Celine Goldberger, MD, PhD

Seltorexant Shows Favorable Metabolic Profile, With Celine Goldberger, MD, PhD

Adjunctive seltorexant was associated with less weight gain and more favorable trends in insulin sensitivity than adjunctive quetiapine XR in adults with 

symptoms, according to new metabolic analyses from a 26-week, double-blind, head-to-head study presented at the American College of Neuropsychopharmacology (ACNP) annual meeting from January 12 – 15 at the Bahamas.

The study compared adjunctive seltorexant, an investigational orexin-2 receptor antagonist, with adjunctive quetiapine XR in patients with MDD and clinically significant insomnia symptoms. While earlier results from the trial demonstrated numerically greater response rates and fewer discontinuations due to adverse events with seltorexant, the current analysis focused on metabolic outcomes, an area of particular importance given the high prevalence of cardiometabolic risk in this population.

The study found that body weight changes over 26 weeks were more limited with seltorexant than with quetiapine XR. The mean weight gain was approximately 0.5 kg with seltorexant compared with 2.1 kg with quetiapine XR, representing a 1.6 kg or 3.5 lb difference in 6 months.

“It's very meaningful to patients and can make a difference between patients continuing the drug and discontinuing the drug,” Celine Goldberger, MD, PhD, vice president of global medical affairs at Johnson & Johnson, told 

Metabolic differences extended beyond weight. In participants with baseline metabolic risk, defined by obesity, diabetes, or a homeostatic model assessment of insulin resistance (HOMA-IR) score ≥ 2.9, investigators observed improvement in HOMA-IR and fasting insulin levels with seltorexant. In contrast, quetiapine XR was associated with trends toward worsening. These shifts occurred in the absence of meaningful changes in fasting glucose or hemoglobin A1c, suggesting a potential effect on insulin sensitivity rather than glycemic control.

Furthermore, a greater proportion of patients with baseline insulin resistance transitioned to insulin sensitivity with seltorexant than with quetiapine XR over the 26 weeks. While Goldberger emphasized that these findings are exploratory and warrant further investigation, she noted that insulin resistance is a recognized marker of cardiovascular risk and may be particularly relevant when selecting long-term adjunctive therapies.

“That is [a] very relevant finding that obviously needs to be confirmed, but [a] very interesting thing,” she said.

Goldberger has no relevant reported disclosures.

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.

Videos

In a 26-week head-to-head study, adjunctive seltorexant led to less weight gain and improved insulin sensitivity trends compared with quetiapine XR in MDD with insomnia.


Celine Goldberger, MD, PhD

Articles