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Managing Psychosis in Patients with PD Managing psychosis is one of the most difficult challenges in the care of patients with Parkinson's disease. This complication occurs in 10 to 15 percent of such patients and consists of visual hallucinations, the belief that one is being persecuted, fears of personal endangerment, or feelings of being followed, spied on, or threatened. (1,2) Psychosis is a major source of distress for patients. It exacerbates the burdens of family members and is associated with earlier transfer to nursing homes and increased mortality. (3) In managing psychosis in patients with Parkinson's disease, clinicians face a "motion-emotion" conundrum. The dopaminergic drugs that can improve the motor disability caused by Parkinson's disease are associated with the emergence of symptoms of psychosis; conversely, the use of conventional neuroleptic drugs to reduce psychosis exacerbates parkinsonism. This problem remained unresolved until the recent development of atypical antipsychotic drugs that can control psychotic symptoms without producing extrapyramidal disturbances. The article by the Parkinson Study Group in this issue of the Journal (4) demonstrates that low doses of the atypical antipsychotic drug clozapine improve psychosis in patients with Parkinson's disease without exacerbating the motor disability caused by parkinsonism. In a randomized, double-blind, parallel-group study of 60 patients with Parkinson's disease and psychosis, treatment with clozapine was associated with global improvement and reduced symptoms of psychosis, as assessed with the Brief Psychiatric Rating Scale and the Scale for the Assessment of Positive Symptoms. There were no deleterious effects with respect to parkinsonism, and tremor was significantly improved in the group receiving clozapine. In the clozapine group there were reductions of approximately 25 percent in the scores on the psychosis scale, as compared with 5 percent in the placebo group; thus, although their psychosis improved, the patients continued to have some residual symptoms. The study group was reasonably typical of patients with Parkinson's disease and psychosis. All the patients had either new-onset psychosis or recent worsening of symptoms. Patients who had received an antipsychotic drug within three months before the study began were excluded. Adjustments of the dosage were allowed until the final week of the study; the mean final dose was approximately 25 mg daily, with a range of 6.25 to 50 mg. The study also demonstrated that clozapine did not impair cognitive function; scores on the Mini-Mental State Examination remained unchanged in both groups. This report describes an important advance in our ability to treat one of the most disabling conditions encountered in patients with Parkinson's disease. Physicians now have better options for the management of the parkinsonian motor syndrome in patients with advanced disability, those in whom psychosis is most likely to occur. The addition of clozapine may allow some patients to continue living at home for longer periods and will facilitate the care of many of those living in nursing homes. Psychosis associated with Parkinson's disease most often occurs in patients who are older, who have more advanced disease, and who manifest greater cognitive impairment. (1,2) Although psychosis is rare in patients with Parkinson's disease before they begin to use dopaminergic drugs, the dose of levodopa is not greater in those with psychosis than in those without it. (2) Moreover, intravenous administration of levodopa in patients prone to have hallucinations does not exacerbate the hallucinatory events. (5) These observations suggest that restoring the dopaminergic function of the central nervous system may permit but does not cause psychosis. Patients with Parkinson's disease and dementia who are at risk for psychosis have atrophy of the nucleus basalis and a cortical cholinergic deficiency. (6) The cholinergic deficiency or the interaction between the cholinergic deficiency and dopaminergic drugs may create the cerebral conditions required for the emergence of psychosis. Dementia with Lewy bodies, an increasingly recognized disorder characterized by parkinsonism, dementia, visual hallucinations, and fluctuating cognition, is also distinguished by cholinergic deficiency, (7) and a deficit in cholinergic function appears to contribute to psychosis in patients with Alzheimer's disease. (8) Thus, several degenerative disorders with overlapping clinical manifestations share the common neurochemical substrate of a deficiency of cholinergic function. Atypical antipsychotic drugs are characterized by less dopamine D2-receptor antagonism and more serotonin 5-HT2-receptor antagonism than classic neuroleptic drugs. (9) The lower D2-receptor occupancy or the altered balance between dopaminergic and serotonergic antagonism results in preserved or improved antipsychotic potency, with a reduction in extrapyramidal symptoms -- parkinsonism, dystonia, and tardive dyskinesia. Side effects must be carefully monitored when atypical antipsychotic drugs are used. Sedation is a common problem, and clozapine induces agranulocytosis in 0.6 to 1.2 percent of patients. This complication can be fatal if not discovered early and requires weekly monitoring of white-cell counts for the first six months of therapy and evaluations every other week after that. (10) The Parkinson Study Group found that low doses of clozapine (average dose, approximately 25 mg per day) are sufficient to control psychosis in patients with Parkinson's disease. This dose is markedly lower than that typically used to treat psychosis in patients with schizophrenia (500 mg per day or more), and clinicians must adjust their prescribing practices to avoid excessive sedation and other side effects in patients with Parkinson's disease. Atypical antipsychotic drugs are substantially more expensive than conventional neuroleptics; these costs may be offset by the savings realized by reducing hospital stays resulting from aspiration pneumonia, decubitus ulceration, and falls and fractures, all of which are associated with the use of conventional neuroleptic drugs. Additional atypical drugs with less demanding requirements for surveillance may also be useful in treating psychosis in patients with Parkinson's disease, but they have not been subjected to the same rigorous study as that reported for clozapine by the Parkinson Study Group. Other atypical drugs that are available and possibly useful in the management of psychosis in these patients are olanzapine, quetiapine, and risperidone. These drugs vary in the degree of D2-receptor antagonism, and their usefulness in treating psychosis in patients with Parkinson's disease without worsening parkinsonism is expected to vary. The ability to control delusions and hallucinations without compromising motor function is a great advance in improving the lives of patients with Parkinson's disease. The use of clozapine in the management of psychosis in these patients represents another example of improved patient care resulting from progress in neuroscience. The public that has consistently supported basic scientific research is reaping the benefits of increased understanding of brain function and an improved ability to intervene in brain disorders so as to increase function and enhance the quality of life. The study by the Parkinson Study Group also illustrates the growing interface between neurology and psychiatry. In this case, drugs developed for the treatment of a psychiatric condition, schizophrenia, have an important role in treating psychosis in patients with neurologic disease. Conversely, the study of psychosis in patients with Parkinson's disease should contribute to our knowledge about the neurobiologic basis of delusions and hallucinations. As neuropsychiatric disorders are increasingly studied, an understanding of the neurobiology of human behavior and emotion may begin to emerge. Ultimately, it is the individual patient who benefits from the development of new treatments. Drug development is expensive, labor intensive, and slow. It is worthwhile, however, when it provides the clinician with a new option to relieve a patient's delusional fear that he or she is in danger of being kidnapped or killed, without reducing the patient to the bed-bound, trembling state characterized by severe parkinsonism. Physicians now have a well-proved addition to their armamentarium of treatments that can drive away the demons and improve the well-being and quality of life of patients with Parkinson's disease. Jeffrey L. Cummings, M.D. UCLA School of Medicine Los Angeles, CA 90095-1769 Copyright 1999 by the Massachusetts Medical Society. All rights reserved. The New England Journal of Medicine March 11, 1999 -- Vol. 340, No. 10 [EDITORIAL] janet paterson - 51 now /41 dx /37 onset - almonte/ontario/canada <http://www.newcountry.nu/pd/members/janet/index.htm> [log in to unmask]