Metabolic profiles of participants with major depressive disorder with insomnia symptoms: phase-3 trial of seltorexant versus quetiapine-XR as adjunctive therapy

Introduction

Compared to atypical antipsychotics, such as quetiapine-XR, with tolerability issues associated with metabolic changes/weight gain, orexin receptor antagonists, such as seltorexant, may offer alternative due to tolerability advantages.

Aims

We examined metabolic profiles of participants with MDD with insomnia symptoms (IS) at baseline and during a 26-week/double-blind/phase-3/randomized controlled trial (NCT04513912) of seltorexant vs quetiapine-XR as adjunctive therapy.

Methods

NCT04513912 included participants 18–74 years with DSM-5 diagnosis of MDD without psychotic features, Insomnia Severity Index total score ≥15 and positive response for IS on SCID-5-CT, and inadequate response to 1–2 antidepressants at adequate dose and duration in the current depressive episode. Participants with Type 1 or 2 controlled diabetes mellitus at screening were eligible if otherwise medically stable and if on a stable regimen of glucose-lowering medications for ≥2 months before screening. Participants were randomized 1:1 to receive oral seltorexant 20mg or quetiapine-XR (flexible, labeled dosage) for 26 weeks while continuing their background SSRI/SNRI. Changes in total body weight (key secondary endpoint), fasting insulin, fasting glucose, and HbA1C values were measured, along with Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) score. Low (<1.9) and high (>2.9) HOMA-IR values imply insulin sensitivity and significant insulin resistance, respectively. BMI (kg/m²) categories: underweight <18.5, normal weight 18.5–25, overweight 25–30, and obese >30.

Results

Of 757 participants randomized, 756 received ≥1 dose of study intervention. At baseline, in seltorexant (n=366)/quetiapine-XR (n=390) groups, mean(SD) HbA1C values were 5.5(0.6)/5.4(0.5); 104(28.4%)/107(27.4%) participants had significant insulin resistance (HOMA-IR>2.9); 39(10.7%)/27(6.9%) had controlled diabetes; 29(7.9%)/16(4.1%) were on a stable regimen of metabolic and lipid-management pharmacotherapies; 125(34.2%)/132(33.8%) were underweight/normal; 110(30.1%)/129(33.1%) were overweight; and 131(35.8%)/129(33.1%) were obese, respectively. The mean(SD) change from baseline to Week (W)26 in total body weight (kg): 0.5(2.9;n=268) for seltorexant and 2.1(3.9;n=263) for quetiapine-XR participants who received ≥1 dose of study intervention and had a baseline MADRS score ≥24; the least-squares mean difference(95% CI) between treatment groups: −1.7([−2.2,−1.1]; nominal p<0.001). On average, all BMI subgroups gained weight at W26; however, mean(SD) increases in total body weight were numerically lower for seltorexant vs quetiapine-XR: underweight/normal=0.8(2.7;n=103) vs 2.5(3.8;n=90); overweight=0.8(2.4;n=79) vs 2.0(3.9;n=91); obese=0.0(3.6;n=97) vs 1.9(4.1;n=93). In separate subgroup analyses of participants with diabetes/obesity/significant insulin resistance (HOMA-IR>2.9) at baseline, mean(SD) changes in HOMA-IR from baseline to W26 showed numerical decreases in seltorexant-treated participants (−3.9[12.1;n=22]/−1.8[8.5;n=84]/−3.6[9.5;n=70]), but numerical increases in quetiapine-XR-treated participants (4.5[12.3;n=13]/2.2[6.5;n=76]/0.2[8.6;n=64]). Similarly, mean(SD) changes in fasting insulin showed numerical decreases in seltorexant-treated participants (−83.4[205.4;n=22]/−42.1[193.2;n=86]/−86.7[209.5;n=71]), but numerical increases in quetiapine-XR-treated participants (92.4[239.5;n=13]/61.8[196.3;n=77]/22.3[239.4;n=65]). No clinically relevant differences in mean glucose/HbA1C levels at W26 were observed between treatment groups, as the majority of participants had baseline HbA1C values within the target range, and glycemic control was already optimized in those with diabetes.

Conclusions

Overall, body weight gain was limited after 26 weeks of seltorexant treatment vs quetiapine-XR. In metabolically compromised subgroups, HOMA-IR and insulin levels displayed improvement from baseline with seltorexant vs worsening with quetiapine-XR. The majority of participants in this trial were overweight/obese and showed significant insulin resistance at baseline, highlighting an unmet need for safer treatment options in MDD.

References

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