Mitigation of Olanzapine-Induced Weight Gain: Not the Sami Old Thing

May 3, 2019

Promising results from a phase 2 trial of olanzapine plus samidorphan in patients with schizophrenia.

Dr Miller is Associate Professor of Psychiatry, Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is the Schizophrenia Section Editor for Psychiatric Times.


Olanzapine is one of the most effective antipsychotics, with a lower discontinuation rate due to inefficacy compared with other agents. However, the adverse metabolic effects of olanzapine have limited its clinical utility.1

Evidence from preclinical studies indicates that the opioid system plays a role in feeding and metabolism. Samidorphan is a mu-opioid receptor antagonist that has been shown to mitigate weight gain associated with olanzapine in healthy volunteers.2

The study

Martin and colleagues3 performed a proof-of-concept, phase 2, placebo-controlled trial of the efficacy, safety, and tolerability of olanzapine plus samidorphan in patients with schizophrenia. Inclusion criteria for the study were age 18 to 50, DSM-IV-TR diagnosis of schizophrenia, clinical stability, stable body weight for at least 3 months (<5% change), and a body mass index (BMI) of 17 to 30.

Patients with current or anticipated use of medications for weight reduction or systemic corticosteroids were excluded. Subjects were also excluded if they had an illness duration of less than 2 years or had their first antipsychotic treatment within the previous 12 months.

The study consisted of a 1-month screening phase, after which patients were switched from their current treatment to 1 week of open-label olanzapine. Thereafter, they entered a 12-week double-blind treatment phase of 5 to 20 mg/d of open-label olanzapine plus samidorphan (5, 10, or 20 mg/d) or placebo (1:1:1:1 randomization), followed by a 12-week extension phase and a 4-week safety follow-up. Randomization was stratified by weight change during the 1-week olanzapine lead-in (no change, weight gain <1 kg, and weight gain >1 kg).

All subjects who were randomized and received at least one dose of study drug and had one post-baseline assessment were analyzed. The change from baseline to week 12 in Positive and Negative Syndrome Scale (PANSS) scores and percent change in body weight were analyzed using mixed models for repeated measures. The proportion of patients with significant weight gain (>7% and >10% change from baseline) was analyzed with the Cochran-Mantel-Haenszel method.

Three hundred forty-seven patients received at least one dose of olanzapine, and 309 (89%) completed the 1-week olanzapine lead-in. Subjects were randomized to olanzapine plus placebo (n=75), or samidorphan 5 mg/d (n=80), 10 mg/d (n=86), or 20 mg/d (n=68).

Of these subjects, 300 had at least one post-baseline PANSS assessment. One hundred ninety-five (65%) of the 300 patients had early weight gain during the 1-week olanzapine lead-in, and 221 completed the treatment phase, with similar rates of discontinuation in the placebo and samidorphin groups. Of those subjects, 187 (86%) completed the extension phase.

The mean age of subjects was approximately 39, the mean baseline BMI was 25, and over 70% of subjects were male. The average olanzapine dose was 11 to 12 mg across the four subject groups.

The results

In the treatment phase, there were no differences in the change in PANSS scores between the olanzapine plus samidorphan versus placebo groups (least square mean change of 2-3 points). The mean change in body weight at week 12 was 37% lower in the olanzapine plus samidorphan group (absolute change, 1.9 kg) compared with the placebo group (absolute change, 2.9 kg).

Patients in the olanzapine plus placebo group were 2.7 times more likely to gain more than 10% of baseline body weight compared with the olanzapine plus samidorphan group. Common adverse events in the olanzapine plus samidorphan group that were at least two times more common than in the placebo group were somnolence, sedation, dizziness, and constipation. A similar pattern of results, with larger treatment effects, was seen in patients with early weight gain during the olanzapine lead-in phase.

The authors concluded that olanzapine plus samidorphan resulted in antipsychotic efficacy equivalent to olanzapine plus placebo, but with mitigation of olanzapine-induced weight gain. They found that the weight-mitigating effects of the samidorphan 10 mg/d dosage were superior to the 5 mg/d dosage and similar to the 20 mg/d dosage, but with fewer adverse effects. One limitation of the study is that some of the benefits of samidorphan on weight were masked because of early weight gain during the olanzapine lead-in phase.

The bottom line

The antipsychotic efficacy of olanzapine plus samidorphan was comparable to that of olanzapine plus placebo, but with clinically meaningful and statistically significant mitigation of weight gain. Phase 3 trials of this combination are warranted.


The author reports that he receives research support from Augusta University, the National Institute of Mental Health, the Brain and Behavior Research Foundation, and the Stanley Medical Research Institute.


1. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353:1209-1223.

2. Silverman BL, Martin W, Memisoglu A, et al. A randomized, double-blind, placebo-controlled proof of concept study to evaluate samidorphan in the prevention of olanzapine-induced weight gain in healthy volunteers. Schizophr Res. 2018;195:245-251.

3. Martin WF, Correll CU, Weiden PJ. 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 Mar 8. doi: 10.1176/appi.ajp.2018.18030280. [Epub ahead of print]