Low Persistence of Antipsychotic Therapy in Parkinson Disease – Intolerance, Ineffectiveness, or Inertia?


 Background: Antipsychotics are used in Parkinson disease (PD) to treat psychosis, mood, and behavioral disturbances. Commonly used antipsychotics differ substantially in their potential to worsen motor symptoms through dopaminergic receptor blockade. Recent real-world data on the use and persistence of antipsychotic therapy in PD are lacking. The objectives of this study are to (1) examine the persistence to overall and initial antipsychotic therapy in individuals with PD and (2) determine whether persistence varies by drug dopamine receptor blocking activity.Methods: We conducted a retrospective cohort study using U.S. commercially insured individuals in Optum 2001-2019. Adults age 40 years or older with PD initiating antipsychotic therapy, with continuous insurance coverage for at least six months following drug initiation, were included. Exposure to pimavanserin, quetiapine, clozapine, aripiprazole, risperidone, or olanzapine was identified based on pharmacy claims. Six-month persistence to overall and initial antipsychotic therapy was estimated by time to complete discontinuation or switching to a different antipsychotic. Cox proportional hazards models evaluated factors associated with discontinuation.Results: Overall, 38.6% of 3,566 PD patients in our sample discontinued antipsychotic therapy after the first prescription, 61.4% continued with overall treatment within six months of initiation. Clozapine use was too rare to include in statistical analyses. Overall therapy discontinuation was more likely for medications with dopamine-receptor blocking activity (adjusted hazard ratios 1.76 [95% confidence interval 1.40-2.20] for quetiapine, 2.15 [1.61-2.86] for aripiprazole, 2.12 [1.66-2.72] for risperidone, and 2.07 1.60-2.67] for olanzapine), compared with serotonin receptor-specific pimavanserin. Initial antipsychotic therapy discontinuation also associated greater dopamine-receptor blocking activity medication use – adjusted hazard ratios 1.57 (95% confidence interval 1.28-1.94), 1.88 (1.43-2.46), 2.00 (1.59-2.52) and 2.03 (1.60-2.58) for quetiapine, aripiprazole, risperidone, and olanzapine, respectively, compared with pimavanserin. Similar results were observed in sensitivity analyses.Conclusions: Over one-third of individuals with PD stop antipsychotic therapy, especially if the initial drug has greater dopamine-receptor blocking activity. Understanding the drivers of antipsychotic discontinuation, including ineffectiveness, potentially inappropriate use, clinician inertia, patient adherence and adverse effects, is needed to inform clinical management of psychosis in PD and appropriate antipsychotic use in this population.


Background
Psychosis occurs in up to 60% of persons with Parkinson disease (PD), typically in later disease stages. [1][2][3] PD progression and treatment with dopaminergic medications are posited to drive PD psychosis (PDP) development; therefore, clinical guidelines recommend that outpatient PDP management begins with reducing or discontinuing anti-parkinsonian medications, if possible. [4] When additional measures are needed, antipsychotic (AP) therapy is recommended. [4,5] Pimavanserin recently became the rst AP approved by the United States (U.S.) Food and Drug Administration speci cally and solely for the PDP treatment. [4,5] However, second-generation or atypical AP -clozapine, quetiapine, risperidone, olanzapine, and aripiprazolehave long been prescribed off-label for PDP, [4][5][6][7] as well as for behavioral or mood disturbance in adults with neurodegenerative disease, [8][9][10] although use for the latter indications and in older adult populations is discouraged by clinical safety guidelines. [5,11,12] Safety and tolerance data for AP use in PD patients has traditionally focused on dopamine receptor antagonism leading to worsening of parkinsonism. Most APs have some dopamine type 2 (D2) receptor antagonism and can cause drug-induced parkinsonism and tardive dyskinesia, although this risk is less in atypical APs than in typical APs (e.g. haloperidol). [13][14][15] In contrast, pimavanserin is a selective serotonin type 2A (5-HT2A) inverse agonist, with negligible binding at almost all other receptors targeted by atypical APs, and thus is expected to treat psychosis symptoms in PD without worsening motor symptoms. [14,16] Data on the use and persistence of AP therapy in the PD population, which would be essential to understand clinical decision making and safety, is limited. [17][18][19] AP discontinuation or switching (i.e., non-persistence to AP therapy) could be due to adverse effects, resolution of a provoked psychosis, or failure to respond to AP therapy. [20,21] The objective of the current study is to determine (1) persistence to overall AP therapy (i.e., the continuation of AP therapy regardless of initial medication prescribed) and (2) persistence to initial AP therapy (i.e., the continuation of initial AP medication prescribed) and (3) the patient, clinical and medication factors associated with AP discontinuation among PD patients. Increasing our understanding of which PD patients potentially have treatment-resistant or transient psychosis will inform end-of-life care, clinical decisionmaking, and doctor-patient discussions.

Overview
We conducted a retrospective cohort study examining persistence to AP therapy in individuals with PDP, focusing on the most commonly prescribed atypical APs, [3] using a large U.S. commercial health insurance database. The O ce of Regulatory Affairs of the University of Pennsylvania (Philadelphia, PA) granted Institutional Review Board exemption for this study. All methods were performed in accordance with the relevant guidelines and regulations.

Data source
For this study, we used the 2001-2019 Optum™ Clinformatics™ Data Mart (Eden Prairie, Minnesota). [22] Optum contains health care claims data from over 60 million commercially-insured persons across the U.S. [22] Available data include sociodemographic information (e.g., age, sex, race, income level, education level, etc.), medical encounters (e.g., inpatient or emergency department [ED] visits), and pharmacy prescription claims and laboratory results, among others. [22] Optum represents the commercially-insured U.S. population, [23] allowing for a large-scale and diverse study of long-term medication use.

Inclusion and exclusion criteria
We identi ed new users of pimavanserin, quetiapine, risperidone, aripiprazole, clozapine, or olanzapine from January 1, 2001, until June 30, 2019, using National Drug Codes from Multum Medisource Lexicon (Denver, Colorado). New users were de ned as individuals without any prescription lls for any AP in the six-month baseline period before initiating one of the APs of interest. [24,25] Individuals with loss of insurance coverage within six months of the rst AP prescription were excluded. The rst qualifying AP prescription was required to have a supply of at least seven days, to minimize the potential for capturing planned short-term therapy.
Within this AP new user cohort, PD patients were identi ed as individuals (1) having at least two separate diagnosis claims for PD documented by International Classi cation of Diseases, 9th and 10th Revisions, Clinical Modi cation (ICD-9-CM and ICD-10-CM) diagnosis codes (i.e., 332, 332.0, and G20), [26,27] and (2) with PD diagnosis preceding AP therapy. We restricted our sample to individuals aged 40-90 years. We excluded individuals with concurrent diagnosis codes for atypical parkinsonian syndromes (multiple systems atrophy, progressive supranuclear palsy, corticobasal degeneration), amyotrophic lateral sclerosis, dementia with Lewy bodies, schizophrenia, and bipolar disorder (eTable 1) or, claims for long-term facility care within six months of starting AP therapy, because these groups would be expected to have differing clinical indications for and response to AP therapy.

Baseline covariates
Sociodemographic data, including age, sex, race/ethnicity (categorized as White, Black, Asian, Hispanic, unknown, or missing), and region of residence (i.e., Northeast, Midwest, South, West, or other) were captured at the time of the rst AP prescription ll.

Antipsychotic persistence
Overall persistence is de ned as the continuation of AP therapy after the rst AP prescription ll, regardless of the initial AP prescribed (i.e., patients are still considered persistent if there is switching to another AP). To examine overall persistence to AP therapy, we identi ed all AP prescription lls occurring up to six months after AP initiation using pharmacy claims dates in Optum. Time to discontinuation of AP treatment was calculated from the initial AP prescription claim date until the end date for the last AP prescription, allowing a standard 14-day grace period (i.e., prescription ll gap) between AP prescription lls. [24,[31][32][33] Individuals with no additional AP medication ll after the end of this grace period were categorized as discontinuing AP therapy.
We de ned persistence to initial therapy as a continuation of the same AP medication initially prescribed. Similar principles were applied to examine persistence to initial AP therapy. Time to switch to new AP drug was calculated from the pharmacy claim date of the initial prescription through the expected end date of the last prescription ll of that same agent (plus the standard allowed 14-day grace period). We only captured the rst prescription ll for a different AP; examining multiple switches was beyond the scope of this study and not in alignment with our study objectives.

Categorizing antipsychotics by dopamine receptor antagonism
We categorized the atypical APs based on published estimates of D2 receptor occupancy for a given AP dose. [15] Per the literature, among atypical APs used in PDP, quetiapine has the lowest a nity for the D2 receptor, followed by clozapine, aripiprazole, risperidone, with the highest D2 receptor antagonism measured in olanzapine. [15] We used pimavanserin users as the reference group as this drug is thought to have no measurable dopaminergic receptor antagonism. [14,16] Statistical analyses SAS v9.4 (Cary, North Carolina) was used to build the analytic dataset and analyze the study cohort. We de ned an alpha level of 0.05 for all statistical tests. Baseline characteristics were compared between new initiators of pimavanserin, quetiapine, aripiprazole, risperidone, and olanzapine, using Chi-square or Kruskal-Wallis tests for categorical and continuous variables, respectively. We constructed Cox proportional hazards models to examine the association of patient, clinical and drug factors on the risk of discontinuation of overall and initial AP therapy. Kaplan-Meier curves were used to illustrate persistence (i.e., freedom from discontinuation) to overall and initial AP therapy. To test the robustness of our initial ndings, we performed several sets of sensitivity analyses in which we (1) extended the follow-up period to 12 months after AP initiation and (2) extended the grace period for prescription re lls from 14 to 30 days, and (3) excluded all individuals with any ED or hospitalization within six months prior to initiation of AP therapy.

Individual baseline characteristics
We identi ed 3,566 individuals meeting our inclusion criteria:153 new users of pimavanserin, 2,452 of quetiapine, 169 of aripiprazole, 462 of risperidone, and 304 of olanzapine. Clozapine use was extremely rare (only 26 users satisfying our inclusion and exclusion criteria) and thus was excluded from further statistical analyses. Table 1  [aripiprazole]), and the distributions of race category and geographical region were similar across individual AP drugs (p = 0.268, and p = 0.194, respectively).

Discontinuation of overall antipsychotic therapy
Overall, 38.6% of 3,566 individuals in our PD sample discontinued AP therapy after the rst prescription; 61.4% continued with overall therapy within six months of initiation. As shown in Table 2, the six-month AP discontinuation rate varied by initial drug choice (p < 0.0001). Overall AP therapy discontinuation was lowest among pimavanserin initiators ( Fig. 1. The Kaplan-Meier curve for the length of time after initiation of APs of interest until discontinuation of overall AP therapy also showed a statistically signi cant difference in the freedom from discontinuation times between the ve groups (p < 0.0001) as shown in eFigure 1.

Persistence to initial antipsychotic therapy
Switching from one AP to another was much less common than stopping treatment altogether; almost 6.0% of subjects switched. AP drug changes occurred most frequently among initiators of olanzapine (10.5%), and least frequently among those taking quetiapine rst (4.9%). As shown in Table 3, persons prescribed pimavanserin, aripiprazole, risperidone, and olanzapine, who switched to another AP, overwhelmingly switched to quetiapine (91.7%, 75.0%, 66.7%, and 62.5%, respectively). PD patients initially prescribed quetiapine who switched were most often given risperidone (28.3%), pimavanserin (26.7%), or olanzapine (20.0%).  Discontinuation of initial AP inversely associated with age ≥ 80 (AHR 0.75, 95%CI 0.63-0.89), but did not associate race, sex, CFI, combined Charlson-Elixhauser comorbidity score, or incremental increases in recent average health care use. Both unadjusted and adjusted Cox proportional hazards models for the six-month follow-up and an allowable gap of 14 days between lls found a higher risk of discontinuation among PD patients initiated on quetiapine (hazard ratio  (Fig. 2). The Kaplan-Meier curve for the length of time after initiation of APs of interest until discontinuation of that speci c AP also showed a statistically signi cant difference in the freedom from discontinuation times between ve treatment options (p < 0.0001) as shown in eFigure 2.
Sensitivity analyses that expanded the observation window for discontinuation from 6 to12 months and the allowable re ll gap from 14 to 30 days yielded similar ndings as our primary analyses (eTables 2-7). Individuals who had no ED visits or hospitalizations in the six months prior to AP therapy initiation also had similar discontinuation rates.

Discussion
Psychotic symptoms in PD are relatively common and consistently associated with negative health outcomes such as caregiver stress, [34] nursing home placement, [2,35] and mortality. [35] Using real-world data, we examined the use of AP drugs most commonly prescribed to PD patients in the United States. Our primary ndings are (1) AP therapy is discontinued often and (2) AP therapy discontinuation and switching are greater among users of APs with complex receptor blocking properties, including greater dopamine-receptor blocking activity (i.e., quetiapine, aripiprazole, risperidone, and olanzapine), as compared to serotonin receptor-speci c pimavanserin.
Our nding that almost 40% of individuals with PD stop overall AP treatment after the rst prescription has multiple potential explanations. One potential explanation is an improvement in the symptoms for which the AP was prescribed. The rst step in the detection and diagnosis of psychosis is to identify treatable or transient triggers. Infection, illness, sleep disruption, depression can lead to reversible psychosis in older adults.
[36-38] Certainly, some of the PD patients in our sample could have had a psychosis cause identi ed and successfully addressed, with no need for long-term AP therapy. However, our sensitivity analyses suggested few patients in our sample had recent inpatient or emergent care that would reasonably be expected to associate with clinical indications for temporary AP therapy. In contrast, psychosis due to PD-related processes usually does not respond to attempts to wean the AP. [39] Adverse drug reactions may also have played a role in the AP use patterns we observed. APs with the highest dopaminereceptor blocking potential (i.e., aripiprazole, risperidone, and olanzapine) had the lowest persistence to therapy and highest switching rate as compared to pimavanserin and quetiapine; this nding could re ect drug intolerance or adverse effects. [13,14,40] Double-blind trials of olanzapine demonstrated no psychosis improvement and consistent worsening of motor function, even at low doses. [5,41] A meta-analysis of risperidone treatment reported that one-third of PD patients experienced increased motor dysfunction. [35,[42][43][44] Aripiprazole is thought to carry a lower risk of extrapyramidal adverse effects due to its high relative a nity for serotonergic receptors as compared to dopamine receptors; [13,14] however, emergent motor dysfunction in a single-arm open-label study of aripiprazole for PDP led to the study termination. [4,42,45,46] Others who discontinued AP therapy may have done so because of a lack of response, partial response, or failure to meet patient/caregiver response expectations.
AP therapy use for behavioral symptoms and insomnia is strongly discouraged in geriatric clinical guidelines because it is likely to be ineffective and cause adverse effects. [9,11,[47][48][49][50] Nevertheless, aborted trials of AP drugs for behavioral symptoms, such as agitation, pacing, yelling, sleep dysfunction, nocturnal restlessness, or insomnia, also likely account for a portion of the observed discontinuations. These symptoms are common in PD, especially in later disease stages, and cause signi cant caregiver distress.[8, 51,52] Pimavanserin may be less likely to be used for behavioral management, as U.S.
prescribers must provide medical documentation of psychosis as the reason for use. [53] If similar clinical documentation was required for all AP prescribing, the unmet need for management of behavioral and sleep disorders would become more evident, as would potentially inappropriate AP use. Future prospective studies will examine the frequency with which AP therapy is being used (in part or whole) for PD-related behavioral disturbances and measure clinical and safety outcomes associated with these off-label, potentially contraindicated uses.

Study strengths
Our study had several strengths. Using a large healthcare database of commercially insured individuals in the U.S. [22] enabled us to examine AP prescribing in a diverse PD population sample, including older adults, women, and minorities, groups that are usually excluded from clinical trials. Prescription lls are well-captured in claims data and are preferred over self-reported medication use for adherence and persistence studies; the latter are subject to reporting and desirability bias. [54] Our methods for eligibility, exposure, and outcome measures are standard for pharmacoepidemiologic studies of treatment adherence and persistence. [24,[31][32][33] Finally, our study provides comparative real-world data on all used medications, including the recently approved pimavanserin; such multi-drug comparisons are only possible using real-world observational data.

Study limitations
Despite these strengths, our study also has limitations. Optum contains commercially insured individuals, which often associates with younger age, fewer or less severe comorbid conditions, and higher average income. Newer, more expensive, or more interaction-prone AP drug choices may therefore be over-represented in our sample. Optum does not contain research instruments or clinical documentation (i.e., psychiatric evaluation results) of AP treatment response or the symptom pro le. To address this limitation, it might be reasonable to consider large electronic health record (EHR) databases, although retrospective analyses of EHR data will still be subject to reporting bias. [55] Psychosis may improve with cholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine), [4] metacognitive therapy, or electroconvulsive therapy,[56] but examining the use of these other treatment was beyond the scope of the current study. Finally, there was a potential for exposure misclassi cation due to the limited grace period allowed between prescription lls of APs.

Conclusions
Our study highlights that persistence to AP therapy is generally low in PD patients. Future studies are needed to parse the contributing effects of treatment intolerance or ineffectiveness, prescribing appropriateness, patient non-adherence, and symptom resolution on psychosis treatment patterns, thus opening better symptom control opportunities. Availability of data and materials: De-identi ed Optum data used in this study are available to any interested researchers for purchase.