Current Medical Research and Opinion
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Pimozide in acute schizophrenia: a pilot study Denise Garton & Trevor Silverstone To cite this article: Denise Garton & Trevor Silverstone (1979) Pimozide in acute schizophrenia: a pilot study, Current Medical Research and Opinion, 5:10, 799-806, DOI: 10.1185/03007997909109017 To link to this article: http://dx.doi.org/10.1185/03007997909109017
Published online: 11 Aug 2008.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [University of California, San Diego]
Date: 07 November 2015, At: 01:04
Current Medical Research and Opinion
Vol. 5 , No. 10, 1979
Pimozide in acute schizophrenia : a pilot study
and
Denise Garton, B.Sc., M.B., Ch.B., Trevor Silverstone, M.A., D.M.,
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
F.R.C.P.,F.R.C.Psych. Academic Unit of Human Psychopharmacology, Medical Colleges of St. Bartholomew's and The London Hospital, German Hospital, London
Curr. Med. Res. Opin., (1979), 5, 799.
Received: 27th November 1978
Summary Pimozide was used in a pilot study to treat I0 patients with jrank symptoms of acutc schizophrenia. Eight patients appeared to respond favourably to doses ranging from 12 to 40 mg daily. Two of the patients responded within I week and all 8 within 5 weeks. It was possible to discharge all 8 patients from hospital within this time period. It is concluded that oralpimozide is an effective treatment for the whole range of symptoms accompanying acute schizophrenia. Brief representative case histories are presented, and dosage recommendations for the effective treatment of acute schizophrenia with pimozide are discussed. Key words: Pimozide - schizophrenia
Introduction Pimozide,? a member of the diphenylbutylpiperidine group of compounds, has been shown in a number of clinical trials to be effective in the maintenance therapy of chronic schizophrenia.5~~ However, its place in the treatment of acute schizophrenia has been the subject of some disagreement. On the one hand is the view of Clark et aL3 which cautions against the use of pimozide in the hyperactive aggressive type of patient; while on the other hand is the recent report from Shopsin and Selzers indicating that, in some patients at least, pimozide in a dosage of up to 60 mg per day is effective in ameliorating the whole range of symptoms, including motor excitement, exhibited by patients presenting with an acute schizophrenic illness. More in keeping with this later view is our own experience of the efficacy of pimozide in the treatment of mania, a condition in which overactivity is a prominent f e a t ~ r e . ~ As Shopsin and Selzers point out, it would be surprising if a drug which was effective in preventing a relapse of a chronic condition were not also effective in the acute phase of the illness. Furthermore, because pimozide is a relatively specific dopamine receptor blocking agent1 it would be expected, on the basis of current views regarding the role of dopamine neurotransmitter systems in the pathogenesis of schizophrenia,6 that a drug with this type of action would be effective in acute schizophrenia. f'orap', trade mark Janssen Pharmaceutical Limited
799
Piniozide in acute schizophrenia: a pilot study
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
-
._
It may be, of course, that the earlier views were based on the results of studies in which the drug was not being administered in sufficient dosage. Until recently, the recommended maximum dose has been 10 mg, whereas Shopsin and Selzer8 gave up to 60 mg daily to over half their patients; in mania we also found it necessary to exceed 10 mg a day.4 In order to examine the place of pimozide in the management of acute schizophrenia, and to attempt to establish an effective dose range, we undertook an open pilot study of pimozide in a group of patients presenting with this illness who required to be admitted to hospital for treatment.
Patients and methods Ten patients entered the study. All exhibited frank symptoms of acute schizophrenia and the diagnosis of schizophrenia was agreed upon by two clinicians. None of the patients had received any neuroleptic medication during the 2 weeks prior to admission. There were 7 women and 3 men whose ages ranged from 19 to 59 years (Table I). Six of the 10 patients had at least one previous episode of schizophrenia, and 2 of them had had several. The dose range of pimozide which was prescribed is given in Table I. Table I. Patient history and pimozide dosage Patient No.
5 6 I 8 9 10
Sex
Age (yrs)
Female Female Male Male
43 26 19 32
Female Female Male Female Female Female
31 19 56 21 59 20
No. previous episodes 10
9
1
1 1 1
Pimozide dosage (mg/day) Start
Days 3to4
Day I
Day 14
16 20 20 20
16 10 20 20
16 10 20 20
16 10 32 20
12 16 20 16 20 24
20 16 20 24 16 24
20 16 32 24 I6 16
Day 21
Day 28
16 16 Discharged 40 40 20 Drug stopped 20 Discharged 24 16 16 32 32 32 24 32 32 Discharged Drug stopped
When it had been decided to include a patient in the study, the following clinical and nursing ratings were made before starting treatment: (a) Brief Psychiatric Rating Scale (BPRS),6 using the glossary devised by Wiles et aL9 In this scale, there are 18 items, each of which is rated from 0 (absent) to 6 (extremely severe). The minimum possible score is 0; (b) the Wing Scale for rating of schizophrenic symptoms.’ O These symptoms are: (i) flatness and incongruity of affect; (ii) poverty of speech; (iii) incoherence of speech; and (iv) coherent delusions. Each symptom is rated from 1 (absence) to 5 (extreme severity). The minimum possible score, therefore, is 4; and (c) the Wing behaviour rating scale.’O This covers 12 items of behaviour which are 800
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Denise Garton and Trevor Silverstone
rated by the ward nursing staff from 0 to 2 in order of severity. Minimum possible score is 0. Ratings were repeated 3, 7, 14,21 and 28 days after starting pimozide. In 4 patients, the later ratings were not obtained; 3 (Patient nos. 2,5,9) having become fit for discharge before the 28-day period was up, and the remaining patient (No. 10) was transferred to a medical ward because of a gastro-intestinal disorder. One patient (No. 9) required intramuscular chlorpromazine on two occasions in the 3 days before she entered the study; another (No. 1) was given a single-dose of 100 mg chlorpromazine on admission. Once entered in the trial, no neuroleptic other than pimozide was administered; the only other drugs allowed were procyclidine for extrapyramidal symptoms, and nitrazepam, if necessary, for insomnia.
Results The patients could be grouped into three categories on the basis of their predominant symptoms : (i) 5 patients exhibited marked thought disorder of the schizophrenic type (Patient nos. 1,2,3,4 and 6). Most of these patients also expressed bizarre delusional ideas concerning the abnormal significanceof everyday events. Another predominant feature in this group was inappropriate giggling or laughing; (ii) 4 patients, although not formally thought disordered, believed their thoughts to be controlled, withdrawn or otherwise interfered with by outside agencies (Patient nos. 5,7,8 and 10); 3 of these patients (Nos. 5, 7 and 8) also experienced vivid auditory hallucinations in which voices referred to them in the third person; and (iii) the remaining patient (No. 9) appeared to be suffering from a purely paranoid psychosis. These three patterns of illness, together with the response to treatment with pimozide, are illustrated by the following brief case histories. Patient No, 2 This was a 26-year old, unmarried university graduate who had been found sitting naked in the street on the day prior to admission. She had not been eating for some 5 days because, as it later emerged, she had felt that in some way she had changed and was in abnormal communication with others. “I could see through people . . . there was another stage of existence I was about to enter. . . I thought I was schizophrenic”. On admission she was virtually mute. When she could be persuaded to talk her answers were abnormal. For example, when asked whether she saw her parents regularly (they lived in another city) she replied, “Yes I am now, at the moment, I’m sitting on my bed as well”. When asked her age she replied, “Officially, 26 . . . unofficially, socially retarded and intellectually advanced”. There was no past history of schizophrenia. Pimozide was started at a dose of 10 mg twice daily; this was reduced to 10 mg daily on the third day and she was maintained on this dose for the remainder of her stay in hospital. By the third day of pimozide treatment she was talking much more freely, but was still deluded, being unconvinced that she was, in fact, in a hospital, and fearing that she was being ‘brainwashed’. She tended to wander about the ward in an aimless fashion. Her BPRS rating had fallen from 24 to 18 by then, and her Wing behaviour score had 801
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Pimozide in acute schizophrenia:a pilot study
fallen from 10 to 9, but her Wing symptom rating scale score had in fact risen from 1 1 to 12 (see Tables 11, 111 and IV). The following day she appeared to regain some insight into her illness and was able to describe how she had felt in the days leading up to her admission. Shortly after this she complained of ‘stiffness’ in her legs. Examination revealed some slight increase in tone and it was thought advisable to add procyclidine. Within a week of starting pimozide her BPRS score had fallen to 7; in particular, the score in the item ‘conceptual disorganization’ had gone from 4 (‘moderately severe’) to 1 (‘very mild’) and she was much less emotionally Aat. The other scores had improved in parallel. By the fourteenth day of pimozide she was considered virtually symptom-free (BPRS score 3, Wing symptom score 5 , Wing behaviour score 0). At her insistence, she was discharged at that time. Patient No. 7
This was a 56-year old gate porter who had a 40-year history of recurrent schizophrenic illnesses. He had been well maintained on regular monthly 25 mg fluphenazine decanoate injections until 6 months before admission when the dose had been reduced to 12.5 mg monthly. His last injection had been given some 4 weeks prior to admission. Four days before admission he failed to go to work and wandered around the neighbourhood frightened that he might die because of an incessant feeling of pressure in his head. He began to hear voices at about this time; there were several voices which sometimes talked to him and sometimes talked about him. He developed ideas of thought withdrawal and ideas of reference in that the radio was giving him messages. On admission he was apathetic, and extremely dirty, being covered in faeces. He was well orientated and co-operative. The following day he became very agressive, fighting both patients and staff without provocation. He was noted to adopt and maintain odd postures and his affect was inappropriate. Pimozide was started in a dosage of 10 mg twice daily. As he failed to improve after 7 days, the dosage was increased to 16 mg twice daily. Within 3 days of this increase he was noted to be much better; he was speaking rationally and his affect was appropriate. Within 3 weeks of admission the nursing staff could detect no abnormality in his behaviour (see Table IV) and his BPRS score had fallen from a maximum of 30 to 7. He continued to improve and he was discharged well 4 weeks after admission. Patient No. 9
A 53-year old English housewife who had for many years unjustifiably believed that her Irish husband was being unfaithful to her, was associated with the IRA, and was doping her at night to consort with other women and to meet with his supposed colleagues in crime. These beliefs had become more obtrusive in recent months, when she had gone so far as to lock her husband in his room every night and to ensure that no one could use the telephone. She insisted on accompanying her husband wherever he went, and believed that they were surrounded by criminal acquaintances of his who were continously passing sign messages. Shortly before admission she had threatened her husband with a knife, and on the day of admission was shouting and swearing at him incessantly. She resisted admission to hospital, insisting: ‘‘I can’t come here, it’s all part of a plot”. She was well-orientated, there was no thought disorder and she did not admit to hallucinations. In view of her disturbed behaviour 802
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Denise Garton and Trevor Silverstone
and attempts to leave, she was given an intramuscular injection of 300 rng chlorpromazine. It was necessary to give her one further intramuscular injection of 200 mg chlorpromazine during the 4-day period before she started on 10 mg pimozide twice daily. This dosage was reduced to 8 mg twice daily 2 days later because of drowsiness. Within 4 days of starting pimozide she admitted that she had been “talking a lot of rubbish”. Within a week, all her paranoid delusions had gone and she was virtually symptom-free for the first time for over 10 years. There was little reason to refuse her request to return home where she has remained well on 8 mg pimozide twice daily. Looking at the results overall it can be seen from Tables 11, I11 and IV that of the 10 patients treated with pimozide, 7 (Nos. 1,2,5,6,7,8 and 9) significantly improved within 28 days of starting pimozide. All 7 patients were discharged from hospital within this period or shortly afterwards. One further patient (No. 3) markedly improved between the fourth and fifth week of treatment and was then discharged. Of the 2 remaining patients, Patient no. 4, who failed to improve significantly on pimozide, was switched onto haloperidol to which he eventually responded. Patient no. 10 seemed to deteriorate on pimozide; she began to vomit her food and was Table 11. Brief Psychiatric Rating Scale scores Patient No.
1 2 3 4 5 6 7 8 9 10
Total scores Start
Days 3 to4
Day I
Day 14
Day21
Day28
34 24 18 44 19 41 18 17 10 11
23 18 18 13 13 34 25 14 6 13
25 I 11 22 0 30 30 10 1 20
21 5 6 3 Discharged 13 15 14 14 24 Drug stopped Discharged 18 3 6 9 7 1 3 7 7 Discharged 26 Drug stopped
Day 14
Table III. Wing 4 symptom scale scores Patient No.
1 2 3 4 5
6 7 8 9 10
Score Start
Days 3 to 4
Day 7
7 11 11 10 9 14 9 11 7 9
I 12 10 11 9 15 11 10
7 I 13 11 8 12 13 9 5 9
5
9
9 5
Day21
Day28
6 Discharged 10 6
11 10 Drug stopped 8 Discharged 11 6 6 5 5 4 8 7 4 Discharged 9 Drug stopped
803
Pirnozide in acute schizophrenia: a pilot study
Table IV. Wing ward behaviour scale scores Patient
Total score
NO.
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Start 1 2 3
4 5 6 I 8 9 10
Days 3t04
1
10 10
6 6 I 16 11 2 3
17 6 1 4
Day 7 2 9 11 5 3 6 16 10 0 1
Day14 1 0 7 - 3 Discharged 5 9 10
1 0
Day21 2 Discharged
4 4
Day28
0
4 Drug stopped
3 2 0 0 3 0 Discharged Drug stopped
transferred to a medical ward where the pimozide was stopped. Her gastro-intestinal symptoms and psychopathology both improved without further medication. With regard to individual symptoms the time course of improvement varied considerably. On the BPRS scale, suspiciousness and hostility improved most rapidly, becoming minimal within a week; conceptual disorganization and unusual thoughts took rather longer to go, requiring a good 3 weeks in most cases and even longer in others. Side-eflects The only troublesome side-effects of any consequence were extrapyramidal symptoms which occurred in 6 patients. The details are given in Table V. None of the patients had an acute dystonic reaction of the oculo-gyric crisis type. In 5, the extrapyramidal symptoms, although definite, were not severe, and remitted rapidly with procyclidine treatment. In only 1 patient (No. 10) was it necessary to stop the pimozide, which was not in any case improving the psychotic symptoms.
Discussion Our results indicate that oral pimozide is an effective treatment for the whole range of symptoms accompanying acute schizophrenia. Our findings, therefore, are in close agreement with those of Shopsin and Selzer8 and contrary to those of Clark et aL3 We would also agree with the former authors in recommending doses of pimozide higher than those generally used. In the light of our experience, we would suggest that a suitable starting dose of pimozide for a fit adult would be 20 mg, followed 12 hours later by a further 20 mg depending on the patient’s clinical state. The dose could then be adjusted up or down as necessary. The frequency of extrapyramidal effects we encountered was similar to that of Shopsin and Selzer;8 8 of their 16 patients who completed 28-days’ treatment developed extrapyramidal symptoms while 6 of our 10 patients did so. In the 804
10 im.
10 i.m.
Tremor, rigidity Dysarthria Stiffness of jaw causing dysarthria Protruding tongue, parkinsonian facies. 15 days after starting pirnozide, severe parkinsonism. Drug stopped
20
16
16
24
4
6
8
10
5 t.i.d. increasing to 10 t.i.d.
+ 20 b.d. orally
+ 5 b.d. orally
10 b.d.
10 b.d.
Excess salivation, mask-like facies
20
10 t.i.d.
Procyclidine dose (mg)
3
Symptoms
Walking stiffly, stiffness in legs/feet, tone increased in all limbs
Daily pimozide dose (mg)
10
No. days pimozide treat rnent before onset
2
No.
Patient
Table V. Extrapyramidal symptoms reported in 6 patients
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Poor
Good
Good
Good
Good
Good
Response
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Pimozide in acute schizophrenia: a pilot study
majority of our patients these extrapyramidal effects responded promptly to procyclidine. Where our findings differ is in the overall rate of response. Only 7 (28 %) out of 16 patients in the Shopsin and Selzer study8 responded in a 25-day period; of our 10 patients, 7 (70%) were well enough to be discharged within a similar treatment period. This difference in rate of response may be related, at least partly, to the difference in patient population. We included all newly admitted patients exhibiting unequivocal symptoms of acute schizophrenia whether or not they had had a previous illness, whereas Shopsin and Selzers restricted their sample to patients who had had previous episodes. We had 6 patients with a history of a previous illness, 4 of whom improved sufficiently to be discharged. It was in this group that both our treatment failures occurred. From a theoretical standpoint, the fact that pimozide, a relatively specific dopaminergic receptor blocking drug, has proved so effective in the treatment of acute schizophrenia is consistent with the view that this illness is associated with, if not actually caused by, an abnormality in the dopaminergic pathways within the central nervous system.2
Acknowledgement The authors would like to thank Janssen Pharmaceutical Limited for their support and for the supply of pirnozide.
References 1 . Anden, N. E., Butcher, S. C., Corrodi, H., Fuxe, K., and Ungerstedt, U., (1970). Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol., 11, 303-314. 2. Carlsson, A., (1977). Does dopamine play a role in schizophrenia? Psychol. Med., 7,583-597. 3. Clark, M. L., Huber, W., Serafetinides, E., and Comrnure, J. P., (1971). Pimozide (Orap): a tolerance study. Clin. Trials J., 8, Suppl. 11,25-32. 4. Cookson, J., and Silverstone, T., (1976). 5-hydroxytryptamine and dopamine pathways in mania: a pilot study of fenfluramine and pimozide. Br. J. Clin. Pharmacol., 3,942-943. 5 . Falloon, I., Watt, D. C., and Shepherd, M., (1978). A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation of therapy of schizophrenia. Psychol. Med., 8,59-70. 6. Overall, J. E., and Gorham, D. R., (1962). The brief psychiatric rating scale. Psychol. Rep., 10,799-812. 7. Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Spencer, R., and Avery, G. S., (1976). Pimozide : a review of its pharmacological properties and therapeutic uses in psychiatry. Drugs, 12, 1-40. 8. Shopsin, B., and Selzer, G., (1977). High dose pimozide in acutely ill, newly admitted schizophrenic patients. Curr. Ther. Res., 21,755-767. 9. Wiles, D. H., Kolakowska, T., McNeilly, A. S., Mandelbrote, B. M., and Gelder, M. G., (1976). Clinical significance of plasma chlorpromazine levels, I. Psychol. Med., 6,407-415. 10. Wing, J. K., (1961). A simple and reliable sub-classification of chronic schizophrenia. J. Ment. Sci., 107, 862-875.
806
ISSN: 0300-7995 (Print) 1473-4877 (Online) Journal homepage: http://www.tandfonline.com/loi/icmo20
Pimozide in acute schizophrenia: a pilot study Denise Garton & Trevor Silverstone To cite this article: Denise Garton & Trevor Silverstone (1979) Pimozide in acute schizophrenia: a pilot study, Current Medical Research and Opinion, 5:10, 799-806, DOI: 10.1185/03007997909109017 To link to this article: http://dx.doi.org/10.1185/03007997909109017
Published online: 11 Aug 2008.
Submit your article to this journal
Article views: 3
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=icmo20 Download by: [University of California, San Diego]
Date: 07 November 2015, At: 01:04
Current Medical Research and Opinion
Vol. 5 , No. 10, 1979
Pimozide in acute schizophrenia : a pilot study
and
Denise Garton, B.Sc., M.B., Ch.B., Trevor Silverstone, M.A., D.M.,
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
F.R.C.P.,F.R.C.Psych. Academic Unit of Human Psychopharmacology, Medical Colleges of St. Bartholomew's and The London Hospital, German Hospital, London
Curr. Med. Res. Opin., (1979), 5, 799.
Received: 27th November 1978
Summary Pimozide was used in a pilot study to treat I0 patients with jrank symptoms of acutc schizophrenia. Eight patients appeared to respond favourably to doses ranging from 12 to 40 mg daily. Two of the patients responded within I week and all 8 within 5 weeks. It was possible to discharge all 8 patients from hospital within this time period. It is concluded that oralpimozide is an effective treatment for the whole range of symptoms accompanying acute schizophrenia. Brief representative case histories are presented, and dosage recommendations for the effective treatment of acute schizophrenia with pimozide are discussed. Key words: Pimozide - schizophrenia
Introduction Pimozide,? a member of the diphenylbutylpiperidine group of compounds, has been shown in a number of clinical trials to be effective in the maintenance therapy of chronic schizophrenia.5~~ However, its place in the treatment of acute schizophrenia has been the subject of some disagreement. On the one hand is the view of Clark et aL3 which cautions against the use of pimozide in the hyperactive aggressive type of patient; while on the other hand is the recent report from Shopsin and Selzers indicating that, in some patients at least, pimozide in a dosage of up to 60 mg per day is effective in ameliorating the whole range of symptoms, including motor excitement, exhibited by patients presenting with an acute schizophrenic illness. More in keeping with this later view is our own experience of the efficacy of pimozide in the treatment of mania, a condition in which overactivity is a prominent f e a t ~ r e . ~ As Shopsin and Selzers point out, it would be surprising if a drug which was effective in preventing a relapse of a chronic condition were not also effective in the acute phase of the illness. Furthermore, because pimozide is a relatively specific dopamine receptor blocking agent1 it would be expected, on the basis of current views regarding the role of dopamine neurotransmitter systems in the pathogenesis of schizophrenia,6 that a drug with this type of action would be effective in acute schizophrenia. f'orap', trade mark Janssen Pharmaceutical Limited
799
Piniozide in acute schizophrenia: a pilot study
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
-
._
It may be, of course, that the earlier views were based on the results of studies in which the drug was not being administered in sufficient dosage. Until recently, the recommended maximum dose has been 10 mg, whereas Shopsin and Selzer8 gave up to 60 mg daily to over half their patients; in mania we also found it necessary to exceed 10 mg a day.4 In order to examine the place of pimozide in the management of acute schizophrenia, and to attempt to establish an effective dose range, we undertook an open pilot study of pimozide in a group of patients presenting with this illness who required to be admitted to hospital for treatment.
Patients and methods Ten patients entered the study. All exhibited frank symptoms of acute schizophrenia and the diagnosis of schizophrenia was agreed upon by two clinicians. None of the patients had received any neuroleptic medication during the 2 weeks prior to admission. There were 7 women and 3 men whose ages ranged from 19 to 59 years (Table I). Six of the 10 patients had at least one previous episode of schizophrenia, and 2 of them had had several. The dose range of pimozide which was prescribed is given in Table I. Table I. Patient history and pimozide dosage Patient No.
5 6 I 8 9 10
Sex
Age (yrs)
Female Female Male Male
43 26 19 32
Female Female Male Female Female Female
31 19 56 21 59 20
No. previous episodes 10
9
1
1 1 1
Pimozide dosage (mg/day) Start
Days 3to4
Day I
Day 14
16 20 20 20
16 10 20 20
16 10 20 20
16 10 32 20
12 16 20 16 20 24
20 16 20 24 16 24
20 16 32 24 I6 16
Day 21
Day 28
16 16 Discharged 40 40 20 Drug stopped 20 Discharged 24 16 16 32 32 32 24 32 32 Discharged Drug stopped
When it had been decided to include a patient in the study, the following clinical and nursing ratings were made before starting treatment: (a) Brief Psychiatric Rating Scale (BPRS),6 using the glossary devised by Wiles et aL9 In this scale, there are 18 items, each of which is rated from 0 (absent) to 6 (extremely severe). The minimum possible score is 0; (b) the Wing Scale for rating of schizophrenic symptoms.’ O These symptoms are: (i) flatness and incongruity of affect; (ii) poverty of speech; (iii) incoherence of speech; and (iv) coherent delusions. Each symptom is rated from 1 (absence) to 5 (extreme severity). The minimum possible score, therefore, is 4; and (c) the Wing behaviour rating scale.’O This covers 12 items of behaviour which are 800
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Denise Garton and Trevor Silverstone
rated by the ward nursing staff from 0 to 2 in order of severity. Minimum possible score is 0. Ratings were repeated 3, 7, 14,21 and 28 days after starting pimozide. In 4 patients, the later ratings were not obtained; 3 (Patient nos. 2,5,9) having become fit for discharge before the 28-day period was up, and the remaining patient (No. 10) was transferred to a medical ward because of a gastro-intestinal disorder. One patient (No. 9) required intramuscular chlorpromazine on two occasions in the 3 days before she entered the study; another (No. 1) was given a single-dose of 100 mg chlorpromazine on admission. Once entered in the trial, no neuroleptic other than pimozide was administered; the only other drugs allowed were procyclidine for extrapyramidal symptoms, and nitrazepam, if necessary, for insomnia.
Results The patients could be grouped into three categories on the basis of their predominant symptoms : (i) 5 patients exhibited marked thought disorder of the schizophrenic type (Patient nos. 1,2,3,4 and 6). Most of these patients also expressed bizarre delusional ideas concerning the abnormal significanceof everyday events. Another predominant feature in this group was inappropriate giggling or laughing; (ii) 4 patients, although not formally thought disordered, believed their thoughts to be controlled, withdrawn or otherwise interfered with by outside agencies (Patient nos. 5,7,8 and 10); 3 of these patients (Nos. 5, 7 and 8) also experienced vivid auditory hallucinations in which voices referred to them in the third person; and (iii) the remaining patient (No. 9) appeared to be suffering from a purely paranoid psychosis. These three patterns of illness, together with the response to treatment with pimozide, are illustrated by the following brief case histories. Patient No, 2 This was a 26-year old, unmarried university graduate who had been found sitting naked in the street on the day prior to admission. She had not been eating for some 5 days because, as it later emerged, she had felt that in some way she had changed and was in abnormal communication with others. “I could see through people . . . there was another stage of existence I was about to enter. . . I thought I was schizophrenic”. On admission she was virtually mute. When she could be persuaded to talk her answers were abnormal. For example, when asked whether she saw her parents regularly (they lived in another city) she replied, “Yes I am now, at the moment, I’m sitting on my bed as well”. When asked her age she replied, “Officially, 26 . . . unofficially, socially retarded and intellectually advanced”. There was no past history of schizophrenia. Pimozide was started at a dose of 10 mg twice daily; this was reduced to 10 mg daily on the third day and she was maintained on this dose for the remainder of her stay in hospital. By the third day of pimozide treatment she was talking much more freely, but was still deluded, being unconvinced that she was, in fact, in a hospital, and fearing that she was being ‘brainwashed’. She tended to wander about the ward in an aimless fashion. Her BPRS rating had fallen from 24 to 18 by then, and her Wing behaviour score had 801
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Pimozide in acute schizophrenia:a pilot study
fallen from 10 to 9, but her Wing symptom rating scale score had in fact risen from 1 1 to 12 (see Tables 11, 111 and IV). The following day she appeared to regain some insight into her illness and was able to describe how she had felt in the days leading up to her admission. Shortly after this she complained of ‘stiffness’ in her legs. Examination revealed some slight increase in tone and it was thought advisable to add procyclidine. Within a week of starting pimozide her BPRS score had fallen to 7; in particular, the score in the item ‘conceptual disorganization’ had gone from 4 (‘moderately severe’) to 1 (‘very mild’) and she was much less emotionally Aat. The other scores had improved in parallel. By the fourteenth day of pimozide she was considered virtually symptom-free (BPRS score 3, Wing symptom score 5 , Wing behaviour score 0). At her insistence, she was discharged at that time. Patient No. 7
This was a 56-year old gate porter who had a 40-year history of recurrent schizophrenic illnesses. He had been well maintained on regular monthly 25 mg fluphenazine decanoate injections until 6 months before admission when the dose had been reduced to 12.5 mg monthly. His last injection had been given some 4 weeks prior to admission. Four days before admission he failed to go to work and wandered around the neighbourhood frightened that he might die because of an incessant feeling of pressure in his head. He began to hear voices at about this time; there were several voices which sometimes talked to him and sometimes talked about him. He developed ideas of thought withdrawal and ideas of reference in that the radio was giving him messages. On admission he was apathetic, and extremely dirty, being covered in faeces. He was well orientated and co-operative. The following day he became very agressive, fighting both patients and staff without provocation. He was noted to adopt and maintain odd postures and his affect was inappropriate. Pimozide was started in a dosage of 10 mg twice daily. As he failed to improve after 7 days, the dosage was increased to 16 mg twice daily. Within 3 days of this increase he was noted to be much better; he was speaking rationally and his affect was appropriate. Within 3 weeks of admission the nursing staff could detect no abnormality in his behaviour (see Table IV) and his BPRS score had fallen from a maximum of 30 to 7. He continued to improve and he was discharged well 4 weeks after admission. Patient No. 9
A 53-year old English housewife who had for many years unjustifiably believed that her Irish husband was being unfaithful to her, was associated with the IRA, and was doping her at night to consort with other women and to meet with his supposed colleagues in crime. These beliefs had become more obtrusive in recent months, when she had gone so far as to lock her husband in his room every night and to ensure that no one could use the telephone. She insisted on accompanying her husband wherever he went, and believed that they were surrounded by criminal acquaintances of his who were continously passing sign messages. Shortly before admission she had threatened her husband with a knife, and on the day of admission was shouting and swearing at him incessantly. She resisted admission to hospital, insisting: ‘‘I can’t come here, it’s all part of a plot”. She was well-orientated, there was no thought disorder and she did not admit to hallucinations. In view of her disturbed behaviour 802
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Denise Garton and Trevor Silverstone
and attempts to leave, she was given an intramuscular injection of 300 rng chlorpromazine. It was necessary to give her one further intramuscular injection of 200 mg chlorpromazine during the 4-day period before she started on 10 mg pimozide twice daily. This dosage was reduced to 8 mg twice daily 2 days later because of drowsiness. Within 4 days of starting pimozide she admitted that she had been “talking a lot of rubbish”. Within a week, all her paranoid delusions had gone and she was virtually symptom-free for the first time for over 10 years. There was little reason to refuse her request to return home where she has remained well on 8 mg pimozide twice daily. Looking at the results overall it can be seen from Tables 11, I11 and IV that of the 10 patients treated with pimozide, 7 (Nos. 1,2,5,6,7,8 and 9) significantly improved within 28 days of starting pimozide. All 7 patients were discharged from hospital within this period or shortly afterwards. One further patient (No. 3) markedly improved between the fourth and fifth week of treatment and was then discharged. Of the 2 remaining patients, Patient no. 4, who failed to improve significantly on pimozide, was switched onto haloperidol to which he eventually responded. Patient no. 10 seemed to deteriorate on pimozide; she began to vomit her food and was Table 11. Brief Psychiatric Rating Scale scores Patient No.
1 2 3 4 5 6 7 8 9 10
Total scores Start
Days 3 to4
Day I
Day 14
Day21
Day28
34 24 18 44 19 41 18 17 10 11
23 18 18 13 13 34 25 14 6 13
25 I 11 22 0 30 30 10 1 20
21 5 6 3 Discharged 13 15 14 14 24 Drug stopped Discharged 18 3 6 9 7 1 3 7 7 Discharged 26 Drug stopped
Day 14
Table III. Wing 4 symptom scale scores Patient No.
1 2 3 4 5
6 7 8 9 10
Score Start
Days 3 to 4
Day 7
7 11 11 10 9 14 9 11 7 9
I 12 10 11 9 15 11 10
7 I 13 11 8 12 13 9 5 9
5
9
9 5
Day21
Day28
6 Discharged 10 6
11 10 Drug stopped 8 Discharged 11 6 6 5 5 4 8 7 4 Discharged 9 Drug stopped
803
Pirnozide in acute schizophrenia: a pilot study
Table IV. Wing ward behaviour scale scores Patient
Total score
NO.
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Start 1 2 3
4 5 6 I 8 9 10
Days 3t04
1
10 10
6 6 I 16 11 2 3
17 6 1 4
Day 7 2 9 11 5 3 6 16 10 0 1
Day14 1 0 7 - 3 Discharged 5 9 10
1 0
Day21 2 Discharged
4 4
Day28
0
4 Drug stopped
3 2 0 0 3 0 Discharged Drug stopped
transferred to a medical ward where the pimozide was stopped. Her gastro-intestinal symptoms and psychopathology both improved without further medication. With regard to individual symptoms the time course of improvement varied considerably. On the BPRS scale, suspiciousness and hostility improved most rapidly, becoming minimal within a week; conceptual disorganization and unusual thoughts took rather longer to go, requiring a good 3 weeks in most cases and even longer in others. Side-eflects The only troublesome side-effects of any consequence were extrapyramidal symptoms which occurred in 6 patients. The details are given in Table V. None of the patients had an acute dystonic reaction of the oculo-gyric crisis type. In 5, the extrapyramidal symptoms, although definite, were not severe, and remitted rapidly with procyclidine treatment. In only 1 patient (No. 10) was it necessary to stop the pimozide, which was not in any case improving the psychotic symptoms.
Discussion Our results indicate that oral pimozide is an effective treatment for the whole range of symptoms accompanying acute schizophrenia. Our findings, therefore, are in close agreement with those of Shopsin and Selzer8 and contrary to those of Clark et aL3 We would also agree with the former authors in recommending doses of pimozide higher than those generally used. In the light of our experience, we would suggest that a suitable starting dose of pimozide for a fit adult would be 20 mg, followed 12 hours later by a further 20 mg depending on the patient’s clinical state. The dose could then be adjusted up or down as necessary. The frequency of extrapyramidal effects we encountered was similar to that of Shopsin and Selzer;8 8 of their 16 patients who completed 28-days’ treatment developed extrapyramidal symptoms while 6 of our 10 patients did so. In the 804
10 im.
10 i.m.
Tremor, rigidity Dysarthria Stiffness of jaw causing dysarthria Protruding tongue, parkinsonian facies. 15 days after starting pirnozide, severe parkinsonism. Drug stopped
20
16
16
24
4
6
8
10
5 t.i.d. increasing to 10 t.i.d.
+ 20 b.d. orally
+ 5 b.d. orally
10 b.d.
10 b.d.
Excess salivation, mask-like facies
20
10 t.i.d.
Procyclidine dose (mg)
3
Symptoms
Walking stiffly, stiffness in legs/feet, tone increased in all limbs
Daily pimozide dose (mg)
10
No. days pimozide treat rnent before onset
2
No.
Patient
Table V. Extrapyramidal symptoms reported in 6 patients
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Poor
Good
Good
Good
Good
Good
Response
Downloaded by [University of California, San Diego] at 01:04 07 November 2015
Pimozide in acute schizophrenia: a pilot study
majority of our patients these extrapyramidal effects responded promptly to procyclidine. Where our findings differ is in the overall rate of response. Only 7 (28 %) out of 16 patients in the Shopsin and Selzer study8 responded in a 25-day period; of our 10 patients, 7 (70%) were well enough to be discharged within a similar treatment period. This difference in rate of response may be related, at least partly, to the difference in patient population. We included all newly admitted patients exhibiting unequivocal symptoms of acute schizophrenia whether or not they had had a previous illness, whereas Shopsin and Selzers restricted their sample to patients who had had previous episodes. We had 6 patients with a history of a previous illness, 4 of whom improved sufficiently to be discharged. It was in this group that both our treatment failures occurred. From a theoretical standpoint, the fact that pimozide, a relatively specific dopaminergic receptor blocking drug, has proved so effective in the treatment of acute schizophrenia is consistent with the view that this illness is associated with, if not actually caused by, an abnormality in the dopaminergic pathways within the central nervous system.2
Acknowledgement The authors would like to thank Janssen Pharmaceutical Limited for their support and for the supply of pirnozide.
References 1 . Anden, N. E., Butcher, S. C., Corrodi, H., Fuxe, K., and Ungerstedt, U., (1970). Receptor activity and turnover of dopamine and noradrenaline after neuroleptics. Eur. J. Pharmacol., 11, 303-314. 2. Carlsson, A., (1977). Does dopamine play a role in schizophrenia? Psychol. Med., 7,583-597. 3. Clark, M. L., Huber, W., Serafetinides, E., and Comrnure, J. P., (1971). Pimozide (Orap): a tolerance study. Clin. Trials J., 8, Suppl. 11,25-32. 4. Cookson, J., and Silverstone, T., (1976). 5-hydroxytryptamine and dopamine pathways in mania: a pilot study of fenfluramine and pimozide. Br. J. Clin. Pharmacol., 3,942-943. 5 . Falloon, I., Watt, D. C., and Shepherd, M., (1978). A comparative controlled trial of pimozide and fluphenazine decanoate in the continuation of therapy of schizophrenia. Psychol. Med., 8,59-70. 6. Overall, J. E., and Gorham, D. R., (1962). The brief psychiatric rating scale. Psychol. Rep., 10,799-812. 7. Pinder, R. M., Brogden, R. N., Sawyer, P. R., Speight, T. M., Spencer, R., and Avery, G. S., (1976). Pimozide : a review of its pharmacological properties and therapeutic uses in psychiatry. Drugs, 12, 1-40. 8. Shopsin, B., and Selzer, G., (1977). High dose pimozide in acutely ill, newly admitted schizophrenic patients. Curr. Ther. Res., 21,755-767. 9. Wiles, D. H., Kolakowska, T., McNeilly, A. S., Mandelbrote, B. M., and Gelder, M. G., (1976). Clinical significance of plasma chlorpromazine levels, I. Psychol. Med., 6,407-415. 10. Wing, J. K., (1961). A simple and reliable sub-classification of chronic schizophrenia. J. Ment. Sci., 107, 862-875.
806
