Oral versus Depot Antipsychotic Drugs for Schizophrenia—a Critical Systematic Review and Meta-Analysis of Randomised Long-Term Trials

Department of Psychiatry and Psychotherapy, Klinikum rechts der Isar der Technischen Universität München, Ismaningerstr. 22, 81675 München, Germany.
Schizophrenia Research (Impact Factor: 3.92). 04/2011; 127(1-3):83-92. DOI: 10.1016/j.schres.2010.11.020
Source: PubMed


Non-adherence is a major problem in the treatment of schizophrenia. Depot antipsychotic drugs are thought to reduce relapse rates by improving adherence, but a systematic review of long-term studies in outpatients is not available.
We searched the Cochrane Schizophrenia Group's register,, Cochrane reviews on depot medication, and the reference sections of included studies for randomised controlled trials lasting at least 12 months in outpatients that compared depot with oral antipsychotics in schizophrenia. Data on relapse (primary outcome), rehospitalisation, non-adherence, and dropout due to any reason, inefficacy of treatment and adverse events were summarised in a meta-analysis using a random-effects model. Study quality was assessed with the Cochrane collaboration's risk of bias tool, and publication bias with funnel plots.
Ten studies with 1700 participants met the inclusion criteria. Depot formulations significantly reduced relapses with relative and absolute risk reductions of 30% and 10%, respectively (RR 0.70, CI 0.57-0.87, NNT 10, CI 6-25, P=0.0009), and dropout due to inefficacy (RR 0.71, CI 0.57-0.89). Limited data on non-adherence, rehospitalisation and dropout due to any reason and adverse events revealed no significant differences. There were several potential sources of bias such as limited information on randomisation methods, problems of blinding and different medications in the depot and oral groups. Other studies reduced a potential superiority of depot by excluding non-adherent patients.
Depot antipsychotic drugs significantly reduced relapse. Due to a number of methodological problems in the single trials the evidence is, nonetheless, subject to possible bias.

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    • "Consequently, they suggest that using a LAI AP formulation in a naturalistic setting might confer additional benefit over the corresponding daily oral formulation (Kane et al., 2013a). Supporting this consideration , in randomized-controlled trials where adherence was formally assessed, no differences were observed in adherence between LAI and daily oral AP formulations (Leucht et al., 2011; Kishimoto et al., 2014). "
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    ABSTRACT: Trial design characteristics related to the explanatory : pragmatic spectrum may contribute toward the inconsistent results reported in studies comparing long-acting injectable (LAI) versus daily oral antipsychotic (AP) treatments in schizophrenia. A novel approach examined the hypothesis that a more pragmatic design is important to show the advantages of LAI versus oral APs. A literature search identified comparative studies assessing the clinical efficacy/effectiveness of LAI versus oral APs in more than 100 schizophrenia patients, with 6-month or more duration/follow-up, and published between January 1993 and December 2013 (n=11). Each study's design was rated using the six-domain ASPECT-R (A Study Pragmatic : Explanatory Characterization Tool-Rating). Nonparametric Wilcoxon rank-sum tests compared ratings of studies supporting (n=7) and not supporting (n=4) a LAI advantage. ASPECT-R total and domain scores were significantly higher (more pragmatic) in studies finding a LAI versus oral AP treatment advantage than those that did not. The rank order of this significance among domains was as follows: 'participant compliance assessment' (P=0.005), 'medical practice setting/practitioner expertise' (P=0.006), 'intervention flexibility' (P=0.007), 'follow-up intensity/duration' (P=0.009), 'primary trial outcomes' (P=0.012), and 'participant eligibility' (P=0.015). Findings support that more pragmatic, less explanatory design features are important to show advantages for LAI treatment. Explanatory studies may introduce features that obscure advantages related to adherence.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
    International clinical psychopharmacology 06/2015; 30(5). DOI:10.1097/YIC.0000000000000082 · 2.46 Impact Factor
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    • "The question of whether long-acting injectable (LAI) antipsychotics offer meaningful advantages over oral antipsychotics in the treatment of individuals with schizophrenia has been addressed in recent studies with inconsistent results (Chue et al., 2005; Bai et al., 2006; Emsley et al., 2008; Weiden et al., 2009; Gaebel et al., 2010; Macfadden et al., 2010; Rosenheck et al., 2011; Schooler et al., 2011; Weiden et al., 2012; Zhornitsky and Stip 2012; Barrio et al., 2013). Meta-analytical reviews of these studies have been similarly inconsistent (Leucht et al., 2011; Fusar-Poli et al., 2013; Kirson et al., 2013; Kishimoto et al., 2013, 2014). Consequently, whether treatment with oral or LAI formulations of antipsychotics produces meaningfully different outcomes remains a matter of debate. "
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    ABSTRACT: This article reviews key methodological considerations for clinical trials that utilize explanatory and pragmatic trial designs and relates these contrasting approaches to the interpretation of results from comparisons of oral versus long-acting injectable (LAI) antipsychotics in schizophrenia. Explanatory randomized controlled trials (RCTs) generally measure the efficacy of a treatment in a homogeneous population with intensive, frequent, and often clinical trial-specific assessments. In contrast, pragmatic trials measure effectiveness in routine clinical practice and frequently aim to inform choices between treatments. Comparative effectiveness outcomes with pragmatic designs in naturalistic settings for schizophrenia treatments are of increasing interest to healthcare providers because outcomes of treatment (both efficacy and safety) may vary significantly when identified in an explanatory setting compared with a naturalistic pragmatic setting. Indeed, it has been suggested that the inconsistent outcomes observed in trials comparing oral and LAI antipsychotic medications may be a function of the use of explanatory or pragmatic trial designs. In practice, clinical trial designs are seldom purely explanatory or pragmatic. To identify the predominant orientation of a trial, one must consider multiple features. This paper reviews the relative impact of these features when comparing LAI and oral antipsychotic treatments and makes recommendations for improving these comparative designs.
    Schizophrenia Research 07/2014; 156(2-3). DOI:10.1016/j.schres.2014.04.024 · 3.92 Impact Factor
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    • "Long-acting injectable antipsychotics are an important treatment option for patients with schizophrenia who have difficulty adhering to oral regimens, as long-acting formulations ensure that the patient has received treatment, and it is immediately known when the patient does not return for treatment (Kane, 2006; Leucht et al., 2011). Guidelines for the long-term treatment of schizophrenia (Hasan et al., 2013) recommend these formulations as the treatment of choice when the ‘avoidance of covert nonadherence with antipsychotic drugs is a clinical priority’ and even recommend that, in certain cases, ‘patients should be actively motivated and educated’ about using long-acting formulations. "
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    ABSTRACT: The objective of this study was to assess the long-term safety and efficacy of olanzapine long-acting injection (LAI). A 6-year, single-arm, open-label extension study of olanzapine LAI was conducted at 127 sites in 25 countries. Patients were 18-76 years of age, were diagnosed with schizophrenia or schizoaffective disorder (N=931), and had been previously enrolled in one of three clinical trials of olanzapine LAI. Patients received flexibly dosed (45-405 mg) olanzapine LAI every 2-4 weeks. The mean duration of exposure was ∼3 years. A total of 393 (42.2%) patients completed the study. The mean weight change was +2.1 kg (P<0.001), with 40.6% of patients experiencing 7% or higher weight gain. Treatment-emergent categorical changes occurred in fasting glucose, total cholesterol, and triglyceride levels. Pharmacokinetic analyses revealed no systemic accumulation of olanzapine after long-term treatment. There were 36 occurrences of post-injection delirium/sedation syndrome, all resolving within 72 h. The mean Positive and Negative Syndrome Scale total and subscale scores did not change significantly over the course of the study, indicating clinical stability. Olanzapine LAI appeared effective as a long-term maintenance treatment, with a safety profile generally consistent with the known profile of oral olanzapine, except for injection-related events (including post-injection delirium/sedation syndrome).
    International Clinical Psychopharmacology 05/2014; 29(6). DOI:10.1097/YIC.0000000000000038 · 2.46 Impact Factor
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