Lybalvi is a new combo pill that aims to overcome the dreaded metabolic effects of olanzapine by pairing it with the opioid antagonist samidorphan. Patients still gain weight on Lybalvi, though not as much as they do on olanzapine. In the three controlled trials that compared the two drugs, the weight gain on Lybalvi was 5 lb less at six months, 3 lb less at three months, and no different at one month (Srisurapanont M et al, Sci Rep 2021;11(1):7583).

Where the drug falls short is in comparison to metformin, which reduced weight gain on various antipsychotics by 7 lb compared with placebo in a meta-analysis of 10 trials, most of which lasted three months, at a dose range of 750–2000 mg/day (Mizuno Y et al, Schizophr Bull 2014;40(6):1385–1403). Moreover, metformin improved insulin sensitivity, hemoglobin A1C, dyslipidemia, and prolactinemia on antipsychotics, while Lybalvi improved none of these.

Lybalvi could also be compared with naltrexone, an opioid antagonist with a similar pharmacodynamic profile to samidorphan. Naltrexone has weaker evidence when it comes to reducing weight gain on antipsychotics, showing effectiveness in only one of two trials. However, the naltrexone trials enrolled patients with actual obesity (BMI > 30 kg/m2), while patients in the Lybalvi trials were barely overweight (BMI 18–30, mean 25). This may have made a difference, as Lybalvi tended to work better in patients with lower BMI.

Lybalvi is approved in schizophrenia and bipolar I disorder, although the studies were limited to schizophrenia. The drug does not seem to exacerbate psychosis or add to the side effect burden of olanzapine. The manufacturer also sought approval for schizophrenia with alcohol use disorder, but a negative phase II trial halted that pursuit. To prevent opioid withdrawal, Lybalvi should not be started within seven days of taking a short-acting opioid or 14 days of a long-acting one. Most insurers require documentation of significant weight gain on olanzapine or failure of two generic atypical antipsychotics to cover Lybalvi, which retails for $1300 per month.

TCPR’S TAKE
Metformin is preferred over Lybalvi for weight gain on antipsychotics, as it brings about more meaningful metabolic benefits beyond the reduction in BMI.