Psychopharmacology
Psychopharmacology 56, 7 5 - 80 (1978)
9 by Springer-Verlag 1978
Clozapine in Tardive Dyskinesia GEORGE M. SIMPSON*, J. HILLARY LEE, and RAM K. SHRIVASTAVA Rockland Research Institute, Orangeburg, New York 10962, U.S.A.
Abstract. C l o z a p i n e , which has h a d limited clinical testing in the U . S . A . , was e v a l u a t e d in 12 c h r o n i c s c h i z o p h r e n i c p a t i e n t s with t a r d i v e dyskinesia. Its a n t i p s y c h o t i c activity was a g a i n d e m o n s t r a t e d a n d it s u p p r e s s e d the s y m p t o m s o f t a r d i v e d y s k i n e s i a with a m a r k e d r e b o u n d o c c u r r i n g in these s y m p t o m s w h e n it was w i t h d r a w n ; there was n o r i g i d i t y o r o t h e r P a r k i n s o n i a n s y m p t o m s . H o w e v e r , o u t o f a t o t a l o f 12 patients, n e u t r o p e n i a (800 a n d 1120) o c c u r r e d in t w o patients, c o n v u l s i o n s in one p a t i e n t , m a r k e d w i t h d r a w a l effects in three patients, a n d a h y p o t e n s i v e c o l l a p s e with a t r i a l fibrillation in one patient. I f these a d v e r s e effects are c o n f i r m e d in a larger s a m p l e size, t h e n d e s p i t e the novel desirable effects o f c l o z a p i n e it w o u l d seem u n l i k e l y t h a t it will gain w i d e s p r e a d o r r o u t i n e use 1.
s y s t e m a t i c a l l y the effect o f c l o z a p i n e in t a r d i v e dyskinesia. T h e p a t i e n t s were h o s p i t a l i z e d c h r o n i c schizop h r e n i c s with l o n g - s t a n d i n g d y s k i n e t i c s y m p t o m s .
Key words." C l o z a p i n e - S c h i z o p h r e n i a - T a r d i v e dyskinesia - Parkinsonism - Neutropenia - Convulsions
Procedure. The study began with a two-week baseline period when placebo identical to clozapine was administered, one tablet b.i.d. Clozapine was then given for 18 weeks and the study concluded with a 2-week placebo period. In three patients, clozapine was reintroduced after the final placebo and these patients were followed as during the study period. The patients were seen weekly by the research team. The psychiatrist completed the Rockland Tardive Dyskinesia Rating Scale (TDRS) (Simpson, unpublished), the Abnormal Involutionary Movement Scale (AIMS), the Global Psychiatric Evaluation (PE), the Neurological Rating Scale (NRS) (Simpson and Angus, 1970), and a progress note each week. A Brief Psychiatric Rating Scate (BPRS) (Overall and Gorham, 1962) and Clinical Global Impressions (CGI) were completed at the end of the baseline period, every four weeks during clozapine administration, and at the end of the postdrug period. Physiological measurements were collected twice daily throughout the study. Blood pressure and pulse rate were measured lying, sitting, and standing; axillary temperature and respiration rate were also recorded. A physical examination including an EKG were carried out before the study, at the end of the baseline period, and every 4 weeks throughout the trial. A chest x-ray was taken during the baseline and at the end of the trial. Laboratory tests were carried out regularly during the trial. A WBC and differential were done twice weekly; blood chemistry, complete hematology, and urinalysis were done at the end of the baseline period and every 4 weeks during the trial. The WBCs were
C l o z a p i n e is a new i n v e s t i g a t i o n a l a n t i p s y c h o t i c agent t h a t has been i n v e s t i g a t e d a n d m a r k e t e d in a n u m b e r o f E u r o p e a n c o u n t r i e s for several years ( G r o s s a n d L a n g e r , 1966; H i p p i u s a n d Stille, 1973). O u r s t u d y in this c o u n t r y f o u n d it to be effective in the t r e a t m e n t o f c h r o n i c s c h i z o p h r e n i a ( S i m p s o n a n d Varga, 1974). In t h a t s t u d y we also n o t e d t h a t it h a d a suppressive effect on the s y m p t o m s o f t a r d i v e dyskinesia, a finding also r e p o r t e d in a E u r o p e a n i n v e s t i g a t i o n ( R u t h e r , 1974). T h e p r e s e n t s t u d y was designed to e v a l u a t e * Present address: USC Metro Unit, Metropolitan State Hospital, 11400 So. Norwalk Blvd., Norwalk, CA 90650, U.S.A.
1 Since this study was completed, the rapid development of agranulocytosis in a patient on Clozapine has been reported in the U.S.A. and further studies with the drug have been stopped
MATERIALS AND METHODS Subjects. Twelve hospitalized chronic schizophrenic patients participated in the study. There were six men and six women with a mean age of 50 years (range, 35-64 years) and a mean tength of hospitalization 0f 22 years (range, 6-40 years). Each patient was required to have both facial involvement and choreoathetoid movements of the limbs for entry into the study. The patients' pretrial psychotropic medications follow: three patients were on fluphenazine (5-20 mg daily), two were on loxapine (50-150 mg daily), three were on chlorpromazine (200-600 mg daily), two were on baclofen (120 mg daily), and one patient each was on thiothixene (30 mg) and butaperazine (50 mg).
0033-3:158/78/0056/0075/$ 1.20
76 carried out frequently because of one report from southwest Finland of a number of deaths on clozapinefrom agranulocytosis.
Dosage. The daily dosageranged from 20-900 mg administered on a b.i.d, schedule. The dosage was gradually increased during the first half of the trial (by 10-45 mg weekly) and more during the second half(by 100 mg weekly).The most frequent dosage schedule by weekwas 20, 30, 45, 60, 75, 100, 130, 175,200, 250, 300,400, 500, 600, 700, 800, 900, and 950. However, some patients' dosage was raised more rapidly and some more slowly. The mean dosage by week for the 12 patients was 20, 33, 55, 83, 123, 157, 203, 244, 281, 339, 414, 523, 586, 668, 745, 820, 806, and 775. This gradually increasing dosage schedule was selected because in earlier investigations there weresomereports of dose-relatedhypotension(Gershon, 1974). In addition, in our own study (Simpson and Varga, 1974) we followeda dosage regimen similar to the present study and did not have any problems. Finally, it seemedappropriate in an elderly schizophrenicpopulation that also had neurologicalproblems.
RESULTS Five patients were dropped prior to completion of the trial. In one, after 14 weeks of clozapine, the patient's hemoglobin dropped five points and he was subsequently found to have a hiatal hernia. A second patient fell and fractured her leg in the 15th week of clozapine administration. She was transferred to another hospital for treatment of the fracture and the clozapine was discontinued. Three other patients were dropped during the 10th, 15th, and 16th weeks of clozapine administration because of side effects, which will be discussed below. The remaining seven patients completed the 22-week trial. Because of the variable trial duration, two (partially overlapping) analyses of variance (ANOVA) were carried out on each set of data. In all cases, the ANOVA was a randomized blocks design; one analysis, an onset assessment, was run on the 11 patients who completed 14 weeks of clozapine to determine when significant improvement occurred over the baseline; another, a withdrawal analysis, was run on the five final drug ratings and two postdrug ratings for the 11 patients to determine whether there was a withdrawal effect. The onset ANOVA of the T D R S indicated that the scores of three clusters and eight items changed significantly during this period. However, Scheff6 tests failed to yield significant comparisons. Generally, scores on the facial, core symptoms, and total clusters remained unchanged for the first half of the trial and then decreased over the latter half. The eight significant items were tremor of eyelids, pouting of the lower lip, puckering of lips, smacking of lips, grimacing, choreoathetoid movements of the fingers, toe movements, and crossing and uncrossing legs when sitting. Although the scores on these items tended to fluctuate considerably during clozapine administration, they were generally lower during the
Psychopharmacology56 (1978) second half of the trial. Of the remaining 36 analyses, 13 items yielded nonsignificant analysis of variance results, and in each case the mean scores were very low (less than one). The other 23 symptoms were totally absent in the study population. Ten of these were the 'write-in' items that are used for additional symptoms. (The seventh and eighth clozapine ratings, which were completed by a replacement rater, differed from the regular ratings and hence are not considered in the description.) The withdrawal analyses were similar to the onset analyses in that only items with means above 1, i.e., symptoms that were present in approximately a moderate degree, yielded significant analyses. One cluster (facial) and four items (blinking of eyes, tongue protrusion, choreoathetoid movements of the tongue, and choreoathetoid movements fingers) were significant. The latter item was also significant in the onset analysis. In general, the scores tended to increase during the postdrug period. The mean total scores of the seven patients who completed all phases of the study are shown in Figure 1. Here both the fluctuations and the decrease in scores over the trial can be seen. On the AIMS, five of the ten clinical items were significant in the onset analysis (muscles of facial expression, lips and perioral area, tongue, upper (arms, wrists, fingers), and severity of abnormal movements). Inspection of the means indicated that in the onset analysis the symptoms severity varied considerably but there was a tendency for the severity to increase until approximately midtrial, when it began to decrease. In the withdrawal analysis, there was an increase in the severity of symptoms when clozapine was stopped. These results, which are not completely in keeping with the T D R S results, may have reflected the rater's relatively brief experience with the AIMS in comparison with the heavy training in the TDRS. The psychiatric condition of the patients improved over the trial as compared with the placebo baseline. Significant improvement occurred in emotional withdrawal, tension, and blunted affect on the BPRS. There was also improvement in the anergia and activation factors and total score. On the CGI, the changein-condition items also indicated there was improvement in the global psychiatric status of the patients. The condition of three patients improved so that it was decided to return them to clozapine at the end of the trial.
Physiological Data. A number of onset analyses were significant. The analysis of temperature was significant because of small fluctuations over the trial. The means ranged from 96.5 ~ to 97.6 ~. Similarly, the significant
G. M. Simpson et al. : Ctozapinein Tardive Dyskinesia 28 26
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Psychopharmacology 56, 7 5 - 80 (1978)
9 by Springer-Verlag 1978
Clozapine in Tardive Dyskinesia GEORGE M. SIMPSON*, J. HILLARY LEE, and RAM K. SHRIVASTAVA Rockland Research Institute, Orangeburg, New York 10962, U.S.A.
Abstract. C l o z a p i n e , which has h a d limited clinical testing in the U . S . A . , was e v a l u a t e d in 12 c h r o n i c s c h i z o p h r e n i c p a t i e n t s with t a r d i v e dyskinesia. Its a n t i p s y c h o t i c activity was a g a i n d e m o n s t r a t e d a n d it s u p p r e s s e d the s y m p t o m s o f t a r d i v e d y s k i n e s i a with a m a r k e d r e b o u n d o c c u r r i n g in these s y m p t o m s w h e n it was w i t h d r a w n ; there was n o r i g i d i t y o r o t h e r P a r k i n s o n i a n s y m p t o m s . H o w e v e r , o u t o f a t o t a l o f 12 patients, n e u t r o p e n i a (800 a n d 1120) o c c u r r e d in t w o patients, c o n v u l s i o n s in one p a t i e n t , m a r k e d w i t h d r a w a l effects in three patients, a n d a h y p o t e n s i v e c o l l a p s e with a t r i a l fibrillation in one patient. I f these a d v e r s e effects are c o n f i r m e d in a larger s a m p l e size, t h e n d e s p i t e the novel desirable effects o f c l o z a p i n e it w o u l d seem u n l i k e l y t h a t it will gain w i d e s p r e a d o r r o u t i n e use 1.
s y s t e m a t i c a l l y the effect o f c l o z a p i n e in t a r d i v e dyskinesia. T h e p a t i e n t s were h o s p i t a l i z e d c h r o n i c schizop h r e n i c s with l o n g - s t a n d i n g d y s k i n e t i c s y m p t o m s .
Key words." C l o z a p i n e - S c h i z o p h r e n i a - T a r d i v e dyskinesia - Parkinsonism - Neutropenia - Convulsions
Procedure. The study began with a two-week baseline period when placebo identical to clozapine was administered, one tablet b.i.d. Clozapine was then given for 18 weeks and the study concluded with a 2-week placebo period. In three patients, clozapine was reintroduced after the final placebo and these patients were followed as during the study period. The patients were seen weekly by the research team. The psychiatrist completed the Rockland Tardive Dyskinesia Rating Scale (TDRS) (Simpson, unpublished), the Abnormal Involutionary Movement Scale (AIMS), the Global Psychiatric Evaluation (PE), the Neurological Rating Scale (NRS) (Simpson and Angus, 1970), and a progress note each week. A Brief Psychiatric Rating Scate (BPRS) (Overall and Gorham, 1962) and Clinical Global Impressions (CGI) were completed at the end of the baseline period, every four weeks during clozapine administration, and at the end of the postdrug period. Physiological measurements were collected twice daily throughout the study. Blood pressure and pulse rate were measured lying, sitting, and standing; axillary temperature and respiration rate were also recorded. A physical examination including an EKG were carried out before the study, at the end of the baseline period, and every 4 weeks throughout the trial. A chest x-ray was taken during the baseline and at the end of the trial. Laboratory tests were carried out regularly during the trial. A WBC and differential were done twice weekly; blood chemistry, complete hematology, and urinalysis were done at the end of the baseline period and every 4 weeks during the trial. The WBCs were
C l o z a p i n e is a new i n v e s t i g a t i o n a l a n t i p s y c h o t i c agent t h a t has been i n v e s t i g a t e d a n d m a r k e t e d in a n u m b e r o f E u r o p e a n c o u n t r i e s for several years ( G r o s s a n d L a n g e r , 1966; H i p p i u s a n d Stille, 1973). O u r s t u d y in this c o u n t r y f o u n d it to be effective in the t r e a t m e n t o f c h r o n i c s c h i z o p h r e n i a ( S i m p s o n a n d Varga, 1974). In t h a t s t u d y we also n o t e d t h a t it h a d a suppressive effect on the s y m p t o m s o f t a r d i v e dyskinesia, a finding also r e p o r t e d in a E u r o p e a n i n v e s t i g a t i o n ( R u t h e r , 1974). T h e p r e s e n t s t u d y was designed to e v a l u a t e * Present address: USC Metro Unit, Metropolitan State Hospital, 11400 So. Norwalk Blvd., Norwalk, CA 90650, U.S.A.
1 Since this study was completed, the rapid development of agranulocytosis in a patient on Clozapine has been reported in the U.S.A. and further studies with the drug have been stopped
MATERIALS AND METHODS Subjects. Twelve hospitalized chronic schizophrenic patients participated in the study. There were six men and six women with a mean age of 50 years (range, 35-64 years) and a mean tength of hospitalization 0f 22 years (range, 6-40 years). Each patient was required to have both facial involvement and choreoathetoid movements of the limbs for entry into the study. The patients' pretrial psychotropic medications follow: three patients were on fluphenazine (5-20 mg daily), two were on loxapine (50-150 mg daily), three were on chlorpromazine (200-600 mg daily), two were on baclofen (120 mg daily), and one patient each was on thiothixene (30 mg) and butaperazine (50 mg).
0033-3:158/78/0056/0075/$ 1.20
76 carried out frequently because of one report from southwest Finland of a number of deaths on clozapinefrom agranulocytosis.
Dosage. The daily dosageranged from 20-900 mg administered on a b.i.d, schedule. The dosage was gradually increased during the first half of the trial (by 10-45 mg weekly) and more during the second half(by 100 mg weekly).The most frequent dosage schedule by weekwas 20, 30, 45, 60, 75, 100, 130, 175,200, 250, 300,400, 500, 600, 700, 800, 900, and 950. However, some patients' dosage was raised more rapidly and some more slowly. The mean dosage by week for the 12 patients was 20, 33, 55, 83, 123, 157, 203, 244, 281, 339, 414, 523, 586, 668, 745, 820, 806, and 775. This gradually increasing dosage schedule was selected because in earlier investigations there weresomereports of dose-relatedhypotension(Gershon, 1974). In addition, in our own study (Simpson and Varga, 1974) we followeda dosage regimen similar to the present study and did not have any problems. Finally, it seemedappropriate in an elderly schizophrenicpopulation that also had neurologicalproblems.
RESULTS Five patients were dropped prior to completion of the trial. In one, after 14 weeks of clozapine, the patient's hemoglobin dropped five points and he was subsequently found to have a hiatal hernia. A second patient fell and fractured her leg in the 15th week of clozapine administration. She was transferred to another hospital for treatment of the fracture and the clozapine was discontinued. Three other patients were dropped during the 10th, 15th, and 16th weeks of clozapine administration because of side effects, which will be discussed below. The remaining seven patients completed the 22-week trial. Because of the variable trial duration, two (partially overlapping) analyses of variance (ANOVA) were carried out on each set of data. In all cases, the ANOVA was a randomized blocks design; one analysis, an onset assessment, was run on the 11 patients who completed 14 weeks of clozapine to determine when significant improvement occurred over the baseline; another, a withdrawal analysis, was run on the five final drug ratings and two postdrug ratings for the 11 patients to determine whether there was a withdrawal effect. The onset ANOVA of the T D R S indicated that the scores of three clusters and eight items changed significantly during this period. However, Scheff6 tests failed to yield significant comparisons. Generally, scores on the facial, core symptoms, and total clusters remained unchanged for the first half of the trial and then decreased over the latter half. The eight significant items were tremor of eyelids, pouting of the lower lip, puckering of lips, smacking of lips, grimacing, choreoathetoid movements of the fingers, toe movements, and crossing and uncrossing legs when sitting. Although the scores on these items tended to fluctuate considerably during clozapine administration, they were generally lower during the
Psychopharmacology56 (1978) second half of the trial. Of the remaining 36 analyses, 13 items yielded nonsignificant analysis of variance results, and in each case the mean scores were very low (less than one). The other 23 symptoms were totally absent in the study population. Ten of these were the 'write-in' items that are used for additional symptoms. (The seventh and eighth clozapine ratings, which were completed by a replacement rater, differed from the regular ratings and hence are not considered in the description.) The withdrawal analyses were similar to the onset analyses in that only items with means above 1, i.e., symptoms that were present in approximately a moderate degree, yielded significant analyses. One cluster (facial) and four items (blinking of eyes, tongue protrusion, choreoathetoid movements of the tongue, and choreoathetoid movements fingers) were significant. The latter item was also significant in the onset analysis. In general, the scores tended to increase during the postdrug period. The mean total scores of the seven patients who completed all phases of the study are shown in Figure 1. Here both the fluctuations and the decrease in scores over the trial can be seen. On the AIMS, five of the ten clinical items were significant in the onset analysis (muscles of facial expression, lips and perioral area, tongue, upper (arms, wrists, fingers), and severity of abnormal movements). Inspection of the means indicated that in the onset analysis the symptoms severity varied considerably but there was a tendency for the severity to increase until approximately midtrial, when it began to decrease. In the withdrawal analysis, there was an increase in the severity of symptoms when clozapine was stopped. These results, which are not completely in keeping with the T D R S results, may have reflected the rater's relatively brief experience with the AIMS in comparison with the heavy training in the TDRS. The psychiatric condition of the patients improved over the trial as compared with the placebo baseline. Significant improvement occurred in emotional withdrawal, tension, and blunted affect on the BPRS. There was also improvement in the anergia and activation factors and total score. On the CGI, the changein-condition items also indicated there was improvement in the global psychiatric status of the patients. The condition of three patients improved so that it was decided to return them to clozapine at the end of the trial.
Physiological Data. A number of onset analyses were significant. The analysis of temperature was significant because of small fluctuations over the trial. The means ranged from 96.5 ~ to 97.6 ~. Similarly, the significant
G. M. Simpson et al. : Ctozapinein Tardive Dyskinesia 28 26
ID
24 ._~ ~ 22 u
0')
'~ uo a--6 "~ --
20
g
16
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14
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aill
77
&
