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

Approved adjunctive treatments of major depressive disorder (MDD), like quetiapine XR, belong to the atypical antipsychotic class and have tolerability issues leading to non-adherence. Seltorexant—a novel, selective orexin-2 receptor antagonist—may be a valuable alternative with tolerability advantages. We assessed metabolic profiles of participants with MDD with insomnia symptoms (IS) in a 26-week, double-blind, phase 3, randomized controlled trial (NCT04513912) of seltorexant vs quetiapine XR (QTP-XR) as adjunctive therapy. Participants (aged 18-74 years) had MDD without psychotic features, Insomnia Severity Index total score ≥15, positive IS response on SCID-5-CT scale, and inadequate response to 1-2 antidepressants. Those with controlled type 1 or 2 diabetes for ≥2 months prior to screening were eligible. Participants received seltorexant 20 mg or QTP-XR (flexible dosage) in 1:1 ratio adjunctive to SSRI or SNRI. Changes from baseline to week 26 were assessed for total body weight (BW, key secondary endpoint), fasting insulin, fasting glucose, HbA1C, and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Low ( < 1.9) HOMA-IR implied insulin sensitivity and high ( > 2.9) HOMA-IR significant insulin resistance. Body mass index (BMI, kg/m2) categories were: underweight < 18.5, normal 18.5-25, overweight 25-30, and obese > 30. Of the 757 randomized participants, 756 received ≥1 study drug dose. At baseline, the seltorexant (n=366) and QTPXR (n=390) groups had mean (SD) HbA1C values of 5.5 (0.6) and 5.4 (0.5), respectively; 104 (28.4%) and 107 (27.4%) had significant insulin resistance; 39 (10.7%) and 27 (6.9%) had controlled diabetes; 29 (7.9%) and 16 (4.1%) were stable on metabolic-and lipidmanagement regimens; 125 (34.2%) and 132 (33.8%) were underweight/normal;110 (30.1%) and 129 (33.1%) were overweight; and 131 (35.8%) and 129 (33.1%) were obese. Mean (SD) change in BW (kg) was 0.5 (2.9) for seltorexant (n=268) and 2.1 (3.9) for QTP-XR (n=263) participants who received ≥1 dose and had baseline MADRS score ≥24 (LS mean difference [95% CI]: -1.7 [-2.2, -1.1], nominal P < .001). On average, participants in all BMI categories gained weight (kg); however, mean (SD) increases were numerically lower with seltorexant than QTP-XR: underweight/normal=0.8 (2.7) seltorexant (n=103), 2.5 (3.8) QTP-XR (n=90); overweight=0.8 (2.4) seltorexant (n=79), 2.0 (3.9) QTP-XR (n=91); obese=0.0 (3.6; n=97) seltorexant, 1.9 (4.1; n=93) QTP-XR. In subgroup analyses of participants with diabetes, obesity, or significant insulin resistance at baseline, mean (SD) changes in HOMA-IR numerically decreased with seltorexant (-3.9 [12.1; n=22], -1.8 [8.5; n=84], and -3.6 [9.5; n=70]), respectively vs numerically increased with QTP-XR (4.5 [12.3; n=13], 2.2 [6.5; n=76], and 0.2 [8.6; n=64]). Mean (SD) changes in fasting insulin also numerically decreased with seltorexant (-83.4 [205.4; n=22], -42.1 [193.2; n=86], -86.7 [209.5; n=71], respectively) vs numerically increased with QTP-XR (92.4 [239.5; n=13], 61.8 [196.3; n=77], 22.3 [239.4; n=65]). For glucose or HbA1C, no clinically relevant differences between treatment groups were observed; this is likely attributable to baseline HbA1C being within target range in the majority of participants and optimized glycemic control in those with diabetes. Seltorexant yielded less weight gain than QTP-XR after 26 weeks. In subgroups of metabolically compromised participants, HOMA-IR and insulin changes trended towards improvement with seltorexant but worsening with QTP-XR. Most participants were overweight/obese and had significant insulin resistance at baseline, highlighting the need for safer treatment options in MDD.