Seltorexant Limits Weight Gain in Obesity, MDD, With Celine Goldberger, MD, PhD

Subgroup analyses from a 26-week, double-blind, head-to-head study suggest that the metabolic benefits associated with adjunctive seltorexant for major depressive disorder (MDD) may be particularly pronounced in patients with obesity.1,2

Celine Goldberger, MD, PhD, vice president of global medical affairs at Johnson & Johnson, discussed the findings with HCPLive following the study’s presentation at the American College of Neuropsychopharmacology (ACNP) annual meeting from January 12 – 15, 2026, in the Bahamas.

“We see that there is less weight gain with seltorexant than quetiapine, and when you look at the obese population—the patients were obese at baseline—there was actually no change on average with seltorexant, [compared with an] increase in weight with quetiapine [of] about 1.9 kilograms,” Goldberger told HCPLive.

The trial compared adjunctive seltorexant, an investigational orexin-2 receptor antagonist, with adjunctive quetiapine XR in adults with major depressive disorder (MDD) and clinically significant insomnia symptoms. While the primary endpoint assessed antidepressant response, showing numerically greater response rates and fewer discontinuations due to adverse events with seltorexant, the ACNP poster focused on longer-term metabolic outcomes, including body weight and insulin resistance.

In the interview, Goldberger emphasized that insomnia is highly prevalent in MDD, affecting roughly two-thirds of patients, and that a substantial proportion continue to experience residual insomnia despite treatment with SSRIs or SNRIs. Depression with comorbid insomnia is also associated with greater rates of obesity, diabetes, and other cardiovascular risk factors, underscoring the importance of considering metabolic effects when selecting adjunctive therapies.

Goldberger noted that weight gain remains a common reason for discontinuation of psychiatric medications, especially antipsychotics used adjunctively for their sedative properties. In this context, she suggested that having an adjunctive option with a more favorable tolerability profile could support longer-term treatment continuity and help patients remain engaged in care as they work toward remission. She said the next step is assessing seltorexant in real-world settings, as well as assessing its safety profile in further studies.

“[Seltorexant] will really help patients in their quest to achieve remission of their depressive episodes,” Goldberger said. “It’s really having an additional option in the moratorium…to be able to really offer a great efficacy…with a very nice probability profile and some benefits compared to what's available.”

Goldberger has no relevant reported disclosures.

References

1. Wajs E, Trombello JM, Kelly R, et al. Metabolic profiles of participants with major depressive disorder with insomnia symptoms in a phase 3 trial of seltorexant versus quetiapine extended release as adjunctive therapy. Poster presented at American College of Neuropsychopharmacology 64th Annual Meeting 64th annual meeting; January 12-15; Bahamas. Accessed January 19, 2026.

2. Goldberger C. Seltorexant Shows Favorable Metabolic Profile, With Celine Goldberger, MD, PhD. HCPLive. Accessed on January 19, 2026. Published on January 19, 2026. https://www.hcplive.com/view/seltorexant-shows-favorable-metabolic-profile-celine-goldberger-md-phd