Samidorphan Mitigates Metabolic Syndrome Risk Associated With Olanzapine

Combination olanzapine-samidorphan reduced the risk for developing obesity, hypertension, and metabolic syndrome.

Olanzapine (OLZ) is associated with increased risk for worsening cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome compared with OLZ plus the opioid receptor antagonist samidorphan (SAM) among individuals with schizophrenia. These study findings were published in Schizophrenia Bulletin.

Researchers conducted a phase 3, double-blind trial in which patients (N=538) with schizophrenia were randomly assigned in a 1:1 ratio to receive either 10 mg daily OLZ (n=276) or 10 mg daily OLZ with 10 mg SAM (n=274) for 24 weeks. All treatments were increased to 20 mg at week 2. Between weeks 2 and 4, doses could be lowered due to tolerability reasons. Normal blood pressure (BP) was defined as lower than 120/<80 mm Hg, stage 1 hypertension as 130/80 mm Hg to 139/89 mm Hg, and stage 2 hypertension as 140/90 mm Hg or higher. Metabolic syndrome was defined as the presence of at least 3 relevant features.

The OLZ and OLZ/SAM cohorts included patients with mean ages 40.1 (SD, 10.05) and 40.3 (SD, 9.82) years, 74.6% and 70.7% were men, 69.9% and 72.6% were Black, 99.3% and 100.0% had a body mass index (BMI)  greater than 30 kg/m2. Mean blood pressure was 121.8/77.3 mm Hg and 121.4/77.2 mm Hg, and 8.5% and 12.5% had metabolic syndrome at baseline, respectively.

Smaller increases in BMI during the treatment period were observed among the OLZ/SAM recipients compared with OLZ (least-squares mean difference [LSMD], -0.65; 95% CI, -1.01 to -0.28 kg/m2), which indicated a lower risk for obesity at week 24 for OLZ/SAM (odds ratio [OR], 0.52; 95% CI, 0.32-0.82).

The OLZ monotherapy recipients had significantly higher supine systolic BP at 24 weeks compared with baseline (LSMD, 2.32; 95% CI, 0.79-3.85 mm Hg), but OLZ/SAM dual therapy recipients did not (LSMD, -0.31; 95% CI, -1.84 to 1.23 mm Hg). Regarding diastolic BP, OLZ was not associated with significantly higher levels at follow-up (LSMD, 0.68; 95% CI, -0.43 to 1.79 mmHg), but OLZ/SAM was (LSMD, 1.43; 95% CI, 0.33-2.52 mm Hg). Among the subset of patients who had normal BP at baseline, risk for developing hypertension was lower for the OLZ/SAM cohort compared with OLZ (OR, 0.48; 95% CI, 0.24-0.96).

Of the patients without metabolic syndrome at baseline, 9.2% of OLZ/SAM recipients and 16.9% of OLZ recipients developed metabolic syndrome, corresponding to a significantly reduced risk for developing metabolic syndrome at week 24 for OLZ/SAM (OR, 0.55; 95% CI, 0.31-0.99).

The metabolic risk factors of weight gain of at least 10% (absolute risk differences [ARD], -13.7%), BMI of 30 kg/m2 or higher (ARD, 10.6%), waist circumference increase of at least 5 cm (ARD, -17.1%), and progression to stage 1 or 2 hypertension (ARD, -14.8%) were all lower among the OLZ/SAM group compared with OLZ.

Limitations of the study include the fact that nearly 40% of patients discontinued treatment early, and dropout was greater in the dual therapy group.

Study authors conclude, “These post hoc analyses build on earlier findings from ENLIGHTEN-2, where OLZ/SAM mitigated olanzapine-associated weight gain. Patients with schizophrenia were less likely to experience worsening of certain cardiometabolic risk factors related to obesity, hypertension, and metabolic syndrome when treated with OLZ/SAM compared with olanzapine.”

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Correll CU, Stein E, Grahm C, et al. Reduction in multiple cardiometabolic risk factors with combined olanzapine/samidorphan compared with olanzapine: post hoc analyses from a 24-week phase 3 study. Schizophr Bull. Published online October 28, 2022. doi:10.1093/schbul/sbac144