(R)-(-)-Ketamine: The Promise of a Novel Treatment for Psychiatric and Neurological Disorders

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6804 - 6804

Published: June 20, 2024

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative epilepsy, traumatic brain injury, substance abuse disorder (SUD), major depressive (MDD). (S)-ketamine was the first of a novel class antidepressants, rapid-acting to be approved medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development treatment-resistant depression (TRD). compound has demonstrated efficacy multiple animal models. Two clinical studies disclosed TRD bipolar depression. A study by drug sponsor recently failed reach priori endpoints but post hoc analysis revealed efficacy. value supported experimental data humans rodents, showing that it less sedating, does not produce marked psychotomimetic or dissociative effects, than (S)-ketamine, produces models range disorders. mechanisms action antidepressant effects are hypothesized due antagonism and/or non-NMDA mechanisms. We suggest further experimentation with will create improved medicines some disorders underserved current medications.

Language: Английский

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Novel rapid treatment options for adolescent depression

Pharmacological Research, Journal Year: 2024, Volume and Issue: 201, P. 107085 - 107085

Published: Feb. 2, 2024

There is an urgent need for novel fast-acting antidepressants adolescent treatment-resistant depression and/or suicidal risk, since the selective serotonin reuptake inhibitors that are clinically approved age (i.e., fluoxetine or escitalopram) take weeks to work. In this context, one of main research lines our group characterize at preclinical level approaches rapid-acting adolescence. The present review summarizes potential use in adolescence non-pharmacological options, such as neuromodulators (electroconvulsive therapy and other innovative types brain stimulation), well pharmacological including consciousness-altering drugs (mainly ketamine but also classical psychedelics) cannabinoids cannabidiol), with promising responses. Following a brief analytical explanation depression, we general introduction each therapeutical approach together clinical evidence supporting its beneficial extrapolated from prior successful examples adults), then report recent ongoing studies will aid improving inclusion these therapies clinic, by considering sex-, age-, dose-related differences, factors might affect efficacy long-term safety. Finally, conclude providing future avenues maximize treatment response, more importance designing testing options safe depression.

Language: Английский

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The interplay of gut microbiota, obesity, and depression: insights and interventions

Cellular and Molecular Life Sciences, Journal Year: 2024, Volume and Issue: 81(1)

Published: Oct. 30, 2024

Language: Английский

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Intranasal dantrolene nanoparticles inhibit lipopolysaccharide-induced depression and anxiety behavior in mice

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

This study investigates the therapeutic effectiveness of intranasal dantrolene nanoparticles pretreatment to inhibit lipopolysaccharide (LPS)-induced pathological inflammation and synapse destruction depressive anxiety behavior in mice. B6SJLF1/J adult mice were pretreated with (dantrolene: 5mg/kg), daily, Monday Friday, 5 days per week, for 4 weeks. Then, treated an intraperitoneal injection LPS (5mg/kg) one time. Behavioral tests depression performed 24 hours after a one-time injection. Biomarkers pyroptosis-related cytokines (IL-1β IL-18) blood brain measured using enzyme-linked immunosorbent assay (ELISA) immunoblotting, respectively. The changes primary proteins activation inflammatory pyroptosis (NLRP3: NLR family pyrin domain containing 3, Caspase-1, N-GSDMD: N terminal protein gasdermin D) (PSD-95 synpatin-1) brains immunoblotting. Intranasal robustly inhibited LPS-induced behavior. significantly elevation IL-1β IL-18 pyroptosis. ameliorated decrease PSD-95 synpatin-1 brains. Thus, have demonstrated neuroprotection against inflammation-mediated behaviors should be studied further as future effective drug treatment major disorder or psychiatric disorder.

Language: Английский

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Engeletin alleviates depression‐like phenotype by increasing synaptic plasticity via the BDNF‐TrkB‐mTORC1 signalling pathway

Journal of Cellular and Molecular Medicine, Journal Year: 2023, Volume and Issue: 27(23), P. 3928 - 3938

Published: Oct. 6, 2023

Abstract Major depressive disorder (MDD) is a severe mental associated with high rates of morbidity and mortality. Current first‐line pharmacotherapies for MDD are based on enhancement monoaminergic neurotransmission, but these antidepressants still insufficient produce significant side‐effects. Consequently, the development novel therapeutic targets desired. Engeletin, natural Smilax glabra rhizomilax derivative, compound proven efficacy in treating ischemic stroke, yet its effects mechanisms depression remain unexplored. The engeletin were assessed forced swimming test (FST) tail suspension (TST) mice. Engeletin was also investigated chronic restraint stress (CRS) mouse model fluoxetine (FLX) as positive control. Changes prefrontal cortex (PFC) spine density, synaptic plasticity‐linked protein expressions brain‐derived neurotrophic factor (BDNF)‐tyrosine kinase B (TrkB)‐ mammalian target rapamycin complex 1 (mTORC1) signalling pathway after treatment then investigated. TrkB mTORC1 selective inhibitors, ANA‐12 rapamycin, respectively, utilized to assess engeletin's antidepressive mechanisms. Our data shows that exhibited antidepressant‐like activity FST TST mice without affecting locomotor activity. Furthermore, it efficiency against CRS model. Moreover, enhanced BDNF‐TrkB‐mTORC1 PFC during altered reduction dendritic density levels induced by CRS. In conclusion, has antidepressant via activation upregulation plasticity.

Language: Английский

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TAARs as Novel Therapeutic Targets for the Treatment of Depression: A Narrative Review of the Interconnection with Monoamines and Adult Neurogenesis

Biomedicines, Journal Year: 2024, Volume and Issue: 12(6), P. 1263 - 1263

Published: June 6, 2024

Depression is a common mental illness of great concern. Current therapy for depression only suitable 80% patients and often associated with unwanted side effects. In this regard, the search development new antidepressant agents remains an urgent task. review, we discuss current available evidence indicating that G protein-coupled trace amine-associated receptors (TAARs) might represent targets treatment. The most frequently studied receptor TAAR1 has already been investigated in treatment schizophrenia, demonstrating anxiolytic properties. fact, agonist Ulotaront currently undergoing phase 2/3 clinical trials testing its safety efficacy major depressive disorder generalized anxiety disorder. Other members TAAR family (TAAR2, TAAR5, TAAR6, TAAR8, TAAR9) are not involved innate olfaction volatile amines, but also expressed limbic brain areas. Furthermore, animal studies have shown TAAR2 TAAR5 regulate emotional behaviors thus may hold promise as potential targets. Of particular interest their connection dopamine serotonin systems involvement regulation adult neurogenesis, known to be affected by drugs use. Further non-clinical necessary validate (and potentially other TAARs) novel therapeutic depression.

Language: Английский

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Unlocking the healing power of psilocybin: an overview of the role of psilocybin therapy in major depressive disorder, obsessive-compulsive disorder and substance use disorder

Frontiers in Psychiatry, Journal Year: 2024, Volume and Issue: 15

Published: June 11, 2024

Resistance to traditional treatment methods is still a major obstacle in modern psychiatry. As result, several studies are currently being conducted find effective alternatives therapies. One of these psilocybin, psychedelic substance that has been tested clinical trials as an adjunct psychotherapy. These focus on patients with depressive disorder (MDD), obsessive-compulsive (OCD) and use (SUD), particularly alcohol nicotine dependence. This article looks at the current understanding including data from conducted, psilocybin’s mechanism action, its safety level risk associated it.

Language: Английский

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A cell type-specific mechanism driving the rapid antidepressant effects of transcranial magnetic stimulation

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 30, 2025

Abstract Repetitive transcranial magnetic stimulation (rTMS) is an emerging treatment for brain disorders, but its therapeutic mechanism unknown. We developed a novel mouse model of rTMS with superior clinical face validity and investigated the neural by which accelerated intermittent theta burst (aiTBS) – first rapid-acting antidepressant protocol reversed chronic stress-induced behavioral deficits. Using fiber photometry, we showed that aiTBS drives distinct patterns activity in intratelencephalic (IT) pyramidal tract (PT) projecting neurons dorsomedial prefrontal cortex (dmPFC). However, only IT exhibited persistently increased during both subsequent depression-related behaviors. Similarly, stress-related loss dendritic spines on IT, not PT neurons, further demonstrating cell type-specific effects stimulation. Finally, chemogenetic inhibition dmPFC blocked antidepressant-like aiTBS. Thus, demonstrate linking rapid aiTBS-driven to circuit plasticity.

Language: Английский

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A New Trick of Old Dogs: Can Kappa Opioid Receptor Antagonist Properties of Antidepressants Assist in Treating Treatment-Resistant Depression (TRD)?

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(2), P. 208 - 208

Published: Feb. 3, 2025

Background/Objectives: Approximately one in five individuals will experience major depressive disorder (MDD), and 30% exhibit resistance to standard antidepressant treatments, resulting a diagnosis of treatment-resistant depression (TRD). Historically, opium was used effectively treat depression; however, when other medications were introduced, its use discontinued due addiction hazards. Recently, kappa opioid receptor (KOR) antagonism has been proposed as potential mechanism for treating TRD. The main research question is whether commonly psychotropic possess KOR antagonist properties this characteristic could contribute their efficacy Methods: We investigated the antinociceptive effects many interactions with system. Mice tested hotplate or tail-flick after being injected different doses these agents. Results: antidepressants mianserin mirtazapine (separately) induced dose-dependent antinociception, each yielding biphasic dose–response curve. Similarly, venlafaxine produced potent effect reboxetine weak effect. antipsychotics risperidone amisulpride exhibited sedative–hypnotic zolpidem bi-phasic All seven elicited which reversed by non-selective opiate naloxone and, separately, kappa-selective Nor-BNI. Conclusions: Clinical studies are mandatory establish augmentation treatment drugs persons optimal dosage prescribed. suggest possible beneficial antagonistic properties.

Language: Английский

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Regulatory Alignment of Psilocybin Clinical Trials in Major Depressive Disorder on ClinicalTrials.gov: A Cross-Sectional Analysis

Pharmacopsychiatry, Journal Year: 2025, Volume and Issue: unknown

Published: April 17, 2025

Abstract Regulatory compliance is crucial in the clinical development of psychedelic substances, including psilocybin. This study aimed to examine alignment trial protocols for psilocybin treatment major depressive disorder (MDD) and treatment-resistant depression (TRD) with established regulatory requirements. A cross-sectional investigation was conducted on ClinicalTrials.gov using keywords: “Psilocybin” “Psilocin” identify interventional studies posted protocols. Only MDD TRD were included. Data extraction focused key aspects, safety, functional unblinding, expectancy bias, distribution investigational medical products. Eleven identified, four meeting inclusion criteria. The most commonly studied dose 25 mg. Two trials double-blind. Although analyzed superficially adhered requirements, there gaps addressing potential drug interactions, acute chronic concurrent use antidepressants, prohibited medications. Certain such as unblinding or did not share all pathways. Risk mitigation strategies primarily based external Patients bipolar spectrum disorders schizoaffective excluded. underscores importance conducting psychedelics strict adherence standards. Future research should focus improving exploring efficacy broader patient populations.

Language: Английский

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