seltorexant (MIN-202) / Minerva Neurosciences, J&J, Royalty - LARVOL DELTA

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Apr 2027 ➔ Dec 2027

Trial completion date • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Evaluating seltorexant as a treatment option for major depressive disorder. (PubMed, Expert Rev Neurother) - "Seltorexant 20 mg has shown a promising antidepressant effect, particularly in patients with clinically significant insomnia, and a favorable tolerability profile. The mixed phase-3 results, the modest effect sizes, and gaps on core symptoms of depression, including anhedonia and suicidality, and on long-term safety warrant a measured positive view, pending confirmatory data."

Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Dec 2026 ➔ Apr 2027

Trial completion date • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Acute Sleep Deprivation in Adolescence Produces Transcriptional Changes in the Orexin System and Regulates Motivation for Reward. (PubMed, Biol Psychiatry Glob Open Sci) - "The orexin system, particularly the orexin 2 receptor (OX2R), was strongly upregulated in the mPFC and NAc, so we determined the effect of the OX2R antagonist seltorexant (10 mg/kg) on sleep deprivation-induced motivation for reward and found that seltorexant acutely reduced responding for sucrose under both sleep deprivation and sleep recovery conditions. These results suggest that acute sleep deprivation induces profound changes in the reward system and cellular function in adolescents, including the orexin system, that may modulate motivation for reward."

Journal

A Study of Seltorexant as Monotherapy in Adults and Elderly Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=600 | Recruiting | Sponsor: Janssen Research & Development, LLC | Not yet recruiting ➔ Recruiting

Enrollment open • Monotherapy • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

A Study of Seltorexant as Monotherapy in Adults and Elderly Participants With Major Depressive Disorder (clinicaltrials.gov) - P3 | N=600 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC

Monotherapy • New P3 trial • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Unveiling the binding mechanism of orexin 2 receptor antagonists with computational chemistry. (PubMed, Phys Chem Chem Phys) - "In this study, we investigated the molecular interactions of three dual orexin receptor antagonists (daridorexant, lemborexant, suvorexant) and the selective OXR2 antagonist seltorexant using an integrated computational approach that combined classical molecular docking, explicit-membrane molecular dynamics (MD) simulations of 700 ns, and quantum-based molecular fractionation with conjugate caps (MFCC) calculations coupled with density functional theory (DFT) at the B97D/6-311+G(d,p) level. These findings shed light on the structural and energetic factors that determine OXR2-ligand recognition. The results provide a solid molecular framework for the rational optimization of orexin receptor antagonists with enhanced selectivity and improved pharmacological profiles."

Journal • CNS Disorders • Mental Retardation • Psychiatry

Is seltorexant, an orexin-2 receptor antagonist, showing promise in insomnia? (PubMed, Expert Opin Investig Drugs) - "As seltorexant is showing promise in insomnia, further trials are needed. However, at present there are no phase 3 clinical trials registered for the treatment of insomnia by seltorexant alone or in comparison with zolpidem, and such trials need consideration."

Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Psychiatry • Sleep Disorder

Safety, tolerability, and preliminary efficacy of seltorexant versus quetiapine extended release as adjunctive therapy in major depressive disorder: a randomized, flexible-dose, 6-month, parallel-group, exploratory study. (PubMed, Int J Neuropsychopharmacol) - P2 | "Results support the favorable tolerability and preliminary efficacy of seltorexant 20 mg daily as adjunctive treatment in patients with MDD, especially those with insomnia symptoms, and suggest potential approaches to differentiate seltorexant from quetiapine-XR in future adequately powered studies. Trial registration. Clinicaltrials.gov  identifier: NCT03321526."

Journal • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: May 2027 ➔ Dec 2026

Trial completion date • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Emerging neurobiological targets in psychiatric treatment. (PubMed, Eur Neuropsychopharmacol) - "Recent evidence suggests that sodium channel modulators, such as evenamide, may offer therapeutic benefits for treatment-resistant schizophrenia by stabilizing glutamatergic neurotransmission...Additionally, Sigma-1 receptor agonists, including Blarcamesine and Pridopidine, have shown neuroprotective and cognitive-enhancing properties, making them attractive candidates for psychiatric and neurodegenerative disorders. Orexin receptor antagonists, such as suvorexant and seltorexant, have potential in mood disorders and substance dependence, highlighting the broader therapeutic applications of targeting the orexinergic system...The identification of biomarkers for patient stratification will be critical in the hitherto elusive goal of developing precision medicine approaches. Targeted pharmacological interventions offer a path toward more effective, well-tolerated, and potentially individualized treatment options for patients with severe mental illness."

Journal • Review • Bipolar Disorder • CNS Disorders • Depression • Inflammation • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • Schizophrenia

Efficacy and Safety of Seltorexant for Insomnia and Major Depressive Disorder (ASHP 2025) - No abstract available

Clinical • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Phase 3 Study of Adjunctive Treatment With Seltorexant in Adult and Elderly Participants With Major Depressive Disorder and Insomnia Symptoms (clinicaltrials.gov) - P3 | N=752 | Recruiting | Sponsor: Janssen Research & Development, LLC | Trial completion date: Nov 2027 ➔ May 2027

Trial completion date • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Efficacy and safety profiles of FDA-approved dual orexin receptor antagonists in depression: A systematic review of pre-clinical and clinical studies. (PubMed, J Psychiatr Res) - "DORAs show potential in improving sleep parameters in individuals with MDD. While their effects on depressive symptoms in this review are modest, further research is needed to assess long-term efficacy, safety, and their impact on depressive symptoms, as well as to explore potential combination therapies."

FDA event • Journal • Preclinical • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Effect of dual orexin receptor antagonists on sleep: A systematic review and meta analysis (ECNP 2025) - "The DORAs included were suvorexant, lemborexant, daridorexant, seltorexant, filorexant and vornorexant. Most DORAs were found to be of robust efficacy, irrespective of diagnosis, although further research is required for most diagnoses. Most DORAs seem to cause notably more somnolence than placebo, which is of great clinical importance."

Retrospective data • Review • Alzheimer's Disease • Bipolar Disorder • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Movement Disorders • Psychiatry • Restless Legs Syndrome • Sleep Disorder

Developments in adjunctive treatment: Seltorexant versus quetiapine in managing major depressive disorder with insomnia symptoms (ECNP 2025) - P3 | "This presentation will focus on the results from a Phase 3, 26-week, international, double-blind, active-controlled study (NCT04513912) of adjunctive seltorexant 20 mg with quetiapine-extended release (XR) as a comparator in MDD with insomnia symptoms in a subgroup of participants (18-74 years) from the European Union and United Kingdom. Y. Flossbach is a full-time employee of Actelion Pharmaceuticals Ltd., a Johnson & Johnson company, and holds stock in Johnson & Johnson"

CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Seltorexant: a safe and well-tolerated adjunctive treatment for adolescent major depressive disorder with comparable pharmacokinetics to adults (ECNP 2025) - "Most patients were taking fluoxetine (56.7%) or escitalopram (36.7%) at baseline. Based on adequate PK characterization with fewer than planned participants, and absence of new safety findings at the interim analysis, agreement was reached with European Health Authorities to terminate the study early. The safety and PK results from the current study support continued development of seltorexant in the paediatric population."

Clinical • PK/PD data • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder • Suicidal Ideation

Hypocretin: a promising target for the regulation of homeostasis. (PubMed, Front Neurosci) - "Dual hypocretin receptor antagonists (DORAs), such as suvorexant and daridorexant, are clinically approved for insomnia. Selective HCRT-2R agonists-including TAK-861 and ALKS-2680-are in clinical trials for NT1 and show encouraging results. Additionally, HCRT-2R antagonists like seltorexant are being explored for major depressive disorder. This review will highlight the anatomical distribution, receptor mechanisms, and physiological functions of the hypocretin system. It will also focus to discuss its role in narcolepsy, metabolic regulation, and mood disorders, while addressing key challenges and open questions that must be resolved to fully harness hypocretin's therapeutic potential."

Journal • Review • Cataplexy • CNS Disorders • Depression • Excessive Daytime Sleepiness • Insomnia • Major Depressive Disorder • Mood Disorders • Narcolepsy • Psychiatry • Sleep Disorder • LEP

Efficacy and Safety of Seltorexant in Insomnia Disorder: A Randomized Clinical Trial. (PubMed, JAMA Psychiatry) - P2 | "Seltorexant was generally well tolerated. ClinicalTrials.gov Identifier: NCT03375203."

Clinical • Journal • CNS Disorders • Insomnia • Psychiatry • Sleep Disorder

Sleep Deprivation Engages the Orexin/Hypocretin System to Regulate Food Reward Seeking. (PubMed, Int J Neuropsychopharmacol) - "These results highlight Ox2R signaling in counteracting the acute SD effects on food reward seeking in females."

Journal • Sleep Disorder • FOS

A new direction for adjunctive therapy of difficult-to-treat depression: examining the role of orexin receptor antagonists. (PubMed, Eur Arch Psychiatry Clin Neurosci) - "Although it is likely that the currently approved Dual Orexin Receptor Antagonists (DORAs)-suvorexant, lemborexant and daridorexant-are safe and useful options for concomitant therapy of insomnia in antidepressant-treated patients, these medications have not been approved for this indication. By contrast, the investigational ORA seltorexant, which is a selective Orexin 2 receptor antagonist, has shown significant antidepressant effects in Phase 2 and Phase 3 trials. Although at least one more unequivocally positive pivotal study will be needed to garner FDA approval for clinical use in the United States, this drug shows promise as a novel and well-tolerated option for patients with difficult to treat depressive episodes."

Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder

Comparative efficacy and safety of different pharmacological interventions for the treatment of depression associated with insomnia in the elderly population: a systematic review and network meta-analysis. (PubMed, Psychogeriatrics) - "All types of intervention were effective in decreased Insomnia Severity Index (ISI) and depression score, and sertraline had the highest probability of being the most effective intervention in decreasing the ISI (standard mean difference (SMD) = -2.17, 95% confidence interval (95% CI): -2.60, -1.75), Hamilton Depression Scale (HAM-D: SMD = -3.10, 95% CI: -3.60, -2.61) in elderly patients with depression and insomnia...In terms of the number of patients reporting escitalopram and zuranolone, zolpidem, seltorexant and eszopiclone had higher risks of serious adverse events than placebo or other treatments...Escitalopram, zuranolone, and seltorexant did not show overall material benefits in reducing ISI. These results should serve evidence-based clinical practice."

Journal • Retrospective data • Review • CNS Disorders • Depression • Insomnia • Mood Disorders • Psychiatry • Sleep Disorder

Activation of orexin receptor 2 plays anxiolytic effect in male mice. (PubMed, Brain Res) - "In this study, by using behavioral test, stereotaxic surgery and microinjection, virus-mediated knockdown of OX2R and pharmacological method, we found that: (1) Intraperitoneal injection of OX2R antagonist Seltorexant induced increased baseline anxiety-like behaviors in male mice...(3) Intraperitoneal injection of YNT-185 alleviated morphine withdrawal-induced anxiety-like behaviors in male mice. (4) Microinjection of YNT-185 into the VTA played anxiolytic effect in male mice. (5) Virus-mediated OX2R knockdown in the VTA induced anxiety-like behaviors in male mice."

Journal • Preclinical • CNS Disorders • Mental Retardation • Psychiatry

Seltorexant for major depressive disorder. (PubMed, Expert Opin Emerg Drugs) - "Early clinical evidence suggests that seltorexant is effective in treating MDD, both in individuals diagnosed with insomnia and those not, although greater antidepressant effects are observed in individuals with severe sleep disturbance. Results from large phase III clinical trials are needed to confirm efficacy and safety."

Journal • Review • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mental Retardation • Mood Disorders • Psychiatry • Sleep Disorder

Treatment effect and safety of seltorexant as monotherapy for patients with major depressive disorder: a randomized, placebo-controlled clinical trial. (PubMed, Mol Psychiatry) - P1 | "These biomarker data suggest mechanistic hypotheses that may account for the apparent curvilinear dose-response relationship of seltorexant. Trial Registration: ClinicalTrials.gov, NCT03374475."

Clinical • Journal • Monotherapy • CNS Disorders • Depression • Insomnia • Major Depressive Disorder • Mood Disorders • Psychiatry • Sleep Disorder