A clinical trial involving over 500 adults diagnosed with schizophrenia has found that by adding the drug samidorphan to the antipsychotic medicine olanzapine, it was possible to substantially reduce patients’ likelihood of significant weight gain.

Weight gain and related impacts on the body’s metabolism are a common side effect of olanzapine and other atypical or “second-generation” antipsychotic medicines, and have limited their clinical utility to varying degrees. Significant weight gain capable of making patients overweight and even obese can cause major problems beyond increasing cardiovascular and metabolic risks. By damaging self-esteem, significant weight gain can serve as a rationale for avoiding the medication altogether—even though it is the very cornerstone of schizophrenia treatment.

To further test the idea that weight gain and metabolic complications might be minimized or prevented by combining samidorphan and olanzapine, a multicenter clinical trial was led by René Kahn, M.D., Ph.D., of the Icahn School of Medicine at Mount Sinai, and Christoph U. Correll, M.D., of the Feinstein Institutes for Medical Research.

Samidorphan, under development by its maker Alkermes for use in several psychiatric disorders, is an antagonist of the body’s naturally occurring opioid receptors, particularly the mu-opioid receptor. A prior 12-week clinical trial had provided preliminary evidence of the promise of a samidorphan-plus-olanzapine combined treatment.

In the newly reported clinical trial, a single tablet combining samidorphan and olanzapine was compared with a single tablet containing only olanzapine. In all, 561 patients aged 18-55 were randomized to receive the two treatments. The dose of olanzapine was increased from 10mg/day to 20mg/day at the beginning of the second week of the 24-week trial, in order to allow patients to become acclimated to that dosage. For those receiving the combination treatment, the dosage of samidorphan was kept constant at 10mg/day throughout the trial.

Dr. Correll’s 2007 BBRF Young Investigator grant supported his early work focusing on discovering the molecular mechanisms behind the weight gains associated with atypical antipsychotics. In the paper reporting on the new trial, published in the American Journal of Psychiatry, he and colleagues hypothesize that samidorphan minimizes changes in fat mass associated with olanzapine by blocking the uptake of sugar in fatty tissue and/or by preventing insulin resistance induced by olanzapine.

The trial did not shed new light on the mechanism, but it did clearly confirm the impact of the combined treatment. It both mitigated weight gain and reduced the number of patients who had substantial increases in weight and in waist circumference (one way of measuring body fat), as assessed at the end of the trial. Weight gain did occur during the first 4 to 6 weeks of the trial, even in the “combined treatment” group, but it then stabilized in that group, the researchers reported.

The team noted that the risk of “clinically significant” weight gain—at least 10%--was reduced by 50% in the group that received the combined treatment, compared with the group that received olanzapine only.

Importantly, the combined treatment was just as effective as olanzapine alone in continuing to control patients’ psychotic symptoms. Also, patients receiving the combined treatment had about a 50% lower risk of having their waist circumference increase by 5cm (2 inches) or more.

Curiously, measurements of the body’s lipid (fat) and glucose (sugar) metabolism were not significantly impacted in this trial by the combination treatment, relative to olanzapine-only treatment. There are several possible reasons for this, but the researchers noted that there was “extensive evidence [in the scientific literature] supporting the expectation that mitigation of olanzapine-associated weight gain should ultimately lead to metabolic benefit.”

The metabolism of glucose and lipids is directly related to the body’s ability to regulate weight, so this part of the trial results will have to be further examined in current and future trials testing the combination therapy. It is possible, the researchers said, that their trial was too brief to show the ultimate impact of combined treatment on cardio-metabolic indicators.

For now, the team suggested that “by mitigating weight gain after an initial [4- to 6-week] period and reducing the number of patients who have substantial increases in weight and waist circumference, combined treatment mitigates one of the key safety risks that has limited the use of olanzapine.”

The team included John Newcomer, M.D., a 2001 BBRF Independent Investigator and 1998 Young Investigator. Several team members, including Drs. Kahn and Correll, have had consulting relationships with Alkermes, which sponsored the trial.