Psychosis is very common in PD, particularly in patients with dementia, and it is a core feature of DLB. While dopamine replacement therapy likely plays a role in the development of PD psychosis, the etiology appears to be multifactorial. Impairments in the monoaminergic and cholinergic neural circuitry induced by disease-related neuropathological changes help explain the high prevalence of psychosis in both PD and DLB. Appropriate management of psychosis should begin with an evaluation of existing PD medications and withdrawal of offending agents. Clozapine is the only antipsychotic shown to be efficacious for the treatment of PD psychosis, although quetiapine is more frequently used because of convenience. Concerns about antipsychotic sensitivity in DLB patients may prevent antipsychotics from being tested further in this population. There is also preliminary evidence that cholinesterase inhibitors may have antipsychotic properties in both PD with dementia and DLB.
Screening for and treating psychosis in PD is important, as psychotic symptoms are associated with worse outcomes for patients and significant distress for caregivers. Screening can be done quickly in a routine clinic visit by inquiring about perceptual changes, particularly the range of visual disturbances that can occur. Patients should be treated with an atypical antipsychotic only if the symptoms are problematic, after acute medical conditions have been ruled out, and after the antiparkinsonian medications have been reviewed. It is important to monitor for worsening parkinsonism whenever the antipsychotic dosage is increased.
Based on open-label studies and clinical experience, the current first-line antipsychotic treatment is quetiapine (starting dosage, 12.5–25 mg/day; mean maintenance dosage, approximately 75 mg/day; dosage range, 25–300 mg/day). Although clozapine is the only antipsychotic with established efficacy for the treatment of psychosis in PD, it is best reserved for patients who do not tolerate or respond to quetiapine, because of the legal requirement for frequent blood testing to monitor for agranulocytosis. Although cholinesterase inhibitors cannot currently be considered a first-line treatment for psychosis in PD, they may have antipsychotic effects in PD, and their mild cognition-enhancing properties are likely to be of benefit to the large percentage of psychotic patients with comorbid cognitive impairment or dementia.
The natural course of psychosis in PD is not well understood, so there is little empirical evidence to guide clinicians on the appropriate length of treatment for PD psychosis. In one case series, an attempt was made to slowly wean psychiatrically stable (i.e., no longer psychotic) patients off clozapine or quetiapine, but the study was terminated early after 83% of patients experienced a recurrence of psychosis, including several whose symptoms were worse during the recurrent episode than in the initial episode (57
). There is preliminary evidence suggesting that it is possible to switch psychiatrically stable patients from clozapine to quetiapine, provided patients have not previously failed quetiapine treatment and there is no gap in antipsychotic coverage (58
). This strategy might make sense particularly for patients who are in the first year of clozapine treatment, given the burden of having weekly or biweekly blood drawings.
The cholinesterase inhibitors are the only class of psychiatric medications that have been evaluated in randomized clinical trials for treatment of DLB. These agents appear to have positive effects on both cognition and neuropsychiatric symptoms, including psychosis. Given the possibility of sensitivity reactions, antipsychotic medications, particularly quetiapine and clozapine, should be used cautiously in DLB patients, after a thorough discussion of the risk-benefit ratio with both the patient and an informed other, and with close clinical monitoring for adverse effects.
For the patient in the vignette, the follow-up evaluation discussion with the patient and family focused initially on making another attempt to modify the patient’s PD medication regimen. After consideration of the available options in this approach (e.g., again decreasing the dopamine agonist dosage but this time also making a concomitant increase in the l-dopa dosage or adding a catechol O-methyl-transferase [COMT] inhibitor, an MAO inhibitor, or amantadine), it was felt that each option would potentially lead either to a worsening of parkinsonism or an increase in psychotic symptoms. Hence, the focus shifted to adding an antipsychotic medication. Consideration was given to restarting quetiapine at a lower dosage and titrating upward very slowly, but the severity of the current psychosis and uncertainty about the efficacy of quetiapine for psychosis in PD led the physician to recommend a trial of clozapine. The adverse event profile, the need for ongoing blood monitoring, and the overall risk-benefit ratio were reviewed with the patient and his spouse, and together they agreed to a clozapine trial. After going through the necessary baseline laboratory tests and registration process, the patient was started on 12.5 mg of clozapine at bedtime. The dosage was increased by 12.5 mg/day at 2-week intervals, and at a dosage of 37.5 mg/day, the patient’s psychotic symptoms declined markedly. Several months later, the patient remained on 37.5 mg of clozapine at bedtime, and his only ongoing perceptual disturbance was the rare occurrence of fleeting visual hallucinations. The patient tolerated clozapine well, with no apparent worsening of the parkinsonian symptoms. The only side effects were tolerable mild increases in drooling and constipation.