chlorpromazine-treated group, two of which in each group had not been evident at day 0. There was no significant (P < 0.05) difference between the two drugs as regards the adjusted final mean scores for tardive dyskinesia, which showed only a small increase from their starting values (Table 5). Men in either treatment group tended (P < 0.10) to have more lingual movements than women.

Side Effects. The following side effects were significantly more common among chlorpromazine-treated patients than pimozide-treated patients: drowsiness (t6 cases with chlor- promazine, 9 with pimozide; P < 0.01), constipation (ten cases with chlorpromazine, three with pimozide; P < 0.05), headache (five cases with chlorpromazine, one with pimozide, P < 0.10) and moderate to severe dizziness (nine cases with chlorpromazine, one with pimozide; P < 0.01)(Fisher's exact probability tests). Other side effects were mild and no special measures were required for their relief.

Plasma Prolactin Levels. At day 28 the mean plasma prolactin levels of patients treated with either drug were elevated above the normal range: in men the mean value (+_ SD) for pimozide was 27.5 + 13.3 ng/ml and for chlorpromazine was 26.5 + 9.1 ng/mt; in women the mean value (+ SD) for pimozide was 42.7 + 14.0 ng/ml and for chlorpromazine was 58.4 + 23.5 ng/ml. There were no significant (P < 0.05) dif- ferences between the two drugs in this respect (two-tailed t-tests on log plasma prolactin values).

Discussion

In a comprehensive review of the studies of pimozide, Pinder etal . (1976) considered that its efficacy in the treatment Of acutely ill schizophrenic patients remained to be established, especially in view of its relative lack of sedative properties as compared to most antipsychotic drugs. The results of the present study suggest that at high doses pimozide is effi- cacious in the treatment of most acutely ill patients, but somewhat less so than chlorpromazine. This was evident from the higher adjusted final mean scores on the psychiatric rating scales and the greater necessity for PRN medication to control agitation in pimozide-treated patients. The majority of the previous trials ofpimozide have been carried out in the maintenance treatment of schizophrenia and have reported pimozide to be a highly potent neuroleptic (Pinder et al. 1976) with a mg potency ratio in terms of chlorpromazine generally ranging between 1 : 50 and 1 : 100. The results of the present study suggest that in the treatment of the acute phase of the illness the potency of pimozide is considerably lower than this. The initial doses of pimozide were based on a mg ratio in terms of chlorpromazine of 1 : 30, but a weighted mean of the doses given to men and women during week 4 would suggest an equivalence no higher than 1:25. This difference in the estimated relative potency of pimozide in maintenance and acute treatment suggests that pimozide has a different mechanism of action to the classical neuroleptics, having less of an effect on the positive symptoms of schizophrenia that are more in evidence during the acute phase of the illness. The mean daily dose given to men was 42 mg and to women 30 mg, and, when PRN medication is taken into account, the maximum daily dose given was 140mg. In two previous studies of pimozide in the treatment of newly admitted schizophrenics that included a substantial number of patients, the drug was found to be efficacious when given at doses up to 60mg/day (Shopsin and Selzer 1977; Piyakulmala et al. 1977). However, both these studies were uncontrolled, so that reliable estimates of the relative potency of pimozide cannot be made from them.

Pinder etal. (1976) pointed out that claims that pimozide induces less parkinsonian side effects than other antipsychotic drugs remain to be proven. In the present triM, the need for antiparkinsonian medication was substantially greater in pimozide-treated patients, 85 % of whom received procy- clidine, than in those treated with chlorpromazine, 40 % of whom needed it. Thus, pimozide, at the high doses used in this study, would appear to have induced parkinsonism to a greater extent than chlorpromazine. This may be due either to the greater degree ofpostsynaptic blocking effect ofpimozide or to its weaker anticholinergic potency compared to chlor- promazine. Tardive dyskinesia was present in 30 ~/o of patients in either treatment group when they entered the trial and there was only a mild increase in the mean scores for the syndrome in either group during the trial. This is of interest in view of the fact that antiparkinsonian drugs have been shown to uncover or exacerbate dyskinetic movements (Gerlach et al, 1974; Klawans and Rubovits 1974; Gerlach and Thorsen 1976; Chouinard et al. I979b; Burnett et al. t980) and all the pimozide-treated patients had previously been hospi- talized and treated with neuroleptics for considerable periods of time, yet the greater amount of antiparkinsonian drug that they received as compared to the chlorprozamine group did not increase dyskinetic movements to any great extent.

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A major advantage of pimozide was its low incidence of autonomic side effects. The present study confirms the relative specificity of pimozide for dopamine blocking. Compared to pimozide, chlorpromazine had significantly greater antiadrenergic (as evidenced by more dizziness), anticholinergic (more constipation), antihistaminic (more drowsiness), and antiserotinergic (more headache) effects. Motor retardation was also absent from pimozide-treated patients.

Thus, the findings from this study are consistent with the hypothesis that pimozide is a relatively specific dopamine receptor blocker (Janssen et al. 1968; And tn et al. 1970) and that it may have a weaker effect on presynaptic than postsynaptic receptors (Walters and Roth 1976). The ability of the classical neuroleptics, such as chlorpromazine, to block both pre- and postsynaptic receptors is thought to lead to a temporary increase in dopamine turnover followed by a decrease due to an apparent depolarization inhibition (Bunney and Grace 1978). The eventual decrease in dopamine in the synaptic cleft brought about by these drugs is consi- dered to be responsible for their delayed onset of action and for the development of supersensitivity phenomena such as a decline in parkinsonian symptoms with time and the em- ergence of tardive dyskinesia. I f pimozide has only a weak effect on presynaptic receptors, it may not deplete dopamine to such a great extent as neuroleptics which block both pre- and postsynaptic receptors. Pimozide may therefore be less efficacious in the treatment of the acute phase of the illness during which positive symptoms such as hallucinations and thought disturbance predominate, but in the long run may induce less postsynaptic receptor supersensitivity and con- sequently less tardive dyskinesia than the classical neuroleptics.

The finding that women tended to respond better to treatment than men is also of interest. Hogarty et al. (1974) have reported a similar finding in the long-term treatment of schizophrenic patients. It has recently been shown that estrogens have a potent antidopaminergic effect (Raymond et al. 1978), and this suggests the possibility that they may be capable of potentiating the effects of neuroleptics. The superior response of female patients in these studies would be consistent with this idea. Since men did considerably less well on pimozide than chlorpromazine, drugs that are known to block both pre- and postsynaptic dopaminergic receptors may be advantageous in their acute treatment. However, in premenopausal women, because of the hypothesized anti- dopaminergic effect of estrogens, it may not be necessary to deplete the dopaminergic neurons to such an extent as in male patients. I f this is the case, pimozide would appear to be a particularly suitable drug for the treatment of female schizo- phrenic patients.

At the doses used in this study, pimozide appeared to be capable of elevating prolactin plasma levels to an extent similar to chlorpromazine. As pimozide had less of a thera- peutic effect than chlorpromazine, this raises the question of a different mode of action of the two drugs in the tubero- infundibular region. Recent data from animal studies suggest that the effect of pimozide on prolactin secretion could be mediated through a mechanism other than its dopamine blockade effect (Denef et al. 1979). Blood samples for prolactin plasma measurements were taken 24h after the previous dose of pimozide as opposed to 11 h for chlorprom- azine. Thus the continued elevation ofprolactin plasma levels in pimozide-treated patients at this time tends to confirm that

pimozide has a relatively prolonged duration of action and that a single daily dose is sufficient for most patients.

The explanations offered above as regards the possible mechanism of action of pimozide are of course tentative. Long-term studies will be needed to establish whether chronic treatment with pimozide induces less neostriatal dopaminer- gic supersensitivity and consequently less tardive dyskinesia than the classical neuroleptics. Although pimozide does not appear to be the ideal neuroleptic for highly agitated schizo- phrenic patients, its weaker presynaptic blocking effect may be an advantage in maintenance therapy.

Acknowledgements. We thank Dr. R. Collu of St. Justine Hospital, Montreal, in whose laboratory the prolactin assays were carried out. We are also grateful for the assistance of Carmen Morin, R. N., Thierry Petitjean Roget, Annette Gigu+re, and Elaine Lewis, M.A.

References

And6n NW, Butcher SG, Corrodi H, Fuxe K, Ungerstedt U (1970) Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur J Pharmacol 11 : 303 - 314

Ayd FJ (1974) Clozapine: a unique new neuroleptic. Int Drug Therapy Newsletter 9: 5 - 12

Bunney BS, Grace AA (] 978) Acute and chronic haloperidol treatment: comparison of effects on nigral dopaminergic cell activity. Life Sci 23:1715-1728

Burnett GB, Prange AJ Jr, Wilson IC, Jolliff LA, Creese IC, Snyder SH (1980) Adverse effects of anticholinergic antiparkinsonian drugs in tardive dyskinesia. Neuropsychobiology 6:109-1.20

Chouinard G, Lehmann HE, Ban TA (1970) Pimozide in the treatment of chronic schizophrenic patients. Curr Ther Res 12:598-603

Chouinard G, Annable L, Ross-Chouinard A, Kropsky M (1979a) Ethopropazine and benztropine in neuroleptic-induced parkin- sonism. J Clin Psychiatry 40:73-81

Chouinard G, de Montigny C, Annable L (1979b) Tardive dyskinesia and antiparkinsonian medication. Am J Psychiatry 136: 228 - 229

Chouinard G, Ross-Chouinard A, Annable L, Jones BD (1980) Extrapyramidal symptom rating scale. Can J Neurol Sci 7:233

Clark ML, Huber WK, Hill D, Wood F, Costiloe JP (1975) Pimozide in chronic schizophrenic outpatients. Dis Nerv Syst 36:137-141

Denef C, Van Nueten JM, Leysen JE, Janssen PAJ (1979) Evidence that pimozide is not a partial agonist of dopamine receptors. Life Sci 25 : 217- 226

Falloon I, Watt DC, Shepherd M (1978) A comparative controlled trial ofpimozide and fluphenazine decanoate in the continuation therapy of schizophrenia. Psychol Med 8 : 59- 70

Gerlach J, Reisby N, Randrup A (1974) Dopaminergic hypersensitivity and cholinergic hypofunction in the pathophysiology of tardive dyskinesia. Psychopharnlacologia 34:21 - 35

Gerlach J, Thorsen K (1976) The movement pattern of oral tardive dyskinesia in relation to anticholinergic and antidopaminergic treatment. Int Pharmacopsychiatry 11:1- 7

Gibson AC (1978) Depot injections and tardive dyskinesia. Br J Psychiatry 132: 361 - 365

Hogarty GE, Goldberg SC, Sehooler NR (1974) Drug and sociotherapy in the aftercare of schizophrenic patients. Arch Gen Psychiatry 31:609-618

Honma T, Hirose A (1979) Neuroleptic-induced changes of tyrosine hydroxylase activity in rat striatum in vitro and in vivo. Life Sci 24: 2023 - 2030

Janssen PAJ, Niemeggers CJE, Schellekens KHL, Dresse A, Lenaerts FM, Pinchard A, Schaper WKA, Van Nueten JM, Verbruggen FJ (1968) Pimozide, a chemically novel, highly potent and orally long- acting neuroleptic drug. Arzneim Forsch 18: 261 - 279

Klawans HL, Rubovits R (1974) Effect of cholinergic and anticholinergic agents on tardive dyskinesia. J Neurol Neurosurg Psychiatry 27: 941 -- 947

19

National Institute of Mental Health Psychopharmacology Service Center Collaborative Study Group (1964) Phenothiazine treatment in acute schizophrenia. Arch Gen Psychiatry 10:24,5- 261

Overall JE, Gorham DR (1962) The brief psychiatric rating scale. Psychol Rep 10:799-812

Overall JE, Klett CJ (1972) Applied multivariate analysis. McGraw-Hill, New York

Pinder RM, Brogden RN, Sawyer PR, Speight TM, Spencer R, Avery GS (1976) Pimozide: a review of its pharmacological properties and therepeutic uses in psychiatry, Drugs 12:1 - 40

Piyakulmala S, Corbet L, Ahluwalia Y, Berry RA, Meltzer HY (1977) High dose pimozide in the treatment of acutely agitated schizo- phrenia. Curr Ther Res 22:453-461

Raymond V, Beaulieu M, Labrie F, Boissier J (1978) Potent anti- dopaminergic activity of estradiol at the pituitary level on prolactin release. Science 200 : 1173 - 1175

Shopsin B, Selzer G (1977) High-dose pimozide in acutely ill, newly admitted schizophrenic inpatients. Curt Ther Res 21 : 755 - 767

Sinha YN, Selby FW, Lewis UJ, Vanderlaan WP (1973) A homologous radioimmunoassay for human prolactin. J Clin Endocrinol Metab 36:509-516

Spitzer RL, Endicott J, Robins E (1978) Research Diagnostic Criteria, 3rd edition, Biometrics Research. New York State Psychiatric Institute, New York

Tsuang MT, Winokur G (1974) Criteria for subtyping schizophrenia. Arch Gen Psychiatry 31:43-47

Walters JR, Roth RH (1976) Dopaminergic neurons: an in vivo system for measuring drug interactions with presynaptic receptors. Arch Pharmacol 296 : 5 - 14

Wauquier A (1979) Neuroleptics and brain self-stimulation behavior. Int Rev Neurobiol 21 : 335 - 403

Received December 18, 1980; Final version September 16, 1981