Olanzapine Plus Samidorphan for Schizophrenia Associated With Less Weight Gain

woman on sclae weighing herself
woman on sclae weighing herself
In a phase 3, double-blind trial, the effect of combined olanzapine and samidorphan treatment compared with treatment with olanzapine alone on the weight profile of patients with schizophrenia was evaluated.

Olanzapine, which is used to treat schizophrenia and bipolar I disorder, has proven long-term effectiveness. However, it is also associated with weight gain. Combining olanzapine with samidorphan, an opioid receptor antagonist, may mitigate some of that weight gain, according to the results of research reported in The American Journal of Psychiatry.

In a phase 3, multicenter, randomized, double-blind study conducted in the United States (The ENLIGHTEN-2 Study; ClinicalTrials.gov Identifier: NCT02694328), participants (n=561) with a primary diagnosis of schizophrenia were assigned to receive treatment with either olanzapine plus samidorphan or olanzapine alone for 24 weeks. Participants who completed the study were eligible to enroll in a long-term, open-label safety study evaluating the combination treatment for 52 weeks. Those who declined or dropped out of the study underwent a 4-week follow-up period.

Combination treatment was administered as 10 mg olanzapine/10 mg samidorphan the first week and increased to 20 mg olanzapine/10 mg samidorphan the second week. Assessments took place weekly for the first 6 weeks and biweekly for the subsequent 18 weeks. The researchers measured body weight, waist circumference, and vital signs; performed electrocardiography; and assessed adverse events and extrapyramidal symptoms.

Co–primary endpoints were percent change in body weight from baseline at week 24 and the proportion of patients with ≥10% weight gain from baseline at week 24. The main secondary endpoint was the amount of patients with ≥7% weight gain at week 24.

A total of 352 patients completed the study. The mean change in body weight was 4.21% for the olanzapine-plus-samidorphan group and 6.59% for the group receiving olanzapine alone. Weight stabilized in the olanzapine-plus-samidorphan group at week 6 and later but continued to climb for the olanzapine group.

Adverse events were reported in 74.1% and 82.2% of the patients in the olanzapine-plus-samidorphan and olanzapine-alone groups, respectively. The most common adverse events included weight gain, somnolence, dry mouth, and increased appetite and were reported as being mild to moderate in severity. The only serious adverse advent reported was worsening schizophrenia symptoms in 1 patient in the combined group and in 3 patients in the olanzapine-alone group.

Reported study limitations include almost 40% of patients discontinuing the study early, leading to a relatively high volume of missing data. However, this discontinuation rate is consistent with those reported in other 6-month studies of antipsychotics in patients with schizophrenia. Additionally, fasting status was based solely on self-reporting, without independent confirmation. Exclusion of patients aged ≥55 years represents another limitation of the study.

Although no single treatment works for every patient, “combined olanzapine/samidorphan provides a potential new treatment option that possesses the antipsychotic efficacy of olanzapine with significantly less weight gain,” the authors concluded. “[B]y mitigating weight gain after th[e] initial period and reducing the number of patients who have substantial increases in weight and waist circumference, combined olanzapine/samidorphan mitigates one of the key safety risks of olanzapine that has limited its clinical use.”

Disclosure: This study was sponsored by Alkermes. Several study authors declared affiliations with Alkermes, as well as with other pharmaceutical companies. Please see the original reference for a full list of authors’ disclosures.


Correll CU, Newcomer JW, Silverman B, et al. Effects of olanzapine combined with samidorphan on weight gain in schizophrenia: a 24-week phase 3 study. Am J Psychiatry. Published August 14, 2020. doi:10.1176/appi.ajp.2020.19121279

This article originally appeared on Psychiatry Advisor