Metabolic Risk, Residual Insomnia, and Seltorexant

Jane Tiller, MD, discussed the relationship between metabolic risk factors, residual insomnia, and the development of seltorexant, an investigational orexin-2 receptor antagonist under study as adjunctive therapy for major depressive disorder (MDD) with insomnia symptoms.

Tiller reported that within the seltorexant trial population, approximately 70% of patients had identifiable metabolic risk factors, including insulin resistance, overweight status, or obesity. She emphasized that patients with comorbid MDD and insomnia carry elevated cardiovascular risk, making it clinically important to avoid treatments that exacerbate metabolic dysfunction and, ideally, to identify agents that confer metabolic benefit. In a post hoc analysis restricted to patients with baseline metabolic risk factors—insulin insensitivity, obesity, or elevated blood glucose—Tiller reported a trend toward metabolic improvement with seltorexant, alongside significantly less weight gain than was observed with quetiapine.

Tiller noted that sleep disturbance is a core diagnostic feature of MDD, affecting approximately 80% of patients, and is independently associated with increased relapse risk and other adverse outcomes—a relationship she noted has been demonstrated in data from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial.¹ She argued that adequately treating both depressive and insomnia symptoms, rather than depressive symptoms alone, is therefore clinically important, and proposed that seltorexant's distinct mechanism may target a shared causal pathway underlying both low mood and sleep disturbance, rather than treating 2 separate symptom domains. Tiller further noted that among patients with partial antidepressant response, persistent insomnia symptoms are associated with greater healthcare utilization and impaired occupational and daily functioning, underscoring the clinical significance of residual insomnia as a treatment target.²

Dr Tiller is global head of clinical development for neuroscience at Johnson & Johnson.

References

1. Nierenberg AA, Husain MM, Trivedi MH, et al. Residual symptoms after remission of major depressive disorder with citalopram and risk of relapse: a STAR*D report. Psychol Med. 2010;40(1):41-50.

2. Manber R, Thase ME, Wisniewski SR, et al. Efficacy of cognitive-behavioral therapy for insomnia combined with antidepressant pharmacotherapy in patients with comorbid depression and insomnia: a randomized controlled trial. J Clin Psychiatry. 2016;77(10):e1316–e1323