Glutamate-Mediated Excitotoxicity in the Pathogenesis and Treatment of Neurodevelopmental and Adult Mental Disorders

International Journal of Molecular Sciences, Год журнала: 2024, Номер 25(12), С. 6521 - 6521

Опубликована: Июнь 13, 2024

Glutamate is the main excitatory neurotransmitter in brain wherein it controls cognitive functional domains and mood. Indeed, areas involved memory formation consolidation as well fear emotional processing, such hippocampus, prefrontal cortex, amygdala, are predominantly glutamatergic. To ensure physiological activity of brain, glutamatergic transmission finely tuned at synaptic sites. Disruption mechanisms responsible for glutamate homeostasis may result accumulation excessive levels, which turn leads to increased calcium mitochondrial abnormalities, oxidative stress, eventually cell atrophy death. This condition known glutamate-induced excitotoxicity considered a pathogenic mechanism several diseases central nervous system, including neurodevelopmental, substance abuse, psychiatric disorders. On other hand, these disorders share neuroplasticity impairments areas, accompanied by structural remodeling neurons. In current narrative review, we will summarize role both pathophysiology therapeutic interventions neurodevelopmental adult mental with focus on autism spectrum disorders, drugs under preclinical clinical development treatment different that dysfunctions. Although evidence still limited more studies required, regulation attracting attention potential crucial target control diseases.

Язык: Английский

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Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions

Journal of Anesthesia and Translational Medicine, Год журнала: 2024, Номер 3(3), С. 65 - 75

Опубликована: Июль 11, 2024

Ketamine, a dissociative anesthetic, is widely utilized in both human and veterinary anesthesia. Its (S)-enantiomer, esketamine, similarly employed for anesthesia analgesia. The anesthetic effects of ketamine esketamine arise from their antagonism the N-methyl-D-aspartate receptor (NMDAR). In field psychiatry, rapid-acting antidepressant properties severe depression have generated significant interest, resulting its increased off-label usage United States (U.S.). 2019, nasal spray received approval use U.S. Europe. However, concerns emerged regarding potential adverse effects, including long-term efficacy, addiction risks, suicide risk clinical settings. contrast, arketamine, (R)-enantiomer ketamine, exhibits superior longer-lasting rodent models depression, with fewer side compared to esketamine. Nevertheless, research on efficacy safety arketamine patients remains limited. This article provides concise exploration historical two enantiomers while also delving into future directions application these fields.

Язык: Английский

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Efficacy and safety of ketamine and esketamine for unipolar and bipolar depression: an overview of systematic reviews with meta-analysis

Frontiers in Psychiatry, Год журнала: 2024, Номер 15

Опубликована: Фев. 1, 2024

Background Unipolar and bipolar depression present treatment challenges, with patients sometimes showing limited or no response to standard medications. Ketamine its enantiomer, esketamine, offer promising alternative treatments that can quickly relieve suicidal thoughts. This Overview of Reviews (OoR) analyzed synthesized systematic reviews (SRs) meta-analysis on randomized clinical trials (RCTs) involving ketamine in various formulations (intravenous, intramuscular, intranasal, subcutaneous) for unipolar depression. We evaluated the efficacy safety esketamine treating major depressive episodes across forms, including unipolar, bipolar, treatment-resistant, non-resistant depression, patient populations without ideation, aiming comprehensively assess their therapeutic potential profile. Methods Following PRIOR guidelines, this OoR’s protocol was registered Implasy (ID:202150049). Searches PubMed, Scopus, Cochrane Library, Epistemonikos focused English-language meta-analyses RCTs as monotherapy add-on, evaluating outcomes like suicide risk, symptoms, relapse, rates, side effects. included studies both non-suicidal patients; all routes administration intranasal) were considered, well available comparisons control interventions. excluded which intervention used anesthesia electroconvulsive therapy a ascending dose design. The selection, data extraction, quality assessment carried out by pairs reviewers blinded manner. Data efficacy, acceptability, tolerability extracted. Results Our analysis 26 SRs 44 RCTs, 3,316 subjects. is effective well-tolerated, although original poor, resulting low certainty evidence. Limitations study poor-quality studies, Additionally, insufficient prevents differentiation between effects Conclusion While show potential, current evidence suffers from quality. Enhanced methodological rigor future research will allow more informed application these interventions within guidelines Systematic review registration [ https://inplasy.com/inplasy-2021-5-0049/ ], identifier (INPLASY202150049).

Язык: Английский

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Novel rapid treatment options for adolescent depression

Pharmacological Research, Год журнала: 2024, Номер 201, С. 107085 - 107085

Опубликована: Фев. 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.

Язык: Английский

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Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects?

Molecular Psychiatry, Год журнала: 2024, Номер 29(9), С. 2849 - 2858

Опубликована: Апрель 4, 2024

Язык: Английский

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Efficacy and Safety of Esmethadone (REL-1017) in Patients With Major Depressive Disorder and Inadequate Response to Standard Antidepressants

The Journal of Clinical Psychiatry, Год журнала: 2024, Номер 85(3)

Опубликована: Июнь 17, 2024

Objective: To test esmethadone (REL-1017) as adjunctive treatment in patients with major depressive disorder (MDD) and inadequate response to standard antidepressants. Methods:In this phase 3, double-blind, placebo-controlled trial, outpatients MDD (DSM-5) were randomized daily oral (75 mg on day 1, followed by 25 days 2 through 28) or placebo between December 2020 2022.The primary efficacy measure was change from baseline (CFB) 28 the Montgomery-Asberg Depression Rating Scale (MADRS) score.The intent-to-treat (ITT) population included all participants.The per-protocol (PP) completers without protocol deviations impacting assessment.Post hoc analyses participants severe depression (baseline MADRS score ≥35).Results: For ITT analysis (n = 227), mean CFB 15.1 (SD 11.3) for 113) 12.9 10.4) 114), a difference (MD) of 2.3, which not statistically significant (P .154;Cohen effect size [ES] 0.21).Remission rates 22.1% 13.2% .076),and 39.8% 27.2% .044)with placebo, respectively.For PP 198), 15.6 11.2) 101) 12.5 9.9) 97), an MD 3.1 .051;ES 0.29).In post ≥35 112), 6.9; P .0059;ES 0.57, 98), 7.9; .0015;ES 0.69.Adverse events (AEs) predominantly mild moderate transient, no differences groups. Conclusions:The end point met.Esmethadone showed stronger than analyses, discrepancy attributable AEs adherence.Significant occurred depression.Esmethadone well tolerated, consistent prior studies.

Язык: Английский

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Effects of epidural esketamine versus sufentanil on labor analgesia and postpartum depression: a retrospective cohort study

BMC Anesthesiology, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 7, 2025

There is a lack of research on epidural esketamine for labor analgesia. The purpose this to compare the efficacy and sufentanil analgesia postpartum depression. A total 187 cephalic full-term parturients with single-fetus vaginal delivery were collected in retrospective study from Jan 2022 2023. Parturients categorized into two groups according anesthetics: group (Group KR, n = 97) patient-controlled 0.3 mg/ml 0.083% ropivacaine 240 ml normal saline Sufentanil SR, 90) µg/ml saline. Visual Analogue Scale, Ramsay Sedation Modified Bromage Score recorded before, 5, 10, 30 min after analgesia, when uterine orifice was fully opened, delivery. Edinburgh Postnatal Depression Scale(EPDS) scores at 3 42 days recorded. maternal infant outcomes occurrence adverse reactions VAS 5,10,30 cervix opened higher Group KR than SR (all P < 0.05). RSS lower Compared significant decreases shown EPDS incidence depression has considerably decreased rates pruritus compared (P other effects showed no difference > neonatal not significantly different between In comparison sufentanil, may exhibit better sedative effect, low pruritus, but limited analgesic effect. It be associated risk Further exploration optimal regimen dosage would necessary.

Язык: Английский

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Esketamine reduces postoperative depression in breast cancer through TREK-1 channel inhibition and neurotransmitter modulation

Cancer Cell International, Год журнала: 2025, Номер 25(1)

Опубликована: Фев. 18, 2025

Postoperative depression significantly affects the quality of life breast cancer patients. This study explores potential therapeutic effects esketamine on postoperative through modulation TREK-1 two-pore domain potassium channel. We analyzed data from 54 female patients who underwent surgery at our hospital between 2019 and 2023, dividing them into experimental control groups based treatment. Transcriptomic sequencing hippocampal neurons rats identified ion-related pathways key regulatory genes, including TREK-1, influenced by esketamine. In vitro studies showed that primarily alleviates depressive symptoms inhibiting protein expression, enhancing GABA neurotransmitter release, improving neuronal activity, while overexpression reversed these effects. Esketamine's inhibition channels promotion neuron activity effectively alleviate in patients, suggesting a novel strategy.

Язык: Английский

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Ketamine for treatment-resistant major depressive disorder: Double-blind active-controlled crossover study

Journal of Psychopharmacology, Год журнала: 2024, Номер 38(2), С. 162 - 167

Опубликована: Янв. 31, 2024

Background: The N-methyl-D-aspartate antagonist ketamine has rapid onset antidepressant activity in treatment-resistant depression (TRD). Aims: To evaluate mood rating, safety and tolerability data from patients with TRD treated the psychoactive control fentanyl, as part of a larger study to explore EEG biomarkers associated response. Methods: We evaluated efficacy intramuscular racemic 25 TRD, using double-blind active-controlled randomized crossover design. Ketamine doses were 0.5 1 mg/kg, was fentanyl 50 mcg, given at weekly intervals. Results/outcomes: Within h dosing, reported reduced anxiety ratings, which persisted for up 7 days. A dose–response profile noted dissociative side effects, adverse events changes blood pressure; however, ratings broadly similar both doses. Overall, 14/25 (56%) responders (⩾50% reduction 24 compared baseline) either dose Hospital Anxiety Depression Scale (HADS), 18/25 (72%) HADS-anxiety scale. After only 1/25 (HADS-depression) 3/25 (HADS-anxiety) responders. generally safe well tolerated this population. Conclusions: Our findings add literature confirming ketamine’s against depressive symptoms TRD.

Язык: Английский

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Mechanisms of SSRI Therapy and Discontinuation

Current topics in behavioral neurosciences, Год журнала: 2023, Номер unknown, С. 21 - 47

Опубликована: Янв. 1, 2023

Язык: Английский

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