International Journal of Neuropsychopharmacology, 2024, 27, 1–11

https://doi.org/10.1093/ijnp/pyad067
Advance access publication 1 February 2024
Regular Research Article

Regular Research Article

Relapse Rates With Paliperidone Palmitate in Adult

Patients With Schizophrenia: Results for the 6-Month
Formulation From an Open-label Extension Study
Compared to Real-World Data for the 1-Month and
3-Month Formulations
Ibrahim Turkoz, Mehmet Daskiran, Uzma Siddiqui, R. Karl Knight, Karen L Johnston, Christoph U. Correll

Janssen Research & Development, LLC, Titusville, NJ, USA (Drs Turkoz, Daskiran, Siddiqui, and Knight); 2Janssen Scientific Affairs, LLC, Titusville, New Jersey, USA (Dr
Johnston); Zucker Hillside Hospital, Department of Psychiatry, Glen Oaks, New York, USA (Dr Correll); Donald and Barbara Zucker School of Medicine at Hofestra/
Northwell, Department of Psychiatry and Molecular Medicine, Hempstead, New York, USA (Dr Correll); Charité – Universitätsmedizin, Berlin, Department of Child
and Adolescent Psychiatry, Germany (Dr Correll).
Correspondence: Ibrahim Turkoz, PhD, Janssen Research & Development, LLC 1125 Trenton-Harbourton Road Titusville, NJ, 08560, USA (Itukoz@its.jnj.com).

Abstract
Background: The 3 paliperidone palmitate (PP) long-acting injectable antipsychotic formulations, PP 1-month (PP1M), PP 3-month
(PP3M), and PP 6-month (PP6M), have shown to reduce the risk of relapse in schizophrenia. The current phase-4 study constructed
external comparator arms (ECAs) using real-world data for PP3M and PP1M and compared relapse prevention rates with PP6M from
an open-label extension (OLE) study in adult patients with schizophrenia.
Methods: PP6M data were derived from a single-arm, 24-month, OLE study (NCT04072575), which included patients with schizophre-
nia who completed a 12-month randomized, double-blind, noninferiority, phase-3 study (NCT03345342) without relapse. Patients in
the PP3M and PP1M ECAs were identified from the IBM® MarketScan® Multistate Medicaid Database based on similar eligibility criteria
as the PP6M cohort.
Results: A total of 178 patients were included in each cohort following propensity score matching. Most patients were men (>70%;
mean age: 39–41 years). Time to relapse (primary analysis based on Kaplan-Meier estimates) was significantly delayed in the PP6M
cohort (P < .001, log-rank test). The relapse rate was lower in the PP6M cohort (3.9%) vs PP3M (20.2%) and PP1M (29.8%) cohorts. Risk of
relapse decreased significantly (P < .001) by 82% for PP6M vs PP3M (HR = 0.18 [95% CI = 0.08 to 0.40]), 89% for PP6M vs PP1M (HR = 0.11
[0.05 to 0.25]), and 35% for PP3M vs PP1M (HR = 0.65 [0.42 to 0.99]; P = .043). Sensitivity analysis confirmed findings from the primary
analysis. Although the ECAs were matched to mimic the characteristics of the PP6M cohort, heterogeneity between the groups could
exist due to factors including prior study participation, unmeasured confounders, variations in data capture and quality, and com-
pleteness of clinical information.
Conclusions: In a clinical trial setting, PP6M significantly delayed time to relapse and demonstrated lower relapse rates compared
with PP3M and PP1M treatments in real-world settings among adult patients with schizophrenia.
Trial registration: ClinicalTrials.gov Identifier: NCT04072575; EudraCT number: 2018-004532-30

Keywords: Paliperidone palmitate 6-month, paliperidone palmitate 3-month, paliperidone palmitate 1-month, real-world data,
relapse prevention, schizophrenia

Significance Statement

Paliperidone palmitate (PP), an injectable antipsychotic medicine used to treat schizophrenia, decreases relapse risk (reappearance
of clinically relevant symptoms). Relapse prevention rates of PP 6-month (PP6M), an injection administered once every 6 months,
were compared with PP 3-month (PP3M; administered once every 3 months) and PP 1-month (PP1M; administered once every
month). Data for PP6M were derived from a single-arm phase-3 clinical study in adults with schizophrenia. Data for PP3M and PP1M
were obtained from the IBM® MarketScan® Multistate Medicaid Database, which collects real-life, routine medical and healthcare
service use data for individuals enrolled in the US Medicaid program. The study showed that the longer-acting PP6M (in a clinical

Received for publication: July 28, 2023. Accepted: XXX XX, XXX. Editorial decision: December 12, 2023.
© The Author(s) 2024. Published by Oxford University Press on behalf of CINP.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which
permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
2 | International Journal of Neuropsychopharmacology, 2024, Vol. 27, No. 2
trial setting) substantially delayed the time to occurrence of relapse, with fewer patients experiencing relapse (3.9%) compared
with the shorter-acting PP3M (20.2%) and PP1M (29.8%) in routine treatment settings among adults with schizophrenia. These find-
ings could aid doctors’ treatment choices for maintaining effective therapy in patients with schizophrenia.
INTRODUCTION
Relapses in schizophrenia increase the risk of treatment refrac-
toriness, impose further stigmatization on patients, and have
detrimental effects on the overall disease trajectory (Emsley
et al., 2013). Nonadherence to schizophrenia medications
resulting in treatment discontinuation is recognized as one
of the primary risk factors for relapse (Robinson et al., 1999;
Kemmler et al., 2005; Novick et al., 2010). Addressing nonadher-
ence has proven to be a catalyst in developing safe and effec-
tive long-acting injectable (LAI) antipsychotics. Unlike their oral
counterparts, LAI antipsychotics allow for less frequent dosing
and facilitate adherence by providing reliable medication deliv-
ery, predictable pharmacokinetics, and transparent monitoring
(Agid et al., 2010; Brissos et al., 2014; Correll et al., 2016). An
updated systematic review and meta-analysis comparing LAIs
with oral antipsychotics reported a significantly lower risk of
hospitalization or relapse with LAI use (29 RCTs: risk ratio [RR] =
0.88 [95% CI .79 to .99], P = .033; 44 cohort studies: RR = 0.92 [0.88
to 0.98]; 28 pre-post studies: RR 0.44 [0.39 to 0.51], P < .0001)
(Kishimoto et al., 2021).
Recent real-world studies have also reported reductions in
hospital readmission rates and emergency room visits with LAI
treatment versus oral antipsychotics, with evidence supporting
a reduced healthcare burden of schizophrenia (Kim et al., 2020;
Latorre et al., 2020). Furthermore, a systematic review of 19 clini-
cal practice guidelines reported consistent agreement in terms of
LAI treatment, with 13 guidelines recommending LAIs as main-
tenance therapy and 5 advocating LAI use in patients with first-­
episode schizophrenia (Correll et al., 2022). The use of LAIs has
also been associated with improvements in tangible measures
such as daily functioning and quality-of-life that are often valued
by patients and encourage treatment adherence (Kaplan et al.,
2013; Brissos et al., 2014; Correll et al., 2016; Blackwood et al.,
2020).
Paliperidone palmitate 1-month (PP1M) and 3-month (PP3M)
LAI formulations have shown meaningful symptomatic control,
functional improvements, and reductions in hospitalization and
relapse rates in several clinical studies (Gopal et al., 2010; Hough
et al., 2010; Berwaerts et al., 2015; Savitz et al., 2016; Di Lorenzo
et al., 2018). Evidence from real-world studies also suggests that
PP1M and PP3M are more effective than oral antipsychotics in
delaying time to relapse or treatment failure (Alphs et al., 2015;
Emond et al., 2019a; Patel et al., 2020; Segarra et al., 2021).
The PP6M LAI formulation was developed to provide an
extended dosing window of 6 months and is currently the first
and only available twice-yearly treatment for adults living
with schizophrenia (Milz et al., 2023). PP6M is approved for the
maintenance treatment of schizophrenia in adult patients who
have been clinically stabilized on PP1M or PP3M. In a 12-month,
double-blind (DB), randomized, noninferiority phase 3 study, 2
sequential injections of PP6M demonstrated comparable efficacy
to PP3M in preventing schizophrenia relapses without raising any
new safety concerns (Najarian et al., 2022). Subsequently, the
long-term efficacy of PP6M with low relapse rates (3.9%) over 2
years was reported in a phase 3, single-arm, open-label extension
(OLE) study (Najarian et al., 2023). Investigating the comparative
efficacy of PP6M versus PP3M and PP1M will provide insights into
the clinical benefits of longer dosing intervals and fewer injec-
tions in preventing relapses in patients with schizophrenia.
The present phase 4 study was designed to leverage real-world
data (RWD) in extending the interpretability of clinical study
findings and generate comparative analysis to inform clinical
­decision-making. Thus, external comparator arms (ECAs) were
created for PP1M and PP3M by utilizing RWD from the IBM®
MarketScan® Multistate Medicaid Database (IBM MDCD) while
PP6M data were obtained from the phase 3 OLE study. The pri-
mary objective was to compare the effectiveness of PP6M, PP3M,
and PP1M formulations in delaying and preventing relapse among
adult patients with schizophrenia.
METHODS
Study Design and Data Sources
This retrospective phase 4 study derived data for PP6M from
a 24-month, single-arm, phase 3 OLE study (NCT04072575)
(Najarian et al., 2023). The administrative claims data from the
IBM MDCD were used to extract data for the PP1M and PP3M
cohorts that served as the ECAs. The IBM MDCD contains health-
care claims data including coverage eligibility and service use for
individuals enrolled in Medicaid or Medicaid-managed programs
in the United States. The database contains records pertaining
to enrollment (e.g., medical and prescription records of enroll-
ment, including patient demographics and plan type), inpatient
and outpatient services, long-term care (i.e., medical and phar-
macy claims), and financial information for more than 10 million
Medicaid beneficiaries from 10 states.
All cohorts included patients who received moderate or high
doses of PP1M, PP3M, or PP6M injections. Patients were assigned
to 1 of the 2 dose categories based on their PP injection dose at
study entry (supplementary Table 1).
The index date for the PP6M cohort was the start date
(September 2019) of the OLE phase, and the end of the 12-month
DB phase of the phase 3 study (NCT03345342) was considered the
baseline period. The data collection period for the PP1M and PP3M
cohorts was from January 1, 2017, until the end of available IBM
MDCD data (last patient out December 2021) (Fig. 1). The date of
the first eligible claim for PP1M or PP3M injection was deemed
as the index date for the PP1M and PP3M cohorts. The baseline
period for these cohorts was considered as the period between
the index PP injection date and up to 12 months before this date.
All patients had continuous medical and prescription coverage
based on their insurance enrollment records during this period.
The study follow-up period for all 3 cohorts was up to 24 months
after the respective index dates. The IBM MDCD patients were
required to have at least 1-year pre-index (baseline) and 1-year
post-index continuous medical and drug coverage.
Ethical Practices
The OLE study was conducted in accordance with the Declaration
of Helsinki and applicable local laws and regulations; the study
protocol was approved by an independent ethics committee or
institutional review board. The present phase 4 study involved
 Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia | 3

Figure 1. Study design. IBM MDCD, IBM MarketScan Multistate Medicaid Database; mo, month; PP1M, paliperidone palmitate 1-month formulation;
PP3M, paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation; RWD, real-world data; Rx, treatment.

retrospective analyses of clinical study data and de-identified medical and prescription Medicaid insurance coverage before and
data from a claims database and is not considered human sub- after their index PP injection. Patients were included in the PP3M
ject research. Therefore, an institutional review board approval or cohort if they received continuous treatment with PP1M or PP3M
waiver was not required, and the study was exempted from the for ≥6 months before the index PP3M date. The last 2 doses of
Health Insurance Portability and Accountability Act requirements. PP1M and first dose of PP3M were required to be the same and/or
equivalent to the index PP3M dose. Similarly, patients in the PP1M
Patients cohort were included if they received continuous treatment with
PP1M for ≥6 months before the index PP1M date. Subsequently,
The PP6M cohort included patients who were transitioned from
patients in the PP3M cohort received ≥2 injections, and those in
a randomized, DB, noninferiority phase study of PP6M (Najarian
the PP1M cohort received ≥5 injections after the corresponding
et al., 2022) and met the eligibility criteria for the OLE study
index dates (supplementary Table 2). This criterion was incor-
(Najarian et al., 2023). The DB phase 3 study included patients
porated to mimic the high completion rate observed in the OLE
aged 18 to 70 years with a diagnosis of schizophrenia (per the
study (Najarian et al., 2023).
DSM-5) for ≥6 months before screening and a Positive and
Patients who met any of the following criteria were excluded
Negative Syndrome Scale total score of <70 points (no minimum
from the study: treatment with antipsychotics other than PP LAI
cut-off) at screening. Patients were eligible for the OLE study if
within the 6-month pre-index date except for injectable risperi-
they had completed the 12-month DB phase without relapse,
done; diagnosis of autism, dementia, manic episode, or bipolar
were willing to continue PP6M treatment, were deemed able to
disorder before the index date; the presence of any severe chronic
continue treatment at the same dose level (moderate or higher
conditions, such as diabetes with complications, cancer, heart
dose) as used during the DB phase of the noninferiority study at
conditions, coagulation disorders, or hematologic, pulmonary,
the time of screening for the OLE study, and were able to partici-
thyroid, or renal diseases; body mass index >40 (morbidly obese
pate for the duration of the study.
patients); clozapine use within 2 months of the index date for
Eligible patients in the PP3M and PP1M cohorts from the IBM
PP injection. Patients enrolled with “medical insurance only” or
MDCD were selected using similar inclusion and exclusion criteria
indicating dual eligibility (both Medicare and Medicaid) were not
as the PP6M cohort. The International Classification of Diseases
included in the analysis.
procedure codes were identified and applied to create inclusion
and/or exclusion criteria concepts. Eligible patients were ≥18
years of age (at index PP injection), received medium-/high-dose Propensity Score Matching (PSM)
PP injections during the study period, were relapse-free during PSM was used to enable adjusted comparisons between the
the 12-month baseline period, and had ≥1 year of continuous cohorts and create a homogeneous subset of patients from the
4 | International Journal of Neuropsychopharmacology, 2024, Vol. 27, No. 2
large real-world database, similar to patients from the phase
3 PP6M OLE study based on selected covariates. PSM was per-
formed in the following order: PP3M-PP1M, PP6M-PP3M, and
PP6M-PP1M. The propensity score model included covariates
shown to affect both treatment assignment and outcomes as
predictors.
For the PP3M-PP1M matching, all eligible PP3M and PP1M
patients from the IBM MDCD database were included in the
matching process. Propensity scores were calculated using the
following factors: exact matching categories (index drug dose, age
category, sex) and others (race, presence of baseline depressive
disorder, Charlson Comorbidity Index score categories [0, 1 and
>1], and Elixhauser Comorbidity Index score categories [0, 1, 2, 3
and >3]). The comorbidity scores were calculated using a medical
coding algorithm (Quan et al., 2005). Patients were matched using
a 1-to-1 nearest neighbor matching algorithm with a caliper of 0.2
SDs without replacement, such that the index drug dose, gender,
and age category were an exact match. The success of matching
was assessed using the standardized mean differences (SMD) for
each covariate and SMDs before and after matching were com-
pared. An SMD up to 0.20 was considered acceptable, and an
SMD <0.10 was deemed a good match (Austin, 2014).
All PP6M patients were matched with the PP3M patients who
were previously matched with eligible PP1M patients from the
IBM MDCD database. Propensity scores were calculated using the
relevant covariates chosen based on previous clinical findings
and included PP dose, gender, and age categories. PP1M patients
were then mapped to PP6M patients based on the previous PP6M-
PP3M and PP3M-PP1M propensity scores.
Relapse Analysis
The primary endpoint for the study was the time to first relapse.
A relapse event was defined as the time to first occurrence of at
least 1 or a combination of the following events during the study:
psychiatric inpatient hospitalization for schizophrenia (involun-
tary or voluntary admission to a psychiatric hospital for decom-
pensation of the patient’s schizophrenia symptoms); emergency
room visits for worsening symptoms of schizophrenia not leading
to a hospital admission (only PP6M cohort); self-injury or vio-
lent behavior resulting in a suicide attempt or injury to another
person or significant property damage; suicidal or homicidal
ideation. Emergency room visits that did not lead to a psychiat-
ric hospitalization were not considered as relapse events in the
PP3M and PP1M real-world cohorts because the visits could be
for a variety of acute or surgical or medical reasons other than
worsening of schizophrenia symptoms per se. For all 3 cohorts,
if a patient relapsed, days to relapse were calculated based on
the difference between the event date minus the index date +1.
Patients who did not experience a relapse were censored.
Statistical Analyses
No formal sample size determination was performed for this
study. The primary analysis was based on a 1: 1: 1 greedy PSM
approach. Kaplan-Meier survival curves were used to describe
time to first relapse distributions in the 3 matched cohorts, and
the reasons for relapses were summarized. Comparative anal-
ysis between the cohorts was based on log-rank test statistics.
Hazard ratio (HR) and 95% confidence interval (CI) from the Cox
proportional hazards models were computed to describe reduc-
tion in risk of relapses. The primary analysis was performed using
the intent-to-treat analysis set, which included all patients who
received PP6M during the phase 3 OLE study and matched PP3M
and PP1M patients from IBM MDCD.
Robustness of the primary analysis was assessed using a
sensitivity analysis based on a 1: 2: 2 matching ratio and a PSM
approach, similar to the primary analysis. Model-based sensitiv-
ity analyses were also conducted to assess to what extent the
primary analytical results become null using multi-bias E-value.
The multi-bias E-value describes the minimum value that all of
the sensitivity parameters for outcome misclassification, meas-
urement error, and selection biases would have to take on for a
calculated HR to be compatible with a truly null HR.
RESULTS
Propensity Score Matching
The propensity score distribution was almost identical for the
PP3M-PP1M, PP6M-PP3M, and PP6M-PP1M cohorts following PSM
(Fig. 2). Using a 1: 1: 1 propensity score matching, 178 patients
from each of the PP6M, PP3M, and PP1M cohorts who were the
closest in propensity score values to their counterparts were
selected for the primary analysis. Results indicated that after
matching, the PP3M and PP1M cohorts derived from the RWD had
comparable baseline patient characteristics to the PP6M cohort
and therefore were used as ECAs in the study.
Patient Disposition
A total of 178 patients from the DB phase 3 study who completed
the 12-month DB phase were enrolled in the phase 3 OLE study
as the PP6M cohort. All 178 patients enrolled in the OLE study
were treated with at least 1 dose of PP6M and included in the
primary analysis of the current study; of the 178 patients, 154
(86.5%) completed the study (supplementary Figure 1).
A total of 747 patients on PP3M and 1739 patients on PP1M from
the IBM MDCD were included in the study, of which 736 patients
from each cohort were successfully matched (PP3M-PP1M match-
ing). After the subsequent PSM, 178 patients from each of the
PP3M and PP1M cohorts were matched with the PP6M patients,
serving as the ECAs for the primary analysis. In each of the PP3M
and PP1M cohorts, a total of 128/178 patients (71.9%) completed
the study. Patient withdrawal information for the PP3M and PP1M
cohorts was not available, and patients could not complete the
study due to either interruption in 2-year Medicaid eligibility or
2-year post-index data availability in the claims database.
Demographics
Patient demographics before and after propensity matching were
generally similar across the 3 cohorts (Table 1). The majority of
SMDs post matching were <0.1, indicating well-balanced and
optimally matched cohorts, with the largest SMD being 0.176,
indicating an acceptable match. Patients included in the pri-
mary analysis had similar median ages of 40 (PP6M), 41 (PP3M),
and 39 (PP1M) years. The majority of patients were men (>70%),
and a high proportion of patients received high-PP index doses
(>60%) across all 3 cohorts. The mean duration of total drug expo-
sure was 682.1, 571.9, and 526.3 days for PP6M, PP3M, and PP1M,
respectively.
Primary Analysis for Relapse
During the 2-year follow-up period, treatment with PP6M was
associated with a significantly lower risk of relapse compared
with PP3M and PP1M treatment. Patients in the PP6M cohort
experienced a significant delay in time to relapse (P < .001), and
 Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia | 5

Figure 2. (A) PP3M and PP1M. (B) PP6M and PP3M propensity score distribution before and after PSM. PP1M, paliperidone palmitate 1-month
formulation; PP3M, paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation; PSM, propensity score
matching.

the median time to relapse was not estimable for all 3 cohorts
during the study period (Table 2; Figure 3). Overall, 3.9% (7/178)
of patients in the PP6M cohort, 20.2% (36/178) in the PP3M cohort,
and 29.8% (53/178) in the PP1M cohort experienced a relapse
event. Risk of relapse decreased by 82% for PP6M vs PP3M (HR:
0.18 [95% CI: .08 to .40]; P < .001), 89% for PP6M vs PP1M (HR: 0.11
[95% CI: .05 to .25]; P < .001), and 35% for PP3M versus PP1M (HR:
0.65 [95% CI: .42 to .99]; P = .043). Psychiatric hospitalization was
the most common reason for relapse in all 3 cohorts (PP6M: 2.2%;
PP3M: 14.0%; PP1M: 25.8%) (Table 3).
Sensitivity Analysis for Relapse
PSM for the sensitivity analysis was performed using a 1: 2: 2
matching ratio and resulted in a final sample of 178 in the PP6M
cohort and 356 patients each in the PP3M and PP1M cohorts. A
total of 248/356 patients on PP3M (69.7%) and 247/356 patients
on PP1M (69.4%) completed the study in the sensitivity analysis.
Baseline patient characteristics for the sensitivity analyses before
and after PSM were well-balanced across the 3 cohorts and com-
parable with the primary analysis (supplementary Table 3).
Results from the sensitivity analysis revealed similar trends
of relapse rates and time to relapse as observed in the primary
analysis (Table 2; Figure 4). Treatment with PP6M was associated
with a significantly lower relative risk of relapse compared with
the PP3M (HR 0.17; P < .001) and PP1M cohorts (HR 0.13; P < .001).
Relative risk between the PP3M and PP1M cohorts did not sig-
nificantly differ (HR 0.76; P = .074). The rates of and reasons for
first relapse were consistent with the primary intent-to-treat
6 | International Journal of Neuropsychopharmacology, 2024, Vol. 27, No. 2

Table 1. Demographic and baseline characteristics of patients in the PP6M, PP3M, and PP1M cohorts before and after PSM (ITT
population)

Parameter Before PSM After PSM

PP6M PP3M PP1M PP6M PP3M PP1M

n = 178 n = 736 n = 736 n = 178 n = 178 n = 178

Sex, n (%)
 Women 52 (29.2) 137 (18.6) 137 (18.6) 52 (29.2) 44 (24.7) 44 (24.7)
 Men 126 (70.8) 599 (81.4) 599 (81.4) 126 (70.8) 134 (75.3) 134 (75.3)
 SMD PP1M vs PP6M vs PP3M 0.250 0.000 0.101 0.000
 SMD PP3M vs PP6M 0.250 0.101
Age category, n (%)
18–25 y 10 (5.6) 93 (12.6) 93 (12.6) 10 (5.6) 9 (5.1) 9 (5.1)
 SMD PP1M vs PP6M vs PP3M −0.246 0.000 0.025 0.000
 SMD PP3M vs PP6M −0.246 0.025
26–50 y 135 (75.8) 527 (71.6) 527 (71.6) 135 (75.8) 138 (77.5) 138 (77.5)
 SMD PP1M vs PP6M vs PP3M 0.096 0.000 −0.040 0.000
 SMD PP3M vs PP6M 0.096 −0.040
≥50 y 33 (18.5) 116 (15.8) 116 (15.8) 33 (15.8) 31 (17.4) 31 (17.4)
 SMD PP1M vs PP6M vs PP3M 0.074 0.000 0.029 0.000
 SMD PP3M vs PP6M 0.074 0.029
Index PP dose, n (%)
 High 113 (63.5) 393 (53.4) 393 (53.4) 113 (63.5) 113 (63.5) 113 (63.5)
 Moderate 65 (36.5) 343 (46.6) 343 (46.6) 65 (36.5) 65 (36.5) 65 (36.5)
 SMD PP1M vs PP6M vs PP3M 0.206 0.000 0.000 0.000
 SMD PP3M vs PP6M 0.206 0.000
Age
 Mean (SD), y 40 (10.8) 37 (11.2) 37 (11.2) 40 (10.8) 41 (10.2) 39 (10.6)
 SMD PP1M vs PP6M vs PP3M 0.301 0.000 0.152 0.176
 SMD PP3M vs PP6M 0.300 −0.019

Abbreviations: ITT, intent-to-treat; PP, paliperidone palmitate; PP1M, paliperidone palmitate 1-month formulation; PP3M, paliperidone palmitate 3-month
formulation; PP6M, paliperidone palmitate 6-month formulation; PSM, propensity score matching; SMD, standardized mean differences.

population, with the most common reason being psychiatric hos-
pitalization (PP6M: 2.2%; PP3M: 16.6%; PP1M: 20.8%).
The multi-bias E-value was 3.05 for the calculated HR of 0.18
between PP6M vs PP3M. This E-value implies that all 3 parameters
for each of the 3 assumed sources of bias (outcome misclassifica-
tion, measurement error, and selection bias) would have to take a
value of 3.05 for the observed HR between PP6M vs PP3M of 0.18
to be compatible with a true null effect. Similarly, a multi-bias
E-value was 3.99 for the calculated HR of 0.11 between PP6M vs
PP1M.
DISCUSSION
This phase 4 study compared the effectiveness of PP6M with its
shorter-acting counterparts, PP1M and PP3M, in delaying and pre-
venting relapse among adult patients with schizophrenia. The
present study is among the first few to construct ECAs (PP3M
and PP1M cohorts) using RWD, enabling comparison of PP6M
from an OLE study with PP3M and PP1M (Turkoz et al., 2023). The
PSM yielded well-matched cohorts of PP6M, PP3M, and PP1M that
were used for comparative analysis. Treatment with PP6M during
the phase 3 OLE study significantly delayed time to relapse and
was associated with a lower relapse rate (3.9%) compared with
the matched real-world PP3M (20.2%) and PP1M (29.8%) arms.
Supporting this finding, PP6M also demonstrated a clear advan-
tage in terms of relapse prevention and showed the greatest
magnitude of reduction in risk of relapses compared with PP3M
and PP1M. The sensitivity analysis using less restrictive matching
criteria included more patients in the ECA cohorts and yielded
consistent results for PP6M, further substantiating the primary
findings.
Over the years, injectable antipsychotic formulations with
longer half-lives have been developed to provide extended
medication exposure and potentially delay relapses even after
treatment interruptions. Corroborating this hypothesis, a post
hoc analysis reported longer relapse-free periods in patients
who withdrew PP3M (13 months) compared with PP1M (6
months) or oral paliperidone extended-release formulation (2
months), with a significantly lower risk of relapse for PP3M vs
PP1M (P < .001; Weiden et al., 2017). Pragmatic evidence from
real-world studies has also shown the benefits of continuous
medication exposure with LAI antipsychotics for improving
medication adherence and lowering the rates of discontinua-
tion and relapse in schizophrenia. In a retrospective analysis of
health claims data from the IBM MDCD, patients in the PP3M
vs PP1M cohort reported higher rates of adherence in terms of
proportion of days covered (87% vs 78%; P < .0001) and corre-
sponding lower relapse rates (10.5% vs 15.7%; Li et al., 2021).
Similar analyses conducted with commercially insured patients
who transitioned from PP1M to PP3M have reported compara-
ble trends of improved adherence and treatment persistence
and reduced healthcare resource utilization for schizophrenia
and other comorbidities (Joshi et al., 2017; DerSarkissian et al.,
2018; Emond et al., 2019b; Lin et al., 2021). Taken together, these
 Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia | 7

Table 2. Risk of relapse analysis

PP6M PP3M PP1M

(n = 178) (n = 178) (n = 178)

Primary analysis (ITT population)

Number assessed 178 178 178
Number censored (%) 171 (96.1) 142 (79.8) 125 (70.2)
Number of relapse (%) 7 (3.9) 36 (20.2) 53 (29.8)
Time to relapse (days)a
 25% percentile (95% CI) NE NE NE
 Median (95% CI) NE NE NE
 75% percentile (95% CI) NE NE NE
Relative risk, HR (95 % CI)
 PP6M vs PP3M and PP1M — 0.18 (0.08, 0.40) 0.11 (0.05, 0.25)
 p-value — <0.001 <0.001
 PP3M vs PP1M 0.65 (0.42, 0.99)
 p-value 0.043
PP6M PP3M PP1M
(n = 178) (n = 356) (n = 356)

Sensitivity analysis (sensitivity ITT population)

Number assessed 178 356 356
Number censored (%) 171 (96.1) 281 (78.9) 261 (73.3)
Number of relapse (%) 7 (3.9) 75 (21.1) 95 (26.7)
Relative risk, HR (95 % CI)
PP6M vs PP3M and PP1M — 0.17 (0.08, 0.36) 0.13 (0.06, 0.27)
P value — <0.001 <0.001
PP3M vs PP1M 0.76 (0.56, 1.03)
P value 0.074

Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; NE, not estimable; PP1M, paliperidone palmitate 1-month formulation; PP3M,
paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation.
a
Based on Kaplan-Meier estimates.

observations are consistent with the current study, confirming
the enduring benefits and efficacy of longer-acting LAIs such
as PP6M in preventing relapses in patients with schizophrenia.
PP6M offers an extended treatment window with twice-yearly
dosing that could enhance adherence and help maintain clin-
ical stability for improved long-term prognosis. Furthermore,
PP6M may be beneficial for patients who are homeless, with-
out caregiver support, or living in remote areas with limited
proximity to healthcare providers (Sajatovic et al., 2013; Milz
et al., 2023). Regardless of these circumstances, patients may
still prefer PP6M LAI for the assurance of consistent medication
delivery and extended protection with fewer yearly injections
(Pietrini et al., 2019; Milz et al., 2023).
Pairing clinical trial data and high-quality RWD with adjust-
ments for clinical covariates can broaden the understanding of
treatment effects and allow rigorous evaluation of treatments
(Yap et al., 2021). This study applied statistical and methodologi-
cal approaches to generate ECAs for a PP6M OLE study using RWD
for assessing clinical outcomes in patients with schizophrenia.
External comparator designs are emerging as useful methods to
generate supportive evidence and augment data from single-arm
clinical studies while eliminating extensive resource require-
ments and high costs (Loiseau et al., 2022). However, causal
inferences in external comparator studies with nonrandomized
designs are prone to selection bias and confounding bias due to
differences in baseline covariates. Therefore, a PSM approach was
used to balance the baseline clinical characteristics of patients
between the 3 cohorts and mitigate confounding and selection
bias (Lu et al., 2022).
Leveraging RWD to construct ECAs allows access to large, clin-
ically relevant populations of patients who may be underrepre-
sented in clinical trials (Corrigan-Curay et al., 2018). The present
study derived data from the Medicaid claims database, one of the
largest payers for mental health services, and therefore is likely
representative of the diverse population of patients with schizo-
phrenia in the United States. The IBM MDCD collects standardized
patient-level data on services and filled prescriptions allowing
access to granular data on the key patient baseline, treatment,
and demographic characteristics. Furthermore, patients in the
real-world PP3M and PP1M cohorts were treated and followed
up over the same time period as the patients in the PP6M OLE
study (contemporaneous control), suggesting that the patients
may have broadly comparable treatment histories, reflecting the
ongoing standard of care (Carrigan et al., 2022).
Findings from this study should be considered in light of
certain limitations inherent to RWD. In contrast to randomized
controlled trials, ECAs derived from RWD cannot control for
unmeasured or unknown confounders; PSM only allows adjust-
ments for known confounders available in both the trial data
and the claims database. Thus, factors such as substance abuse,
presence of other psychiatric comorbidities, and need for other
psychiatric comedications, which are common predictors of
relapse, could not be matched. In some cases, relevant informa-
tion recorded in the trial, such as laboratory values and mental
health-related scales, may not be collected in the real-world
dataset. Thus, multi-bias E-values were estimated to determine
the potential impact of unmeasured and residual confounding
on the findings. The large E-values suggest that unmeasured
8 | International Journal of Neuropsychopharmacology, 2024, Vol. 27, No. 2

Figure 3. Kaplan-Meier estimate of time to first relapse (ITT population). ITT, intent-to-treat; PP1M, paliperidone palmitate 1-month formulation;
PP3M, paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation.

Table 3. Reasons for first relapse (ITT population)

PP6M PP3M PP1M

n = 178 n = 178 n = 178

Patients with relapse, n (%) 7 (3.9) 36 (20.2) 53 (29.8)

Reason for relapsea, n (%)
Psychiatric hospitalization 4 (2.2) 25 (14.0) 46 (25.8)
Emergency room visit 2 (1.1)b NA NA
Suicidal ideation 2 (1.1) 6 (3.4) 13 (7.3)
Suicidal or homicidal ideation 2 (1.1) 0 1 (0.6)
Violent behavior resulting in suicide/injury or property damage 1 (0.6) 9 (5.1) 8 (4.5)
Homicidal ideation 1 (0.6) 2 (1.1) 1 (0.6)
Deliberate self-injury, violent behavior 1 (0.6) 1 (0.6) 1 (0.6)

Abbreviations: ITT, intent-to-treat; NA, not applicable; PP1M, paliperidone palmitate 1-month formulation; PP3M, paliperidone palmitate 3-month formulation;
PP6M, paliperidone palmitate 6-month formulation.
a
Reasons for relapse are not mutually exclusive; patients may have ≥1 reason for a given relapse.
b
Two patients had emergency room visit due to worsening of schizophrenia symptoms and both resulted in hospitalization on the same day.

confounders are less likely to influence the observed results. For
the IBM MDCD, although large, the selection of patients is lim-
ited to those insured under Medicaid from 10 states and may
not be fully generalizable to patients who are not insured or are
commercially insured. Additional research comparing PP6M with
PP3M and PP1M using comprehensive data derived from patients
enrolled in the US Medicaid program are warranted. Furthermore,
patients with schizophrenia who have functional impairments
are more likely to use healthcare resources and be included in
the Medicaid pool, potentially leading to underdetection (Leucht
et al., 2007). RWD reflects real-world patterns of care and varies
in data quality and completeness. Inherent to any administra-
tive claims database, the possibility of imprecise coding, incom-
plete clinical information, and delayed data entry could affect the
 Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia | 9

Figure 4. Kaplan-Meier estimate of time to first relapse (sensitivity ITT population). ITT, intent-to-treat; PP1M, paliperidone palmitate 1-month
formulation; PP3M, paliperidone palmitate 3-month formulation; PP6M, paliperidone palmitate 6-month formulation.

validity of the current findings. Notably, claims databases reflect CONCLUSIONS

more of the “payer’s perspective” and less of the “physician” or
In summary, well-matched ECAs of PP3M and PP1M were created
“patient” perspectives, although relapse and hospitalization are
using RWD from an administrative claims database to assess
outcomes that matter to all stakeholders. All clinical study out-
and compare outcomes with the PP6M cohort derived from a
comes could not be fully reproduced in the ECAs due to a lack of
­single-arm, phase 3 OLE study. Treatment with PP6M significantly
similar outcomes in the claims database. Thus, safety endpoints
delayed time-to-relapse and was associated with lower relapse
including adverse events were not assessed because comparable
rates and risk of relapse compared with the real-world derived
data for the PP3M and PP1M cohorts from the IBM MDCD were not
PP3M and PP1M cohorts. These findings further support the use of
available. Although important covariates that mimic the eligibil-
PP6M as an effective maintenance therapy with the longest dos-
ity criteria and help minimize selection bias were considered, not
ing window in the management of schizophrenia.
all inclusion and exclusion criteria from the OLE study could be
applied to patients in the IBM MDCD. Patients in the PP6M cohort
showed a clear response to PP6M during the DB phase 3 study,
Supplementary Materials
which demonstrated relapse prevention with PP6M. The patients
were adherent to PP6M under controlled clinical trial conditions Supplementary data are available at International Journal of
during the OLE study. Thus, they may have had a higher likeli- Neuropsychopharmacology (IJNPPY) online.
hood of showing response than patients from the RWD-derived
cohorts. It is also challenging to ascertain the treatment adher-
ence among patients from the RWD ECAs because pharmacy
Acknowledgments
claims may not necessarily indicate that patients received the The authors thank the study patients and investigators for their
medication and complied with the prescribing label. Additionally, support. The authors also recognize our colleague Dr Dean
the omission of emergency room visits in relapse assessment for Najarian (Janssen Scientific Affairs), who unfortunately passed
the RWD cohorts could have impacted the estimation of relapse away recently, for his invaluable contributions to the study. Priya
rates between PP6M and the RWD cohorts. These factors could Ganpathy, MPharm, MPH CMPP (SIRO Clinpharm UK Limited), pro-
introduce heterogeneity between the cohorts and affect the com- vided medical writing assistance and Ellen Baum, PhD (Janssen
parability of findings from the clinical study and RWD. Global Services, LLC), provided additional editorial support.
10 | International Journal of Neuropsychopharmacology, 2024, Vol. 27, No. 2
Statement of Interest
IT, MD, US, and RKK are employees of Janssen Research &
Development, LLC (a Johnson & Johnson company) and may hold
company stocks or stock options. KLJ is an employee of Janssen
Scientific Affairs, LLC and stockholder of Johnson & Johnson. CUC
has been a consultant and/or advisor to or has received hono-
raria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo,
Biogen, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX
Therapeutics, Compass Pathways, Darnitsa, Denovo, Gedeon
Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J,
Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell,
Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine,
Neurelis, Newron, Noven, Novo Nordisk, Otsuka, Pharmabrain,
PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, SK Life
Science, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and
Viatris. He provided expert testimony for Janssen and Otsuka. He
served on a Data Safety Monitoring Board for Compass Pathways,
Denovo, Lundbeck, Relmada, Reviva, Rovi, Sage, Supernus, Tolmar,
and Teva. He has received grant support from Janssen and Takeda.
He received royalties from UpToDate and is also a stock option
holder of Cardio Diagnostics, Mindpax, LB Pharma, PsiloSterics,
and Quantic.
Funding
This study was sponsored by Janssen Research & Development,
LLC.
Data Sharing Statement
The data sharing policy of Janssen Pharmaceutical Companies
of Johnson & Johnson is available at https://www.janssen.com/
clinical-trials/transparency. As noted on this site, requests for
access to the study data can be submitted through Yale Open
Data Access [YODA] Project site at http://yoda.yale.edu.
Author Contributions
Ibrahim Turkoz (Conceptualization [Lead], Formal analysis [Lead],
Methodology [Lead], Software [Equal], Validation [Equal], Writing—
review & editing [Equal]), Mehmet Daskiran (Conceptualization
[Equal], Data curation [Equal], Formal analysis [Equal], Methodology
[Equal], Software [Equal], Validation [Equal], Writing—review &
editing [Equal]), Uzma Siddiqui (Conceptualization [Equal], Data
curation [Equal], Formal analysis [Equal], Methodology [Equal],
Writing—review & editing [Equal]), Robert Knight (Conceptualization
[Equal], Data curation [Equal], Formal analysis [Equal], Methodology
[Equal], Writing—review & editing [Equal]), Karen L Johnston
(Conceptualization [Equal], Data curation [Equal], Formal analysis
[Equal], Methodology [Equal], Writing—review & editing [Equal]),
and Christoph U. Correll (Conceptualization [Equal], Data curation
[Equal], Formal analysis [Equal], Methodology [Equal], Writing—
review & editing [Equal]).
References
Agid O, Foussias G, Remington G (2010) Long-acting injectable antip-
sychotics in the treatment of schizophrenia: their role in relapse
prevention. Expert Opin Pharmacother 11:2301–2317.
Alphs L, Benson C, Cheshire-Kinney K, Lindenmayer JP, Mao
L, Rodriguez SC, Starr HL (2015) Real-world outcomes of
paliperidone palmitate compared to daily oral antipsychotic
therapy in schizophrenia: a randomized, open-label, review
board-blinded 15-month study. J Clin Psychiatry 76:554–561.
Austin PC (2014) The use of propensity score methods with sur-
vival or time-to-event outcomes: reporting measures of effect
similar to those used in randomized experiments. Stat Med
33:1242–1258.
Berwaerts J, Liu Y, Gopal S, Nuamah I, Xu H, Savitz A, Coppola D,
Schotte A, Remmerie B, Maruta N, Hough DW (2015) Efficacy
and safety of the 3-month formulation of paliperidone palmi-
tate vs placebo for relapse prevention of schizophrenia: a rand-
omized clinical trial. JAMA Psychiatry 72:830–839.
Blackwood C, Sanga P, Nuamah I, Keenan A, Singh A, Mathews M,
Gopal S (2020) Patients’ preference for long-acting injectable
versus oral antipsychotics in schizophrenia: results from the
patient-reported medication preference questionnaire. Patient
Prefer Adherence 14:1093–1102.
Brissos S, Veguilla MR, Taylor D, Balanza-Martinez V (2014) The role
of long-acting injectable antipsychotics in schizophrenia: a crit-
ical appraisal. Ther Adv Psychopharmacol 4:198–219.
Carrigan G, Bradbury BD, Brookhart MA, Capra WB, Chia V, Rothman
KJ, Sarsour K, Taylor MD, Brown JS (2022) External comparator
groups derived from real-world data used in support of reg-
ulatory decision making: use cases and challenges. Current
Epidemiology Reports 9:326–337.
Correll CU, Citrome L, Haddad PM, Lauriello J, Olfson M, Calloway
SM, Kane JM (2016) The use of long-acting injectable antip-
sychotics in schizophrenia: evaluating the evidence. J Clin
Psychiatry 77:1–24.
Correll CU, Martin A, Patel C, Benson C, Goulding R, Kern-Sliwa J, Joshi
K, Schiller E, Kim E (2022) Systematic literature review of schiz-
ophrenia clinical practice guidelines on acute and maintenance
management with antipsychotics. Schizophrenia (Heidelb) 8:5.
Corrigan-Curay J, Sacks L, Woodcock J (2018) Real-World evidence
and real-world data for evaluating drug safety and effective-
ness. JAMA 320:867–868.
DerSarkissian M, Lefebvre P, Joshi K, Brown B, Lafeuille MH, Bhak RH,
Hellstern M, Bobbili P, Shiner B, El Khoury AC, Young-Xu Y (2018)
Health care resource utilization and costs associated with tran-
sitioning to 3-month paliperidone palmitate among US veter-
ans. Clin Ther 40:1496–1508.
Di Lorenzo R, Cameli M, Piemonte C, Bolondi M, Landi G, Pollutri
G, Spattini L, Moretti V, Ferri P (2018) Clinical improvement,
relapse and treatment adherence with paliperidone palmitate
1-month formulation: 1-year treatment in a naturalistic outpa-
tient setting. Nord J Psychiatry 72:214–220.
Emond B, Joshi K, Khoury ACE, Lafeuille MH, Pilon D, Tandon N,
Romdhani H, Lefebvre P (2019a) Adherence, healthcare resource
utilization, and costs in Medicaid beneficiaries with schizophre-
nia transitioning from once-monthly to once-every-3-months
paliperidone palmitate. PharmacoEcon Open 3:177–188.
Emond B, El Khoury AC, Patel C, Pilon D, Morrison L, Zhdanava M,
Lefebvre P, Tandon N, Joshi K (2019b) Real-world outcomes
post-transition to once-every-3-months paliperidone palmitate
in patients with schizophrenia within US commercial plans.
Curr Med Res Opin 35:407–416.
Emsley R, Chiliza B, Asmal L, Harvey BH (2013) The nature of relapse
in schizophrenia. BMC Psychiatry 13:50.
Gopal S, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie
BM, Eerdekens MH, Brown DW (2010) Efficacy and safety of pali-
peridone palmitate in adult patients with acutely symptomatic
schizophrenia: a randomized, double-blind, placebo-controlled,
dose-response study. Int Clin Psychopharmacol 25:247–256.
 Relapse Rates With Paliperidone Palmitate in Adult Patients With Schizophrenia | 11
Hough D, Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens M
(2010) Paliperidone palmitate maintenance treatment in delay-
ing the time-to-relapse in patients with schizophrenia: a rand-
omized, double-blind, placebo-controlled study. Schizophr Res
116:107–117.
Joshi K, Lafeuille MH, Brown B, Wynant W, Emond B, Lefebvre P,
Tandon N (2017) Baseline characteristics and treatment pat-
terns of patients with schizophrenia initiated on once-every-
three-months paliperidone palmitate in a real-world setting.
Curr Med Res Opin 33:1763–1772.
Kaplan G, Casoy J, Zummo J (2013) Impact of long-acting injecta-
ble antipsychotics on medication adherence and clinical, func-
tional, and economic outcomes of schizophrenia. Patient Prefer
Adherence 7:1171–1180.
Kemmler G, Hummer M, Widschwendter C, Fleischhacker WW
(2005) Dropout rates in placebo-controlled and active-control
clinical trials of antipsychotic drugs: a meta-analysis. Arch Gen
Psychiatry 62:1305–1312.
Kim HO, Seo GH, Lee BC (2020) Real-world effectiveness of long-­
acting injections for reducing recurrent hospitalizations in
patients with schizophrenia. Ann Gen Psychiatry 19:1.
Kishimoto T, Hagi K, Kurokawa S, Kane JM, Correll CU (2021) Long-
acting injectable versus oral antipsychotics for the mainte-
nance treatment of schizophrenia: a systematic review and
comparative meta-analysis of randomised, cohort, and pre-post
studies. Lancet Psychiatry 8:387–404.
Latorre V, Papazacharias A, Lorusso M, Nappi G, Clemente P, Spinelli
A, Carrieri G, D’Ambrosio E, Gattullo M, Uva AE, Semisa D (2020)
Improving the “real life” management of schizophrenia spec-
trum disorders by LAI antipsychotics: a one-year mirror-image
retrospective study in community mental health services. PLoS
One 15:e0230051.
Leucht S, Burkard T, Henderson J, Maj M, Sartorius N (2007) Physical
illness and schizophrenia: a review of the literature. Acta
Psychiatr Scand 116:317–333.
Li G, Keenan A, Daskiran M, Mathews M, Nuamah I, Orman C, Joshi
K, Singh A, Godet A, Pungor K, Gopal S (2021) Relapse and treat-
ment adherence in patients with schizophrenia switching from
paliperidone palmitate once-monthly to three-monthly formu-
lation: a retrospective health claims database analysis. Patient
Prefer Adherence 15:2239–2248.
Lin D, Pilon D, Zhdanava M, Joshi K, Lafeuille MH, Cote-Sergent A,
Vermette-Laforme M, Lefebvre P (2021) Medication adherence,
healthcare resource utilization, and costs among Medicaid ben-
eficiaries with schizophrenia treated with once-monthly pali-
peridone palmitate or once-every-three-months paliperidone
palmitate. Curr Med Res Opin 37:675–683.
Loiseau N, Trichelair P, He M, Andreux M, Zaslavskiy M, Wainrib G,
Blum MGB (2022) External control arm analysis: an evaluation
of propensity score approaches, G-computation, and doubly
debiased machine learning. BMC Med Res Methodol 22:335.
Lu N, Wang C, Chen WC, Li H, Song C, Tiwari R, Xu Y, Yue LQ (2022)
Propensity score-integrated power prior approach for augmenting
the control arm of a randomized controlled trial by incorporating
multiple external data sources. J Biopharm Stat 32:158–169.
Milz R, Benson C, Knight K, Antunes J, Najarian D, Lopez Rengel PM,
Wang S, Richarz U, Gopal S, Kane JM (2023) The effect of longer
dosing intervals for long-acting injectable antipsychotics on out-
comes in schizophrenia. Neuropsychiatr Dis Treat 19:531–545.
Najarian D, Sanga P, Wang S, Lim P, Singh A, Robertson MJ, Cohen K,
Schotte A, Milz R, Venkatasubramanian R, T’Jollyn H, Walling
DP, Galderisi S, Gopal S (2022) A Randomized, double-blind,
multicenter, noninferiority study comparing paliperidone
palmitate 6-month versus the 3-month long-acting injectable
in patients with schizophrenia. Int J Neuropsychopharmacol
25:238–251.
Najarian D, Turkoz I, Knight K, Galderisi S, Lamaison H, Zalitacz P,
Aravind S, Richarz U (2023) Long-term efficacy and safety of
paliperidone 6-month formulation: an open-label 2-year exten-
sion of a 1-year double-blind study in adult participants with
schizophrenia. Int J Neuropsychopharmacol 26:537–544.
Novick D, Haro JM, Suarez D, Perez V, Dittmann RW, Haddad PM
(2010) Predictors and clinical consequences of non-adherence
with antipsychotic medication in the outpatient treatment of
schizophrenia. Psychiatry Res 176:109–113.
Patel C, Emond B, Lafeuille MH, Cote-Sergent A, Lefebvre P, Tandon
N, El Khoury AC (2020) Real-world analysis of switching patients
with schizophrenia from oral risperidone or oral paliperidone
to once-monthly paliperidone palmitate. Drugs Real World
Outcomes 7:19–29.
Pietrini F, Albert U, Ballerini A, Calo P, Maina G, Pinna F, Vaggi M,
Boggian I, Fontana M, Moro C, Carpiniello B (2019) The modern
perspective for long-acting injectables antipsychotics in the
patient-centered care of schizophrenia. Neuropsychiatr Dis
Treat 15:1045–1060.
Quan H, Sundararajan V, Halfon P, Fong A, Burnand B, Luthi JC,
Saunders LD, Beck CA, Feasby TE, Ghali WA (2005) Coding algo-
rithms for defining comorbidities in ICD-9-CM and ICD-10
administrative data. Med Care 43:1130–1139.
Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S,
Koreen A, Sheitman B, Chakos M, Mayerhoff D, Lieberman JA
(1999) Predictors of relapse following response from a first epi-
sode of schizophrenia or schizoaffective disorder. Arch Gen
Psychiatry 56:241–247.
Sajatovic M, Levin J, Ramirez LF, Hahn DY, Tatsuoka C, Bialko CS,
Cassidy KA, Fuentes-Casiano E, Williams TD (2013) Prospective
trial of customized adherence enhancement plus long-acting
injectable antipsychotic medication in homeless or recently
homeless individuals with schizophrenia or schizoaffective dis-
order. J Clin Psychiatry 74:1249–1255.
Savitz AJ, Xu H, Gopal S, Nuamah I, Ravenstijn P, Janik A, Schotte
A, Hough D, Fleischhacker WW (2016) Efficacy and safety of
paliperidone palmitate 3-month formulation for patients with
schizophrenia: a randomized, multicenter, double-blind, nonin-
feriority study. Int J Neuropsychopharmacol 19:pyw018.
Segarra R, Recio-Barbero M, Saenz-Herrero M, Mentxaka O, Cabezas-
Garduno J, Eguiluz JI, Callado LF (2021) Oral and palmitate
paliperidone long-acting injectable formulations’ use in schizo-
phrenia spectrum disorders: a retrospective cohort study from
the First Episode Psychosis Intervention Program (CRUPEP). Int J
Neuropsychopharmacol 24:694–702.
Turkoz I, Wong J, Chee B, Siddiqui U, Knight RK, Correll CU, Richarz
U (2023) Comparative effectiveness study of paliperidone pal-
mitate 6-month with a real-world external comparator arm of
paliperidone palmitate 1-month or 3-month in patients with
schizophrenia. Ther Adv Psychopharmacol 13.
Weiden PJ, Kim E, Bermak J, Turkoz I, Gopal S, Berwaerts J (2017) Does
half-life matter after antipsychotic discontinuation? a relapse
comparison in schizophrenia with 3 different formulations of
paliperidone. J Clin Psychiatry 78:e813–e820.
Yap TA, Jacobs I, Baumfeld Andre E, Lee LJ, Beaupre D, Azoulay
L (2021) Application of real-world data to external control
groups in oncology clinical trial drug development. Front Oncol
11:695936.