Oral versus depot antipsychotic drugs for schizophrenia—A critical systematic review and meta-analysis of randomised long-term trials
Introduction
Maintenance treatment with antipsychotic drugs is highly effective in reducing the relapse rates of people with schizophrenia (Davis et al., 1980, Gilbert et al., 1995). However, this effect is jeopardized by high rates of non-adherence to oral medication which has been estimated to occur in as many as 42% of the patients (Cramer and Rosenheck, 1998).
The introduction of second-generation antipsychotic drugs generated enormous hope that medication-adherence would be improved due to fewer side effects, in particular extrapyramidal side effects (Borison, 1997, Buckley, 1997). However, a number of epidemiological analyses have shown that non-adherence to second-generation antipsychotics is not much different than conventional compounds (Dolder et al., 2002, Gilmer et al., 2004, Valenstein et al., 2004).
Depot antipsychotic drugs could have clear advantages in relapse prevention, because medication intake is assured and because the doctor immediately knows when a patient stops treatment. Nevertheless due to various reasons such as refusal of patients or reservations by psychiatrists (Hamann et al., 2010, Heres et al., 2007, Heres et al., 2008), in some countries such as the US (Ahn et al. 2008) depot formulations are rarely prescribed, while in others such as the UK (Barnes et al., 2009) they are used quite frequently. According to a survey among German psychiatrists less than 36% of patients have ever been offered an antipsychotic depot treatment (Heres et al., 2006).
Moreover, the evidence whether depot formulations really reduce relapse is unclear. While an early meta-analysis by Davis et al. (1994) suggested a significant superiority compared to oral medication, the Cochrane reviews of the various depots did not find any convincing difference (Abhijnhan et al., 2007, Da Silva Freire Coutinho et al., 1999, David et al., 1999, David et al., 2004, David et al., 2005, Dinesh et al., 2004, Hosalli and Davis, 2003, Quraishi et al., 1999, Wong et al., 2004; summarised by Adams et al., 2000). However, these reviews also included studies in inpatients and short-term trials of just a few weeks duration. The inclusion of inpatient studies might have reduced the “depot-effect”, because in hospitals medication is usually administered by nurses thereby improving adherence. Therefore outpatient settings are more appropriate to investigate the value of depot antipsychotics. Furthermore, short-term studies are not adequate to examine depot medication, because relapses usually do not occur right after stopping the medication, but often occur after a delay of several months (Gilbert et al., 1995).
Section snippets
Inclusion criteria
We searched for randomised controlled trials (RCT) that compared intramuscular depot with oral formulations of antipsychotic drugs in people with schizophrenia or related disorders (schizophreniform, schizoaffective or delusional disorder, any diagnostic system, any age and gender, no language restrictions). As people with schizophrenia often do not relapse immediately after stopping medication, we included only long-term studies defined as 1 year or longer. In addition, we included only
The search
Of 5536 retrieved references 40 publications were ordered for full inspection. 32 studies were excluded (2 not randomised, 10 no depot versus oral, 3 duration less than 12 months, 1 no outpatients and 2 ongoing) and 10 were included (Supplemental Fig. 1 presents a PRISMA-diagram, Liberati et al., 2009).
Characteristics of included studies and participants
The 10 studies were published from 1975 to 2010 and included 1700 participants. Seven studies lasted 52 weeks and three 104 weeks (one was terminated early at 69 weeks (Del Giudice et al., 1975), and
Discussion
In this systematic review of long-term studies depot antipsychotic drugs reduced relapse rates of outpatients with schizophrenia from an average of 33.2% to 21.5%. This difference means a 10% absolute risk reduction and a 30% relative reduction of the relapse risk. The finding was corroborated by significantly fewer participants dropping out due to inefficacy of treatment.
These numbers are relatively large compared with the effects of other psychiatric or medical interventions. For example,
Conclusions
We conclude that the currently available evidence suggests a clinically meaningful superiority of depot medication compared to oral antipsychotic drugs in outpatients with schizophrenia. However, due to a number of important methodological problems, the quality of this evidence is subject to bias. Future studies should a) compare the same substances in the oral and depot groups, b) always investigate hospitalisation and adherence, and c) possibly use a single-blind design with blind raters. The
Role of funding source
There is no funding source to declare.
Contributors
All authors contributed to the study design and interpretation of results. CL selected the articles and SH verified the selection in a random sample of 20%. CL and SL independently extracted data from the included trials onto standard forms. Disagreements were resolved by discussion or by involving a third reviewer (JD). CL and SL led the statistical analysis and drafted the manuscript. All authors participated in critical revision of manuscript drafts and approved the final version.
Conflict of interest
JD declares no conflict of interest. SL received speaker/consultancy/advisory board honoraria from Sanofi-Aventis, BMS, Actelion, EliLilly, Essex Pharma, AstraZeneca, GlaxoSmithKline, Janssen/Johnson and Johnson, Lundbeck and Pfizer. Sanofi-Aventis and EliLilly supported research projects by SL.
CL is SL's spouse, therefore, the same conflicts of interest apply. She declares no additional conflicts of interest.
SH received speaker and/or advisor honoraria from Janssen-Cilag, Eli Lilly,
Acknowledgements
We thank Profs. and Drs. Andrey Potapov, Celso Arango, Nina Schooler, Keith Nuechterlein, Richard Subotnik, Roubing Li, Thomas Barnes, Peter Weiden and Robert Rosenheck for further information on their trials. We thank Prof. Chunbo Li for data extraction of a Chinese article.
We are indebted to the Cochrane Schizophrenia Group for its support and endorsement during the search.
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