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 showed more weight gain, cholesterol and glucose elevation than all other SGA’s except for clozapine where no difference with olanzapine was demonstrated. To illustrate the results of our primary outcome weight change, olanzapine produced about two kilograms of weight gain more than amisulpride and four kilograms more than aripiprazole in 2 to 6 months study durations. Clozapine produced about three kilograms more than risperidone (MD 2.9 kg), risperidone produced more weight gain than amisulpride (MD 0.99 kg), and sertindole more than risperidone (MD 0.99). Weight gain is rapid in the first few weeks, and the rapid rate decreases gradually until the weight gain plateaus after several months, after 4-9 months for olanzapine and after 42-46 months for clozapine (Bai et al., 2009
; Henderson et al., 2000
; Kinon et al., 2005
). Our meta-regressions ‘duration of study’ could explain some of the heterogeneity found, as longer studies produced more weight gain than shorter studies; e.g. in short-term studies (≤12 weeks) olanzapine produced 2.5 kg more weight gain than ziprasidone, whereas in long-term studies the difference was about 4 kg. The number of studies for individual drug comparisons was too small for a meta-regression of each. Over the long term the absolute changes will grow, and therefore this is not an absolute estimate of these outcomes, but a relative one. Other factors potentially explaining parts of the heterogeneity were the washout periods, the race distribution, sponsorship, and the dose of medication: short washout periods, often only 24 hours in clinical reality, make the differences in the outcome smaller than they actually are and women seem to be more vulnerable for weight gain with clozapine and quetiapine than men. Sponsorship was found to be some factor in three comparisons in our meta-regressions for sponsorship, but not in the majority of studies as the studied outcomes are rather “hard” outcomes that are difficult to be influenced. The dose of antipsychotic medication was shown in some of our meta-regressions to influence the results: e.g. the higher the olanzapine dose, the higher the difference in the outcome in favor of the comparator antipsychotic. Furthermore, the prior antipsychotic medication taken before the currently tested agent might have also influenced the results on the metabolic outcomes; however, such data were not available and therefore could not be analyzed.
Olanzapine caused the most elevation in cholesterol, clearly more than aripiprazole, risperidone, and ziprasidone. No differences were found in comparison with amisulpride, clozapine and quetiapine. However, quetiapine showed more cholesterol increase than risperidone and was close to that observed with olanzapine. Interestingly, CATIE also found quetiapine had more elevation of cholesterol than risperidone (Lieberman et al., 2005
) as well as elevations in triglycerides (Lieberman et al., 2005
; Meyer et al., 2008b
). This suggests that quetiapine has a greater metabolic effect than the conventional wisdom that it was the same as risperidone (Diabetes Expert Group, 2004
). Risperidone showed more cholesterol increase than aripiprazole and ziprasidone. Our results demonstrate that aripiprazole and ziprasidone have the least effects on the lipid status (Greenberg and Citrome, 2007
; Casey, 2004
The major finding in our third outcome – changes in glucose utilisation – is similar to the general pattern of the first two outcomes: olanzapine showed significantly more increase in glucose levels compared with the other SGAs. Again, no difference was found between olanzapine and clozapine. The ‘change in glucose levels’ may be somewhat ‘weaker’ than the two other metabolic outcomes, e.g. because glucose changes will be more affected in the long-term (Diabetes Expert Group, 2004
), and because of the fact that patients might not always be fasting when the blood samples are taken. Nevertheless, these findings clearly show that changes in glucose utilisation significantly differ between the SGAs, and that olanzapine is producing more increase in the glucose metabolism than the other SGAs except for clozapine.
We found substantial differences in the metabolic side effects of weight, cholesterol and glucose changes of the available SGAs. At least in terms of standardized effect sizes these differences are generally larger than the differences in efficacy. To illustrate this, the standardized effect sizes of olanzapine for efficacy ranged from .11 to .29 in comparison to the other SGAs (Leucht et al., 2009b
), similar to those of the glucose changes of olanzapine (.16 to .26). The effect sizes for cholesterol (.34, .46, 1.15) and weight changes (.39, .42. .47, .52, .72) were clearly larger. For perspective, as a rule of thumb, effect sizes of 0.2 represent a small effect, 0.5 a moderate effect, and ≥0.8 a large effect (Cohen, 1988
). Even though, these effect sizes cannot be compared 1:1, as there are qualitative differences between efficacy and side effects (Leucht et al., 2009a
), the differences in efficacy and the three metabolic outcomes need to be projected throughout the patients lifetime because even small differences are magnified over the years and impact both, on quality of life (Leucht et al., 2009a
) and length of life.
Patients being treated with antipsychotics need to be informed about the differences in efficacy and side effects as different patients have different values, preferences and tolerability for side effects (Hamann et al., 2003
): e.g., for some patients extrapyramidal side effects frequently caused by high-potency typical antipsychotics and by the atypical antipsychotic risperidone are extremely critical, for others elevation in prolactin serum levels with associated sexual side effects - often seen during the treatment with e.g. risperidone or amisulpride – are difficult. Sedation, common with e.g. clozapine and low-potency typical antipsychotics, is problematic for other patients. However, differences in metabolic side effects as shown in this meta-analysis are especially important in this context as they have significant long-term consequences, such as cardiovascular disease (CVD). Overweight, especially abdominal obesity and dyslipidemia seem to play an important role as an early marker for the metabolic syndrome (Schorr et al., 2009
). Schorr et al. showed that the metabolic syndrome is dynamic, i.e. can be reversed, but chances of reversing are smaller for overweight patients.
In line with our finding that olanzapine showed the most changes on weight, cholesterol and glucose, Daumit et al. found significant differences in the antipsychotic effects on the estimated 10-year coronary heart disease risk in the CATIE study with olanzapine and quetiapine being associated with increased risks, while risks decreased with perphenazine, risperidone and ziprasidone (Daumit et al., 2008
). The largest differences between these antipsychotics were seen for older patients and patient with baseline coronary risk factors.
Risk factors for CVD such as obesity, smoking, diabetes, hypertension and dyslipidemia are more common in patients with schizophrenia than in the general population (Fleischhacker et al., 2008
), and, in addition, antipsychotic medication can induce weight gain or worsen CVD risk factors (De Hert et al., 2009
). As a result, people with schizophrenia have a reduced life expectancy compared to the general population (Fleischhacker et al., 2008
). It therefore seems essential to focus on reducing the risk factors, as the beneficial effects of interventions to reduce the risks of CVD have been well studied: if blood cholesterol is reduced by 10%, the risk of coronary heart disease is reduced by 20 - 30% and an ideal body weight (BMI 18.5 -25) is reducing the risk by 35 – 60% (Rich-Edwards et al., 1995
); a reduction of 6 mmHg in diastolic blood pressure reduces the risk by 16% (Hennekens, 1998
) and an active lifestyle (at least 30 minutes walk daily) by 30 -50% (Bassuk and Manson, 2005
In order to prevent well studied long-term consequences of the metabolic risk factors such as hypertension, type 2 diabetes, strokes and heart attacks (Anderson et al., 2003
; Casey, 2004
; Colton and Manderscheid, 2006
) a careful individual decision for an antipsychotic, a close monitoring for metabolic side effects of the chosen antipsychotic, switching the antipsychotic therapy if appropriate (Arango et al., 2008
) and focusing on how to improve physical activity of the individual patient (Vancampfort et al., 2010
) are essential.