623168

research-article2015
TPP0010.1177/2045125315623168Therapeutic Advances in PsychopharmacologyM Cordiner, P Shajahan

Therapeutic Advances in Psychopharmacology Original Research

Effectiveness of long-acting antipsychotics

Ther Adv Psychopharmacol

2016, Vol. 6(1) 2232

in clinical practice : 1. A retrospective, DOI: 10.1177/

2045125315623168

18-month follow up and comparison

The Author(s), 2015.
Reprints and permissions:
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between paliperidone palmitate, risperidone

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long-acting injection and zuclopenthixol

decanoate
Matthew Cordiner, Polash Shajahan, Sarah McAvoy, Muhammad Bashir and Mark Taylor

Abstract
Objectives: In the UK, nine different compounds are available as long-acting antipsychotic
injections (LAIs). There are few clinical guidelines for determining which LAIs are most
effective in specific patient groups. To measure the clinical effectiveness of LAIs we aimed to
determine the now-established concept of antipsychotic discontinuation rates and measure
Clinical Global Impression (CGI) outcomes.
Method: The population (n was approximately 560,000) was a secondary care NHS adult
mental health service in Lanarkshire, Scotland, UK. This was a retrospective, electronic case
note search of LAI-nave patients commenced on paliperidone palmitate (n = 31), risperidone
long-acting injection (RLAI) (n = 102) or zuclopenthixol decanoate (n = 105), with an 18-month
follow up. KaplanMeier survival statistics for discontinuation rates and hospital admission
were calculated. CGI severity and improvement scores were retrospectively assigned by the
investigating team.
Results: Paliperidone palmitate performed less favourably than risperidone long-
acting injection (RLAI) or zuclopenthixol decanoate. Paliperidone palmitate had higher
discontinuation rates due to any cause, inefficacy and increased hospitalization risk.
Paliperidone palmitate had the smallest proportion of patients assigned a clinically desirable
CGI-I score of 1 (very much improved) or 2 (much improved).
Conclusions: Paliperidone palmitate had less favourable discontinuation and CGI outcomes
compared with RLAI and zuclopenthixol decanoate. This could not be adequately explained
by patients in the paliperidone group being more chronically or severely unwell, nor by the
presence of comorbidities such as alcohol or substance misuse, or by the use of lower mean
Correspondence to:
dosages compared with RLAI or zuclopenthixol decanoate. We considered that prescribers are Polash Shajahan, MBChB,
MPhil, MRCP, FRCPsych
familiarizing themselves with paliperidone and outcomes may improve over time. NHS Lanarkshire, Bellshill
Clinic, Greenmoss Place,
Bellshill ML4 1PS, UK
Keywords: antipsychotics, clinical effectiveness, discontinuation, long-acting psychotics polash.shajahan@
lanarkshire.scot.nhs.uk
Matthew Cordiner,
MBChB, MRCPsych
Sarah McAvoy, MBChB
Introduction terms of which LAI to select [Kane and Garcia- Muhammad Bashir,
Increasing numbers of second-generation antipsy- Ribera, 2009; Llorca et al. 2013] and there is a MBBS, DCP, DPM
NHS Lanarkshire,
chotics have been made available in long-acting dearth of head-to-head comparison trials available Bellshill, UK
injectable (LAI) form, expanding the choice in the to bridge this gap [Covell et al. 2012; McEvoy Mark Taylor, MD,
FRCPsych
UK to nine different compounds. There are few et al. 2014; Fleischhacker, 2009]. First-episode NHS Lothian, Edinburgh,
recommendations or guidelines for prescribers in psychosis [Kahn etal. 2008] and cost effectiveness UK

22 http://tpp.sagepub.com

[Achilla and McCrone, 2013] studies have
reported mixed results generally favouring sec-
ond-generation over first-generation antipsychot-
ics. For chronic schizophrenia, the advantage of
oral second-generation antipsychotics remains
unclear [Leucht et al. 2009; Goff et al. 2005;
Geddes etal. 2000]. The question of clinical effec-
tiveness (combining measures of efficacy plus tol-
erability) remains for LAIs and whether the new
second-generation LAIs offer superior clinical and
cost effectiveness. Since 2003, three of the most
frequently prescribed LAIs within our health board
organization were paliperidone palmitate (paliperi-
done), risperidone long acting injection (RLAI)
and zuclopenthixol decanoate (zuclopenthixol)
and were chosen for evaluation. They provided a
comparison of a well-established first-generation
LAI (zuclopenthixol decanoate) against two sec-
ond-generation LAIs. We aimed to measure clini-
cal effectiveness using the established concept of
antipsychotic discontinuation [McEvoy etal. 2014;
Kahn etal. 2008; Goff etal. 2005]. We also aimed
to examine improvement by assigning Clinical
Global Impression (CGI) [Guy, 1976] scores
(severity and improvement).
Methods
NHS Lanarkshire is a health board in Scotland
serving a population of around 560,000 people,
with a spread of deprivation and rural- and urban-
based areas. Patients in contact with secondary-
care mental health services have an electronic
record on a document management system,
Genisys (see http://www.genisystechnology.co.uk/)
that has been used since 2002. This system has
search functionality allowing keywords to be iden-
tified in all files held within the database. For this
study, permission to search the database was
granted from the local Caldicott Guardian and the
study was registered with NHS Lanarkshires
Clinical Quality Department. No other ethical
issues related to patient care or confidentiality were
identified due to the studys retrospective, case or
chart note nature.
The Genisys database was searched for generic
and trade name of the three LAIs, [paliperidone
(Xeplion), risperidone (Risperdal Consta) proxy marker of effectiveness is that of hospital
and zuclopenthixol decanoate (Clopixol)], as
well as subtle variations if common spelling errors
were noted. Importantly, this initial population
was filtered to include only LAI-nave patients.
Records that contained insufficient information
to allow analysis were excluded, as was one record
http://tpp.sagepub.com 23
M Cordiner, P Shajahan et al.
for which the LAI being used was for challenging
behaviour in a patient with moderate learning dis-
ability. No further exclusions were applied.
Demographic and clinical variables
Information was obtained from the electronic
patient records and is listed in Table 1.
Coprescription with adjunctive oral antipsychot-
ics was recorded if it was a regular (not an as
required or prn prescription) and was present
from examining clinical correspondence for
greater than 50% of the time the patient was on
the LAI of interest. Among our study population,
no patients received clozapine to augment their
LAI. The proportion and combined dosage of
patients who received adjunctive oral antipsy-
chotics was also considered a possible marker of
LAI effectiveness, the hypothesis being that addi-
tional oral antipsychotics would be prescribed if
the LAI was deemed ineffective as a sole agent;
this is the subject of the accompanying paper.
Duration of contact with psychiatric services and
a record of clozapine being trialled before the pre-
scription of the LAI of interest were considered
putative markers of illness severity and treatment
refractoriness.
Discontinuation, hospitalization and clozapine
switch
The time to LAI treatment discontinuation within
18 months for any cause was the main outcome
measure of interest and was regarded as a determi-
nant of clinical effectiveness. This 18-month
period was chosen as it is clinically regarded as a
meaningful time to assess the effects of a first-
prescribed LAI and provided comparison with the
figures from the widely influential CATIE trial
[Goff et al. 2005]. For medications discontinued
before 18 months, the reason was established from
the electronic records and if necessary, consulta-
tion between the authors and individual clinicians.
Discontinuation was further categorized to ineffi-
cacy, adverse effects, or other reasons. Where
more than one reason was listed, the most signifi-
cant clinical reason by consensus decision among
the authors was chosen for analysis. A further
admission. Theoretically, if an antipsychotic is
considered clinically effective, in terms of prevent-
ing relapse of psychosis, be it oral or LAI, it should
prolong the time before admission to psychiatric
hospital is required [McEvoy et al. 2014;
Kishimoto etal. 2013]. For each LAI, if a patient
Therapeutic Advances in Psychopharmacology 6(1)

Table 1. Clinical and demographic details of patients commenced on long-acting injections.

Paliperidone Risperidone LAI Zuclopenthixol p value

palmitate (n = 31) (n = 102) decanoate (n = 105)
Male gender 68% (21) 71% (72) 46% (48) <0.001
Age (years) at start of LAI treatment Mean 36.0 [31.3 40.8] 35.1 [32.9 37.3] 42.4 [39.8 45.0] <0.001
[95% CI]
Contact With Less than 1 16% (5) 4% (4) 10% (10)
Services (Years) 1 to 3 10% (3) 17% (17) 11% (12)
Over 3 68% (21) 78% (80) 77% (81) 0.11
Unknown 6% (2) 1% (1) 2% (2)
Compulsory Treatment Orders 48% (15) 36% (37) 33% (35) 0.31
Primary Diagnosis
Schizophrenia/psychotic disorders a 68% (21) 84% (86) 70% (73) 0.008 c
Bipolar disorder 23% (7) 8% (8) 17% (18)
EUPD 6% (2) 1% (1) 6% (6)
Depressive disorders 3% (1) 4% (4) 7% (7)
Other b 0% (0) 3% (3) 1% (1)
Coprescription with oral antipsychotic 26% (8) 37% (38) 46% (50) 0.057
Coprescription with antidepressant 61% (19) 41% (42) 42% (44) 0.12
Coprescription with mood stabilizer 29% (9) 11% (11) 27% (28) 0.007
Comorbid alcohol misuse 48% (15) 45% (46) 25% (26) 0.003
Comorbid drug misuse 45% (14) 36% (37) 22% (23) 0.02
Previous clozapine treatment 3% (1) 8% (8) 3% (3)
Previous oral antipsychotic prior to LAI
First-generation antipsychotic 0% (0) 3% (3) 12% (13)
Second-generation antipsychotic 94% (29) 73% (74) 47% (49)
Combination antipsychotics 6% (2) 2% (2) 5% (5) <0.0001d
No antipsychotic 0% (0) 15% (15) 16% (17)
Unknown treatment 0% (0) 8% (8) 20% (21)
Reason for switching to LAI
Inefficacy 36% (11) 30% (31) 32% (34)
Nonconcordance 58% (18) 45% (46) 41% (43) 0.21e
Other 6% (2) 25% (25) 27% (28)
Mean daily dose of LAI
Milligrams [95% CI] 4.4 [3.85.0] 2.5 [2.32.7] 25 [2029]
As percentage of BNF maximum 88 74 29
Additional APP dose (% BNF maximum dose)
Median [Range] 50 [15100] 25 [5115] 30 [2.5158] 0.20 f
Geometric mean (after log transformation) 43.1 23.4 27.0
BNF, British National Formulary; LAI, long-acting injectable; CI, confidence interval; APP, antipsychotic polypharmacy; RLAI, risperidone long-
acting injectable.
aIncludes drug-induced psychoses.
bFor RLAI alcoholic hallucinosis (n = 2), avoidant personality disorder (n = 1). For zuclopenthixol decanoate schizotypal disorder (n = 1).
c2 = 9.6, d.f. = 2, p = 0.008 (psychotic versus nonpsychotic disorders).
d2 = 36.8, d.f. = 8, p < 0.001 (second-generation versus others).
e2 = 5.9, d.f. = 4, p = 0.21.
fF
(2,91) = 1.6, p = 0.2.

was admitted to an acute psychiatric unit during starting clozapine was also recorded, as a marker of
the 18 months follow up, the date of this admission treatment refractoriness prior to initiation of the
was recorded and used to calculate the time to LAI and also putatively towards LAI treatment
admission outcome. In a similar fashion, time to failure due to emergent treatment refractoriness.

24 http://tpp.sagepub.com

Clinical Global Impression
The clinical status of individual patients was
assessed using the CGI score for severity and
improvement. The patient records had CGI
severity (CGI-S) scores assigned at the outset of
treatment with the long-acting antipsychotic
injection and then after 18 months or the date of
discontinuation, whichever came sooner. The
CGI-I was also assigned retrospectively, accord-
ing to information within the clinical records. All
CGI scoring was assigned by four of the authors,
all clinical psychiatrists (MC, PS, SM and MB)
working within the Health Authority. Individual
patient records were assigned randomly to the
investigators, to reduce possible inter-rater dis-
crepancy. Throughout data collection, there were
regular discussions and joint assessments to
reduce this further. Raters involved clinically and
directly with patients records were asked to give
the CGI assignment to author MC who also
repeated all CGI measures independently of the
other three assessors. At the conclusion of data
collection, our CGI scores suggested a strong
degree of inter-rater correlation. CGI-I scores
were aggregated into three categories, (A) = (1)
very much improved and (2) much improved, (B)
= (3) minimally improved and (4) no change,
and finally category (C) = (5) minimally worse,
(6) much worse and (7) very much worse. The
reason being that all LAIs are powerful, long-
term psychotropic medications with significant
adverse effects and some are potentially costly
compared with others. As clinicians, we should
strive for the best gains (an A rating) in terms of
CGI improvement, that is, CGI-I (1) and (2)
from interventions such as LAIs and cautiously
review all other improvement categories, partic-
ularly if harm is being done. We felt that a CGI-I
of category (B) that was (3) minimally improved
and (4) no change, was of low clinical utility as it
reflected patients exposed to medications they
had little control over, risk of adverse effects and
the possibility of no significant clinical gain.
Analysis
The results were tabulated using Microsoft Excel
2007, which was also used for the majority of sta-
tistical analysis. Histograms were created to assess
the distribution of numerical data. Continuous
data was reported as means with 95% confidence
intervals (CIs) and compared using analysis of
variance and two-tailed t tests as appropriate.
Categorical data were analysed by way of chi-
square tests, with significance levels requiring a p
http://tpp.sagepub.com 25
M Cordiner, P Shajahan et al.
value of less than 0.05. KaplanMeier survival
curves were computed using MedCalc statistical
software for Microsoft Windows (http://www.
medcalc.org), to calculate percentages, censored
data and to demonstrate time to discontinuation,
hospitalization or switch to clozapine. Overall dif-
ferences within the three groups were assessed for
significance using the log-rank test [Bland and
Altman, 2004]. Differences between LAIs in
terms of risk for discontinuation, hospitalization
and time to clozapine were presented as hazard
ratios (HR) with 95% CIs.
Results
A total of 651 patients were found with mention
of at least 1 of the LAIs of interest. Of these
patients, 394 were excluded as they had previ-
ously received another LAI. A further 18 patients
were excluded due to insufficient information in
their case record for data collection: RLAI (n =
3), zuclopenthixol decanoate (n = 15), 2 = 10.6,
d.f. = 2, the p value was equal to 0.005. The
remaining 238 eligible patient records comprised
paliperidone palmitate (n = 31), RLAI (n = 102)
and zuclopenthixol decanoate (n = 105).
Table 1 shows pretreatment demographic and
clinical features for the three LAI patient cohorts.
There was a statistically significant increased pro-
portion of female patients in the zuclopenthixol
decanoate group at 54% compared with 32% for
paliperidone palmitate and 29% for RLAI, 2 =
14.3, d.f. = 2, p = 0.0008. Patients commenced
on zuclopenthixol decanoate also tended to be
older with a mean age of 42.4 years compared
with 36.0 for paliperidone palmitate and 35.1 for
RLAI (F(2,235) = 9.6, p = 0.001). Between the
three LAIs there were no significant differences in
length of contact with psychiatric services or the
use of compulsory measures to provide treatment
without the patients consent. There was a pro-
portionally higher number of patients with a pri-
mary diagnosis of bipolar affective disorder who
received treatment with paliperidone palmitate.
Stratifying patients into psychotic and nonpsy-
chotic disorders revealed a greater proportion of
patients (86%) with psychotic disorder treated
with RLAI, 2 = 9.6, d.f. = 2, p = 0.008. A
greater proportion of patients on paliperidone
palmitate (61%) were coprescribed an antide-
pressant medication compared with RLAI (41%)
and zuclopenthixol (42%), although this was not
statistically significant, 2 = 4.3, d.f. = 2, p =
0.12. Patients receiving RLAI were less likely to
Therapeutic Advances in Psychopharmacology 6(1)
be prescribed a mood stabilizer: RLAI (11%),
zuclopenthixol decanoate (27%), paliperidone
palmitate (29%), 2 = 10.5, d.f. = 2, p = 0.005.
Almost half of zuclopenthixol decanoate patients
were treated with at least one additional antipsy-
chotic during the 18-month period, this
approached statistical significance (2 = 5.7, d.f.
= 2, p = 0.057). Expressed as a percentage of the
maximum dose stated in the BNF, zuclopenthixol
decanoate was used at lower doses than paliperi-
done palmitate or RLAI. Patients prescribed
zuclopenthixol decanoate were also significantly
less likely to have recorded comorbid alcohol mis-
use at 25%, 2 = 9.1, d.f. = 2, p = 0.01; or drug
misuse at 22%, 2 = 8.2, d.f. = 2, p = 0.01.
There were low numbers of patients having had
previous trials of clozapine, therefore statistical
testing was not performed.
Figure 1 demonstrates KaplanMeier survival
curves calculated for discontinuation, hospitaliza-
tion and clozapine switch. The statistics for this
are shown on Table 2.
Table 2 shows results for treatment discontinua-
tion, hospitalization and clozapine switch. These
results are derived from KaplanMeier survival
analysis and refer to days to treatment discontin-
uation, hospitalization and clozapine switch. The
log-rank chi-square test result is given to show
overall differences within the groups and Cox
model treatment comparisons using HRs with
95% CIs are given to show the differences
between the LAIs using paliperidone as the com-
parator drug.
Treatment discontinuation for any cause differed
between the LAIs and was highest in the paliperi-
done group. This was statistically significant
when compared with RLAI [HR = 0.45 (95% CI
0.220.91), p = 0.03], but not when compared
with zuclopenthixol decanoate.
Treatment discontinuation due to inefficacy also
differed between the LAIs and was highest in the
paliperidone group. This was statistically signifi-
cant when compared with RLAI [HR = 0.27
(95% CI 0.080.86), p = 0.007], but not when
compared with zuclopenthixol. Treatment dis-
continuation due to adverse effects did not differ
significantly between the LAIs, although showed
a trend (p = 0.09) with lowest discontinuation
due to adverse effects associated with RLAI. The
risk of hospital admission differed between the
LAIs and was highest in the paliperidone group.
26 http://tpp.sagepub.com
This was statistically significant when compared
with zuclopenthixol [HR = 0.38 (95% CI 0.16
0.91), p = 0.02], but not when compared with
RLAI.
Table 3 depicts CGI scores for severity and
improvement during treatment. The mean CGI
at start of treatment was similar for all three LAIs
(paliperidone = 4.5, RLAI = 4.6 and zuclopen-
thixol = 4.5, F(2,235) = 0.11, p = 0.89). The end-
point CGI differed (higher for paliperidone
compared with RLAI and zuclopenthixol) but
this failed to achieve statistical significance (F(2,235)
= 2.4, p = 0.096). Analysis of variance did not
show statistically significant differences for mean
CGI-I scores (F(2,235) = 1.8, p = 0.18). However,
following stratification of CGI-I into aggregated
groups, (A) = (1) and (2), (B) = (3) and (4), and
(C) = (5), (6) and (7), paliperidone was associ-
ated with the lowest proportion of patients being
assigned CGI-I category (A) (1, very much
improved, or 2, much improved); 2 = 11.0, d.f.
= 4, p = 0.026.
Discussion
The likelihood of discontinuation due to any
cause, discontinuation due to perceived clinical
inefficacy and psychiatric hospitalization was
highest for paliperidone. The likelihood of dis-
continuation due to adverse effects was similar for
all three LAIs. Compared with RLAI and zuclo-
penthixol, treatment with paliperidone palmitate
was associated with the smallest proportion of
patients assigned a desirable CGI-I score of 1
(very much improved) or 2 (much improved). We
consider why paliperidone was associated with
these unfavourable outcomes.
Clinical and demographic descriptions
There were fewer men prescribed zuclopenthixol
compared with paliperidone and RLAI, of inter-
est, given its association with reduction in aggres-
sion [Haessler etal. 2009], which is commoner in
men. Patients on zuclopenthixol were older than
those taking RLAI or paliperidone palmitate.
This may be a reflection of the higher proportion
of women, and a tendency for women to develop
psychotic illnesses at an older age [Castle et al.
1998]. Paliperidone was prescribed in a signifi-
cantly higher proportion of individuals with bipo-
lar affective disorder than either of the other LAIs,
in keeping with evidence to its effectiveness as an
antimanic treatment [Vieta etal. 2010]. This may

Figure 1. KaplanMeier graphs for discontinuation events.
Legend
1. Paliperidone palmitate
2. Risperidone long-acting injection
3. Zuclopenthixol decanoate
also be linked to the significantly higher copre-
scription of antidepressants in patients receiving
paliperidone. The lower rates of comorbid alco-
hol and substance misuse with zuclopenthixol in
our study may have influenced a more favourable
outcome whilst for paliperidone, higher rates of
alcohol and substance misuse may have influ-
enced a more unfavourable outcome, although
this may not be the case as similar comorbidity
was seen with RLAI. Our comorbidity rates were
of interest and inconsistent with a randomized
6-month trial showing lower severity of alcohol
and substance misuse following RLAI treatment
[Rubio etal. 2006].
http://tpp.sagepub.com 27
M Cordiner, P Shajahan et al.
Future studies examining prospective changes in
alcohol and drug misuse following LAI treatment
will be of significant clinical interest. There were
no significant differences in previous treatment
with clozapine, important as these individuals
would be considered treatment resistant and
improvement with any LAI would be harder to
achieve. Interestingly, RLAI which performed
favourably across discontinuation and CGI meas-
ures had a higher proportion of patients previ-
ously treated with clozapine. Time to clozapine
initiation did not differ between LAIs, suggesting
that all three groups had similar proportions of
treatment-refractory patients, consistent with the
Therapeutic Advances in Psychopharmacology 6(1)

Table 2. KaplanMeier tests for discontinuation, hospitalization and clozapine switch.

Paliperidone Risperidone Zuclopenthixol p value

(n = 31) (n = 102) (n = 105)
Discontinuation for any cause 52% (16) 28% (29) 38% (40)
Days to discontinuation [95% CI] 365 [292439] 457 [424489] 425 [390460]
Cox model treatment Paliperidone 0.45 [0.220.91] 0.64 [0.311.31]
comparisons HR [95% CI] RLAI 1.42 [0.912.24] p = 0.033
Zuclopenthixol
Discontinuation due to inefficacy 29% (9) 10% (10) 12% (13)
Survival (days) [95% CI] 442 [377509] 516 [494537] 510 [489531]
Cox model treatment Paliperidone 0.27 [0.080.86] 0.37 [0.111.18]
comparisons HR [95% CI] RLAI 1.36 [0.652.82] p = 0.007
Zuclopenthixol
Discontinuation due to adverse effects 13% (4) 8% (8) 18% (19)
Survival (days) [95% CI] 492 [439545] 517 [495539] 480 [451510]
Cox model treatment Paliperidone 0.51 [0.151.63] 1.24 [0.384.00]
comparisons HR [95% CI] RLAI 2.44 [1.155.15] p = 0.09
Zuclopenthixol
Hospital admission 39% (12) 25% (25) 18% (19)
Survival (days) [95% CI] 386 [314459] 474 [446503] 491 [464517]
Cox model treatment Paliperidone 0.52 [0.211.27] 0.38 [0.160.92]
comparisons HR RLAI 0.72 [0.421.26] p = 0.02
[95% CI] Zuclopenthixol
Clozapine switch 16% (5) 7% (7) 8% (8)
Survival (days) [95% CI] 502 [455550] 522 [503543] 526 [511542]
Cox model treatment Paliperidone 0.41 [0.101.68] 0.45 [0.111.84]
comparisons HR [95% CI] RLAI 1.10 [0.432.81] p = 0.25
Zuclopenthixol
Log-rank test: Discontinuation for any cause (2 = 6.8, d.f. = 2, p = 0.033), discontinuation due to inefficacy (2 = 9.9, d.f. = 2, p = 0.007), discon-
tinuation due to adverse effects (2 = 4.8, d.f. = 2, p = 0.09), hospital admission (2 = 7.5, d.f. = 2, p = 0.02), clozapine switch (2 = 2.8, d.f. = 2,
p = 0.25). Statistically significant HRs depicted in bold.
Discontinuation due to other causes: paliperidone palmitate (n = 2), RLAI (n = 9), zuclopenthixol (n = 6). Discontinuation due to unknown reasons:
paliperidone palmitate (n = 1), RLAI (n = 2), zuclopenthixol decanoate (n = 1).
HR, hazard ratio; CI, confidence interval; RLAI, risperidone long-acting injectable.

consensus that between 20% and 30% of patients
with schizophrenia require clozapine therapy
[Correll etal. 2009].
Treatment discontinuation and other markers
of effectiveness
52% of patients started on paliperidone palmitate
discontinued treatment before 18 months, higher
than both RLAI (28%) and zuclopenthixol
(38%). The reason for discontinuation of pali-
peridone palmitate in the majority of cases was
inefficacy. This is consistent with the pattern
recorded in the CGI severity and improvement
subscales. There is a notable step in the Kaplan
Meier (discontinuation due to inefficacy) curve at
the 100-day mark. Clinical experience suggests
that beneficial effects of LAIs emerge after three
doses. For paliperidone, this being 100 days, sug-
gested prescribers allowed sufficient time to
elapse before making discontinuation decisions
regarding inefficacy. Discontinuation due to
adverse effects showed no significant differences
between the LAIs. However, 50% of those dis-
continuing zuclopenthixol did so due to adverse
effects, more than either paliperidone (25%) or
RLAI (28%). This was in keeping with the pro-
pensity for first-generation antipsychotic drugs,
such as zuclopenthixol, to cause poorly tolerated
sedation and dopaminergic side effects including
bradykinesia and rigidity. Proportionally more
patients on paliperidone (39%) required admis-
sion during the 18-month follow up and median
time to admission was shortest by approximately

28 http://tpp.sagepub.com
 M Cordiner, P Shajahan et al.

Table 3. Clinical Global Impression severity and improvement outcomes.

Paliperidone RLAI Zuclopenthixol p value

(n = 31) (n = 102) (n = 105)
CGI severity
Start Mean [95% CI] 4.5 [4.14.9] 4.6 [4.44.8] 4.5 [4.34.7] 0.89
End Mean [95% CI] 3.5 [3.13.9] 3.0 [2.73.3] 2.9 [2.63.2] 0.1
CGI improvement
Mean [95% CI] 3.1 [2.73.5] 2.7 [2.52.9] 2.9 [2.63.1] 0.18
A 1, very much improved 6% (2) 29% (9) 15% (15) 40% (41) 12% (13) 45% (48)
2, much improved 23% (7) 25% (26) 33% (35)
B 3, minimally improved 32% (10) 64% (20) 32% (33) 46% (47) 31% (33) 51% (41)
4, no change 32% (10) 14% (14) 20% (21) 0.02*
C 5, minimally worse 6% (2) 6% (2) 12% (12) 14% (14) 2% (2) 3% (3)
6, much worse 0% (0) 2% (2) 1% (1)
7, very much worse 0% (0) 0% (0) 0% (0)
RLAI, risperidone long-acting injectable; CGI-S, Clinical Global Impression score severity; CGI-I, clinical global impression score improvement;
CI, Confidence Interval; *CGI groups tested, (A) versus (B & C combined) (2 = 11.8, d.f. = 4, p = 0.02).

100 days. Admission rates are of particular inter-
est given that over the period of introduction of
paliperidone (2010 onwards), acute psychiatric
admissions beds in the health authority reduced
by one third; the assumption being that admis-
sion threshold to hospital prior to 2010 was lower
and would be reflected in increased admission
rates for RLAI and zuclopenthixol, which was not
the case. Hospital admission has significant impli-
cations for patients and additional financial cost
to healthcare systems. Aside from small differ-
ences in primary diagnosis and age, there were no
other differences between LAI cohorts that
explained different discontinuation rates.
Assessment of illness severity using Clinical
Global Impression
The mean starting severity of illness was similar
between the LAIs, between moderately (where
CGI-S was 4) and severely (where CGI-S was 5)
unwell. However, there were differences at the
end of treatment or 18 months. Patients receiving
paliperidone had the highest mean endpoint
CGI-S scores (3.5), a change of 1 point on the
CGI-S from start of treatment, with more favour-
able outcomes in the RLAI (mean CGI-S was
3.0) and zuclopenthixol (mean CGI-S was 2.9)
cohorts. Our study showed CGI-S outcomes at
18 months or discontinuation in keeping with the
EUFEST study [Kahn etal. 2008], where patients
achieved end-point severity outcomes at 12
months of borderline ill (where CGI-S was 2) to
mildly ill (where CGI-S was 3). This was
encouraging, as our patients were unlikely to be
in their first episode of psychosis and were more
likely to have shown significant past contact with
psychiatric services (over two thirds having con-
tact greater than three years, indicating generally
more chronic illness). When mean CGI-I scores
were used, there were no statistically significant
differences between LAIs. Forming the CGI-S
ratings into categories (A, B and C) suggested
that compared with zuclopenthixol or RLAI, pali-
peridone was associated with a significantly lower
proportion of patients assigned to the clinically
desirable category A (where CGI-I was 1 or 2).
These less favourable CGI-S and improvement
category outcomes for paliperidone may be a
reflection of the lower proportion of patients with
a primary psychotic illness suggesting that LAIs
bring about greater improvements in psychotic
rather than nonpsychotic disorders.
Limitations
Given the retrospective nature of this study, there
is reliance on quality documentation of clinical
findings. In most cases, it was possible to make a
reasoned judgment about patient details and ill-
ness severity. Accurately measuring the titration
rate of the LAI dose was not possible, partly due
to the wide variety of dosing strategies for zuclo-
penthixol decanoate (one to four weekly), and
variable quality of prescription change recording.
Potentially, incorrect titration and low immedi-
ate prediscontinuation dose may arguably be of
greater importance for paliperidone palmitate

http://tpp.sagepub.com 29
Therapeutic Advances in Psychopharmacology 6(1)
where less favourable effectiveness was shown.
However, the high median doses of paliperidone
palmitate suggest that it was used in proposed
therapeutic [Scottish Medicine Consortium,
2011] and higher doses than RLAI zuclopen-
thixol decanoate. In some electronic case records,
there was a dearth of information and these
patients were excluded (as outlined in methods).
There is also a risk that descriptions about illness
severity were not conveyed accurately in the
records available, but this was not unique to one
particular LAI and thus should not bias findings
towards one particular LAI. However, this may
influence the magnitude of effect detected. The
CGI was originally designed to be used prospec-
tively, but has been used retrospectively by our-
selves [Shajahan et al. 2008, 2010], and others
[Barbee et al. 2004; Centorrino et al. 2005] for
similar studies; it may not have the ability to
define changes in specific symptoms, however is
arguably more applicable to routine clinical prac-
tice and carries more meaning for patients and
clinicians. The consistent findings between CGI
results and objective markers such as discontinu-
ation or hospitalization suggested that efforts to
minimize inter-rater differences were successful.
Time taken to hospitalization, although a useful
marker of effectiveness, is at risk of influence
from other variables, such as a patients social
and family support, that are unrelated to the LAI
medication. However, we feel it can be reasona-
bly assumed within our free-to-access National
Health Service, that these factors (social and
family support) were distributed across all three
LAI cohorts and consequently unlikely to bias
results.
The effectiveness of paliperidone palmitate
Our study was a noninterventional, naturalistic
study examining prescribing patterns and out-
comes for the three most-prescribed LAIs in the
local health board. Such naturalistic studies
describe a broad range of patients and give out-
come data that can be helpful in routine clinical
practice [Centorrino et al. 2005]. Our findings
suggest that for our main outcome measure, all
cause discontinuation; paliperidone palmitate did
not perform as favourably as RLAI or zuclopen-
thixol decanoate. In addition, paliperidone was
associated with a higher risk of hospital admission
compared with RLAI and was not associated with
desired levels of CGI-I scores (1) and (2). Aside
from higher rates of discontinuation due to
adverse effects in the zuclopenthixol decanoate
30 http://tpp.sagepub.com
group, which did not reach statistical significance,
there was little to distinguish RLAI and zuclopen-
thixol decanoate in terms of clinical effectiveness.
The relatively unfavourable outcomes with pali-
peridone cannot be explained by evidence that
the patients in that group were more severely or
chronically ill to start with or more likely to be
treatment refractory. There was evidence that
patients on paliperidone and RLAI had a greater
proportion of comorbid alcohol and drug misuse
(almost double the proportion compared with
that recorded for zuclopenthixol decanoate). This
still does not adequately explain the difference in
effectiveness between paliperidone and RLAI.
We had previously seen mixed and some unfa-
vourable discontinuation rates with RLAI com-
pared with zuclopenthixol five years after the
introduction of RLAI to our locality [Shajahan
etal. 2008]. Five years later, there is little to dif-
ferentiate zuclopenthixol from RLAI across the
measures of effectiveness that we examined. It is
possible that there were unknown factors result-
ing in the unfavourable outcomes for the rela-
tively new paliperidone. It is possible that a similar
pattern will be seen over time with improved
effectiveness, as clinicians grasp a fuller under-
standing of patients most likely to benefit from
paliperidone. This study requires replication with
a greater number of patients commenced on pali-
peridone. It is possible that we have not arrived at
the correct dosing structure or schedule for
paliperidone.
As stated in a recent editorial in JAMA Psychiatry
the need to integrate specific knowledge, gen-
eral knowledge, and sometimes best hunches in
clinical care of individual patients [Carpenter
and Buchanan, 2015] may be something that
evolves after physicians are given time to become
familiar with a medication. Further open trials
with a broad range of patients may help us decide
whether there are true differences in clinical
effectiveness between these LAIs. Meanwhile, we
welcome the introduction of new LAIs to provide
a wider range of treatments available for patients.
Funding
This research received no specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest statement
All the authors are employed by the NHS. MT
has received hospitality and fees from Janssen;
Lundbeck; Otsuka; and Roche in the last 3 years.

References
Achilla, E. and McCrone, P. (2013) The cost
effectiveness of long-acting/extended-release
antipsychotics for the treatment of schizophrenia:
a systematic review of economic evaluations. Appl
Health Econ Health Policy. 11: 95106.
Barbee, J., Conrad, E. and Jamhour, N. (2004) The
effectiveness of olanzapine, risperidone, quetiapine
and ziprasidone as augmentation agents in treatment-
resistant major depressive disorder. J Clin Psychiatry
65: 975981.
Bland, J. and Altman, D. (2004) The log-rank test.
Br Med J 328: 1073.
Carpenter, W. and Buchanan, R. (2015) Expanding
therapy with long-acting antipsychotic medication
in patients with schizophrenia. J Am Med Assoc
Psychiatry 72: 659667.
Castle, D., Sham, P. and Murray, R. (1998)
Differences in distribution of ages of onset in males
and females with schizophrenia. Schizophr Res 33:
179183.
Centorrino, F., Fogarty, K., Cimbolli, P.,
Salvatore, P., Thompson, T., Sani, G. etal. (2005)
Aripiprazole: initial clinical experience with 142
hospitalized psychiatric patients. J Psychiatr Pract 11:
241247.
Correll, C., Rummel-Kluge, C., Corves, C., Kane,
J. and Leucht, S. (2009) Antipsychotic combinations
versus monotherapy in schizophrenia: a meta-analysis
of randomized controlled trials. Schizophr Bull 35:
443457.
Covell, N., Schooler, N., Stroup, T., Jackson, C.,
Rojas, I., Essock, S. etal. (2012) Effectiveness of
switching from long-acting injectable fluphenazine
or haloperidol decanoate to long-acting injectable
risperidone microspheres. J Clin Psych 73: 669675.
Fleischhacker, W. (2009) Second-generation
antipsychotic long-acting injections: systematic review.
Br J Psych 195: 2936.
Geddes, J., Freemantle, N., Harrison, P. and
Bebbington, P. (2000) Atypical antipsychotic in
the treatment of schizophrenia: systematic overview
and meta-regression analysis. Br Med J 321:
13711376.
Goff, D., Sullivan, L., McEvoy, J., Meyo, J.,
Nasrallah, H., Daumit, G. etal. (2005) A comparison
of ten-year cardiac risk estimates in schizophrenia
patients from the CATIE study and matched controls.
Schizophr Res 80: 4553.
Grech, P. and Taylor, D. (2012) Long-term
antipsychotic polypharmacy: how does it start, why
http://tpp.sagepub.com 31
M Cordiner, P Shajahan et al.
does it continue? Ther Adv Psychopharmacol 2:
511.
Guy, W. (1976) ECDEU Assessment Manual for
Psychopharmacology. Rockville, MD, US Department
of Health, Education.
Haessler, F., Glaser, T., Beneke, M., Pap, A.,
Bodenschatz, R. and Olaf, R. (2009) Zuclopenthixol
in adults with intellectual disabilities and aggressive
behaviours, Discontinuation study. Br J Psych 190:
447448.
Hasan, A., Falkai, P., Wobrock, T., Lieberman,
J., Glenthoj, B., Gattaz, W. etal. (2012) World
Federation of Societies of Biological Psychiatry
(WFSBP) Guidelines for Biological Treatment of
Schizophrenia, part 1: update 2012 on the acute
treatment of schizophrenia and the management
of treatment resistance. World J Biol Psychiatry 13:
31878.
Kahn, R., Fleischhacker, W., Boter, H., Davidson,
M., Vergouwe, Y., Keet, I. etal. (2008) Effectiveness
of antipsychotic drugs in first-episode schizophrenia
and schizophreniform disorder: an open randomised
clinical trial. Lancet 371: 10851097.
Kane, J. and Garcia-Ribera, C. (2009) Clinical
guideline recommendations for antipsychotic long-
acting injections. Br J Psych 195: 6367.
Kishimoto, T., Nitta, M., Borenstein, M., Kane, J.
and Correll, C. (2013) Long-acting injectable versus
oral antipsychotics in schizophrenia. J Clin Psychiatry
74: 957965.
Leucht, S., Corves, C., Arbter, D., Engel, R., Li, C.
and Davis, J. (2009) Second-generation versus first-
generation antipsychotic drugs for schizophrenia: a
meta-analysis. Lancet 373: 3141.
Llorca, P., Abbar, M., Courtet, P., Guillaume, S.,
Lancrenon, S. and Samalin, L. (2013) Guidelines
for the use and management of long-acting injectable
antipsychotics in serious mental illness. BMC
Psychiatry 13: 340357.
McEvoy, J., Byerly, M., Hamer, R., Dominik, R.,
Swartz, M., Rosenheck, R. etal. (2014) Effectiveness
of paliperidone palmitate versus haloperidol decanoate
for maintenance treatment of schizophrenia: a
randomised clinical trial. J Am Med Assoc 311:
19781987.
Rubio, G., Martnez, I., Ponce, G., Jimnez-Arriero,
M., Lpez-Muoz, F. and lamo, C. (2006)
Long-acting injectable risperidone compared with
zuclopenthixol in the treatment of schizophrenia with
substance abuse comorbidity. Can J Psychiatry 51:
531539.
Therapeutic Advances in Psychopharmacology 6(1)
Scottish Medicine Consortium (2011) Advice on
Paliperidone, https://www.scottishmedicines.org.uk/
files/advice/paliperidone_xeplion_resubmission_final_
october_2011_for_website.pdf (accessed on
11 October 15).
Shajahan, P., MacRae, A., Bashir, M. and Taylor,
M. (2008) Who responds to aripiprazole in clinical
Visit SAGE journals online practice? An observational study of combination
http://tpp.sagepub.com
versus monotherapy. J Psychopharmacol 22:
SAGE journals 778783.
32 http://tpp.sagepub.com
Shajahan, P., Spence, E., Taylor, M., Daniel, D. and
Pelosi, A. (2010) Comparison of the effectiveness
of depot antipsychotics in routine clinical practice.
Psychiatrist 34: 273279.
Vieta, E., Nuamah, I., Lim, P., Yuen, E., Palumbo, J.,
Hough, D. and Berwaerts, J. (2010) A randomized,
placebo- and active-controlled study of paliperidone
extended release for the treatment of acute manic and
mixed episodes of bipolar I disorder. Bipolar Disord
12: 230243.