Seltorexant vs Quetiapine: Metabolic Profiles of Participants With MDD and Insomnia Symptoms in Phase 3 Trial

According to a poster presentation at the American College of Neuropsychopharmacology 64th Annual Meeting, seltorexant showed overall less total body weight change and more favorable trends in insulin resistance in participants who have major depressive disorder (MDD), insomnia symptoms, and metabolic risk compared with quetiapine extended release (XR) in a phase 3 trial.¹

Insomnia symptoms are prevalent among around two-thirds of individuals with MDD and can even exacerbate their condition.^2,3 Clinicians often use quetiapine XR or other atypical antipsychotics as an adjunctive therapy in cases of inadequate improvement of depressive symptoms and also insomnia symptoms in patients with MDD; however, these atypical antipsychotics have tolerability issues due to metabolic/weight changes.

In a 26-week, double-blind, phase 3 randomized controlled trial, investigators compared seltorexant and quetiapine as adjunctive therapy to antidepressants in participants with MDD and insomnia symptoms who did not adequately respond to treatment. While seltorexant and quetiapine XR had similar Montogmery-Asberg Depression Rating Scale response scores, seltorexant resulted in fewer treatment-emergent adverse events and a higher completion rate than quietiapine XR.

Participants aged 18 to 74 with MDD, insomnia symptoms, and inadequate response to 1-2 antidepressants were randomly assigned 1:1 to receive oral seltorexant 20 mg or quetiapine XR for 26 weeks as an adjunct to their current antidepressant. Investigators measured total body weight, fasting insulin, fasting glucose, and HbA1C values, as well as Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) scores.

Overall, seltorexant showed more favorable trends in insulin resistance in those with metabolic risk, and offers promise as a long-term adjunctive treatment compared with antipsychotics for patients with underlying risk factors. Over 26 weeks, there was less total body weight change with seltorexant compared with quetiapine XR (P <.001); weight change with seltorexant was comparable with those observed in long-term studies of selective serotonin reuptake inhibitors.^4,5 Additionally, weight change at week 26 was generally observed in all BMI subgroups; but mean increases in total body weight were numerically lower for seltorexant than for quetiapine XR. In participants who had diabetes or were obese, HOMA-IR and insulin levels showed a trend toward improvement from baseline after seltorexant treatment, while the trend worsened with quetiapine XR treatment. Shifts in HOMA-IR and fasting insulin levels in the absence of significant changes in fasting glucose or HbA1C value show that seltorexant may be associated with a higher likelihood of improving insulin sensitivity; researchers believe this is worth further investigation.

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 16, 2026.

2. Franzen PL, Buysse DJ. Sleep disturbances and depression: risk relationships for subsequent depression and therapeutic implications. Dialogues Clin Neurosci. 2008;10(4):473-481.

3. Sunderajan P, Gaynes BN, Wisniewski SR, et al. Insomnia in patients with depression: a STAR*D report. CNS Spectr. 2010;15(6):394-404.

4. Blumenthal SR, Castro VM, Clements CC, et al. An electronic health records study of long-term weight gain following antidepressant use. JAMA Psychiatry. 2014;71(8):889-896.

5. Petimar J, Young JG, Yu H, et al. Medication-induced weight change across common antidepressant treatments: a target trial emulation study. Ann Intern Med. 2024;177(8):993-1003.