Esmethadone-HCl (REL-1017): a promising rapid antidepressant

Fava, Maurizio; Stahl, Stephen M.; Martin, Sara De; Mattarei, Andrea; Bettini, Ezio; Comai, Stefano; Alimonti, Andrea; Bifari, Francesco; Pani, Luca; Folli, Franco; Guidetti, Clotilde; Furlan, Alberto; Sgrignani, Jacopo; Locatelli, Patrizia; Cavalli, Andrea; O’Gorman, Cedric; Traversa, Sergio; Inturrisi, Charles E.; Pappagallo, M.; Manfredi, Paolo L.

doi:10.1007/s00406-023-01571-4

Cited by 17 publications

(13 citation statements)

References 52 publications

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“…Rel-1017, another NMDAR antagonist, demonstrated rapid efficacy in MDD, with the persistence of antidepressant activity up to 1 week after treatment discontinuation (Fava et al, 2022). Additionally, changes in anhedonia, motivation, and reward have accompanied antidepressant-like activity in rodent models, after a single dose (Fogaça et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Clinical specificity profile for novel rapid acting antidepressant drugs

Scala

Fanelli

Ronchi

et al. 2023

International Clinical Psychopharmacology

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Mood disorders are recurrent/chronic diseases with variable clinical remission rates. Available antidepressants are not effective in all patients and often show a relevant response latency, with a range of adverse events, including weight gain and sexual dysfunction. Novel rapid agents were developed with the aim of overcoming at least in part these issues. Novel drugs target glutamate, gamma-aminobutyric acid, orexin, and other receptors, providing a broader range of pharmacodynamic mechanisms, that is, expected to increase the possibility of personalizing treatments on the individual clinical profile. These new drugs were developed with the aim of combining a rapid action, a tolerable profile, and higher effectiveness on specific symptoms, which were relatively poorly targeted by standard antidepressants, such as anhedonia and response to reward, suicidal ideation/behaviours, insomnia, cognitive deficits, and irritability. This review discusses the clinical specificity profile of new antidepressants, namely 4-chlorokynurenine (AV-101), dextromethorphan-bupropion, pregn-4-en-20-yn-3-one (PH-10), pimavanserin, PRAX-114, psilocybin, esmethadone (REL-1017/dextromethadone), seltorexant (JNJ-42847922/MIN-202), and zuranolone (SAGE-217). The main aim is to provide an overview of the efficacy/tolerability of these compounds in patients with mood disorders having different symptom/comorbidity patterns, to help clinicians in the optimization of the risk/benefit ratio when prescribing these drugs.

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Section: Discussionmentioning

confidence: 99%

Clinical specificity profile for novel rapid acting antidepressant drugs

Scala

Fanelli

Ronchi

et al. 2023

International Clinical Psychopharmacology

View full text Add to dashboard Cite

show abstract

“…Interestingly the antidepressant effect extended also to an enhancement in cognitive and social functioning, anxiety, agitation, anger, irritability, and sleep quality. It also showed a favorable safety profile, characterized by dose-related nausea and somnolence only at higher doses [ 30 - 33 ]. It therefore received the FDA fast-track designation as an adjunctive treatment for major depression disorder.…”

Section: Dextromethadonementioning

confidence: 99%

A Critical View on New and Future Antidepressants

Serretti

2024

Clin Psychopharmacol Neurosci

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For the first time after many decades, many new antidepressants have been approved and many more are under various stages of development and will soon be available in the market. The new drugs present a range of new mechanisms of action with benefits in terms of speed of action, tolerability and range of treatable disorders. Neurosteroids have been recently approved and their rapid benefit may extend from postpartum depression to anxious depression and bipolar depression, dextromethorphan and bupropion combination may prove useful in major depression but also in treatment resistant depression, dextromethadone is a possible augmentation in partial antidepressant response, psychedelic drugs have the potential of long lasting benefits after a single administration, though are still experimental treatments. Botulinum has the same advantage of psychedelics of a single administration and its antidepressant effects may last for weeks or more. Further potentially interesting new antidepressant mechanisms include new drug targets, drug repurposing and genetic or epigenetic manipulations. It is therefore important that clinicians are kept up to date with new evidence so that new evidence can be rapidly translated into clinical practice.

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“…Another trial explored the use of adjunctive esmethadone, another uncompetitive NMDA receptor antagonist [154]. This trial demonstrated rapid and robust reductions in depressive symptoms, although this was not consistently replicated in a subsequent phase 3 trial.…”

Section: Antidepressant Breakthroughs: Advancements In Pharmacotherap...mentioning

confidence: 99%

Advancements Exploring Major Depressive Disorder: Insights on Oxidative Stress, Serotonin Metabolism, BDNF, HPA Axis Dysfunction, and Pharmacotherapy Advances

Correia,

Vale

2024

IJTM

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Major depressive disorder (MDD), a prevalent mental illness, is marked by a complex mixture of biological factors. This review focuses on the roles of oxidative stress, tryptophan-serotonin metabolism, brain-derived neurotrophic factor (BDNF), and the hypothalamic–pituitary–adrenal (HPA) axis in MDD’s pathophysiology. Oxidative stress, defined as an imbalance between pro-oxidants and antioxidants, is closely linked to MDD’s neurobiological changes. The tryptophan (TRP)-/serotonin (5-HT) metabolic pathway is also known to be crucial in mood regulation, with its dysregulation being a central aspect of MDD. Additionally, BDNF, key for neuronal growth and plasticity, often shows alterations in MDD patients, supporting its role in the disorder’s progression. Furthermore, the HPA axis, which manages stress response, is frequently disrupted in MDD, further contributing to its complex pathology. In addition to exploring these biological mechanisms, this review also explores the pharmacotherapy of MDD, including new advances. These advancements in treatment strategies are crucial for managing MDD effectively. Understanding these mechanisms and the latest pharmacological interventions is essential for developing more effective treatments for MDD.

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Esmethadone-HCl (REL-1017): a promising rapid antidepressant

Cited by 17 publications

References 52 publications

Clinical specificity profile for novel rapid acting antidepressant drugs

Clinical specificity profile for novel rapid acting antidepressant drugs

A Critical View on New and Future Antidepressants

Advancements Exploring Major Depressive Disorder: Insights on Oxidative Stress, Serotonin Metabolism, BDNF, HPA Axis Dysfunction, and Pharmacotherapy Advances

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