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Clozapine for the Treatment of Levodopa-Induced Psychosis in Parkinson’s Disease
We report a case in which clozapine was used to treat a severe levodopa-induced psychosis in a man with far-advanced Parkinson’s disease. The case demonstrates the potential use of clozapine in situations that may be life-threatening and in which, until recently, little effective treatment has been available.
Case Report Mr. Q, a 64-year-old man, had suffered from Parkinson’s disease for 10 years. Despite taking increasing doses of levodopaicarbidopa (Sinemet 25/250), up to a total dosage of 875-1000 mg of levodopa a day, as well as triaIs on adjunctive selegiline hydrochloride, bromocriptine, and amantadine, he became progressively debilitated. Over a period of 6 months, Mr. Q developed progressive insomnia, agitation, and then paranoia. He developed visual and auditory hallucinations, and in a state of acutely heightened paranoia, he barricaded himself in a room; police intervention was necessary to remove him. Mr. Q, suffering from severe paranoia and visual and auditory hallucinations, was admitted to an inpatient medical-psychiatric unit. At the time of admission, he was taking only levodopalcarbidopa and amitriptyline (50 mg orally at bedtime). He had no previous history of psychiatric illness. The amitriptyline was stopped and the levodopai carbidopa withheld. Within several days, the patient’s paranoia had resolved completely. Efforts to restart the levodopa were confounded by the rapid recurrence of a severe paranoid psychosis, accompanied by agitation and combativeness. Mr. Q was unable to take more than 400 mg of levodopa a day without developing incapacitating psychosis. At lower dosages, however, the physical symptoms of his Parkinson’s disease became life-threatening. He became bedridden, developed pronounced dysphagia, and required frequent suctioning to prevent aspiration. General Hospital Psychiatry 14,285-286, 1992 0 1992 Elsevier Science Publishing CO., Inc.
655 Avenue of the Americas, New York, NY 10010
Detailed discussions were carried on with the patient and his family regarding treatment options. Consideration was given to electroconvulsive therapy (ECT) and treatment with standard neuroleptic agents. The family and patient preferred a trial of clozapine because of concern that the potential benefits of ECT would not be long-lasting and that standard neuroleptics would exacerbate Mr. Q’s already compromised physical condition. Oral clozapine was begun in gradually increasing dosages up to 150 mglday, given in two divided doses. The patient tolerated this therapy well and was also able to tolerate an increase in his dose of levodopalcarbidopa to 251100 mg, given eight times a day with a 6-hour hiatus during the night. On this regimen, he stopped having insomnia and his paranoia and hallucinations resolved completely. He was able to swallow and ambulate with little difficulty.
Discussion Shaw et al. [l] observed that the development of mental status changes, including toxic, confusional states and overt psychosis, is the principal reason for stopping levodopa in patients with Parkinson’s disease. In their patients, mortality was highest among those who discontinued levodopa, with bronchopneumonia being the most frequent cause of death. In a small percentage of patients, tremor has been described as a potential side effect of clozapine. Several open trials, however, have found that clozapine reduces the tremor associated with Parkinson’s disease [2,3]. This effect, which is most often noted in the first few days of treatment, may be significant. Case reports have further suggested that the rigidity and bradykinesia associated with Parkinson’s disease may improve during treatment with clozapine [4,5]. Dosages of oral clozapine found to be effective in treating levodopa-induced psychosis in patients 285 ISSN 0163~8343/92/$5.00
Letter to the Editor
without
a concurrent
major
mental
illness
range
25 to 150 mg/day [4,5]. These dosages are lower than those recommended for treating major mental illness (300-600 mg/day). In patients in whom higher dosages are initially required, the amount of drug can sometimes be tapered once control of psychotic symptoms is achieved. The sedative properties of clozapine can be a limiting side effect [6]. We wonder if the ability of some patients to tolerate higher dosages of clozapine is a function of less diffuse central nervous system impairment, as reflected by lack of underlying dementia. This might have been the case with Mr. Q. Both clozapine and levodopa can induce or exacerbate orthostatic hypotension, and this occurred temporarily in Mr. Q. The potential of clozapine to cause sialorrhea, which might complicate dysphagia, was not a problem for our patient. The potential for clozapine to induce agranulocytosis in l%-2% of patients has been well publicized [7]. In addition, several recent reports suggest that clozapine, like standard neuroleptics, may be associated with the development of neuroleptic malignant syndrome [g-lo]. Whether the risk of this syndrome and agranulocytosis in patients with Parkinson’s disease is higher than that in younger, healthier persons is unknown. from
STEPHEN
H.
MARTIN DAVID
ROSENTHAL,
M.D.
L. FENTON,
M.D.
S. HARNETT,
M.D.
Lawrence Memorial Hospital of Medford Medford, Massachusetts
286
References 1. Shaw K, Lees A, Stern G: The impact of treatment with levodopa on Parkinson’s disease. Q J Med 195:283-293, 1980 2. Pakkenberg H, Pakkenberg B: Clozapine in the treatment of tremor. Acta Neurol Stand 73:295-297,1986 3. Fischer PA, Baas H, Hefner R: Treatment of parkinsonian tremor with clozapine. J Neural Transm 2:233-238, 1990 4. Roberts HE, Dean RC, Stoudemire A: Clozapine treatment of psychosis in Parkinson’s disease. J Neuropsychiatry 1:190-192, 1989 5. Friedman JH, Lannon MC: Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 39:1219-1221, 1989 6. Pfeiffer R, Kang J, Graber B, Hufman R, Wilson: Clozapine for psychosis in Parkinson’s disease. Mov Disord 5:239-242, 1990 7. Kane J, Honigfeld G, Singer J, Meltzer H, and the Clozaril Collaborative Study Group: Clozapine for the treatment-resistant schizophrenic: a doubleblind comparison with chlorpromazine. Arch Gen Psychiatry 45:789-796, 1988 8. Miller DD, Sharafuddin M, Kathol R: A case of clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry 52:99-101, 1991 9. Anderson ES, Powers PS: Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry 52:102-104, 1991 10. DasGupta K, Young A: Clozapine-induced neuroleptic syndrome. J Clin Psychiatry 52:105-107, 1991
Clozapine for the Treatment of Levodopa-Induced Psychosis in Parkinson’s Disease
We report a case in which clozapine was used to treat a severe levodopa-induced psychosis in a man with far-advanced Parkinson’s disease. The case demonstrates the potential use of clozapine in situations that may be life-threatening and in which, until recently, little effective treatment has been available.
Case Report Mr. Q, a 64-year-old man, had suffered from Parkinson’s disease for 10 years. Despite taking increasing doses of levodopaicarbidopa (Sinemet 25/250), up to a total dosage of 875-1000 mg of levodopa a day, as well as triaIs on adjunctive selegiline hydrochloride, bromocriptine, and amantadine, he became progressively debilitated. Over a period of 6 months, Mr. Q developed progressive insomnia, agitation, and then paranoia. He developed visual and auditory hallucinations, and in a state of acutely heightened paranoia, he barricaded himself in a room; police intervention was necessary to remove him. Mr. Q, suffering from severe paranoia and visual and auditory hallucinations, was admitted to an inpatient medical-psychiatric unit. At the time of admission, he was taking only levodopalcarbidopa and amitriptyline (50 mg orally at bedtime). He had no previous history of psychiatric illness. The amitriptyline was stopped and the levodopai carbidopa withheld. Within several days, the patient’s paranoia had resolved completely. Efforts to restart the levodopa were confounded by the rapid recurrence of a severe paranoid psychosis, accompanied by agitation and combativeness. Mr. Q was unable to take more than 400 mg of levodopa a day without developing incapacitating psychosis. At lower dosages, however, the physical symptoms of his Parkinson’s disease became life-threatening. He became bedridden, developed pronounced dysphagia, and required frequent suctioning to prevent aspiration. General Hospital Psychiatry 14,285-286, 1992 0 1992 Elsevier Science Publishing CO., Inc.
655 Avenue of the Americas, New York, NY 10010
Detailed discussions were carried on with the patient and his family regarding treatment options. Consideration was given to electroconvulsive therapy (ECT) and treatment with standard neuroleptic agents. The family and patient preferred a trial of clozapine because of concern that the potential benefits of ECT would not be long-lasting and that standard neuroleptics would exacerbate Mr. Q’s already compromised physical condition. Oral clozapine was begun in gradually increasing dosages up to 150 mglday, given in two divided doses. The patient tolerated this therapy well and was also able to tolerate an increase in his dose of levodopalcarbidopa to 251100 mg, given eight times a day with a 6-hour hiatus during the night. On this regimen, he stopped having insomnia and his paranoia and hallucinations resolved completely. He was able to swallow and ambulate with little difficulty.
Discussion Shaw et al. [l] observed that the development of mental status changes, including toxic, confusional states and overt psychosis, is the principal reason for stopping levodopa in patients with Parkinson’s disease. In their patients, mortality was highest among those who discontinued levodopa, with bronchopneumonia being the most frequent cause of death. In a small percentage of patients, tremor has been described as a potential side effect of clozapine. Several open trials, however, have found that clozapine reduces the tremor associated with Parkinson’s disease [2,3]. This effect, which is most often noted in the first few days of treatment, may be significant. Case reports have further suggested that the rigidity and bradykinesia associated with Parkinson’s disease may improve during treatment with clozapine [4,5]. Dosages of oral clozapine found to be effective in treating levodopa-induced psychosis in patients 285 ISSN 0163~8343/92/$5.00
Letter to the Editor
without
a concurrent
major
mental
illness
range
25 to 150 mg/day [4,5]. These dosages are lower than those recommended for treating major mental illness (300-600 mg/day). In patients in whom higher dosages are initially required, the amount of drug can sometimes be tapered once control of psychotic symptoms is achieved. The sedative properties of clozapine can be a limiting side effect [6]. We wonder if the ability of some patients to tolerate higher dosages of clozapine is a function of less diffuse central nervous system impairment, as reflected by lack of underlying dementia. This might have been the case with Mr. Q. Both clozapine and levodopa can induce or exacerbate orthostatic hypotension, and this occurred temporarily in Mr. Q. The potential of clozapine to cause sialorrhea, which might complicate dysphagia, was not a problem for our patient. The potential for clozapine to induce agranulocytosis in l%-2% of patients has been well publicized [7]. In addition, several recent reports suggest that clozapine, like standard neuroleptics, may be associated with the development of neuroleptic malignant syndrome [g-lo]. Whether the risk of this syndrome and agranulocytosis in patients with Parkinson’s disease is higher than that in younger, healthier persons is unknown. from
STEPHEN
H.
MARTIN DAVID
ROSENTHAL,
M.D.
L. FENTON,
M.D.
S. HARNETT,
M.D.
Lawrence Memorial Hospital of Medford Medford, Massachusetts
286
References 1. Shaw K, Lees A, Stern G: The impact of treatment with levodopa on Parkinson’s disease. Q J Med 195:283-293, 1980 2. Pakkenberg H, Pakkenberg B: Clozapine in the treatment of tremor. Acta Neurol Stand 73:295-297,1986 3. Fischer PA, Baas H, Hefner R: Treatment of parkinsonian tremor with clozapine. J Neural Transm 2:233-238, 1990 4. Roberts HE, Dean RC, Stoudemire A: Clozapine treatment of psychosis in Parkinson’s disease. J Neuropsychiatry 1:190-192, 1989 5. Friedman JH, Lannon MC: Clozapine in the treatment of psychosis in Parkinson’s disease. Neurology 39:1219-1221, 1989 6. Pfeiffer R, Kang J, Graber B, Hufman R, Wilson: Clozapine for psychosis in Parkinson’s disease. Mov Disord 5:239-242, 1990 7. Kane J, Honigfeld G, Singer J, Meltzer H, and the Clozaril Collaborative Study Group: Clozapine for the treatment-resistant schizophrenic: a doubleblind comparison with chlorpromazine. Arch Gen Psychiatry 45:789-796, 1988 8. Miller DD, Sharafuddin M, Kathol R: A case of clozapine-induced neuroleptic malignant syndrome. J Clin Psychiatry 52:99-101, 1991 9. Anderson ES, Powers PS: Neuroleptic malignant syndrome associated with clozapine use. J Clin Psychiatry 52:102-104, 1991 10. DasGupta K, Young A: Clozapine-induced neuroleptic syndrome. J Clin Psychiatry 52:105-107, 1991
