Abstract
Background:
Antipsychotics, especially the second-generation of antipsychotic drugs (SGAs), are commonly used to treat schizophrenia and bipolar disorder. However, their use is linked to high metabolic and cardiovascular risks such as weight gain, dyslipidemia, hyperglycemia and QTc prolongation. These side effects can have a negative impact on the patient's health outcomes and adherence to treatment. This systematic review and meta-analysis aimed to assess and compare the metabolic and cardiovascular risks associated with four widely used SGAs: Olanzapine, Risperidone, Quetiapine and Aripiprazole.
Objectives:
This systematic review and meta-analysis aimed to assess and compare the effects of these four SGAs on weight gain, dyslipidemia, hyperglycemia, and QTc prolongation in patients with schizophrenia or bipolar disorder. The secondary goal was to determine the safety and tolerability of these medications in general as well as regarding long-term metabolic and cardiovascular risks.
Methods:
A detailed search of the literature was performed to identify relevant studies published from 2000 to 2025. Randomized controlled trials (RCTs), observational studies and meta-analyses that assessed the metabolic and cardiovascular effects of Olanzapine, Risperidone, Quetiapine and Aripiprazole were included. The extraction of data was based on the principal results: weight gain, fasting blood glucose, lipid areas (total cholesterol, the HDL, LDL, and triglycerides), and QTc prolongation. They were used to estimate pooled effect sizes and heterogeneity through random-effects models in a meta-analysis to compute them.
Results:
From the five quantitative studies included in the meta-analysis, Olanzapine and Risperidone were associated with the greatest risk of weight gain and dyslipidemia. Specifically, Olanzapine led to a significant increase in weight (mean difference of +4.23 kg, 95% CI: 3.24-5.23), triglycerides (+79.4 mg/dL, 95% CI: 68-92) and total cholesterol (+16.3 mg/dL, 95% CI: 10-22). In comparison, Aripiprazole was associated with little weight change (mean difference of -1.37 kg, 95% CI: -2.56 to -0.18) and beneficial metabolic effects including a decrease in total cholesterol (-1.13 mg/dL, 95% CI: -3.22 to 0.96) and triglycerides (+6.5 mg/dL, 95% CI: 2.5-10.5). Quetiapine demonstrated moderate metabolic disturbances with an increase in weight (+2.56 kg, 95% CI: 1.84-3.27) and triglycerides (+15.33 mg/dL, 95% CI: 12-19). As regards glucose metabolism, Olanzapine and Risperidone provided significant increases in fasting blood glucose (+33.8 mg/dL; 95% CI: 20.7-46.9, Risperidone: +16.6 mg/dL, 95% CI: 10.4-22.8). Olanzapine and Risperidone (Olanzapine: 37%, Risperidone: 32%) showed the highest incidence of QTc prolongation than Aripiprazole (14) and Quetiapine (15). The heterogeneity analysis demonstrated high variability in studies concerning weight gain (I2 = 45), levels of cholesterol (I2 = 60), and glucose levels (I2 = 50). Additionally, more than 20 supportive studies were reviewed to help substantiate the findings and provide context to the findings and outcomes in the quantitative studies.
Conclusion:
Olanzapine and Risperidone have a greater metabolic risk profile compared to Aripiprazole and Quetiapine. These results underscore the importance of monitoring of the metabolic and cardiovascular health of patients under SGAs. Aripiprazole, with its favorable metabolic profile may be a better option for those patients at risk of metabolic disturbances.