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First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: Systematic review and meta-analysis

  • M. Smith (a1), D. Hopkins (a2), R. C. Peveler (a3), R. I. G. Holt (a3), M. Woodward (a4) and K. Ismail (a5)...

The increased prevalence of diabetes in schizophrenia is partly attributed to antipsychotic treatment, in particular second-generation antipsychotics, but the evidence has not been systematically reviewed.


Systematic review and meta-analysis comparing diabetes risk for different antipsychotics in people with schizophrenia.


We searched MEDLINE, PsycINFO, EMBASE, International Pharmaceutical Abstracts, CINAHL and Web of Knowledge until September 2006. Studies were eligible for inclusion if the design was cross-sectional, case-control, cohort or a controlled trial in individuals with schizophrenia or related psychotic disorders, where second-generation antipsychotics (defined as clozapine, olanzapine, risperidone and quetiapine) were compared with first-generation antipsychotics and diabetes was an outcome. Data were pooled using random effects inverse variance weighted meta-analysis.


Of the studies that met the inclusion criteria (n=14), 11 had sufficient data to include in the meta-analysis. Four of these were retrospective cohort studies. The relative risk of diabetes in patients with schizophrenia prescribed one of the second-generation v. first-generation antipsychotics was 1.32 (95% CI 1.15-1.51). There were insufficient data to include aripiprazole, ziprasidone and amisulpride in this analysis.


There is tentative evidence that the second-generation antipsychotics included in this study are associated with a small increased risk for diabetes compared with firstgeneration antipsychotics in people with schizophrenia. Methodological limitations were found in most studies, leading to heterogeneity and difficulty interpreting data. Regardless of type of antipsychotic, screening for diabetes in all people with schizophrenia should be routine.

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Corresponding author
M. Smith, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 9RJ, UK. Email:
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Declaration of interest

R.P. has received fees for speaking and consulting from makers of antipsychotics, including Eli Lilly and Company, Bristol Myers Squibb, Sanofi, Pfizer, Janssen and Astra Zeneca. R.H. has received educational grants and fees for lecturing and consultancy work from Eli Lilly and Company, Bristol Myers Squibb and GlaxoSmithKline.

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First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: Systematic review and meta-analysis

  • M. Smith (a1), D. Hopkins (a2), R. C. Peveler (a3), R. I. G. Holt (a3), M. Woodward (a4) and K. Ismail (a5)...
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Author's reply

Michelle A Smith
27 November 2008

We acknowledge Smith et al’s interest in the reasons for why we did not focus on the relationship between merely starting any antipsychotic and developing diabetes, but instead reviewed the evidence for an association between diabetes and type of antipsychotic medication. There has been increasing concern that second generation antipsychotics may be more diabetogenic than first generation anitpsychotics in patients with schizophrenia. Despite this concern, there is a lack of good evidence to support this apparent phenomenon and so it was essential to carry out our systematic review prior to developing guidelines for diabetes screening and management.

We agree with Smith et al that our paper has found strong heterogeneity between studies which is clearly an important finding from our study. It is only by undertaking systematic reviews that one can determine that heterogeneity exists. Therefore, without our systematic review this would not have been clear. Our meta-analysis uses random effects methodology which means we have analysed the average effect over the studies. This is a meaningful concept in the presence of heterogeneity. As for looking at absolute risks, the heterogeneity betweenstudies is so great as to make even random effects pooling absurd. This iswhy pooled analyses virtually always pool relative risks rather than risk differences.

Smith et al have highlighted our conclusions that methodological limitations were found in most studies. As current evidence is poor, it should not be used alone in making clinical decisions concerning diabetes screening and management for patients with schizophrenia. Regardless of whether first or second generation antipsychotics are prescribed, routine screening for diabetes in all patients with schizophrenia should be undertaken.
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Conflict of interest: None Declared

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Antipsychotics and risk for diabetes in schizophrenia

Michael Smith, Registrar
25 October 2008

Antipsychotics and risk for diabetes in schizophrenia

Smith et al state that there is increasing concern about the association between second generation antipsychotics and diabetes among clinicians1.

It is interesting then that while commenting on the lack of systematic reviews and meta-analyses that support this concern the authorsgo on to investigate, not the relationship between starting antipsychoticsand developing diabetes, but the relative risk of developing diabetes between groups of patients commenced on first generation and second generation antipsychotics. As such it is questionable whether this meta-analysis addresses, in any clinically meaningful way, the risk of developing diabetes after starting an antipsychotic, whether second or first generation. This would appear to be more usefully addressed by looking at the absolute risk.

The authors report on the difficulties in finding high quality trialsto include in their study. This is illustrated by the inclusion of only 11trials out of an identified 1974. Smith et al then go on to outline their own criteria for a study to be considered of ‘high quality’. These criteria include a prospective design and at least one year of follow up recorded. It is of note then that of the 11 studies eventually included inthe analysis, only three were prospective. Furthermore, of these three prospective trials none was longer than three months. All trials included in the review could therefore be classified as low quality. The test for heterogeneity between studies, applied by the authors, further illustratesthe highly significant methodological heterogeneity between studies.

We would suggest that given the overall poor quality of studies foundin the review there seems to be no rationale for going on to conduct a meta-analysis. One common pitfall of any meta-analysis is that if you put only poor quality data in you will get poor quality data out. As such thismeta-analysis would seem to add little to the current evidence base with regards to Antipsychotics and Diabetes, except, perhaps, the confirmation that the studies on this subject are heterogeneous and generally of poor quality.

If one does want to consider whether a significant relationship exists between antipsychotic use and diabetes, or a metabolic syndrome, then The CATIE Study2 would seem to provide reasonably robust evidence that such a relationship does exist. This large, randomised, prospective study, carried out over a period of eighteen months has data collected at baseline and following the introduction of antipsychotic, and demonstratesclinically and statistically significant adverse changes in blood glucose,weight and cholesterol. This is particularly the case for those patients commenced on olanzapine.

References:1.Smith M et al,. First- v. second-generation antipsychotics and risk fordiabetes in schizophrenia: systematic review and meta-analysis. B J Psychiatry 2008; 192: 406-411.2.Lieberman J A et al,. Effectiveness of Antipsychotic Drugs in Patients with Chronic Schizophrenia. New England Journal of Medicine; 2005; 353: 1209-1223.

Dr Mike SmithHillmorton HospitalCanterbury District Health BoardPrivate Bag 4710Christchurch, New ZealandTelephone: 0064 3 364 0640Email:

Associate Professor Richard PorterDepartment of Psychological MedicineUniversity of Otago, ChristchurchPO Box 4345Christchurch, New ZealandTelephone: 0064 3 372 0400Fax: 0064 3 372 0407Email:,nz

Declaration of Interest

Richard Porter has received Speakers Honoraria from Janssen-Cilag, Eli Lilly and Wyeth Pharmaceuticals.
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