Use of atypical antipsychotics (APs) to treat the behavioral symptoms of dementia is associated with an increased risk of morbidity and mortality, but the research to date is limited as it has been primarily conducted with patients with Alzheimer's disease. Parkinson's disease (PD) is the second most common neurodegenerative disease and dementing illness in the United States, with up to 80% of patients developing dementia and 60% psychosis. Although dementia, psychosis and AP use in PD are all common, little research has examined the morbidity or mortality risks associated with AP use in this population. To evaluate the risks of morbidity and mortality in PD patients taking APs, studies require large samples, statistical methodologies, and experience with large complex datasets. The Veterans Affairs (VA) Healthcare System has approximately 75,000 PD patients receiving care, has 6 national PD centers (PADRECC), and offers unmatched opportunities for large-scale assessments of treatment practices and patient outcomes.
The objectives of this study were to: (1) determine if AP use in PD is associated with increased morbidity; (2) determine if AP use in PD is associated with increased mortality; and (3) determine baseline moderators of morbidity and mortality risks associated with AP use in PD.
Our research team used a retrospective cohort (fiscal years 1999 - 2010) to address study objectives utilizing both national VA data registries and free-text clinical data from the VA electronic medical records for patients with PD who receive care at a PADRECC. For the primary analyses, we used a matched case-control design. Every PD patient who filled a new AP prescription was matched with a control PD patient who did not start an AP. Other matching variables included age, gender, race, index year, presence and duration of dementia, PD duration, delirium, hospitalization, Charlson Comorbidity Index, and new non-psychiatric medications. Secondary analyses examined other potential moderators of morbidity and mortality risks in PD patients initiating AP medication at a PADRECC.
The final sample for Aim 1 included 6,679 matched pairs of patients with PD who survived the 180-day follow-up period. Any AP use was associated with an increased risk of emergency room (ER) visit (ITT HR=1.64, 95% CI=1.51, 1.77, p<0.001), inpatient care (ITT HR=1.58, 95% CI=1.46, 1.71, p<0.001) and outpatient visits (ITT IRR=1.08, 95% CI=1.05, 1.12), p<0.001). The risk was significantly higher for atypical AP use compared with nonuse for all three morbidity outcomes, was similar for atypical and typical AP use, and was elevated for the use of atypical APs compared with nonuse on all three outcomes.
The final sample for Aim 2 included 7,877 matched pairs of patients with PD. AP use was associated with more than twice the hazard ratio (HR) of death compared with nonuse (ITT HR, 2.35; 95%CI, 2.08-2.66; P < .001). The HR was significantly higher for patients who used typical vs atypical APs (ITT HR, 1.54; 95%CI, 1.24-1.91; P < .001). Among the atypical APs used, HRs relative to nonuse of APs in descending order were 2.79 (95%CI, 1.97-3.96) for olanzapine, 2.46 (95%CI, 1.94-3.12) for risperidone, and 2.16 (95%CI, 1.88-2.48) for
The final sample for Aim 3 included 281 PD patients receiving care at a PADRECC and treated with an antipsychotic. A total of 19 patients (6.1% of the sample) died in the 180-day observation period. Severity of disease, psychiatric symptoms, cognitive impairment, swallowing problems, gait/balance disturbances, and orthostasis did not predict mortality in AP-treated patients. Although not statistically significant, we found moderate to severe PD as determined by H&Y score 3-5 (vs. less than 3) to be associated with 3.3 (p = 0.13) times higher risk of 180-day mortality even after adjusting for age, gender, race, marital status, # psych op visits, cholinesterase inhibitors use, COPD, and days in nursing home.
The recognition that AP use in PD is associated with increased risk of both morbidity and mortality will inform national policies and care practices, improving the care of Veterans with PD and co-morbid psychosis. The findings of this study highlights the need for cautious use of APs in patients with PD and the development of alternative treatment strategies.
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