Ketamine-assisted psychotherapy, psychedelic methodologies, and the impregnable value of the subjective—a new and evolving approach

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

Published: Feb. 1, 2024

Psychiatry is in a growth phase which several psychedelic medicines have entered its arena with great promise. Of these, presently, ketamine the only medicine that may be legally prescribed. We hypothesize at subanesthetic doses, produces unique spectrum of altered states, ranging from psychoactive to deep ego-dissolving experiences, are intrinsic ketamine’s therapeutic effects. When these experiences embedded relationship—a setting—that fosters an amplification recipient’s subjective consciousness, personal growth, inner healing, greater clarity, and better relationships well ensue. While much literature on labels dissociative effects as ‘side effects’, alteration consciousness component unavoidable ‘effect’ impact. From inception clinical trials 1960s, was recognized for producing dissociative, subjects they emerged ketamine-induced anesthesia. Unanticipated unintegrated, ‘emergence phenomena’ were felt disturbing. Accordingly, such been typically labeled side However, conducive set settings, demonstrated positive use psychiatry psychotherapy, providing time-out usual states mind facilitate reshaping self-experience along symptomatic relief. In this way, ketamine-assisted psychotherapy (KAP) offers new potential powerfully valanced toward recognizing experience, individuality, imagination. Essential successful experience outcome KAP close attention expression by recipient integration healing opportunity.

Language: Английский

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Brain region–specific roles of brain-derived neurotrophic factor in social stress–induced depressive-like behavior

Neural Regeneration Research, Journal Year: 2024, Volume and Issue: 20(1), P. 159 - 173

Published: April 3, 2024

Brain-derived neurotrophic factor is a key in stress adaptation and avoidance of social behavioral response. Recent studies have shown that brain-derived expression stressed mice brain region–specific, particularly involving the corticolimbic system, including ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala, hippocampus. Determining how participates processing different regions will deepen our understanding psychopathology. In this review, we discuss regulation stress-sensitive closely related to pathophysiology depression. We focused on associated molecular pathways neural circuits, with special attention factor–tropomyosin receptor kinase B signaling pathway area–nucleus accumbens dopamine circuit. determined stress-induced alterations levels are likely nature, severity, duration stress, especially above-mentioned system. Therefore, BDNF might be biological indicator regulating stress-related processes various regions.

Language: Английский

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Enhancing proteasome activity by NMDAR antagonists explains their therapeutic effect in neurodegenerative and mental diseases

Scientific Reports, Journal Year: 2025, Volume and Issue: 15(1)

Published: Jan. 13, 2025

NMDAR antagonists, such as memantine and ketamine, have shown efficacy in treating neurodegenerative diseases major depression. The mechanism by which these drugs correct the aforementioned is still unknown. Our study reveals that antagonists significantly enhance 20S proteasome activity, crucial for degrading intrinsically disordered, oxidatively damaged, or misfolded proteins, factors pivotal like Alzheimer's Parkinson's. In our mouse model experiment, ketamine administration notably altered brain synaptic protein profiles within two hours, downregulating proteins strongly associated with Parkinson's diseases. Furthermore, exhibited enrichment terms related to plasticity potentiation, including retrograde endocannabinoid signaling—a pathway both short- long-term may elucidate long-lasting effects of Via ubiquitin-independent (UIPS), maintain cellular homeostasis, activity declines age, leading aggregation disease symptoms. Therefore, findings hold promise new treatment options not only but also other systemic conditions unfolded proteins.

Language: Английский

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Demystifying the Antidepressant Mechanism of Action of Stinels, a Novel Class of Neuroplastogens: Positive Allosteric Modulators of the NMDA Receptor

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(2), P. 157 - 157

Published: Jan. 24, 2025

Plastogens are a class of therapeutics that function by rapidly promoting changes in neuroplasticity. A notable example, ketamine, is receiving great attention due to its combined rapid and long-term antidepressant effects. Ketamine an N-methyl-D-aspartate receptor (NMDAR) antagonist, and, addition therapeutic activity, it associated with psychotomimetic dissociative side Stinels—rapastinel, apimostinel, zelquistinel—are also plastogens not only effects but improved safety tolerability profiles compared ketamine. Previous descriptions the mechanism which stinels modulate NMDAR activity have been inconsistent at times, contradictory. The purpose this review clarify action contextualize within broader NMDAR-targeting therapeutics. In review, we present rationale behind targeting NMDARs for treatment-resistant depression other psychiatric conditions, describe various mechanisms regulated different classes therapeutics, evidence stinel mechanism. contrast previous glycine-like partial agonists, define as positive allosteric modulators novel regulatory binding site.

Language: Английский

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Molecular Regulation and Therapeutic Applications of Brain-Derived Neurotrophic Factor–Tropomyosin-Related Kinase B Signaling in Major Depressive Disorder Though Its Interaction with Vascular Endothelial Growth Factor and N-Methyl-D-Aspartic Acid Receptors: A Narrative Review

Biologics, Journal Year: 2025, Volume and Issue: 5(1), P. 7 - 7

Published: March 3, 2025

The molecular regulation and therapeutic applications of brain-derived neurotrophic factor (BDNF)–tropomyosin-related kinase B (TrkB) signaling in major depressive disorder (MDD) through interaction with vascular endothelial growth (VEGF) N-methyl-D-aspartic acid (NMDA) receptors show promise. While BDNF-TrkB is implicated antidepressant action, the association between BDNFs depression has not yielded conclusive results. Some studies decreased BDNF levels depression, while others indicate that increased expression certain brain regions can induce susceptibility. role varies across different regions, necessitating further study individual mechanisms. This regional variability complicates development targeted therapies. antidepressant-like actions require VEGF signaling, but there also a reciprocal interdependence, as are dependent on BDNFs. complex relationship

Language: Английский

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From Synaptic Plasticity to Neurodegeneration: BDNF as a Transformative Target in Medicine

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(9), P. 4271 - 4271

Published: April 30, 2025

The brain-derived neurotrophic factor (BDNF) has become one of the cornerstones neuropathology, influencing synaptic plasticity, cognitive resilience, and neuronal survival. Apart from its molecular biology, BDNF is a powerful target for transformative benefit in precision medicine, leading to innovative therapeutic approaches neurodegenerative psychiatric diseases like Alzheimer’s disease (AD), Parkinson’s (PD), major depressive disorder (MDD), post-traumatic stress (PTSD). Nevertheless, clinical applicability obstructed by hurdles delivery, patient-specific diversity, pleiotropic signaling. Here, we summarize findings research, including regulatory pathways diagnostic/prognostic biomarkers integrative approaches. We describe delivery systems, such as lipid nanoparticle-based mRNA therapies CRISPR-dCas9-based epigenetic editing that bypass obstacles BBB (blood–brain barrier) enzymatic degradation. recent implementation multiplex panels combining biodynamic indicators with tau amyloid-β signaling markers showcases novel levels specificity both early detection potential monitoring. Humanized preclinical models iPSC-derived neurons organoids point key role neurodeveloping processes, paralleling advances bridging observation environments. Moreover, tools delivering TrkB activators or AI-based dynamic care platforms enable tailored scalable treatments. This review also aims extend framework used understanding BDNF’s relevance traditional situating more work detailing actions ischemic tissues gut–brain axis context systemic health. Finally, outline roadmap incorporation BDNF-centered into worldwide healthcare, highlighting ethical issues, equity, interdisciplinary decomposition. heralds new era neuroscience revolutionizing brain health paving way advancement medicine.

Language: Английский

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Molecular and Medical Aspects of Psychedelics

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 25(1), P. 241 - 241

Published: Dec. 23, 2023

Psychedelics belong to the oldest psychoactive drugs. They arouse recent interest due their therapeutic applications in treatment of major depressive disorder, substance use end-of-life anxiety,= and anxiety symptoms, obsessive-compulsive disorder. In this review, current state preclinical research on mechanism action, neurotoxicity, behavioral impact psychedelics is summarized. The effect selective 5-HT2A receptor agonists, 25I- 25B-NBOMe, after acute repeated administration characterized compared with effects a less drug, psilocybin. data show significant NBOMes glutamatergic, dopaminergic, serotonergic, cholinergic neurotransmission frontal cortex, striatum, nucleus accumbens. increases extracellular levels neurotransmitters were not dose-dependent, which most likely resulted from stimulation subsequent activation 5-HT2C receptors. This was also observed wet dog shake test locomotor activity. Chronic elicited rapid development tolerance, genotoxicity, microglia. Acute psilocybin affected monoaminergic aminoacidic accumbens, hippocampus but amygdala. Psilocybin exhibited anxiolytic properties resulting intensification GABAergic neurotransmission. indicate that as agonists exert behavior rats while inducing oxidative DNA damage. contrast NBOMes, induced by suggest broader index drug.

Language: Английский

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Ketamine’s Amelioration of Fear Extinction in Adolescent Male Mice Is Associated with the Activation of the Hippocampal Akt-mTOR-GluA1 Pathway

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(6), P. 669 - 669

Published: May 22, 2024

Fear-related disorders, including post-traumatic stress disorder (PTSD), and anxiety disorders are pervasive psychiatric conditions marked by persistent fear, stemming from its dysregulated acquisition extinction. The primary treatment for these exposure therapy (ET), relies heavily on fear extinction (FE) principles. Adolescence, a vulnerable period developing is characterized neurobiological changes in the circuitry, leading to impaired FE increased susceptibility relapse following ET. Ketamine, known relieving reducing PTSD symptoms, influences fear-related learning processes synaptic plasticity across circuitry. Our study aimed investigate effects of ketamine (10 mg/kg) adolescent male C57 BL/6 mice at behavioral molecular levels. We analyzed protein gene expression markers hippocampus (HPC) prefrontal cortex (PFC) sought identify neural correlates associated with ketamine’s learning. Ketamine ameliorated males, likely affecting consolidation and/or recall memory. also Akt mTOR activity GluA1 GluN2A levels HPC upregulated BDNF exon IV mRNA PFC fear-extinguished mice. Furthermore, c-Fos specific brain regions, ventral (vHPC) left infralimbic ventromedial (IL vmPFC). Providing comprehensive exploration mechanisms FE, our suggests that males activation hippocampal Akt-mTOR-GluA1 signaling, vHPC IL vmPFC as proposed correlates.

Language: Английский

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Activation of σ1-Receptors by R-Ketamine May Enhance the Antidepressant Effect of S-Ketamine

Biomedicines, Journal Year: 2023, Volume and Issue: 11(10), P. 2664 - 2664

Published: Sept. 28, 2023

Ketamine is a racemic mixture composed of two enantiomers, S-ketamine and R-ketamine. In preclinical studies, both enantiomers have exhibited antidepressant effects, but these effects are attributed to distinct pharmacological activities. The S-enantiomer acts as an NMDA-channel blocker opioid μ-receptor agonist, whereas the R-enantiomer binds σ1-receptors believed act agonist. As racemate, ketamine potentially triggers four biochemical pathways involving AGC-kinases, PKA, Akt (PKB), PKC RSK that ultimately lead inhibitory phosphorylation GSK3β in microglia. patients with major depressive disorder, administered nasal spray has shown clear activity. However, when compared intravenously infused ketamine, response rate, duration action anti-suicidal activity appear be less pronounced. σ1-protein interacts μ-opioid TrkB-receptors, experiments σ1-agonists reduce desensitization improve TrkB signal transduction. activation occurs NMDA blockade. So, σ1-activity R-ketamine may not only enhance via which produces response, it furthermore provides its own right. These factors could explain apparently superior effect observed alone.

Language: Английский

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Interplay of G-proteins and Serotonin in the Neuroimmunoinflammatory Model of Chronic Stress and Depression: A Narrative Review

Current Pharmaceutical Design, Journal Year: 2023, Volume and Issue: 30(3), P. 180 - 214

Published: Dec. 28, 2023

Introduction: This narrative review addresses the clinical challenges in stress-related disorders such as depression, focusing on interplay between neuron-specific and pro-inflammatory mechanisms at cellular, cerebral, systemic levels. Objective: We aim to elucidate molecular linking chronic psychological stress with low-grade neuroinflammation key brain regions, particularly roles of G proteins serotonin (5-HT) receptors. Methods: comprehensive literature employs systematic, narrative, scoping methodologies, combined approaches general pathology. It synthesizes current research shared signaling pathways involved responses neuroinflammation, including calcium-dependent mechanisms, mitogen-activated protein kinases, transcription factors like NF-κB p53. The also focuses role protein-coupled neurotransmitter receptors (GPCRs) immune responses, a detailed analysis how 13 14 types human 5-HT contribute depression neuroinflammation. Results: reveals complex interaction signals immunoinflammatory pathologies. highlights GPCRs canonical inflammatory mediators influencing both pathological physiological processes nervous tissue. Conclusion: proposed Neuroimmunoinflammatory Stress Model (NIIS Model) suggests that proinflammatory pathways, mediated by metabotropic ionotropic receptors, are crucial for maintaining neuronal homeostasis. Chronic mental can disrupt this balance, leading increased states contributing neuropsychiatric psychosomatic disorders, depression. model integrates traditional theories pathogenesis, offering understanding multifaceted nature condition.

Language: Английский

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