Improved symptom control, functioning and satisfaction

L’Encéphale (2008) 34, 170—178
Disponible en ligne sur www.sciencedirect.com
journal homepage: www.elsevier.com/locate/encep
PSYCHOPATHOLOGY
Improved symptom control, functioning and
satisfaction in French patients treated with
long-acting injectable risperidone
La rispéridone injectable à action prolongée
améliore le contrôle des symptômes, le
fonctionnement et la satisfaction dans une
population de patients français
P.-M. Llorca a,∗, P. Bouhours b, V. Moreau-Mallet b ,
the French investigators group
a
b
Centre hospitalier universitaire, psychiatrie B, place Henri-Dunand, 63003 Clermont-Ferrand cedex 1, France
Janssen-Cilag S.A., 1, rue Camille-Desmoulins, TSA 91003, 92787 Issy-les-Moulineaux cedex 9, France
Received 11 December 2006; accepted 7 June 2007
Available online 1 November 2007
KEYWORDS
Long-acting
risperidone;
Functioning;
Tolerability;
Quality of life
∗
Summary
Objective. — To investigate the efficacy and tolerability of direct initiation of long-acting
injectable risperidone (LAIR) in adults with schizophrenia or other psychotic disorders requiring
a change of treatment.
Methods. — Patients clinically stable for one month or more on their previous medication
received 25 mg of LAIR (increased to 37.5 or 50 mg, if necessary) every 14 days for six months.
Results. — Of 202 patients (70% male, mean age 38 years), the majority (86%) had DSM-IV
schizophrenia (mainly paranoid). Previous treatments were atypical antipsychotics (65%), depot
(34%) and oral (9%) conventional neuroleptics. Mean total positive and negative syndrome scale
(PANSS) score was significantly reduced from baseline to treatment endpoint (79.4 versus 68.3,
P < 0.001), as were all subscale and symptom factor scores. The clinical global impressiondisease severity (CGI-S), general assessment of functioning (GAF), health-related quality of life
Corresponding author.
E-mail addresses: [email protected], Pmlfl[email protected] (P.-M. Llorca).
0013-7006/$ — see front matter © L’Encéphale, Paris, 2008.
doi:10.1016/j.encep.2007.06.004
Improvements with RLAI in French patients
171
(SF-36) and patient satisfaction with treatment were also improved significantly. At endpoint,
31% rated the treatment as ‘very good’ compared with 8% at baseline. The total extrapyramidal symptoms rating scale (ESRS) and Parkinsonism subscale scores were reduced significantly
(P < 0.001) from baseline at one month and further improved until treatment endpoint.
Conclusion. — LAIR significantly improved disease symptoms, patient functioning, movement
disorders, health-related quality of life and treatment satisfaction. It therefore provides a
useful option for the management of patients with psychotic disorders.
© L’Encéphale, Paris, 2008.
MOTS CLÉS
Rispéridone à action
prolongée ;
Fonctionnement ;
Tolérance ;
Qualité de vie
Résumé
Objectif. — Évaluer l’efficacité et la tolérance d’un passage direct à la rispéridone injectable à
libération prolongée (RILP) chez des adultes qui souffrent de schizophrénie ou d’autres troubles
psychotiques et qui nécessitent un changement de traitement.
Méthodes. — Des patients cliniquement stables depuis au moins un mois sous leur traitement
antipsychotique antérieur ont reçu 25 mg de RILP (augmentée à 37,5 ou 50 mg en cas de besoin)
toutes les deux semaines pendant six mois.
Résultats. — De 202 patients (70 % hommes, âge moyen 38 ans) la majorité (86 %) souffrait
d’une schizophrénie diagnostiquée à l’aide du DSM-IV, principalement de forme paranoı̈de.
Les traitements antérieurs étaient des antipsychotiques atypiques (65 %), des neuroleptiques à
action prolongée (34 %) et des neuroleptiques conventionnels (9 %). Le score total moyen selon
la Positive and Negative Syndrome Scale (PANSS) a diminué de manière significative entre le
début et la fin (endpoint) du traitement (79,4 contre 68,3 ; p < 0,001). Le même résultat a
été observé pour les sous-échelles de la PANSS et les facteurs liés aux symptômes. De plus, une
amélioration importante a été constatée à la fin de l’étude dans les points suivants : l’évaluation
de la gravité de la maladie Clinical Global Impression-disease severity (CGI-sévérité), l’échelle
globale de fonctionnement (EGF), la qualité de vie liée à la santé (QoL) par l’intermédiaire
du questionnaire sur la santé à 36 items SF et la satisfaction des patients. La proportion des
patients qualifiant le traitement comme « très bon » a augmenté entre le début (8 %) et la fin
de l’étude (31 %). Les scores Extrapyramidal Symptoms Rating Scale (ESRS) totaux et les scores
de la sous-échelle du parkinsonisme ont diminué significativement (p < 0,001) après un mois de
traitement et ont montré une amélioration continue jusqu’à la fin du traitement.
Conclusion. — La RILP améliore significativement les symptômes associés à la maladie, le fonctionnement, les troubles moteurs, la qualité de la vie liée à la santé et la satisfaction des
patients au traitement. La rispéridone injectable à libération prolongée représente une alternative intéressante pour les patients qui souffrent de troubles psychotiques.
© L’Encéphale, Paris, 2008.
Introduction
There is growing recognition that the optimal management
of patients with schizophrenia or other psychotic disorders
needs to extend beyond symptom control to encompass
relapse prevention and improvement in the patient’s overall functional capacity and quality of life [22,27]. Studies
with the atypical antipsychotics have shown that they can
provide considerable improvements in global psychopathology and in the control of positive, negative, affective and
cognitive symptoms compared with the conventional neuroleptics [22]. There is also evidence that they are more
effective for the prevention of relapse [13,14,29] and that
their use is associated with improved quality of life and satisfaction with treatment [4,27]. In the meantime it has even
been suggested that symptomatic remission is an achievable objective for a significant proportion of patients with
schizophrenia [3].
Whilst socioeconomic factors have an important impact
on the quality of life of patients with schizophrenia, poorly
controlled symptoms also adversely affect this important
aspect of the patient’s overall perception of health [6,27].
Importantly, good adherence to antipsychotic medication
regimens can contribute to a good quality of life, if the
patient’s symptoms are reduced and few adverse effects
are experienced [36]. However, the majority of patients are
only partially compliant with oral antipsychotic regimens
[32] and this has not improved with the introduction of the
atypical antipsychotics [7,15,19,26,31].
Depot preparations of the conventional neuroleptics have
a well-established role in the management of patients with
schizophrenia. In addition to ensuring delivery of medication, their pharmacokinetic profiles reduce the daily
fluctuations in plasma drug concentrations that are seen
with orally administered drugs and so, can help to maximise both the efficacy and tolerability of treatment [5,17].
Patients who are established on treatment with a depot
neuroleptic have a high degree of acceptance and satisfaction with their medication [37]. Nevertheless, the
conventional depot neuroleptics have several limitations,
including less efficacy and poorer tolerability, particularly
with respect to movement disorders [7], than the atypical
antipsychotics. The development of risperidone long-acting
injectable (RLAI) has combined the advantages of a longacting antipsychotic formulation with the benefits of the
atypical agents [11,17].
172
Clinical studies with RLAI have shown that it is effective
for both the short-term [24], and long-term [18] treatment of patients with schizophrenia. Patients have been
shown to have significant improvements in psychopathology
[18,24,28,35,40] and in health-related quality of life [35,36]
after being changed to treatment with RLAI, regardless of
their previous antipsychotic therapy. The change of treatment also led to a significant reduction in the severity of
movement disorders [18,24,28,35,40].
In most previous trials patients received an oral risperidone run-in before beginning treatment with RLAI. This
study, however, investigated the antipsychotic efficacy and
safety of a direct transition to RLAI, without an oral
risperidone run-in, in patients with schizophrenia or other
psychotic disorders who required a change of treatment. We
present here the results of a subgroup analysis performed in
all patients from French study centres that were included in
an international trial.
P.-M. Llorca et al.
Treatment
Data were derived from a six-month, nonrandomized, single
arm, open-label, European trial that evaluated the safety
and tolerability of a direct transition to RLAI without an oral
risperidone run-in. The trial was performed in accordance
with the guidelines of the International Conference on Harmonisation for Good Clinical Practice, as contained in the
Declaration of Helsinki. In addition, the study protocol was
approved by the Independent Ethics Committee at each of
the participating study centres.
RLAI (Risperdal Consta® ) was injected into the gluteal
muscle every two weeks. The recommended starting dose
was 25 mg but patients with persistent symptoms or who
were known to respond only to higher dosages of antipsychotics could receive initial doses of either 37.5 or 50 mg.
Thereafter, the dosage could be adjusted according to the
patient’s symptoms and response to treatment.
Patients were transitioned directly from their previous
antipsychotic medication to RLAI without an oral risperidone
run-in. It was recommended that the tolerability of oral
risperidone should be investigated before initiating treatment with RLAI in patients who had no history of previous
risperidone use. All patients continued with their previous
antipsychotic regimen for 21 days after the first injection of
RLAI, after which it was stopped or tapered off over three
days [35]. Patients being treated with conventional depots
were changed according to a defined scheme based on the
interval of the injection.
Patients could receive other psychotropic agents that had
been initiated prior to the trial for other reasons (e.g. sleep
induction or sedation) but the dose was required to remain
stable. Oral risperidone supplementation could be used to
manage any exacerbation of psychotic symptoms between
study visits that required an immediate dose adjustment
and also for up to 21 days following an increase in the dose
of RLAI if an immediate clinical effect was needed. Finally,
benzodiazepines could be used as rescue medication for
periods of no more than 10 consecutive days.
Patients
Assessments
Patients, aged 18 years or older, with schizophrenia or other
psychotic disorders according to the Diagnostic and Statistical Manual, fourth edition (DSM-IV), [2] treated with
any antipsychotic medication, could be included in the
study if the treating physician considered them to require a
change of medication for any reason (e.g. lack of efficacy,
side effects or poor compliance with current therapy). All
patients were required to have been symptomatically stable
and on constant doses of one or more antipsychotic agents
for at least one month before the screening visit. Patients
could be either hospitalised or outpatients at the time of
enrolment and throughout the study.
Patients receiving their first antipsychotic treatment,
who had received clozapine during the previous three
months, participated in an investigational drug trial in the
previous 30 days or had previously been shown to be either
intolerant or a non-responder to risperidone therapy were
excluded from the study. Other exclusion criteria included
the presence of a serious unstable medical condition, including clinically relevant laboratory abnormalities, a history
or current symptoms of tardive dyskinesia and a history of
neuroleptic malignant syndrome. Pregnant or breast-feeding
female patients were also ineligible and all other female
subjects of childbearing potential were required to use adequate contraception and to have a negative urine pregnancy
test at the screening visit.
All patients or their legal representatives provided written informed consent before their enrolment in the study.
Efficacy was assessed at baseline and after one, three and six
months of treatment (or treatment endpoint) using the positive and negative syndrome scale [25,33] and the clinical
global impression-disease severity (CGI-S) [20]. Functional
status was evaluated at baseline and six months by the
global assessment of functioning (GAF) scale, in which a
score of 100 represents best possible functioning [2]. The
patient-rated SF-36 quality of life questionnaire [34,41],
completed at baseline, three and six months was used to
assess health-related quality of life, while patient satisfaction with treatment was rated at baseline and six months
using a 5-point scale: very good, good, moderate, poor or
very poor. Severity of movement disorders was assessed
at baseline and after one, three and six months using the
extrapyramidal symptoms rating scale (ESRS) [10]. Adverse
events, vital signs and body weight were recorded by the
investigator at each study visit.
Subjects and methods
Data analysis
The intention-to-treat (ITT) data set included all patients
who received at least one injection of RLAI and completed
at least one post-baseline efficacy assessment. This population formed the basis for all safety analyses and also for
efficacy analyses using a last-observation-carried-forward
(LOCF) analysis with respect to endpoint visits. Changes
from baseline to endpoint in PANSS scores, CGI, SF-36, GAF,
patient satisfaction with treatment and ESRS scores were
Improvements with RLAI in French patients
analysed using the Wilcoxon signed rank test at the 5% significance level.
173
Table 2
Survey of previous antipsychotic drugs.
Drug
Results
A total of 202 patients were enrolled at study centres in
France. One patient received no trial medication and so
was not included in the ITT analysis. Of the remaining 201
patients, 69% completed the six-month study. The most common reason for early discontinuation was withdrawal of
consent (10% of patients enrolled in the study). Other reasons for early discontinuation were insufficient efficacy (6%),
loss to follow-up (4%), adverse events (4%), noncompliance
(3%), death (0.5%) and other reasons (3%).
Baseline demographic data and disease characteristics
for all patients who entered the study are shown in Table 1.
Of those patients with schizophrenia, 64% had the paranoid
subtype.
At trial entry, the most common treatment was an atypical antipsychotic (65%) or a conventional depot neuroleptic
(34%; Table 2). The majority of patients (83%) were on
monotherapy. Among the 34 patients (17%) on polytherapy,
25 were changed to RLAI monotherapy, while RLAI replaced
one agent in the regimens of the remaining nine patients.
The most frequently cited reasons for changing treatment to
RLAI were noncompliance with previous medication according to physician assessment (49%), insufficient efficacy (24%)
and side effects (mainly movement disorders) with the previous regimen (22%).
The majority of patients (82%) were started on RLAI at the
25 mg dose, while the remainder received the 37.5 mg (12%)
or 50 mg dose (6%). At endpoint, 44% of patients were receiv-
Table 1
Baseline demographic and disease characteristics.
Number of patients
Males/females
202
141 (70%)/61 (30%)
Race
Caucasian
Hispanic
Black
Oriental
Other
167 (83%)
5 (3%)
9 (5%)
13 (6%)
8 (4%)
Age (years)a
Height (m)a
Weight (kg)a
Body mass index (kg/m2 )a
37.5 ± 12.0
1.71 ± 0.09
76.3 ± 15.3
26.1 ± 5.1
Diagnosis (DSM-IV)
Schizophrenia
Schizoaffective disorder
Schizophreniform disorder
Other
174 (86%)
18 (9%)
4 (2%)
6 (3%)
Disease history
Age at onset of symptoms (years)a
Age at diagnosis (years)a
Ever hospitalised
Currently hospitalized
23.5 ± 7.5
26.1 ± 8.4
199 (99%)
86 (43%)
a
Mean ± S.D.
Number of
patientsa
Mean dose
(mg/day)
Oral neuroleptics
Fluphenazine hydrochloride
Haloperidol
Levomepromazine
Penfluridol
Zuclopenthixol
18 (9%)
1
9
5
1
2
200.0
25.6 ± 26.2
170.0 ± 103.7
2.9
47.5 ± 38.9
Depot neuroleptics
Flupenthixol decanoate
Fluphenazine decanoate
Haloperidol decanoate
Pipotiazine palmitate
Zuclopenthixol decanoate
68 (34%)
6
8
30
11
13
2.4 ± 2.4
9.0 ± 12.0
6.0 ± 2.9
3.9 ± 2.9
11.8 ± 10.1
131 (65%)
13
13
105
538.5 ± 352.5
19.2 ± 10.0
6.4 ± 3.0
Atypical antipsychotics
Amisulpride
Olanzapine
Risperidone
a
Patients could have been changed from more than one agent.
ing the 25 mg dose, while 22 and 33% were receiving 37.5 and
50 mg, respectively. During the six-month treatment period,
20% of patients received oral risperidone supplementation at
a mean modal dose of 3.5 ± 1.7 mg and for a mean duration
of 34.2 ± 40.5 days.
Symptom control
At baseline, the mean PANSS score was 79.4 ± 22.4 (range
31—129) and this was significantly reduced at treatment
endpoint (68.3 ± 26.3, range 30—145; P < 0.001). Improvement was apparent after one month of treatment and
further reductions were seen with ongoing treatment during the six-month study period (Fig. 1). At endpoint,
40% of patients had a ≥20% improvement in the PANSS
total score compared with baseline. In addition, significant
improvements from baseline to endpoint (P < 0.001) were
seen in the subscores for the PANSS positive (16.3 ± 6.5
versus 14.8 ± 7.7), negative (23.6 ± 7.9 versus 19.2 ± 7.9)
Figure 1 PANSS total score (mean ± S.D.) at each visit and at
study endpoint (P ≤ 0.001 all shifts versus baseline).
174
P.-M. Llorca et al.
Figure 4 Patient satisfaction with treatment at baseline and
endpoint (P ≤ 0.001 shift versus baseline).
Figure 2 Clinical global impression (disease severity) at baseline and endpoint (P ≤ 0.001 shift versus baseline).
and general psychopathology subscales (39.5 ± 11.7 versus
34.2 ± 13.3) and also in the positive symptoms (20.9 ± 7.2
versus 18.3 ± 8.4), negative symptoms (22.1 ± 7.7 versus 17.8 ± 7.2), disorganized thoughts (18.8 ± 5.9 versus 16.1 ± 6.6) and anxiety/depression (9.9 ± 3.8 versus
8.5 ± 3.8) factors of Marder [33].
There was a significant improvement from baseline to
endpoint in the CGI-S (P < 0.001). At baseline, no patients
were considered to be ‘normal, not ill’, and this had
increased to 9% at endpoint (Fig. 2).
Functioning and quality of life
There was an improvement in patients’ functioning over the
duration of the study, with a significant increase in the mean
GAF score from 54.3 ± 15.8 at baseline to 61.1 ± 19.5 at
endpoint (P < 0.001).
There was an overall improvement in health-related
quality of life during the six-month treatment period, with
increases from baseline to endpoint (P < 0.05) reported in
the mean scores for all factors of the SF-36 except bodily pain (Fig. 3). Clinically significant improvements (i.e. >5
points) [38] were seen for the role physical, general health,
social functioning, role emotional and mental health factors.
Figure 3 Change from baseline to endpoint in health-related
quality of life (mean SF-36 scores; all shifts P < 0.05 versus baseline, except bodily pain).
Satisfaction with treatment
Patient satisfaction with treatment was significantly
improved at endpoint compared with baseline (P < 0.001).
The proportion of patients who rated their satisfaction as
‘very good’ increased from 8% at baseline to 31% at endpoint
(Fig. 4).
Safety
Overall, 79% of patients reported an adverse event during
the six-month treatment period, the majority of which were
considered to be either mild (39%) or moderate (44%) in
severity. The most frequently reported treatment-emergent
adverse events were anxiety (15%), insomnia and weight gain
(both 9%). One patient reported impotence, one patient had
a treatment-emergent glucose-related adverse event (newonset diabetes mellitus) and two patients reported adverse
events associated with the injection site. Adverse events
were the main reason for treatment discontinuation in seven
patients (4%). One patient died during the study (suicide).
There were significant reductions from baseline in the
mean scores for both the total ESRS and the Parkinsonism subscale after one month of treatment (P < 0.001) and
further improvements were seen up to treatment endpoint
(Fig. 5). Significant improvements from baseline to endpoint
(P ≤ 0.001) were also seen in all the other ESRS subscales.
Analysis of improvements in ESRS total scores according to
previous therapy revealed significant reductions from baseline to endpoint (P < 0.001) in patients previously receiving
Figure 5 Total ESRS and Parkinsonism subscale scores at each
study visit and endpoint (all shifts P ≤ 0.001 versus baseline).
Improvements with RLAI in French patients
monotherapy with either an atypical antipsychotic (n = 110;
−2.7 points), or a conventional depot neuroleptic (n = 48;
−7.2 points).
There were no clinically significant changes in vital
signs during the six-month treatment period. Overall, the
patients experienced small but nonsignificant increases from
baseline to endpoint in mean body weight (76.1 ± 14.9 versus 76.6 ± 15.1 kg) and body mass index (26.0 ± 5.0 versus
26.2 ± 5.1 kg/m2 ).
Discussion
In this study, patients were transitioned directly from
their previous antipsychotic therapy to treatment with RLAI
without an oral risperidone run-in. They experienced significant improvement in symptom control, overall functioning
and health-related quality of life. All these improvements were consistent with those reported in studies with
RLAI that included an oral risperidone transition period
[18,24,36] and also with other studies which have described
a treatment change to RLAI without an oral run-in phase
[30,35,39].
Patients entering the present study were required to be
symptomatically stable and on a stable dose of their previous antipsychotic regimen in the month prior to enrolment.
Thus, in the opinion of the investigator, there had been
no appreciable change in psychotic symptoms during the
previous month, regardless of the severity of those symptoms. It is striking, therefore, that antipsychotic efficacy
was not simply maintained following the change of treatment to RLAI but that there were significant improvements
in symptom control, as demonstrated by the reductions in
PANSS scores and in the CGI-S, compared with the previous
treatment. These improvements in symptom control were
sustained throughout the study period and a downward trend
in the PANSS total score was still apparent after six months of
treatment with RLAI. Importantly, these improvements were
apparent across all symptom types, as demonstrated by the
significant reductions in the PANSS positive and negative
subscales and symptom factors, in the general psychopathology subscale and in the anxiety/depression and disorganised
thoughts factors. Furthermore, 9% of patients were considered to be ‘normal, not ill’ after six months of treatment
with RLAI.
The reductions in the severity of psychotic symptoms
were accompanied by improvements in the patients’ overall functional capacity, as demonstrated by the increased
scores on the physician-assessed GAF and in the patientreported SF-36 health-related quality of life questionnaire.
These improvements were achieved without the need to
treat the majority of patients with the highest available dose
of RLAI; at treatment endpoint, only one-third of patients
were receiving the 50 mg dose.
The change to treatment with RLAI was also associated
with a beneficial effect on movement disorders, as evidenced by the significant reduction in ESRS scores after only
one month of treatment and the sustained improvements
that were seen with ongoing RLAI therapy. It is also notable
that significant improvements in movement disorders were
apparent even among those patients previously treated with
an oral atypical antipsychotic.
175
The study had a high completion rate, while the dropout
rate due to adverse events was low (4%). Overall, the
tolerability profile in the present study was comparable
with that reported previously for RLAI [11,16,18,24,35].
Only one patient reported sexual dysfunction as an adverse
event. Nevertheless, the benefits of the current treatment
with respect to potentially hormone-related adverse events
may be due to the more stable plasma levels that are
achieved with RLAI compared with oral risperidone [11,17].
In recent years, attention has been paid to a possible association between weight gain induced by some of the atypical
antipsychotics and the risk of abnormal glucose metabolism
and diabetes mellitus [1,9,12]. The small increase in body
weight observed in the present study is similar to that
reported previously for oral risperidone and RLAI [12]. In
addition, the single case of new-onset diabetes mellitus in
the present study (i.e. 0.5% incidence over six months) is
in line with the annual incidence of 1% for type 2 diabetes
among white Europeans aged 40—79 years [8].
In addition to the overall reduction in psychopathology, important findings of the present study were the
improvements in functioning and patient satisfaction with
treatment. Thus, the significant increase (6.8 points) in
mean scores on the physician-assessed GAF indicated that
an overall improvement in the patients’ functional capacity, towards levels enjoyed by the general population, was
apparent in addition to the improvements in the symptoms
of schizophrenia. The patients themselves reported significant improvements in their quality of life. Thus, statistically
significant increases were seen in the mean scores for all
components of the SF-36 questionnaire, except bodily pain
and the improvements in the role physical, general health,
social functioning, role emotional and mental health factors
were considered to be clinically significant. These improvements in health-related quality of life were consistent with
the findings of a previous placebo-controlled study of RLAI
in patients with schizophrenia [36] and also of six-month
and 12-month open-label trials [21,35]. Furthermore, the
patients reported high levels of satisfaction with their treatment at the end of the six-month study period, with more
than two-thirds rating it as ‘good’ or ‘very good’.
A number of different factors influence the healthrelated quality of life of patients with schizophrenia,
including persistent psychopathology (particularly negative
symptoms) [27] and the adverse effects of treatment,
particularly movement disorders, sexual dysfunction and
neuroleptic-induced dysphoria [4,27]. These factors can also
adversely influence adherence with antipsychotic therapy.
Thus, the overall reduction in symptom severity, including
the significant decreases in scores on the PANSS negative
subscale and the negative symptoms factor, seen in the
present study along with the significant improvements in
movement disorders would help to explain the improvements in health-related quality of life and satisfaction with
treatment. In turn, these improvements may have contributed to enhanced compliance with therapy. Only 3% of
patients were withdrawn from the study early due to poor
compliance with the RLAI regimen, whereas noncompliance
with previous therapy was cited as a reason for changing
treatment in almost half of the study population.
The role of long-acting antipsychotic formulations in
facilitating compliance with medication and thereby helping
176
to prevent relapse and improve functional outcomes, is wellestablished [5,23]. The development of RLAI now makes it
possible to provide this treatment with an atypical antipsychotic. The present study has shown that its use can improve
symptom control, functioning and quality of life in patients
who are considered to be clinically stable on other treatments, including conventional depot neuroleptics and oral
atypical antipsychotics. RLAI is an important addition to the
armamentarium of treatment options for patients requiring
long-term antipsychotic therapy.
Acknowledgement
This study was supported by Janssen Cilag Medical Affairs
EMEA, Beerse, Belgium.
Appendix A List of French investigators
Acknowledgements
Dr Isabelle Chereau, centre hospitalier universitaire,
Clermont-Ferrand.
Dr Serge Schong, CMP La Faı̈encerie, Mont-Saint-Martin.
Dr Catherine Chassagne, CMP La Faı̈encerie, Mont-SaintMartin.
Dr Véronique Adnet Markovitch, CMP La Faı̈encerie, MontSaint-Martin.
Dr Stéphane Keller, CMP La Faı̈encerie, Mont-SaintMartin.
Dr Amal Baddou, centre hospitalier Camille-Claudel, La
Couronne.
Dr Paul Bonnan, centre hospitalier de Cadillac, Cadillac.
Dr Thierry Bottai, centre hospitalier de Martigues, hôpital
du Vallon, Martigues.
Dr Eric Pellegrin, centre hospitalier de Martigues, hôpital
du Vallon, Martigues.
Dr Véronique Roure, centre hospitalier spécialisé LéonJean-Grégory, Thuir.
Dr René Cariou, centre hospitalier spécialisé Léon-JeanGrégory, Thuir.
Dr Alexandre Christodoulou, EPS de Perray Vaucluse,
Épinay-sur-Orge.
Dr Philippe Coffinet, centre hospitalier spécialisé de
Saint-Rémy, Saint-Rémy.
Dr Bruno Richelet, centre hospitalier spécialisé de SaintRémy, Saint-Rémy.
Dr Padrig Cullerre, clinique Saint-Vincent, Larmor-Plage.
Pr Jean-Marie Danion, CHRU hôpital civil, Strasbourg.
Dr Marie-Agathe Zimmermann, CHRU hôpital Civil, Strasbourg.
Dr Renaud de Beaurepaire, établissement psychiatrique
spécialisé Paul-Guirau, Villejuif.
Dr Jacques Debieve, centre de soins Ulysse-Trélat, StAndré-lez-Lille.
Dr Laurent Desbancs, CMP du-Bas-Landreau, Reze.
Dr Dominique Drapier, CHSP Guillaume-Regnier, Rennes.
Dr Philippe Dumont, centre médicopsychologique,
Roubaix.
Dr Catherine van Nedervelde, centre médicopsychologique, Roubaix.
P.-M. Llorca et al.
Dr Sylvie Platteau, centre médicopsychologique,
Roubaix.
Dr Xavier Xiberas, CH de Mont-de-Marsan-Site, SainteAnne, Mont-de-Marsan.
Dr Philippe Durst, centre hospitalier Ste-Marie, Privas.
Dr Bernard Etchegaray, centre hospitalier spécialisé
Charles-Perrens, Bordeaux.
Dr André Gassiot, centre hospitalier Ste-Marie, Rodez.
Dr Didier Mergaux, centre hospitalier Ste-Marie,
Rodez.
Dr Alain Gavaudan, centre hospitalier spécialisé Valvert,
Marseille.
Dr Claude Guinard, centre hospitalier spécialisé Valvert,
Marseille.
Dr Jean Louis Lebeau, centre hospitalier spécialisé
Valvert, Marseille.
Dr Nicolas Lafay, centre hospitalier Henri-Laborit,
Poitiers.
Dr Marie Bénédicte Girard, centre hospitalier HenriLaborit, Poitiers.
Dr Christian Guggiari, centre hospitalier spécialisé Beauregard, Bourges.
Dr Emmanuel Dufumier, centre hospitalier spécialisé SteMarie, Le-Puy-en-Velay.
Dr René Clément, centre hospitalier spécialisé Ste-Marie,
Le-Puy-en-Velay.
Dr Naceur Haddouche, centre hospitalier spécialisé SteMarie, Le-Puy-en-Velay.
Dr Jean-Pierre Kahn, hôpital Jeanne-d’Arc, Toul.
Dr Jean-Lou Lavaud, établissement psychiatrique
spécialisé Paul-Guirau, Villejuif.
Dr Hervé le Duc, centre psychothérapique de Gireugne,
Saint-Maur.
Dr Vincent Delaunay, centre hospitalier universitaire StJacques, Nantes.
Dr Eric Esposito, centre hospitalier universitaire StJacques, Nantes.
Dr Jean-Christophe Loirat, centre hospitalier universitaire St-Jacques, Nantes.
Dr Émile Roger Lombertie, centre hospitalier Esquirol,
Limoges.
Dr Isabelle Alamome, centre hospitalier Esquirol, Limoges.
Dr Pierre Chenivesse, institut Marcel-Rivière, Le-MesnilSt-Denis.
Dr Eric Marcel, institut Marcel-Rivière, Le-Mesnil-StDenis.
Dr Martine Pelicier, institut Marcel-Rivière, Le-Mesnil-StDenis.
Dr Jean-Albert Meynard, hôpital Marius-Lacroix,
La Rochelle.
Dr Pierre Murry, CHS de Saint-Égrève, Saint-Égrève.
Dr Pascal Favre, CHS de Saint-Égrève, Saint-Égrève.
Dr Didier Feray, centre hospitalier général, Dieppe.
Dr Annie Navarre-Coulaud, centre hospitalier général,
Dieppe.
Dr Michel N’Guyen Thanh Tong, CHS de la Sarthe,
Allonnes.
Dr Eric Gokalsing, centre hospitalier spécialisé Ste-Marie,
Nice.
Dr Jérome Palazzolo, centre hospitalier spécialisé SteMarie, Nice.
Improvements with RLAI in French patients
Dr Mohammed Beyadh, centre hospitalier spécialisé de la
Haute-Marne, Saint-Dizier.
Dr Catherine Perdrizet-Chevallier, centre hospitalier
spécialisé de la Haute-Marne, Saint-Dizier.
Pr Charles-Siegfried Peretti, hôpital Robert-Debré,
Reims.
Dr Claire Lise Charrel, hôpital Robert-Debré, Reims.
Dr Philippe Sastre Garau, centre de santé mentale MGEN,
Lille.
Dr Christian Plumecocq, centre de santé mentale MGEN,
Lille.
Pr Dominique Pringuey, CHU de Nice, hôpital Pasteur,
Nice.
Dr Michel Benoit, CHU de Nice, hôpital Pasteur, Nice.
Dr. Christine Lerouge, CH intercommunal Toulon—LaSeyne/Mer, Toulon.
Dr Philippe Raymondet, CH intercommunal Toulon—LaSeyne/Mer, Toulon.
Dr Dominique Robert, centre hospitalier de Saumur,
Saumur.
Dr Christian Amouzou, EPS Paul-Guiraud, Villejuif.
Dr Juliette Gremion, EPS Paul-Guiraud, Villejuif.
Dr Annie Ruat, EPS Paul-Guiraud, Villejuif.
Dr Anne Rauzy, EPS Paul-Guiraud, Villejuif.
Dr Mohamed Saoud, centre hospitalier spécialisé
Le Vinatier, Bron.
Dr Halima Zeroug Vial, centre hospitalier spécialisé Le
Vinatier, Bron.
Dr Hélène Mandran, centre hospitalier spécialisé Le
Vinatier, Bron.
Pr Laurent Schmitt, centre Casselardit, Toulouse.
Dr Virginie Rouch, centre Casselardit, Toulouse.
Dr Stéphane Torres, CHRU, hôpital La Colombière, Montpellier.
Dr Jean-Philippe Boulenger, CHRU, hôpital La
Colombière, Montpellier.
Dr Delphine Capdevielle, CHRU, hôpital La Colombière,
Montpellier.
Dr Yves Tyrode, centre hospitalier spécialisé, Montfavet.
Dr Daniel Choain, centre hospitalier spécialisé, Montfavet.
Dr Pierre Vaneecloo, centre psychothérapeutique
Duchesnois de St-Saulve, St-Saulve.
Dr Annie Viala, établissement psychiatrique spécialisé
Ste-Anne, Paris.
Dr Laurent Masclet, établissement psychiatrique
spécialisé Ste-Anne, Paris.
References
[1] American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North
American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and
diabetes. Diabetes Care 2004;27:596—601.
[2] American Psychiatric Association.Diagnostic and statistical
manual of mental disorders. 4th ed. Washington, DC: American
Psychiatric Association; 1994.
[3] Andreasen NC, Carpenter Jr WT, Kane JM, et al. Remission in
schizophrenia: proposed criteria and rationale for consensus.
Am J Psychiatry 2005;162:441—9.
177
[4] Awad AG, Voruganti LNP. New antipsychotics, compliance,
quality of life and subjective tolerability — are patients better
off? Can J Psychiatry 2004;49:297—302.
[5] Barnes TR, Curson DA. Long-term depot antipsychotics: a riskbenefit assessment. Drug Saf 1994;10:464—79.
[6] Bengtsson-Tops A, Hansson L. Subjective quality of life in
schizophrenic patients living in the community. Relationship to clinical and social characteristics. Eur Psychiatry
1999;1999:256—63.
[7] Bhanji NH, Chouinard G, Margolese HC. A review of compliance,
depot intramuscular antipsychotics and the new long-acting
injectable atypical antipsychotic risperidone in schizophrenia.
Eur Neuropsychopharmacol 2004;14:87—92.
[8] Bonora E, Kiechl S, Willeit J, et al. Population-based incidence
rates and risk factors for type 2 diabetes in white individuals:
the bruneck study. Diabetes 2004;53:1782—9.
[9] Casey DE, Haupt DW, Newcomer JW, et al. Antipsychoticinduced weight gain and metabolic abnormalities: implications
for increased mortality in patients with schizophrenia. J Clin
Psychiatry 2004;65:4—18.
[10] Chouinard G, Ross-Chouinard A, Annable L, et al. Extrapyramidal symptom rating scale. Can J Neurol Sci 1980;7:233.
[11] Chue P. Risperidone long-acting injection. Expert Rev Neurotherapeutics 2003;3:435—46.
[12] Chue P, Cheung R. The impact of weight gain associated with
atypical antipsychotic use in schizophrenia. Acta Neuropsychiatr 2004;16:1—11.
[13] Csernansky JG, Mahmoud R, Brenner R, R-U-S Group. A comparison of risperidone and haloperidol for the prevention
of relapse in patients with schizophrenia. N Engl J Med
2002;346:16-L22.
[14] Csernansky JG, Schuchart EK. Relapse and rehospitalisation
rates in patients with schizophrenia: effects of second generation antipsychotics. CNS Drugs 2002;16:473—84.
[15] Dolder CR, Lacro JP, Dunn LB, et al. Antipsychotic medication
adherence: is there a difference between typical and atypical
agents? Am J Psychiatry 2002;159:103—8.
[16] Eerdekens M, Fleischhacker WW, Xie Y et al. (2002). Long-term
safety of long-acting risperidone microspheres. The American
Psychiatric Nurses Association annual meeting, 5—8 October,
Dallas, Texas. American Psychiatric Nurses Association.
[17] Ereshefsky L, Mascarenas CA. Comparison of the effects
of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics. J Clin Psychiatry
2003;64:18—23.
[18] Fleischhacker WW, Eerdekens M, Karcher K, et al. Treatment
of schizophrenia with long-acting injectable risperidone: a
12-month open-label trial of the first long-acting second generation antipsychotic. J Clin Psychiatry 2003;64:1250—7.
[19] Gilmer TP, Dolder CR, Lacro JP, et al. Adherence to treatment
with antipsychotic medication and health care costs among
Medicaid beneficiaries with schizophrenia. Am J Psychiatry
2004;161:692—9.
[20] Guy W. Clinical global impressions. In: ECDEU assessment manual for psychopharmacology, 76. Rockville: Md: Department of
Health, Education and Welfare; 1976. p. 218—20.
[21] Harrison TH, Goa KL. Long-acting risperidone. A review of its
use in schizophrenia. CNS Drugs 2004;18:113—32.
[22] Kane J. Progress defined — short-term efficacy, long-term
effectiveness. Int Clin Psychopharmacol 2001;16:S1—8.
[23] Kane JM, Aguglia E, Altamura AC, et al. Guidelines for depot
antipsychotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy. Eur
Neuropsychopharmacol 1998;8:55—66.
[24] Kane JM, Eerdekens M, Lindenmayer JP, et al. Longacting injectable risperidone: efficacy and safety of the
first long-acting atypical antipsychotic. Am J Psychiatry
2003;160:1125—32.
178
[25] Kay SR, Fiszbein A, Opler LA. The positive and negative
syndrome scale (PANSS) for schizophrenia. Schizophr Bull
1987;13:261—76.
[26] Keith SJ, Kane JM. Partial compliance and patient consequences in schizophrenia: our patients can do better. J Clin
Psychiatry 2003;64:1308—15.
[27] Lambert M, Naber D. Current issues in schizophrenia: overview
of patient acceptability, functioning capacity and quality of
life. CNS Drugs 2004;18:5—17.
[28] Lasser RA, Bossie CA, Gharabawi G, et al. Patients with
schizophrenia previously stabilized on conventional depot
antipsychotics experience significant clinical improvements
following treatment with long-acting risperidone. Eur Psychiatry 2004;19:219—25.
[29] Leucht S, Barnes TR, Kissling W, et al. Relapse prevention
in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized,
controlled trials. Am J Psychiatry 2003;160:1209—22.
[30] Lindenmayer JP, Eerdekens E, Berry SA, et al. Safety and efficacy of long-acting risperidone in schizophrenia: a 12-Week,
multicenter, open-label study in stable patients switched from
typical and atypical oral antipsychotics. J Clin Psychiatry
2004;65:1084—9.
[31] Mahmoud RA, Engelhart LM, Janagap CC, et al. Risperidone versus conventional antipsychotics for schizophrenia
and schizoaffective disorder. Symptoms, quality of life and
resource use under customary clinical care. Clin Drug Invest
2004;2004:275—86.
[32] Marder SR. Overview of partial compliance. J Clin Psychiatry
2003;64:3—9.
[33] Marder SR, Davis JM, Chouinard G. The effects of risperidone on
the five dimensions of schizophrenia derived by factor analysis:
P.-M. Llorca et al.
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
combined results of the North American trials. J Clin Psychiatry
1997;58:538—46.
McHorney CA, Ware JE, Raczek AE. The MOS 36-item shortform health survey (SF-36® ): II. Psychometric and clinical tests
of validity in measuring physical and mental health constructs.
Med Care 1993;31:247—63.
Moeller H, Llorca P, Sacchetti E, et al. Efficacy and safety
of direct transition to risperidone long-acting injectable in
patients treated with various antipsychotic therapies. Int Clin
Psychopharmacol 2005;20:121—30.
Nasrallah HA, Duchesne I, Mehnert A, et al. Health-related
quality of life in patients with schizophrenia during treatment with long-acting, injectable risperidone. J Clin Psychiatry
2004;65:531—6.
Pereira S, Pinto R. A survey of the attitudes of chronic psychiatric patients living in the community toward their medication.
Acta Psychiatr Scand 1997;95:464—8.
Tunis SL, Croghan TW, Heilman DK, et al. Reliability, validity
and application of the medical outcomes study 36-item shortform health survey (SF-36) in schizophrenic patients treated
with olanzapine versus haloperidol. Med Care 1999;37:678—91.
Turner M, Eerdekens E, Jacko M, et al. Long-acting injectable
risperidone: safety and efficacy in stable patients switched
from conventional depot antipsychotics. Int Clin Psychopharmacol 2004;19:241—9.
van Os J, Bossie CA, Lasser RA. Improvements in stable
patients with psychotic disorders switched from oral conventional antipsychotics therapy to long-acting risperidone. Int
Clin Psychopharmacol 2004;19:229—32.
Ware JE, Sherbourne CD. The MOS 36-item short-form health
survey (SF-36® ): I. Conceptual framework and item selection.
Med Care 1992;30:473—83.