Olivares et al.

Annals of General Psychiatry 2013, 12:32

http://www.annals-general-psychiatry.com/content/12/1/32

REVIEW Open Access

Definitions and drivers of relapse in patients with

schizophrenia: a systematic literature review
José M Olivares1*, Jan Sermon2, Michiel Hemels3 and Andreas Schreiner4

Abstract
Relapse in patients with schizophrenia has devastating repercussions, including worsening symptoms, impaired
functioning, cognitive deterioration and reduced quality of life. This progressive decline exacerbates the burden of
illness on patients and their families. Relapse prevention is identified as a key therapeutic aim; however, the
absence of widely accepted relapse definition criteria considerably hampers achieving this goal. We conducted a
literature review in order to investigate the reporting of relapses and the validity of hospitalization as a proxy for
relapse in patients with schizophrenia. The primary aim was to assess the range and validity of methods used to
define relapse in observational or naturalistic settings. The secondary aim was to capture information on factors
that predicted or influenced the risk of relapse. A structured search of the PubMed database identified articles that
discussed relapse, and hospitalization as a proxy of relapse, in patients with schizophrenia. National and
international guidelines were also reviewed. Of the 150 publications and guidelines identified, 87 defined relapse
and 62% of these discussed hospitalization. Where hospitalization was discussed, this was as a proxy for, or a
component of, relapse in the majority of cases. However, hospitalization duration and type varied and were not
always well defined. Scales were used to define relapse in 53 instances; 10 different scales were used and multiple
scales often appeared within the same definition. There were 95 references to factors that may drive relapse,
including non-adherence to antipsychotic medication (21/95), stress/depression (11/95) and substance abuse (9/95).
Twenty-five publications discussed the potential of antipsychotic therapy to reduce relapse rates—continuous
antipsychotic therapy was associated with reduced frequency and duration of hospitalization. Non-pharmacological
interventions, such as psychoeducation and cognitive behavioural therapy, were also commonly reported as factors
that may reduce relapse. In conclusion, this review identified numerous factors used to define relapse.
Hospitalization was the factor most frequently used and represents a useful proxy for relapse when reporting in a
naturalistic setting. Several factors were reported to increase the risk of relapse, and observation of these may aid
the identification of at-risk patients.
Keywords: Relapse, Hospitalization, Schizophrenia, Definition, Adherence, Drivers

Introduction a significant burden, for both patients and families. The

Schizophrenia is a highly prevalent disorder affecting ap- clinical deterioration associated with each subsequent
proximately 1% of the world's population [1]. Patients relapse only serves to exacerbate this. For patients, re-
with schizophrenia often require antipsychotic medica- lapse can have devastating repercussions such as wor-
tion throughout their lifetime. With correct manage- sening of symptoms, progressive cognitive deterioration,
ment, many patients can achieve symptomatic remission impaired functioning and reduced quality of life [6-9].
[2] as defined, for example, by the Andreasen remission Furthermore, families are affected by the emotional
criteria [3]. However, relapses are a highly prevalent stress and financial burden of living with and caring
component of the disease course [4,5]. Schizophrenia is for a patient with schizophrenia [10,11]. To minimize
the burden on the patient and family, it is vital that
periods of effective symptom control are extended for
* Correspondence: jose.manuel.olivares@gmail.com
1
Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario as long as possible.
Universitario de Vigo, Vigo 36200, Spain
Full list of author information is available at the end of the article

© 2013 Olivares et al.; licensee BioMed Central Ltd. This is an open access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
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International guidelines identify relapse prevention as Abstract review

a key therapeutic aim [4-6]; however, there are currently Identified abstracts were excluded if they were not rele-
no established criteria by which to define relapse, and vant to one of the four domains:
our current understanding of relapse may not be suffi-
cient to combat this problem effectively [6,7,12,13]. 1. Definition of relapse.
We conducted a structured literature search to in- 2. Factors that may predict, drive or reduce relapse.
vestigate the reporting of relapse and the validity of 3. Duration and frequency of relapse.
hospitalization as a proxy for relapse in patients with 4. Cost and resource use associated with relapse.
schizophrenia. Additionally, the factors that may be
used to predict a relapse and those factors associated Guidelines were reviewed using the same criteria as
with increased or decreased risk of relapse were also the abstracts identified in the PubMed search. Following
investigated. this review, the selection of literature included 206 ab-
stracts and five guidelines.
Methods Publications discussing the definition of relapse and
PubMed search and literature review factors that may predict, drive or reduce relapse are
A structured search of the National Center for Bio- reviewed here. Those discussing the duration and fre-
technology Information (NCBI) PubMed database was quency of relapse or associated cost and resource are
performed to identify articles published from 1 January reviewed elsewhere.
2000 to 1 May 2010 that discussed relapse, and hospi-
talization as a proxy for relapse, in patients with schizo- Full article review
phrenia. The search term ‘Schizophrenia [Title/Abstract] Following abstract review, each corresponding full article
AND ((Relapse[Title/Abstract]) OR (Hospitalization was reviewed and excluded if not relevant to one of the
[Title/Abstract]))’ and limits (Humans, Clinical Trial, four domains above. Following this review stage, the se-
Meta-Analysis, Review, Classical Article, Clinical Trial, lection of literature included 156 journal papers and five
Phase IV, Comparative Study, Congresses, Controlled guidelines. A final review of the literature was conduc-
Clinical Trial, Corrected and Republished Article, ted. During this final review, the authors excluded those
Evaluation Studies, Government Publications, Journal papers describing cost-effectiveness modelling studies
Article, Multicenter Study, Published Erratum, English, that constituted secondary research as accurate inter-
French, German, Italian, Spanish) were used to identify pretation and evaluation of such papers require an in-
relevant literature from the database. The latest national depth analysis of the methodologies and assumptions
(France, Spain, Germany, Italy and the UK) and inter- used, which was deemed to be beyond the scope of the
national (World Federation of Societies of Biological current review.
Psychiatry (WFSBP); American Psychiatric Association The final literature selection included 145 journal
(APA)) guidelines were also reviewed. The primary manuscripts and five guidelines from three organisations
objective of this literature search was to determine (APA [6,14], National Institute for Clinical Excellence
whether specific criteria have been used to define re- (NICE) [4] and WFSBP [2,5]). Figure 1 details the full
lapse in observational and naturalistic settings. The literature search process.
secondary aim was to identify possible factors that
may drive or reduce relapse. Results
Randomized clinical trials (RCTs) represent highly Definitions of relapse
controlled situations in which patients are required to Of the final selection of literature, 87 manuscripts in-
meet stringent inclusion criteria. Furthermore, subjects cluded a definition of relapse. None of the identified
are frequently randomized to a fixed medication dose, guidelines defined relapse. Figure 2 describes the factors
without provision for dose optimization to meet individ- used alone or in combination to define relapse. Hospi-
ual requirements, which may likely have an impact on talization was the most widely used factor as a proxy for
patient outcomes. Patients are closely monitored in relapse or as a component of the definition.
RCTs, and specific relapse definitions are imposed for
consistency across study centres. Hence, RCTs are less Hospitalization
informative in regard to routine definitions of relapse ‘Hospitalization’ appeared in 54% (47/87) of the publica-
used in clinical practice and to factors associated with tions that defined relapse, 62% (54/87) if grouped with
relapse in unselected clinical populations. Therefore, ‘exacerbation of symptoms leading to hospitalization’. In
data from primary publications of randomized, placebo- these 54 publications, hospitalization or exacerbation of
controlled clinical trials of pharmacological agents were symptoms leading to hospitalization was discussed in 56
excluded from this literature search. separate instances. In the majority (55%, 31/56) of cases,
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Structured search

Included
1106 PubMed abstracts
5 guidelines

Abstract review

Included Excluded
206 PubMed abstracts 900 PubMed abstracts
5 guidelines

Full article review

Included Excluded
156 articles 50 articles
5 guidelines

Final review of full articles*

Included Excluded
145 Articles 11 articles
5 guidelines

Data extraction

Figure 1 Literature search process. The asterisk denotes that the final review process is described in detail in the main body of the text.

hospitalization was used as a direct proxy for relapse or and subscales used within the relapse criteria. Among
as a component of a relapse definition. In the remainder the 18 instances of using the PANSS to define relapse,
(45%, 25/56), hospitalization was discussed indepen- thresholds included an overall increase in the scale
dently or without reference to relapse (Table 1). The [7,60,61], an increase in the score from baseline [17,18]
majority of publications did not define the length of the and recording of a score >4 for certain individual PANSS
hospitalization or the type of hospitalization—generic items [62-64]. There was wide variation between studies
terms of ‘hospitalization’ and ‘psychiatric hospitali- when using the CGI scale, since many different subscales
zation’ were predominantly used. Two publications, and thresholds were proposed to define relapse. CGI-
published by the same authors, defined hospitalization Severity (CGI-S) was the most commonly cited subscale,
as ‘36 h of full hospitalization or a 5-day partial hos- with CGI-schizophrenia (CGI-SCH) and CGI-Change
pitalization due to an exacerbation of acute psychotic (CGI-C) also frequently used. However, the threshold for
symptoms’. However, the difference between ‘partial’ relapse was broadly similar regardless of the CGI sub-
and ‘full’ hospitalization was not defined in these publi- scale used—with an overall increase (or increase in a sin-
cations [15,16]. gle factor) to a score of 6 or 7 being the most frequent
measure [18,19,60,65,66].
Scales
There were 53 instances of a scale being used to define
Other definitions
relapse; however, multiple scales often appeared within
Sixteen per cent (14/87) of publications defined relapse
the same definition. Ten different scales were used
as a change in behavioural patterns towards more vio-
to define relapse (Figure 2), including the Positive
lent or self-destructive ideation or tendencies. Exacer-
and Negative Syndrome Scale (PANSS), Clinical Global
bation or re-emergence of symptoms was the fourth
Impression (CGI) scale (including the CGI-Severity,
most common component of definitions identified in
CGI-Schizophrenia and CGI-Change subscales), Brief
the literature search, second if combined with those
Psychiatric Rating Scale (BPRS) and Global Assessment
exacerbations that led to hospitalization.
of Functioning (GAF) scale, the most frequently cited
being PANSS and CGI. Generally, the scales used to de-
fine relapse assessed symptom severity and in particular Factors that may increase or decrease the risk of relapse
the positive symptoms of schizophrenia. Ninety-four journal articles and five guidelines discussed
There was considerable variation between studies in the various factors that may drive or reduce relapse rates
the use of each scale, in terms of the thresholds applied, in patients with schizophrenia.
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Figure 2 Reported components of the definition for relapse. Hospitalization [11,15-59]; Positive and Negative Syndrome Scale (PANSS)
[7,15,17,18,60-72]; Clinical Global Impression (CGI) scale [17,18,26,30,52,57,60-62,65,66,68,71,73,74]; exacerbation/re-emergence of symptoms
[7,27,29,34,38,43,63,67,75-81]; deliberate self-harm or violent behaviour, suicidal or homicidal ideation, arrest [18,23,27,43,49,50,57,65,66,71,74,82-84];
Brief Psychiatric Rating Scale (BPRS) [28,43,71,76,84-91]; change of medication or patient management [18,27,38,41,56,66,75,92]; exacerbation/
re-emergence of symptoms leading to hospitalization [20,66,92-96]; clinical assessment of patient notes [38,57,88]; International Classification of
Diseases (ICD) criteria [70,89,97]; Global Assessment of Functioning (GAF) [64,72]; physician interview and/or assessment [86,98]; Present State
Examination (PSE) [84]; Global Assessment Scale (GAS) [84]; Target Symptoms Ratings Scale (TSRS) [76]; Psychiatric Assessment Scale (PAS) [99];
scale for the assessment of positive symptoms [86]; social functioning [75]; Social and Occupational Functioning Assessment Scale (SOFAS) [60].

Factors that may drive relapse Patient-specific, lifestyle and disease-related factors
There were 95 references to factors that may drive re- associated with increased rates of relapse were also iden-
lapse (Figure 3), with non-adherence to antipsychotic tified in the search (Figure 3). Stress/depression and
medication the most frequently reported factor. For ex- substance abuse were the second and third most fre-
ample, in a study of first-episode patients, medication quently reported factors associated with relapse. In a
non-adherence was observed in 70% of patients with re- retrospective cohort study, depression (adjusted hazard
lapse, compared with only 25% of those without relapse, ratio (AHR) = 1.44; 95% CI = 1.05, 1.98; p < 0.05) and
at 1-year follow-up (χ2 = 11.2, p = 0.001) [85]. Further- substance abuse (AHR = 1.80; 95% CI = 1.32, 2.47;
more, in patients with recently diagnosed (≤ 2 years) p < 0.05) were significantly associated with an increased
schizophrenia, a 69% relapse rate was observed in pa- risk of psychiatric hospitalizations [97].
tients non-adherent to oral or depot antipsychotic ther- There were 46 instances where treatment-related fac-
apy compared with a rate of 18% in adherent patients tors, such as side effects, dosing issues, efficacy and gen-
(χ2 = 12.66, p < 0.001) [20]. eric antipsychotic use, were associated with increased
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Table 1 Manuscripts that defined relapse and also discussed hospitalization used a range of definitions
Way in which hospitalization is used Number of times References
in references that also define relapse hospitalization
defined (n)
Hospitalization is discussed, separately 25 Bechdolf et al. [16]; Crown et al. [59]; dos Reis et al. [47]; Dyck et al. [32]; Hayhurst et al.
to relapse [33]; Miettunen et al. [40]; Olivares et al. [56]; Svarstad et al. [31]; Sun et al. [45];
Rabinowitz et al. [30]; Taylor et al. [22]; Thompson et al. [36]; Usall et al. [37]; Ward et al.
[25]; Weiden et al. [26]; Whitehorn et al. [39]; Janicak et al. [48]; Zhu et al. [50]; Bechdolf
et al. [15]; Drake et al. [20]; Novák-Grubic and Tacvar [34]; Olivares et al. [23]; Valencia
et al. [46]; Kim [54]; Peuskens et al. [24]
Hospitalization equates to relapse 10 Buckley et al. [44]; de Sena et al. [35]; Hawley et al. [58]; Leucht et al. [30]; Malik et al.
[11]; Rouillon et al. [49]; Spaniel et al. [52]; Spaniel et al. [53]; Taylor et al. [22];
Turkington et al. [42]
Hospitalization used as a component 14 Almond et al. [38]; Ascher-Svanum et al. [57]; Csernansky et al. [17]; Drake et al. [20];
of relapse definition Emsley et al. [18]; Gaertner et al. [28]; Gasquet et al. [55]; Haro et al. [21]; Haro et al. [51];
Hickling et al. [29]; Hong et al. [19]; Muirhead et al. [41]; Pharoah et al. [27]; Xiang et al. [43]
Exacerbation of symptoms leading 7 Berglund et al. [95]; Chabannes et al. [96]; Drake et al. [20]; Lancon et al. [93]; Simpson
to hospitalization equates to relapse et al. [66]; Tomaras et al. [92]; Wahlbeck et al. [94]

relapse rates (Figure 3). Delay in treatment delivery and

interruptions to treatment due to loss of medical insur-
ance coverage were also identified. In one study, a longer
duration of untreated psychosis was significantly asso-
ciated with mild relapse in the first year after hospitali-
zation (Kruskal-Wallis test χ2 = 5.31, p = 0.02). In this
study, a mild relapse was defined as a recurrence or ex-
acerbation of psychotic symptoms in 1 week for which
an increase in antipsychotic medication was required,
without a significant decline in social functioning [75]. A
regression model analysis in another study indicated that
patients who were subject to interruptions in Medicaid
coverage were more likely to be hospitalized (negative
binomial regression z = 6.9, p < 0.001), experience a
greater number of hospitalizations (negative binomial
regression z = 8.4, p < 0.001) and spend 61% more
days in the hospital compared with patients with con-
tinuous coverage (exponential regression model z = 7.1,
p < 0.001) [112].

Factors that may reduce the rate of relapse

There were 49 occurrences (in 46 publications) of fac-
tors that may reduce the rate of relapse (Figure 4). The
potential for antipsychotic therapy to reduce relapse
Figure 3 Potential drivers of relapse. Adherence problems rates was examined in a total of 25 publications. One
[2,6,7,13,17,25,26,31,34,45,47,53,57,76,85,100-105]; stress, depression,
publication reported the results from a 3-year follow-up
depressive symptoms, neurosis [2,6,7,12,55,59,70,97,106-108];
substance abuse [2,6,7,21,31,57,59,83,97]; lifestyle factors of a large cohort of outpatients with schizophrenia ta-
[7,12,21,38,79,109,110]; hospitalization or relapse history king part in the prospective, observational European
[21,31,38,40,57,59,97]; treatment-related issues [6,7,28,43,61,70,111]; Schizophrenia Outpatient Health Outcomes (SOHO)
treatment interruption or delay [2,6,12,75,85,112,113]; disease-related study (n = 6516) [21]. In this study, relapse rates were
factors [57,70,83,85,97,114]; quetiapine, anticholinergics, mood
higher in patients who took typical antipsychotics (depot
stabilizers (MS), oral neuroleptics, anxiolytics or hypnotics [21,31,51,55];
male gender [30,37,83,115]; use of first-generation antipsychotics (FGA) (relative risk (RR) = 1.689; 95% CI = 1.306, 2.184;
vs second-generation antipsychotics (SGA) [30,85,116]; outpatient vs p < 0.0001) or oral (RR = 1.655; 95% CI = 1.316, 2.081;
inpatient [29,39]; poor patient insight [20,83]; younger age [57,83]; p < 0.0001)) than the atypical antipsychotic olanzapine.
generic vs branded medication [117]; reduced compliance/family Differences in the RR for relapse were also observed bet-
involvement in Information Technology Aided Relapse Prevention in
ween olanzapine and other second-generation antipsy-
Schizophrenia (ITAREPS) programme [53]; depot antipsychotics [76].
chotics (SGAs) [21].
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continued with RLAI treatment were observed, com-

pared with those who discontinued [24].
Non-pharmacological interventions, such as psychoedu-
cation and cognitive behavioural therapy (CBT), were also
commonly reported as factors that may reduce relapse.
However, these interventions were evaluated in patients
already receiving treatment with antipsychotic medication
[4]. Many publications highlighted a ‘trend’ associating
therapies such as CBT and psychoeducation with
relapse reduction but failed to demonstrate statisti-
cally significant effects in observational or naturalis-
tic settings.

Discussion
The consistent and correct assessment and management
Figure 4 Factors that may reduce relapse rates. Individual
citations of each factor: a single reference may include citations of relapse in patients with schizophrenia are vital for
of more than one factor. The antipsychotic medication category clinical practice and important factors for controlled
does not include the other pharmacological therapy factors. Non- clinical trials. As such, an awareness of the factors that
pharmacological therapies [4-6,11,14-16,27,32,41,42,64,82,84,92,118-121]; may be associated with increased and decreased rates of
antipsychotic medication [4,6,23,54,81,122-127]; risperidone/risperidone
relapse should invariably aid clinical practice and benefit
long-acting injectable (RLAI) specifically [22-24,35,65,74,128-131];
medication compliance [25,33,132,133]; Information Technology Aided patients. However, reporting physicians do not always
Relapse Prevention in Schizophrenia (ITAREPS) [52]; good patient state how they define relapse; only 62% (87/145) of the
insight [134]; early detection [135]; greater frequency of final selection of journal articles identified in this litera-
electroconvulsive therapy (ECT) [90]; olanzapine specifically [21]. ture search stated a definition of relapse. Interestingly,
none of the international and national guidelines define
Another study showed that patients who were treated relapse, potentially indicating that in clinical practice, a
with depot antipsychotics had a higher rate of major re- psychiatrist is deemed able to identify a relapsing pa-
lapses and hospitalization compared with patients who tient. Alternatively, acutely exacerbated patients may
had not received depot antipsychotics [76]. However, present with a range of signs and symptoms to such a
this study primarily examined the outcome of therapy in variable degree as to hinder the provision of a unique re-
relation to medication adherence and defined a ‘depot liable definition of relapse.
patient’ as one who had received a depot antipsychotic Csernansky and colleagues [17] proposed a set of
‘at any time during the study’, which included patients multifactorial criteria for defining relapse, including hos-
who started therapy with an oral antipsychotic but were pitalization, and suggested that any single factor could
later switched to a depot antipsychotic due to poor be used as a clinical determinant of relapse. Within the
adherence. Therefore, the extent to which adherence studies identified in this search, many factors were used
problems caused both the switch to depot antipsychotic to define relapse. Hospitalization, usually defined in ge-
therapy and the relapse in these ‘depot patients’ is un- neric terms of ‘hospitalization’ or ‘psychiatric hospita-
clear. Moreover, it was not reported whether relapse oc- lization’, was the single factor most commonly used to
curred prior to, or following, initiation of treatment with define relapse and represents a commonly used proxy
the depot antipsychotic [76]. for examining relapse; however, hospitalization was also
The effect of risperidone long-acting injectable (RLAI) one of the search terms used and so may bias the results.
on relapse rates and duration of hospitalization or re- In particular, the majority of the retrospective database
lapse compared with baseline [22,128] or compared with analyses identified in this literature search specifically in-
patients treated with oral antipsychotics was reported in vestigated hospitalization when conducting their ana-
several publications [18,23]. In one post hoc analysis of lyses, rather than relapse or other parameters that could
two similarly designed 2-year studies (one RLAI and one potentially be used to define relapse (that may not have
oral antipsychotic study), RLAI administration was asso- been available in the original data source). It is also likely
ciated with a relapse rate of 9.3% compared with 42.1% that hospitalization is frequently used to define relapse
in patients treated with oral antipsychotics (p = 0.001) since it is simple to measure and provides tangible data
[18]. In a study comparing hospitalization at 1 and 2 to analyse. However, schizophrenia is a heterogeneous
years after RLAI initiation, greater decreases from base- condition in which a patient might relapse (moderate
line in the number of patients hospitalized and the symptom exacerbation) and not be hospitalized or con-
number and length of hospital stays in patients who versely might be hospitalized for other reasons, such as
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social or somatic causes, but have relatively stable psy- definition of relapse. Nevertheless, hospitalization, due
chiatric symptoms. to an exacerbation of psychotic symptoms, was a key
Clinical scales and criteria were also frequently identi- component of most of the methods used to define
fied in the literature and provide a clinically validated relapse. While the search was designed to capture de-
and standardized method of assessment. In clinical stud- finitions of relapse as they relate to routine clinical
ies, where symptoms are measured at baseline and then practice, rather than more selected clinical popula-
at set intervals, scales are ideal to characterize patients; tions, nevertheless consideration of RCTs of antipsy-
however, they can be time-consuming and require add- chotic treatments is informative, particularly in terms
itional training to perform since most of them are not of their impact on relapse reduction since this is fre-
intuitive, and are therefore often inconvenient for use in quently included as one of the study outcomes. Sys-
routine clinical practice. Behavioural changes and clinical tematic review and meta-analysis of RCTs are often
assessments were least frequently used to define relapse in used as a method of comparing the effects of diffe-
patients with schizophrenia and were poorly defined in rent antipsychotics. One such study suggested that
the literature, but are likely to be used in everyday clinical SGAs may have a greater ability to prevent relapse
practice. The low frequency of use in clinical studies prob- than first-generation antipsychotics (FGAs) [86], but
ably reflects that physician variability may be a significant the influence of patient adherence to treatment on
factor in behavioural and clinical definitions. this finding is uncertain, and the extent of the diffe-
Factors that were associated with an increased or de- rence varied between treatments [137].
creased risk of relapse included adherence to medication, A number of meta-analyses have been conducted of
stress, psychosocial therapies, previous hospitalization/re- relapse rates of depot/long-acting injectable (LAI) anti-
lapse and patient insight. The most prominent factor re- psychotics compared with oral antipsychotics based on
lated to increased risk of relapse was partial/non-adherence RCTs; however, the study conclusions are not all in
to antipsychotic medication [25,76,85]. Indeed, it is well agreement. Leucht et al. [138] reported that in studies of
established that treatment with antipsychotic medication 12 months or more comparing depot with oral antipsy-
can offer an effective option for relapse prevention as well chotics in schizophrenia, depot formulations reduced re-
as other beneficial patient outcomes. For instance, in an lapse significantly, with a relative and absolute risk of
analysis of a nationwide cohort of 2,588 consecutive 30% and 10%, respectively (RR = 0.70; 95% CI = 0.57,
patients hospitalized for the first time with a diagnosis of 0.87; number needed to treat (NNT) = 10; 95% CI = 6,
schizophrenia in Finland, 1,496 patients (57.8%) were 25; p = 0.0009). A similar superiority of depot over oral
rehospitalized due to relapse during a mean follow-up formulations (RR = 0.31; 95% CI = 0.21–0.41 vs RR =
period of 2 years; use of any antipsychotic was associated 0.46; 95% CI = 0.37–0.57; p = 0.03) has been reported in
with a lower risk of rehospitalization compared with a meta-analysis of RCTs of antipsychotics versus placebo
no use of antipsychotics (Cox model hazard ratio = 0.38, for relapse prevention in schizophrenia [139]. However,
95% CI = 0.34–0.43; marginal structural model hazard a meta-analysis published subsequently by some of the
ratio = 0.48, 95% CI = 0.42–0.56) [136]. same authors found no superiority of pooled LAIs com-
Increasing gaps in medication intake over 1 year can pared with oral antipsychotics in relapse prevention
result in a greater risk of hospitalization (up to a four- (studies = 21, n = 4950, RR = 0.93; 95% CI = 0.80, 1.08;
fold increase) [26]. The use of continuous medication, p = 0.35) [140]. The authors speculated that publication
through increased adherence to antipsychotic medica- bias in older studies (prior to requirements for registra-
tion or use of medications that give assured delivery, tion and publication of results of all clinical trials), chan-
was the most frequently identified factor associated with ging definitions of relapse over time and increasing use
reduced relapse or hospitalization rates [18,22,23,128]. of oral SGAs as comparators may all influence the diffe-
These findings highlight the current focus on anti- rence in findings between older and more recent RCTs.
psychotic medication in the literature and the impor- One interpretation of these differences in findings is that
tance of monitoring and improving medication adherence RCTs may over-represent patients with greater adher-
in patients with schizophrenia. ence to treatment, and with less severe illness compared
While primary research articles concerning RCTs were with the wider population of patients with schizophre-
removed from the initial results for the reasons outlined nia. Consistent with this assertion, a meta-analysis of
above (see ‘Methods’), the literature search identified mirror-image open studies (pre- and post-introduction
one meta-analysis performed by Leucht et al. [86], cover- of LAI antipsychotics) within subjects showed a strong
ing 17 RCTs, where the heterogeneity of definitions of superiority of LAI antipsychotics in preventing a next
relapse used mirrored those seen in naturalistic studies. hospitalization (16 studies, n = 4,066; RR = 0.43; 95% CI =
With the exception of RCTs conducted by the same 0.35–0.53; p < 0.001, NNT = 3) and in decreasing the
pharmaceutical company, each study used a distinct number of hospitalizations (15 studies, 6,396 person-
Olivares et al. Annals of General Psychiatry 2013, 12:32 Page 8 of 11
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years, rate ratio = 0.38; 95% CI = 0.28, 0.51; p < 0.001) Author details
1
[141]. This clear superiority was maintained in subgroup Department of Psychiatry, Hospital Meixoeiro, Complejo Hospitalario
Universitario de Vigo, Vigo 36200, Spain. 2Janssen-Cilag NV/SA,
analyses of FGA LAI antipsychotics, SGA LAI antipsy- Antwerpseweg 15-17, Beerse 2340, Belgium. 3Janssen Health Economics
chotics, studies published before 2000, studies published Market Access and Reimbursement, Europe, Middle East and Africa,
after 2000, studies reporting intention-to-treat analyses Hammerbakken 19, Birkerød 3460, Denmark. 4Medical and Scientific Affairs,
Janssen-Cilag Europe, Middle East and Africa, Johnson & Johnson Platz 5a,
and studies reporting observed cases, with the authors Neuss 41470, Germany.
concluding that analyses of naturalistic studies may better
represent the clinical population likely to be treated with Received: 20 November 2012 Accepted: 7 October 2013
Published: 23 October 2013
LAI antipsychotics in routine care.
In non-RCTs identified in the current literature review,
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