Review of: Correll CU et al, Am J Psychiatry 2020;177(12):1168–1178

To date, we have had no FDA-approved medications to mitigate antipsychotic-­associated weight gain (AIWG). This will soon change, thanks to recent research showing that samidorphan, an opioid receptor antagonist, appears to significantly lessen weight gain associated with the use of olanzapine (Editor’s note: The FDA approved the olanzapine/samidorphan combination on June 1, 2021).

In this 24-week, double-blind trial, 352 adults with schizophrenia were randomized to receive either olanzapine alone (n = 176) or a combination tablet of olanzapine and samidorphan (n = 176). Olanzapine doses were 10 or 20 mg daily, and the samidorphan dose was 10 mg daily. Alkermes, the manufacturer of the combination drug, sponsored the study. Exclusion criteria were strict and included treatment-resistant schizophrenia, substance use disorders, any clinically significant medical illness (eg, diabetes or hypertension), obesity (BMI > 30), and recent use of opioids or opioid antagonists.

At the 24-week endpoint of the study, patients on olanzapine/samidorphan gained 4.2% of their body weight, significantly less than the 6.6% gained by those taking olanzapine alone. Other key outcomes favoring olanzapine/samidorphan included the proportion of subjects who gained more than 10% of their baseline body weight (18% in the combined treatment group vs 30% in the olanzapine-only group) and the mean change in baseline waist circumference (2.4 cm in the combined treatment group vs 4.5 cm in the olanzapine-only group). Metabolic changes were minimal for both groups. Dropout rates were primarily associated with adverse events, impacting 12% of the combined treatment group and 9.8% of the olanzapine-only group.

The most common adverse events were weight gain and increased appetite (more in the olanzapine-only group), and somnolence and dry mouth (more in the combined treatment group). The addition of samidorphan did not affect antipsychotic efficacy. About one-third of patients dropped out due to side effects, loss to follow-up, or unspecified reasons.

CHPR’s Take
Adding samidorphan to olanzapine appears to decrease weight gain, but the effect in the study was only moderate. To put these results in perspective, a patient starting the trial at 150 pounds would have gained an average of 9.9 pounds on olanzapine vs 6.3 pounds on the combination. In addition, the exclusion criteria prevented many real-world patients from entering the trial. Especially in the inpatient world, it is unusual to find patients with schizophrenia who do not have either a substance use problem or a significant medical problem, so we don’t know if this study’s findings apply to our typical patients. Still, given how problematic AIWG can be for our patients, this new treatment may become a useful tool.