Exploring Olanzapine Plus Samidorphan and Weight Gain in Schizophrenia


Data from a randomized phase III trial shows promise for new treatment strategy.



Antipsychotics, including olanzapine, are associated with weight gain and cardiometabolic adverse effects in some patients with schizophrenia.1 Antipsychotic-induced weight gain is associated with decreased medication adherence and subsequent adverse outcomes2, and with decreased quality of life.

There is evidence that opioid receptor antagonists may mitigate antipsychotic-associated weight gain and/or cardiometabolic dysfunction. Samidorphan functions in vivo as an opioid receptor antagonist.4 A combination of olanzapine and samidorphan as a single tablet is under development for schizophrenia (and bipolar I disorder), with evidence of antipsychotic efficacy.5 A 12-week phase II trial in schizophrenia found that olanzapine/samidorphan was associated with a 37% reduction in weight gain compared with olanzapine.6

Correll and colleagues7 performed a 24-week phase III study of the weight profile of olanzapine/samidorphan in adults with schizophrenia. The study included outpatients with schizophrenia aged 18 to 55 years with a baseline body mass index (BMI) of 18 to 30, and stable body weight (self-reported change 5% or less) for at least 3 months. Participants were excluded from the study if they had a history of treatment-resistant schizophrenia; were antipsychotic-naïve or it had been less than 1 year since symptom onset; had active alcohol or non-marijuana substance use disorders; or if there was clinically significant or unstable medical illness. Similarly, olanzapine use within 60 days, opioid agonist use within 14 days, and opioid antagonist use within 60 days of screening, or anticipated need for opioid treatment during the study were all exclusionary.

Participants were randomized 1:1 to receive treatment with olanzapine/samidorphan (10 mg) or variable dose olanzapine for 24 weeks. Those who completed the study were eligible to enroll in a 52-week open-label safety study. The olanzapine dose in both groups was 10 mg in week 1, increased to 20 mg in week 2, and could be lowered back to 10 mg by the end of week 4 for tolerability reasons. No dose adjustments were allowed after week 4. Co-treatment with beta-blockers, antihistamine, benzodiazepines, and anticholinergics were allowed. Patients were assessed weekly for 6 weeks, and then biweekly thereafter. Co-primary study endpoints were the percent change from baseline at week 24 in body weight and the proportion of patients with 10% or more weight gain from baseline at week 24. The secondary study endpoint was the proportion of patients with 7% or more weight gain from baseline at week 24. The percent change from baseline in body weight at week 24 was analyzed by analysis of covariance. Missing weight assessments were imputed by multiple imputation sequentially for each visit using a regression method. The 10% or more and 7% or more weight gain from baseline at week 24 endpoint were analyzed using logistic regression models.

The study included 550 patients who entered double-blind treatment (n = 274 olanzapine/samidorphan and n = 276 olanzapine). Mean participant age was 40, 73% were male, and 71% were black. The mean baseline body weight was 77.4 kg and mean baseline BMI was 25.4. Of the 550, 352 (64%) patients completed treatment, with similar rates in both groups. The mean olanzapine dose was 17 mg in both groups, with 80% of patients taking the 20 mg/day dose (See Table).

The least squares mean percent change in body weight at week 24 was 4.2% (3.2 kg) in the olanzapine/samidorphan group and 6.6% (5.1 kg) in the olanzapine group. Weight gain in the olanzapine/samidorphan group stabilized from week 6 onward, whereas it continued to increase in the olanzapine group over 24 weeks.

The proportion of patients with 10% or more weight gain from baseline at week 24 was 18% in the olanzapine/samidorphan group and 30% in the olanzapine group (number needed to treat = 7.3). Similarly, the proportion of patients with 7% or more weight gain from baseline at week 24 was 28% in the olanzapine/samidorphan group and 43% in the olanzapine group.

The most common adverse events (10% or more) in both groups were weight gain, somnolence, dry mouth, and increased appetite. Rates of discontinuation due to adverse events were 12% in the olanzapine/samidorphan group and 10% in the olanzapine group. No deaths occurred during the study. The only serious adverse event occurring in more than one patient was worsening of schizophrenia symptoms in 3 patients in the olanzapine group.

The changes from baseline to week 24 in glycemic and lipid laboratory parameters were generally small and similar for each group. There were no clinically meaningful differences or changes in vital signs, EKG results, movement disorder scale scores, or suicide scale scores between groups. The least squares mean change from baseline to week 24 in the Positive and Negative Syndrome Scale (PANSS) total score was -8.2 in the olanzapine/samidorphan group and -9.4 in the olanzapine group.

The authors concluded that treatment with olanzapine/samidorphan was associated with significantly less weight gain compared with olanzapine monotherapy, in the absence of differences in metabolic laboratory parameters. These differences were apparent by week 6 and were sustained through week 24.

The risk of clinically significant weight gain (defined as 7% or more and 10% or more) with olanzapine/samidorphan was reduced by 50% relative to olanzapine. Olanzapine/samidorphan was generally well tolerated, and results in similar symptom improvement as olanzapine monotherapy.

The authors noted that there are currently no approved treatments to address antipsychotic-associated weight gain. Limitations of the present study include the large discontinuation rate (almost 40%) and the restrictive BMI criterion at study, which may have selected patients who were relatively more resistant to antipsychotic-associated weight gain and metabolic dysfunction.

The bottom line

Olanzapine/samidorphan combination treatment mitigates olanzapine-associated weight gain while maintaining antipsychotic efficacy. This could lead to better adherence and outcomes for patients.


1. Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple treatments meta-analysis. Lancet. 2013;382:951962.

2. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 2: update 2012 on the long-term treatment of schizophrenia and management of antipsychotic-induced side effects. World J Biol Psychiatry. 2013;14:244.

3. Malhotra N, Kulhara P, Chakrabarti S, et al. Lifestyle related factors and impact of metabolic syndrome on quality of life, level of functioning, and self-esteem in patients with bipolar disorder and schizophrenia. Indian J Med Res. 2016;143:434442.

4. Shram MJ, Silverman B, Ehrich E, et al. Use of remifentanil in a novel clinical paradigm to characterize onset and duration of opioid blockade by samidorphan, a potent mu-receptor antagonist. J Clin Psychopharmacol. 2015;35:242249.

5. Potkin SG, Kunovac J, Silverman BL, et al. Efficacy and safety of a combination of olanzapine and samidorphan in adult patients with an acute exacerbation of schizophrenia: outcomes from the randomized, phase 3 ENLIGHTEN-1 study. J Clin Psychiatry. 2020;81:19m12769.

6. 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. Am J Psychiatry. 2019;176:457467.

7. 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. 2020;appiajp202019121279.

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