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Treatment of Tourette disorder with penfluridol
Treatment of Tourette Disorder With Penfluridol Arthur K. Shapiro, Elaine Shapiro, and Gail J. Eisenkraft
D
URING THE PAST 16 YEARS we have observed, studied, or treated over 1000 patients with Tourette’s and other movement disorders. Haloperidol, the drug of choice for the treatment of Tout-rue syndrotnc~ (TS). is effective in a range of 82.5 to 90% ’ 3 but may induce adverse effects even when used at low dosage. For this reason new medications with fewer adverse effects are needed. One medication with such potential is pqfturidol. In addition to using haloperidol, we have utilized pimozide and penfluridol. both diphenylbutylpiperidines, to treat TS. The rationale for their use, derived effects that from animal studies, 4.5 is that each has catecholamine-blocking differ from those of haloperidol. The presumed postsynaptic receptors blocked by haloperidol are dopamine (DA) and to a lesser extent norepinephrine (NE). Pimozide is thought to be a more potent DA blocker, with some 5-hydroxytryptamine (5HT) and little or no NE blocking effects. and penfluridol is thought to be a more specific blocker of DA without significant NE or 5HT blocking effects. Penfluridol has been investigated extensively for the treatment of schizophrenia. Purported advantages are long half-life, permitting weekly administr-ation, and less frequent and less severe extrapyramidal side effects (EPS) than are seen with haloperidol.6 Holomboe, at the 1977 Sixth World Congress of Psychiatry, Honolulu, Hawaii, described six of seven TS patients with inadequate response to haloperidol who improved 50 to 100% at a dosage of 15 to 60 mgiwk of penfluridol.’ We were granted a compassionate IND from the Food & Drug Administration in 1979 with the restriction that the medication be used for the treatment of patients who had inadequate response to treatment with haloperidol and who had symptoms severe enough to warrant treatment. Treatment of the symptoms of TS is indicated when symptoms lead to psychosocial and physical distress and inability to function socially. academically, and vocationally. METHOD This preliminary with penfluridol
for six of the fulfilling
report
is confined
primarily
to comparing
the results of treating
from 1979 to 1981 to the results of their previous eight.
all criteria
Comprehensive
results of previous
treatment
with pimozide.
for the diagnosis of TS,‘. 4 agreement hy
Psychiatv,
Vol. 24,
No.
4,
treatment Criteria
Drs. Shapiro
(July/August),
1983
eight patients
with haloperidol, for inclusion
and.
included
about the diagnosis and
327
328
SHAPIRO
ET AL.
ratings of severity, inadequate response to previous medications, and symptoms that were severe enough to warrant treatment. Severity of symptoms was rated as marked for two and moderate for six patients. Patients, seven males and one female, ranged in age from 10 to 33 yr, with a mean of 16.2 and median of 13.5 yr. Age of onset ranged from 2 to 7 yr, with a mean of 4.6 and median of 4.0 yr. Duration of illness averaged 11.6 yr, with a median of 9.5 and range from 6 to 26 yr. Four patients had moderate to marked attention deficit disorder, hyperactivity, or learning disabilities. The total length of treatment for all drugs ranged from I .8 to 11.8yr, averaging 4.6 yr with a median of 3.6 yr (Table 1). Patients gave informed consent after they had been fully informed of the advantages and disadvantages of the treatment and were evaluated every 3 mo in the doctors’ private offices. Each patient kept a daily record of medication dosage, percent decrease for individual motor and phonic tic symptoms, overall decrease for total motor and phonic tic symptoms, and rating of side effects.’ Hemograms, chemistries, and urinalyses were done quarterly for the first year and biannually thereafter. Breasts and abdomen were examined at each revisit. Penfluridol was initially given at a dosage of 10 mgiwk and incresaed by the same amount each week. This method of titration was deemed too slow, and dosage was subsequently increased 10 mgiday until adequate response was achieved, at which time medication was taken every 3 to 7 days.
RESULTS
The length of treatment, dosage, and percent decrease of motor and phonic tic symptoms for each drug are summarized in Table 1. Dosages and percent decrease of tic symptoms are the average of the daily ratings for the last month of treatment for each drug. Ratings of improvement were based on overall percent decrease of motor and phonic tic symptoms. Dr. A. Shapiro, the patient, and the family agreed in their ratings of improvement. Percent decrease of tic symptoms was significantly higher for penfluridol treatment compared to previous haloperidol treatment (one-tail paired t-test (df 7) = 5.2, p < 0.001). There was a nonsignificant trend for greater improvement with penfluridol compared to pimozide (p < 0.13) and with pimozide compared to haloperidol @ < 0.07) (Table 1). In addition, the patient and family ranked the three drugs in order of effectiveness (Table 2). The overall distribution for the six patients treated with all three drugs was significant (Friedman two-way Table 1. Selected Treatment Variables Previous Therapies Moperidol n=8
Length of treatment (mos) Mean Median Range Dosage at end point Mean Median Range Dosage during treatment Range Percent decrease of tic symptoms at end point Mean Median Range
36.9
16.5 8-132
Penfluridol II=8
Pimozide n=6
10.3 18.5 3-24
10.0
10.5 3-19
22.0
74.4 mglwk 70.0 mglwk
7.5 mglday 7.3 mg/day 2 - 14 mglday
mg/day 20.0 mg/day 8 -40 mglday
20-
140 mg/wk
20-30 mglday
8-64 mg/day
20-
160 mglwk
61.0 % 70.0 % 0-75 %
Paired t-test for penfloridal vs haloperidol,p c 0.001.
67.7 % 70.0 % 36-85 %
74.4 % 80.0 % 30-90 %
329
PENFLURIDOL IN TOURE-iTE DISORDER Table 2.
Haloperidol Pimozide Penfluridol
Drug of Choice Rated by Patient, Family, and Physician First Choice
Second Choice
0 ( 0.0%) 1 (17.5%) 7 (62.5%)
4 (50.0%) 5 (63.3%) 1 (37.5%)
Third Choice 4 (50.0%) 0 ( 0.0%) 0 ( 0.0%)
Friedman two-way ANOVA, p < 0.0001
ANOVA, Xr2= 67.6, p < O.OOOl),indicating that penfluridol was the first drug of choice. Further support for the effectiveness of penfluridol is that all motor and phonic tic symptoms returned in 4 to 6 wk in two patients after penfluridol was discontinued. Percent improvement for the three drugs was highly correlated (Y’S = 0.93 - 0.95, p’s < 0.00011, indicating that the drugs do not affect symptoms or improvement differentially but that penfluridol yields significantly more improvement than haloperidol. Side effects, grouped according to frequency. included: (1) sedation. lethargy. or akinesia: (2) depression; (3) loss of motivation or cognitive dulling: (4) impaired work or school performance; (5) dysphoria; (6) irritability: (7) phobia: (8) weight gain; (9) mydriasis or blurred vision: ( 10) slurred speech: ( 11) xerostomia; (12) salivation: and (13) gynecomastia. Each of the 13 side effects was rated for the three drugs on a 4-point scale varying from none to marked (Table 3). The highest rating for any of the 13 side effects is summarized in Table 3. The overall distribution for the six patients on all three drugs was significant (Friedman two-way ANOVA, x,’ = 61.4. p c. O.OOOl), indicating that side effects occurred significantly less often and were less severe for penfluridol than for the other drugs. Moreover. the proportion of patients using antiparkinson and stimulant drugs for control of side effects’.’ was significantly less (Friedman two-way ANOVA, X,’ = 63.3, /> ,: 0.0001) when treated with penfluridol (/I = 2, 255%)as compared to haioperdol (n = 7. 87”;) and pimozide (n = 4, 67“;). DISCUSSION
The data of this clinical study suggest that pentluridol is an effective drug for the treatment of TS, inducing greater decrease of motor and phonic tic symptoms and fewer side effects than haloperidol. There was a nonsignificant trend toward greater efficacy with penfluridol than pimozide, with signifiktly fewer side effects. The superiority of penfluridol may be related to its antagonizing DA but not to NE and 5HT. Because decreased levels of NE may be associated with Table 3.
Severity of Side Effects Associated
With Halopridol, Pimozide, and Penfluridol
____ Haloperidol (II = 8)
Plmozide (n -- 6)
Penflurldol in = 8)
0 1 3 4
0
2 4 1 1
None Mild Moderate Marked Friedman two-way ANOVA. p <: 0.0001.
1 4 1
330
SHAPIRO
ET AL.
clinical depression, and antidepressants increase the level of NE, drugs that block NE may induce side effects often observed in the treatment of patients with TS, such as sedation, depression, impaired motivation, cognitive dulling, irritability, phobias, and dysphoria.1-4,8 These side effects may limit the use of higher and more effective dosages of haloperidol. Since penfluridol is thought to have no significant NE- or SHT-blocking effects, it is possible that the dosage of penfluridol can be increased, causing more DA blocking, with consequent greater improvement and fewer side effects. Further study of exclusive DA antagonists is warranted. An advantage of penfluridol is weekly or twice-weekly administration. The weekly dosage was 7.5 (standard deviation = 2.0) times the daily dosage of haloperidol. The correlation between the dosage of haloperidol and penfluridol is 0.95 (p < 0.001). Mammary and abdominal examinations, hemograms, chemistries, and urinalyses were unchanged from baseline and essentially within normal range except for high alkaline phosphatase and lactic dehydrogenase (LDH) values in younger patients on all drugs. Limitations of this clinical study include: a small sample; the difficulty of evaluating therapeutic response in TS because of spontaneous variation of symptoms over time; and the absence of the double-blind procedure, random allocation to drugs, crossover procedure, and established reliable and valid dependent measures of change. Furthermore, evaluations of symptomatic improvement in clinical conditions that spontaneously vary are prone to Type 1 errors. Change to another drug usually occurs when symptoms spontaneously increase and the likelihood of spontaneous improvement with subsequent treatment is maximized (regression to the mean). SUMMARY
The results of this study indicate that penfluridol is a worthwhile addition to and alternative drug for the chemotherapy of TS, yielding more improvement and fewer side effects than haloperidol. In addition, the study provides some support for the DA hypothesis of TS. Carefully controlled studies of penfluridol and other drugs with exclusive dopamine-blocking properties are warranted. ACKNOWLEDGMENT Supported by grants from the Tourette, Tic and Movement Disorders Foundation, Gateposts Foundation, Shimberg Foundation, Herman and Faye Sarkowsy, Harold Stein, and other grantors. Penfluridol and pimozide were supplied by McNeil Pharmaceutical.
REFERENCES 1. Shapiro AK, Shapiro E, Bruun RD. et al: Gilles de la Tourette Syndrome. New York, Raven Press, 1978 2. Shapiro E, Shapiro AK: Tic disorders. J Am Med Assoc 245:1583-1585, 1981 3. Shapiro E, Shapiro AK: Tics, Tourette Syndrome and Other Movement Dis-
orders: A Pediatrician’s Guide. New York, Tourette Syndrome Association, 1980 4. Shapiro AK, Shapiro E, Sweet RD: Treatment of tics and Tourette syndrome, in Barbeau A (ed): Disorders of Movement. Lancaster England, MTP Press, Ltd, 1981, pp 105-132
PENFLURIDOL
IN TOURETTE
DISORDER
5. Nose T, Takemoto H: The effect of penfluridol and some psychotropic drugs on monamine metabolism in central nervous system. Eur J Pharmacol 3 1: 3S I 359. 1975 6. Ayd F: Penfluridol: A long-acting oral neuroleptic. Int Drug Ther Newsletter 7:13. 1972
331
7. Holomboe: Paper presented at Sixth World Congress of Psychiatry. Honolulu. Hawaii. 1977 8. Shapiro AK, Shapiro E: Do stimulants provoke, cause or exacerbate tics and Tourette syndrome. Compr Psychiatry 22:265-273, 1981
D
URING THE PAST 16 YEARS we have observed, studied, or treated over 1000 patients with Tourette’s and other movement disorders. Haloperidol, the drug of choice for the treatment of Tout-rue syndrotnc~ (TS). is effective in a range of 82.5 to 90% ’ 3 but may induce adverse effects even when used at low dosage. For this reason new medications with fewer adverse effects are needed. One medication with such potential is pqfturidol. In addition to using haloperidol, we have utilized pimozide and penfluridol. both diphenylbutylpiperidines, to treat TS. The rationale for their use, derived effects that from animal studies, 4.5 is that each has catecholamine-blocking differ from those of haloperidol. The presumed postsynaptic receptors blocked by haloperidol are dopamine (DA) and to a lesser extent norepinephrine (NE). Pimozide is thought to be a more potent DA blocker, with some 5-hydroxytryptamine (5HT) and little or no NE blocking effects. and penfluridol is thought to be a more specific blocker of DA without significant NE or 5HT blocking effects. Penfluridol has been investigated extensively for the treatment of schizophrenia. Purported advantages are long half-life, permitting weekly administr-ation, and less frequent and less severe extrapyramidal side effects (EPS) than are seen with haloperidol.6 Holomboe, at the 1977 Sixth World Congress of Psychiatry, Honolulu, Hawaii, described six of seven TS patients with inadequate response to haloperidol who improved 50 to 100% at a dosage of 15 to 60 mgiwk of penfluridol.’ We were granted a compassionate IND from the Food & Drug Administration in 1979 with the restriction that the medication be used for the treatment of patients who had inadequate response to treatment with haloperidol and who had symptoms severe enough to warrant treatment. Treatment of the symptoms of TS is indicated when symptoms lead to psychosocial and physical distress and inability to function socially. academically, and vocationally. METHOD This preliminary with penfluridol
for six of the fulfilling
report
is confined
primarily
to comparing
the results of treating
from 1979 to 1981 to the results of their previous eight.
all criteria
Comprehensive
results of previous
treatment
with pimozide.
for the diagnosis of TS,‘. 4 agreement hy
Psychiatv,
Vol. 24,
No.
4,
treatment Criteria
Drs. Shapiro
(July/August),
1983
eight patients
with haloperidol, for inclusion
and.
included
about the diagnosis and
327
328
SHAPIRO
ET AL.
ratings of severity, inadequate response to previous medications, and symptoms that were severe enough to warrant treatment. Severity of symptoms was rated as marked for two and moderate for six patients. Patients, seven males and one female, ranged in age from 10 to 33 yr, with a mean of 16.2 and median of 13.5 yr. Age of onset ranged from 2 to 7 yr, with a mean of 4.6 and median of 4.0 yr. Duration of illness averaged 11.6 yr, with a median of 9.5 and range from 6 to 26 yr. Four patients had moderate to marked attention deficit disorder, hyperactivity, or learning disabilities. The total length of treatment for all drugs ranged from I .8 to 11.8yr, averaging 4.6 yr with a median of 3.6 yr (Table 1). Patients gave informed consent after they had been fully informed of the advantages and disadvantages of the treatment and were evaluated every 3 mo in the doctors’ private offices. Each patient kept a daily record of medication dosage, percent decrease for individual motor and phonic tic symptoms, overall decrease for total motor and phonic tic symptoms, and rating of side effects.’ Hemograms, chemistries, and urinalyses were done quarterly for the first year and biannually thereafter. Breasts and abdomen were examined at each revisit. Penfluridol was initially given at a dosage of 10 mgiwk and incresaed by the same amount each week. This method of titration was deemed too slow, and dosage was subsequently increased 10 mgiday until adequate response was achieved, at which time medication was taken every 3 to 7 days.
RESULTS
The length of treatment, dosage, and percent decrease of motor and phonic tic symptoms for each drug are summarized in Table 1. Dosages and percent decrease of tic symptoms are the average of the daily ratings for the last month of treatment for each drug. Ratings of improvement were based on overall percent decrease of motor and phonic tic symptoms. Dr. A. Shapiro, the patient, and the family agreed in their ratings of improvement. Percent decrease of tic symptoms was significantly higher for penfluridol treatment compared to previous haloperidol treatment (one-tail paired t-test (df 7) = 5.2, p < 0.001). There was a nonsignificant trend for greater improvement with penfluridol compared to pimozide (p < 0.13) and with pimozide compared to haloperidol @ < 0.07) (Table 1). In addition, the patient and family ranked the three drugs in order of effectiveness (Table 2). The overall distribution for the six patients treated with all three drugs was significant (Friedman two-way Table 1. Selected Treatment Variables Previous Therapies Moperidol n=8
Length of treatment (mos) Mean Median Range Dosage at end point Mean Median Range Dosage during treatment Range Percent decrease of tic symptoms at end point Mean Median Range
36.9
16.5 8-132
Penfluridol II=8
Pimozide n=6
10.3 18.5 3-24
10.0
10.5 3-19
22.0
74.4 mglwk 70.0 mglwk
7.5 mglday 7.3 mg/day 2 - 14 mglday
mg/day 20.0 mg/day 8 -40 mglday
20-
140 mg/wk
20-30 mglday
8-64 mg/day
20-
160 mglwk
61.0 % 70.0 % 0-75 %
Paired t-test for penfloridal vs haloperidol,p c 0.001.
67.7 % 70.0 % 36-85 %
74.4 % 80.0 % 30-90 %
329
PENFLURIDOL IN TOURE-iTE DISORDER Table 2.
Haloperidol Pimozide Penfluridol
Drug of Choice Rated by Patient, Family, and Physician First Choice
Second Choice
0 ( 0.0%) 1 (17.5%) 7 (62.5%)
4 (50.0%) 5 (63.3%) 1 (37.5%)
Third Choice 4 (50.0%) 0 ( 0.0%) 0 ( 0.0%)
Friedman two-way ANOVA, p < 0.0001
ANOVA, Xr2= 67.6, p < O.OOOl),indicating that penfluridol was the first drug of choice. Further support for the effectiveness of penfluridol is that all motor and phonic tic symptoms returned in 4 to 6 wk in two patients after penfluridol was discontinued. Percent improvement for the three drugs was highly correlated (Y’S = 0.93 - 0.95, p’s < 0.00011, indicating that the drugs do not affect symptoms or improvement differentially but that penfluridol yields significantly more improvement than haloperidol. Side effects, grouped according to frequency. included: (1) sedation. lethargy. or akinesia: (2) depression; (3) loss of motivation or cognitive dulling: (4) impaired work or school performance; (5) dysphoria; (6) irritability: (7) phobia: (8) weight gain; (9) mydriasis or blurred vision: ( 10) slurred speech: ( 11) xerostomia; (12) salivation: and (13) gynecomastia. Each of the 13 side effects was rated for the three drugs on a 4-point scale varying from none to marked (Table 3). The highest rating for any of the 13 side effects is summarized in Table 3. The overall distribution for the six patients on all three drugs was significant (Friedman two-way ANOVA, x,’ = 61.4. p c. O.OOOl), indicating that side effects occurred significantly less often and were less severe for penfluridol than for the other drugs. Moreover. the proportion of patients using antiparkinson and stimulant drugs for control of side effects’.’ was significantly less (Friedman two-way ANOVA, X,’ = 63.3, /> ,: 0.0001) when treated with penfluridol (/I = 2, 255%)as compared to haioperdol (n = 7. 87”;) and pimozide (n = 4, 67“;). DISCUSSION
The data of this clinical study suggest that pentluridol is an effective drug for the treatment of TS, inducing greater decrease of motor and phonic tic symptoms and fewer side effects than haloperidol. There was a nonsignificant trend toward greater efficacy with penfluridol than pimozide, with signifiktly fewer side effects. The superiority of penfluridol may be related to its antagonizing DA but not to NE and 5HT. Because decreased levels of NE may be associated with Table 3.
Severity of Side Effects Associated
With Halopridol, Pimozide, and Penfluridol
____ Haloperidol (II = 8)
Plmozide (n -- 6)
Penflurldol in = 8)
0 1 3 4
0
2 4 1 1
None Mild Moderate Marked Friedman two-way ANOVA. p <: 0.0001.
1 4 1
330
SHAPIRO
ET AL.
clinical depression, and antidepressants increase the level of NE, drugs that block NE may induce side effects often observed in the treatment of patients with TS, such as sedation, depression, impaired motivation, cognitive dulling, irritability, phobias, and dysphoria.1-4,8 These side effects may limit the use of higher and more effective dosages of haloperidol. Since penfluridol is thought to have no significant NE- or SHT-blocking effects, it is possible that the dosage of penfluridol can be increased, causing more DA blocking, with consequent greater improvement and fewer side effects. Further study of exclusive DA antagonists is warranted. An advantage of penfluridol is weekly or twice-weekly administration. The weekly dosage was 7.5 (standard deviation = 2.0) times the daily dosage of haloperidol. The correlation between the dosage of haloperidol and penfluridol is 0.95 (p < 0.001). Mammary and abdominal examinations, hemograms, chemistries, and urinalyses were unchanged from baseline and essentially within normal range except for high alkaline phosphatase and lactic dehydrogenase (LDH) values in younger patients on all drugs. Limitations of this clinical study include: a small sample; the difficulty of evaluating therapeutic response in TS because of spontaneous variation of symptoms over time; and the absence of the double-blind procedure, random allocation to drugs, crossover procedure, and established reliable and valid dependent measures of change. Furthermore, evaluations of symptomatic improvement in clinical conditions that spontaneously vary are prone to Type 1 errors. Change to another drug usually occurs when symptoms spontaneously increase and the likelihood of spontaneous improvement with subsequent treatment is maximized (regression to the mean). SUMMARY
The results of this study indicate that penfluridol is a worthwhile addition to and alternative drug for the chemotherapy of TS, yielding more improvement and fewer side effects than haloperidol. In addition, the study provides some support for the DA hypothesis of TS. Carefully controlled studies of penfluridol and other drugs with exclusive dopamine-blocking properties are warranted. ACKNOWLEDGMENT Supported by grants from the Tourette, Tic and Movement Disorders Foundation, Gateposts Foundation, Shimberg Foundation, Herman and Faye Sarkowsy, Harold Stein, and other grantors. Penfluridol and pimozide were supplied by McNeil Pharmaceutical.
REFERENCES 1. Shapiro AK, Shapiro E, Bruun RD. et al: Gilles de la Tourette Syndrome. New York, Raven Press, 1978 2. Shapiro E, Shapiro AK: Tic disorders. J Am Med Assoc 245:1583-1585, 1981 3. Shapiro E, Shapiro AK: Tics, Tourette Syndrome and Other Movement Dis-
orders: A Pediatrician’s Guide. New York, Tourette Syndrome Association, 1980 4. Shapiro AK, Shapiro E, Sweet RD: Treatment of tics and Tourette syndrome, in Barbeau A (ed): Disorders of Movement. Lancaster England, MTP Press, Ltd, 1981, pp 105-132
PENFLURIDOL
IN TOURETTE
DISORDER
5. Nose T, Takemoto H: The effect of penfluridol and some psychotropic drugs on monamine metabolism in central nervous system. Eur J Pharmacol 3 1: 3S I 359. 1975 6. Ayd F: Penfluridol: A long-acting oral neuroleptic. Int Drug Ther Newsletter 7:13. 1972
331
7. Holomboe: Paper presented at Sixth World Congress of Psychiatry. Honolulu. Hawaii. 1977 8. Shapiro AK, Shapiro E: Do stimulants provoke, cause or exacerbate tics and Tourette syndrome. Compr Psychiatry 22:265-273, 1981