J&J‘s Investigational Seltorexant: Comparable to Quetiapine in Depression With Insomnia, With a Safer Profile

Managing major depressive disorder (MDD) often becomes more challenging when insomnia is present. Sleep problems not only worsen mood symptoms but also increase relapse and suicide risk. While adjunctive therapies such as quetiapine can help but its side effects often limit long-term use. At the 2025 U.S. Psychiatric and Mental Health Congress, Johnson & Johnson presented new Phase 3 results on Seltorexant, an investigational therapy designed to address both depression and insomnia.

About Seltorexant

Seltorexant is a first-in-class selective orexin-2 receptor antagonist. By targeting the orexin system, which regulates sleep–wake balance and stress responses, Seltorexant aims to normalize hyperarousal and improve sleep without next-day sedation. Unlike traditional antidepressants or antipsychotics, it offers a more precise mechanism tailored to the overlap of depression and insomnia.

Major Depressive Disorder with Insomnia

MDD is among the most common psychiatric illnesses worldwide, affecting more than 300 million people. About 60% of patients continue to experience insomnia symptoms even while on SSRIs or SNRIs. Persistent sleep disruption not only impairs quality of life but also undermines the effectiveness of depression treatment. Current add-on medications, such as quetiapine, help with sleep but are often associated with sedation, weight gain, and poor tolerability, creating a need for safer alternatives.

Clinical Evidence: The MDD3005 Trial

The Phase 3 MDD3005 trial (NCT06559306) compared seltorexant to quetiapine XR as an adjunctive treatment alongside standard antidepressants in adults with MDD and insomnia symptoms. Both groups showed significant reductions in depressive symptoms after 26 weeks. Seltorexant achieved a numerically higher response rate (57.4% vs. 53.4%), but the difference was not statistically significant, meaning the trial did not meet its primary endpoint.

Safety and Tolerability Profile

Seltorexant stood out for its safety and tolerability in head on comparison with quetiapine. Both drugs reduced depressive symptoms, but patients stayed on seltorexant more easily because it caused fewer side effects as compared with quetiapine.

Somnolence (Daytime Sleepiness): Quetiapine made almost one in four patients (24%) excessively sleepy during the day. Only 6% of patients on seltorexant reported this problem. This shows that seltorexant helps patients sleep at night without leaving them drowsy the next day.

Weight Gain: Patients on quetiapine gained an average of 2.1 kg in 26 weeks. Those on seltorexant gained only 0.5 kg. By avoiding significant weight gain, seltorexant may improve long-term treatment acceptance.

Overall Tolerability: Fewer patients stopped seltorexant because of side effects. Quetiapine acts on many receptors, which explains its sedation and metabolic changes. Seltorexant targeted orexin-2 action seems to deliver benefit without burden of these side effects.

These differences give seltorexant a clear advantage. It provides similar symptom relief to quetiapine while avoiding the side effects that generally leads to discontinuation of treatment.

Implications Compared to Quetiapine

Quetiapine remains a widely used option in MDD with insomnia but often comes at the cost of over sedation and metabolic effects. Seltorexant comparable efficacy combined with fewer side effects positions it as a potentially safer adjunctive option. For patients who discontinue therapy due to tolerability issues, this could represent a significant advancement.

Key Opinions

Andrew Cutler, M.D., Chief Medical Officer at the National Educational Institute and Associate Clinical Professor of Psychiatry at SUNY Upstate Medical University, noted that seltorexant may help to close a persistent treatment gap in MDD, especially for the nearly 60% of patients who continue to experience insomnia despite being on antidepressants. Bill Martin, Ph.D., Global Therapeutic Area Head for Neuroscience at Johnson & Johnson Innovative Medicine added that, when viewed alongside earlier positive Phase 3 findings, these results highlight the potential value of seltorexant in providing meaningful symptom relief without the considerable tolerability issues seen with current options.

Although the Phase 3 trial did not establish significant superiority over quetiapine, seltorexant demonstrates the potential of orexin-targeted therapy in MDD with insomnia. Its novel mechanism and improved safety profile may address an important unmet need in psychiatric care. Further studies and regulatory reviews will determine whether seltorexant can progress from investigational status to a new treatment option in clinical practice.