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Olanzapine plus samidorphan reduces weight gain in schizophrenia

Treatment with olanzapine plus samidorphan, an opioid antagonist, resulted in 37% lower weight gain than treatment with olanzapine plus placebo in patients with schizophrenia, according to data from a phase 2 study.

In previous preclinical and phase 1 clinical studies, samidorphan has been shown to mitigate weight gain associated with olanzapine use, William F. Martin, PhD, of Alkermes, Inc., and colleagues wrote in American Journal of Psychiatry.

“Preclinical studies have provided evidence for a critical role of the opioid system in mediating food reward, feeding behavior, and metabolism. Thus, adding an opioid antagonist to CNS-active drugs may mitigate metabolic dysregulation,” they wrote. “The combination drug formulation of olanzapine plus samidorphan is intended to provide the antipsychotic efficacy of olanzapine while mitigating the weight gain and concomitant metabolic abnormalities commonly associated with olanzapine alone.”

Researchers conducted a randomized phase 2 study to compare combination therapy of olanzapine plus either samidorphan or placebo for the treatment of schizophrenia in terms of antipsychotic efficacy, olanzapine-induced weight gain and overall safety and tolerability.

After a 1-week olanzapine lead-in phase, adults with schizophrenia were randomly assigned to receive either olanzapine plus samidorphan at 5 mg per day (n = 80), 10 mg per day (n = 86) or 20 mg per day (n = 68), or olanzapine plus placebo (n = 75) for 12 weeks, followed by a 12-week extension phase in which all patients received olanzapine plus samidorphan, and a 4-week safety follow-up.

Martin and colleagues found that the antipsychotic efficacy of olanzapine plus samidorphan was equivalent to that of olanzapine plus placebo as measured via Positive and Negative Syndrome Scale (PANSS) total score. At week 12, the least square mean difference between the groups was 0.6 points (95% CI, –1.2 to 2.5), and the mean PANSS score remained stable from week 12 to 24.

However, patients who received olanzapine plus samidorphan experienced a 37% lower weight gain compared with olanzapine plus placebo (least square mean difference = –1.5%; 95% CI, –2.5 to –0.4). From baseline to week 12, the least square mean percent change in body weight by individual dosage groups was:

• 4.1% (2.9 kg) for the olanzapine plus placebo group;
• 2.8% (2.1 kg) for the olanzapine plus samidorphan 5-mg group;
• 2.1% (1.5 kg) for the olanzapine plus samidorphan 10-mg group; and
• 2.9% (2.2 kg) for the olanzapine plus samidorphan 20-mg group.

In addition, patients in the olanzapine plus placebo group were 2.7 times as likely to gain 10% or more of their baseline body weight than those in the olanzapine plus samidorphan group (OR = 2.73; 95% CI, 1.11-6.67), according to the results.

“The combination of olanzapine and samidorphan assessed in this study represents a new mechanistic approach toward addressing olanzapine-induced weight gain, whereby treatment is initiated before significant weight gain and metabolic dysfunction have occurred,” Martin and colleagues wrote.

Treatment with the combination of olanzapine and samidorphan was generally well-tolerated, the researchers found. Common events — somnolence, sedation, dizziness and constipation — occurred in the olanzapine plus samidorphan groups at a rate at least two times greater than in the olanzapine plus placebo group; however, other safety measures were comparable between the groups.

“The findings from this study identified 10 mg of samidorphan as the daily dose to further assess the mitigation of olanzapine-induced weight gain, and they support the continued development of olanzapine plus samidorphan in a phase 3 program,” Martin and colleagues concluded. – by Savannah Demko

Disclosure: Martin is an employee of Alkermes. Please see the study for all other authors’ relevant financial disclosures.