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Treatment with antipsychotics and the risk of diabetes in clinical practice

  • Lars Vedel Kessing (a1), Anders Frøkjær Thomsen (a1), Ulla Brasch Mogensen (a2) and Per Kragh Andersen (a2)
Abstract
Background

Treatment with antipsychotics seems to increase the risk of developing diabetes but the association is poorly characterised in clinical practice.

Aims

To investigate and characterise the incidence of diabetes for people treated with antipsychotic medication in clinical practice.

Method

The study used the linkage of registers of all prescribed antipsychotics, antidiabetics and diagnoses of diabetes in Denmark during a period from 1996 to 2005 and identified all people treated with antipsychotics in Denmark and a random sample of about 30% of the total Danish population.

Results

In total, 345 937 patients who purchased antipsychotics and 1 426 488 unexposed individuals were included in the study. Among the total population, 50 379 individuals subsequently developed incident diabetes. Compared with unexposed individuals, treatment with first- (rate ratio, RR = 1.53, 95% CI 1.49–1.56) as well as second-generation (RR = 1.32, 95% CI 1.22–1.42) antipsychotics was associated with increased risk of subsequent incident diabetes. The rate of incident diabetes varied substantially between individual second-generation antipsychotic drugs (olanzapine, risperidone clozapine compared with unexposed individuals: low to moderate rate ratio between 1.17 and 1.57; ziprasidone and sertindol: two or more times increased rate ratio; amisulpride, quetiapine and aripiprazole: no significantly increased rate ratio). For both first- and second-generation antipsychotics, the incidence of diabetes increased with the number of prescriptions. Additionally, the incidence of diabetes increased with the number of combined antipsychotic drugs.

Conclusions

In clinical practice, treatment with first- and second-generation antipsychotics is associated with an increased risk of developing incident diabetes with large differences between individual drugs. The risk increases with the duration of treatment and with polypharmacy of antipsychotic drugs.

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Copyright
Corresponding author
Lars Vedel Kessing, Department of Psychiatry, University Hospital of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK 2100 Copenhagen Ø, Denmark. Email: lars.vedel.kessing@regionh.dk
Footnotes
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Declaration of interest

L.V.K. has been a consultant for Bristol-Myers Squibb, Eli Lilly, Lundbeck, AstraZenica, Pfizer, Wyeth, Servier and Janssen-Cilag.

Footnotes
References
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Treatment with antipsychotics and the risk of diabetes in clinical practice

  • Lars Vedel Kessing (a1), Anders Frøkjær Thomsen (a1), Ulla Brasch Mogensen (a2) and Per Kragh Andersen (a2)
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eLetters

Diabetogenic potential of age and antipsychotic medications

Thilagavathy Palanivel, Trainee in Psychiatry
15 October 2010

Dear Editor,The topic of metabolic abnormalities and antipsychotic medication has always attracted our attention. We feel that it is an area which will require higher level of awareness and medical knowledge for any psychiatrist who is prescribing these medications regularly. The recent article in your Journal titled ‘Treatment with antipsychotics and the risk of diabetes in clinical practice’ by Kessing et al has naturally attracted our attention. We are particularly drawn towards the finding that patients who take first generation antipsychotics may face higher risk than those who take second generation antipsychotics. A number of previous studies have reported findings that are the other way around (second generation posing higher risk than the first generation (1). Authors offered a very good explanation for their finding. They wrote that (2) individuals at higher risk in their study population, because of their personal history, obesity etc., may have been prescribed first generation antipsychotics because they confer low risk of diabetes. We feel that this could be true but may not explain the whole picture. Age being an independent risk factor in the development of diabetes especially type 2 is well known (3). Authors have identified that increasing age is a significant risk factor in the development of diabetes. In Table 3 of their article they have given details about the age at first prescription for selected antipsychotics. We can note that there is a significant difference between age at first prescription of first and second generation antipsychotics (e.g Age at first prescription for Haloperidol is 72.2 and for Ziprasidone is 32.7). From our medical knowledge we can ascertain that a patient who is older is more likely to develop diabetes for the first time in their life as opposed to someone who is younger. Hence we are wondering whether the increase age at the time of first prescription of first generation antipsychotics could be a possible reason for the unusual finding in this study. We also found similar higher degree of age difference between controls (Mean age = 36.) and exposure group (Mean age as high as 59.7 in second generation antipsychotic group). Even though the authors claim that results were adjusted for age at the level of statistical analyses, the impact of age difference between groups at the level of patient selection cannot be completely ruled out.Other concerns like lack of information like past history of exposure, ascertaining continuity of exposure to medications during the study period and the exclusion of dose calculation in determining the strength of exposure cast shadow of doubt about the validity of the study results.References:1. First- v. second-generation antipsychotics and risk for diabetes in schizophrenia: systematicreview and meta-analysis - M. Smith, D. Hopkins, R. C. Peveler, R. I. G. Holt, M. Woodward and K. Ismail; The British Journal of Psychiatry (2008) 192, 406–411. 2. Treatment with antipsychotics and the risk of diabetes in clinical practice – Lars Vedel Kessing, Anders Frokjear Thomsen, Ulla Brasch Mogensen and Per Kragn Andersen; The British Journal of Psychiatry (2010) 197, 266-271.3. Oxford Handbook of Clinical Practice, second edition; oxford university press (2005): 405. ... More

Conflict of interest: None Declared

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Potentially differential frequency of glucose testing among people taking antipsychotic medications

Takefumi Suzuki, Psychiatrist
08 October 2010

Dear Editor:

Drs. Kessing et al. conducted a very important study in which they evaluated, using a huge Danish database, incident diabetes mellitus (DM) among people taking antipsyhotic medications over the ten years. (1) They found that in comparison with no exposure, both first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) were associated with increased risk of DM. Somewhat surprisingly, they found a higher risk with sertindole and ziprasidone but not with aripiprazole, although these antipsychotics are generally considered to be relatively benign in terms of metabolic adversities. (2) The authors noted a plausible possibility that physicians are likely reluctant to prescribe antipsychotics known to be detrimental in metabolic parameters for people who deem at high risk or would switch to a less problematic antipsychotic upon a suspicion of metabolic derangements.

Apart from a wide range in 95% confidence intervals with some antipsychotics, there is another caveat in interpreting their crucial findings, namely the differential frequency of metabolic testing across antipsychotics in question and their timing of introduction into the market in relation with the study period of 1996-2005. In this study, DM was diagnosed either with a first purchase of anti-diabetic medications ora hospital diagnosis. In other words, DM diagnosis was likely derived fromblood glucose levels, which would have been performed in response to clinical suspicion – without testing the presence of DM is frequently unknown (which could also be confounded with less optimal communication with physicians of their subjective, DM-associated symptoms among antipsychotic consumers), leaving underdiagnosis a critical issue. In fact, except for rare situations such as diabetic ketoacidosis, many people may have milder condition that could render DM left undetected. (3)

It is for instance more likely that people who gained substantial weight with drug X and then switched to a more weight-friendly antipsychotic are tested for blood glucose (and other metabolic parameters) more frequently than those who stayed well with drug X (both in terms of psychopathology and body weight). This in turn may uncover more incidence of DM in the former people, thereby resulting in less underdiagnosis. It is also plausible that the more risk factors they have,the more frequently they are tested for DM (even in the absence of weight gain). Therefore, differential frequency of blood testing remains a sound possibility. An insignificant finding with aripiprazole might be because of its later appearance in the market, affording less time for DM to be detected, which could potentially stem from the less number of bloodwork. As such, any speculation on a causation of antipsychotics in DM should be made with caution unless the number of glucose testing is controlled for. Admittedly however, this would be practically very challenging.

Declaration of interest

Dr Suzuki has received grants from Mochida Memorial Foundation, KanaeFoundation, Government of Canada Post-Doctoral Research Fellowships, and Japanese Society of Clinical Neuropsychopharmacology.

References

1. Kessing LV, Thomsen AF, Mogensen UB, Andersen PK. Treatment with antipsychotics and the risk of diabetes in clinical practice. Br J Psychiatry 2010;197:266-71.

2. Rummel-Kluge C, Komossa K, Schwarz S, Hunger H, Schmid F, Lobos CA, et al. Head-to-head comparisons of metabolic side effects of second generation antipsychotics in the treatment of schizophrenia: A systematic review and meta-analysis. Schizophr Res 2010 Aug 6. [Epub ahead of print]

3. Sugawara N, Yasui-Furukori N, Sato Y, Umeda T, Kishida I, Yamashita H, et al. Prevalence of metabolic syndrome among patients with schizophrenia in Japan. Schizophr Res 2010 Sep 16. [Epub ahead of print]
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