Insights on Seltorexant as Adjunctive Treatment for Major Depressive Disorder: A Conversation With Andrew Cutler, MD

CLINICAL CONVERSATIONS

Investigators presented new phase 3 data on seltorexant compared with quetiapine extended release (XR) as adjunctive treatment for major depressive disorder (MDD) with insomnia symptoms at the 2025 Psych Congress in San Diego, CA. While seltorexant did not meet the primary end point of a recent phase 3 study, it may still effectively address an important unmet medical need in MDD.¹ Psychiatric Times sat down with Andrew Cutler, MD, to learn more about these results.

Psychiatric Times: Seltorexant did not meet its primary endpoint in a recent phase 3 trial but showed comparable efficacy with quetiapine extended release. Can you share why seltorexant could still be an important potential adjunctive treatment option in MDD? How could it help address unmet need in this disease state?

Andrew Cutler, MD: This study showed that seltorexant, in combination with an oral antidepressant, demonstrated a numerically greater response rate at week 26 with a more favorable safety and tolerability profile compared to adjunctive quetiapine XR for MDD patients experiencing insomnia symptoms.

Although the primary endpoint was not met, the outcomes of this study are important because seltorexant demonstrated efficacy similar to a well-established therapy, quetiapine XR, that is associated with notably challenging side effects for patients, like weight gain. A prior placebo-controlled study with seltorexant, with a more traditional primary endpoint, was positive—and the medication’s robust clinical program significantly advances our understanding of its mechanism of action and biological effect. It is not unusual to have a study not meet its primary endpoint in psychiatry, even for FDA approved medications.

I believe seltorexant represents a promising advancement in the treatment of MDD by offering patients an effective treatment option without a considerable compromise on tolerability. These and prior findings, along with its novel targeted mechanism of action, suggest that seltorexant, if approved by the US FDA, may effectively address an important unmet medical need in MDD.

PT: What makes seltorexant stand out from other potential treatments that are in development?

Cutler: MDD is a complex psychiatric disorder involving multiple regions of the brain and can present with more than 250 different symptom combinations. However, most conventional therapies for depression follow a “one-size-fits-all” model with a similar mechanism of action, acting on monoamines, such as serotonin, which can lead to suboptimal patient outcomes.

Seltorexant is a novel, selective, first-in-class antagonist of the human orexin-2 receptor. It is the only selective orexin-2 receptor antagonist in development for MDD and is currently being investigated as an adjunctive treatment for MDD with insomnia symptoms.

Orexin is a neurotransmitter that was only discovered in 1998, and it functions as a master regulator of arousal, sleep, mood, motivation, and reward, as well as aspects of cognition. There are 2 orexin receptors, called orexin-1 and orexin-2. When orexin-2 receptors are stimulated for too long or at inappropriate times, their overactivation can cause hyperarousal manifestations, including sleep disturbances and excessive cortisol release, which may contribute to a bidirectional relationship between depression and insomnia symptoms.

Seltorexant is believed to work by selectively antagonizing these orexin-2 receptors, which may help improve mood and insomnia symptoms associated with MDD better than nonselective dual antagonists of both orexin-1 and orexin-2, which are only effective for insomnia. Additionally, the antidepressant effects of seltorexant have been shown to reduce the core symptoms of depression, even when controlling for decreases in insomnia symptoms and sleep disturbances. It can therefore be considered an antidepressant that also helps with insomnia, which is a common symptom in patients with MDD.

PT: What impact do insomnia symptoms have on patients with MDD? Why is targeting this set of symptoms important for improving patient outcomes?

Cutler: Depression and insomnia symptoms are closely linked, with patients often experiencing sleep disturbances such as insomnia or hypersomnia. Insomnia symptoms—including trouble falling asleep, staying asleep, or getting good quality sleep—can worsen depression. This can lead to a frustrating cycle for many patients where their depression leads to sleep disturbances, which in turn worsens their depression. These challenging insomnia symptoms can also negatively impact patients’ quality of life, overall health, and day-to-day functioning, and can even exacerbate the risk of depressive relapse and suicide.

Approximately 60% of patients with MDD experience clinically relevant insomnia symptoms despite being on a standard SSRI/SNRI antidepressant, which can actually interfere with sleep architecture. Insomnia is one of the most common residual symptoms of depression, even in patients who have responded to an antidepressant, and there are no therapies currently approved to treat MDD with insomnia symptoms.

There is a real, urgent need for novel, differentiated treatment options that address each patient’s unique disease biology and help to alleviate their symptoms. Targeting the orexin system is one such approach.

PT: Can you share some information on how seltorexant compared with quetiapine XR on other efficacy endpoints, such as total body weight, PHQ-9 total score, and PROMIS-SD T-score?

Cutler: A numerically higher, though statistically insignificant, MADRS response rate was observed with adjunctive seltorexant vs adjunctive quetiapine XR treatment (57.4 vs 53.4 percent), along with less total body weight gain (0.5 kg for seltorexant vs 2.1 kg for quetiapine XR), which was a key secondary endpoint.

Seltorexant and quetiapine XR also showed large and clinically meaningful improvements in depressive symptoms (-23.0 and -22.7, respectively), as measured by change in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline.

These results show that compared with quetiapine XR, seltorexant demonstrated a more favorable safety and tolerability profile, with more participants completing the 26-week period and experiencing less total body weight gain.

In a secondary endpoint, the Patient Health Questionnaire-9 (PHQ-9), a self-report scale assessing depressive symptoms, seltorexant and quetiapine XR also showed large and clinically meaningful decreases in depressive symptoms (-12.1 and -12.5, respectively).

Patients on seltorexant and quetiapine XR reported sleeping much better (-20.18 and -21.07, respectively), as measured by changes in the Patient-Reported Outcome Measurement Information System-Sleep Disturbance (PROMIS-SD) T- score, which was an exploratory endpoint.

PT: Data show that seltorexant had enhanced safety and tolerability compared with quetiapine XR, which is known for its challenging side effects such as weight gain and sedation. Could you share your thoughts on why this is of particular importance?

Cutler: As a practicing health care provider, I pay close attention to the metabolic side effects of any treatment I consider for my patients who are living with depression. Metabolic side effects, including weight gain, are a common concern with adjunctive MDD treatments that often lead to treatment discontinuation in patients. They also can significantly impact a patient’s physical health and self-esteem, further contributing to potential treatment discontinuation. It is therefore considered both a tolerability (troubling to the patient) and a safety (adversely affecting health) issue.

In this study, weight was used as a key secondary endpoint to help others assess the overall benefit-risk profile of a treatment. The fact that seltorexant demonstrated less weight gain than quetiapine XR is clinically meaningful, as it suggests a potentially more favorable safety and tolerability profile, which could improve adherence and outcomes for patients, if approved.

PT: Anything else you would like to share?

Cutler: As a clinician, I see many patients with MDD who also struggle with insomnia symptoms. Despite being on oral antidepressants, a substantial number of patients continue to experience residual symptoms that significantly impact quality of life. We often add another medication to address sleep issues, but this can add the potential for additional side effects and drug-drug interactions. If approved, seltorexant could offer a meaningful new treatment option without adding a significant burden of side effects for patients, which should always be carefully considered in one’s treatment plan when evaluating potential benefits and risks of medications.

PT: Thank you!

Dr Cutler is a clinical associate professor in the Department of Psychiatry and Behavioral Sciences at Norton College of Medicine, State University of New York Upstate Medical University, in Syracuse, NY. He is also the chief medical officer at the Neuroscience Education Institute in Malvern, PA.

Reference

1. Kuntz L. New poster data: seltorexant compared with quetiapine XR as adjunctive treatment for MDD with insomnia symptoms. Psychiatric Times. https://www.psychiatrictimes.com/view/new-poster-data-seltorexant-compared-with-quetiapine-xr-as-adjunctive-treatment-for-mdd-with-insomnia-symptoms