Movement Disorders Vol. 5, No. 3, 1990, pp. 23!3-242, 0 1990 Movement Disorder Society
Clozapine for Psychosis in Parkinson’s Disease Ronald F. Pfeiffer, *Jasbir Kang, *Benjamin Graber, Ruth Hofman, and “James Wilson Section of Neurology and *Department of Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.
Summary: The clinical efficacy of clozapine, an atypical antipsychotic, in treating levodopa-induced hallucinations was investigated in five patients with Parkinson’s disease under open label conditions. Two patients could not tolerate clozapine, even in doses as low as 12.5-25 mg daily, because of extreme sedation. Three patients could tolerate clozapine and experienced improvement or elimination of their hallucinations at doses below 100 mg daily. Despite a significant risk of adverse effects, cautious use of clozapine in low doses may be beneficial for patients with levodopa-induced psychosis who do not respond to more conservative measures. Key Words: Clozapine-PsychosisParkinson’s disease.
ing parkinsonism (7). These characteristics suggest that clozapine might be particularly useful in individuals with Parkinson’s disease and levodopainduced psychosis.
The treatment of Parkinson’s disease may be complicated by psychosis induced by dopaminomimetic medications such as levodopa and bromocriptine, particularly if there is preexistent dementia (1). Dosage reduction may alleviate the psychosis but often results in an unacceptable increase in parkinsonism. Conventional neuroleptics are generally contraindicated because of their adverse effects on extrapyramidal function, presumably mediated by their effects on nigrostriatal dopamine D2 receptors. Clozapine is a dibenzodiazepine derivative that appears to preferentially block dopamine D1 receptors (2), perhaps in the adenylate cyclase-coupled conformation (3). It has no significant effect on prolactin production (4). It has been suggested to act predominantly at mesolimbic, rather than nigrostriatal, sites (5). It has also been noted to have potent noradrenolytic, anticholinergic, antihistaminic, and antiserotonergic properties (6). Clinically, clozapine has been shown to be an effective antipsychotic agent with, as might be predicted from its neuropharmacological profile, very little risk of induc-
MATERIALS AND METHODS Patients with Parkinson’s disease and presumed levodopa-induced psychosis were invited to participate in the study. Informed consent was obtained. Individuals with severe dementia were excluded. All patients were actively hallucinating at the time of inclusion. Further levodopa reduction had been precluded by exacerbation of parkinsonism. In one patient, a levodopa “holiday” had been undertaken with only temporary improvement in psychosis. Baseline evaluation included a complete physical and neurological examination, along with assessment of extrapyramidal function utilizing the Unified Parkinson’s Disease Rating Scale (UPDRS) (8). Baseline laboratory studies included a complete blood count (CBC), chemistry profile, and electrocardiogram. Patients were placed on clozapine in an open label fashion, beginning with a dose of 25 mg daily. Clozapine dosage was then titrated upward as necessary in increments of 25 mg at intervals of no less than 3 days until either the psychosis resolved or adverse effects precluded further increases.
Address correspondence and reprint requests to Dr. R. F. Pfeiffer, Section of Neurology, University of Nebraska Medical Center, 600 South 42nd St, Omaha, NE 68198-2045, U.S.A.
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Patients were initially evaluated twice weekly and later weekly. At each visit the UPDRS was repeated and the presence and severity of psychosis assessed. CBC was monitored weekly. After a stable dose of clozapine was achieved, levodopal carbidopa dosage was increased, as necessary, to achieve maximal antiparkinson effect. RESULTS
Five patients were selected and gave consent for study participation. All were men, ranging in age from 73 to 77 years (mean, 75). Parkinson’s disease had been present for 5-10 years (mean, 6.6) and was moderately advanced, with UPDRS motor scores ranging from 30 to 39 (mean, 34.6) at baseline (maximum possible motor score, 108) and an average Hoehn and Yahr grade of 3 (range, 2-4). Patients had been taking levodopa for 7-60 + months (mean 37.2) and were, at baseline, taking an average of 551340 mg of carbidopdlevodopa daily, with a levodopa range of 200-500 mg. None were taking bromocriptine, and only one was on amantadine. Psychosis, typically characterized by visual hallucinations that the individuals could not separate from reality, had been present for 1-21 months (mean, 9) and all patients demonstrated some degree of dementia with minimental status examination scores ranging from 14 to 27 (mean, 21; best score possible, 30). Two patients were unable to tolerate clozapine. Patient 2 developed extreme drowsiness and obtundation within several hours of ingestion of the initial 25 mg dose of clozapine. Rechallenge with 25 mg and later with 12.5 mg reproduced the symptoms and forced clozapine discontinuation. The sedation cleared within 24 h after each dose. Patient 5 experienced both extreme sedation and orthostatic hypotension with syncope on clozapine 25 mg, leading to drug discontinuation after 2 days of therapy. Warfarin, which the patient was taking because of a porcine aortic valve, was subsequently discontinued to allow a full-mouth dental extraction. While the patient was off warfarin a large cerebral infarction, presumably embolic in origin, occurred. Clozapine had been reintroduced 2 days prior to this, with recurrence of the sedation but not of any documented orthostatic changes. It was subsequently discontinued again. After an extended course the patient ultimately died. Mild sedation occurred in patient 1 but did not
Movement Disorders, Voi. 5, N o . 3, 1990
require any medication adjustment. Patient 3 experienced several syncopal episodes, the etiology for which was never clearly defined. Prominent hypersalivation also developed in patient 3 and continued throughout the period of follow-up. Patients 1, 3, and 4 were able to tolerate clozapine. Dosages of clozapine and levodopa, UPDRS motor scores, and assessment of hallucination severity in these three are detailed in Fig. 1. Patient 4 did not feel he was deriving sufficient benefit from clozapine and discontinued it after 6 weeks; he was subsequently lost to follow-up. Patients 1 and 3 continued on clozapine long-term with sustained benefit. In patient 1 , clozapine was purposely discontinued after 12 weeks of therapy and hallucinations promptly recurred, disappearing again with clozapine reintroduction. DISCUSSION
In 1985 Scholz and Dichgans reported improvement in four parkinsonian patients with levodopainduced psychosis treated with clozapine (9). Friedman et al. achieved similar results in an individual with concomitant schizophrenia and parkinsonism (10). More recently Friedman and Lannon reported additional favorable experiences with clozapine in patients with Parkinson’s disease and psychosis (1 1). Wolters et al., using clozapine doses of 100250 mg daily, found the usefulness of clozapine in parkinsonian patients severely limited by adverse effects (12). Roberts et al. reported both resolution of psychosis and improvement of parkinsonism, especially tremor, in a single patient on 25 mg of clozapine daily (13). Our findings, for the most part, parallel those of the others. Unlike patients with schizophrenia, who typically tolerate up to 900 mg of clozapine daily, patients with Parkinson’s disease appear to be exquisitely sensitive to the drug. Two of our patients were unable to tolerate clozapine even in doses as low as 12.5-25 mg daily, while the other three patients demonstrated improvement in their psychosis with doses less than 100 mg daily. Marked daytime sedation, occurring at doses of 12.5-25 mg daily even when given at bedtime, was responsible for drug discontinuation in the two individuals in whom clozapine had to be abandoned. Orthostatic hypotension with syncope was documented in one individual, while another experienced several syncopal episodes of undetermined
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CLOZAPINE, PSYCHOSIS, AND PARKINSON’S DISEASE A
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FIG. 1. Dosages (mg/day) of clozapine and levodopa, UPDRS motor scores, and assessment of hallucination seventy in (A) patient I , (B) patient 3, and (C) patient 4. The UPDRS motor score is derived from the motor examination portion of the UPDRS. Higher scores indicate increased disability. Hallucinations are graded on a 0-3 scale: 0, no hallucinations; 1, hallucinations with a clear sensorium; 2, hallucinations with failure to recognize their hallucinatory character; 3, level 2 hallucinations with additional paranoid ideation or other delusions. All factors were assessed at each visit.
10 12 14 16 18 20 22 24 26 28 30 32 34 36
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WEEKS
etiology. Hypersalivation occurred in one individual. No significant hematologic changes were encountered. Patient 3 demonstrated an increase in parkinsonism at clozapine doses of 100 mg daily with a subsequent return to baseline parkinson scores when
clozapine dosage was reduced to 50 mg daily. In patients 1 and 4, no increase in parkinsonism was noted with clozapine doses of 50-100 mg daily; in fact, parkinson scores deteriorated when clozapine was withdrawn. The basis for this seemingly paradoxical deterioration is not entirely clear but echoes
Movement Disorders, Vol. 5 , No. 3, 1990
R . F . PFEIFFER ET AL.
242
the experience of Roberts et al. (13). In patient 1, this change might be attributed to impaired ability to concentrate on and complete motor tasks in the UPDRS because of reemergence of psychosis. Our experience indicates that clozapine can be of benefit in the treatment of levodopa-induced psychosis. This improvement can occur without aggravation of parkinsonism as long as clozapine doses of less than 100 mg daily are utilized. Patients with Parkinson’s disease appear to be exquisitely sensitive to clozapine, with both beneficial and adverse responses occurring at very low doses. Adverse effects may preclude clozapine use in a significant percentage of patients. Nevertheless, cautious use of clozapine may be beneficial for patients with levodopa-induced psychosis who do not respond adequately to more conservative measures. A double-blind, placebo-controlled trial with larger patient numbers is needed to more definitively assess the utility of clozapine in this clinical situation. Acknowledgment: We thank Vickie Stuetelberg for her expert assistance in manuscript preparation. Clozapine was generously supplied by Sandoz Pharmaceuticals.
REFERENCES I . Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease, J Neurol Neurosurg Psychiatr 1988;51 :1498-1 502. 2. Andersen PH, Nielsen EB, Gronvald FC, Braestrup C.
Movement Disorders, Vol. 5 , No. 3, 1990
Some atypical neuroleptics inhibit [3H]SCH 23390 binding. Eur J Pharmacol 1986;120:143-144. 3. Andersen PH, Braestrup C. Evidence for different states of the dopamine Dl receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor. J Neurochem 1986;47:1822-1831. 4. Kane JM, Cooper TB, Sachar EJ, Halpern FS, Bailine S. Clozapine: plasma levels and prolactin response. Psychopharmacology 1981;73:184-187. 5 . Skarsfeldt T. Differential effects after repeated treatment with haloperidol, clozapine, thioridazine and tefludazine on SNC and VTA dopamine neurons in rats. Life Sci 1988; 42: 1037-1044. 6. Investigator’s brochure. Sandoz Pharmaceuticals, 1985. 7. Tully EM. Clozapine: a review. A m J Prev Psychiatr Neurol 1988;1 :19-23. 8. Fahn S, Elton RL, and Members of the UPDRS Development Committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent developments in Parkinson’s disease: volume 11. Florham Park, New Jersey: MacMillan Healthcare Information, 1987:153-1 63. 9. Scholz E, Dichgans J. Treatment of drug-induced exogenous psychosis in parkinsonism with clozapine and fluperlapine. Eur Arch Psychiatr Neurol Sci 1985;235:60-64. 10. Friedman JH, Max J, Swift R. Idiopathic Parkinson’s disease in a chronic schizophrenic patient: long-term treatment with clozapine and L-dopa. Clin Neuropharmacol 1987; 10:470475. 11. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 1989;39:12191221. 12. Wolters EC, Hurwitz TA, Peppard RF, Calne DB. Clozapine: an antipsychotic agent in Parkinson’s disease? Clin Neuropharmacol 1989;1293-90. 13. Roberts HE, Dean RC, Stoudemire A. Clozapine treatment of psychosis in Parkinson’s disease. J Neuropsychiatr Clin Neurosci 1989;l:190-192.
Clozapine for Psychosis in Parkinson’s Disease Ronald F. Pfeiffer, *Jasbir Kang, *Benjamin Graber, Ruth Hofman, and “James Wilson Section of Neurology and *Department of Psychiatry, University of Nebraska Medical Center, Omaha, Nebraska, U.S.A.
Summary: The clinical efficacy of clozapine, an atypical antipsychotic, in treating levodopa-induced hallucinations was investigated in five patients with Parkinson’s disease under open label conditions. Two patients could not tolerate clozapine, even in doses as low as 12.5-25 mg daily, because of extreme sedation. Three patients could tolerate clozapine and experienced improvement or elimination of their hallucinations at doses below 100 mg daily. Despite a significant risk of adverse effects, cautious use of clozapine in low doses may be beneficial for patients with levodopa-induced psychosis who do not respond to more conservative measures. Key Words: Clozapine-PsychosisParkinson’s disease.
ing parkinsonism (7). These characteristics suggest that clozapine might be particularly useful in individuals with Parkinson’s disease and levodopainduced psychosis.
The treatment of Parkinson’s disease may be complicated by psychosis induced by dopaminomimetic medications such as levodopa and bromocriptine, particularly if there is preexistent dementia (1). Dosage reduction may alleviate the psychosis but often results in an unacceptable increase in parkinsonism. Conventional neuroleptics are generally contraindicated because of their adverse effects on extrapyramidal function, presumably mediated by their effects on nigrostriatal dopamine D2 receptors. Clozapine is a dibenzodiazepine derivative that appears to preferentially block dopamine D1 receptors (2), perhaps in the adenylate cyclase-coupled conformation (3). It has no significant effect on prolactin production (4). It has been suggested to act predominantly at mesolimbic, rather than nigrostriatal, sites (5). It has also been noted to have potent noradrenolytic, anticholinergic, antihistaminic, and antiserotonergic properties (6). Clinically, clozapine has been shown to be an effective antipsychotic agent with, as might be predicted from its neuropharmacological profile, very little risk of induc-
MATERIALS AND METHODS Patients with Parkinson’s disease and presumed levodopa-induced psychosis were invited to participate in the study. Informed consent was obtained. Individuals with severe dementia were excluded. All patients were actively hallucinating at the time of inclusion. Further levodopa reduction had been precluded by exacerbation of parkinsonism. In one patient, a levodopa “holiday” had been undertaken with only temporary improvement in psychosis. Baseline evaluation included a complete physical and neurological examination, along with assessment of extrapyramidal function utilizing the Unified Parkinson’s Disease Rating Scale (UPDRS) (8). Baseline laboratory studies included a complete blood count (CBC), chemistry profile, and electrocardiogram. Patients were placed on clozapine in an open label fashion, beginning with a dose of 25 mg daily. Clozapine dosage was then titrated upward as necessary in increments of 25 mg at intervals of no less than 3 days until either the psychosis resolved or adverse effects precluded further increases.
Address correspondence and reprint requests to Dr. R. F. Pfeiffer, Section of Neurology, University of Nebraska Medical Center, 600 South 42nd St, Omaha, NE 68198-2045, U.S.A.
239
R . F . PFEIFFER ET AL.
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Patients were initially evaluated twice weekly and later weekly. At each visit the UPDRS was repeated and the presence and severity of psychosis assessed. CBC was monitored weekly. After a stable dose of clozapine was achieved, levodopal carbidopa dosage was increased, as necessary, to achieve maximal antiparkinson effect. RESULTS
Five patients were selected and gave consent for study participation. All were men, ranging in age from 73 to 77 years (mean, 75). Parkinson’s disease had been present for 5-10 years (mean, 6.6) and was moderately advanced, with UPDRS motor scores ranging from 30 to 39 (mean, 34.6) at baseline (maximum possible motor score, 108) and an average Hoehn and Yahr grade of 3 (range, 2-4). Patients had been taking levodopa for 7-60 + months (mean 37.2) and were, at baseline, taking an average of 551340 mg of carbidopdlevodopa daily, with a levodopa range of 200-500 mg. None were taking bromocriptine, and only one was on amantadine. Psychosis, typically characterized by visual hallucinations that the individuals could not separate from reality, had been present for 1-21 months (mean, 9) and all patients demonstrated some degree of dementia with minimental status examination scores ranging from 14 to 27 (mean, 21; best score possible, 30). Two patients were unable to tolerate clozapine. Patient 2 developed extreme drowsiness and obtundation within several hours of ingestion of the initial 25 mg dose of clozapine. Rechallenge with 25 mg and later with 12.5 mg reproduced the symptoms and forced clozapine discontinuation. The sedation cleared within 24 h after each dose. Patient 5 experienced both extreme sedation and orthostatic hypotension with syncope on clozapine 25 mg, leading to drug discontinuation after 2 days of therapy. Warfarin, which the patient was taking because of a porcine aortic valve, was subsequently discontinued to allow a full-mouth dental extraction. While the patient was off warfarin a large cerebral infarction, presumably embolic in origin, occurred. Clozapine had been reintroduced 2 days prior to this, with recurrence of the sedation but not of any documented orthostatic changes. It was subsequently discontinued again. After an extended course the patient ultimately died. Mild sedation occurred in patient 1 but did not
Movement Disorders, Voi. 5, N o . 3, 1990
require any medication adjustment. Patient 3 experienced several syncopal episodes, the etiology for which was never clearly defined. Prominent hypersalivation also developed in patient 3 and continued throughout the period of follow-up. Patients 1, 3, and 4 were able to tolerate clozapine. Dosages of clozapine and levodopa, UPDRS motor scores, and assessment of hallucination severity in these three are detailed in Fig. 1. Patient 4 did not feel he was deriving sufficient benefit from clozapine and discontinued it after 6 weeks; he was subsequently lost to follow-up. Patients 1 and 3 continued on clozapine long-term with sustained benefit. In patient 1 , clozapine was purposely discontinued after 12 weeks of therapy and hallucinations promptly recurred, disappearing again with clozapine reintroduction. DISCUSSION
In 1985 Scholz and Dichgans reported improvement in four parkinsonian patients with levodopainduced psychosis treated with clozapine (9). Friedman et al. achieved similar results in an individual with concomitant schizophrenia and parkinsonism (10). More recently Friedman and Lannon reported additional favorable experiences with clozapine in patients with Parkinson’s disease and psychosis (1 1). Wolters et al., using clozapine doses of 100250 mg daily, found the usefulness of clozapine in parkinsonian patients severely limited by adverse effects (12). Roberts et al. reported both resolution of psychosis and improvement of parkinsonism, especially tremor, in a single patient on 25 mg of clozapine daily (13). Our findings, for the most part, parallel those of the others. Unlike patients with schizophrenia, who typically tolerate up to 900 mg of clozapine daily, patients with Parkinson’s disease appear to be exquisitely sensitive to the drug. Two of our patients were unable to tolerate clozapine even in doses as low as 12.5-25 mg daily, while the other three patients demonstrated improvement in their psychosis with doses less than 100 mg daily. Marked daytime sedation, occurring at doses of 12.5-25 mg daily even when given at bedtime, was responsible for drug discontinuation in the two individuals in whom clozapine had to be abandoned. Orthostatic hypotension with syncope was documented in one individual, while another experienced several syncopal episodes of undetermined
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CLOZAPINE, PSYCHOSIS, AND PARKINSON’S DISEASE A
PATIENT x 3 (KR)
PATIENT X1 (GF)
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FIG. 1. Dosages (mg/day) of clozapine and levodopa, UPDRS motor scores, and assessment of hallucination seventy in (A) patient I , (B) patient 3, and (C) patient 4. The UPDRS motor score is derived from the motor examination portion of the UPDRS. Higher scores indicate increased disability. Hallucinations are graded on a 0-3 scale: 0, no hallucinations; 1, hallucinations with a clear sensorium; 2, hallucinations with failure to recognize their hallucinatory character; 3, level 2 hallucinations with additional paranoid ideation or other delusions. All factors were assessed at each visit.
10 12 14 16 18 20 22 24 26 28 30 32 34 36
0
WEEKS
etiology. Hypersalivation occurred in one individual. No significant hematologic changes were encountered. Patient 3 demonstrated an increase in parkinsonism at clozapine doses of 100 mg daily with a subsequent return to baseline parkinson scores when
clozapine dosage was reduced to 50 mg daily. In patients 1 and 4, no increase in parkinsonism was noted with clozapine doses of 50-100 mg daily; in fact, parkinson scores deteriorated when clozapine was withdrawn. The basis for this seemingly paradoxical deterioration is not entirely clear but echoes
Movement Disorders, Vol. 5 , No. 3, 1990
R . F . PFEIFFER ET AL.
242
the experience of Roberts et al. (13). In patient 1, this change might be attributed to impaired ability to concentrate on and complete motor tasks in the UPDRS because of reemergence of psychosis. Our experience indicates that clozapine can be of benefit in the treatment of levodopa-induced psychosis. This improvement can occur without aggravation of parkinsonism as long as clozapine doses of less than 100 mg daily are utilized. Patients with Parkinson’s disease appear to be exquisitely sensitive to clozapine, with both beneficial and adverse responses occurring at very low doses. Adverse effects may preclude clozapine use in a significant percentage of patients. Nevertheless, cautious use of clozapine may be beneficial for patients with levodopa-induced psychosis who do not respond adequately to more conservative measures. A double-blind, placebo-controlled trial with larger patient numbers is needed to more definitively assess the utility of clozapine in this clinical situation. Acknowledgment: We thank Vickie Stuetelberg for her expert assistance in manuscript preparation. Clozapine was generously supplied by Sandoz Pharmaceuticals.
REFERENCES I . Girotti F, Soliveri P, Carella F, et al. Dementia and cognitive impairment in Parkinson’s disease, J Neurol Neurosurg Psychiatr 1988;51 :1498-1 502. 2. Andersen PH, Nielsen EB, Gronvald FC, Braestrup C.
Movement Disorders, Vol. 5 , No. 3, 1990
Some atypical neuroleptics inhibit [3H]SCH 23390 binding. Eur J Pharmacol 1986;120:143-144. 3. Andersen PH, Braestrup C. Evidence for different states of the dopamine Dl receptor: clozapine and fluperlapine may preferentially label an adenylate cyclase-coupled state of the D1 receptor. J Neurochem 1986;47:1822-1831. 4. Kane JM, Cooper TB, Sachar EJ, Halpern FS, Bailine S. Clozapine: plasma levels and prolactin response. Psychopharmacology 1981;73:184-187. 5 . Skarsfeldt T. Differential effects after repeated treatment with haloperidol, clozapine, thioridazine and tefludazine on SNC and VTA dopamine neurons in rats. Life Sci 1988; 42: 1037-1044. 6. Investigator’s brochure. Sandoz Pharmaceuticals, 1985. 7. Tully EM. Clozapine: a review. A m J Prev Psychiatr Neurol 1988;1 :19-23. 8. Fahn S, Elton RL, and Members of the UPDRS Development Committee. Unified Parkinson’s disease rating scale. In: Fahn S, Marsden CD, Calne D, Goldstein M, eds. Recent developments in Parkinson’s disease: volume 11. Florham Park, New Jersey: MacMillan Healthcare Information, 1987:153-1 63. 9. Scholz E, Dichgans J. Treatment of drug-induced exogenous psychosis in parkinsonism with clozapine and fluperlapine. Eur Arch Psychiatr Neurol Sci 1985;235:60-64. 10. Friedman JH, Max J, Swift R. Idiopathic Parkinson’s disease in a chronic schizophrenic patient: long-term treatment with clozapine and L-dopa. Clin Neuropharmacol 1987; 10:470475. 11. Friedman JH, Lannon MC. Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 1989;39:12191221. 12. Wolters EC, Hurwitz TA, Peppard RF, Calne DB. Clozapine: an antipsychotic agent in Parkinson’s disease? Clin Neuropharmacol 1989;1293-90. 13. Roberts HE, Dean RC, Stoudemire A. Clozapine treatment of psychosis in Parkinson’s disease. J Neuropsychiatr Clin Neurosci 1989;l:190-192.
