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Figure 10: Weight Gain per Month of Treatment in the increase in the risk of developing diabetes. Data from the Framingham
CATIE Study (Phase 1)
Heart Study have been used to calculate the excess number of
diabetes cases per 100,000 over the next decade based on initial BMI
and degree of weight gain over the observation period.
with a baseline BMI >27 who gained 12.5kg were estimated to
develop 3,166 excess cases of diabetes per 100,000 over the next 10
years. This cohort is most representative of patients with
0.5 schizophrenia who tend to be overweight or obese at the start of a
treatment trial. From these figures, it is clear that a major treatment
goal should be to decrease the number of new cases of diabetes,
Olz Que Ris Per Zip
achievable in part through careful choice of an antipsychotic agent,
and active monitoring of the effects of antipsychotics on lipid levels,
insulin resistance or glucose levels.
Weight change (lb/mo of treatment)
Olanzapine Quetiapine Risperidone Perphenazine Ziprasidone
Mean±SE 2.0±0.3 0.5±0.2 0.4±0.3 -0.2±0.2 -0.3±0.3
Several studies had previously suggested an association between
Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) phase I trial results denoting
olanzapine use and hyperlipidaemia.
Using data from the
the weight gain per month of treatment. Source: Lieberman et al., 2005.
England- and Wales-based General Practice Research Database, a large
study found that olanzapine exposure increased the odds of developing
Figure 11: Effects of Staying on or Switching from
hyperlipidaemia by nearly five-fold compared with no antipsychotic
Olanzapine on Bodyweight
exposure, and by more than three-fold compared with treatment with
conventional agents, with no increased risk associated with risperidone
treatment in this analysis.
Treatment-related adiposity is an important
predictor of insulin sensitivity: as body fat increases, insulin sensitivity
tends to decrease.
However, there is some evidence that there may be
an effect of some antipsychotic drugs on insulin resistance independent
W of weight gain.
A homeostasis model assessment of insulin
resistance in patients with schizophrenia matched for age and adiposity
showed that olanzapine and clozapine treatment was associated with
1 3 6 9 12 15 18 modestly increased insulin resistance compared with those patients
receiving treatment with high-potency typical antipsychotics (p<0.05
Stay on Olz Switch to Que Switch to Ris Switch to Zip and p=0.06, respectively).
Moreover, a recent study in rats
demonstrated a dose-dependent reduction in insulin sensitivity by
Post hoc analysis of Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) phase I
data showing weight change by stay or switch status among patients treated with
approximately 50% within two hours of exposure to clozapine or
olanzapine at baseline (least square means). Source: Rosenheck et al., 2009.
olanzapine, a time-scale in which fat mass is not altered.
Figure 12: Adjusted Hazard Ratio for Incident Diabetes
Data from the first large-scale pharmaco-epidemiological study, where
with Antipsychotic Usage
all the currently available atypical antipsychotics can be evaluated
together with respect to risk of the development of diabetes, has
Simple cohort recently been reported.
Using information from US healthcare
systems, this study identified a simple cohort of chronic antipsychotic
+ users and an inception cohort of ‘new users’, in which patients had no
D D 1.77
antipsychotic treatment in the previous three months. Following these
2 1.05 1.05 1.21 1.20
1.71 cohorts over time to monitor the emergence of indicators of newly
1.04 treated diabetes, researchers found similar rates of diabetes associated
0 with use of aripiprazole, quetiapine, risperidone and ziprasidone
Ari Zip Ris Que Olz Clz
compared with typical antipsychotic treatment, while exposure to
n=4,528 n=2,606 n=14,838 n=17,620 n=17,119 n=147
n=5,925 n=4,012 n=21,469 n=22,999 n=24,368 n=680
olanzapine and clozapine was associated with an increased rate of
diabetes, with similar results in both cohorts (see Figure 12).
partially reversed by switching to a treatment with a lower propensity
for weight gain. Summary of Metabolic Effects
Available evidence indicates that the choice of antipsychotic used in
Development of Dyslipidaemia, schizophrenia treatment can have important implications for a
Insulin Resistance and Diabetes patient’s metabolism and their risk of long-term adverse health
Treatment with antipsychotic agents can alter lipid fractions and outcomes. Drug-induced weight gain can promote the onset of
decrease insulin sensitivity. In particular, those with the greatest effect dyslipidaemia, insulin resistance and diabetes, with some medications
on bodyweight are also associated with elevated plasma triglycerides, associated with greater risk of larger weight increases compared with
insulin resistance and risk of dysfunction in glucose homeostasis, others. In addition, some medications may increase insulin resistance
leading to reduced glucose tolerance and, ultimately, elevated levels independent of weight gain. This information regarding risks
of fasting plasma glucose (FPG). It is well-accepted that populations associated with specific antipsychotic treatments can be used by
that undergo an increase in bodyweight will face a corresponding physicians in considering treatment options for their patients.
32 EUROPEAN PSYCHIATRIC REVIEW