Rossi et al.

BMC Psychiatry 2012, 12:122

http://www.biomedcentral.com/1471-244X/12/122

RESEARCH ARTICLE Open Access

Long-acting antipsychotic drugs for the treatment

of schizophrenia: use in daily practice from
naturalistic observations
Giuseppe Rossi1*†, Sonia Frediani2†, Roberta Rossi1† and Andrea Rossi3†

Abstract
Background: Current guidelines suggest specific criteria for oral or long-acting injectable antipsychotic drugs (LAIs).
This review aims to describe the demographic and clinical characteristics of the ideal profile of the patient with
schizophrenia treated with LAIs, through the analysis of nonrandomized studies.
Methods: A systematic review of nonrandomized studies in English was performed attempting to analyze the
factors related to the choice and use of LAIs in daily practice. The contents were outlined using the Cochrane
methods for nonrandomized studies and the variables included demographic as well as clinical characteristics. The
available literature did not allow any statistical analysis that could be used to identify the ideal profile of patients
with schizophrenia to be treated with LAIs.
Results: Eighty publications were selected and reviewed. Prevalence of LAI use ranged from 4.8% to 66%. The only
demographic characteristics that were consistently assessed through retrieved studies were age (38.5 years in the
1970’s, 35.8 years in the 1980’s, 39.3 years in the 1990’s, to 39.5 years in the 2000’s) and gender (male > female).
Efficacy was assessed through the use of various symptom scales and other indirect measurements; safety was
assessed through extrapyramidal symptoms and the use of anticholinergic drugs, but these data were inconsistent
and impossible to pool. Efficacy and safety results reported in the different studies yielded a good therapeutic
profile with a maximum of 74% decrease in hospital admissions and the prevalence of extrapyramidal symptoms
with LAIs consistently increased at 6, 12, 18, and 24 months (35.4%, 37.1%, 36.9%, and 41.3%, respectively).
Conclusions: This analysis of the available literature strongly suggests that further observational studies on patients
with schizophrenia treated with LAIs are needed to systematically assess their demographic and clinical
characteristics and the relationships between them and patient outcome.
Besides the good efficacy and safety profile of LAIs, health care staff must also take into account the importance of
establishing a therapeutic alliance with the patient and his/her relatives when selecting the most appropriate
treatment. LAIs seem to be a good choice not only because of their good safety and efficacy profile, but also
because they improve compliance, a key factor to improving adherence and to establishing a therapeutic alliance
between patients with schizophrenia, their relatives, and their health care providers.
Keywords: Delayed-action preparations, Antipsychotic agents, Schizophrenia, Patients, Review

* Correspondence: [email protected]
†
Equal contributors
1
U.O. Psichiatria, IRCCS “Centro San Giovanni di Dio” Fatebenefratelli, via
Pilastroni 4, Brescia, Italy
Full list of author information is available at the end of the article

© 2012 Rossi 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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Background ensuring adequate control of the disease, fewer

Schizophrenia is a chronic disabling illness with a world- relapses, and good adherence to the treatment—factors
wide lifetime prevalence of about 1% [1]. It is character- that will translate into a better quality of life (QoL),
ized by relapses alternating with periods of partial or full fewer adverse events, fewer rehospitalizations, and a
remission [2] and poor adherence to antipsychotic treat- comprehensive improvement. To achieve this goal, a
ment, leading to multiple rehospitalizations [3] and holistic approach has to be established with the aid of
increased direct and indirect costs [4-11]. health care personnel, patient relatives, and the
Antipsychotic medications have evolved in order to patients themselves.
achieve a better control of schizophrenia. Long-acting The aim of this systematic review is to describe the
injectable antipsychotic drugs (LAIs), introduced for the profile of the ideal patient with schizophrenia to be trea-
first time in the 1960’s, demonstrated their benefits by ted with LAI through the naturalistic observation of age,
lowering relapse rates and durations of hospitalization gender, ethnicity, adherence to and compliance with LAI
[3,12-14], although the high prevalence and severity of by both patient and physician and their relative percep-
extrapyramidal symptoms (EPS) made it necessary to de- tion of LAI together with treatment efficacy and safety
velop new treatments. Second-generation antipsychotics profile.
(SGAs) provided a better tolerability profile compared to
the first-generation antipsychotics (FGAs), but a high
nonadherence rate was still observed [15]. About 57% of Methods
outpatients treated with oral SGAs adhere to the therapy Study design
after 6 months [16]. The efficacy and safety of LAIs have A systematic literature review [49] was performed on
been well established through several randomized con- the data reported in nonrandomized studies for the use
trolled trials and therapy choice criteria for these of LAIs. The contents of this systematic review were
patients have been published recently [17], categorized outlined using Cochrane methods for nonrandomized
by disease severity, patients’ socioeconomic level, and studies [50] in line with the Meta-analysis of Observa-
patients’ autonomy. tional Studies in Epidemiology (MOOSE) methods [51].
The recently released LAI SGAs provide the same fa- Nonrandomized studies were chosen because rando-
vorable profile of oral SGAs, with an increased likeli- mized clinical trials, having strict inclusion and exclusion
hood of improving antipsychotic treatment adherence criteria, are not likely to assess clinical judgment of the
[3,13]. physicians in the routine clinical practice regarding
To determine the ideal profile of the patient suitable patients suitable for LAI treatment.
for treatment with LAIs, several characteristics should
be analyzed in order to understand which of these will
predict a better clinical outcome. Relevant information Search strategy
about all these characteristics is available in the litera- A comprehensive literature search of the Medline (dat-
ture and important associations between these and LAIs ing back to 1966), Embase (dating back to 1988), and
have been established. These features include the follow- Cochrane (dating back to 1964) databases was con-
ing: compliance with and adherence to the treatment ducted using the OvidSPW interface (Ovid Technolo-
[18-21]; attitudes of psychiatrists [22-25], relatives [26], gies, Inc.; New York, NY) on May 15, 2011 by the
and/or patients [27,28] towards antipsychotic medica- medical information team at Primo Scientific Corpor-
tion; patients’ insight about the disease [29-34]; history ation (Panama City, Panama). The search strategy and
of relapses [35]; previous treatment with antipsychotic results are summarized in Figure 1A. All the possible
medication [36]; number of previous hospitalizations combinations of the key terms “neuroleptic agent” or
[3,37]; duration of illness [31]; presence of positive [35] “antipsychotic” and “depot” or “long-acting” or “inject-
and/or negative [38,39] symptoms; medication-related able” or “extended release” were employed to obtain
adverse events [31,40]; and patient experience with relevant reports, regardless of their publication type.
medication [41], among others. The search was then restricted to nonrandomized
Additionally, demographic features such as age, gen- studies published in English, reporting information on
der, ethnicity, educational background, insurance cover- the use of LAIs for the different study variables fulfill-
age, polypharmacy, and history of substance abuse ing the inclusion criteria (ie, patient demographics; ad-
should also be taken into account when considering herence to and compliance with LAI treatment;
treatment with LAIs [40,42-48]. physician, patient, and relatives perception of LAIs;
The ideal candidate for LAI treatment should be a and the efficacy and safety profiles of LAIs). All the
patient who has an unsatisfactory adherence to treat- electronic or hard copy publications were retrieved by
ment and who needs to follow a treatment plan the library staff of Eli Lilly and Company (Indianapolis,
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studies, as these were not restricted by the inclusion

criteria.

Statistical analysis
A formal meta-analysis was not performed because only
gender and age were consistently reported throughout
the studies and these two characteristics have poor prog-
nostic value to determine which patients benefit the
most from the use of LAIs.
The available literature did not allow any statistical
analysis that could be used to identify the ideal profile of
patients with schizophrenia to be treated with LAIs.
Only five of the publications retrieved (all publications
derived from the European Schizophrenia Outpatient
Health Outcomes [SOHO], a large observational study)
included both patients using LAIs and patients using dif-
ferent oral antipsychotics [52-56]. This study did not re-
port any statistical comparisons to assess differences in
clinical or demographic characteristics between the two
cohorts.
All of the studies retrieved were grouped per publica-
tion decade, and the weighted mean age of patients
using LAIs was calculated for each decade to assess a
Figure 1 Search strategy and results. A. Search strategy and possible trend.
results in the OVID interface. B. Study selection and results
algorithm. Limitations of the study

IN) and no abstracts-only or personal communications 1) Study presents nonrandomized studies for the use of
with the authors were required. LAIs published in English
2) Literature available at resources Medline (dating
back to 1966), Embase (dating back to 1988), and
Inclusion and exclusion criteria Cochrane (dating back to 1964) databases was used
Inclusion criteria were nonrandomized studies (retro- in this study
spective or prospective, observational, open-label, mir- 3) There are inconsistencies in reporting the drugs and
ror-image, before and after, and/or case reports/series) dosages (in terms of absolute drug concentrations
in English about the use of LAIs in patients with schizo- and mg of chlorpromazine equivalents [CPZE]) used
phrenia, schizophreniform disorder, or schizoaffective in the different studies
disorder. 4) Formal quality assessment of study could not be
Studies were excluded if they were randomized or done as studies included are narrative in nature
double-blind; investigated only pharmacokinetic or phar- 5) Only gender and mean age are consistently reported
macodynamic characteristics of LAIs; patients included among majority of the studies considered
were not treated by their psychiatrist according to usual 6) Possible selection and information biases may exist
clinical practice; and/or if patients had other psychiatric as data are derived from nonsystematic,
pathologies. nonrandomized allocation to treatments and the
A flow chart is presented in Figure 1B to illustrate the existence of unobserved covariates that might have
study selection process and results. A detailed list of the influenced the outcome
studies included is presented in the Additional file 1. 7) Some results were reported in only one paper and
Abstracts and full-text articles were screened according thus they must be interpreted/taken with caution
to the inclusion and exclusion criteria and the publica-
tion full texts were retrieved for those matching the in- Results
clusion criteria. Various settings (eg, hospital-based LAI Eighty publications were included in this analysis (Add-
clinics, outpatient clinics) in different countries and itional file 1). Several studies assessed the prevalence of
populations (eg, young populations, patients in prison, LAI use among patients with schizophrenia, which ran-
pregnant women) were included in the nonrandomized ged from 11.9% to 66.0% [44,45,47,55,57-61]. Because of
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inconsistencies in reporting the drugs and dosages used with 325 beds mostly devoted to treating patients with
in the different studies, it was not possible to perform schizophrenia used significantly higher doses (p = .05) of
comparisons regarding the doses of LAIs. As this study antipsychotic drugs (N = 58; dose 773.8 ± 784.6 mg
is narrative in nature [49], demographic and clinical CPZE) when compared to a university-affiliated psychi-
characteristics were grouped without a formal assess- atric teaching hospital with 85 beds (N = 52; dose
ment of study quality. All of the studies reporting either 424.8 ± 317.2 mg CPZE), and to a 25-bed inpatient psy-
type of factors were included and discussed. With these chiatric unit (N = 53; dose: 355 ± 283.1 mg CPZE), re-
findings in mind, identifying the characteristics of the spectively. Conventional and depot antipsychotic
ideal profile of the patient to receive treatment with medication were the ones mostly used at provincial hos-
LAIs entails analyzing several key demographic and clin- pitals (99%; 43%), while the novel antipsychotics were
ical variables, trying to assess the main aspects of effi- the most commonly used at university and community
cacy and safety of these drugs. hospitals (56%; 55%) [63]. Patients on LAIs were also
found to receive higher doses of neuroleptic drugs in
Demographic aspects terms of chlorpromazine equivalent doses (525 mg
Only gender and mean age were consistently reported CPZE; p<.001) [61].
in all of the studies, while other demographic factors
were scarcely or inconsistently reported. The studies by Clinical aspects
Lindström et al., (1996) [57] and Sim et al., (2004) [58] Several key clinical elements are reported as being asso-
report a higher proportion of male patients (58.15% ciated with the use of antipsychotic treatment for
[57]; 55.9% [58]) treated with LAIs as compared to schizophrenia.
females (41.85%; 44.1%) [57,58]. The calculated mean
weighted age at treatment has been mostly stable Perception of LAIs
throughout the decades, from 38.5 years in the 1970’s, Less than 20% of patients with schizophrenia receive
35.8 years in the 1980’s, 39.3 years in the 1990’s, to LAIs and less than 10% of psychiatrists offer LAIs after a
39.5 years in the 2000’s. One article [62] reported that first psychotic episode, prescribing them in a very con-
older age was associated with lower doses of LAIs servative manner and only when other therapeutic
(275 ± 239 mg CPZE) and, though no significant correl- options have failed [26], even though there is no evi-
ation of age with LAI daily dose for either haloperidol dence supporting this practice [64]. It is important to
decanoate (28 days 3.5 ± 2.5 mg; p = .50) or fluphenazine note that psychiatrists have decreased their LAI pre-
decanoate (16 days 1.5 ± 1.3; p = .70) was found, a scribing rates in the last five years by approximately
pooled analysis of LAIs revealed that patients using 50%, although LAIs are shown to be very efficacious, are
them in low doses (≤300 mg CPZE) were significantly associated with higher compliance rates, and are cur-
older (p = .005) [44]. rently more available [25]. A questionnaire-based survey
In terms of ethnicity, another study [47] reported that of 198 German psychiatrists found that LAI was only
African American descent is a stronger predictor of prescribed to 13.3% out of 26.7% of patients with first
FGA use (odds ratio [OR] 1.53; 95% confidence interval episode schizophrenia [65]. Principal reasons for lower
[CI] 1.12-2.09), at 53% higher doses (>1000 mg CPZE) prescription rate were: difficulty in presenting the bene-
than other ethnic groups [48], but less likely (p<.001) to fits of LAI to patients for first treatment option; poor
receive LAIs or oral SGAs. availability of the LAI version of risperidone, olanzapine
Results of a prospective comparative study of treat- pamoate, and paliperidone palmitate [22,25,66], specific-
ment for schizophrenia conducted from 1997 to 2003 in ally preferred second generation LAI antipsychotics
the use of first-generation depot antipsychotic at any [AP2G] [67,68]; and lower preference of psychiatrists for
time during the three-year study (N = 569) and those prescribing LAI due to perception of adverse effects of
treated with only oral antipsychotics (N = 1,617) showed depot antipsychotics and related impact on the relation-
a low-education background (p<.001) and poor insur- ship with the patient [65].
ance coverage (p = .009) and further these were also Psychiatrists prescribe oral tablet antipsychotics 88%
reported to be significantly different among patients of the time [26]. When LAIs are prescribed, SGAs are
using LAIs versus oral antipsychotics (75% vs. 66% and preferred (66%) over FGAs for LAI-naïve patients [25].
6% vs. 8%) [47]. Polypharmacy was also frequently There is a report of patients having lower relapse rates
reported [44] in patients with schizophrenia on LAI after using LAI risperidone after 2 years of treatment
treatment and is a predictor for lower doses of anti- following their first episode of psychosis [64].
psychotic drugs (OR 0.42; 95% CI 0.40-0.44; p<.001). Regarding patient attitudes toward LAI formulations,
Remington et al. [63] found differences in the setting 24% of patients reported LAIs as their first choice of
where patients were treated: a large provincial hospital treatment, while 88% reported the acceptance of oral
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tablets as their first choice. There is a marked contrast on treatment, taking into consideration the most rele-
when the patients are separated into three different vant aspects found in the literature. These predictors
groups (LAI-naïve patients, patients currently receiving must be incorporated into the concept that all those
LAIs, and patients previously treated with LAIs). LAI- involved in the integral care of the patient with schizo-
naïve patients preferred oral tablets over LAIs (94% vs. phrenia must engage in a therapeutic alliance [21].
23%), whereas patients on LAI treatment chose it over
oral tablets (73% vs. 67%). Compared to LAI-naïve
patients, patients with previous LAI experience chose Efficacy
LAI more often, but curiously, had a greater preference The efficacy of LAIs in general, and SGAs in particular,
for tablet formulations [36]. seems to be consistently shown throughout studies
The results from a clinical survey evaluating the pre- where patients reported improvement on the most com-
scription rate of antipsychotics by psychiatrists corrobo- mon efficacy measures.
rated the belief that patients with a poor course of One such measure is the CGI scale, which has become
schizophrenia fit the ideal profile to receive LAI treat- one of the most widely used assessment tools in psych-
ment [69]. iatry since it was first published [79]. A greater baseline
Patients with a better course of illness are character- overall CGI score was found to be a predictor of discon-
ized by having good insight about their illness, high edu- tinuation for antipsychotic medication [54]. Studies re-
cational levels, high levels of participation in treatment port that CGI scales significantly improved in patients
decisions, knowledge of their condition, and a desire to using LAI SGAs [52,53,55,56,80], zuclopenthixol decan-
maintain a therapeutic alliance with the psychiatrist. A oate [81], perphenazine decanoate [82,83], or LAI risper-
new approach could also include these patients as candi- idone [84,85]. PANSS, which is not an outcome rating
dates to receive LAIs [45]. Many studies have reported instrument per se, but originated from the growing need
that patients with better relationships with their physi- to reduce the heterogeneity of what was known about
cians have better compliance rates compared to those schizophrenia, [86] was also used in observational stud-
with “fair” or “poor” relationships (74% vs. 26%, respect- ies [87]. PANSS score also consistently improved in
ively) [21,70]. studies where LAI risperidone was used [88,89]. The
There is a high prevalence of poor insight among Comprehensive Psychiatric Rating Scale (CPRS) has also
patients with schizophrenia [71]. Poor insight is the been used in another study [90], reporting significant
most common symptom of schizophrenia [34]; approxi- correlations (p<.001) with the serum levels of zuclo-
mately 57% of patients are moderately or severely un- penthixol decanoate.
aware of having a mental illness [33]. Poor insight has Other authors have attempted to evaluate the QoL
been related to poor compliance [72], which is the main experienced by patients using LAIs. This has been
cause of nonadherence to treatment in patients with assessed by different studies using various scales, such
schizophrenia [73]. The consequences of poor patient as the Global Assessment of Functioning (GAF), the
insight about their illness are reflected in a greater risk Short Form Health Survey (SF-36), and the EuroQoL 5-
of relapse and more frequent and longer hospital admis- Dimensions Visual Analog Scale (EQ-VAS). Studies on
sions [21]. Treatment with LAI risperidone improved the use of LAIs in different settings have reported sig-
insight scores in patients previously treated with oral nificant improvements (p<.01) in the total GAF score
SGAs or typical LAIs. Additionally, insight improvement [47,79,91-94] or in the SF-36 overall score [95], as well
corresponded to favorable changes in other symptom as in some of its items [71,84,91,93,96]. Although the
domains, such as the Positive and Negative Symptoms use of the EQ-VAS, another scale for assessing QoL
Scale (PANSS) and the Clinical Global Impression used through the SOHO cohorts, has not yielded sig-
(CGI)-Severity subscale [71]. nificant improvements in QoL for all pooled LAIs
[52,53], its baseline value has been found to be a signifi-
Adherence to and compliance with LAI treatment cant factor associated with achieving long-lasting symp-
Nonadherence rates with antipsychotics are often tomatic remission (OR 1.026; 95% CI not reported;
reported as being 40%-60% [74,75]. When comparing p<.0001) [56].
treatment adherence to preference between patients on An indirect measurement of efficacy is the hospitalization
oral antipsychotic tablets or LAIs, patients prescribed rate which, despite having different operational definitions,
with LAIs were significantly more compliant than those improved in patients treated with LAIs. Studies of treat-
receiving oral antipsychotics [11,27,40,76-78]. Figure 2 ment with LAIs consistently report significant decreases in
presents an algorithm of compliance predictors, that can the different quantifiers expressing the length of
help the mental-health specialists choose the best next hospitalization (ie, absolute hospital days, days per patient,
step in the management of patients with schizophrenia number of hospitalizations, bed-days per patient, or
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Figure 2 Decision algorithm for choosing a long-acting antipsychotic based on treatment compliance predictors reported in the
literature.

number of hospitalizations per patient) [9,47,80,85,97-106]. Safety

Only one small study (n = 46) found no statistical differ- Many patients switching to LAI risperidone after treat-
ences in rehospitalization rates between patients using oral ment with conventional antipsychotics showed a signifi-
antipsychotics versus LAIs [107]. A greater length of cant improvement in EPS, measured primarily by the
hospitalization was related to an increased number of pre- Extrapyramidal Symptom Rating Scale (ESRS)
scriptions of LAIs versus oral antipsychotics and the his- [90,91,93,95,96,110-113]. The ESRS has also been used in
tory of psychiatric hospitalization in the prior year was a patients treated with perphenazine decanoate [82,83] and
predictor of LAI FGA use [47]. The frequency of previous fluphenazine decanoate [114] with similar results. When
admissions was a predictor of rehospitalizations in a one- the Drug-Induced EPS Scale (DIEPSS) was applied to
year observational trial [98]. The annual risks of readmis- patients treated with LAI risperidone, no significant differ-
sion for patients using fluphenazine decanoate or halo- ences were found in the rate of EPS [94]. In the SOHO
peridol decanoate were 21% and 35%, respectively [46] study [53], the prevalence of EPS in the Italian cohort trea-
and a decrease in rehospitalization rates was reported in ted with LAIs consistently increased at 6, 12, 18, and
studies with LAI fluphenazine (74% decrease in hospital 24 months (35.4%, 37.1%, 36.9%, and 41.3%, respectively).
admissions compared with previous treatment) [105], per- In the same cohort, the proportion of EPS at 12 months
phenazine (59% decrease in relative risk compared with was significantly higher in patients treated with typical
haloperidol) [108]; and LAI risperidone (27% reduction in LAIs (32%) and oral typical antipsychotics (30%) com-
hospitalization rates) [9]. Patients using haloperidol decano- pared to risperidone (16%), quetiapine (10%), clozapine
ate presented statistically significantly greater differences in (9%), and olanzapine (8%) [52]. Among patients with or
rehospitalization risk when compared to oral risperidone without EPS treated with typical LAIs, the GAF and total
(Holm’s adjusted p = .001), olanzapine (Holm’s adjusted BPRS scores differed at hospital discharge [115]. An indir-
p = .0008), and clozapine (Holm’s adjusted p = .049) [46]. ect measure of EPS is the use of anticholinergic drugs,
Frequency of hospitalizations was positively related with which was reported as significantly higher in patients
duration of illness, with current dose of neuroleptics (i.e., using LAIs (47%) compared with patients using oral SGAs
fluphenazine), and with overall neuroleptic exposure [109]. (13%) [116] and has a rate ranging from 30.9% to 32.0%
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for overall LAIs [52,117]. Lower values of anticholinergic significantly (p = .004) higher in patients treated with flu-
drug use were reported in patients using LAI risperidone phenazine decanoate (117.4 μg/dL; 95% CI 111.2-
(5.2%) [118] and higher values were reported in those 123.6 μg/dL) versus healthy controls (105.6 μg/dL; 95%
using fluphenazine decanoate (67.0%) [114]. Common CI 96.9-114.2 μg/dL); mean serum zinc levels did not
EPS and non-EPS adverse events and their frequencies are differ between the two groups.
summarized in Tables 1 and 2, respectively. The largest re-
port on prolactin-related adverse events was found in the
Italian cohort of the SOHO study (n = 3016) [52] after Discussion
12 months of treatment with different antipsychotic drugs Long-acting injectable antipsychotic drugs were devel-
(risperidone, quetiapine, clozapine, typical oral anti- oped to become a therapeutic option especially for those
psychotic drugs, and typical LAI). A significant proportion patients where nonadherence is a major clinical concern,
of patients using typical LAIs reported prolactin-related with consequences of subsequent relapse episodes and
adverse events, the most common being loss of libido, rehospitalizations [46,122,123]. Although there is a
which was reported by 38.1% of these patients. strong, but perhaps misguided, belief that LAIs cannot
For LAIs, small but statistically significant increases in be used as first-line treatment for schizophrenia, new
body weight and BMI have been reported; contrasting guidelines state that the clinician should consider offer-
reports of nonsignificant increases in these parameters ing them to LAI-naïve patients with schizophrenia [124-
were also found in the literature (Table 3). These weight 131].
and BMI increases were not dose-dependent [117]. The most favorable conditions for the development of
Pain caused by injections is another safety measure an effective therapeutic alliance occur in patients who
reported that is most often evaluated through the visual are well-informed about their illness and are compliant
analog scale (VAS). One study [119] found that zuclo- with treatment, in conjunction with medical staff who
penthixol injections were significantly more painful than are willing to provide explanations and to offer a holistic
flupenthixol, fluphenazine, and haloperidol and that pain therapeutic approach [132-134]. This type of therapeutic
score measured by VAS was correlated to the Hamilton alliance promotes the patient’s adherence to their treat-
Scale for Depression (HAM-D). Another study found ment and facilitates open lines of communication, so
that injection-site pain with LAI risperidone significantly that patients can meaningfully participate in treatment
decreased over 50 weeks [96]. An additional LAI pooled decisions.
study (haloperidol, fluphenazine, zuclopenthixol, and flu- Even though nonrandomized studies have some well-
penthixol) found no significant correlation between VAS known limitations (uncertainty of data collected, differ-
measures 5 minutes after the injection, but found a sig- ences in their design and implementation, lower level of
nificant correlation after 2 days of the injection adminis- evidence than randomized controlled studies, and not
tration [119]. No relationship was found between VAS being included in study registries) [50], they are the only
pain score, patient weight, or the score in the Udvalg for studies in which patients were enrolled and treated
Kliniske Undersøgelser (UKU) 48-Item Side-Effect Rat- according to physicians’ clinical judgment. Consequently,
ing Scale [8]. nonrandomized studies are the only studies that, in a
Some studies report the results while using LAIs in naturalistic setting, allow researchers to understand how
peculiar situations. One report [120] on the use of LAI physicians, based on their clinical judgment, select
risperidone during pregnancy was found, and it did not patients with schizophrenia who have the ideal profile
report any immediate complication at birth. Another for LAI treatment and who should benefit the most from
study [121] found that mean serum copper levels were it. Moreover, they provide naturalistic observation of

Table 1 Percentages of extrapyramidal adverse events reported for different long-acting antipsychotic drugs
Drug FL FE R R R Ry Ra R R P V V Z
Reference [131] [132] [80] [132] [90] [91] [91] [107] [133] [77] [8] [58] [76]
n 16 5 19 87 249 66 351 725 529 42 53 368 19
Dystonia — — — 1.1 — — — — — — 15.1 0.5 —
Akathisia 12.5 40.0 5.3 2.3 2.0 19.7 11.1 17.0 3.4 — 43.4 2.4 —
Parkinsonism/tremor 6.2 — — 4.6 — — — — 6.0 2.4 30.2 7.6 —
Tardive dyskinesia — — — 3.4 — — — — — — — 3.0 15.8
Hypertonia — — — 2.3 — — — — — — 24.5 — —
Abbreviations: Z = zuclopenthixol decanoate; R = risperidone; y = in young patients; a = in adult patients; FL = flupenthixol; FE = fluphenazine; V = various long-acting
antipsychotic drugs; — = not reported.
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Table 2 Percentages of the most frequent and selected general adverse events reported for different long-acting
antipsychotic drugs
Drug FL R R R R, in no r R in r R R vs oral R R Ry Ra R R R R V Z
Reference [131] [15] [79] [86] [84] [84] [85] [88] [89] [90] [91] [91] [105] [107] [132] [133] [88] [76]
n 16 715 192 202 312 82 1476 100 40 249 66 351 336 725 87 529 565 19
Anxiety 12.5 12 12 15 28.7 24.5 6.9 11.0 — 11 21 23 22.3 26 16.1 23.9 — —
Insomnia 6.2 10 9 9 26.5 25.0 7.0 9.0 5.0 6 29 19 23.5 22 16.1 18.7 — 8
Disease exacerbation — — 10 — 20.1 15.8 6.1 5.0 — 6 12 12 18.2 15 19.5 7.4 — —
Depressive reactions 17 — 6 — 19.8 15.7 — 5.0 — — 17 14 19.3 15 — 11.3 — 25
Headache — — — — 14.7 14.7 — — 2.5 6 21 11 — 11.5 7.7 — —
GI symptomsa — — — — — — — — — — 11 3 — — — — — 17
Glucose-related AEs — — — 0.5 b
— — — — — — — — — — 0.0 0.8 c
0.0 —
Prolactin-related AEsd — — — 0.5 — — — 6.0 2.5f 2.8 — — — — — — 0.4e —
Sedation/Somnolence — — — — — — — — — — 12 5 — — — — — —
Rhinitis — — — — — — — — — — 18 11 — — — — — —
Fatigue — — — — — — — — — — 15 7 — — — — — —
Others 6.2h — — — — — — — 2.5g,h — — — — — — — — 17h
Abbreviations: FL = flupenthixol; R = risperidone; r = remission; y = in young patients; a = in adult patients; V = various; Z = zuclopenthixol decanoate;
GI = gastrointestinal; AEs = adverse events; — = not reported.
a
Includes dyspepsia, nausea, and vomiting.
b
New onset type 2 diabetes mellitus (n = 1).
c
New onset type 2 diabetes mellitus (n = 3) and hyperglycemia (n = 1).
d
Includes loss of libido, sexual impotence, galactorrhea, and gynecomastia.
e
Impotence (n = 1) and galactorrhea (n = 1).
f
Irregular menstruation (n = 1).
g
Disturbances in accommodation.
h
Dizziness.

efficacy, safety and compliance to the treatment chosen of life, and satisfaction [142,143]. These observations
by the physician as the most appropriate for each suggest that there is a need for prescribing LAI for
patient. effecting an increase in efficacy and functioning.
We found no obvious explanation for the decrease in Even when the validity of using certain scales as effi-
the prescription rates of LAIs by psychiatrists cacy endpoint measurements has been criticized [86,87],
[25,57,135] even when LAIs have specific advantages these and other efficacy endpoints such as good symp-
over oral FGAs and SGAs, especially in noncompliant tomatic control, improved QoL, and reduced
patients [136,137]. This could also be due to the percep- hospitalization rates seem to be consistently achieved by
tion that depots and LAIs are old-fashioned and they are patients with schizophrenia treated with LAIs.
reserved for the most chronic and disabled patients Safety, which can be evaluated using different tools,
[138-140]. Furthermore, due to higher availability of oral might be a concern when considering the use of LAIs.
atypical antipsychotics in the 1990s, with associated The frequency of EPS seems to be reduced when
heavy marketing, the decline in prescription of depot patients switch from oral to LAIs and the most frequent
has continued due to the assumptions that patients al- EPS reported were akathisia and parkinsonism/tremor
ways prefer oral to depots even though clinician’s atti- (Table 1). Tardive dyskinesia was generally reported less
tude towards these medications is marginally improved. frequently, but was more commonly reported in patients
The adverse impacts of patient preference of depots to using zuclopenthixol decanoate than those using LAI
LAIs, in relation to relapse prevention are rarely risperidone or LAIs in general [81]. Other frequently
explained and discussed with the patient [141]. A six- reported side effects of LAIs are anxiety, insomnia, dis-
month, open-label study with LAI risperidone in 382 ease exacerbation, depression, headache, and weight
patients with recent schizophrenia or schizoaffective dis- gain, but the data retrieved cannot be considered con-
order (diagnosed ≤3 years ago) showed significant de- clusive. It is fundamental to consider side effects, since
crease of severity of schizophrenic symptomatology in patient attitude towards these strongly influence their at-
73%: among these, in 40% of patients, total PANSS score titude towards the entire treatment [8].
decreased by at least 20%. At the same time, patients Unfortunately, the data reported in the literature
showed an improvement of overall functioning, quality cannot be combined any further to identify the ideal
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Table 3 Weight and BMI changes reported in selected LAI improve efficacy, safety, and cost-effectiveness out-
publications comes (Figure 2) [5-7,9,69,122].
LAI(s) used Reference n Weight change, BMI change, Authors agree that the most common reason for pre-
mean difference, mean difference, scribing LAIs is noncompliance, but these drugs on their
kg kg/m2
own do not overcome the problem of treatment nonad-
Risperidone [15] 715 1.4*** 0.5***
herence. This is why therapeutic alliance plays a key role
a
Various [48] 293 0.0 NR [16,26,28,43,69]. Greater illness insight is related to bet-
Various [52] 176 0.1 NR ter attitudes toward treatment, improved compliance,
Various [53] 540 2.9 b
0.7b and fewer relapses and hospitalizations [29,30]. Patients’
Various [55] 1173 NR 0.2b and their relatives’ opinions must be taken into consider-
ation before initiating or switching to a new therapeutic
Various [58] 2399 −1.0 b
NR
plan. A survey among patients with schizophrenia
Various [61] 534 1.3c NR
revealed that 67% of them had not received any informa-
d
Perphenazine [78] 42 No weight change NR tion about LAI treatment from their psychiatrists [25].
Risperidone [79] 192 0.0 −0.1 Ultimately, patients have the right to make an informed
Risperidone [85] 1476 0.9 0.3 decision about LAI treatment. Its overall negative per-
Risperidone [86] 202 0.5 0.2 ception could be reduced if psychiatrists were to provide
broader and more comprehensive information to
Various [88] 565 0.9* NR
patients with schizophrenia and their relatives. Further-
Risperidone [90] 249 1.4*** 0.5***
more, patients’ decisions regarding treatment should be
Risperidone [105] 336 2.5 0.8 guided by healthcare providers (Figure 3), after the most
Risperidone [108] 50 NR 0.0 relevant topics and concerns have been evaluated, dis-
Various [112] 97 NR 1.5b cussed and understood by the patients and their
Risperidone [132] 67 −0.3 NR relatives.
***
Risperidone [133] 529 1.0 0.6***
Various [134] 5950 NR −0.7e Conclusions
Abbreviations: BMI = body mass index; LAI = long-acting injectable Though LAI prescription rates have been decreasing,
antipsychotic drugs; NR = not reported; pts = patients. they still prove to have good efficacy and safety profiles.
a
Pts treated with in-range chlorpromazine-equivalent doses versus patients
treated with higher chlorpromazine-equivalent doses. The important question, therefore, is to determine which
b
c
Versus oral antipsychotics. patients with schizophrenia are the most suitable for
Pts treated with LAI and anticholinergic drugs versus patients treated with LAI
without anticholinergic drugs.
treatment with LAIs. Our research might reveals indica-
d
This study reported no weight change, with 16 pts gaining a range of 1-9 kg tors that could support psychiatrists tailor their answer
and 7 pts losing a range of 1-2 kg. to this question when dealing with particular cases. Psy-
e
Patients achieving persistent remission versus patients with prolonged
disease. chiatrists seeking to improve the therapeutic alliance
*
p ≤ .05; ** p ≤ .01; ***p ≤ .001. with patients who need to improve treatment compli-
ance and adherence should consider LAIs when estab-
lishing a therapeutic plan. Efficacy and safety must also
profile of the patient using LAIs, due to the inconsist-
be taken into account. Naturalistic setting trials aimed at
ency in the way the results are reported. Even those
understanding how therapeutic alliance can be improved
variables, such as age and gender, reported in all
by the use of LAIs should be carried out in order to sys-
studies retrieved have poor prognostic value in terms
tematically identify those patients who would most
of understanding how physicians select the ideal pro-
benefit from the use of LAIs.
file of the patient with schizophrenia to be treated
with LAIs. The only consistently reported reason why
certain patient profiles are identified as “ideal” to re- Additional file
ceive LAI treatment is because this type of adminis-
tration ensures treatment delivery. Patient insight, Additional file 1: Observational studies included in the data
attitude toward, and compliance with LAIs are crucial analysis. This data table includes the 80 studies that fulfilled the
inclusion criteria for this review and their general description.
factors that influence physician’s LAI choice, especially
when a good therapeutic alliance has been established
[69,144]. Nowadays, the therapeutic alliance seems to Competing interests
be the most influential factor related to successful This article was sponsored by Eli Lilly and Company.
Giuseppe Rossi and Sonia Frediani have acted as invited speakers for Eli Lilly.
compliance and adequate adherence to the schizo- Andrea Rossi is a full time employee at Eli Lilly Italy.
phrenia treatment [16,26,28,43,69]. This factor can Roberta Rossi declares no conflicts of interest.
Rossi et al. BMC Psychiatry 2012, 12:122 Page 10 of 13
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