Clinical Psychopharmacology and Neuroscience 2018; 16(4): 361-375  https://doi.org/10.9758/cpn.2018.16.4.361
Comparative Efficacy and Safety of Long-acting Injectable and Oral Second-generation Antipsychotics for the Treatment of Schizophrenia: A Systematic Review and Meta-analysis
Seon-Cheol Park1,*, Mi Young Choi2,*, Jina Choi2, Eunjung Park2, Ha Jin Tchoe2, Jae Kyung Suh2, Young Hoon Kim3, Seung Hee Won4, Young-Chul Chung5, Kyung-Yeol Bae6, Sang-Kyu Lee7, Chan Mi Park2, and Seung-Hwan Lee8
1Department of Psychiatry, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea, 2National Evidence-based Healthcare Collaborating Agency, Seoul, Korea, 3Department of Psychiatry, Gongju National Hospital, Gongju, Korea, 4Department of Psychiatry, School of Medicine, Kyungpook National University, Daegu, Korea, 5Department of Psychiatry, Chonbuk National University Hospital, Jeonju, Korea, 6Department of Psychiatry, Chonnam National University Medical School, Gwangju, Korea, 7Department of Psychiatry, Hallym University Chuncheon Sacred Hospital, Hallym University College of Medicine, Chuncheon, Korea, 8Department of Psychiatry, Inje University Ilsan Paik Hospital, Goyang, Korea
Correspondence to: Address for correspondence: Seung-Hwan Lee, MD, PhD, Department of Psychiatry, Ilsan Paik Hospital, Inje University College of Medicine, 170 Juhwa-ro, Ilsanseo-gu, Goyang 10380, Korea, Tel: +82-31-910-7260, Fax: +82-31-910-7268, E-mail: lshpss@hanmail.net, ORCID: https://orcid.org/0000-0003-0305-3709, Chan Mi Park, PhD, National Evidence-based Healthcare Collaborating Agency, Namasan Square (Kukdong B/D) 7F, 173 Toegye-ro, Jung-gu, Seoul 04554, Korea, Tel: +82-2-2174-2720, Fax: +82-2-747-4916, E-mail: chpark@neca.re.kr
Received: February 1, 2018; Accepted: March 5, 2018; Published online: November 30, 2018.
© The Korean College of Neuropsychopharmacology. All rights reserved.

This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

We aimed to compare the efficacy and safety of long-acting injectable (LAI) and oral second-generation antipsychotics (SGAs) in treating schizophrenia by performing a systematic review and meta-analysis. MEDLINE, EMBASE, PsycINFO, CINAHL, and the Cochrane Library, as well as five Korean databases, were systemically searched to identify studies published from 2000 to 16 April 2015, which compared the efficacy and safety of LAI and oral SGAs. Using data from randomized controlled trials (RCTs), meta-analyses were conducted. In addition, the GRADE (the Grading of Recommendations, Assessment, Development and Evaluation) approach was applied to explicitly assess the quality of the evidence. A total of 30 studies including 17 RCTs and 13 observational studies were selected. The group treated with LAI SGAs was characterized by significantly lower relapse rates, longer times to relapse and fewer hospital days, but also by a higher occurrence of extrapyramidal syndrome and prolactin-related symptoms than that in the group treated with oral SGAs. Our findings demonstrate that there is moderate to high level of evidence suggesting that in the treatment of schizophrenia, LAI SGAs have higher efficacy and are associated with higher rates of extrapyramidal syndrome and prolactin-related symptoms. Additionally, the use of LAI SGAs should be combined with appropriate measures to reduce dopamine D2 antagonism-related symptoms.

Keywords: Efficacy, Long-acting injectable, Safety, Schizophrenia, Second-generation antipsychotics
INTRODUCTION

In terms of the global burden of mental disorders, schizophrenia has been identified as an important mental health issue by the Grand Challenges in Global Mental Health Initiative.14) Antipsychotic medication non-compliance occurs in 80% or more of patients with schizophrenia, and can last for substantial periods of time, despite recommendations from clinical psychiatrists.5) The European Schizophrenia Health Outcome Study (SOHO) demonstrated that non-compliance was associated with recurrence risk, hospitalization rate, and suicidal risk, among more than 7,000 patients with schizophrenia.6) In addition, antipsychotic non-compliance has been shown to be significantly associated with an increased risk of re-hospitalization, emergency room visits, homelessness, and symptom exacerbation.7) Hence, “long-acting injectable” (LAI) or depot antipsychotics have been proposed as one of the most promising potential alternative treatments to overcome non-compliance in patients with schizophrenia. A meta-analysis of 10 randomized clinical trials lasting at least 12 months, and including 1,700 patents with schizophrenia showed that LAI antipsychotics are associated with significant reductions in relapses and dropouts due to the lack of efficacy when compared with oral antipsychotics.8)

The efficacy and tolerability profiles of LAI and oral an-tipsychotics have been compared in several studies using a systematic review and/or meta-analysis approach.917) Most of the systematic reviews and meta-analyses conceptualized LAI and oral antipsychotics as the intervention and the comparator, respectively, without regard for whether the medications were classified as first-generation antipsychotics (FGAs) or second-generation anti-psychotics (SGAs). In terms of FGAs and SGAs, “atypicality”, which is associated with SGAs, can be defined as a favorable antipsychotic effect with a reduced risk of extrapyramidal side effects.1821) Moreover, LAI FGAs are rarely used in real-world psychiatry and, particularly in the United States, only haloperidol decanoate and fluphenazine decanoate are used.22) However, since most of the systematic reviews and meta-analyses concerning the efficacy and safety of LAI antipsychotics have been evaluated without regard for the distinction of LAI FGAs and SGAs, to our knowledge, the comprehensive efficacy and safety of LAI SGAs in real-world settings have not been well reported. In addition, extrapyramidal side effects and other adverse effects may be associated with discontinuation of antipsychotics in patients with schizophrenia.15,23) The present systematic review and meta-analysis aimed to compare overall profiles for both efficacy (relapse rate, time to relapse, hospitalization rate, remission rate, hospital days, non-compliance, quality of life, and changes in symptom severity) and safety (all cause discontinuation, extrapyramidal side effects, abnormal involuntary movements, and other variables) of LAI and oral SGAs among schizophrenia patients.

METHODS

Study Overview

A systematic search was performed using international databases including MEDLINE, EMBASE, the Cochrane Library, CINAHL, and PsycINFO, and also several Korean domestic databases, including KoreaMed, Korean Medicine Database (KMBASE), Korean Studies Information Service System (KISS), National Digital Science Library (NDSL), and the Research Information Sharing Service (RISS), with a date range limit for publications from 2000 to 16 April 2015. The key questions and the PICO framework (Patient, Intervention, Comparator, Outcome)24) were defined with the advice of an expert group of psychiatry specialists in the field of schizophrenia research (KYH, WSH, CYC, BKY, LSK, PSC, and LSH). Extensive searches of the databases using the terms “schizophrenia,” “long acting injection,” and each of the generic names of the SGAs, as defined by Tandon et al.,25) were performed. Terms were related to the databases’ index terms, such as Medical Subject Headings (MeSH) and EMTREE.

Eligibility Criteria

Articles that met the following criteria were included: 1) study subjects were adults with schizophrenia (including initial and relapsed patients); 2) the intervention and the active comparator were LAI and oral SGAs, respectively; 3) at least one of the predetermined outcomes was reported; 4) the study was designed as a randomized controlled trial (RCT), non-RCT, cohort study, case-control study, or mirror-image study; and 5) articles were published in English or Korean. Articles that met the following criteria were excluded: 1) reports on animal trials or pre-clinical studies, and non-original research articles such as reviews, editorials, letters, and comments; 2) articles not published in English or Korean, and those with duplicate subjects (studies using the same outcome indicators and publishing in duplicate) were also excluded.

Outcome Measures

Relapse rate, non-compliance rate, time to relapse, hospitalization rate, remission rate, hospital days, quality of life, and changes in assessment scales, including the Clinical Global Impression-Severity (CGI-S),26) Positive and Negative Syndrome Scale (PANSS),27) and the Montgomery-Asberg Depression Rating Scale (MADRS)28) were used as measures of efficacy. The discontinuation rate, drug-related side effects, and changes in assessment scales, including the Extrapyramidal Symptom Rating Scale (ESRS),29) and the Abnormal Involuntary Movement Scale (AIMS)30) were used as safety measures.

Selection of Studies and Quality Assessment

Study selection was initially conducted by the researchers in pairs (CMY, PSC, THJ, CJ, PCM, SJK, PE, and LSH). Namely, screening of all studies by title and abstract, and selection of studies according to the eligibility criteria were conducted by independent pairs of investigators. Selected studies were then discussed and agreed upon in consensus meetings, with consultation from the expert group. The literature selection process was conducted in accordance with the “preferred reporting items for systematic reviews and meta-analysis protocols” (PRISMA-P) 2015 statement.31) Quality assessment of the selected studies was conducted using the Cochrane Risk of Bias Tools32) for the RCTs, and the revised risk of bias tool for non-randomized studies (RoBANS),33) for the observational studies. Quality assessments were conducted by independent pairs of investigators and a consensus was achieved by discussion, with consultation from the expert group.

Data Extraction and Management

According to the pre-defined data extraction format, researchers worked in pairs to extract data from the selected studies. Detailed data, including patient characteristics and primary and secondary outcomes, were extracted from the selected studies. Continuous variables such as mean change from baseline, median range and standard deviation were converted according to the formula described in the Cochrane Handbook for Systematic Reviews of Interventions.32) The extracted data were synthesized in terms of quantity and quality.

Data Synthesis and Analysis

The data analyses were conducted in terms of both research type (RCT vs. observational study) and medication type (LAI vs. oral antipsychotic). The standardized mean difference (SMD) or relative risk (RR) and 95% confidence interval (CI) from each of the individual RCTs were calculated, and meta-analysis using the fixed effect model was fitted. The fixed effect model assumed that all of the studies had the same treatment effect, and variation in research findings was assumed to be caused by sampling variation or random effects. Along with an evaluation of publication bias, sensitivity analysis and subgroup analysis were also conducted. The publication bias test (funnel plot asymmetry) was only used when at least 10 studies were included in the meta-analysis. Heterogeneity of effects was evaluated using the Higgins I2 statistic. All statistical analyses were performed using Cochrane RevMan version 5.3 (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and R Software (R version 3.1.2; R Foundation for Statistical Computing, Vienna, Austria), including meta packages.

Level of Evidence

The level of evidence was evaluated using the methodology developed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) working group.33) The GRADE methodology first evaluates the importance of individual outcomes and then determines the level of evidence for each individual outcome as high, moderate, low, or very low. The factors associated with reducing the level of evidence in terms of the risk of bias were as follows: if the presence of performance bias was considered in an association with the open-label designed studies, the level of evidence was reduced by one level. The Summary of Findings table using the GRADE methodology contained a maximum of seven findings, ranked by importance. Measures of clinical efficacy included relapse rate, time to relapse, hospitalization rate, remission rate, hospital days, non-compliance, and quality of life. Measures of safety outcomes included all-cause discontinuation rate, drug-related side effects, ESRS, AIMS, and other side effects. The level of evidence was evaluated using the methodology developed by the GRADE working group.34) Confidence in the estimate of effect was categorized into four levels, including very low, low, moderate and high. Factors associated with lowering the level of evidence were risk of bias, inconsistency, indirectness, imprecision, and publication bias. For the observational studies, factors associated with heightening the level of evidence were a large magnitude of effect, a dose-response gradient, and an effect of plausible residual confounding. Evidence summary of findings tables for each research question were prepared using GRADEpro (McMaster University, Hamilton, ON, Canada; available at: http://ims.cochrane.org/revman/other-resources/gradepro/download).

RESULTS

Study Characteristics

A total of 3,062 articles were retrieved from the databases. After exclusion of duplicates, 1,933 articles remained. According to the selection criteria, 17 RCTs and 13 observational studies were selected.3564) All selection steps are presented as a PRISMA flowchart. Finally, the 17 RCTs are selected for our meta-analysis (Fig. 1).

In terms of the geographical locations in which the studies were conducted, most of the studies (70.6%) were conducted internationally (eight studies were conducted globally, three studies were conducted in Europe, and one study was conducted in Asia), 17.6% of studies were conducted in North America (three studies were conducted in the United States), 5.9% were conducted in Europe (one study was conducted in the United Kingdom), and 5.9% were conducted in Asia (one study was conducted in Taiwan). In addition, the follow-up periods for 37% and 36% of articles were two years and less than one year, respectively. The periods for 17%, 7%, and 3% of the studies were between one and two years, three years, and five years, respectively. All studies were published between 2005 and 2015 (Table 1).

The LAI antipsychotics used as the intervention treatments in the selected articles included risperidone LAI (70.6%), olanzapine LAI (17.6%), and aripiprazole LAI (11.8%). Oral antipsychotics used as active comparators included aripiprazole (23.5%), olanzapine (23.5%), quetiapine (17.6%), and risperidone (11.8%), with an unspecified oral SGA used in the remainder of the studies (23.5%) (Table 1).

Risk of Bias Assessment of Selected Studies

Risk of bias for the 17 RCTs was assessed using the Cochrane Risk of Bias Tool.30) Random sequence generation, allocation concealment, incomplete outcome, and selective reporting showed approximately low risks of bias. In contrast, blinding of participants and blinding of outcome assessment showed a high or an unclear risk of bias.

Risk of bias for the 13 observational studies was assessed using the revised RoBANS tool. The results for the risk of bias were as follows: the blinding of outcome assessment presented a high or unclear risk of bias in the prospective studies, whereas participant comparability, selection of participants, and confounding variables presented relatively high risks of bias in the retrospective studies. Blinding of outcome assessment and confounding variables presented unclear risks of bias in the mirror-image studies (Fig. 1).

Efficacy Outcomes

A summary of the efficacy outcomes, including relapse rate, non-compliance, time to relapse, hospitalization rate, remission rate, quality of life, hospital days, and other variables are shown in Table 2.

Relapse Rate

Because the findings of Rouillon et al.54) and Gaebel et al.45) were obtained from the same subjects, the relapse rate reported in Gaebel et al.45) was considered a major measure and the findings in Rouillon et al.54) were excluded from the meta-analysis. Ultimately, only six studies were used for this analysis. Overall, the group treated with LAI SGAs showed significantly lower relapse rates than did the oral SGAs group (RR, 0.85; 95% CI, 0.74 to 0.99).

In the subgroup based on the length of the follow-up period, the relapse rate in the LAI SGAs group was 17% lower than that in the group treated with oral SGAs, in studies lasting ≥1 year (RR, 0.83; 95% CI, 0.71 to 0.97). However, there were no significant differences in relapse rates in studies lasting ≤ 1 year (RR, 1.03; 95% CI, 0.66 to 1.60). In addition, there were no significant differences between the groups with the relatively long and short follow-up periods (χ2=0.78, degree of freedom [df]=1, p=0.38) (Table 2).

Non-compliance

Although non-compliance was described in two articles, both of the articles investigated the same study subjects. Therefore, only the findings of Weiden et al.62) were used and no meta-analyses were conducted. Weiden et al.62) compared non-compliance between schizophrenia patients treated with risperidone long-acting injection and oral SGAs. In their study, non-compliance was defined as “the complete discontinuation of all anti-psychotic medication for more than 14 consecutive days.” There was no significant difference in non-compliance among patients treated for less than one year (RR, 0.58; 95% CI, 0.09 to 3.35), patients treated for one year (RR, 0.79; 95% CI, 0.47 to 1.31), and patients treated for more than one year (RR, 0.92; 95% CI, 0.51 to 1.66) (Table 2).

Time to Relapse

Time to relapse (days) was reported in two articles. Both studies used risperidone long-acting injection as the intervention and conducted follow-up assessments for 24 months. In the study by de Arce Cordón et al.,41) the proportion of schizophrenia patients was 83% in the intervention group and 82.2% in the control group. In the study by Macfadden et al.,52) all the subjects were schizophrenia patients in the groups treated with LAI and oral SGAs. The mean disease duration of schizophrenia in the study by de Arce Cordón et al.41) was 9.9 years in the group treated with LAI SGAs and 8.1 years in the group treated with oral SGA-treated group, respectively, the study of Macfadden et al.,52) included patients that experienced at least two episodes of relapse in the past two years as the study subjects. In results of the meta-analysis, we found that the group treated with LAI SGAs had significantly longer time to relapse than did the group treated with oral SGAs (SMD, 0.42; 95% CI, 0.29 to 0.54) (Table 2).

Hospitalization Rate

Hospitalization rate was reported in three articles. Rehospitalization was defined as the subjects’ psychiatric admission associated with psychotic and/or other psychiatric symptoms occurred after randomization in all studies. Weiden et al.62) reported separate findings for one-year and two-year follow-up periods. In results of the meta-analysis, there was no statistically significant difference in the hospitalization rates of the groups treated with LAI and oral SGAs (RR, 0.83; 95% CI, 0.62 to 1.11; I2=29%).

In the subgroup analysis, there were no significant differences according to the follow-up period. In addition, considering inter-group differences caused by the follow-up duration, there was no significant difference (χ2=0.04, df=1, p=0.84) (Table 2).

Remission Rate

Remission rate was reported in five articles.41,44,47,48,57) Most of the studies used the schizophrenia remission criteria proposed by Andreasen et al.,65) although Keks et al.48) defined remission as a 20% or more decline in the total PANSS score. Since the remission criteria of Andreasen et al.65) and Keks et al.48) were similar, in the data synthesis, the remission rates reported in each of the studies were used without modification. The meta-analysis showed no significant difference in remission rates for the groups treated with LAI or oral SGAs (RR, 1.07; 95% CI, 0.99 to 1.15; I2=70.5%).

In subgroup analysis, based on follow-up duration, the remission rate for the group treated with LAI SGAs was significantly greater than that for the oral SGAs group, in studies lasting ≥1 year (RR, 1.42; 95% CI, 1.18 to 1.71) (Table 2).

Quality of Life

Quality of life measures were reported in two articles.35,41) Since the two studies used quite different assessment scales to measure quality of life, we could not synthesize the data quantitatively. In other words, the relatively high scores on the Schizophrenia Quality of Life Scale (SQLS)66) which was used in the study by de Arce Cordón et al.,41) indicate a relatively low quality of life, whereas the relatively high scores in the Heinrichs Carpenter Quality of Life Scale (HQLS),67) which was used in the study by Ascher-Svanum et al.,35) indicate a high quality of life. However, in all the groups treated with LAI and oral SGAs, the mean changes between the initial and final values were significant, and there were no inter-group comparisons (Table 2).

Hospital Days

“Hospital days” was defined as the duration of psychiatric admission associated with psychotic and/or other psychiatric symptoms in patients with schizophrenia. Two articles were included in the meta-analysis, and both studies used olanzapine long-acting injection as the intervention treatment. Detke et al.42) evaluated hospital days associated with schizophrenia for a two-year follow-up period, and Ascher-Svanum et al.35) evaluated hospital days for a six-month follow-up period. The mean hospital days for the group treated with LAI SGAs was significantly shorter than that for the oral SGAs group (SMD, −0.11; 95% CI, −0.22 to −0.01) (Table 2).

Positive and Negative Syndrome Scale (PANSS)

Total score on the PANSS was reported in nine studies included in the meta-analysis. The groups treated with LAI and oral SGAs were compared in terms of the mean change in the total score on the PANSS before and after SGA medications. In the meta-analysis, the decrease in total PANSS score in the group treated with LAI SGAs was greater than that in the oral SGAs group. However, this difference was not significant (SMD, −0.05; 95% CI, −0.12 to 0.12).

In subgroup analysis according to follow-up period, the decrease in total PANSS score was greater in the group treated with LAI SGAs than in the oral SGAs group. However, again, this difference was not significant. In addition, considering inter-group differences caused by the follow-up period, there was no significant difference (χ2=1.59, df=1, p=0.21) (Table 2).

Clinical Global Impression Scale (CGI-S)

Scores on the CGI-S were reported in eight studies included in the meta-analysis. The groups treated with LAI and oral SGAs were compared in terms of the mean change in score on the CGI-S before and after treatment with SGA medications. In the meta-analysis, the decrease in the CGI-S score in the group treated with LAI SGAs was greater than that in the oral SGAs group. However, this difference was not significant (SMD, −0.05; 95% CI, −0.13 to 0.04; I2=35.5%).

In the subgroup analysis, according to follow-up period, there was no significant difference. In addition, considering inter-group differences caused by the follow-up period, there was no significant difference (χ2=0.57, df=1, p=0.45) (Table 2).

Montgomery-Asberg Depression Rating Scale (MADRS)

Scores on the MADRS were reported in two articles. Both studies were included in the ConstaTRE study.40) de Arce Cordón et al.41) used risperidone long-acting injection for intervention and oral aripiprazle for control and Smeraldi et al.57) used risperidone long-acting injection for intervention and oral quetiapine for control for the follow-up period of 24 months. In the meta-analysis, the decrease in the MADRS score was significantly greater in the group treated with LAI SGAs than in the group treated with oral SGAs (SMD, −1.69; 95% CI, −2.95 to −0.43) (Table 2).

Safety Outcomes

A summary of the safety outcomes, including all-cause discontinuation rate, drug-related side effects, ESRS, AIMS, and other side effects are shown in Table 3.

All-cause Discontinuation Rate

All-caused discontinuation rates were described in three articles included in the meta-analysis. Olanzapine long-acting injection was used in the study of Detke et al.42) and aripiprazole long-acting injection was used in the other two studies. In the meta-analysis, the group treated with LAI SGAs had a lower discontinuation rate than did the oral SGAs group. However, this difference was not significant (RR, 0.93; 95% CI, 0.82 to 1.05) (Table 3).

Extrapyramidal Symptom Rating Scale (ESRS)

Scores on the ESRS were reported in two studies. In the meta-analysis, the decreased sore in the ESRS score was greater in the group treated with LAI SGAs than in the oral SGAs group (SMD, −0.01; 95% CI, −0.15 to 0.12) (Table 3).

Drug-related Side Effects

In the meta-analysis, there was no statistically significant difference between the two groups in terms of all drug-related side effects (RR, 1.02; 95% CI, 0.98 to 1.07) or severe drug-related side effects (RR, 0.90; 95% CI, 0.70 to 1.16) (Table 3).

Abnormal Involuntary Movement Scale (AIMS)

Scores on the AIMS were reported in two studies. In the meta-analysis, the decrease in the AIMS score was greater in the group treated with LAI SGAs than in the oral SGAs group, although this difference was not statistically significant (SMD, −0.02; 95% CI, −0.14 to 0.09) (Table 3).

Other Adverse Effects

Extrapyramidal side effects occurred significantly more often in the group treated with LAI SGAs than in the group treated with oral SGAs (RR, 1.61; 95% CI, 1.27 to 2.04), whereas there was no significant difference between the two groups in terms of all other drug-related adverse effects (Table 3). Prolactin-related side effects also occurred more often in the group treated with LAI SGAs than in the group treated with oral SGAs (RR, 2.48; 95% CI, 1.60 to 3.84). However, there was no significant difference between the two groups in terms of the incidence of other adverse effects, including akathisia, insomnia, and weight gain (Table 3).

DISCUSSION

In summary, with respect to outcome measures, the group treated with LAI SGAs was characterized by a significantly lower relapse rate, longer time to relapse, and fewer hospital days than the group treated with oral SGAs. However, there were no significant differences in hospitalization rate, remission rate, or non-compliance between the two groups. In terms of outcome measures, subgroup analysis limited to the studies lasting ≥1 year showed that the group treated with LAI SGAs was characterized by significantly lower relapse rate and higher remission rate than the oral SGAs group. In addition, in terms of safety outcome measures, the group treated with LAI SGAs was characterized by higher rates of extrapyramidal syndrome and prolactin-related symptoms than the group treated with oral SGAs. However, there was no significant difference in the all-cause discontinuation rate between the two groups.

In the context of comparing the efficacy of LAI and oral antipsychotics in relapse prevention, the study findings were somewhat consistent as follows: Our study showed that the mean relapse prevention rate for schizophrenia patients treated with oral SGAs was significantly lower than that for patients treated with LAI SGAs. However, a meta-analysis limited to the studies lasting ≤ 1 year showed that there were no significant differences in the relapse rate between patients treated with oral versus LAI SGAs. In findings similar to ours, superiority of LAI anti-psychotics to oral antipsychotics for relapse prevention was supported by several naturalistic and mirror-image studies.6873) For example, the rehospitalization risk in schizophrenia or schizoaffective disorder patients treated with LAI antipsychotics was significantly lower than that in those patients treated with oral antipsychotics, in a nationwide cohort of the United States patients.70) In addition, in a systematic review limited to mirror-image studies,71) the group treated with LAI antipsychotics was characterized by significantly lower hospitalization rate than was the group treated with oral antipsychotics.

In contrast to our findings, a previous meta-analysis, which included 21 RCTs (n=5,176) for both LAI FGAs and SGAs,11) reported that there were no significant differences in the outcome measures, including relapse prevention, between the groups treated with LAI and oral antipsychotics (12 studies; RR, 0.93; 95% CI, 0.80 to 1.08; p=0.35). In the subgroup analyses confined to the FGAs, LAI formulations were characterized by greater relapse prevention than were oral formulations (10 studies; RR, 0.82; 95% CI, 0.65 to 0.97; p=0.02). Herein, Kishimoto et al.11) explained that the findings could be associated with a publication bias and/or changes in relapse definitions, and the superiority of LAIs to oral antipsychotics with respect to relapse prevention could not be clearly concluded. Moreover, whereas LAI antipsychotics are usually be prescribed to schizophrenia patients with non-compliance and greater illness severity in clinical psychiatry, LAI antipsychotics might also be prescribed to those with compliance and less illness severity. Herein, the RCTs for LAI and oral antipsychotics could present no significant differences in the efficacy in relapse prevention.72) However, our findings showed that LAI SGAs had greater efficacy in terms of relapse prevention and were associated with higher rates of compliance in the relapse prevention than were oral SGAs, in patients with schizophrenia. The superior efficacy of LAI antipsychotics to oral antipsychotics was often shown in studies lasting more than 1 year, rather than in studies lasting less than 1 year. Leucht et al.8) conducted a meta-analysis including only the LAI RCTs lasting more than 1 year and concluded that LAI antipsychotics result in greater relapse prevention than do oral antipsychotics in schizophrenia patients. In our systematic review and meta-analysis, most of the selected RCTs were continued for longer than 1 year. Moreover, differences in the study findings could be caused by variation in the definitions used to characterize relapse and hospitalization.

Kish et al.13) found no significant differences in all-cause death or suicide death between schizophrenia patients treated with LAI antipsychotics and placebo or oral antipsychotics in a meta-analysis including 52 RCTs. However, the authors speculated that extrapyramidal syndromes were more prevalent in the group treated with LAI antipsychotics, although the evidence was not well-captured by the meta-analysis.9) There were no significant differences in extrapyramidal symptoms, prolactin increase, or other adverse events between the LAI and oral anti-psychotics treatments in a meta-analysis of 18 RCTs, including data for risperidone, olanzapine, aripiprazole, zuclopenthixol, fluphenazine and haloperidol.17) In contrast to these findings, a meta-analysis showed that LAI SGAs were characterized by a greater risk of developing extrapyramidal side effects than were LAI FGAs (RR, 1.451; p=0.048).23) Moreover, our systematic review and meta-analysis have a virtue of presenting the evidence for significantly increased extrapyramidal syndrome and prolactin-related adverse effects in the group treated with LAI SGAs compared with the group treated with oral SGAs. Herein, with the high level of evidence, our findings suggest that anticholinergic medications and other countermeasures against dopamine D2 antagonism-related effects might be more necessary with LAI SGAs than with oral SGAs.

Several limitations of our study should be considered: First, the study subjects were limited to adults with schizophrenia. Second, in subgroup analysis, differences in the length of the follow-up period may contribute to high heterogeneity. The differences in disease severity in study subjects can be another contributor to high heterogeneity. Third, despite differences associated with the different pharmacological ingredients used in the intervention and control groups, we did not have a sufficient number of studies to enable a quantitative analysis of these differences. Fourth, cognitive symptoms were not included as a component of the efficacy outcomes, since the domain was not evaluated in previous clinical trials.

Despite these limitations, this systematic review and meta-analysis was able to demonstrate that LAI SGAs showed improved efficacy with respect to relapse rate, time to relapse, and hospital days, but also higher rates of dopamine D2 antagonism-related adverse effects, when compared with oral SGAs, with moderate to high levels of evidence. The superior efficacy of LAI SGAs to oral SGAs in our meta-analysis may be associated with the fact that most of the selected trials chosen for analysis continued for more than 1 year.

Acknowledgments

This study was supported by a grant from the National Evidence-based Healthcare Collaborating Agency (NC15-004).

Figures
Fig. 1. Disposition of the selected articles for a systemic review and meta-analysis. KMBASE, Korean Medicine Database; KISS, Korean Studies Information Service System; RISS, the Research Information Sharing Service; NDSL, National Digital Science Library (NDSL); LAI, long-acting injectable.
Tables

Overview of the selected articles

Author (year)Study designCountryStudy subjectsAntipsychotics (n)Funding

Follow-up periodIntervention groupControl group
Ascher-Svanum et al. (2013)35)RCTEuropeAdults with schizophrenia2 yrOlanzapine depot (598)Olanzapine (322)1
Bai et al. (2006)36)RCTTaiwanAdults with schizophrenia12 wkRisperidone consta (25)Risperidone (25)3
Barrio et al. (2013)37)Case-controlSpainAdults with schizophrenia2 yrRisperidone consta (26)Olanzapine, Risperidone, Aripiprazole, Perphenazine, Paliperidone (26)4
Beauclair et al. (2007)38)Retrospective cohortCanadaPatients with schizophrenia or schizoaffective disorder3 yrRisperidone consta (69)Oral SGAs (93)1
Buckley et al. (2015)39)RCTUSAdults with schizophrenia or schizoaffective disorder30 moRisperidone consta (153)Oral SGAs (152)2
Chue et al. (2005)40)RCTInternationalAdults with schizophrenia12 wkRisperidone consta (319)Risperidone (321)1
de Arce Cordon et al. (2012)41)RCTInternationalAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (329)Aripiprazole (45)1
Detke et al. (2014)42)RCTInternationalAdults with schizophrenia2 yrOlanzapine depot (264)Olanzapine (260)1
Fe Bravo-Ortiz et al. (2011)43)Prospective cohortSpainPatients with schizophrenia6 moRisperidone consta (1,085)Oral SGAs (467)1
Fleischhacker et al. (2014)44)RCTInternationalAdults with schizophrenia38 wkAripiprazole depot (265)Aripiprazole (266)1
Gaebel et al. (2010)45)RCTInternationalAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (329)Quetiapine (337)1
Huang et al. (2013)46)Retrospective cohortTaiwanPatients with schizophrenia or schizoaffective disorder5 yrRisperidone consta (207)Risperidone and other SGAs (6,302)2
Ishigooka et al. (2015)47)RCTAsiaAdults with schizophrenia1 yrAripiprazole depot (228)Aripiprazole (227)1
Keks et al. (2007)48)RCTEuropePatients with schizophrenia or schizoaffective disorder53 wkRisperidone consta (247)Olanzapine (300)1
Kim et al. (2008)49)Non-RCTKoreaAdults with schizophrenia2 yrRisperidone consta (22)Risperidone (28)2
Lang et al. (2010)50)Retrospective cohortUSAdults with schizophrenia3 yrLong-acting injectable SGAs (643)Oral SGAs (7,790)1
Llorca et al. (2006)51)Mirror-image studyEuropePatients with schizophrenia or psychotic disorders6 moRisperidone consta (130)Oral SGAs (130)1
Macfadden et al. (2010)52)RCTInternationalAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (177)Aripiprazole (172)1
McDonnell et al. (2011)53)RCTInternationalAdults with schizophrenia24 wkOlanzapine depot (599)Olanzapine (322)1
Rouillon et al. (2013)54)RCTEuropeAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (329)Quetiapine (337)1
Schmauss et al. (2007)55)Mirror-image studyEuropeAdults with schizophrenia or psychotic disorders6 moRisperidone consta (572)Risperidone (572)4
Schmauss et al. (2010)56)Mirror-image studyGermanyAdults with schizophrenia or schizoaffective disorder12 wkRisperidone consta (205)Risperidone, Olanzapine, Quetiapine, Amisulpride, Ziprasidone (205)1
Smeraldi et al. (2013)57)RCTInternationalAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (329)Quetiapine (337)1
Spill et al. (2010)58)Mirror-image studyGermanyAdults with schizophrenia or schizoaffective disorder18 moRisperidone consta (119)Oral SGAs (63)1
Suzuki and Gen (2012)59)Prospective cohortJapanInpatients with chronic schizophrenia2 yrRisperidone consta (18)Risperidone (17)4
Suzuki et al. (2012)60)Prospective cohortJapanPatients with chronic schizophrenia24 wkRisperidone consta (11)Risperidone (10)4
Weiden et al. (2009)61)RCTUSAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (19)Oral SGAs (11)1
Weiden et al. (2012)62)RCTUSAdults with schizophrenia or schizoaffective disorder2 yrRisperidone consta (19)Oral SGAs (11)1
Willis et al. (2010)63)Mirror-image studySwedenPatients with schizophrenia or psychotic disorders1 yrRisperidone consta (164)Oral SGAs (164)1
Wykes et al. (2013)64)RCTUKAdults with schizophrenia12 wkRisperidone consta (26)Oral SGAs (24)1

RCT, randomized controlled trial; SGA, second-generation antipsychotic.

Funding source: 1, industry; 2, public; 3, industry and public; 4, none or declare of conflict of interest.

Summary of the efficacy outcomes

Efficacy measureAnticipated absolute effects (95% CI)Relative effect (95% CI)No. of subjects (studies)Quality of the evidence (GRADE)Comments

Risk with oral SGAsRisk with LAI SGAs
Relapse rateStudy subjects 211 per 1,000179 per 1,000 (156 to 209)RR=0.85 (95% CI, 0.74 to 0.99)2,886 (6 RCTs)⊕⊕⊕○
Moderate*
Long-term follow-up (RR=0.83; 95% CI, 0.71 to 0.97)
Moderate 226 per 1,000192 per 1,000 (167 to 223)
Time to relapseThe mean time to relapse was 0.The mean time to relapse in the intervention group was 0.42 standard deviations more (0.29 more to 0.54 more).-1,003 (2 RCTs)⊕⊕⊕○
Moderate
SMD=0.42 (95% CI, 0.29 to 0.54)
Hospitalization rateStudy subjects 99 per 1,00082 per 1,000 (61 to 110)RR=0.83 (95% CI, 0.62 to 1.11)1,518 (4 RCTs)⊕⊕⊕○
Moderate
Moderate 352 per 1,000292 per 1,000 (218 to 390)
Remission rateStudy subjects 521 per 1,000558 per 1,000 (516 to 599)RR=1.07 (95% CI, 0.99 to 1.15)2,161 (5 RCTs)⊕⊕⊕○
Moderate*
Long-term follow-up (RR=1.42; 95% CI, 1.18 to 1.71)
Moderate 532 per 1,000570 per 1,000 (527 to 612)
Hospital daysThe mean of hospital days was 0.The mean of hospital days in the intervention group was 0.11 standard deviations fewer (0.22 fewer to 0.01 fewer).-1,444 (2 RCTs)⊕⊕⊕○
Moderate*
SMD=−0.11 (95% CI, −0.22 to −0.01)
Non-complianceRR for short term (<1 yr)=0.58 (95% CI, 0.09 to 3.55)
RR for long term (>1 yr)=0.92 (95% CI, 0.51 to 1.66)
-(1 RCT)⊕⊕⊕○
Moderate§
Not significant
Quality of lifeSignificantly increased from baseline to final change, in both intervention and control group.-(2 RCTs)⊕⊕⊕○
Moderate||

CI, confidence interval; SGAs, second-generation antipsychotics; LAI, long-acting injectable; RR, relative risk; RCTs, randomized controlled trials.

Quality of the evidence:

*open-label trial;

high heterogeneity (I2=90%);

confidence interval including non-significance (RR=1);

§not sufficient for optimal information size;

||differences in the scale-directions for outcome measurement.

Summary of the safety outcomes

Safety measureAnticipated absolute effects (95% CI)Relative effect (95% CI)No. of subjects (studies)Quality of the evidence (GRADE)Comments

Risk with oral SGAsRisk with LAI SGAs
All cause discontinuationStudy subjects 393 per 1,000366 per 1,000 (322 to 413)RR=0.93 (95% CI, 0.82 to 1.05)1,510 (3 RCTs)⊕⊕⊕○
Moderate*
Moderate 335 per 1,000311 per 1,000 (275 to 352)
ESRSThe mean score on the ESRS was 0.The mean score on the ESRS in the intervention group was 0.01 standard deviations fewer (0.15 fewer to 0.12 more).-1,014 (2 RCTs)⊕⊕⊕○
Moderate*
Drug-related adverse eventsStudy subjects 523 per 1,000534 per 1,000 (513 to 555)RR=1.02 (95% CI, 0.98 to 1.06)4,055 (6 RCTs)⊕⊕⊕○
Moderate*
Subgroup significance: Any adverse event (RR=1.02, 95% CI, 0.98 to 1.06)
Moderate 677 per 1,000690 per 1,000 (663 to 718)Serious adverse event (RR=0.90, 95% CI, 0.70 to 1.16)
AIMSThe mean score on the AIMS was 0.The mean score on the AIMS in the intervention group was 0.02 standard deviations fewer (0.14 fewer to 0.09 more).-1,257 (4 RCTs)⊕⊕⊕○
Moderate*
Other adverse effectsStudy subjects 82 per 1,00096 per 1,000 (86 to 107)RR=1.17 (95% CI, 1.05 to 1.31)14,147 (10 RCTs)⊕⊕⊕⊕
High
Subgroup significance: Prolactin-increased (RR=2.48, 95% CI, 1.60 to 3.84)
Moderate68 per 1,00079 per 1,000 (71 to 89)
EPSE-related effectsStudy subjects83 per 1,000134 per 1,000 (106 to 170)RR=1.61 (95% CI,1.27 to 2.04)2,608 (6 RCTs)⊕⊕⊕⊕
High
Moderate 87 per 1,000139 per 1,000 (110 to 176)

CI, confidence interval; SGAs, second-generation antipsychotics; LAI, long-acting injectable; RR, relative risk; RCTs, randomized controlled trials; ESRS, Extrapyramidal Symptom Rating Scale; AIMS, Abnormal Involuntary Movement Scale; EPSE, extrapyramidal side effects. Quality of the evidence:

*open-label trial.

References
  1. Collins, PY, Patel, V, Joestl, SS, March, D, Insel, TR, Daar, AS, and Scientific Advisory Board and the Executive Committee of the Grand Challenges on Global Mental Health (2011). Grand challenges in global mental health. Nature. 475, 27-30.
    Pubmed KoreaMed CrossRef
  2. Kim, YK, Choi, J, and Park, SC (2017). A novel bio-psychosocial-behavioral treatment model in schizophrenia. Int J Mol Sci. 18, E734.
    Pubmed KoreaMed CrossRef
  3. Karadag, F, Sengul, CB, Enli, Y, Karakulah, K, Alacam, H, and Kaptanoglu, B (2017). Relationship between serum bilirubin levels and metabolic syndrome in patients with schizophrenia spectrum disorders. Clin Psychopharmacol Neurosci. 15, 153-162.
    Pubmed KoreaMed CrossRef
  4. Tripathi, A, Kar, SK, and Shukla, R (2018). Cognitive deficits in schizophrenia: Understanding the biological correlates and remediation strategies. Clin Psychopharmacol Neurosci. 16, 7-17.
    Pubmed KoreaMed CrossRef
  5. Corrigan, PW, Liberman, RP, and Engel, JD (1990). From noncompliance to collaboration in the treatment of schizophrenia. Hosp Community Psychiatry. 41, 1203-1211.
    Pubmed
  6. Novick, D, Haro, JM, Suarez, D, Perez, V, Dittmann, RW, and Haddad, PM (2010). Predictors and clinical consequences of non-adherence with antipsychotic medication in the outpatient treatment of schizophrenia. Psychiatry Res. 176, 109-113.
    Pubmed CrossRef
  7. Olfson, M, Mechanic, D, Hansell, S, Boyer, CA, Walkup, J, and Weiden, PJ (2000). Predicting medication noncompliance after hospital discharge among patients with schizophrenia. Psychiatr Serv. 51, 216-222.
    Pubmed CrossRef
  8. Leucht, C, Heres, S, Kane, JM, Kissling, W, Davis, JM, and Leucht, S (2011). Oral versus depot antipsychotic drugs for schizophrenia--a critical systematic review and meta-analysis of randomised long-term trials. Schizophr Res. 127, 83-92.
    Pubmed CrossRef
  9. Adams, CE, Fenton, MK, Quraishi, S, and David, AS (2001). Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry. 179, 290-299.
    Pubmed CrossRef
  10. Kishimoto, T, Nitta, M, Borenstein, M, Kane, JM, and Correll, CU (2013). Long-acting injectable versus oral antipsychotics in schizophrenia: a systematic review and meta-analysis of mirror-image studies. J Clin Psychiatry. 74, 957-965.
    Pubmed CrossRef
  11. Kishimoto, T, Robenzadeh, A, Leucht, C, Leucht, S, Watanabe, K, and Mimura, M (2014). Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: a meta-analysis of randomized trials. Schizophr Bull. 40, 192-213.
    KoreaMed CrossRef
  12. Manchanda, R, Chue, P, Malla, A, Tibbo, P, Roy, MA, and Williams, R (2013). Long-acting injectable antipsychotics: evidence of effectiveness and use. Can J Psychiatry. 58, 5S-13S.
    Pubmed CrossRef
  13. Kishi, T, Matsunaga, S, and Iwata, N (2016). Mortality risk associated with long-acting injectable antipsychotics: a systematic review and meta-analyses of randomized controlled trials. Schizophr Bull. 42, 1438-1445.
    Pubmed KoreaMed CrossRef
  14. Kishi, T, Oya, K, and Iwata, N (2016). Long-acting injectable antipsychotics for the prevention of relapse in patients with recent-onset psychotic disorders: a systematic review and meta-analysis of randomized controlled trials. Psychiatry Res. 246, 750-755.
    Pubmed CrossRef
  15. Lafeuille, MH, Dean, J, Carter, V, Duh, MS, Fastenau, J, and Dirani, R (2014). Systematic review of long-acting injectables versus oral atypical antipsychotics on hospitalization in schizophrenia. Curr Med Res Opin. 30, 1643-1655.
    Pubmed CrossRef
  16. Misawa, F, Kishimoto, T, Hagi, K, Kane, JM, and Correll, CU (2016). Safety and tolerability of long-acting injectable versus oral anti-psychotics: A meta-analysis of randomized controlled studies comparing the same antipsychotics. Schizophr Res. 176, 220-230.
    Pubmed CrossRef
  17. Ostuzzi, G, Bighelli, I, So, R, Furukawa, TA, and Barbui, C (2017). Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies. Schizophr Res. 183, 10-21.
    CrossRef
  18. Meltzer, HY, Matsubara, S, and Lee, JC (1989). Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther. 251, 238-246.
    Pubmed
  19. Fischer-Barnicol, D, Lanquillon, S, Haen, E, Zofel, P, Koch, HJ, Dose, M, and Working Group ‘Drugs in Psychiatry’ (2008). Typical and atypical antipsychotics: the misleading dichotomy. Results from the Working Group ‘Drugs in Psychiatry’ (AGATE). Neuropsychobiology. 57, 80-87.
    CrossRef
  20. Charych, EI, Liu, F, Moss, SJ, and Brandon, NJ (2009). GABA(A) receptors and their associated proteins: implications in the etiology and treatment of schizophrenia and related disorders. Neuropharmacology. 57, 481-495.
    Pubmed KoreaMed CrossRef
  21. Gründer, G, Hippius, H, and Carlsson, A (2009). The ‘atypicality’ of anti-psychotics: a concept re-examined and re-defined. Nat Rev Drug Discov. 8, 197-202.
    CrossRef
  22. Kim, YS, Ahn, YM, and Jeong, SH (2010). Principle and practice of long-acting injectable antipsychotics. Seoul: Seoul National University Press, pp. 40-41
  23. Fusar-Poli, P, Kempton, MJ, and Rosenheck, RA (2013). Efficacy and safety of second-generation long-acting injections in schizophrenia: a meta-analysis of randomized-controlled trials. Int Clin Psychopharmacol. 28, 57-66.
    CrossRef
  24. Huang, X, Lin, J, and Demner-Fushman, D (2006). Evaluation of PICO as a knowledge representation for clinical questions. AMIA Annu Symp Proc, 359-363.
  25. Tandon, R, Nasrallah, HA, and Keshavan, MS (2010). Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present, and future. Schizophr Res. 122, 1-23.
    Pubmed CrossRef
  26. Guy, W (1976). ECDEU assessment manual for psychopharmacology, Revised 1976. Rockville: National Institute for Mental Health
  27. Kay, SR, Fiszbein, A, and Opler, LA (1987). The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull. 13, 261-276.
    Pubmed CrossRef
  28. Montgomery, SA, and Asberg, M (1979). A new depression scale designed to be sensitive to change. Br J Psychiatry. 134, 382-389.
    Pubmed CrossRef
  29. Chouinard, G, and Margolese, HC (2005). Manual for the Extrapyramidal Symptom Rating Scale (ESRS). Schizophr Res. 76, 247-265.
    Pubmed CrossRef
  30. Munetz, MR, and Benjamin, S (1988). How to examine patients using the Abnormal Involuntary Movement Scale. Hosp Community Psychiatry. 39, 1172-1177.
    Pubmed
  31. Moher, D, Shamseer, L, Clarke, M, Ghersi, D, Liberati, A, Petticrew, M, and PRISMA-P Group (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 4, 1.
    Pubmed KoreaMed CrossRef
  32. Higgins, JPT, and Green, SS (2008). Cochrane handbook for systematic reviews of interventions. Chichester: Wiley-Blackwell
    CrossRef
  33. Kim, SY, Park, JE, Lee, YJ, Seo, HJ, Sheen, SS, and Hahn, S (2013). Testing a tool for assessing the risk of bias for nonrandomized studies showed moderate reliability and promising validity. J Clin Epidemiol. 66, 408-414.
    Pubmed CrossRef
  34. Guyatt, G, Oxman, AD, Akl, EA, Kunz, R, Vist, G, and Brozek, J (2011). GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 64, 383-394.
    Pubmed CrossRef
  35. Ascher-Svanum, H, Novick, D, Haro, JM, Bertsch, J, McDonnell, D, and Detke, H (2013). Predictors of psychiatric hospitalization during 6 months of maintenance treatment with olanzapine long-acting injection: post hoc analysis of a randomized, double-blind study. BMC Psychiatry. 13, 224.
    Pubmed KoreaMed CrossRef
  36. Bai, YM, Chen, TT, Wu, B, Hung, CH, Lin, WK, and Hu, TM (2006). A comparative efficacy and safety study of long-acting risperidone injection and risperidone oral tablets among hospitalized patients: 12-week randomized, single-blind study. Pharmacopsychiatry. 39, 135-141.
    Pubmed CrossRef
  37. Barrio, P, Batalla, A, Castellví, P, Hidalgo, D, García, M, and Ortiz, A (2013). Effectiveness of long-acting injectable risperidone versus oral antipsychotics in the treatment of recent-onset schizophrenia: a case-control study. Int Clin Psychopharmacol. 28, 164-170.
    Pubmed
  38. Beauclair, L, Chue, P, McCormick, J, Camacho, F, Lam, A, and Luong, D (2007). Impact of risperidone long-acting injectable on hospital-isation and medication use in Canadian patients with schizophrenia. J Med Econ. 10, 427-442.
    CrossRef
  39. Buckley, PF, Schooler, NR, Goff, DC, Hsiao, J, Kopelowicz, A, Lauriello, J, and PROACTIVE Study (2015). Comparison of SGA oral medications and a long-acting injectable SGA: the PROACTIVE study. Schizophr Bull. 41, 449-459.
    KoreaMed CrossRef
  40. Chue, P, Eerdekens, M, Augustyns, I, Lachaux, B, Molcan, P, and Eriksson, L (2005). Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol. 15, 111-117.
    CrossRef
  41. de Arce Cordón, R, Eding, E, Marques-Teixeira, J, Milanova, V, Rancans, E, and Schreiner, A (2012). Descriptive analyses of the aripiprazole arm in the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Eur Arch Psychiatry Clin Neurosci. 262, 139-149.
    CrossRef
  42. Detke, HC, Weiden, PJ, Llorca, PM, Choukour, M, Watson, SB, and Brunner, E (2014). Comparison of olanzapine long-acting injection and oral olanzapine: a 2-year, randomized, open-label study in outpatients with schizophrenia. J Clin Psychopharmacol. 34, 426-434.
    Pubmed CrossRef
  43. Fe Bravo-Ortiz, M, Gutiérrez-Casares, JR, Rodríguez-Morales, A, García, MA, and Hidalgo-Borrajo, R (2011). Influence of type of treatment on the well-being of Spanish patients with schizophrenia and their caregivers. Int J Psychiatry Clin Pract. 15, 286-295.
    Pubmed CrossRef
  44. Fleischhacker, WW, Sanchez, R, Perry, PP, Jin, N, Peters-Strickland, T, and Johnson, BR (2014). Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study. Br J Psychiatry. 205, 135-144.
    Pubmed CrossRef
  45. Gaebel, W, Schreiner, A, Bergmans, P, de Arce, R, Rouillon, F, and Cordes, J (2010). Relapse prevention in schizophrenia and schizoaffective disorder with risperidone long-acting injectable vs quetiapine: results of a long-term, open-label, randomized clinical trial. Neuropsychopharmacology. 35, 2367-2377.
    Pubmed KoreaMed CrossRef
  46. Huang, SS, Lin, CH, Loh, el-W, Yang, HY, Chan, CH, and Lan, TH (2013). Antipsychotic formulation and one-year rehospitalization of schizophrenia patients: a population-based cohort study. Psychiatr Serv. 64, 1259-1262.
    Pubmed CrossRef
  47. Ishigooka, J, Nakamura, J, Fujii, Y, Iwata, N, Kishimoto, T, Iyo, M, and ALPHA Study Group (2015). Efficacy and safety of aripiprazole once-monthly in Asian patients with schizophrenia: a multi-center, randomized, double-blind, non-inferiority study versus oral aripiprazole. Schizophr Res. 161, 421-428.
    Pubmed CrossRef
  48. Keks, NA, Ingham, M, Khan, A, and Karcher, K (2007). Long-acting injectable risperidone v. olanzapine tablets for schizophrenia or schizoaffective disorder. Randomised, controlled, open-label study. Br J Psychiatry. 191, 131-139.
    Pubmed CrossRef
  49. Kim, B, Lee, SH, Choi, TK, Suh, S, Kim, YW, and Lee, E (2008). Effectiveness of risperidone long-acting injection in first-episode schizophrenia: in naturalistic setting. Prog Neuropsychopharmacol Biol Psychiatry. 32, 1231-1235.
    Pubmed CrossRef
  50. Lang, K, Meyers, JL, Korn, JR, Lee, S, Sikirica, M, and Crivera, C (2010). Medication adherence and hospitalization among patients with schizophrenia treated with antipsychotics. Psychiatr Serv. 61, 1239-1247.
    Pubmed CrossRef
  51. Llorca, PM, Kahn, JP, Moreau-Mallet, V, Bouhours, P, and The French StoRMi Investigators Group (2006). Symptom control, functioning, and hospitalization status in French patients changed from oral atypical antipsychotics to risperidone long-acting injectable. Int J Psychiatry Clin Pract. 10, 276-284.
    Pubmed CrossRef
  52. Macfadden, W, Ma, YW, Thomas Haskins, J, Bossie, CA, and Alphs, L (2010). A prospective study comparing the long-term effectiveness of injectable risperidone long-acting therapy and oral aripiprazole in patients with schizophrenia. Psychiatry (Edgmont). 7, 23-31.
  53. McDonnell, DP, Kryzhanovskaya, LA, Zhao, F, Detke, HC, and Feldman, PD (2011). Comparison of metabolic changes in patients with schizophrenia during randomized treatment with intramuscular olanzapine long-acting injection versus oral olanzapine. Hum Psychopharmacol. 26, 422-433.
    Pubmed
  54. Rouillon, F, Eriksson, L, Burba, B, Raboch, J, Kaprinis, G, and Schreiner, A (2013). Functional recovery results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Acta Neuropsychiatr. 25, 297-306.
    CrossRef
  55. Schmauss, M, Sacchetti, E, Kahn, JP, and Medori, R (2007). Efficacy and safety of risperidone long-acting injectable in stable psychotic patients previously treated with oral risperidone. Int Clin Psychopharmacol. 22, 85-92.
    Pubmed CrossRef
  56. Schmauss, M, Diekamp, B, Gerwe, M, Schreiner, A, and Ibach, B (2010). Does oral antipsychotic pre-treatment influence outcome of a switch to long-acting injectable risperidone in patients with schizophrenia?. Pharmacopsychiatry. 43, 73-80.
    Pubmed CrossRef
  57. Smeraldi, E, Cavallaro, R, Folnegović-Šmalc, V, Bidzan, L, Emin Ceylan, M, and Schreiner, A (2013). Long-term remission in schizophrenia and schizoaffective disorder: results from the risperidone long-acting injectable versus quetiapine relapse prevention trial (ConstaTRE). Ther Adv Psychopharmacol. 3, 191-199.
    Pubmed KoreaMed CrossRef
  58. Spill, B, Konoppa, S, Kissling, W, Maino, K, Messer, T, and Heres, S (2010). Long-term observation of patients successfully switched to risperidone long-acting injectable: A retrospective, naturalistic 18-month mirror-image study of hospitalization rates and therapy costs. Int J Psychiatry Clin Pract. 14, 53-62.
    Pubmed CrossRef
  59. Suzuki, H, and Gen, K (2012). The influence of switching from oral risperidone to risperidone long-acting injection on the clinical symptoms and cognitive function in schizophrenia. Ther Adv Psychopharmacol. 2, 23-29.
    Pubmed KoreaMed CrossRef
  60. Suzuki, H, Inoue, Y, and Gen, K (2012). A study of the efficacy and safety of switching from oral risperidone to risperidone long-acting injection in older patients with schizophrenia. Ther Adv Psychopharmacol. 2, 227-234.
    CrossRef
  61. Weiden, PJ, Schooler, NR, Weedon, JC, Elmouchtari, A, Sunakawa, A, and Goldfinger, SM (2009). A randomized controlled trial of long-acting injectable risperidone vs continuation on oral atypical antipsychotics for first-episode schizophrenia patients: initial adherence outcome. J Clin Psychiatry. 70, 1397-1406.
    Pubmed CrossRef
  62. Weiden, PJ, Schooler, NR, Weedon, JC, Elmouchtari, A, and Sunakawa-McMillan, A (2012). Maintenance treatment with long-acting injectable risperidone in first-episode schizophrenia: a randomized effectiveness study. J Clin Psychiatry. 73, 1224-1233.
    Pubmed CrossRef
  63. Willis, M, Svensson, M, Löthgren, M, Eriksson, B, Berntsson, A, and Persson, U (2010). The impact on schizophrenia-related hospital utilization and costs of switching to long-acting risperidone injections in Sweden. Eur J Health Econ. 11, 585-594.
    Pubmed CrossRef
  64. Wykes, T, Rose, D, Williams, P, and David, AS (2013). Working alliance and its relationship to outcomes in a randomized controlled trial (RCT) of antipsychotic medication. BMC Psychiatry. 13, 28.
    Pubmed KoreaMed CrossRef
  65. Andreasen, NC, Carpenter, WT, Kane, JM, Lasser, RA, Marder, SR, and Weinberger, DR (2005). Remission in schizophrenia: proposed criteria and rationale for consensus. Am J Psychiatry. 162, 441-449.
    Pubmed CrossRef
  66. Martin, CR, and Allan, R (2007). Factor structure of the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4). Psychol Health Med. 12, 126-134.
    Pubmed CrossRef
  67. Heinrichs, DW, Hanlon, TE, and Carpenter, WT (1984). The Quality of Life Scale: an instrument for rating the schizophrenic deficit syndrome. Schizophr Bull. 10, 388-398.
    Pubmed CrossRef
  68. Lambert, T, Olivares, JM, Peuskens, J, DeSouza, C, Kozma, CM, and Otten, P (2011). Effectiveness of injectable risperidone long-acting therapy for schizophrenia: data from the US, Spain, Australia, and Belgium. Ann Gen Psychiatry. 10, 10.
    Pubmed KoreaMed CrossRef
  69. Peng, X, Ascher-Svanum, H, Faries, D, Conley, RR, and Schuh, KJ (2011). Decline in hospitalization risk and health care cost after initiation of depot antipsychotics in the treatment of schizophrenia. Clinicoecon Outcomes Res. 3, 9-14.
    Pubmed KoreaMed
  70. Tiihonen, J, Wahlbeck, K, Lönnqvist, J, Klaukka, T, Ioannidis, JP, and Volavka, J (2006). Effectiveness of antipsychotic treatments in a nationwide cohort of patients in community care after first hospitalisation due to schizophrenia and schizoaffective disorder: observational follow-up study. BMJ. 333, 224.
    Pubmed KoreaMed CrossRef
  71. Tiihonen, J, Haukka, J, Taylor, M, Haddad, PM, Patel, MX, and Korhonen, P (2011). A nationwide cohort study of oral and depot anti-psychotics after first hospitalization for schizophrenia. Am J Psychiatry. 168, 603-609.
    Pubmed CrossRef
  72. Grimaldi-Bensouda, L, Rouillon, F, Astruc, B, Rossignol, M, Benichou, J, Falissard, B, and CGS Study Group (2012). Does long-acting injectable risperidone make a difference to the real-life treatment of schizophrenia? Results of the Cohort for the General study of Schizophrenia (CGS). Schizophr Res. 134, 187-194.
    CrossRef
  73. Correll, CU, Kishimoto, T, and Kane, JM (2011). Randomized controlled trials in schizophrenia: opportunities, limitations, and trial design alternatives. Dialogues Clin Neurosci. 13, 155-172.
    Pubmed KoreaMed


This Article


Cited By Articles
  • CrossRef (0)

Author ORCID Information

Funding Information

Services
Social Network Service

e-submission

Archives