The World Journal of Biological Psychiatry

ISSN: 1562-2975 (Print) 1814-1412 (Online) Journal homepage: http://www.tandfonline.com/loi/iwbp20

Treatment response and tolerability with

once-monthly paliperidone palmitate initiated
shortly after hospital admission in patients with
schizophrenia

Ludger Hargarter, Marjolein Lahaye, Pierre Cherubin, Martin Lambert,

Marnina Swarz, Gali Joldygulov, Flavio Vischia, Veronica Chomskaya, Vasilis
P. Bozikas, Eva-Maria Tsapakis & Andreas Schreiner

To cite this article: Ludger Hargarter, Marjolein Lahaye, Pierre Cherubin, Martin Lambert, Marnina
Swarz, Gali Joldygulov, Flavio Vischia, Veronica Chomskaya, Vasilis P. Bozikas, Eva-Maria
Tsapakis & Andreas Schreiner (2017): Treatment response and tolerability with once-monthly
paliperidone palmitate initiated shortly after hospital admission in patients with schizophrenia, The
World Journal of Biological Psychiatry, DOI: 10.1080/15622975.2017.1315176

To link to this article: http://dx.doi.org/10.1080/15622975.2017.1315176

Published online: 08 Jun 2017.

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THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY, 2017
http://dx.doi.org/10.1080/15622975.2017.1315176

ORIGINAL INVESTIGATION

Treatment response and tolerability with once-monthly paliperidone

palmitate initiated shortly after hospital admission in patients with
schizophrenia
Ludger Hargartera, Marjolein Lahayeb, Pierre Cherubinc, Martin Lambertd, Marnina Swarze, Gali Joldygulovf
,
Flavio Vischiag, Veronica Chomskayah, Vasilis P. Bozikasi, Eva-Maria Tsapakisj and Andreas Schreinera
a
Medical & Scientific Affairs, Janssen Cilag EMEA, Neuss, Germany; bBiostatistics & Programming, Janssen Cilag Benelux, Tilburg,
The Netherlands; cMedical Affairs, Janssen Cilag EMEA, Issy-les-Moulineaux, France; dUniversity Medical Center, Eppendorf, Hamburg,
Germany; eAbarbanel Mental Health Center, Bat Yam, Israel; fRepublican Scientific Center of Psychiatry, Almaty, Kazakhstan;
g
Dipartimento di Salute Mentale, Ospedale Amedeo di Savoia, Torino, Italy; hState Institution of Healthcare City Psychoneurological
Dispensary #3, St Petersburg, Russia; i1st Psychiatric Clinic of the Aristotle University of Thessaloniki, General Hospital “Papageorgiou”,
Thessaloniki, Greece; jAghios Charalambos’ Mental Health Clinic, Heraklion, Crete, Greece

ABSTRACT ARTICLE HISTORY

Objectives: Partial or non-adherence in patients with schizophrenia is common and increases Received 25 February 2016
the risk of relapse. This study explored safety, tolerability and treatment outcomes in patients Revised 9 March 2017
hospitalised for an exacerbation of schizophrenia initiated on maintenance treatment of once- Accepted 30 March 2017
monthly paliperidone palmitate (PP1M).
Methods: A 6-week, observational cohort study of patients initiated on PP1M within 3 weeks KEYWORDS
after hospital admission. Schizophrenia; paliperidone
Results: Overall, 367 patients were documented, 85.8% with paranoid schizophrenia subtype. palmitate; hospitalisation;
Mean time from hospital admission to PP1M initiation was 9.4 ± 7.7 days. Treatment-emergent antipsychotics; maintenance
adverse events were reported by 22.9% of patients. From baseline to endpoint, significant treatment
improvements were observed in psychotic symptoms (Brief Psychiatric Rating Scale total score
mean change –19.3 ± 12.6, P < .0001) and functioning (Personal and Social Performance scale
total score mean change 14.3 ± 12.4, P < .0001). Overall, 6.0% of patients were very or extremely
satisfied with their prior antipsychotic medication at baseline compared with 47.2% very or
extremely satisfied with PP1M treatment at endpoint.
Conclusions: Initiating PP1M in patients with exacerbated schizophrenia shortly after hospital
admission was well tolerated and resulted in statistically significant and clinically relevant
improvements in symptoms and patient functioning, suggesting that patients may benefit from
early initiation of PP1M during their hospital stay.

Introduction result in an almost five-fold increase in the risk of

relapse (Robinson et al. 1999).
Relapse rates after hospitalisation for schizophrenia are Although oral antipsychotics are recommended for
high, with more than half of patients discontinuing the treatment of acute schizophrenia (National
their antipsychotic medication within 1 month after Institute for Health & Care Excellence 2014), more
discharge (Tiihonen et al. 2011) and a similar propor- than half of patients with schizophrenia (54%) do not
tion relapsing in the first year after discharge collect their prescription within 1 month after hos-
(Schennach et al. 2012). Both partial adherence and pital discharge (Tiihonen et al. 2011). In addition,
non-adherence to oral antipsychotic medication are patients with a recent hospitalisation (within 6
challenging aspects of schizophrenia treatment, and months) are 22% less likely to adhere to treatment
are associated with increased risk of relapse, rehospi- (Novick et al. 2010). Long-acting injectable anti-
talisation and suicide (Ascher-Svanum et al. 2010; psychotic therapies (LATs) help to overcome the
Novick et al. 2010; Higashi et al. 2013). Non-adherence problems of partial adherence and non-adherence
to oral antipsychotic medication has been shown to (Brissos et al. 2014) and may improve outcomes

CONTACT Ludger Hargarter [email protected] Medical Affairs Director Psychiatry, Medical & Scientific Affairs, Janssen Cilag Europe, Middle East
& Africa, Johnson & Johnson Platz 1, 41470 Neuss, Germany

G. Joldygulov is currently an employee of Janssen Cilag EMEA, but was an external investigator at the time of study conduct.
ß 2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
2 L. HARGARTER ET AL.

for patients. Indeed, naturalistic studies have shown participate only if all treatment decisions were made
that patients treated with LATs have a significantly at the discretion of the treating physician before the
longer time to discontinuation (Bitter et al. 2013) and start of the study, and study participation in no way
reduced rates of hospitalisation (Kishimoto et al. impacted on the regular care of the patient, or on any
2013) compared with those treated with oral antipsy- benefits to which they were otherwise entitled. Study
chotics. A meta-analysis of mirror-image studies com- duration was limited to 6 weeks to capture a reason-
paring LATs with oral antipsychotics found that able timeframe for a hospital stay and to have the first
patients receiving LATs had a 57% reduced risk of three injections documented. Data were only collected
rehospitalisation and a 62% lower number of hospi- in patients who, in the opinion of the treating phy-
talisations compared with those receiving oral anti- sician, were capable of providing consent. Written
psychotics (both P < .001) (Kishimoto et al. 2013). informed consent was obtained prior to any study
Similarly, a US-based study found that, 1 year after documentation. Applicable regulatory requirements
initiation of LAT, the number of all-cause hospitalisa- and the study protocol were approved by
tions and number of hospital days were significantly Independent Ethics Committees in each country. The
lower compared with the period before initiation of study was carried out in accordance with the
LAT (P < .0001), regardless of patient age (Kamat Declaration of Helsinki. The trial is registered at
et al. 2015). Guidelines for the treatment of schizo- ClinicalTrials.gov (NCT01926912).
phrenia indicate that, in patients with one or more
relapses due to partial or non-adherence, the transi- Key selection criteria
tion from oral antipsychotics to long-term treatment
with LATs may already be initiated in the acute Adult (18 years) patients with an established schizo-
phase (American Psychiatric Association 2010), and phrenia diagnosis who were admitted to hospital due
should be considered at any stage of the disease, to an exacerbation of their disease prior to any study
including the earlier stages (Malla et al. 2013). activity and who, in the investigator’s opinion, could
The recommended initiation regimen for paliperi- benefit from long-term maintenance treatment with
done palmitate (PP1M), an atypical once-monthly LAT, PP1M, were initiated within the first 3 weeks after
is two injections (150 mg eq. on Day 1 and 100 mg eq. admission to hospital. The decision to initiate treat-
on Day 8), allowing for a rapid attainment of thera- ment with PP1M must have been made prior to offer-
ing enrolment and in accordance with routine clinical
peutic plasma concentrations (Janssen Cilag et al.
practice. Patients were not eligible for documentation
2016). Long-term maintenance treatment with PP1M
in this study if they had previous exposure to PP1M;
may be initiated early within a hospital setting in
exposure to any other LAT and/or to clozapine within
symptomatic patients with previous responsiveness to
the previous 3 months; or were involuntarily hospita-
oral paliperidone extended release (ER) or risperidone
lised at study entry (i.e. at the beginning of data
if psychotic symptoms are mild to moderate and a
collection).
long-acting injectable treatment is needed. The object-
ive of this study was to explore treatment outcomes,
appropriate use, and safety and tolerability in patients Study objectives
hospitalised for an exacerbation of schizophrenia
The primary objective of the study was to assess treat-
where maintenance treatment with once-monthly
ment response, tolerability and appropriate use of
PP1M was initiated at the discretion of the treating
PP1M initiation in clinical practice in symptomatic
physician within the first 3 weeks after the patient’s
patients with schizophrenia admitted to hospital due
admission to hospital.
to an exacerbation of the disease.

Methods
Outcome measures
Study design
Outcome measures included change from baseline in
This was an international, 6-week, prospective, obser- Brief Psychiatric Rating Scale (BPRS) (Overall & Gorham
vational, non-interventional, non-comparative cohort 1962), Clinical Global Impression – Severity (CGI–S)
study conducted at 61 sites in nine countries (Belgium, score, Clinical Global Impression – Change (CGI–C)
Bulgaria, Denmark, Germany, Greece, Israel, Italy, score (Guy 1976), Personal and Social Performance
Kazakhstan and Russia). Owing to the non-interven- (PSP) scale score (Morosini et al. 2000; Nasrallah 2008)
tional nature of this study, patients were eligible to and treatment response.
 THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 3

Treatment response relationships; (c) self-care; and (d) disturbing and

aggressive behaviour. The score for each domain rates
Treatment response was assessed through psychiatric
the difficulty within that domain, with scores ranging
symptoms and disease severity, as measured by actual
from 1 (absent) to 6 (very severe). The results of the
values and changes from baseline in BPRS (Overall &
assessment are converted to a total score ranging
Gorham 1962), CGI–S and CGI–C (Guy 1976) scores.
from 1 to 100, with higher scores representing better
Patient functioning was assessed using the PSP scale
functioning. A score of 71 to 100 indicates mild to no
(Morosini et al. 2000; Nasrallah 2008). Patient’s treat-
impairment; 31 to 70 indicates varying degrees of dis-
ment satisfaction was assessed via the Medication
ability ranging from severe (31–40) to manifest but
Satisfaction Questionnaire (MSQ) (Vernon et al. 2010),
not marked (61–70); and a score 30 indicates func-
completed at baseline (for previous antipsychotic med-
tioning so poor that the patient requires intensive
ication[s]) and endpoint (for PP1M).
supervision.
Clinically relevant improvement
Safety and tolerability
A 20% and 50% reduction from baseline BPRS scores
Safety assessments included monitoring of treatment-
indicates ‘minimally clinically improved’ and ‘much
emergent adverse events (TEAEs), body weight and
clinically improved’, respectively (Leucht et al. 2005).
extrapyramidal motor symptoms (EPMS), as measured
The CGI–C rating scale compares the change in clinical
by the Extrapyramidal Symptom Rating Scale (ESRS)
status of a patient since the start of treatment
(Chouinard & Margolese 2005).
(1 ¼ very much improved since the initiation of treat-
ment; 2 ¼ much improved; 3 ¼ minimally improved;
4 ¼ no change; 5 ¼ minimally worse; 6 ¼ much worse; Data analysis
and 7 ¼ very much worse). Finally, a 10-point incre-
Baseline data were collected at the initiation of PP1M
ment in PSP has been reported as a clinically meaning-
(Day 1). During the observation period, data were col-
ful improvement (Nicholl et al. 2010).
lected weekly until Week 6 (Day 43 ± 7 days) or at
early study discontinuation. Data for BPRS and CGI–S
Assessment scales
were collected at all visits during the study. Data for
The BPRS is a validated scale, specific for the measure- CGI–C and PSP were collected at Day 43 and endpoint
ment of psychiatric symptoms in schizophrenia, and only. The MSQ was assessed at baseline (for previous
comprises the following 18 symptom items: Somatic antipsychotic medication[s]) and endpoint (for PP1M).
concern; Anxiety; Emotional withdrawal; Conceptual All documented patients who provided written con-
disorganisation; Guilt feelings; Tension; Mannerisms sent and who received at least one dose of PP1M
and posturing; Grandiosity; Depressive mood; Hostility; (documented population) were included in the statis-
Suspiciousness; Hallucinatory behaviour; Motor retar- tical analyses. Analysis of treatment response was con-
dation; Uncooperativeness; Unusual thought content; ducted using the efficacy analysis set, comprising all
Blunted affect; Excitement; and Disorientation. Each patients in the documented population who provided
item is scored on a scale of 1 (not present) to 7 at least one post-baseline treatment-response assess-
(extremely severe). The total BPRS score is calculated ment. Safety analyses were conducted using the safety
as the sum of the scores from the 18 items. The BPRS analysis set, defined as all patients in the documented
was assessed at those sites where this scale is used as population who received at least one dose of PP1M
part of routine clinical practice. and provided any post-baseline safety information. In
The CGI–S rating scale is used to rate the severity this study, the safety population is identical to the
of a patient’s psychotic condition at a particular time documented population.
on a seven-point scale (0 ¼ normal, not at all ill; The study was designed to generate naturalistic
1 ¼ borderline mentally ill; 2 ¼ mildly ill; 3 ¼ moderately data on treatment response, tolerability and appropri-
ill; 4 ¼ markedly ill; 5 ¼ severely ill; and 6 ¼ among the ate use of PP1M initiation in a hospital setting. The
most extremely ill patients) and allows a global evalu- target sample size was selected to allow collection of
ation of the patient’s condition at a given time. data on a representative sample of symptomatic
The PSP scale assesses the degree of dysfunctiona- patients with schizophrenia who were admitted to
lity that a patient exhibits over the 1-week period prior hospital due to exacerbation of their disease and to
to the visit within four domains of behaviour: (a) allow for potential exploratory analyses in various
socially useful activities; (b) personal and social patient subgroups. A sample size of approximately
4 L. HARGARTER ET AL.

100 patients was considered reasonable for any poten- AEs with onset during the observational period and/or
tial subgroup to enable detection of small incidence AEs that worsened from baseline (i.e. TEAEs), were
rates (i.e. incidence rates of specific AEs or discontinu- included in the AE analysis. Any AEs reported by
ation rate due to AEs with an expected incidence rate patients or their caregivers, as well as those assessed
of 5–15% in an expected proportion of 5%, and a cor- during study visits, were recorded and monitored by
responding distance of 4% from the observed inci- the treating physician. All AEs were coded using the
Medical Dictionary for Regulatory Activities (MedDRAV
R
dence rates for a one-sided 95% confidence interval.
The target sample size of 450 patients was selected to version 15.1) (International Federation of
collect data on a sample of symptomatic subjects with Pharmaceutical Manufacturers & Associations 2012).
schizophrenia, admitted to hospital due to an exacer- For all reported TEAEs, frequency distributions
bation of their disease and allow for potential sub- included severity of the events (mild, moderate,
group analyses, three to four subgroups of 96 patients severe), causal relationship to treatment (not related,
each. The total number of patients that were docu- doubtful, possible, probable, very likely), action taken
mented and received at least one dose of PP1M was and outcome.
367, which was large enough for the overall analysis
and did not impact the final results. In addition, the
Results
main subgroup of interest (‘acute subjects’) that was
analysed and reported contained more than 96 sub- Demographics and patient disposition
jects, thereby meeting the target sample size. For con- Patient disposition is described in Figure 1. In total,
tinuous variables and those measured at ordinal level, 371 patients were enrolled, of whom 367 received at
all values presented are mean ± standard deviation, least one dose of PP1M and were included in the
unless otherwise specified, and changes from baseline documented population. Overall, 91.6% of patients
were tested using the Wilcoxon-signed rank test. All completed the 6-week observation period.
statistical tests were interpreted at the 5% significance Baseline characteristics are summarised in Table 1.
level (two-tailed), unless otherwise specified. Most patients were male (65.9%); mean age
Kaplan–Meier survival curve estimates were used to 39.8 ± 12.1 years. The most frequently diagnosed sub-
analyse time from admission and time from first PP1M type was paranoid schizophrenia (85.8%). Most
injection until discharge. Frequency distributions are (91.3%) patients had at least one previous psychiatric
reported for categorical variables. The last observation hospitalisation; mean time from schizophrenia diagno-
carried forward (at Week 6 or early discontinuation) sis to start of documentation in the study was
method was used for endpoint analysis. All reported 11.4 ± 10.5 years.

Figure 1. Patient disposition. ‘Documented’ refers to all patients who provided written consent and received at least one dose of
PP1M.
Efficacy analysis set consisted of all patients who received at least one dose of PP1M and had at least one post-baseline
efficacy assessment. †Safety analysis set consisted of all patients who received at least one dose of PP1M and had at least one
post-baseline safety assessment. ‡Patients who completed all study documentation up until Week 6. PP1M: paliperidone palmitate.
 THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 5

Table 1. Baseline demographics and dosing information (documented population; n ¼ 367).

Mean age, years (SD) 39.8 (12.1)
Male, % 65.9
Paranoid subtype of schizophrenia, % 85.8
Mean time from first diagnosis to start of the study, years (SD) (n ¼ 354) 11.4 (10.5)
Mean body weight, kg (SD) (n ¼ 363) 76.5 (15.6)
Mean BMI, kg/m2 (SD) (n ¼ 363) 26.0 (4.8)
Patients with 1 comorbidity, n (%)a 142 (38.7)
Patients with 1 previous hospitalisation, n (%) 335 (91.3)
Mean number of previous hospitalisations (SD) 6.7 (7.1)
Median number of previous hospitalisations (min; max) 4.5 (1; 53)
Prior antipsychotic medication (received in the 4 weeks prior to the first PP1M injection)
Patients with 1 antipsychotic medication, n (%) 354 (96.5)
Oral atypical antipsychoticb 252 (68.7)
Paliperidone ER 108 (29.4)
Risperidone 91 (24.8)
Olanzapine 42 (11.4)
Quetiapine 31 (8.4)
Oral conventional antipsychoticc 217 (59.1)
Haloperidol 139 (37.9)
Chlorpromazine 56 (15.3)
Levomepromazine 27 (7.4)
Trifluoperazine 24 (6.5)
Chlorprothixene 22 (6.0)
PP1M dosing
Patients receiving PP1M initiation regimen according to the label,d n (%) 326 (88.8)
Mean time from hospital admission to PP1M initiation, days (SD) 9.4 (7.7)
Last PP1M dose received, %
50 mg eq. 1.1
75 mg eq. 28.1
100 mg eq. 40.9
150 mg eq. 30.0
Received a third dose of PP1M during the study, %
Total 89.6
50 mg eq. 1.1
75 mg eq. 27.8
100 mg eq. 32.7
150 mg eq. 28.1
Benzodiazepine use during the study, n (%)
At baseline and continuede 75 (20.4)
Newly initiated during studye 66 (18.0)
At endpointf (n ¼ 365) 66 (18.1)
At Week 6f (n ¼ 338) 59 (17.5)
Anticholinergic use during the study, n (%)
At baseline and continuede 64 (17.4)
Newly initiated during studye 82 (22.3)
At endpoint (n ¼ 365) 77 (21.1)
At Week 6 (n ¼ 338) 72 (21.3)
Concomitant oral medications used during the study in >5% of the documented population
Patients with 1 concomitant medication, n (%)f 320 (87.2)
Nervous system 314 (85.6)
Trihexyphenidyl 67 (18.3)
Paliperidone 59 (16.1)
Risperidone 58 (15.8)
Biperiden 57 (15.5)
Haloperidol 56 (15.3)
Valproate sodium 46 (12.5)
Lorazepam 39 (10.6)
Diazepam 37 (10.1)
a
Individual patients can be labelled for >1 comorbidity.
b
Other oral atypical antipsychotic medications (taken by <5% of the documented population) included aripiprazole (4.9%), ami-
sulpride (4.1%), clozapine (1.9%), ziprasidone (1.1%) and asenapine (0.5%).
c
Other oral conventional antipsychotic medications (taken by <5% of the documented population) included zuclopenthixol (4.1%),
promazine (1.6%), thioridazine (1.4%), clotiapine (0.5%), flupentixol (0.5%), perazine (0.5%), perphenazine (0.5%), pipamperone
hydrochloride (0.5%), tiapride (0.5%) and prothipendyl (0.3%).
d
Recommended initiation regimen is PP1M 150 mg eq. on Day 1 and 100 mg eq. on Day 8, both given in the deltoid muscle.
e
There may be an overlap between some patients in these groups.
f
Other concomitant medications (taken by 5–10% of the documented population) included chlorpromazine (7.9%), quetiapine
(7.1%), levomepromazine (6.5%), phenazepam (6.0%), chlorprothixene (5.7%) and olanzapine (5.2%).
BMI: body mass index; PP1M: paliperidone palmitate; SD: standard deviation.
6 L. HARGARTER ET AL.

The vast majority of patients (96.5%; n ¼ 354) ESRS total score at all time points throughout the study
received treatment with at least one oral antipsychotic (all P values < .0001), with a score of 3.0 ± 5.3 (mean
in the 4 weeks prior to the first PP1M injection; 68.7% change 0.7 ± 2.5) at Day 8 and 2.0 ± 4.7 at endpoint
received oral atypical antipsychotics, the most common (mean change –1.7 ± 4.8).
of which were paliperidone ER (29.4%) and risperidone
(24.8%), whereas conventional oral antipsychotics
Treatment response
were used in 59.1% of patients, the most common of
which were haloperidol (37.9%) and chlorpromazine In the efficacy analysis population, at endpoint, 86.0%
(15.3%). The main reasons for initiating treatment with and 69.6% of patients had achieved a 30% and
PP1M included partial or non-adherence to previous 50% improvement in BPRS total score, respectively.
treatment (40.1%); lack of efficacy with previous In this population, mean BPRS total score decreased
treatment (37.9%); convenience of LAT medication from baseline (50.2 ± 13.6) to endpoint (30.8 ± 9.9),
regimen (11.2%); lack of tolerability with previous treat- reflecting a statistically significant and clinically rele-
ment (9.5%); and patient’s wish (1.1%). Mean time from vant symptom improvement (mean change
hospital admission to PP1M initiation was 9.4 ± 7.7 days 19.3 ± 12.6, P < .0001; Figure 2). Statistically signifi-
(range 0–63). Most patients (88.8%) received the PP1M cant improvements in BPRS total score were observed
initiation regimen according to the approved label. as early as Day 8 (the earliest post-baseline time point
Overall, 89.6% (n ¼ 329) of patients received a third when treatment response was measured), with a
injection of PP1M within the study period. mean change from baseline to Day 8 of 6.5 ± 8.6,
P < .0001.
Statistically significant improvements were also
Safety and tolerability
observed in disease severity from Day 8 onwards
Overall, in the safety population, 22.9% (84/367) of (change from baseline 0.3 ± 0.7, P < .0001). Mean
patients reported 1 TEAE, and a causally, i.e. at least CGI–S score at endpoint was 2.3 ± 1.1 (change from
possibly, related TEAE was reported in 11.4% (n ¼ 42) of baseline 1.4 ± 1.1, P < .0001). The proportion of
patients. Most TEAEs (93.4%, 142/152) were mild or patients categorised in CGI–S as ‘markedly ill’ (CGI–S
moderate in intensity. One or more serious TEAEs were score: 4), ‘severely ill’ (CGI–S score: 5) and ‘among the
reported in 3.5% (n ¼ 13) of patients. Four patients most severely ill subjects’ (CGI–S score: 6) decreased
experienced a TEAE leading to treatment discontinu- from 55.7% at baseline to 11.9% at endpoint. From
ation. Two patients were discontinued due to a TEAE baseline to endpoint, 62.9% (214/340) of patients were
with fatal outcome (viral pneumonia (n ¼ 1) and loss of much or very much improved, as assessed by the
consciousness (n ¼ 1)). Both deaths were considered not CGI–C scale.
to be related to PP1M treatment by the treating physi- Statistically significant and clinically relevant
cians. Two patients discontinued due to akathisia (n ¼ 1) improvements were observed in patient functioning
and extrapyramidal disorder (n ¼ 1). TEAEs reported (PSP total score) from baseline (49.4 ± 14.7) to end-
in 2% of patients included tremor (n ¼ 9, 2.5%) and point (63.7 ± 14.9; mean change 14.3 ± 12.4, P < .0001;
schizophrenia (n ¼ 8, 2.2%). Overall, 54.6% (83/152) of Figure 3). In addition, statistically significant improve-
TEAEs resulted in initiation of concomitant medication. ments were observed in all four PSP domains from
The majority of TEAEs (75.7%) were resolved at the end baseline to endpoint, P < .0001: socially useful ac-
of the study. One female patient reported a potentially tivities (2.7 ± 1.2 vs 1.9 ± 1.1; mean change: –0.8 ± 1.0);
prolactin-related TEAE (galactorrhoea). No blood meas- personal and social relationships (2.5 ± 1.0 vs 1.6 ± 1.0;
urements for prolactin were required as part of this mean change: 0.9 ± 1.1); self-care (1.5 ± 1.2 vs
non-interventional study. The mean change in body 0.9 ± 1.1; mean change: 0.6 ± 1.0); and disturbing and
weight from baseline (76.4 ± 15.5 kg) to endpoint aggressive behaviours (1.3 ± 1.3 vs 0.3 ± 0.7; mean
(77.4 ± 15.5 kg) was 1.0 ± 3.1 kg, and the mean change in change: 0.9 ± 1.2). The frequency of PSP functional
body mass index from baseline (26.0 ± 4.8 kg/m2) to impairment categories at baseline and endpoint is dis-
endpoint (26.3 ± 4.8 kg/m2) was 0.3 ± 1.0 kg/m2. At end- played in Figure 4. At endpoint, 74.8% of patients
point, 9.7% of patients had a 7% increase in body showed an improvement of at least one ten-point
weight. The most common EPMS were tremor, occur- category in the PSP scale
ring in nine patients (2.5%), and akathisia, occurring in At baseline, 23.7% (79/334) of patients were some-
seven patients (1.9%). Mean ESRS total score (scale what, very or extremely satisfied with their prior anti-
range 0–102) at baseline was 3.7 ± 5.9. There was a psychotic medication; whereas at endpoint, 80.9%
statistically significant reduction, i.e. improvement, in (271/335) of patients were somewhat, very or
 THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 7

Figure 2. Change in mean BPRS total score over time (efficacy analysis set; n ¼ 365). Statistically significant improvements in BPRS
total score were observed at each timepoint after baseline, starting as early as Day 8.


Mean change P < .0001 vs BL, Wilcoxon-
signed rank test. BPRS total score calculated as sum of 18 single-item scores on a scale of 1 (not present) to 7 (extremely severe),
ranging from 18 to 126. Scores of BPRS, both at baseline and post-baseline, were available for 329 patients within the efficacy
analysis set. Error bars represent SD. BL: baseline; BPRS: Brief Psychiatric Rating Scale.

Figure 3. Patient functioning, as assessed by PSP total score (efficacy analysis set; n ¼ 365). Statistically significant improvements
were observed in PSP total score from baseline to Day 43 and to endpoint.


Mean change P < .0001 vs baseline, Wilcoxon-
signed rank test. Error bars represent SD. PSP: Personal and Social Performance.

extremely satisfied with PP1M treatment, as measured spitalised and discharged again and six patients were
using the MSQ. At study endpoint, 41.4% (151/365) of discharged and re-hospitalised afterwards.
patients were discharged from hospital.
Mean time from admission to first PP1M injection
Discussion
was 9.4 days (range 0–63). The estimated mean hos-
pital stay (time from admission to first discharge) ± In the present study exploring safety, tolerability and
standard error was 41.7 ± 1.1 days. The estimated treatment response of patients with schizophrenia
mean time from the first PP1M injection to first admitted to hospital due to disease exacerbation, and
discharge was 30.1 ± 0.8 days. Of the 167 subjects who were initiated on PP1M treatment within the first
discharged, five patients were discharged then re-ho- 3 weeks of their hospital stay, PP1M treatment
8 L. HARGARTER ET AL.

Figure 4. Patient functioning as assessed by PSP three-category distribution (efficacy analysis set; n ¼ 365). The proportion of
patients categorised as having mild difficulty increased from baseline to endpoint. PSP: Personal and Social Performance.

demonstrated a good safety and tolerability profile restoration of functioning (Hasan et al. 2012). Oral anti-
and was associated with an early, statistically signifi- psychotic medications are recommended for the treat-
cant and clinically meaningful improvement in psych- ment of acutely exacerbated schizophrenia, whereas
otic symptoms, disease severity and patient LATs are generally reserved for long-term maintenance
functioning. of poorly adherent patients, and, as such, there is lim-
Treatment with PP1M was generally well tolerated ited information on their initiation in a hospital setting.
during the 6-week observation period. The side-effect A study evaluating the efficacy of risperidone long-act-
profile was consistent with the well-studied tolerability ing injectable therapy in hospitalised patients with
and safety profile of PP1M (Janssen Cilag et al. 2016), acute schizophrenia found significant improvements
with no new safety issues identified. versus placebo in reducing symptoms, as measured by
In the current study, the main reason for initiating the Positive and Negative Syndrome Scale (PANSS)
PP1M was partial/non-adherence to previous medica- total score and individual PANSS factor scores: Positive
tion, similar to the findings of another naturalistic symptoms, Negative symptoms and Disorganised
study of PP1M given in the inpatient and/or outpatient thoughts (Lauriello et al. 2005). One reason why LATs
settings (Attard et al. 2014). LATs help with adherence may be perceived as not being suitable for treatment
issues (Brissos et al. 2014), and may improve patient of acute schizophrenia is that they may take months
outcomes, including reducing relapses (Schreiner et al. to reach steady state (American Psychiatric Association
2015) and hospitalisations (Kishimoto et al. 2013). A 2010) and there is a need for rapid titration in severely
previous observational study of PP1M found that hos- ill patients (Brissos et al. 2014). Of note is that,
pitalisations were significantly reduced following PP1M although reaching steady-state plasma concentrations
initiation (Taylor & Olofinjana 2014; Taylor et al. 2016). of PP1M may take several months, the approved initi-
Consistent with those observations, in the current ation regimen allows for rapid achievement of thera-
study, of the patients who were discharged, 93% peutic plasma concentrations within 2 weeks of
remained discharged during the 6-week study period. starting PP1M treatment (Janssen Cilag et al. 2016).
The majority of patients achieved a 30% and even Accordingly, in the current study, most patients
a 50% improvement in BPRS total score, the latter (88.8%) were initiated on PP1M about 9 days after hos-
being a recognised clinically meaningful improvement pital admission, and statistically significant and rele-
in acutely exacerbated patients (Leucht et al. 2005, vant improvements in psychotic symptoms (BPRS) and
2006). Comparable PP1M treatment effects have been disease severity (CGI–S) were observed as early as 8
observed in other pragmatic studies of symptomatic, days after PP1M initiation (earliest timepoint measured
exacerbated patients (Hargarter et al. 2015) and non- in the study), indicating an early treatment effect. The
acute patients with schizophrenia (Schreiner et al. early onset of treatment response observed in this
2014, 2015). study is in line with the results of an earlier rando-
Important goals of therapy in acute schizophrenia mised controlled trial of PP1M that demonstrated an
are the reduction of psychotic symptoms and early, statistically significant improvement in psychotic
 THE WORLD JOURNAL OF BIOLOGICAL PSYCHIATRY 9

symptoms versus placebo (Bossie et al. 2011), even in may in turn lead to improved treatment adherence.
markedly to severely ill patients with schizophrenia This naturalistic study provides valuable information
(Alphs et al. 2011). It should be noted, however, that on safety, tolerability and appropriate use of PP1M ini-
PP1M is indicated without prior stabilisation on oral tiation in the hospital setting, and suggests that
antipsychotics only if psychotic symptoms are mild to patients may benefit from early initiation of PP1M dur-
moderate (Janssen Cilag et al. 2016), and is not suit- ing the hospital stay.
able for patients who require immediate symptom
control. Paliperidone as a molecule has little sedating
Geolocation
properties (Jones et al. 2010). Accordingly, during the
present study, approximately 32% of patients received This was an international study conducted in Belgium,
a benzodiazepine, which could be discontinued before Bulgaria, Denmark, Germany, Greece, Israel, Italy,
the end of the study. Kazakhstan and Russia.
In addition to the improvements observed in psy-
chotic symptoms, disease severity and patient func-
Acknowledgements
tioning in this study, more patients were satisfied with
PP1M treatment at endpoint than were satisfied with The authors wish to thank all of the investigators who par-
their prior oral antipsychotic at baseline. Treatment ticipated in the study, as well as Dr Irina Usankova for pro-
ject execution management and her input during
satisfaction has been recognised as an important
discussions regarding data interpretation. The study was
aspect of determining treatment effectiveness (Juckel sponsored by Janssen Pharmaceutica NV. Medical writing
et al. 2014), and is also an important factor for treat- assistance was provided by ApotheCom Ltd, London, and
ment adherence (Atkinson et al. 2004; Fujikawa et al. funded by Janssen Pharmaceutica NV.
2008).
Although there has been conflicting evidence
Statement of interest
regarding the superiority of LATs over oral antipsy-
chotics (Leucht et al. 2011; Kishimoto et al. 2013, Dr Hargarter and Dr Schreiner are full-time employees of
2014), the outcomes of these studies are highly related Janssen Cilag and are shareholders of Johnson & Johnson.
Mr Cherubin is a full-time employee of Janssen Cilag. Dr
to the trial design (Kirson et al. 2013). Naturalistic and
Lahaye is a part-time employee of Janssen Cilag. Dr Tsapakis,
pragmatic studies, such as the current and other Dr Joldygulov, Dr Lambert, Dr Vischia, Dr Swarz and Dr
recent studies in acute (Hargarter et al. 2015) and non- Chomskaya have no conflict of interest to declare. Dr Bozikas
acute patients with schizophrenia (Schreiner et al. has received research support from, or has been an advisor
2014, 2015), provide valuable information in popula- to, or has received speaker’s honoraria from Astra Zeneca,
tions more akin to those encountered in routine clin- Gallenica, Elpen, Janssen Cilag, Lundbeck, and Pharmaserve
Lilly. This study was sponsored by Janssen Cilag.
ical practice (Alphs et al. 2011), by allowing patients
with relevant comorbidities, co-medications and sub-
stance abuse to be included. Funding
The current study design was chosen to balance This work was supported by Janssen-Cilag International NV.
between the study objectives and the limitations of a
non-interventional trial. This study did not aim to com-
pare initiation of PP1M in the hospital setting with References
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