Olanzapine for Psychosis in Patients With Parkinson's Disease With and Without Dementia

Psychosis is a common phenomenon in patients with Parkinson's disease (PD)¹ and may represent a severe clinical problem. Recent open-label studies have shown the atypical neuroleptic agents to be effective and well tolerated for psychotic symptoms in PD, but the samples have usually been selective, including rather young and cognitively intact subjects.² The aim of the current study, therefore, was to assess efficacy and safety of olanzapine in a more representative sample of patients with PD and psychotic symptoms.

METHODS

Subjects

Consecutive outpatients or inpatients with PD and psychosis at the Departments of Neurology and Geriatric Psychiatry, Stavanger, Norway, were included after having signed informed consent forms. Patients with a previous history of a psychotic disorder were not included.

Measurement

Patients were diagnosed by a neurologist according to explicit criteria,³ and the antiparkinsonian treatment was reviewed by a neurologist. When indicated, dose reductions were attempted before patients were included in the study. Severity and stage of disease were assessed with the Unified Parkinson's Disease Rating Scale (UPDRS)⁴ and the Hoehn and Yahr scale.⁵ During the month prior to and the first 4 weeks after inclusion, no change of the antiparkinsonian medication was allowed. Thereafter, dose increases were made according to the clinical situation.

Prior to study start, most patients had undergone a comprehensive cognitive evaluation program, consisting of a clinical interview of a caregiver based on the DSM-III-R dementia criteria,⁶ the Mini-Mental State Examination (MMSE),⁷ and a neuropsychological battery with tests of visual memory, attention, visuospatial ability, and executive function. A diagnosis of dementia was based on the interview and the test scores.

Three subscales of the Neuropsychiatric Inventory (NPI)⁸ were used to identify and rate psychotic symptoms: the Delusion, Hallucination, and Agitation subscales. The NPI was administered to the caregiver and patient by a psychiatrist or a neurologist with experience in neuropsychiatry. Prior to study start, the raters met to get acquainted with the scale and underwent training. A Clinical Global Impression (CGI) of psychotic symptoms was scored by the clinician on the basis of information from patient and caregiver.

Procedure

This was a prospective, open-label, uncontrolled study, and the protocol was approved by the Committee of Ethics in Medical Research, University of Bergen, Norway. Subjects were assessed at baseline and 2, 4, and 8 weeks later. The starting dosage of olanzapine was 5 mg/day, given as a single dose at night. Because of frequently occurring side effects, the starting dosage was reduced to 2.5 mg/day after the first 8 patients had been included. Dosing was flexible, with a maximum dosage of 10 mg/day. Other neuroleptics were not allowed, but other psychotropics could be continued. Side effects were assessed by using a checklist from the UKU Side Effect Scale.⁹

Statistics

Differences between the treatment group and the population-based sample¹ and between completers and noncompleters were tested for statistical difference by using two-tailed t-tests for continuous and Fisher's exact tests for categorical variables. Wilcoxon signed-ranks tests were used to test for differences between baseline and final evaluation. Linear regression analyses were used to analyze how the three NPI subscores changed with time, using the NPI subscores as the dependent variable and time as the independent variable.

RESULTS

Demographic and Clinical Characteristics

Twenty-one patients were included. The patients were rather old (mean age±SD: 74.4±6.4 years), the male/female ratio was 10/11, and they had a long duration of disease (12.5±4.7 years) and advanced PD (median Hoehn & Yahr stage=4, range 2–5). Eleven subjects were living at home, 7 were living in a nursing home, and 3 were admitted to a psychiatric ward. At baseline, hallucinations were reported in all subjects, delusions in 12 (57%), and agitation in 7 (33%). All patients were treated with levodopa (mean daily dose=738±474 mg). Ten received one and 4 received two other antiparkinsonian agents. These demographic and clinical characteristics did not differ from those of a population-based sample of PD patients with psychosis,¹ with the exception of a higher mean MMSE score in the treatment group: mean MMSE of 22.4 vs. 16.3 (t=2.6, df=33, P<0.05). Eight patients (38%) were diagnosed as demented (mean MMSE score=13.5±7.5). Five subjects (24%) were depressed at baseline, having at least a score of 2 (sustained depression for a week or more) on the UPDRS Depression subscale,⁴ but not on the final evaluation. Four of these patients had been treated with antidepressants before inclusion in the study, and this treatment was continued for 3 subjects.

Outcome

Twelve of the 15 subjects (80%) who completed 8 weeks of treatment were rated Very Much (n=11) or Much (n=1) improved on the final CGI. Scores for delusions (F=11.4, df=1,50, P=0.002), hallucinations (F=33.2, df=1,50, P=0.000), and agitation (F=4.0, df=1,50, P=0.05) decreased during the treatment period (Table 1). Improvement in scores was noted already after 2 weeks of treatment for delusions (t=3.2, df=14, P<0.01), hallucinations (t=4.3, df=14, P=0.001), and agitation (t=2.2, df=14, P<0.05). The summed score of the three NPI items decreased by 85%, and for 12 subjects (80%) there was at least a 50% reduction. At week 8, 5 subjects were receiving 2.5 mg olanzapine, 9 were receiving 5 mg, and 1 was receiving 10 mg per day. Dopaminergic treatment was increased in 4 patients without exacerbation of psychosis.

Safety

The mean UPDRS motor and MMSE scores did not change during treatment. However, 6 patients (29%) withdrew from the study, 3 of them within the first week, mainly due to severe drowsiness. Subjects who withdrew from the study were more likely to be demented (P<0.05), had lower MMSE (t=3.2, df=19, P=0.005) and NPI (t=2.2, df=19, P<0.05) scores, and tended to have received an initial dose of 5 mg olanzapine more often than those who continued treatment. The following side effects were reported in more than 50% at least once during the study: concentration difficulties, memory impairment, increased sleep duration (which was usually rated as a positive effect), and dryness of mouth. Side effects tended to be of short duration and of mild intensity. At the final evaluation, only drowsiness and dryness of mouth were reported in more than 50% of the subjects.

DISCUSSION

The results in this study suggest that olanzapine may be useful for patients with PD and psychosis. The summed score of the NPI items Delusions, Hallucinations, and Agitation decreased by 85%, and 80% of those who completed 8 weeks of treatment were considered much or very much improved. The major strength of the study is the inclusion of elderly subjects with cognitive impairment and advanced PD. Previous studies have shown that these features are associated with psychosis in PD.¹ This is important, since previous studies of olanzapine for psychosis in PD have included more selected patients.²

Side effects were commonly reported, and a substantial proportion (29%) withdrew from treatment due to adverse events. The main reason for withdrawal was drowsiness, which was usually reported in those with cognitive impairment who received an initial dosage of 5 mg olanzapine. Thus, the initial dose should not exceed 2.5 mg per day, and particular attention should be paid to cognitively impaired subjects. Worsening of parkinsonism or cognition was not observed.

Psychosis increases the burden for patients with PD and their caregivers,¹⁰ and it has been found to be associated with increased risk for nursing home admission^10,11 and with a higher mortality.¹² Thus, it is of great importance to find psychotropic agents that are effective and well tolerated by this frail patient group. The results from this open-label study suggest that olanzapine is useful. However, the conclusions in this and other open-label studies need to be addressed in controlled clinical trials.

ACKNOWLEDGMENTS

This work was reported in a poster presentation at the 11th European College of Neuropsychopharmacology Congress, Paris, October 31-November 4, 1998.

TABLE 1. Severity of psychotic symptoms, parkinsonism, and cognitive impairment before and after treatment with olanzapine in patients with Parkinson's disease

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