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Drug Combination Eases Weight Gain in Schizophrenia

March 18, 2019

Adding the experimental agent samidorphan to the antipsychotic drug olanzapine was associated with clinically meaningful and statistically significant mitigation of weight gain in patients with schizophrenia, compared with adding placebo, according to a study published online in The American Journal of Psychiatry.

“Preclinical evidence and data from a proof-of-concept study in healthy volunteers suggest that samidorphan, an opioid antagonist, mitigates weight gain associated with olanzapine,” researchers explained. “This study prospectively compared combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia.”

The international, multicenter, phase 2 trial included 309 patients with schizophrenia. After a 1-week open-label olanzapine lead-in period, participants were randomized to 12 weeks of double-blind treatment consisting of one of the following regimens: olanzapine plus placebo, olanzapine plus 5 mg of samidorphan, olanzapine plus 10 mg of samidorphan, or olanzapine plus 20 mg of samidorphan.

Olanzapine plus samidorphan resulted in 37% lower weight gain compared with olanzapine plus placebo, the study found, while offering equivalent antipsychotic efficacy.

Combining Antidepressant, Antipsychotic Drugs May Offer Benefit in Schizophrenia

Weight gain with antipsychotics such as olanzapine is common during the early weeks of treatment, researchers explained, according to Psychiatric News coverage of the trial. Although weight gain occurred in each participant group in this study, it was mitigated with samidorphan.

“The least square mean percent change from baseline in body weight was 4.1% (2.9 kg) for the olanzapine plus placebo group and 2.6% (1.9 kg) for the olanzapine plus samidorphan group (2.8% [2.1 kg] for the 5 mg group, 2.1% [1.5 kg] for the 10 mg group, and 2.9% [2.2 kg] for the 20 mg group),” researchers reported.

Adverse events with olanzapine plus samidorphan included somnolence, sedation, dizziness, and constipation.

“The findings from this study identified 10 mg of samidorphan as the daily dose to further assess the mitigation of olanzapine-induced weight gain,” Psychiatric News quoted from the study, “and they support the continued development of olanzapine plus samidorphan in a phase 3 program.”

—Jolynn Tumolo


Martin WF, Correll CU, Weiden PJ, et al. Mitigation of olanzapine-induced weight gain with samidorphan, an opioid antagonist: a randomized double-blind phase 2 study in patients with schizophrenia. The American Journal of Psychiatry. 2019 March 8;[Epub ahead of print].

Drug combination mitigates weight gain in patients with schizophrenia, study shows. Psychiatric News. March 12, 2019.

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