Seltorexant, Major Depressive Disorder, and Insomnia: Thoughts on the New Data

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CLINICAL CONVERSATIONS

Psychiatric Times sat down with Wayne Drevets, MD, and Andrew Krystal, MD, to discuss the recent data on seltorexant, an investigational first-in-class therapy in major depressive disorder (MDD) with insomnia symptoms, presented at the American Society of Clinical Psychopharmacology (ASCP) Annual Meeting.

PT: How can clinicians screen for insomnia in their patients with MDD? How often is it comorbid?

Andrew Krystal, MD: It should be routine for all clinicians to assess for insomnia among patients being evaluated or treated for depression. This is because insomnia is one of the cardinal symptoms of MDD and, as a result, is among the diagnostic criteria which all much be reviewed in order to determine a diagnosis. That insomnia is among the diagnostic criteria for MDD is consistent with the fact that the available literature suggests that approximately 70% of those with MDD suffer from insomnia.

PT: How does sleep impact MDD and vice versa?

Wayne Drevets, MD: MDD shares a strong link with sleep disturbances such as insomnia or hypersomnia.¹ Patients with MDD who experience insomnia commonly complain of difficulties falling asleep, staying asleep, or feeling rested after sleep. Disturbed sleep and insomnia symptoms can have a significant impact on a patient’s quality of life. When encountered within the course of MDD these symptoms are also associated with increases in the risk of depressive relapse and suicidal behavior, health care costs, and rates of workplace absenteeism and presenteeism.^2-4

Unfortunately, insomnia symptoms associated with MDD are often undertreated. Despite being one of the most common residual symptoms, approximately 60% of MDD patients on standard-of-care oral antidepressants still experience residual insomnia symptoms.⁵

PT: What has been the previous treatment strategy for addressing sleep issues in patients with MDD? Why do you think it has failed?

Drevets: MDD is a heterogeneous disease, characterized by mechanistically distinct features such as anxiety, anhedonia, and insomnia. However, under the current standard-of-care, 7 out of 10 patients still experience residual symptoms.⁶

Currently, there are no approved adjunctive therapies specifically for the treatment of MDD with insomnia symptoms. If a patient experiences these residual symptoms on an oral antidepressant, health care providers will typically try switching to another antidepressant agent before turning to augmentation agents, such as atypical antipsychotics or combinations with sedative-hypnotic agents. Patients may initially endure the adverse effects that come with these therapies, but often discontinue use if they are unsatisfied with the relative benefit over time.⁷

A significant unmet need remains for continued research and novel therapies in this space, since the common persistence of residual insomnia symptoms putatively reflects pathophysiological mechanisms that are inadequately addressed by current treatments.

PT: What benefits does a selective orexin-2 receptor antagonist have in addressing both insomnia and MDD?

Drevets: When orexin-2 receptors are stimulated for too long or at inappropriate times, their activation can cause hyperarousal manifestations, including wakefulness during the sleep period and excessive cortisol release, which may contribute to depression and insomnia symptoms.

Johnson & Johnson (J&J) is conducting a phase 3 program to evaluate the safety and efficacy of seltorexant, an investigational first-in-class selective antagonist of the human orexin-2 receptor, as an adjunctive treatment for MDD with insomnia symptoms.

Seltorexant aims to selectively antagonize the orexin-2 receptors, potentially improving both the mood and sleep symptoms associated with depression. The current clinical program builds on previous studies of seltorexant which demonstrated improvement in the core symptoms of depression, as well as in sleep onset and maintenance.

PT: Can you tell readers about the latest studies and their results and why they are important?

Drevets: At the ASCP Annual Meeting that took place last week, we presented positive topline results from the pivotal phase 3 MDD3001 study of seltorexant as an adjunctive treatment to baseline antidepressants in adult and elderly patients with MDD with insomnia symptoms who had experienced inadequate response to current treatment with an SSRI/SNRI antidepressant.

The study met all primary and secondary endpoints, with seltorexant demonstrating both a statistically significant and clinically meaningful improvement in depressive symptoms based on the Montgomery-Asberg Depression Rating Scale (MADRS) total score at day 43, and improved sleep disturbance outcomes, in patients who had a prior inadequate response to SSRI/SNRI antidepressants alone. Notably, seltorexant also resulted in significant improvement vs placebo in mean MADRS scores that were adjusted by removing the sleep item from the MADRS scale, reflecting its beneficial effects on core depressive symptoms. Seltorexant was safe and well-tolerated in the study, with similar rates of common adverse events seen in both trial arms, consistent with previous seltorexant clinical trials.

These positive results, along with consistent data from phase 2 studies, support further development of seltorexant and its potential as a significant step forward in the adjunctive treatment for patients with MDD with insomnia symptoms.

PT: How might seltorexant impact functional outcomes in patients with comorbid MDD and insomnia?
Drevets: MDD and insomnia can each significantly impact a person’s capacity to carry out functions associated with daily living and/or employment that are often taken for granted. There is an established body of research emphasizing the high burden faced by MDD patients who experience insomnia symptoms, including around their mental and physical health, work productivity, and general activity levels.⁸ Additionally, they encounter greater health care costs and socioeconomic burden associated with MDD, as evidenced by both direct and indirect costs.³

In the current trial, seltorexant demonstrated improvement in prespecified exploratory endpoints on insomnia and functional impairment, among others. These findings warrant further exploration and may hold profound implications for MDD patients with insomnia symptoms.

PT: What are the next steps?
Drevets: Following these topline findings for seltorexant, J&J looks forward to sharing full results from the phase 3 program in the future. We are confident in the potential of seltorexant as an adjunctive treatment for MDD with insomnia symptoms and have another pivotal trial in this patient population currently underway.

As part of our work to deliver transformational options for individuals living with serious mental illness, our team is focused on developing therapies that target the underlying mechanism of disease. Our late-stage neuropsychiatry pipeline includes another potential first-in-class therapy, aticaprant, targeting the subtype of MDD with residual anhedonia, or the persistent inability to experience pleasure, despite current antidepressant treatment. We are excited to share results from this clinical program in the near future.

PT: Thank you!

Andrew Krystal, MD

Dr Krystal is the Ray and Dagmar Dolby Distinguished Professor in the Departments of Psychiatry and Neurology, vice-chair for Research in the Department of Psychiatry, director of the Dolby Family Center for Mood Disorders, director of the UCSF Interventional Psychiatry program and codirector of the TMS & Neuromodulation Clinic.

Wayne Drevets, MD

Dr Drevets is vice president and neuropsychiatry disease area stronghold leader at Johnson & Johnson.

References

1. Nutt D, Wilson S, Paterson L. Sleep disorders as core symptoms of depression. Dialogues Clin Neurosci. 2008;10(3):329-336.

2. Chopra A. Understanding the relationship between insomnia disorder and MDD. Psychopharmacology Institute. December 1, 2023. Accessed June 5, 2024. https://psychopharmacologyinstitute.com/section/understanding-the-relationship-between-insomnia-disorder-and-mdd-2765-5602 

3. Chow W, Doane MJ, Sheehan J, et al. Economic burden among patients with major depressive disorder: an analysis of healthcare resource use, work productivity, and direct and indirect costs by depression severity. AJMC. February 19, 2019. Accessed June 5, 2024. https://www.ajmc.com/view/economic-burden-mdd

4. Johnston DA, Harvey SB, Glozier N, et al. The relationship between depression symptoms, absenteeism and presenteeism. J Affect Disord. 2019;256:536-540.

5. Emery PC, Wilson KG, Kowal J. Major depressive disorder and sleep disturbance in patients with chronic pain. Pain Res Manag. 2014;19(1):35-41.

6. Israel JA. The impact of residual symptoms in major depression. Pharmaceuticals (Basel). 2010;3(8):2426-2440.

7. Janssen Deck – “165127 Assessment of Orexin Monotherapy Presentation Detailed Findings.”

8. Joshi K, Cambron-Mellott MJ, Costantino H, et al. The clinical, economic, and patient-centric burden of insomnia symptom severity in adults with major depressive disorder in the United States. Brain Behav. 2023;13(8):e3143.