Individual baseline characteristics
We identified 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 displays demographic, clinical, and health care use characteristics of the final study sample. Individuals initiating aripiprazole were the youngest with a median age of 72 years (interquartile range [IQR] 64–78), whereas risperidone users were the oldest at 78 years (IQR 72–83) at initiation (p < 0.0001). Male users were the majority for all AP medications except aripiprazole (68.0% female) and risperidone (51.3% female). The majority of PD patients using APs were white (range: 60.0% [risperidone] – 65.7% [aripiprazole]), and the distributions of race category and geographical region were similar across individual AP drugs (p = 0.268, and p = 0.194, respectively).
Table 1
Characteristics of individuals with Parkinson disease initiated on antipsychotic therapy, Optum 2001–2019
Characteristic Type
|
Pimavanserin
(n = 153)
|
Quetiapine
(n = 2,452)
|
Aripiprazole
(n = 169)
|
Risperidone
(n = 462)
|
Olanzapine
(n = 304)
|
p-value
|
Demographic
|
Age at initiation, years median (IQR)
|
75 (69–80)
|
77 (69–82)
|
72 (64–78)
|
78 (72–83)
|
76 (70–82)
|
< 0.0001‡
|
Age groups, n (col%)
|
|
|
|
|
|
< 0.0001†
|
40–59 years
|
4 (2.6)
|
166 (6.8)
|
18 (10.6)
|
21 (4.5)
|
22 (7.2)
|
|
60 to 79 years
|
108 (70.6)
|
1,389 (56.6)
|
119 (70.4)
|
249 (53.9)
|
179 (58.9)
|
|
≥80 years
|
41 (26.8)
|
897 (36.6)
|
32 (18.9)
|
192 (41.6)
|
103 (33.9)
|
|
Sex categories, n (col%)
|
|
|
|
|
|
< 0.0001†
|
Male
|
94 (61.4)
|
1,429 (58.3)
|
54 (32.0)
|
225 (48.7)
|
155 (51.0)
|
|
Female
|
59 (38.6)
|
1,023 (41.7)
|
115 (68.0)
|
237 (51.3)
|
149 (49.0)
|
|
Race categories, n (row%)
|
|
|
|
|
|
0.268†
|
White
|
96 (62.7)
|
1,542 (62.9)
|
111 (65.7)
|
277 (60.0)
|
198 (65.1)
|
|
Nonwhite
|
31 (20.3)
|
450 (18.3)
|
27 (16.0)
|
100 (21.6)
|
41 (13.5)
|
|
Unknown/Missing
|
26 (17.0)
|
460 (18.8)
|
31 (18.3)
|
85 (18.4)
|
65 (21.4)
|
|
Region, n (col %)
|
|
|
|
|
|
0.194†
|
Midwest
|
29 (18.3)
|
515 (21.0)
|
37 (21.9)
|
102 (22.1)
|
70 (23.0)
|
|
Northeast
|
12 (7.8)
|
287 (11.7)
|
22 (13.0)
|
63 (13.6)
|
31 (10.2)
|
|
South
|
70 (45.8)
|
984 (40.1)
|
81 (47.9)
|
183 (39.6)
|
115 (37.8)
|
|
West
|
42 (27.4)
|
657 (26.8)
|
29 (17.2)
|
114 (24.7)
|
88 (28.9)
|
|
Other
|
1 (0.6)
|
9 (0.4)
|
0 (0)
|
0 (0)
|
0 (0)
|
|
Clinical
|
Combined Charlson-Elixhauser comorbidity score, mean (SD)
|
1.6 (1.9)
|
1.9 (2.4)
|
1.9 (2.1)
|
2.2 (2.5)
|
2.2 (2.4)
|
0.0002‡
|
Claims-based frailty index, mean (SD)
|
0.20 (0.05)
|
0.22 (0.06)
|
0.22 (0.06)
|
0.23 (0.07)
|
0.23 (0.07)
|
< 0.0001‡
|
CFI categories, n (col%)
|
|
|
|
|
|
< 0.0001†
|
Robust
|
24 (15.7)
|
301 (12.3)
|
15 (8.9)
|
40 (8.7)
|
28 (9.2)
|
|
Prefrail
|
104 (68.0)
|
1,526 (62.2)
|
100 (59.2)
|
253 (54.8)
|
173 (56.9)
|
|
Mildly frail
|
20 (13.1)
|
514 (21.0)
|
48 (28.4)
|
149 (32.3)
|
84 (27.6)
|
|
Moderate to severely frail
|
5 (3.3)
|
111 (4.5)
|
6 (3.5)
|
20 (4.3)
|
19 (6.2)
|
|
Healthcare and medication use in 6 months prior to AP initiation
|
# Medications filled per month, mean (SD)
|
3.5 (1.8)
|
4.1 (2.4)
|
5.4 (2.7)
|
4.5 (2.5)
|
4.5 (2.5)
|
< 0.0001‡
|
# Neurology visits, mean (SD)
|
1.3 (1.2)
|
1.2 (1.6)
|
0.9 (1.2)
|
1.0 (2.7)
|
0.9 (1.3)
|
< 0.0001‡
|
# ED visits, mean (SD)
|
0.3 (0.7)
|
0.5 (1.4)
|
0.8 (2.5)
|
0.6 (1.2)
|
0.7 (2.2)
|
0.0484‡
|
# Inpatient admissions, mean (SD)
|
0.5 (3.3)
|
1.3 (4.0)
|
1.4 (3.6)
|
2.2 (6.9)
|
2.0 (5.1)
|
< 0.0001‡
|
AP: antipsychotic; CFI: claims-based frailty index; ED: emergency department; IQR: interquartile range; SD: standard deviation
† Chi-square for categorical variables; ‡ Kruskal-Wallis for continuous variables
|
The mean combined Charlson-Elixhauser comorbidity score differed significantly (p = 0.0002) across AP medications. However, the maximum difference of 0.6 points was well below the 2–3-point difference threshold associated with measurable variations in mortality and other health outcomes.[28, 29] Most study subjects met criteria for being “pre-frail” according to the CFI (54.8% [risperidone] – 68.0% [pimavanserin]). Quetiapine and pimavanserin users differed from initiators of the other APs by being more frequently categorized as “robust” (not frail) or “pre-frail” (p < 0.0001); having fewer ED visits and hospitalizations, more outpatient neurology visits, and fewer medications in the six months prior to AP initiation (p-values < 0.05).
Discontinuation of overall antipsychotic therapy
Overall, 38.6% of 3,566 individuals in our PD sample discontinued AP therapy after the first 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 (22.9%), and highest among individuals initially treated with risperidone (42.2%). The median time to discontinuation of overall AP therapy was greatest among individuals started on pimavanserin at 168 days (IQR 71–213), followed by persons started on quetiapine (96.5 days, IQR 44–203), aripiprazole (85 days, IQR 44–190), and olanzapine (78 days, IQR 44-193.5). Risperidone therapy initiators had the shortest duration of therapy (72 days, IQR 44–186).
Table 2
Treatment status after first antipsychotic prescription fill and time to discontinuation of overall antipsychotic therapy
|
Pimavanserin
(n = 153)
|
Quetiapine
(n = 2,452)
|
Aripiprazole
(n = 169)
|
Risperidone
(n = 462)
|
Olanzapine
(n = 304)
|
p-value
|
Treatment status after first AP prescription fill
|
Discontinued overall AP therapy, n (col%)
|
35 (22.9)
|
960 (39.1)
|
69 (40.8)
|
195 (42.2)
|
111 (36.5)
|
0.0006†
|
Persisted overall AP therapy, n (col%)
|
118 (77.1)
|
1,492 (60.8)
|
100 (59.2)
|
267 (57.8)
|
193 (63.5)
|
|
|
Continued initial AP drug
|
105 (68.6)
|
1,369 (55.8)
|
92 (54.4)
|
225 (48.7)
|
161 (53.0)
|
0.0005†
|
|
Switched to another AP medication
|
13 (8.5)
|
123 (5.0)
|
8 (4.7)
|
42 (9.1)
|
32 (10.5)
|
< 0.0001†
|
Median time to discontinuation of overall AP therapy, days (IQR)
|
168 (71–213)
|
96.5 (44–203)
|
85 (44–190)
|
72 (44–186)
|
78 (44-193.5)
|
< 0.0001‡
|
Average supply of initial AP Rx, days (SD)
|
32.8 (12.6)
|
35.8 (19.8)
|
37.6 (22.2)
|
32.0 (15.5)
|
33.7 (19.4)
|
0.0007‡
|
AP: antipsychotic; ED: emergency department; IQR: interquartile range; Rx: prescription; SD: standard deviation
† Chi-square for categorical variables; ‡ Kruskal-Wallis for continuous variables
|
Overall AP discontinuation was less likely in higher age groups as compared to those ages < 60: adjusted hazard ratios (AHRs) 0.83 (95%CI 0.70–0.97) in the 60–79 years group and 0.73 (95%CI 0.62–0.87) in the ≥ 80 years group, as well as in females (AHR 0.89, 95%CI 0.89–0.97) as compared to males. Increasing frequency of ED or outpatient neurology visits associated with a slightly higher risk of discontinuation (AHRs 1.04, 95%CI 1.01–1.08, and 1.03, 95%CI 1.01–1.05, respectively). After adjusting for study covariates, the estimated AHRs for overall AP discontinuation were 1.76 (95% CI 1.40–2.20) for quetiapine, 2.15 (95%CI 1.61–2.86) for aripiprazole, 2.12 (95%CI 1.66–2.72) for risperidone, 2.07 (95%CI 1.60–2.67) for olanzapine as compared to pimavanserin, as shown in 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 significant difference in the freedom from discontinuation times between the five 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 first (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%).
Table 3
Switching proportion and patterns from initial therapy within 6 months, stratified by initial antipsychotic prescribed
Initial Agent
|
Switched,
n (row%)
|
Switching to drug, n (row %)
|
P
|
Q
|
A
|
R
|
O
|
Other antipsychotic
|
Pimavanserin
(n = 153)
|
12 (7.8)
|
-
|
11 (91.7)
|
0 (0)
|
0 (0)
|
0 (0)
|
1 (8.3)
|
Quetiapine
(n = 2,452)
|
120 (4.9)
|
32 (26.7)
|
-
|
6 (5.0)
|
34 (28.3)
|
24 (20.0)
|
24 (20.0)
|
Aripiprazole
(n = 169)
|
8 (4.7)
|
0 (0)
|
6 (75.0)
|
-
|
1 (12.5)
|
1 (12.5)
|
0 (0)
|
Risperidone
(n = 462)
|
39 (8.4)
|
0 (0)
|
26 (66.7)
|
2 (5.1)
|
-
|
7 (17.9)
|
4 (10.3)
|
Olanzapine
(n = 304)
|
32 (10.5)
|
2 (6.2)
|
20 (62.5)
|
1 (3.1)
|
6 (18.7)
|
-
|
3 (9.4)
|
A: aripiprazole; O: olanzapine; P: pimavanserin; Q: quetiapine; R: risperidone
|
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 fills found a higher risk of discontinuation among PD patients initiated on quetiapine (hazard ratio [HR] 1.44, 95%CI 1.17–1.79; AHR 1.57, 95%CI 1.28–1.94), aripiprazole (HR 1.61, 95%CI 1.23–2.12; AHR 1.88, 95%CI 1.43–2.46), risperidone (HR 1.87, 95%CI 1.48–2.36; AHR 2.00, 95%CI 1.59–2.52), and olanzapine (HR 1.86, 95%CI 1.45–2.37; AHR 2.03, 95%CI 1.60–2.58) as compared to pimavanserin (Fig. 2). The Kaplan-Meier curve for the length of time after initiation of APs of interest until discontinuation of that specific AP also showed a statistically significant difference in the freedom from discontinuation times between five 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 refill gap from 14 to 30 days yielded similar findings 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.