A Randomised, Controlled Trial to Investigate the Effect of an Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression in Subjects Who Had a First-time Treatment Failure on Their First-line Treatment.

Schizophrenia, bipolar and major depressive disorders collectively affect over 10 million people across the EU and are associated with annual healthcare and societal costs in excess of 100 billion Euros. When diagnosed with one of these disorders, patients are prescribed psychotropic medication such as antidepressants, mood stabilisers or antipsychotics. It is unknown whether this first-line treatment will be successful. After this first-line treatment fails, usually a second-line treatment is initiated, and when this is not successful either a third-line treatment is initiated. Third-line treatments are quite successful, especially when compared to second-line treatments. The research question is whether the third-line treatments (early-intensified treatments) would be more efficacious than the current second-line treatments (treatment as usual) for schizophrenia, bipolar and major depressive disorders. If this is indeed the case, this could lead to the prevention of unnecessary trials of ineffective treatments and adaptations of worldwide guidelines as well as a reduction of healthcare and societal costs.

Start Date30 Jan 2025

Sponsor / Collaborator

University Medical Center of Utrecht

[+1]

ChiCTR2400088162 / SuspendedPhase 4IIT

Clinical study on the application of remimazolam combined with esketamine in hysteroscopic surgery

Start Date01 Jan 2025

Sponsor / Collaborator

Zhuji People's Hospital

ChiCTR2400093358 / CompletedEarly Phase 1

The safety and efficacy of habenular nucleus injected Esketamine and DBS in the treatment of treatment-resistant depression

Start Date31 Dec 2024

Sponsor / Collaborator-

100 Clinical Results associated with Esketamine Hydrochloride

100 Translational Medicine associated with Esketamine Hydrochloride

100 Patents (Medical) associated with Esketamine Hydrochloride

1,988

Literatures (Medical) associated with Esketamine Hydrochloride

01 Mar 2025·JOURNAL OF AFFECTIVE DISORDERS

Effect of continuous esketamine infusion on brain white matter microstructure in patients with major depression: A diffusion tensor imaging study

Article

Author: Liu, Xiang ; Peng, Dechang ; Wan, Xin ; Li, Jiangping ; Deng, Yingke ; Wu, Guojiang ; Wei, Zhipeng ; Liu, Yumeng ; Li, Lifeng ; Li, Haijun

INTRODUCTION:

Esketamine has demonstrated acute antidepressant effects in patients with major depressive disorder (MDD). This study investigated whether these effects associate with reversible white matter fiber integrity recovery using diffusion imaging.

METHOD:

Twenty patients with MDD and 20 healthy controls received 2-week esketamine treatment. Patients received 0.25 mg/kg intravenous esketamine. Emotional and cognitive recovery were assessed. Diffusion tensor imaging and tract-based spatial statistics evaluated white matter fiber integrity pre/post-treatment. Correlation analyses examined associations between white matter changes and clinical scales.

RESULTS:

Compared to controls, patients with MDD exhibited decreased fractional anisotropy (FA) values of cerebral white matter fibers involving the association fibers, the commissural fibers and projection fibers. Esketamine effectively reduced depression, anxiety, and suicidal ideation scores while improving cognitive function. However, no reversible recovery of compromised white matter integrity was observed after 2 weeks of esketamine treatment. FA reductions in projection fibers correlated with anxiety and suicidal ideation severity.

LIMITATIONS:

Concurrent sertraline use and lack of placebo control limited our ability to isolate esketamine's effects. The wide age range may have introduced response variability. We used minimal effective dosages based on previous research. The small sample size limited statistical power. Larger, more controlled studies are needed to validate these preliminary findings.

DISCUSSION:

This study enhances MDD neuropathological understanding, with widespread white matter impairment and associations between projection fibers and symptom severity. While producing significant antidepressant effects, short-term esketamine did not recover compromised white matter microstructure.

01 Feb 2025·PSYCHIATRY RESEARCH

Perioperative administration of esketamine during cesarean section is a double-edged sword

Letter

Author: Nagamine, Takahiko

01 Jan 2025·JOURNAL OF AFFECTIVE DISORDERS

Repeated subcutaneous esketamine on treatment-resistant depression: An open-label dose titration study

Article

Author: de Almeida, Victor Rocha Nobrega ; Barbosa, David C. ; da Costa Gonçalves, Kaike Thiê ; Santos, Nestor Caetano ; Araujo, Draulio ; Cavalcanti-Ribeiro, Patricia ; Falchi-Carvalho, Marcelo ; de Medeiros Lima, Nicole Bezerra ; de Araújo Ferreira, Marcos André ; de Brito, Aldielyson Jorge Cavalcanti ; Arcoverde, Emerson ; Bolcont, Raynara ; Lopes, Eduardo Igor Torquato Cardoso ; Palhano-Fontes, Fernanda ; Galvão-Coelho, Nicole Leite ; De Souza, Lara Carvalho Araújo Melo ; Barbosa, David C ; Cavalcanti-Ribeiro, Patrícia

BACKGROUND:

Ketamine has gained prominence as one of the most effective therapeutic options in unipolar treatment-resistant depression (TRD). However, most studies related to the antidepressant action of ketamine used intravenous (IV) or intranasal (IN) administration. The subcutaneous (SC) route of administration is a promising alternative, as it results in plasma levels comparable to IV, causes fewer side effects, and is easier and cheaper to administer than both IV and/or IN routes.

METHODS:

In this context, we conducted an open-label clinical trial for investigating the efficacy and safety of 8 weekly sessions of SC esketamine in TRD patients (n = 30).

RESULTS:

At the end of the treatment, a partial response rate of 26.09 %, a response rate of 52.17 % and remission rate of 34.78 % were observed, assessed by Montgomery-Åsberg Depression Rating Scale. Moreover, the self-reported depressive symptoms, as measured by the Beck Depression Inventory II (BDI-II), significantly decreased from the baseline to the final session, and the improvements were sustained throughout the week. Follow-up evaluations (BDI-II) up to the sixth month consistently showed scores lower than the baseline.

LIMITATIONS:

The small sample size and the drop-out during the follow-up phase may limit the generalizability of the findings. Additionally, the absence of a control group necessitates cautious interpretation of causality.

CONCLUSIONS:

This groundbreaking study, which addresses SC esketamine treatment for TRD, reported promising response and remission rates, as well as sustained antidepressant effects. It highlights the need for further research to improve and expand our knowledge of this innovative, more accessible, and cost-effective therapeutic approach.

277

News (Medical) associated with Esketamine Hydrochloride

18 Dec 2024

·www.businesswire.com

RECOVER Clinical Study Shows Meaningful Benefits of LivaNova’s VNS Therapy System in Select Secondary Endpoints for Unipolar Patients with Treatment-Resistant Depression

LONDON--( BUSINESS WIRE )--LivaNova PLC (Nasdaq: LIVN), a market-leading medical technology company, today announced that the journal Brain Stimulation has published two pivotal articles chronicling the unipolar cohort data set for the RECOVER clinical study . The researchers evaluated the safety and efficacy of LivaNova’s VNS Therapy™ System and its effectiveness on quality of life and daily function in this population of patients with treatment-resistant unipolar depression. Overall, the articles concluded that active VNS Therapy, as compared with a no-stimulation control (or sham VNS Therapy), safely and effectively demonstrated clinically meaningful therapeutic effects on depressive symptoms and positive effects on quality of life and daily function. These findings support the use of VNS Therapy to deliver vagus nerve stimulation (VNS) in treatment-resistant depression (TRD) patients. A total of 493 adults with at least four documented unsuccessful attempts with antidepressant treatments participated in the unipolar cohort of the RECOVER study. At baseline, unipolar patients in the study failed more than 13 antidepressant treatments (on average) – this included, for the majority, one or more interventional therapies (e.g., transcranial magnetic stimulation, electroconvulsive therapy, or esketamine). While the RECOVER study did not meet the primary endpoint due to a strong and unforeseen response in the sham group, the active treatment arm demonstrated statistically significant and clinically meaningful improvement from the treatment arm’s baseline. Further, the RECOVER study demonstrated statistically significant and clinically meaningful benefits in select secondary endpoints for this cohort. Based upon these findings and the positive effects for those who received VNS Therapy, the Company conducted additional in-depth data analyses and plans to submit three additional critical manuscripts to report on the outcomes. “ Participants in the trial had severe, refractory depression that could not be treated effectively with other FDA-approved treatments, and most have had large portions of their lives profoundly negatively impacted by depression,” said Charles Conway, MD, director of the Washington University Resistant Mood Disorders Center at Washington University School of Medicine in St. Louis. Conway is the study's lead investigator and first author of the mood outcomes article. “ For this sample of markedly ill TRD participants, I am encouraged by the findings, which revealed that active VNS performed better than sham VNS treatment in all measures, and that active VNS demonstrated clinically meaningful, safe therapeutic effects. Multiple clinician, patient, and independent observer ratings separated between the active and sham unipolar arms.” The first article , “ Vagus Nerve Stimulation in Treatment-Resistant Depression: A One-Year, Randomized, Sham-Controlled Trial,” 1 outlines the safety and effectiveness of adjunctive VNS Therapy in treating patients with unipolar TRD. The primary endpoint measured the difference in the percentage of time in antidepressant response between active VNS Therapy and sham VNS Therapy, with response defined as at least a 50% reduction from baseline using the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. While the predetermined p-value was p<0.023, the observed mean percentage of time in response was p=0.137. Analyses of secondary endpoints revealed antidepressant benefits significantly favoring active VNS Therapy as opposed to sham VNS Therapy as measured by ratings from on-site clinicians (Clinical Global Impression-Improvement, or CGI-I), patients themselves (Quick Inventory of Depressive Symptomology–Self Report, or QIDS-SR), and offsite masked raters (Quick Inventory of Depressive Symptomology–Clinical, or QIDS-C). Results included: Participants with active VNS Therapy had significantly more percentage of time in response with CGI-I ( P =0.004) and QIDS-SR ( P =0.049) compared with sham VNS Therapy. For percentage of time in partial response, active VNS Therapy showed significant benefit with QIDS-C ( P =0.006) and CGI-I ( P <0.001) compared with sham VNS Therapy. Partial response is defined as improvement of ≥30% from baseline for QIDS-C or a score of ≤3 for CGI-I. No differences between treatment groups were observed in suicidal ideation and intent as measured by the S-STS 2 items 6 and 8 ( P =0.239). “ The composite of the mood findings, especially in the partial response rates on multiple ratings scales, along with the low rate of adverse events, support that this device demonstrated safe antidepressant efficacy for these patients,” said Conway. The second article , “ Effects of Vagus Nerve Stimulation on Daily Function and Quality of Life in Markedly Treatment-Resistant Major Depression: Findings from a One-Year, Randomized, Sham-Controlled Trial,” 3 assesses VNS Therapy’s ability to improve quality of life (QoL) and daily function in patients with unipolar TRD. The results of this analysis demonstrated that adjunctive VNS Therapy provided greater improvements in QoL and daily function in patients with unipolar TRD when compared with sham VNS Therapy. Results included: The active VNS Therapy group showed greater improvements over the sham control group as measured by the mean change in scores from baseline in the Mini-Q-LES-Q 4 ( P =0.050) and WPAI 5 item 6 (health condition’s effect on regular activities; P =0.050) used as continuous variables. Time spent in a state of clinically meaningful benefit was significantly greater with active VNS Therapy compared to sham VNS Therapy, using the Q-LES-Q 6 ( P =0.029), Mini-Q-LES-Q ( P =0.011) and WPAI item 6 ( P =0.039). No differences between treatment groups were observed in the mean change in score from baseline with the WHODAS 7 2.0 ( P =0.304) and the EQ-5D 8 visual analog scale ( P =0.125). “ Adjunctive VNS Therapy improves quality of life and psychosocial function in patients with major depression who have not benefited from multiple antidepressant treatments,” said A. John Rush, MD, Professor Emeritus at Duke-National University of Singapore Medical School and lead author on this article. “ For these patients who are profoundly impaired, largely unemployed, and markedly treatment-resistant, depressive symptoms alone are an incomplete gauge of the clinical impact of treatments. Symptoms, function, and quality of life taken together present a more complete picture of treatment effectiveness.” These two articles published in Brain Stimulation are the first in a series that will detail the RECOVER unipolar cohort data. Three subsequent, supportive manuscripts will feature outcomes from in-depth data analyses on select secondary endpoints. The totality of data presented in these five complementary articles will serve as the basis for LivaNova’s formal request to the U.S. Centers for Medicare and Medicaid Services (CMS) for VNS Therapy coverage. “ Patients in the RECOVER study are some of the most critically ill among those with treatment-resistant depression and they need more treatment options when existing therapies fail,” said Vladimir Makatsaria, Chief Executive Officer of LivaNova. “ The data from the RECOVER study and predecessor studies has shown that VNS Therapy is a safe and effective treatment option for these patients, providing hope for patients and families in similar situations who have few viable options. We look forward to sharing more of the important outcomes from the unipolar cohort with the intent to offer VNS Therapy as an important adjunctive treatment for these patients.” RECOVER launched in 2019 as part of a Coverage with Evidence Development framework per the CMS National Coverage Determination process. For the unipolar cohort of RECOVER, enrollment was completed in March 2023, and the 12-month follow-up for those patients was completed in March 2024. No new safety issues were identified in the study. About RECOVER LivaNova’s VNS Therapy™ System has been approved for the treatment of depression since earning CE Mark in 2001 and 510(k) from the U.S. Food and Drug Administration in 2005. RECOVER stands for A P r ospective, Multi-c e nter, Randomized C ontrolled Blinded Trial Dem o nstrating the Safety and Effectiveness of V NS Therapy System as Adjunctiv e Therapy Versus a No Stimulation Control in Subjects With Treatment- R esistant Depression. The largest randomized clinical study of its kind, RECOVER is examining up to 1,000 patients ages 18 or older who have unipolar or bipolar depression that is difficult to treat. The double-blind, randomized controlled study is assessing how VNS Therapy can offer patients relief from their depressive symptoms and improve quality of life. It is being carried out at up to 100 leading hospitals and medical centers across the United States. About VNS Therapy for Depression The VNS Therapy™ System, Symmetry™, is U.S. Food and Drug Administration-approved and indicated in the U.S. for the adjunctive long-term treatment of chronic or recurrent depression for patients 18 years of age or older who are experiencing a major depressive episode and have not had an adequate response to four or more adequate antidepressant treatments The most commonly reported side effects are voice alteration or hoarseness, prickling or tingling in the skin, increased coughing, shortness of breath, and sore throat. Infection is the most common complication of the surgical procedure. Important safety information is available at www.livanova.com/depression/en-us/safety-information . References Conway CR, et al. Vagus nerve stimulation in treatment-resistant depression: A one-year, randomized, sham-controlled trial. Brain Stimulation. Dec. 18, 2024. DOI: 10.1016/j.brs.2024.12.1191. The Sheehan Suicidality Tracking Scale (S-STS) is a clinician-administered rating scale that tracks treatment-emergent suicidal ideation and behaviors. Rush AJ, et al. Effects of vagus nerve stimulation on daily function and quality of life in markedly treatment-resistant major depression: Findings from a one-year, randomized, sham-controlled trial. Brain Stimulation. Dec. 18, 2024. DOI: 10.1016/j.brs.2024.12.1187. Mini-Q-LES-Q (Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form) is a quality-of-life measure from a self-report assessing the patient’s degree of enjoyment and satisfaction across seven domains as a subset of the Q-LES-Q. WPAI item 6 is a function measure from the Work Productivity and Activity Impairment (WPAI) Questionnaire. Q-LES-Q is a quality-of-life measure from a self-report assessing the patient’s degree of enjoyment and satisfaction experienced over the previous seven days across 14 domains. WHODAS (World Health Organization Disability Assessment Schedule) assesses the patient’s ability to perform activities in the previous month in six domains. The EuroQoL Five-Dimension Questionnaire (EQ-5D) is a generic QoL measure that assesses mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. About LivaNova LivaNova PLC is a global medical technology company built on nearly five decades of experience and a relentless commitment to provide hope for patients and their families through medical technologies, delivering life-changing solutions in select neurological and cardiac conditions. Headquartered in London, LivaNova employs approximately 2,900 employees and has a presence in more than 100 countries for the benefit of patients, healthcare professionals, and healthcare systems worldwide. For more information, please visit www.livanova.com . Safe Harbor Statement This news release contains “forward-looking statements” concerning the Company’s goals, beliefs, expectations, strategies, objectives, plans, underlying assumptions, and other statements that are not necessarily based on historical facts. These statements include, but are not limited to, statements regarding the RECOVER study and the VNS Therapy™ System, Symmetry™. Actual events may differ materially from those indicated in our forward-looking statements as a result of various factors, including those factors set forth in Item 1A of the Company’s most recent Annual Report on Form 10-K, as supplemented by any risk factors contained in Quarterly Reports on Form 10-Q and Current Reports on Form 8-K. LivaNova undertakes no obligation to update the information contained in this press release to reflect subsequently occurring events or circumstances.

Clinical ResultClinical Study

10 Dec 2024

·www.globenewswire.com

Neuronetics and Greenbrook TMS Announce Closing of Transaction

MALVERN, Pa. and TORONTO, Dec. 10, 2024 (GLOBE NEWSWIRE) -- Neuronetics, Inc. (NASDAQ: STIM) (“Neuronetics”) and Greenbrook TMS Inc. (OTCMKTS: GBNHF) (“Greenbrook”, and together with Neuronetics, the “Combined Company”) today announced that they have successfully completed the previously announced transaction whereby Neuronetics acquired all of the issued and outstanding common shares of Greenbrook (the “Greenbrook Shares”) by way of a court-approved plan of arrangement under the Business Corporations Act (Ontario) (the “Arrangement”). Each Greenbrook Share outstanding immediately prior to the effective time of the Arrangement was exchanged for 0.01021 of a share of common stock of Neuronetics (the “Exchange Ratio”) upon closing of the Arrangement. In connection with and prior to closing of the Arrangement, Madryn Asset Management, LP and its affiliates (collectively, “Madryn”) converted (i) all of the outstanding amount owing under Greenbrook’s credit agreement into 2,056,453,835 Greenbrook Shares, representing 95.3% of the Greenbrook Shares (including the Greenbrook Shares held by Madryn prior to such conversion) immediately prior to closing of the Arrangement and (ii) all of the interim period funding provided by Madryn to Greenbrook into an additional 252,999,770 Greenbrook Shares, which Greenbrook Shares were exchanged for shares of common stock of Neuronetics (“Neuronetics Shares”) at the Exchange Ratio upon closing of the Arrangement. As a result of the Arrangement, the Greenbrook Shares will be removed from the OTCQB Market. Neuronetics has also caused Greenbrook to apply to cease to be a reporting issuer under the securities legislation of each of the provinces and territories of Canada, and intends to otherwise terminate Greenbrook’s public reporting requirements. The Combined Company will continue to operate as Neuronetics, Inc., and the Neuronetics Shares will continue to trade on the NASDAQ Global Market under the ticker “STIM”. “The completion of this transaction marks a transformative moment in the delivery of mental health therapy in the United States,” said Keith Sullivan, President and Chief Executive Officer of Neuronetics. “By bringing together Neuronetics' innovative technology platform with Greenbrook's established network of treatment centers and service offerings, we are better positioned than ever to expand patient access to life-changing mental health treatments by capitalizing on the Combined Company’s stronger revenue base and cost synergy opportunities. We look forward to working alongside our new colleagues to realize the full potential of this combination, build shareholder value and advance our shared mission of improving mental health care.” Keith Sullivan continued, “Our integration planning teams have already made significant progress in mapping out how we'll bring together the best of both organizations. Our immediate focus is on maintaining operational excellence while we begin to implement the strategic initiatives that will drive profitable growth, positive cash flow and ultimately long-term value for our shareholders.” Bill Leonard, President and Chief Executive Officer of Greenbrook, commented: “We are both excited and optimistic about our future as a combined company. Together, we will be able to better serve the mental health industry by increasing our leadership position and providing innovative solutions to help patients struggling with depression. As we move forward, we are grateful for the opportunity to be working alongside the Neuronetics team and building an even stronger foundation for growth and success. Greenbrook and Neuronetics are mutually aligned in our values and commitment to the mental health space and are well-positioned to continue that mission together as one.” Information for Former Greenbrook Shareholders Registered holders of Greenbrook Shares are reminded that they must properly complete, sign and return the letter of transmittal to Computershare Investor Services Inc., as depositary (“Computershare”), in order to receive the share consideration to which they are entitled in connection with the Arrangement. Holders of Greenbrook Shares (“Greenbrook Shareholders”) who hold their Greenbrook Shares through a broker, investment dealer or other intermediary should carefully follow the instructions provided by such broker, investment dealer or other intermediary in order to receive the share consideration to which they are entitled in connection with the Arrangement. Former Greenbrook Shareholders who have questions or require assistance may direct their questions to Computershare Investor Services Inc., by telephone at 1-800-564-6253 (toll free) or by e-mail at corporateactions@computershare.com. As a result of the labour dispute at Canada Post, registered holders of Greenbrook Shares are encouraged to contact Computershare with any questions by e-mail at corporateactions@computershare.com in the event that registered holders of Greenbrook Shares have not received copies of their DRS statement(s) or certificate(s) representing their Neuronetics Shares following the closing of the Arrangement and completion and delivery of their letter of transmittal to Computershare. Advisors Canaccord Genuity is serving as financial advisor to Neuronetics, and Ballard Spahr LLP as well as Stikeman Elliott LLP are serving as its legal counsel. A.G.P./Alliance Global Partners is serving as financial advisor to Greenbrook, and Torys LLP is serving as its legal counsel. About Neuronetics and Greenbrook Neuronetics, Inc. believes that mental health is as important as physical health. As a global leader in neuroscience, Neuronetics is redefining patient and physician expectations by offering exceptional treatments that produce extraordinary results. Neuronetics’ NeuroStar Advanced Therapy for Mental Health is a non-drug, noninvasive treatment that can improve the quality of life for people suffering from neurohealth conditions when traditional medication has not helped. In addition to selling the NeuroStar system and associated treatment sessions to customers, Greenbrook operates treatment centers across the United States, offering both NeuroStar Advanced Therapy (transcranial magnetic stimulation or “TMS”) and Spravato® (esketamine nasal spray) for the treatment of major depressive disorder (“MDD”) and other mental health disorders. NeuroStar Advanced Therapy is the leading TMS treatment for MDD in adults with more than 6.9 million treatments delivered and is backed by the largest clinical data set of any TMS treatment system for depression, including the world’s largest depression outcomes registry. Spravato® is offered to treat adults with treatment-resistant depression and depressive symptoms in adults with MDD with suicidal thoughts or actions. Greenbrook has provided more than 1.68 million treatments to over 51,000 patients struggling with depression. The NeuroStar Advanced Therapy System is cleared by the U.S. Food and Drug Administration (the FDA) for adults with Major Depressive Disorder (MDD), as an adjunct for adults with obsessive-compulsive disorder, and to decrease anxiety symptoms in adult patients with MDD that may exhibit comorbid anxiety symptoms (anxious depression), and as a first line adjunct for the treatment of MDD in adolescent patients aged 15-21. For safety information and indications for use, visit NeuroStar.com. Neuronetics Contact: Investors:Mike Vallie or Mark KlausnerICR Healthcare443-213-0499ir@neuronetics.com Media: EvolveMKD 646-517-4220 NeuroStar@evolvemkd.com “Safe harbor” statement under the Private Securities Litigation Reform Act of 1995: This document includes “forward-looking statements” within the meaning of Section 27A of the Securities Act of 1933, as amended (the “Securities Act”), Section 21E of the Securities Exchange Act of 1934, as amended, which are intended to be covered by the safe harbors created by those laws and other applicable laws and “forward-looking information” within the meaning of applicable Canadian securities laws. Statements in the press release that are not historical facts constitute “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements may be identified by terms such as “outlook,” “potential,” “believe,” “expect,” “plan,” “anticipate,” “predict,” “may,” “will,” “could,” “would” and “should” as well as the negative of these terms and similar expressions. These statements include those relating to the Combined Company’s business outlook and current expectations for upcoming quarters and fiscal year 2024, including with respect to revenue, expenses, growth, and any statements of assumptions underlying any of the foregoing items, as well as statements relating to removal of the Greenbrook Shares from the OTCQB Market and Greenbrook ceasing to be a reporting issuer under the securities legislation of each of the provinces and territories of Canada. These statements are subject to significant risks and uncertainties and actual results could differ materially from those projected. The Combined Company cautions investors not to place undue reliance on the forward-looking statements contained in this release. These risks and uncertainties include, without limitation, risks and uncertainties related to: the effect of the transaction with Greenbrook, on our business relationships, operating results and business generally; the Combined Company’s ability to execute its business strategy; the Combined Company’s ability to achieve or sustain profitable operations due to its history of losses; the Combined Company’s ability to successfully complete the announced restructuring plans; the Combined Company’s reliance on the sale and use of its NeuroStar Advanced Therapy system to generate revenues; the scale and efficacy of the Combined Company’s salesforce; the Combined Company’s ability to retain talent; availability of coverage and reimbursement from third-party payors for treatments using the Combined Company’s products; physician and patient demand for treatments using the Combined Company’s products; developments in competing technologies and therapies for the indications that the Combined Company’s products treat; product defects; our revenue has been concentrated among a small number of customers; the Combined Company’s ability to obtain and maintain intellectual property protection for its technology; developments in clinical trials or regulatory review of NeuroStar Advanced Therapy system for additional indications; developments in regulation in the U.S. and other applicable jurisdictions; the terms of our credit facility; our ability to successfully roll-out our Better Me Provider program on the planned timeline; our self-sustainability and existing cash balances; and our ability to achieve cash flow break-even in the third quarter of 2025. For a discussion of these and other related risks, please refer to the Combined Company’s recent filings with the U.S. Securities and Exchange Commission (the “SEC”), which are available on the SEC’s website at www.sec.gov, including, without limitation, the factors described under the heading “Risk Factors” in Neuronetics’ Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and its Quarterly Report on Form 10-Q for the quarter ended September 30, 2024, and Greenbrook’s Annual Report on Form 10-K for the fiscal year ended December 31, 2023 and its Quarterly Report on Form 10-Q for the quarter ended June 30, 2024, as each may be updated or supplemented by subsequent reports that Neuronetics has filed or files with the SEC. These forward-looking statements are based on the Combined Company’s expectations and assumptions as of the date of this press release. Except as required by law, the Combined Company undertakes no duty or obligation to update any forward-looking statements contained in this press release as a result of new information, future events, or changes in the Combined Company’s expectations.

25 Nov 2024

·www.prnewswire.com

Major Depressive Disorder Market to Register Immense Growth by 2034 Owing to a Robust Pipeline | DelveInsight

With the anticipated introduction of new treatments such as COMP360 (COMPASS Pathways), Zuranolone (SAGE Therapeutics/Biogen), LY03005 (Luye Pharma), REL-1017 (Relmada Therapeutics), Seltorexant (Minerva Neurosciences/Janssen Pharmaceutical), ABV-1504 (BioLite/ABVC BioPharma), and other and increasing disease awareness, it's reasonable to expect a significant transformation in the major depressive disorder market in the coming years. LAS VEGAS, Nov. 25, 2024 /PRNewswire/ -- Major depressive disorder (MDD), commonly referred to as depression, is a serious medical condition that affects a person's mood, behavior, thinking, and physical well-being. It is different from the temporary feelings of sadness that everyone experiences and should not be confused with the deep grief following the loss of a loved one. MDD is typically a recurrent and episodic condition, meaning that someone who has experienced depression and recovered is likely to face additional episodes, often within 2 to 3 years. As per DelveInsight analysis, the total diagnosed prevalent cases of MDD in the 7MM were found to be approximately 44 million cases in 2023, which is expected to increase during the forecast period (2024–2034). Among the severity-specific diagnosed prevalent cases of MDD, the highest prevalence was observed in moderate cases accounting for approximately 17 million cases in the 7MM in 2023 followed by severe cases and mild cases. Major depressive disorder can be addressed through several treatment approaches, including pharmacological interventions, psychotherapy, interventional methods, and lifestyle changes. Initial treatment often involves either medication, psychotherapy, or a combination of both, with combined therapy proving more effective than using either alone. For severe cases of major depression, electroconvulsive therapy is the most effective option. The current range of recommended pharmacological treatments for major depressive disorder primarily includes antidepressants such as monoamines, tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs), and selective reuptake inhibitors, including medications like VRAYLAR, BRINTELLIX (now TRINTELLIX), SPRAVATO, REXULTI, and FETZIMA. In the upcoming major depressive disorder treatment market landscape, there are a plethora of companies investigating agents for use in major depressive disorder which includes Sage Therapeutics, Relmada Therapeutics, Johnson & Johnson Services, Inc., Biogen, COMPASS Pathways, Luye Pharma, and others. Many more pharma companies are conducting clinical trials for therapies for major depressive disorder. To know more about upcoming major depressive disorder therapies showing positive results, visit @ Drugs for Major Depressive Disorder Treatment DelveInsight estimates that the market size for major depressive disorder is expected to grow from USD 7.1 billion in 2023 with a significant CAGR by 2034. The disease awareness and the emergence of new products in the pipeline will add to the market growth in the future. In addition, persistently rising cases of MDD in the forecast period will contribute to the rise in the MDD treatment market. The current pipeline for major depressive disorder includes a range of drugs with diverse mechanisms of action (MoA). COMP360 (COMPASS Pathways) , Zuranolone (SAGE Therapeutics/Biogen) , LY03005 (Luye Pharma) , REL-1017 (Relmada Therapeutics) , seltorexant (Minerva Neurosciences/Janssen Pharmaceutical) , ABV-1504 (BioLite/ABVC BioPharma), and some others are the most promising drugs of this indication. Ongoing research and current trials have the potential to change the MDD market. Keen to know how the MDD market will evolve by 2034? Find out @ Major Depressive Disorder Market Report The potential for effective major depressive disorder treatment in the future is expected to grow with the addition of numerous drugs to the pipeline of new therapeutics. Currently, a variety of candidate drugs for the treatment of major depressive disorder are being tested in various clinical trials, with some showing positive results. Any drug approved with increased safety and efficacy is expected to cause significant changes in the overall major depressive disorder market. Now, let's examine the pipeline therapies under investigation for major depressive disorder COMP360: COMPASS Pathways Phase III COMPASS Pathways is investigating the use of its experimental psilocybin therapy, COMP360, for treating serious mental health conditions like major depressive disorder. COMP360 is a synthesized version of psilocybin, the active compound found in certain "magic mushrooms," and is administered alongside psychological support. Psilocybin has shown promise in therapeutic applications, and COMP360 has been granted Breakthrough Therapy status by the US FDA as well as an Innovative Licensing and Access Pathway (ILAP) designation in the UK for treatment-resistant depression (TRD). Currently, COMPASS Pathways is running a Phase II trial for MDD, with a Phase III trial underway in partnership with Massachusetts General Hospital to further explore its potential in meeting mental health treatment needs. The company is anticipated to release top-line data from two key trials, COMP005 and COMP006, by the fourth quarter of 2024 and mid-2025, respectively, for the treatment of TRD. Zuranolone: SAGE Therapeutics/Biogen Phase III Zuranolone, being developed by SAGE Therapeutics and Biogen, is a next-generation oral, highly potent, and selective positive allosteric modulator, designed for specific targeting of synaptic and extrasynaptic GABAA receptors. The binding sites for neuroactive steroids (NASs) are different from those for GABA, benzodiazepines, and barbiturates. The GABA system, which is the primary inhibitory signaling pathway in the brain and central nervous system (CNS), plays a key role in regulating CNS function. SAGE-217 is currently in phase III clinical development for major depressive disorder and is being evaluated through the LANDSCAPE and NEST clinical trial programs, which include multiple studies involving thousands of participants, with varying dosing regimens, clinical endpoints, and treatment approaches. In February 2023, the US FDA accepted the New Drug Application (NDA) for zuranolone in the treatment of MDD. However, in August 2023, the FDA issued a Complete Response Letter (CRL) regarding the NDA for zuranolone for treating adults with MDD. Sage and Biogen are now assessing the feedback and determining their next steps. LY03005: Luye Pharma LY03005, developed by Luye Pharma, is one of the company's key products in the CNS therapeutic space. It is their exclusive extended-release tablet formulation of ansofaxine hydrochloride, a serotonin-norepinephrine-dopamine triple reuptake inhibitor (SNDRI) designed for treating major depressive disorder. LY03005 aims to offer improved efficacy and fewer side effects compared to conventional antidepressants like SSRIs and SNRIs. Ansofaxine, a prodrug of desvenlafaxine, strongly inhibits dopamine reuptake in addition to serotonin and norepinephrine, demonstrating superior efficacy in clinical trials. In March 2020, the US FDA accepted the NDA submission for LY03005, which is currently in Phase III pivotal clinical trials for MDD treatment. Seltorexant: Minerva Neurosciences/Janssen Pharmaceutical Phase III Seltorexant, developed by Minerva Neurosciences and Janssen Pharmaceutical, is a selective orexin-2 receptor antagonist intended as an adjunctive treatment for major depressive disorder and for managing insomnia. It is the most advanced ORX2-specific molecule in clinical development, acting as an antagonist by binding to its receptor. Seltorexant is being studied for two main uses: insomnia without psychiatric disorders and MDD in patients who do not respond adequately to SSRIs or SNRIs. In May 2024, Johnson & Johnson reported positive topline results from the pivotal Phase III MDD3001 trial, which assessed its efficacy and safety as an add-on therapy to antidepressants in adults and elderly MDD patients. Discover which therapies are expected to grab major MDD market share @ New Treatments for Major Depressive Disorder REL-1017: Relmada Therapeutics Phase III REL-1017, being developed by Relmada Therapeutics, is a novel chemical entity (NCE) and an NMDA receptor (NMDAR) channel blocker that specifically targets overactive channels while preserving normal glutamatergic neurotransmission. The U.S. FDA has granted it Fast Track Designation as an immunotherapy for treating major depressive disorder. In a Phase II trial, REL-1017 exhibited rapid, strong, and lasting antidepressant effects, with statistically significant improvements over placebo in depression measures. The study also indicated a favorable safety, tolerability, and pharmacokinetic profile for the drug. Currently, it is in late-stage development for MDD, being tested in Phase III trials for both adjunctive and monotherapy. In June 2024, Relmada published clinical data from the Reliance I Study. The company is actively enrolling patients in ongoing trials for REL-1017, including Reliance II (Study 302), with top-line results expected in the latter half of 2024, and Relight (Study 304), which is anticipated to provide results about six months after the completion of Study 302. ABV-1504: ABVC BioPharma Phase II ABV-1504, developed by ABVC BioPharma, features PDC-1421 as its active ingredient and is classified as a botanical investigational new drug. Through its subsidiary BioLite, ABVC has completed a Phase II trial of ABV-1504, a botanical Norepinephrine Transporter (NET) inhibitor. This trial, conducted at Stanford University, showed that the PDC-1421 capsule was safe and well-tolerated among six enrolled adult patients. Both low and high doses of PDC-1421 successfully achieved the study's primary endpoints, showing a necessary 40% improvement in ADHD-RS-IV test scores. In April 2023, PDC-1421 was awarded a US patent (US 11,554,154 B2) for the treatment of Major Depressive Disorder (MDD). The drug has also completed a Phase II trial in MDD patients, and the company intends to hold an End of Phase II (EOP II) meeting with the FDA in the near future. Itruvone (PH10): VistaGen Therapeutics Phase II Itruvone (PH10), being developed by VistaGen Therapeutics, is an investigational first-in-class synthetic neurosteroid that is odorless and fast-acting, showing promise for various neuropsychiatric conditions related to depression and suicidal thoughts. VistaGen is focusing on PH10 as a potential quick-acting, non-sedating, and non-addictive treatment for MDD that patients can conveniently self-administer at home. When self-administered, a microgram-level dose of PH10 sprayed into the nose interacts with nasal chemosensory receptors, activating brain neural circuits to produce rapid antidepressant effects without the side effects, systemic exposure, or safety issues associated with FDA-approved treatments for MDD, such as oral antidepressants and esketamine. After successfully completing Phase IIa trials for MDD, VistaGen is now gearing up for the planned Phase IIb clinical development of PH10 for this condition. Moreover, in December 2022, PH10 received fast-track designation from the US FDA. LPCN 1154: Lipocine Phase II LPCN 1154, developed by Lipocine, is an oral formulation of brexanolone designed for rapid relief of postpartum depression. Its active ingredient is a naturally occurring positive allosteric modulator of the GABAa receptor. This medication is intended to provide an "at-home" treatment option, making it more accessible than the current standard care, which involves invasive procedures and hospitalization. In September 2022, the FDA approved Lipocine's proposal to demonstrate the efficacy of LPCN 1154 through a single pivotal pharmacokinetic bridge to the approved IV infusion of brexanolone via a 505(b)(2) NDA submission. In June 2024, Lipocine announced positive topline results from a pivotal pharmacokinetic study, confirming that LPCN 1154 is bioequivalent to IV brexanolone for PPD treatment. Lipocine aims to submit the NDA by the end of the fourth quarter of 2024. Discover more about drugs for major depressive disorder in development @ Major Depressive Disorder Clinical Trials DelveInsight's latest published market report titled as Major Depressive Disorder Market Insight, Epidemiology, and Market Forecast – 2034 will help you to discover which market leader is going to capture the largest market share. The report provides comprehensive insights into the major depressive disorder country-specific treatment guidelines, patient pool analysis, and epidemiology forecast to help understand the key opportunities and assess the market's underlying potential. The major depressive disorder market report proffers epidemiological analysis for the study period 2020–2034 in the 7MM segmented into: Total Diagnosed Prevalent Cases of MDD Gender-specific Diagnosed Prevalent Cases of MDD Severity-specific Diagnosed Prevalent Cases of MDD The report provides an edge while developing business strategies by understanding trends shaping and driving the 7MM major depressive disorder market. Highlights include: 11-year Forecast 7MM Analysis Epidemiology-based Market Forecasting Historical and Forecasted Market Analysis upto 2034 Emerging Drug Market Uptake Peak Sales Analysis Key Cross Competition Analysis Industry Expert's Opinion Access and Reimbursement Download this major depressive disorder market report to assess the epidemiology forecasts, understand the patient journeys, know KOLs' opinions about the upcoming treatment paradigms, and determine the factors contributing to the shift in the major depressive disorder market. Also, stay abreast of the mitigating factors to improve your market position in the major depressive disorder therapeutic space. Related Reports Major Depressive Disorder Pipeline Major Depressive Disorder Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key major depressive disorder companies, including GH Research, Praxis Precision Medicines, AbbVie, Gedeon Richter, Intra-Cellular Therapies, Bristol-Myers Squibb, Relmada Therapeutics, SAGE Therapeutics, Janssen Research & Development, Minerva Neurosciences, Takeda, Neurocrine Biosciences, Pherin Pharmaceuticals, among others. Treatment-Resistant Depression Market Treatment-Resistant Depression Market Insights, Epidemiology, and Market Forecast – 2032 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, market share of the individual therapies, and key TRD companies, including Navitor Pharmaceuticals, Supernus Pharmaceuti, Novartis, Relmada Therapeutics, Beckley Psytech, COMPASS Pathways, Axsome Therapeutics, Celon Pharma, among others. Treatment-Resistant Depression Pipeline Treatment-Resistant Depression Pipeline Insight – 2024 report provides comprehensive insights about the pipeline landscape, pipeline drug profiles, including clinical and non-clinical stage products, and the key treatment-resistant depression companies, including Axsome Therapeutics, COMPASS Pathways, Merck Sharp & Dohme Corp., Navitor Pharmaceuticals, Inc., Taisho Pharmaceutical Co., Ltd., GH Research Limited, Novartis Pharmaceuticals, Reckitt Benckiser LLC, Relmada Therapeutics, Inc., SAGE Therapeutics, Navitor Pharmaceuticals, Sumitomo Dainippon Pharma, Alkermes, AbbVie, Janssen Pharmaceuticals, Celon Pharma, ACADIA Pharmaceuticals, Pherin Pharmaceuticals, ATAI Life Sciences, among others. Postpartum Depression Market Postpartum Depression Market Insights, Epidemiology, and Market Forecast – 2034 report delivers an in-depth understanding of the disease, historical and forecasted epidemiology, as well as the market trends, market drivers, market barriers, and key postpartum depression companies, including Sage Therapeutics, Epharmix, Inc., among others. About DelveInsight DelveInsight is a leading Business Consultant and Market Research firm focused exclusively on life sciences. It supports pharma companies by providing comprehensive end-to-end solutions to improve their performance. Get hassle-free access to all the healthcare and pharma market research reports through our subscription-based platform PharmDelve . Contact Us Shruti Thakur [email protected] +14699457679 Logo: SOURCE DelveInsight Business Research, LLP WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

Phase 2Phase 3Clinical ResultFast TrackBreakthrough Therapy

100 Deals associated with Esketamine Hydrochloride

External Link

KEGG	Wiki	ATC	Drug Bank
D10627	Esketamine Hydrochloride	N01AX14 N06AX27	DB11823

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Depressive Disorder	CN	Janssen-Cilag International NV	17 Apr 2023
Major depressive disorder, moderate (MDD)	AU	Janssen-Cilag Pty Ltd.	09 Mar 2021
Depressive Disorder, Major	EU	Janssen-Cilag International NV	18 Dec 2019
Depressive Disorder, Major	IS	Janssen-Cilag International NV	18 Dec 2019
Depressive Disorder, Major	LI	Janssen-Cilag International NV	18 Dec 2019
Depressive Disorder, Major	NO	Janssen-Cilag International NV	18 Dec 2019
Anesthesia	CN	Jiangsu Hengrui Pharmaceuticals Co., Ltd.	18 Nov 2019
Depressive Disorder, Treatment-Resistant	US	Janssen Pharmaceuticals, Inc.	05 Mar 2019
Pain	DE	Pfizer Inc.	01 Aug 1997

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Suicidal Ideation	Phase 3	US	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	BG	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	EE	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	DE	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	HU	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	MY	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	SK	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	ZA	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	KR	Janssen Research & Development LLC	09 Jun 2017
Suicidal Ideation	Phase 3	ES	Janssen Research & Development LLC	09 Jun 2017

Clinical Result

Indication

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03373253 \| NCT02497287 (ICEBERG, Pubmed \| Front Psychiatry)	Phase 3	Functional disorder	696	Esketamine nasal spray + SSRI/SNRI	qavktkphci(oaejeangoi) = bssogeacfs oaqvgsgows (nxlhkzprle, 21.8 - 29.4)	Positive	07 Oct 2024
				esketamine nasal spray (Real-world treatment (RWT))	qavktkphci(oaejeangoi) = pwujpxfagm oaqvgsgows (nxlhkzprle, 6.9 - 16.1)
ChiCTR2200061956 (not available, Pubmed \| BMC Anesthesiol)	Phase 4	Hip Fractures brain-derived neurotrophic factor (BDNF) \| 5-hydroxytryptamine (5-HT)	90	Esketamine	vkdbmcxvdj(kfaykubzlp) = xbeelznept tryxvycaqj (kuxspztetd ) View more	Positive	28 Sep 2024
				Saline	vkdbmcxvdj(kfaykubzlp) = rnhitmbvml tryxvycaqj (kuxspztetd ) View more
NCT04757675 (Pubmed \| Transl Pediatr)	Early Phase 1	Strabismus	-	Intranasal esketamine 2 mg/kg	zmwfhqrzkr(rsdayulnts) = More gastrointestinal events were observed in Group K (P<0.001) ufvxuqlyem (hdhpdklanu )	Negative	01 Aug 2024
				Intranasal esketamine 1 mg/kg and dexmedetomidine 1 µg/kg
ChiCTR2100054199 (Pubmed \| JAMA Netw Open)	Early Phase 1	Depression, Postpartum	298	Esketamine	ljeczgihon(nwytychpvd) = orygocaner ugclhqhwmo (ijmjnpbbjp )	Positive	06 Mar 2024
				Control (Saline)	ljeczgihon(nwytychpvd) = dhkzbzzwrk ugclhqhwmo (ijmjnpbbjp )
ChiCTR2200060387 (Pubmed \| BMC Pharmacol Toxicol)	Phase 4	Depression, Postpartum stress \| inflammation	120	Esketamine 0.2 mg/kg	vqkpwhivml(acbqehcnjo) = ypkvvahtki xtootlevdy (urcjgxjnmg )	Positive	23 Nov 2023
				Placebo	vqkpwhivml(acbqehcnjo) = pezteosolw xtootlevdy (urcjgxjnmg )
ChiCTR2000041187 (Pubmed \| Laryngoscope)	Phase 2	-	-	Esketamine 0.5 mg kg−1	xvvpzhlqeq(oxzotudevz) = dmewrbdofd qvytearflv (hzedvyvmhf ) View more	Positive	01 Nov 2023
				Sufentanil 0.125 μg kg−1	xvvpzhlqeq(oxzotudevz) = igcjsblpzn qvytearflv (hzedvyvmhf ) View more
NCT04338321 (ESCAPE-TRD, PipelineReview) Manual	Phase 3	Depressive Disorder, Major	676	Esketamine	owqnrzdiii(opriaspkaa) = nxtajxtlyw wdvsruyfzs (bskqrppxsa ) View more	Positive	09 Oct 2023
				Quetiapine	owqnrzdiii(opriaspkaa) = ljfxlfarji wdvsruyfzs (bskqrppxsa ) View more
NCT04338321 (ESCAPE-TRD, Pubmed \| Br Dent J)	Phase 3	Depressive Disorder, Treatment-Resistant	-	Esketamine nasal spray	jqrsuodwig(aonqopuron) = hhakilnqlb plakgrdfzh (iayjkgqfgf ) View more	Positive	05 Oct 2023
				Extended-release quetiapine	jqrsuodwig(aonqopuron) = ntkqkzyugo plakgrdfzh (iayjkgqfgf ) View more
NCT02782104 (SUSTAIN-3, Pubmed \| CNS Drugs)	Phase 3	Depressive Disorder, Treatment-Resistant Maintenance	96	Esketamine nasal spray + oral antidepressant	euqmwwwhps(veevuvlipd) = During the IND and OP/M phases, 58.3% and 83.3% of patients experienced a treatment-emergent AE, respectively. No patients discontinued due to an AE during the second IND. ggwbjjphlh (rngqlnpttx )	Positive	01 Aug 2023
				Oral antidepressant + placebo nasal spray
ChiCTR2100052830 (Pubmed \| BMC Anesthesiol)	Phase 4	-	26	Esketamine combined with propofol	uchfswmgso(guaiathgpc) = recorded in two cases mbrfzjjdsf (jjpkeeenab ) View more	-	18 Jul 2023

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