Guidelines for the Use and Management of SCHIZOPHRENIA

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
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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

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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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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

Documents

Guidelines for the Use and Management of SCHIZOPHRENIA