A systematic review and meta-analysis of the effect of depot antipsychotic frequency on compliance and outcome

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Abstract

Background

Depot antipsychotics are commonly used to improve adherence and clinical outcomes such as relapse and readmission. Dosing regimens vary but are commonly two- and four-weekly. To date, the effect of administration at two-weekly or four-weekly intervals on outcome has not been examined in a meta-analysis.

Aims

A systematic review and meta-analysis on whether the frequency of depot antipsychotic administration (e.g., two- vs four-weekly) makes any difference to compliance and outcome.

Methods

A systematic search of Medline, EMBASE and PsycInfo for RCTs that compared the frequency of depot administration (e.g., two- vs four-weekly) for an equivalent dose. Outcomes were compliance, psychiatric symptomatology, quality of life, adverse drug reactions (ADRs), patient preference, admission rates, bed-days and costs.

Results

Seven studies from eight papers (n = 3994) were found covering olanzapine, paliperidone, risperidone, haloperidol and fluphenazine enanthate/decanoate with follow-up of up to one year. Meta-analyses were possible for psychotic symptoms and ADRs. There were no differences in psychotic symptoms or quality of life between two- and four-weekly doses. Health service use was not reported. For ADRs, the only significant difference detected was that two-weekly injections were less likely to lead to site pain (RR 0.16, 95% CI 0.07–0.38; 2 studies n = 1667). There were no differences in other ADRs.

Conclusions

There were surprisingly little data on the effect of dosing frequency for an equivalent dose on clinical outcomes. There is a need for long-term studies of a wide range of outcomes including cost-effectiveness. Claims for advantages of new preparations over others require careful evaluation.

Introduction

Psychotropic medications play a key role in the treatment of serious mental illness. However, adherence is often poor resulting in poorer psychosocial outcomes (Gray et al., 2010, Hill et al., 2010).

Several studies have reported advantages of long-acting injectable (LAI) over oral medication in terms of relapse prevention and adherence. A meta-analysis of 10 randomised trials showed a statistically significant reduction in relapse rates with the use of depots as opposed to orals (Leucht et al., 2011). A further study found that risk of rehospitalisation for patients receiving depots was about one-third of that for patients receiving equivalent oral medications (Tiihonen et al., 2011). Discontinuation rates with orals can reach 74% (Lieberman et al., 2005) compared to around a third for an atypical LAI (Fleischhacker et al., 2003a, Fleischhacker et al., 2003b, Kissling et al., 2005, Keks et al., 2007, Baker et al., 2012). Long-term benefits may be greater as few studies extend over one year (Patel and David, 2005).

There have been relatively few depot head-to-head comparisons although comparisons with oral medications have shown no convincing advantages for one depot over another (Adams et al., 2001, Fleischhacker, 2009). Where there have been head-to-head comparisons, no depot appears to have superiority over another, including comparisons between first and second generation antipsychotics (FGA, SGA) (Quraishi and David, 2000, Adams et al., 2001, David et al., 2005, Fricchione Parise et al., 2010, Einarson, 2011, Fleischhacker et al., 2012, McEvoy et al., 2014).

One area that has not been studied in depth is dosing frequency. Dosing regimens vary but are commonly two- and four-weekly. The effect of administration at two-weekly or four-weekly intervals on subsequent compliance and outcome is unknown. This is topical because many patients are currently being changed from two-weekly depot risperidone to the four-weekly depot of its metabolite, paliperidone on the basis that this benefits patients and the health service. A Cochrane review reported on two studies comparing risperidone depot with paliperidone and found little difference between the two. However it did not expressly investigate dosing frequency, and combined the results of studies with very different follow-up periods (13 and 53 weeks respectively) with no usable intermediate data points. Importantly, it did not investigate other depot psychotropics (Nussbaum and Stroup, 2012).

Reducing dosing frequency may save resources, including time, travel and reduced outreach visits. An industry-sponsored cost analysis of potential savings from changing from a two-weekly to monthly regime estimated an average saving of US$58 per injection avoided, potentially saving US$8.5 million per year (Dalton et al., 2011). In addition, this might give staff more time for other duties, and be more convenient for patients.

Conversely, reduced frequency of contact may mean that opportunities are missed for concurrent non-pharmacological interventions. Comparisons of standard care with either intensive case management or assertive community treatment have consistently shown that greater intensity of contact improves patient compliance and outcomes (Marshall and Lockwood, 2000, Zygmunt et al., 2002, Dieterich et al., 2010, Guhne et al., 2014). Where compulsory community treatment has shown advantages over treatment as usual, it has been suggested that it is through more frequent contact with mental health clinicians (Kisely et al., 2013).

We therefore undertook a systematic review comparing outcomes of two-weekly versus four-weekly administration on clinical and health service outcomes.

Section snippets

Method

The review was registered with PROSPERO, an international database of prospectively registered systematic reviews in health and social care based in the United Kingdom (registration number: CRD42015015764) (Booth et al., 2012). In addition, we followed recommendations for the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement including background, search strategy, methods, results, discussion and conclusions (Moher et al., 2009).

Results

We found 220 citations of interest representing 178 papers once duplicates were removed. Of these, 13 full-text papers were potentially relevant and assessed for eligibility. Five papers were excluded for reasons listed in Fig. 1. This left eight papers from seven studies (Fig. 1). The sum of enrolled patients was 3994 at baseline and 3160 at follow-up. Meta-analyses were possible for five of these studies (Fig. 1).

Three studies compared two-weekly injections of risperidone with equivalent

Discussion

There were surprisingly little data from RCTs on the effect of dosing frequency for an equivalent dose on clinical outcomes (n = 7). Indeed, studies comparing depots often ensured that both active treatments were given at similar time intervals. This removes any consideration of the effects of dosing frequency on outcomes. On the limited evidence from these meta-analyses, two-weekly or four-weekly injections do not lead to notable differences in clinical outcomes. If anything, two-weekly

Role of funding source

This project was supported by the University of Queensland Summer Research programme. This funding source provided funds for a research assistant only.

Contributors

Author SK designed the study and wrote the protocol. Literature searches and analyses were completed by SK and ES.

Statistical analyses were undertaken by SK and DS. The first draft of the manuscript was written by SK. All authors edited and contributed to drafts of the manuscript. The final draft of the manuscript was approved by all authors.

Conflict of interest

The authors have none to disclose.

Acknowledgements

This project was supported by the University of Queensland Summer Research programme.

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