We found that half of patients with PDP are prescribed an AP in routine clinical care, most commonly an atypical AP. In addition, comorbid dementia in a patient with PD and comorbid PD in a patient with dementia increase the likelihood of AP use. Finally, despite 2005 and 2008 FDA warnings regarding associations between AP use and mortality in patients with dementia, a common comorbid condition in PD, overall AP use in PD was unchanged between FY2002 and FY2008.
The overwhelming majority of AP prescriptions in PD were for atypical agents. Clinical trials and case series suggest that olanzapine and risperidone have limited efficacy in PD and can worsen parkinsonism, so their infrequent use would be expected.21
However, we found that risperidone or olanzapine were prescribed in almost 30% of treated patients with PDP. Also of concern, 7% of treated patients were prescribed a high-potency typical AP. Because of the potential exacerbation of parkinsonism with AP use in PD,22
typical or conventional APs, especially high-potency ones, are not recommended for use in patients with PD.23
Finally, by FY2008, aripiprazole was the third most commonly prescribed AP in patients with PDP, although initial open-label experience suggests poor tolerability of aripiprazole in PD.24,25
Anecdotally, quetiapine has become the most frequently prescribed AP for PDP, and our data confirm that impression, with two-thirds of treated patients taking this medication. Clinical experience suggests that quetiapine is well tolerated from a motor standpoint and often effective at commonly used doses, but the findings of all 3 placebo-controlled studies in patients with PDP have been negative, perhaps related in part to methodological issues.26–28
Only clozapine has demonstrated efficacy for the treatment of psychosis in PD,29–31
and only its use has been recommended by a Quality Standards Subcommittee of the American Academy of Neurology23
and on the basis of a meta-analysis.32
However, clozapine accounted for less than 2% of AP prescriptions in our PD sample. The length of the application process to get approval from the National Clozapine Center, concern for the rare but potentially life-threatening adverse effect of agranulocytosis, and requirements for routine blood cell count monitoring are likely deterrents to greater clozapine use.
For all the patients with a diagnosis of dementia, a comorbid PD diagnosis increased the likelihood of AP use. Approximately one-third of our PD sample had comorbid dementia, and many more likely had mild cognitive impairment (MCI). This has significant clinical implications in PD given the increased morbidity and mortality associated with typical and atypical AP use in dementia populations.15,33–36
As the cumulative dementia rate in PD may be as high as 80% to 90%, of concern is the impact of AP use on morbidity and mortality in patients with PD and comorbid dementia. However, it is also possible that the higher rates of AP use in patients with PD compared with patients without PD was an artifact of clinician coding, with a higher severity of psychosis being required in patients with PD for clinicians to code psychosis as a comorbid disorder. The association between younger age and AP prescribing in PD may reflect the fact that clinicians have less concern about AP adverse effects in younger patients with PD, who also have less severe disease on average.
Antipsychotic use in PD was unchanged over a period that encompassed the publication of black box warnings for AP use in patients with dementia. Within PD, over this period there was a significant decrease in high-potency atypical AP (olanzapine and risperidone) use, increases in quetiapine and ziprasidone use, and the introduction and relatively common use of aripiprazole. Thus, there has been a recent shift in AP use in PD to medications that overall may be better tolerated from a motor standpoint but not clearly more efficacious or safer. There is preliminary research reporting that patients with PD treated with atypical APs lose weight, while comparable patients with Alzheimer disease gain weight,37
so future research needs to determine if the increased mortality and morbidity associated with patients with dementia in general extend to patients with PD.
The fact that almost half of patients who have PDP are not treated with an AP suggests several possibilities. First, the recommended initial management strategy for patients with PDP focuses on the treatment of medical comorbidities and the discontinuation of non-PD medications that might cause or contribute to psychosis, in conjunction with a decrease in the number or dosage of nonessential PD medications.38
Such a strategy has been shown to decrease the need for acute AP treatment in a substantial percentage of patients with PD.39
Second, psychotic symptoms in PD may often not be clinically significant enough to warrant treatment. Third, clinicians may not perceive a favorable risk-benefit ratio for AP use in many patients with PD, given concerns over possible worsening of parkinsonism and other problematic adverse events.21,40
This study has several limitations. First, the databases we used lacked data about the severity of PD, dementia, and psychosis, including if psychotic symptoms were active. Such factors potentially impact providers’ AP prescribing, both in frequency and type. Second, diagnoses were based on coding entered by health care providers, and these data could not be verified. Third, we only included patients with a comorbid psychosis diagnosis, which may have biased our sample toward those patients with more severe psychosis, as well as have obscured long-term changes in AP prescribing that others have reported for patients with dementia in general.20
Fourth, our results may not be generalizable to prescribing practices for psychosis in patients with PD outside the VA system, due to complex issues such as cost, formulary guidelines, and policies on who can prescribe APs. Fifth, because updated diagnostic criteria for dementia with Lewy bodies were not published until 2005,41
it is impossible to know what percentage of patients with PDP + D actually met clinical criteria for dementia with Lewy bodies.
Given the high frequency of psychosis and common use of APs in PD, as well as frequent comorbidity of dementia, additional research is needed to further understand what factors contribute to both overall and specific AP use in this population, and longitudinal studies should assess the impact of AP treatment on morbidity, mortality, and progression of parkinsonism.