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