Literature Reviewed

Effects of Olanzapine Combined With Samidorphan on Weight Gain in Schizophrenia: A 24-Week Phase 3 Study by Correll CU, Newcomer JW, Silverman B, et al. Am J Psychiatry. 2020;177(12):1168-1178.

Original Abstract

Objective: A combination of olanzapine and the opioid receptor antagonist samidorphan is under development for the treatment of schizophrenia and bipolar I disorder. The single tablet combination treatment is intended to provide the efficacy of olanzapine while mitigating olanzapine-associated weight gain. In this phase 3 double-blind trial, the authors evaluated the weight profile of combined olanzapine/samidorphan compared with olanzapine in patients with schizophrenia.

Methods: Adults (ages 18‒55 years) with schizophrenia were randomly assigned to receive either combination treatment with olanzapine and samidorphan or olanzapine treatment for 24 weeks. Primary endpoints were percent change from baseline in body weight and proportion of patients with ≥10% weight gain at week 24. The key secondary endpoint was the proportion of patients with ≥7% weight gain. Waist circumference and fasting metabolic laboratory parameters were also measured.

Results: Of 561 patients who underwent randomization (olanzapine/samidorphan combination, N=280; olanzapine, N=281), 538 had at least one postbaseline weight assessment. At week 24, the least squares mean percent weight change from baseline was 4.21% (SE=0.68) in the olanzapine/samidorphan group and 6.59% (SE=0.67) in the olanzapine group (the difference of 22.38% [SE=0.76] was significant). Significantly fewer patients in the olanzapine/samidorphan combination group compared with the olanzapine group had weight gain ≥10% (17.8% and 29.8%, respectively; number needed to treat [NNT]=7.29; odds ratio=0.50) and weight gain ≥7% (27.5% and 42.7%, respectively; NNT=6.29; odds ratio=0.50). Increases in waist circumference were smaller in the olanzapine/samidorphan combination group compared with the olanzapine group. Schizophrenia symptom improvement was similar between treatment groups. Adverse events (in ≥10% of the groups) in the olanzapine/samidorphan and olanzapine groups included weight gain (24.8% and 36.2%), somnolence (21.2% and 18.1%), dry mouth (12.8% and 8.0%), and increased appetite (10.9% and 12.3%). Metabolic changes were small and similar between treatments.

Conclusions: Olanzapine/samidorphan combination treatment was associated with significantly less weight gain and smaller increases in waist circumference than olanzapine and was well tolerated. The antipsychotic efficacy of the combination treatment was similar to that of olanzapine monotherapy.

Read the full paper.

Olanzapine and Samidorphan: Commentary and Clinical Takeaways

This 24-week, phase 3 multicenter, randomized, double-blind study, known as the ENLIGHTEN-2 trial, evaluated the weight profile of combined olanzapine and samidorphan compared with olanzapine in patients with schizophrenia.5 Patients were assigned in a 1:1 ratio to receive olanzapine and samidorphan or olanzapine monotherapy. Assessments were done weekly for the first 6 weeks then biweekly for the remaining 18 weeks of the study to assess metabolic side effects. Primary endpoints included percentage change from baseline at week 24 in body weight and the proportion of patients with over 10% weight gain from baseline at week 24.5

Of the 352 patients that completed the entire study, the average weight change at 24 weeks was 4.21% in the olanzapine and samidorphan group and 6.59% in the olanzapine monotherapy group. Weight gain over 10% from baseline occurred in 17.8% of olanzapine and samidorphan patients and 29.8% in olanzapine monotherapy. After 24 weeks, 26.8% of olanzapine and samidorphan and 43.2% olanzapine monotherapy patients had a waist circumference increase of ≥ 5 cm from baseline. The authors of the ENLIGHTEN-2 study concluded that olanzapine and samidorphan was associated with less weight gain and waist circumference increases without sacrificing antipsychotic efficacy (comparable scores on both the Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impressions severity (CGI-S) scale between groups).5

The strengths of this study noted by the authors included the extended study period from the previous study of 12 weeks, the addition of a medication approved by the FDA to address antipsychotic weight gain without sacrificing antipsychotic efficacy, and the use of patients with a baseline PANSS score of 68.2. They also encouraged participants to continue current lifestyle without changes to “more accurately focus on weight differences due to treatment.”5 Limitations noted by the authors include almost 40% of patients discontinuing therapy before the end of the study (consistent with the discontinuation rate of other antipsychotic) and a fairly restrictive BMI criteria range of 18-30 which may have selected patients that were resistant to antipsychotic-associated weight gain and/or metabolic dysregulation.5

Factors for Prescribing Olanzapine and Samidorphan

While not covered explicitly in the Correll paper, it is important to consider patient-specific factors when prescribing this medication. For example, if a patient is requiring pain medications, the provider would need to consider the mu opioid receptor antagonist, samidorphan, when choosing medications for adequate pain control. With that being said, this study shows the impact of the newly approved olanzapine and samidorphan combination medication and its use in schizophrenia. While the data is limited as this is a newly approved medication, this drug could be a great option for patients who require olanzapine therapy and have an elevated BMI to mitigate weight gain and increased weight circumference without sacrificing antipsychotic efficacy. Along with limited data available on efficacy and safety, cost is also a consideration as this is a newly FDA-approved medication. There are other mitigation strategies (as mentioned in our review of the Carli et al study that could be utilized if cost is a concern.

Prior Paper in the Literature Review: Antipsychotic Polypharmacy. Focus (Am Psychiatr Publ) by Foster A, King J. 2020.

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Last Updated: Sep 1, 2021