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8/10/2019 Guidelines for the Use and Management of SCHIZOPHRENIA
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R E S E A R C H A R T I C L E Open Access
Guidelines for the use and management oflong-acting injectable antipsychotics in seriousmental illnessPierre Michel Llorca1, Mocrane Abbar2, Philippe Courtet3, Sebastien Guillaume3, Sylvie Lancrenon4
and Ludovic Samalin1*
Abstract
Background:Long-acting injectable (LAI) formulations are not widely used in routine practice even though they
offer advantages in terms of relapse prevention. As part of a process to improve the quality of care, the FrenchAssociation for Biological Psychiatry and Neuropsychopharmacology (AFPBN) elaborated guidelines for the use and
management of antipsychotic depots in clinical practice.
Methods:Based on a literature review, a written survey was prepared that asked about 539 options in 32 specific
clinical situations concerning 3 fields: target-population, prescription and use, and specific populations. We
contacted 53 national experts, 42 of whom (79%) completed the survey. The options were scored using a 9-point
scale derived from the Rand Corporation and the University of California in the USA. According to the answers, a
categorical rank (first-line/preferred choice, second-line/alternate choice, third-line/usually inappropriate) was
assigned to each option. The first-line option was defined as a strategy rated as 79 (extremely appropriate) by at
least 50% of the experts. The following results summarize the key recommendations from the guidelines after data
analysis and interpretation of the results of the survey by the scientific committee.
Results:LAI antipsychotics are indicated in patients with schizophrenia, schizoaffective disorder, delusional disorder
and bipolar disorder. LAI second-generation antipsychotics are recommended as maintenance treatment after thefirst episode of schizophrenia. LAI first-generation antipsychotics are not recommended in the early course of
schizophrenia and are not usually appropriate in bipolar disorder. LAI antipsychotics have long been viewed as a
treatment that should only be used for a small subgroup of patients with non-compliance, frequent relapses or
who pose a risk to others. The panel considers that LAI antipsychotics should be considered and systematically
proposed to any patients for whom maintenance antipsychotic treatment is indicated. Recommendations for medication
management when switching oral antipsychotics to LAI antipsychotics are proposed. Recommendations are also given
for the use of LAI in specific populations.
Conclusion: In an evidence-based clinical approach, psychiatrists, through shared decision-making, should be
systematically offering to most patients that require long-term antipsychotic treatment an LAI antipsychotic as a
first-line treatment.
Keywords: Guidelines, Long-acting injectable, Depot formulation, Antipsychotic, Schizophrenia, Bipolar disorder,
Treatment
* Correspondence:[email protected] Clermont-Ferrand, EA 7280, Clermont-Ferrand University,
Clermont-Ferrand, France
Full list of author information is available at the end of the article
2013 Llorca et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the original work is properly cited.
Llorcaet al. BMC Psychiatry2013,13:340
http://www.biomedcentral.com/1471-244X/13/340
mailto:[email protected]://creativecommons.org/licenses/by/2.0http://creativecommons.org/licenses/by/2.0mailto:[email protected]8/10/2019 Guidelines for the Use and Management of SCHIZOPHRENIA
2/17
BackgroundSchizophrenia and bipolar disorder are examples of
some chronic illnesses for which there exists a high risk
of relapse associated with major functional conse-
quences. The pharmacologic strategy can be considered
as the cornerstone of the treatment for these patients.
Compliance is often mediocre with deleterious conse-
quences [1]. For example, the majority of patients with
schizophrenia (84%) discontinue their index anti-
psychotic during the follow-up period [2] and in the
long-term perspective, 40 to 50% seem to be non-
compliant [3], with no real difference in terms of adher-
ence between first-generation antipsychotics (FGA) and
second-generation antipsychotics (SGA) [4].
Long-acting injectable (LAI) antipsychotics have been
part of the pharmacopoeia for over 40 years. Various
meta-analyses highlight their interest as a relapse pre-
vention strategy in schizophrenia [5-7]. With regards tonon-adherence, most of the guidelines and algorithms
(except PORT 2009) state that depot antipsychotics are
an effective approach [8-10], with some guidelines actu-
ally recommending that switching the antipsychotic
formulation from oral to depot should be considered in
maintenance treatment [11].
Nevertheless, depot formulations are still poorly used
overall in routine practice, with prescription rates in dif-
ferent countries generally no more than 25% [12,13].
However, use of the depot forms varies between coun-
tries. Prescription rates are higher in France (23.5%) [14]
and the United Kingdom (29%) [12] compared to otherEuropean countries. Several factors that deter psychia-
trists from using depot forms have been identified, stem-
ming from mistaken beliefs about good adherence,
patient refusal, perceived coercion or a presumed risk of
lower tolerance [13,15]. At a practical level, psychiatrists
need to be confident and competent in presenting pa-
tients with sufficient information to enable them to
make an informed choice about whether to accept oral
or LAI medication or neither. We state that the develop-
ment and diffusion of specific guidelines, addressing all
the aspects of the use of LAI antipsychotics, will in-
crease clinicians perceived competence. It will also help
to increase the percentage of patients to whom LAIantipsychotics will be offered by psychiatrists as a
therapeutic option.
The objective of these guidelines is to propose a pre-
scription framework to clinicians for the use of a specific
formulation of antipsychotics (LAI) in diverse thera-
peutic indications and specific clinical situations. The
aim is to allow clinicians to offer the most appropriate
pharmaceutical strategies to the patients and to facilitate
the use of LAI antipsychotics in clinical practice. The rec-
ommendations presented here from a consensus-based
guidelines methodology (Formal Consensus Guidelines) are
based on scientific data and the consensus of a panel of
experts.
MethodsQuestionnaire development
Initially, we performed an analysis and a literature re-
view concerning the indications and the use of LAI
antipsychotics. A literature search using the keywords
antipsychotic, neuroleptic, first-generation anti-
psychotic, atypical antipsychotic, second-generation
antipsychotic, long-acting injectable, depot, depot
neuroleptic was performed in PubMed and EMBASE
to find all the relevant studies published. Additional refer-
ences were identified fromhttp://www.fda.govandhttp://
www.ema.europa.eu.
Data from all of these sources was discussed and an
overview of the current evidence has been graded and
summarized using the French National Authority forHealth (HAS) levels of evidencecriteria [16].
Following this first step, the scientific committee
(PML, LS, MA, PC, SG, SL) created a questionnaire con-
sisting of 32 questions that covered 539 therapeutic op-
tions. The 32 questions were regrouped into 3 areas that
were judged as essential:
Target-population: Description of the differentindications of the LAI antipsychotics and of themost appropriate period of the illness to introducethe treatment.
Prescription and use: Choice of the molecule,
methods of introduction, specific strategiesdepending on the psychiatric disorder or co-morbidities, and treatment monitoring.
Specific population: Use of LAI antipsychotics inpregnant women, elderly patients, subjects in aprecarious situation, and subjects having to betreated in a prison establishment.
This questionnaire was designed to be completed by
an experts panel. The time required for its administra-
tion was estimated at around 3 hours.
At the time of development, all the LAI antipsy-chotics available in France were proposed as thera-
peutic options (Table 1). They were regrouped into 2
categories:
Long-acting injectable first-generation antipsychotics(LAI FGA).
Long-acting injectable second-generation antipsy-chotics (LAI SGA).
This artificial separation FGA/SGA is not consen-
sual due to their heterogeneous profiles of efficacy
Llorcaet al. BMC Psychiatry2013,13:340 Page 2 of 17
http://www.biomedcentral.com/1471-244X/13/340
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and tolerability (especially for SGA) [17,18]. However,
we maintained both these categories to facilitate the
elaboration, the reading and the understanding of this
guideline.
Rating scale
The experts were able to express their level of agreement
or disagreement for each question. The rules that de-
scribe, on the one hand the agreement (or the disagree-
ment), and on the other hand the degree of convergence
of the expert opinions, were predefined.
Each expert answered each question with the help
of a graduated scale from 0 to 9 (0 meaning a total
disagreement or a formal contraindication and 9 in-
dicating a total agreement or a formal indication)
(Figure1).This scale is derived from a variation of the Nominal
Groupmethod, developed by the Rand Corporation and
the University of California in the USA (RAND/UCLA
appropriateness rating method).
The scale has the advantage of being well stan-
dardized, used in medicine and of having been pub-
lished [19].
Expert selection
The Scientific Committee (Appendix 1) selected 53
French psychiatrists considered to be experts in the use
of LAI antipsychotics.
The selection criteria were:
Clinical activity in the field of schizophrenia orbipolar disorder.
Publication (s) or communication (s) of researchwork in the field of LAI antipsychotics in national orinternational congresses.
Each expert was consulted individually for his or her
expertise using the supplied questionnaire. A follow-
up was established to ensure, essentially, the sending
and returning of these documents. A reminder of the
expert's mission was made. Written commitment from
each expert was requested. The experts participating inthis project were not paid.
Data analysis
The answers to each question or proposition were
quantitatively analyzed (number of answers, median,
mean, standard deviation, minimum, maximum)
(Table 2).
First-line treatment/strategy was defined if at least50% of the answers to the question were in the zone79 and less than 20% were in the zone 0. The
treatment/strategy of choice was kept if at least 50%of the experts had rated it 9. Second-line treatment/strategy was defined if less
than 50% of the answers to the question were in thezone 79, at least 50% were in the cumulated zones79 and 46, and less than 20% were in the zone 0.
Third-line treatment/strategy was defined if lessthan 50% of the answers to the question were in the
Table 1 LAI antipsychotics available in France (when the
survey was completed)
LAI second-generationantipsychotics
Risperidone microsphere
Olanzapine pamoate
LAI first-generation antipsychotics Haloperidol decanoateZuclopenthixol decanoate
Flupentixol decanoate
Fluphenazine decanoate
Pipotiazine palmitate
Note: as paliperidone palmitate had a marketing authorization date after the
development of these guidelines, it could not be taken into account.
Figure 1Rating scale.
Llorcaet al. BMC Psychiatry2013,13:340 Page 3 of 17
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8/10/2019 Guidelines for the Use and Management of SCHIZOPHRENIA
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cumulated zones 79 and 46, and less than 20%
were in the zone 0. Contraindication was defined if at least 50% of the
answers were in the zone 0.
For all other cases the question was considered as
non-consensual. An example is given in Figure 2. The
results were interpreted by the scientific committee and
permitted the development of the recommendations. An
independent committee (Appendix 1) validated the final
version of recommendations (EH, CL, PT). Two mem-
bers of the scientific committee elaborated the final
document (LS, PML).
ResultsThe following sections summarize the key recommenda-
tions from the guidelines after data analysis and inter-
pretation of the results of the survey by the scientific
committee. The complete database (with questions and
answers) is available on the website www.afpbn.org.
However, several examples of questions, with the ex-
perts answers, are presented here to facilitate under-
standing of the results section.
Description of the expert population
Forty-two experts completed the questionnaire (Appendix 2),
representing 79% of those contacted. The reasons for the
non-participation of the remaining 11 experts were that
they had either too much consultancy work or insufficient
availability to reply within the time limits. The socio-
demographic data and professional activities of the experts
panel are presented in Table3.
Target population
Indications
Indications for the use of LAI FGA and LAI SGA are
summarized in Table4.
The relevant question from the survey with the ex-
pertsanswers are given in Figure2.
Table 2 Data analysis
Percentage of answers in thezones
0 1-3 4-6 7-9
< 20% - < 50% 50% First-line treatment/strategy
< 20% < 50% 50% and