Elsevier

Schizophrenia Research

Volume 183, May 2017, Pages 10-21
Schizophrenia Research

Does formulation matter? A systematic review and meta-analysis of oral versus long-acting antipsychotic studies

https://doi.org/10.1016/j.schres.2016.11.010Get rights and content

Abstract

Recently, many authors highlighted the potential advantages of a broader prescription of long-acting injectable antipsychotics (LAIs) based on various assumptions, including favorable pharmacokinetic features. In this systematic review, data from randomized controlled trials comparing LAIs versus the oral formulation of the same antipsychotic were meta-analyzed in order to ascertain whether the route of administration may be associated with a different efficacy and tolerability profile. Of 21 included studies, 18 contributed to the meta-analysis, providing data for risperidone, olanzapine, aripiprazole, zuclopenthixol, fluphenazine and haloperidol. For all drugs, the number of dropouts for any reason (primary outcome) did not differ between the two formulations, except for a small effect in favor of LAI aripiprazole (2 comparisons; 986 patients; relative risk (RR) 0.78; 95% confidence interval (CI) 0.64 to 0.95). Similarly, no differences emerged in terms of dropouts for adverse events, extrapyramidal symptoms, prolactin increase (except for a small advantage for LAI risperidone), weight gain, non-response rate, relapse rate, and dropouts for inefficacy (except for a small advantage for oral olanzapine). Data on aripiprazole proved to be of high quality according to the GRADE approach (Grading of Recommendations, Assessment, Development and Evaluation), therefore we are confident that the effect estimate is close to the true effect. Data on risperidone were of moderate quality, while data on olanzapine, fluphenazine, zuclopenthixol and haloperidol were of low quality. In conclusion, there is no robust evidence to support doctors in choosing LAI instead of oral formulations in order to obtain better tolerability and efficacy.

Introduction

Schizophrenia is among the top 20 causes of disability worldwide (Vos et al., 2012). The burden of schizophrenia is evident in terms of decreased quality of life, mortality, and social and financial costs (McGrath et al., 2008). According to current evidence, a continued treatment from the early phases of disease may represent a key point for preserving neurocognitive abilities, for preventing structural brain changes, and for hindering the progression towards chronic functional deterioration (McEvoy, 2007, Murray et al., 2016, Pantelis et al., 2003, Perkins et al., 2005). However, treatment adherence is a major issue, considering that up to half patients suffering from schizophrenia may not take their medications as prescribed (Nosé et al., 2003), with serious repercussions on the course of disease in terms of relapse, hospitalization, chronic course and burden of family and caregivers (Haddad et al., 2014, Narasimhan et al., 2009, Wyatt, 1991). Long-acting injectable (LAI) antipsychotics were developed with the primary aim of addressing both hidden and overt non-adherence. Although the well-known disadvantages of LAIs, including pain on the injection site, lack of flexibility in dose adjustments and patients' perception of stigma and coercion (Brissos et al., 2014), several authors highlighted potential advantages of a broader and earlier prescription of these formulations on the basis of various assumptions. First, as LAIs allow a complete tracking of the drug consumption, they may prevent the devastating impact of the loss of even few doses of antipsychotic in early stages of the disease (Llorca et al., 2013, Patel, 2005, Stahl, 2014, Tiihonen et al., 2011). Second, LAIs allow avoiding daily administration, which may be perceived by patients as a practical advantage, and also minimize the risk of self-medication and harmful drug use (Maia-de-Oliveira et al., 2013, Patel, 2005, Taylor and Ng, 2013). Third, considering patients' experience of an overall good balance of efficacy and tolerability in the long term, some authors pointed out the need of de-stigmatizing LAIs and overcoming old misconceptions (Iyer et al., 2013, Patel, 2005, Patel et al., 2010, Pietrini et al., 2016, Stevens et al., 2015).

In recent years, it has been suggested that pharmacokinetic differences associated with the route of administration may also be at the basis of possible advantages for LAI over oral formulations. The higher bioavailability of LAI formulations may help identify the lower effective dose, reducing unnecessary toxic serum levels of the drug (Ereshefsky and Mascarenas, 2003). Further, a reduced fluctuation of serum drug levels, and therefore a more stable receptor occupancy (Mannaert et al., 2005), may reduce the troublesome impact of adverse events, including for instance motor symptoms, a challenging problem with oral formulations (Ereshefsky and Mascarenas, 2003, Fleischhacker et al., 1994). Such mechanisms may also lower the phenomenon of up-regulation of dopamine receptors, which underpins the so-called “super-sensitivity psychosis”, a severe disease relapse triggered by sudden antipsychotic withdrawal (Moncrieff, 2006). These pharmacokinetic differences seem to primarily impact antipsychotics' tolerability, which may, in turn, affect adherence and overall effectiveness.

It is unclear, however, if these theoretical benefits are also supported by clinical studies comparing the two formulations (LAI versus oral) of the same antipsychotic. So far, in most systematic reviews comparing LAI with oral formulations, patients treated with a mix of different antipsychotics were pooled together and compared (Kirson et al., 2013, Kishimoto et al., 2013, Kishimoto et al., 2014, Leucht et al., 2011). Thus, these reviews are unable to answer whether the formulation alone may explain a different efficacy and tolerability of the same antipsychotic. A narrative review by Zhornitsky and Stip (2012) retrieved 14 randomized trials and 4 observational studies comparing LAI versus oral formulations of the same antipsychotic. A qualitative analysis of data for haloperidol, fluphenazine, zuclopenthixol, risperidone and olanzapine suggested that there may be relevant differences between formulations, however a meta-analysis was not performed. Four Cochrane Reviews (Hosalli and Davis, 2003, Quraishi and David, 2000, Sampson, 1996, Sampson et al., 1996) attempted to address this issue for different antipsychotics, but their searches are outdated and therefore very few studies were included, failing to show any difference between the two formulations. A recent meta-analysis by Misawa et al. (2016) retrieved 16 randomized controlled trials, however data from studies on different antipsychotics were pooled together in the meta-analysis, which prevents from detecting possible differences related to the specificity of each antipsychotic. Further, this review was strictly focused on safety outcomes, while possible differences in terms efficacy or cognition were not investigated. No differences between oral and LAIs emerged in terms of safety (treatment discontinuation due to adverse events: 3570 patients, RR 1.163, 95% CI 0.887 to 1.524).

Against this background, the present systematic review has the following objectives: (a) to ascertain whether the same antipsychotic may show a different tolerability and efficacy profile when given orally or as a LAI; (b) to critically appraise the quality of the evidence using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology (Guyatt et al., 2008), in order to produce a tabular synoptic overview of the main review findings and quality, easily understandable for patients, policy makers, research planners, guideline developers and other stakeholders.

Section snippets

Methods

The protocol for this review was registered in advance with PROSPERO (International Prospective Register of Systematic Reviews) (www.crd.york.ac.uk/PROSPERO/) (CRD42016029651). This review was reported in accordance with PRISMA guidelines (see Supplementary material).

Study selection

We retrieved 3536 records from electronic databases and 23 records from hand-searching of additional sources (Fig. 1). After duplicate removal, 1536 records were screened for eligibility. 1417 were excluded on the basis of title or abstract. For the remaining 119 records, full-texts were retrieved for evaluation. Sixty-one articles were excluded and six were labeled as “awaiting assessment”. Overall, 52 full-text articles fulfilled the criteria for eligibility and were included in the review.

Discussion

Despite a theoretical pharmacokinetic basis suggesting potential advantages of LAI over oral antipsychotic formulations (Ereshefsky and Mascarenas, 2003, Mannaert et al., 2005, Moncrieff, 2006), meta-analysis of data from almost 5000 participants found no robust evidence in support of better tolerability or efficacy of LAIs, with the possible exception of aripiprazole. To our knowledge, this is the first meta-analysis directly comparing each single antipsychotic given orally or as LAI

Conflict of interests

GO, IB, RS and CB declare that they have no conflict of interest.

TAF has received lecture fees from Eli Lilly, Janssen, Meiji, MSD, Otsuka, Pfizer and Tanabe-Mitsubishi, and consultancy fees from Sekisui Chemicals and Takeda Science Foundation. He has received royalties from Igaku-Shoin and Nihon Bunka Kagaku-sha publishers. He has received grant or research support from the Japanese Ministry of Education, Science, and Technology, the Japanese Ministry of Health, Labour and Welfare, the Japan

Contributors

GO, IB and CB conceived and wrote the protocol of the study. GO and IB performed the search and assessed the references for inclusion. GO, IB, RS and TAF extracted data from the studies. GO, IB and CB performed the analyses. GO and IB produced the manuscript, which was critically revised by RS, CB and TAF.

Role of funding source

Funders had no role in the study at any stage.

Acknowledgements

The authors wish to thank Dr. Ichiro Kusumi (Hokkaido University Graduate School of Medicine) and Dr. Akihide Wakamatsu (Janssen Pharmaceutical K.K.) for having kindly provided relevant data from the unpublished study NCT00240708.

References (85)

  • F. Pietrini et al.

    LAI versus oral: a case-control study on subjective experience of antipsychotic maintenance treatment

    Eur. Psychiatry

    (2016)
  • J.A. Sterne et al.

    Publication and related bias in meta-analysis: power of statistical tests and prevalence in the literature

    J. Clin. Epidemiol.

    (2000)
  • T. Vos et al.

    Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

    Lancet

    (2012)
  • D.G. Altman et al.

    Detecting skewness from summary information

    BMJ

    (1996)
  • Y.M. Bai et al.

    Equivalent switching dose from oral risperidone to risperidone long-acting injection: a 48-week randomized, prospective, single-blind pharmacokinetic study

    J. Clin. Psychiatry

    (2007)
  • M. Bak et al.

    Almost all antipsychotics result in weight gain: a meta-analysis

    PLoS One

    (2014)
  • C. Barbui

    Sharing all types of clinical data and harmonizing journal standards

    BMC Med.

    (2016)
  • C. Barbui et al.

    Effectiveness of paroxetine in the treatment of acute major depression in adults: a systematic re-examination of published and unpublished data from randomized trials

    CMAJ

    (2008)
  • C. Barbui et al.

    Challenges in developing evidence-based recommendations using the GRADE approach: the case of mental, neurological, and substance use disorders

    PLoS Med.

    (2010)
  • C. Barbui et al.

    Implementing a data sharing culture

    Epidemiol. Psychiatr. Sci.

    (2016)
  • P.J. Blanchet et al.

    Clinimetric evaluation of the Simpson-Angus Scale in older adults with schizophrenia

    J. Clin. Psychopharmacol.

    (2014)
  • S. Brissos et al.

    The role of long-acting injectable antipsychotics in schizophrenia: a critical appraisal

    Ther. Adv. Psychopharmacol.

    (2014)
  • J. del Giudice et al.

    Prevention of recidivism of schizophrenics treated with fluphenazine enanthate

    Psychosomatics

    (1975)
  • H.C. Detke et al.

    Comparison of olanzapine long-acting injection and oral olanzapine

    J. Clin. Psychopharmacol.

    (2014)
  • R.A. Emsley et al.

    Treatment of schizophrenia in low-income countries

    Int. J. Neuropsychopharmacol.

    (1999)
  • L. Ereshefsky et al.

    Comparison of the effects of different routes of antipsychotic administration on pharmacokinetics and pharmacodynamics

    J. Clin. Psychiatry

    (2003)
  • W.W. Fleischhacker et al.

    Compliance with antipsychotic drug treatment: influence of side effects

    Acta Psychiatr. Scand. Suppl.

    (1994)
  • W.W. Fleischhacker et al.

    Aripiprazole once-monthly for treatment of schizophrenia: double-blind, randomised, non-inferiority study

    Br. J. Psychiatry

    (2014)
  • T.A. Furukawa et al.

    Imputing response rates from means and standard deviations in meta-analyses

    Int. Clin. Psychopharmacol.

    (2005)
  • D.M. Gardner et al.

    International consensus study of antipsychotic dosing

    AJP

    (2010)
  • A.I. Green et al.

    Long-acting injectable vs oral risperidone for schizophrenia and co-occurring alcohol use disorder: a randomized trial

    J. Clin. Psychiatry

    (2015)
  • G.H. Guyatt et al.

    GRADE: an emerging consensus on rating quality of evidence and strength of recommendations

    BMJ

    (2008)
  • P. Haddad et al.

    Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies

    PROM

    (2014)
  • I. Haider

    A controlled trial of fluphenazine enanthate in hospitalized chronic schizophrenics

    Br. J. Psychiatry

    (1968)
  • G. Higgins

    Cochrane handbook for systematic reviews of interventions

    (2011)
  • G.E. Hogarty et al.

    Fluphenazine and social therapy in the aftercare of schizophrenic patients. Relapse analyses of a two-year controlled study of fluphenazine decanoate and fluphenazine hydrochloride

    Arch. Gen. Psychiatry

    (1979)
  • P. Hosalli et al.

    Depot risperidone for schizophrenia

    Cochrane Database Syst. Rev.

    (2003)
  • S. Iyer et al.

    A qualitative study of experiences with and perceptions regarding long-acting injectable antipsychotics: part I-patient perspectives

    Can. J. Psychiatr. Rev. Can. Psychiatr.

    (2013)
  • S. Janno et al.

    Validity of Simpson-Angus Scale (SAS) in a naturalistic schizophrenia population

    BMC Neurol.

    (2005)
  • L. Janssen Korea

    NCT00992407 - an efficacy and safety study of long acting injectable risperidone and oral risperidone in participants with schizophrenia or schizoaffective disorder

  • Janssen Pharmaceutical K.K

    NCT00240708 - a study of the efficacy and safety of long-acting injectable risperidone and risperidone tablets in patients with schizophrenia

  • J.M. Kane et al.

    Olanzapine long-acting injection: a 24-week, randomized, double-blind trial of maintenance treatment in patients with schizophrenia

    AJP

    (2010)
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