Spravato (esketamine intranasal) / J&J - LARVOL DELTA

AVENUE: A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (clinicaltrials.gov) - P3 | N=258 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC | Initiation date: Nov 2025 ➔ Feb 2026

Trial initiation date • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry • Suicidal Ideation

Esketamine and Quality of Life Improvement in Treatment-Resistant Depression Patients: A Real-World Clinical Study. (PubMed, J Clin Psychopharmacol) - "Significant improvement in QoL was observed among patients with TRD treated with ESK-NS; ESK-NS in combination with an oral AD appears to offer meaningful benefit as a treatment option for patients with TRD who generally have substantial QoL and functioning limitations as a result of their depressive illness."

Clinical • HEOR • Journal • Real-world evidence • CNS Disorders • Depression • Mood Disorders • Psychiatry

Efficacy and safety of esketamine for "treatment resistant depression": registered report for a systematic review with an individual patient data meta-analysis of randomized, double-blind, placebo-controlled trials. (PubMed, BMC Med) - "Based on the IPD used for approval, esketamine in combination with an antidepressant showed an advantage over placebo that was statistically significant but small. The clinical relevance of this benefit is unclear, particularly given the risks of adverse events."

Clinical • Journal • Retrospective data • Anesthesia • CNS Disorders • Depression • Mood Disorders • Psychiatry

Real-world evaluation of change in depressive symptoms among patients with treatment-resistant depression treated with esketamine. (PubMed, BMC Psychiatry) - "Among patients with TRD treated with esketamine in real-world settings, significant improvements in depressive symptoms were observed over the six months following treatment initiation."

HEOR • Journal • Real-world evidence • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

The role of frontal EEG in predicting clinical response of major depressive disorder to intranasal ketamine and esketamine. (PubMed, J Affect Disord) - "Although, we did not find a predictive effect of aperiodic spectral parameters, we observed decreased values in responders compared to non-responders. Our results emphasize the role of frontal EEG as possible biomarker [area under the ROC curve of 0.7065 (Renyi entropy), 0.7101 (Tsallis entropy) and 0.7283 (PLI)] in predicting antidepressant effects of (es)ketamine."

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

The Impact of Intranasal Esketamine on Emergence Agitation in Children Undergoing Adenotonsillectomy: A Randomized Controlled Study. (PubMed, Drug Des Devel Ther) - "Anesthesia was maintained with sevoflurane during surgery, and the children were transferred to the post-anesthesia care unit (PACU) after extubation...Relative to Group C, children in Group LE also showed significantly lower PAED (P = 0.010) and m-CHEOPS scores (P = 0.023), along with reduced requirements for rescue propofol (P = 0.005) and rescue fentanyl (P = 0.013)...Intranasal esketamine at a dose of 0.5 mg/kg significantly reduces the incidence of EA following pediatric adenotonsillectomy. Increasing the dose to 1 mg/kg does not confer additional benefit in preventing EA and may instead delay extubation."

Clinical • Journal • Anesthesia • CNS Disorders • Pain • Pediatrics

Efficacy of intranasal esketamine versus rTMS for treatment-resistant depression: analysis of individual participant data from two clinical trials. (PubMed, EClinicalMedicine) - P=N/A, P3 | "Support for this work was provided by the Delaney Family Foundation. THREE-D was funded by the Canadian Institutes of Health Research and TRANSFORM-2 was funded by Johnson and Johnson Pharmaceuticals."

Journal • CNS Disorders • Depression • Mood Disorders • Psychiatry

Intravenous ketamine versus esketamine for depression: a systematic review and meta-analysis. (PubMed, Ther Adv Psychopharmacol) - "Large head-to-head RCTs are needed to confirm these findings. The study protocol was prospectively registered on the Open Science Framework (OSF) at https://osf.io/5jzev."

Journal • Retrospective data • Bipolar Disorder • CNS Disorders • Depression • Mood Disorders • Psychiatry

Comparative safety and tolerability of ketamine and esketamine for major depressive disorder: a systematic review and meta-analysis. (PubMed, Front Pharmacol) - "These findings require further validation through direct head-to-head clinical trials comparing these two drugs. https://www.crd.york.ac.uk/PROSPERO/view/CRD42023389486."

Journal • Retrospective data • Review • Alzheimer's Disease • Anesthesia • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mood Disorders • Otorhinolaryngology • Psychiatry • Vertigo

The perspectives of patients with depression toward esketamine, and the influence of their medication adherence on their viewpoints: a Saudi cross-sectional study. (PubMed, Front Psychiatry) - "It also highlights non-adherence as a significant issue in patients with depression. These findings highlight the importance of patients' education, family involvement, and logistical supports."

Journal • Observational data • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry

Caution Is Warranted in Prescribing Ketamine for Mental Health. (PubMed, J Gen Intern Med) - "Ketamine has expanded into a multibillion-dollar industry, with three delivery models: (1) in-person clinics offering off-label racemic ketamine; (2) clinic visits for esketamine (Spravato); and (3) telehealth services prescribing off-label racemic ketamine. Providers should evaluate: (1) whether sound evidence exists to prescribe; (2) whether drug benefits outweigh the risks; (3) and whether prescribing serves the patient's best interests. As a dissociative anesthetic, ketamine raises significant concerns regarding whether the purpose and function of the drug meet legal requirements for appropriate prescribing of controlled substances."

Journal • Anesthesia

AVENUE: A Study to Evaluate the Efficacy and Safety of Esketamine for Reduction of Symptoms of Major Depressive Disorder (clinicaltrials.gov) - P3 | N=258 | Not yet recruiting | Sponsor: Janssen Research & Development, LLC

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

Personalizing ketamine therapy: Real-world predictors of response to IV ketamine and intranasal esketamine in treatment-resistant depression. (PubMed, Psychiatry Res) - "IV ketamine may offer superior antidepressant effects compared to esketamine, particularly in patients with severe treatment resistance. However, comorbid psychiatric conditions, especially BPD, attenuate the benefits of both ketamine and esketamine. Personalized approaches considering comorbidity profiles are critical to optimizing outcomes in TRD."

Journal • Real-world evidence • Borderline Personality Disorder • CNS Disorders • Depression • Mood Disorders • Personality Disorder • Post-traumatic Stress Disorder • Psychiatry

Requirements for Payer Recognition of Disease-Modifying Effect in New Drug Launches (ISPOR-EU 2025) - "The study examined recurring features cited by payers as value drivers, including clinical innovation, trial design, safety, and cost-effectiveness. All products achieving premium pricing addressed high unmet need, either by treating severe orphan diseases (e.g., Fintepla, Cablivi) or late-line settings (e.g., Omvoh)...Safety advantages and cost offsets (e.g., with Fintepla, Takhzyro, Tavneos) played a supportive role in reinforcing the perception of value. Achieving a disease-modifying profile and premium pricing is most viable when targeting high unmet need with compelling efficacy and clinical innovation... Achieving a disease-modifying profile and premium pricing is most viable when targeting high unmet need with compelling efficacy and clinical innovation. Novel mechanisms and clear differentiation enhance payer acceptance. While safety and economic benefits can reinforce value, they are insufficient without demonstrable clinical impact."

Cognitive Disorders

A New Era for Esketamine in Managing Treatment-Resistant Depression: A Systematic Review of Its Use From Adjunct to First-Line Therapy. (PubMed, Cureus) - "Esketamine, the S-enantiomer of ketamine, has emerged as a novel therapeutic option. Despite this limitation, molecular insights suggest that TRD is associated with glutamatergic system dysfunction, impaired neuroplasticity, hypothalamic-pituitary-adrenal (HPA) axis abnormalities, and neuroinflammatory processes. Intranasal esketamine demonstrates potential as a rapid-acting and effective standalone therapy for TRD; nevertheless, further robust, large-scale randomized controlled trials are essential to confirm its therapeutic benefit, establish optimal dosing strategies, and overcome current research limitations."

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

The effects of ketamine and esketamine on functional outcomes in major depressive disorder and treatment-resistant depression: A systematic review. (PubMed, J Psychiatr Res) - "Esketamine alleviates depressive symptoms and improves functioning, notably in workplace domains. Future studies should include functional outcomes as key secondary or co-primary outcomes, reflecting the ultimate goal of recovery in TRD/MDD."

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

Study on the application of dexmedetomidine combined with Esketamine nasal drops before tonsillectomy in children (ChiCTR) - P=N/A | N=100 | Recruiting | Sponsor: Huzhou First People's Hospital; Huzhou First People's Hospital

New trial

Rapid-acting NMDA and GABAergic Modulators in Mood Disorders: From Synaptic Mechanisms to Clinical Practice. (PubMed, Clin Psychopharmacol Neurosci) - "Two rapid-acting therapeutic classes, NMDA receptor modulators (ketamine, esketamine) and neuroactive-steroid GABA-A positive allosteric modulators (brexanolone, zuranolone), offer complementary approaches to restore circuit function. Robust efficacy/tolerability predictors remain limited, though early symptomatic change is clinically informative. In conclusion, NMDA receptor modulators and neuroactive-steroid GABA-A positive allosteric modulators have improved the treatment for mood disorders and accelerated a transition to mechanism-driven care."

Journal • Review • Anesthesia • Bipolar Disorder • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Postpartum Depression • Psychiatry • Suicidal Ideation

Gender Differences in Suicidal and Self-Harming Responses to Esketamine: A Real-World Retrospective Study. (PubMed, Curr Neuropharmacol) - "Esketamine rapidly improved suicidality and depression in TRD, with preliminary evidence suggesting gender-specific responses, and highlighting the importance of tailored interventions to maximize outcomes. Further research is needed to confirm these differences, explore the long-term effects, and understand the underlying mechanisms."

Journal • Real-world evidence • Retrospective data • CNS Disorders • Depression • Psychiatry • Suicidal Ideation

Rebuilding the Atrophied Brain: Nasal Esketamine 6-month Therapy Expands Key Frontal and Hippocampal Regions and reduces neurofilaments serum levels in patients with major depressive disorder. The proof-of-concept of the depTesk (DEPression Treatment with. (PubMed, CNS Spectr) - No abstract available

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

An Implementation Science Assessment of Intranasal Esketamine's Limited Integration into Mainstream Psychiatric Treatment. (PubMed, J Behav Health Serv Res) - "Despite established efficacy and effectiveness, most psychiatric treatment settings do not offer intranasal esketamine. This limited implementation is reviewed using the Consolidated Framework for Implementation Research (CFIR), and steps forward are proposed to improve accessibility for patients with TRD."

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

Is intranasal esketamine versus intravenous ketamine a therapeutic innovation or a divide in access to care? (PubMed, Gen Hosp Psychiatry) - No abstract available

Journal

Esketamine Nasal Spray for Treatment-Resistant Bipolar II Depression: A Case Report. (PubMed, Psychiatry Investig) - "Nifedipine was offered when his systolic blood pressure exceeded 160 mm Hg, accompanied by headache or dizziness. Blood pressure monitoring was essential throughout ESK-NS treatment. This report highlights esketamine's potential for bipolar depression treatment and calls for further studies on its cardiovascular effects and proper management."

Journal • Bipolar Disorder • Cardiovascular • CNS Disorders • Depression • Hypertension • Mood Disorders • Pain • Psychiatry

Improvements in health-related quality of life with esketamine nasal spray versus quetiapine extended release. (PubMed, Eur Psychiatry) - No abstract available

HEOR • Journal • CNS Disorders • Depression • Psychiatry

HEALTH TECHNOLOGY ASSESSMENT LINKED TO PATIENT-CENTERED CARE: AN EXPERIENCE REPORT FROM A HEALTH INSURANCE PROVIDER (WCN 2025) - "The available evidence presents significant methodological limitations, and the high cost of the drug poses a challenge to the sustainability of the healthcare system. More robust and real-world studies are essential to assess the efficacy, safety, and clinical impact of Esketamine Hydrochloride, ensuring evidence-based and responsible decision-making."

Clinical • Reimbursement • US reimbursement • CNS Disorders • Depression • Major Depressive Disorder • Mood Disorders • Psychiatry