Olanzapine, Clozapine Show Worst Metabolic Effects Among Antipsychotics

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Symptom reduction was significantly correlated with poor metabolic adverse effects, including weight gain, elevated BMI, and higher total cholesterol.

Among common antipsychotics, olanzapine and clozapine rank as the worst for metabolic-related adverse effects in the acute treatment of patients with schizophrenia, according to study results published in Lancet Psychiatry. For patients with schizophrenia, antipsychotic medications often result in challenging adverse effects that can negatively affect their physical and mental health.

In a systematic review and network meta-analysis, researchers searched major databases for randomized studies that included adults treated with an antipsychotic for an acute episode of schizophrenia or a related disorder. After applying the search criteria, the team found 6532 citations, including a total of 100 randomized trials in the analysis. The majority of studies were short-term, with a median treatment duration of 6 weeks. Network meta-analysis was used to examine therapy-related changes in several metabolic markers, including body mass index (BMI), cholesterol, glucose levels, and body weight. Meta-regression analyses were also conducted to investigate relationships between metabolic changes and additional parameters.

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Across 25,952 patients (mean age, 35.03 years; 57.50% men; 63.56% white), the researchers compared the effects of 18 different antipsychotics. Considerable differences were observed among antipsychotics for metabolic-related adverse effects, with olanzapine and clozapine exhibiting the worst profiles overall. However, symptom reduction was significantly correlated with poor metabolic adverse effects, including weight gain (r, 0.36; P =.0021), elevated BMI, (r, 0.84; P <.0001), and higher total cholesterol (r, 0.31; P =.047).

Compared with placebo, mean differences for weight gain were lowest for haloperidol (−0.23 kg; 95% CI, −0.83 to 0.36) and highest for clozapine (3.01 kg; 95% CI, 1.78-4.24). With respect to BMI, mean differences were lowest for haloperidol (−0.25 kg/m2; 95% CI, −0.68 to 0.17) and highest for olanzapine (1.07 kg/m2; 95% CI, 0.90-1.25).

In addition, the researchers found no evidence for weight gain with haloperidol, aripiprazole, ziprasidone, fluphenazine, cariprazine, lurasidone, flupenthixol, and amisulpride compared with placebo.

Compared with white patients, the investigators found that nonwhites had significantly higher increases in total cholesterol (P =.040). They also revealed that higher baseline bodyweight and male sex “predict greater vulnerability to antipsychotic-induced metabolic dysregulation, suggesting an overlap between risk factors for metabolic disease in the general population and in people with antipsychotic-induced metabolic disease.”

One key limitation of the analysis was the inclusion of studies with a short duration of follow-up. The researchers concluded, “Aripiprazole, brexpiprazole, cariprazine, lurasidone, and ziprasidone are associated with the best metabolic outcomes and these drugs can be considered the safest options…. However, clinical decisions to use preferentially antipsychotics with fewer metabolic side-effects should consider that clinical improvement is associated with development of these side-effects.”

In a related editorial, Yoav Domany, MD, and Mark Weiser, MD, from the department of psychiatry at Tel Aviv University in Israel, commented, “Pillinger and colleagues’ study expands on previous knowledge of the harmful effects of antipsychotics by ranking the risk for each metabolic adverse effect for each antipsychotic.”2

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


1. Pillinger T, McCutcheon RA, Vano L, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7(1):64-77.

2. Domany Y, Weiser M. Insights into metabolic dysregulations associated with antipsychotics. Lancet Psychiatry. 2020;7(1):6-7.