Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis

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Abstract

Objective

The metabolic side effects of second-generation antipsychotics (SGA) are serious and have not been compared head to head in a meta-analysis. We conducted a meta-analysis of studies comparing the metabolic side effects of the following SGAs head-to-head: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine.

Method

We searched the register of the Cochrane schizophrenia group (last search May 2007), supplemented by MEDLINE and EMBASE (last search January 2009) for randomized, blinded studies comparing the above mentioned SGA in the treatment of schizophrenia or related disorders. At least three reviewers extracted the data independently. The primary outcome was weight change. We also assessed changes of cholesterol and glucose. The results were combined in a meta-analysis.

Results

We included 48 studies with 105 relevant arms. Olanzapine produced more weight gain than all other second-generation antipsychotics except for clozapine where no difference was found. Clozapine produced more weight gain than risperidone, risperidone more than amisulpride, and sertindole more than risperidone. Olanzapine produced more cholesterol increase than aripiprazole, risperidone and ziprasidone. (No differences with amisulpride, clozapine and quetiapine were found). Quetiapine produced more cholesterol increase than risperidone and ziprasidone. Olanzapine produced more increase in glucose than amisulpride, aripiprazole, quetiapine, risperidone and ziprasidone; no difference was found with clozapine.

Conclusions

Some SGAs lead to substantially more metabolic side effects than other SGAs. When choosing an SGA for an individual patient these side effects with their potential cause of secondary diseases must be weighed against efficacy and characteristics of the individual patient.

Introduction

Second-generation antipsychotics (SGA) are commonly used in the treatment of patients with schizophrenia (Diabetes Expert Group, 2004, Leucht et al., 2009) and have even become the drugs of choice in some countries, such as the United States. However, there are substantial concerns about the metabolic side effects of SGAs. In general, today there is significant agreement on the importance of the metabolic side effects, such as changes in body weight, glucose utilization, or lipid status, unrecognized or unknown at the beginning of the introduction of SGAs (Meyer, 2002). For some physicians these side effects are the most important as they might predispose to type 2 diabetes mellitus and cardiovascular disease (Meyer et al., 2008a, Daumit et al., 2008), while others may weigh them against other side effects such as extrapyramidal side effects or sexual problems.

The metabolic side effects have become an issue in competitive advertising between pharmaceutical companies, thus causing a polarization. Randomized controlled trials (RCTs) are probably the most bias free way to compare such side effects. There is a substantial amount of research in this field, however, currently there is no meta-analysis comparing the metabolic side effects of the SGAs head-to-head.

We therefore conducted a meta-analysis of studies directly comparing the following SGAs to one another: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine. This article is focusing on the metabolic side-effects of second-generation antipsychotics while the data on the efficacy of these medications have been published elsewhere (Leucht et al., 2009).

Section snippets

Search strategy

The register of the Cochrane Schizophrenia Group (CSG) was searched for randomized, blinded trials comparing orally administered second-generation antipsychotics (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, zotepine) head-to-head in the treatment of schizophrenia or related disorder (schizoaffective, schizophreniform, or delusional disorder) without language restrictions. The search terms used were all possible 36 combinations of the names

The search (for QUOROM flow diagram (Moher et al., 1999) see Fig. 1)

The search strategy identified 3750 citations. Of these, 3119 abstracts were excluded because they were clearly not relevant. 631 articles were ordered for more detailed evaluation and 321 of these were excluded. 310 publications on 90 studies were included; however, only 48 studies with 105 relevant arms reported usable data on at least one of the outcomes cholesterol, glucose or weight. Of these 48 studies, 6 studies included amisulpride, 5 aripiprazole, 11 clozapine, 37 olanzapine, 11

Discussion

We present the first head-to-head meta-analysis of the metabolic side effects of second-generation antipsychotics in randomized controlled trials, showing three similar clusters for the three outcomes with olanzapine and clozapine showing the most elevation of weight, cholesterol, and glucose. Quetiapine, risperidone, and sertindole had intermediate elevations. Aripiprazole and amisulpride displayed intermediate or low elevations and ziprasidone the lowest elevations.

We found that olanzapine

Role of the Funding Source

Financial support was provided by a grant from the Technische Universität München (HWP II) (CR), the German Federal Ministry of Education and Research, no FKZ: 01KG 0606, GZ: GFKG01100506 (SL); and a grant from the National Institute of Mental Health, Advanced Center for Intervention and Services Research Center (MH-68580), Grant No. 1 P01MH68580-01 CFDA #93.242, the Maryland Psychiatric Research Center (JD). The funding source had no involvement in study design, collection, analysis and

Contributors

CRK, KK and SL contributed to designing the study, data extraction, statistical analysis, and writing the report. SS, HH, FS and CAS contributed to data extraction and writing of the report. WK and JD contributed to designing the study and writing the report. All authors contributed to and have approved the final manuscript.

Conflict of interest

Christine Rummel-Kluge has received speaker honoraria or travel grants to attend scientific meetings from AstraZeneca, Janssen-Cilag, EliLilly and Pfizer.

Stefan Leucht has received speaker and/or consultancy honoraria from SanofiAventis, BMS, EliLilly, Janssen/Johnson and Johnson, Lundbeck and Pfizer; and he has received funding for research projects from EliLilly and SanofiAventis.

Werner Kissling has received speaker or consultancy honoraria from SanofiAventis, BMS, Lilly, Janssen, Lundbeck,

Acknowledgement

We thank the following authors and pharmaceutical companies for providing additional information on their studies: D. Addington, I. Bitter, R. Conley, D. Daniel, L. De Haan, S. Dollfus, O. Fleurot, H. Heinrich, T. Hwang, D. Jeste, W. Kadus, J. Kane, R. Keefe, D. Kelly, M. Krakowski, M. Kluge, Y. Liu, S. McGurk, K. Mori, A. Mortimer, D. Naber, H. Ozguven, J. Peuskens, B. Quednow, Q. Ren, M. Riedel, N. Schooler, D. Sechter, J. Švestka, J. Volavka, M. Wagner, K. Zhong, AstraZeneca, EliLilly,

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