Abstract: Background: Bipolar disorder secondary to traumatic brain injury (TBI) is common, mechanistically distinct, and notoriously treatment-resistant. Rapid-acting glutamatergic antidepressants such as ketamine are effective in bipolar depression but remain inaccessible to most patients.Case presentation: We describe a woman in her mid-thirties with documented right frontal atrophy after a severe violence-related subdural hematoma in 2009, subsequent onset of cyclothymic-to-bipolar illness, and recent severe depressive relapse with insomnia, auditory hallucinations, PHQ-9 = 22 and GAD-7 = 14. Conventional treatment (valproate, low-dose risperidone, lemborexant, and Deanxit [flupentixol 0.5 mg + melitracen 15 mg]) produced minimal benefit. On 5 November 2025, low-dose dextromethorphan 30 mg nightly and piracetam 600 mg nightly were added. Melitracen, a moderate CYP2D6 inhibitor, inadvertently prolonged dextromethorphan exposure, effectively replicating the pharmacokinetic principle of Auvelity® while piracetam supplied AMPA positive allosteric modulation.Results: Within four weeks the patient reported marked mood stabilization and reduced ruminations. Transient mild hypomania with moria-like inappropriate laughter emerged, prompting spontaneous reduction of dextromethorphan to 22.5 mg nightly and upward titration of piracetam to 1 200 mg, after which euthymia was restored and maintained. No dissociation or worsening psychosis occurred.Conclusions: This case provides the first clinical illustration that an ultra-low-cost, fully oral glutamatergic oral regimen (dextromethorphan + unintended CYP2D6 inhibition + piracetam) can produce ketamine-class speed and magnitude of response in secondary bipolar depression after TBI, even at dextromethorphan doses far below those in licensed combinations. The narrow therapeutic window and hypomanic overshoot highlight the heightened glutamatergic sensitivity of the post-TBI brain.

Abstract: Major depressive disorder (MDD) remains a leading cause of disability worldwide, with conventional antidepressants offering incomplete and often transient relief. Mounting ev-idence highlights disturbances in tryptophan (Trp) metabolism as a key biological axis linking inflammation, neuroplasticity, and mood regulation. Plant-derived compounds that modulate this pathway, including 5-hydroxytryptophan, isoflavones, berberine, and polyphenols, have emerged as promising candidates for integrative treatment strategies. Yet, despite encouraging preclinical and clinical findings, knowledge gaps persist re-garding long-term efficacy, mechanistic specificity, and standardized therapeutic proto-cols. This narrative review explores how plant-derived Trp modulators influence central and peripheral mechanisms relevant to depression, from serotonergic synthesis and kynurenine shunting to gut–brain–immune interactions. Evidence from animal models and randomized clinical trials is critically synthesized, with particular attention to out-comes on mood stabilization, anxiety reduction, cognitive function, and sleep regulation. Special emphasis is placed on translational potential, methodological limitations, and the need for harmonized research frameworks. Here we highlight that phytochemical inter-ventions represent a mechanistically informed and biocompatible strategy for advancing depression management. By bridging neurobiology and clinical psychiatry, these insights may pave the way for next-generation therapeutics that integrate dietary, microbio-ta-targeted, and anti-inflammatory approaches. Broader application of this research could ultimately refine personalized psychiatry, expand therapeutic horizons, and contribute to global mental health resilience.

Abstract: Intranasal esketamine has proven its worth for patients whose depression will not yield to standard medicines, yet the realities of cost and clinic-based monitoring bar many people from long-term use. The situation is especially frustrating for those who respond spectacularly to a first dose only to watch the benefits fade when they can no longer afford repeat treatments.That was the predicament of a 48-year-old office worker who, in 2023, received a single 56 mg spray of esketamine. Within hours his mood lifted and the suicidal thoughts that had haunted him for months vanished, but the HK $6,000 price tag of each session forced him to stop. Over the next two years his illness morphed into severe obsessive–compulsive disorder dominated by violent, self-directed images. Trials of flupentixol/melitracen, bupropion plus over-the-counter dextromethorphan, and other conventional combinations offered only fleeting relief.In 2025 we replaced that patchwork with a mechanistically guided, fully oral "ketamine-like" stack: dextromethorphan 120 mg/day to block NMDA receptors, fluoxetine 20–40 mg/day to slow dextromethorphan metabolism via CYP2D6 inhibition, and piracetam 1.2 g/day to boost downstream AMPA activity. A few low-dose adjuncts (risperidone, valproate, pregabalin) were retained for sleep and anxiety. Four weeks later the change was unmistakeable. Intrusive imagery that once erupted every hour now surfaced only sporadically and could be brushed aside. His PHQ-9 score fell from 17 to the 5–6 range, suicidal ideation disappeared, and he returned to full productivity at work. These gains have held steady for more than eight months at a monthly medication cost of roughly HK $400–600—less than one-tenth the expense of maintenance esketamine.The case suggests that patients who exhibit an early, dramatic response to esketamine may not need to choose between relapse and ruinous expense. A carefully constructed oral regimen that recreates ketamine's NMDA-to-AMPA plasticity cascade can deliver similar, durable results at a price most clinics and patients can manage. Systematic trials are now warranted to test whether this strategy can scale to the wider population for whom intravenous or intranasal ketamine is out of reach.

Abstract: Autism spectrum disorder (ASD) follows an unusual two-stage course of synaptic change. Infancy and early childhood are marked by an exuberant rise in dendritic spines coupled with weak pruning, a profile driven in large part by overactive mTOR signalling. By adolescence and early adulthood, the pendulum appears to swing in the opposite direction, with evidence of compensatory over-pruning and a net loss of functional connections.Against this neurodevelopmental backdrop, we reviewed longitudinal MRI findings, post-mortem histology and mechanistic pharmacology to assess a putative "Cheung glutamatergic regimen." The protocol combines dextromethorphan (an NMDA-channel blocker), a CYP2D6-inhibiting antidepressant, piracetam and the amino-acid precursor l-glutamine.Available data suggest sharply divergent risk–benefit profiles across the lifespan. In children between two and ten years of age—when synaptic numbers can exceed neurotypical levels by as much as 50 per cent—any strategy that further amplifies glutamatergic drive may heighten excitotoxic risk and worsen core autistic features; the regimen is therefore contraindicated in this window. In contrast, once puberty ushers in accelerated pruning and the possibility of synaptic depletion, carefully titrated glutamate enhancement could prove restorative. By pairing transient NMDA blockade with boosted AMPA throughput and substrate support from glutamine, the combination may help re-establish γ-band synchrony and strengthen long-range cortico-cortical connectivity often weakened in older autistic individuals.Taken together, the Cheung glutamatergic regimen may emerge as a low-cost, easily deployed option with genuine promise for post-pubertal autistic patients. Its use in younger children, however, cannot be justified on current evidence and should be strictly avoided until the early surplus of synapses has resolved.

Abstract: Sleep-onset anxiety is a transdiagnostic contributor to difficulty initiating sleep that is maintained through interconnected cognitive, physiological, and neurobiological processes. This narrative review synthesizes current evidence on mechanisms and behavioral interventions for sleep-onset anxiety, highlighting pre-sleep worry, rumination, conditioned arousal, autonomic dysregulation, and brain network alterations as key mechanisms. Evidence-based interventions are reviewed, including cognitive behavioral therapy for insomnia (CBT-I), mindfulness and acceptance-based approaches, relaxation strategies, and environmental optimization. Clinical considerations are examined for individuals with comorbid anxiety disorders, across developmental stages, and across diverse cultural contexts. Digital delivery formats are reviewed as scalable approaches to extend treatment access. Much existing evidence derives from broader insomnia populations rather than sleep-onset anxiety as a distinct construct, limiting mechanistic specificity. Future research directions include mechanistic trials integrating objective biomarkers with clinical outcomes, component optimization studies, and scalable implementation approaches. This review provides an integrative framework linking mechanisms to evidence-based interventions for sleep-onset anxiety across diverse clinical populations and settings.

Abstract: Background: Young adults with mood and anxiety disorders often remain hamstrung by "brain-fog," headaches, and other bodily complaints even after standard antidepressants or sedatives take the edge off their mood. An inexpensive OTC oral augmentation stack proposed by Cheung (2025)—dextromethorphan for NMDA blockade, low-dose fluoxetine to slow its metabolism, and piracetam to boost AMPA signalling—may reproduce ketamine's rapid neuroplastic effects without an infusion suite.Case: A 25-year-old law student arrived with severe depression (PHQ-9 = 23), generalized anxiety (GAD-7 = 15), daily tension headaches, cramping abdominal pain, episodic breathlessness, and crippling cognitive fog that had already cost her an exam. A sedative‐heavy regimen (risperidone 0.5 mg, alprazolam 0.25 mg prn, lemborexant 1.25 mg, flupentixol/melitracen 1 tablet) eased the physical distress and improved sleep, yet panic and mental slowdown roared back when the new term began.Intervention: In early September the medication plan pivoted to the Cheung Glutamatergic Regimen: fluoxetine 10 mg each morning plus dextromethorphan 30 mg and piracetam 600 mg once daily. Somatic and anxiety symptoms calmed within days, but heavy fatigue and poor concentration lingered until the DXM–piracetam pair was given twice daily.Outcome: Within a week of the dosing change the patient reported a sudden "lights-on" clarity, sustained focus, and return to full study hours. By late November her scores had fallen to PHQ-9 = 15, GAD-7 = 8; headaches and abdominal pain were rare and alprazolam use had nearly stopped.Conclusion: This report suggests that pairing oral NMDA antagonism with AMPA potentiation—especially in a morning-and-evening schedule—can quickly lift refractory cognitive and somatic symptoms where serotonergic and sedative strategies fall short. The approach merits systematic study.

Abstract: A 35-year-old office worker came to our clinic after years of unrelieved depression, mounting anxiety, and lifelong distraction. Several antidepressants had failed, and a recent hospitalisation for suicidal thoughts underscored the urgency of her situation. Morning lisdexamfetamine 20 mg sharpened her focus but left mood and worry largely untouched. Because she had not responded to serotonergic strategies, an OTC oral glutamatergic augmentation—dextromethorphan plus piracetam—was considered. The challenge lay in keeping dextromethorphan active with CYP2D6 inhibition without at the same time lengthening the action of lisdexamfetamine, a stimulant that depends in part on the same enzyme for clearance.To thread that needle, the patient started controlled-release paroxetine at a fraction of its usual dose (6.25 mg nightly) together with dextromethorphan 30 mg and piracetam 600 mg, all taken at bedtime. The micro-dose paroxetine was sufficient to slow dextromethorphan metabolism yet too small, and too late in the day, to meaningfully alter stimulant kinetics. Over the next 25 days her Patient Health Questionnaire score dropped from 21 to 11 and her Generalised Anxiety score from 14 to 11; she reconciled with her partner, resumed social plans, and reported no change in the onset or offset of the morning stimulant.This single case suggests that very low, night-time paroxetine can anchor glutamatergic augmentation for mood and anxiety relief while avoiding any alterations in lisdexamfetamine pharmacokinetics. The approach may widen the practical use of dextromethorphan-based regimens in patients who rely on stimulants for comorbid ADHD.

Abstract:

Intravenous ketamine has transformed the care of refractory mood and anxiety disorders, yet its cost and clinical complexity keep many patients on the sidelines. The Cheung glutamatergic regimen tries to bring the same rapid-acting biology to the outpatient clinic with nothing more exotic than pharmacy-shelf capsules. The protocol pairs dextromethorphan, whose σ-1/NMDA activity mirrors ketamine’s, with a CYP2D6 inhibitor to slow its metabolism, then adds piracetam to drive AMPA throughput and oral l-glutamine to bolster the glutamate pool. Case reports and small open series describe sudden, occasionally dramatic recoveries in depression, PTSD, chronic pain and functional somatic syndromes. Those early successes, however, arrive only when the pharmacokinetics are handled with care. The CYP2D6 blocker that keeps dextromethorphan in circulation can just as easily push it—or a co-prescribed psychotropic—into toxic territory.

Abstract:

Background: A sizeable minority of people with obsessive–compulsive disorder (OCD) remain haunted by intrusive thoughts and exhausting rituals even after lengthy courses of high-dose selective serotonin reuptake inhibitors (SSRIs) and antipsychotic add-ons. Because mounting basic-science and imaging data point toward glutamatergic imbalance in OCD, clinicians have begun to explore medicines that target glutamate rather than serotonin alone. Case series: Four consecutive patients—three adults and one 15-year-old—were seen in a community outpatient practice after standard treatments had failed to ease their severe OCD. Each patient was taking (or was started on) fluoxetine 10–40 mg/day, chosen both for mood stabilisation and for its ability to slow CYP2D6 metabolism. Over-the-counter dextromethorphan was then introduced at 30–120 mg/day, divided two or three times daily, making use of the drug’s mild NMDA-receptor blockade. Two patients who continued to report mental fog and vivid intrusive images later received piracetam 1 200 mg/day for its positive allosteric effect on AMPA receptors. Follow-up occurred during routine office visits; no research-specific procedures were added. Results: Within two to four weeks of starting dextromethorphan, all four patients described fewer and less intense obsessions, longer delays before engaging in compulsions, and improved sleep. The two individuals given piracetam reported additional gains in mental clarity and a further drop in obsessive content that persisted for at least eight weeks. Side-effects were mild: one brief episode of tachycardia that resolved after a small SSRI dose reduction, mild tremor in two patients, and transient menstrual spotting in one. No dissociative or psychotic reactions were observed. Conclusion: In this small, naturalistic series, adding low-cost glutamatergic agents—dextromethorphan with or without piracetam—to ongoing fluoxetine was linked to meaningful symptom relief in otherwise treatment-resistant OCD.

Abstract: Cognitive impairment—rather than psychosis or mood instability—often drives long-term disability in schizoaffective disorder, yet current antipsychotic and mood-stabilising regimens offer little relief. We describe a 22-year-old man with schizoaffective disorder, bipolar type, whose persistent "brain fog" jeopardised university graduation despite euthymic mood and quiescent psychosis on lurasidone, olanzapine, and valproate. A mechanistically guided add-on protocol was introduced: Deanxit (flupentixol 0.5 mg + melitracen 10 mg once-daily) to provide mild serotonin–noradrenaline enhancement and moderate CYP2D6 inhibition; dextromethorphan 15 mg twice-daily to deliver gentle, σ₁-supported NMDA antagonism; and piracetam 600 mg twice-daily as a positive allosteric modulator of AMPA receptors. Within two weeks the patient reported clearer thinking and sustained reading; family noted coherent conversation and fewer attentional lapses. By six weeks he completed all coursework, passed mid-term examinations, and maintained social engagement—improvements never achieved with previous therapy. Benefits have persisted for three months with no mood destabilisation, psychotic relapse, or significant side-effects apart from transient nausea. We propose that melitracen's CYP2D6 blockade prolonged dextromethorphan exposure, enabling a steady NMDA "priming" signal, while piracetam amplified downstream AMPA throughput to consolidate synaptic plasticity. This case highlights the potential of inexpensive, orally available agents to target the NMDA–AMPA axis and alleviate the cognitive burden of schizoaffective disorder. Controlled trials are warranted.

Abstract: Background: Binge-eating disorder in teenagers often lingers even after they try the usual medicines and diet plans, especially when low mood is part of the picture. Glutamate-based treatments are attracting interest because they seem to steady reward circuits and lift mood more quickly than standard approaches. Case Presentation: A 16-year-old girl illustrates this possibility. She was bingeing two or three times a day, occasionally making herself vomit, skipping school, and feeling moderately depressed (PHQ-9 = 17). We had already arranged to start bupropion XL 150 mg for her mood and depressive symptoms. On top of it we added three off-the-shelf products: dextromethorphan 60 mg (the cough-suppressant strength sold in pharmacies), piracetam 1 200 mg, and the amino-acid supplement L-glutamine 1 000 mg. She did not receive new therapy sessions or a formal meal plan during the observation period. Results: The change was swift. Within a week the binge-and-purge cycle stopped and has not returned. Two weeks in, she was back at school every day and eating regular meals (PHQ-9 = 12). Six weeks after the start, depressive symptoms were minimal (PHQ-9 = 8); she had re-engaged in classes and sports and managed weekends at home without relapse. Apart from a brief spell of mild restlessness, she felt well. Conclusion: This single case suggests that pairing bupropion with low-cost glutamatergic agents—dextromethorphan, piracetam, and L-glutamine—may offer a fast, practical route to remission for adolescents whose binge-eating and depression resist conventional care. Systematic studies are needed to see whether this accessible strategy can help others in the same situation.

Abstract: Memory constitutes a fundamental cognitive domain with its dysfunction possibly representing a core, transdiagnostic feature across major psychiatric disorders. This review aimed to integrate neurobiological, cognitive, and clinical evidence on domain-specific memory impairments in mood, anxiety, obsessive–compulsive, post-traumatic stress, and psychotic disorders. A comprehensive search was conducted on PubMed, Scopus, and Web of Science up to November 2025 for peer-reviewed studies examining short-term, working, long-term, episodic, semantic, and prospective memory, prioritizing both landmark and recent contributions. The evidence indicates that memory dysfunction clusters primarily around working-memory control and episodic/autobiographical specificity, while procedural memory remains relatively preserved. Disorder-specific profiles include overgeneral autobiographical memory in major depression, enduring working and episodic deficits in bipolar disorder, variable impairments in anxiety disorders, functional rather than structural memory inefficiencies in obsessive–compulsive disorder, broad mnemonic disorganization in post-traumatic stress disorder, and pervasive working and episodic deficits in schizophrenia and related psychoses. Across conditions, converging neurobiological data implicate fronto-hippocampal dysconnectivity, altered plasticity, and impaired consolidation processes. These findings underscore the centrality of memory dysfunction in psychiatric pathophysiology and support a dimensional, mechanism-based approach integrating pharmacological, psychotherapeutic, and neurocognitive interventions to optimize functional recovery and treatment personalization.

Abstract: Background: Persistent physical symptoms can trap adolescents in a cycle of pain, worry, and lost school time—especially when standard antidepressants provide only partial relief. This report describes a 17-year-old girl whose disabling somatic symptom disorder lifted after we tried a simple, fully oral "ketamine-like" combination.Case Summary: She had taken duloxetine 60 mg daily for more than a year yet still woke with pounding headaches, gasped for air without warning, and scratched her nails raw because they felt full of grit. Beginning 2 September 2025 we layered four medicines, one at a time: dextromethorphan (eventually 60 mg/day), fluoxetine 10 mg/day to slow its breakdown, piracetam (up to 1 200 mg/day), and L-glutamine 500 mg/day. She was seen monthly, her mood scored with the PHQ-9 and GAD-7, and her own account of day-to-day functioning recorded.Outcome: By the third visit the change was hard to miss. Headaches came only after late-night study, breathing was easy, the scratching habit had stopped, and she was back at school full-time. Her PHQ-9 dropped from 23 to 11, GAD-7 from 9 to 6, and the only side-effect she recalled was a brief spell of dizziness during the first week.Conclusion: One case cannot prove cause and effect, yet the speed and depth of her recovery suggest that an oral mix targeting NMDA blockade, AMPA support, and glutamate replenishment may deserve a closer look for stubborn somatic symptom disorder.

Abstract: Rapid‐acting antidepressants show that mood can lift within hours when glutamatergic circuits are pushed from an "NMDA-dominant" to an "AMPA-dominant" state. Intravenous ketamine achieves this flip but is hampered by dissociative side-effects and clinical logistics, while the oral pairing of dextromethorphan + bupropion (Auvelity®) delivers only the initial NMDA blockade and therefore yields slower, less durable benefit. We propose a fully oral, low-cost, four-component regimen designed to replicate ketamine's entire plasticity cascade: (1) dextromethorphan (DXM) supplies fast NMDA antagonism; (2) a strong CYP2D6 inhibitor (fluoxetine, paroxetine, or high-dose duloxetine) prolongs DXM exposure without relying on bupropion; (3) the AMPA positive allosteric modulator piracetam amplifies the downstream glutamate burst, driving BDNF- and mTOR-dependent synaptogenesis; and (4) micronized L-glutamine restores presynaptic glutamate pools and buffers against excitotoxicity. Preclinical evidence shows that each element—DXM's ketamine-like behavioral effects, piracetam's enhancement of AMPA currents, and glutamine's reversal of stress-induced glutamatergic depletion—synergizes along the same mechanistic axis. This strategy could democratize ketamine-level efficacy using inexpensive, readily available medications.

Abstract: Traditional monoaminergic medications often offer limited relief for the physical and cognitive symptoms of post-traumatic stress disorder (PTSD) and complex PTSD. Growing data now point to fast-acting, glutamate-based treatments that boost synaptic plasticity and interrupt fear-conditioned neural circuits. We report four sequential cases of hard-to-treat trauma-spectrum disorders—somatic PTSD, acute bereavement-related PTSD, trauma-linked adolescent depression, and complex PTSD complicated by bipolar II disorder, ADHD, and borderline features—that achieved swift, long-lasting remission with an inexpensive, fully oral protocol centered on dextromethorphan (DXM) potentiated by fluoxetine, with optional add-on piracetam and/or bupropion. Within days to weeks, all four patients showed striking declines in intrusive memories, rumination, somatic pain, and functional disability, and none experienced dissociation, hypertension, or mania. These findings broaden the ketamine/Auvelity framework to trauma-related illnesses and highlight the need for controlled studies of low-cost, readily available NMDA–AMPA modulators for both the prevention and treatment of PTSD.

Abstract:

Objectives. To investigate the risk of developing emotional blunting in adolescents with a depressive episode who are prescribed sertraline. To establish associations of carriage of CYP2C19 gene polymorphisms with the antidepressant-induced apathy. Methods. The study included 133 adolescents (89.5% female) aged 12-17 who were prescribed sertraline. The follow-up was carried out for 8 weeks. Emotional blunting was assessed using the Oxford Depression Questionnaire scale (ODQ-26) at the time of activation, after one, three and 8 weeks. We took into account the appointment of additional pharmacotherapy. The polymorphisms CYP2C19*2, *3, *17 were genotyped for all patients. Based on the results of genotyping, the phenotypes of the CYP2C19 isoenzyme were determined. Results. The ODQ score at the time of enrollment was higher (65 [50;79]) compared to after 8 weeks (38 [32;53]). The part 3 of the ODQ-26 questionnaire remained approximately the same for 8 weeks. Patients with higher ODQ-26 values at enrollment (73 [56;83] vs. 59 [44;71], p=0.0006) were more likely to be prescribed antipsychotics. Differences in ODQ scores remained significant up to 3 weeks after enrollment (50.5 [41.5;68], vs. 45.5 [36;54], p=0.015). The comparison of ODQ scores and their dynamics did not show significant differences depending on CYP2C19*2 or *17 polymorphisms, or the type of CYP2C19 metabolism. Conclusion. A negative outcome was observed: there was no improvement in emotional blunting among adolescents with depression who took sertraline for eight weeks. No significant correlations were found between the carriage of CYP2C19 gene variants and the development of apathy induced by antidepressants.

Abstract: Psychedelic-assisted therapies have shown robust antidepressant and transdiagnostic effects in rigorously controlled adult trials. Extending this work to adolescents is scientifically compelling yet ethically complex, given neurodevelopmental vulnerabilities and the paucity of pediatric data. This review examines the historical context of psychedelic use, summarizes adult efficacy and mechanistic insights, explores adolescent-specific opportunities and risks, and considers applications in co-occurring neurodevelopmental disorders. Finally, it proposes a phased research and policy roadmap that emphasizes safety, transparency, and equitable access. The central conclusion is that investigation in adolescents is justified, but clinical use should proceed only within rigorously governed research frameworks.

Abstract: The paradigm of set, developed by the Georgian psychologist D.N. Uznadze, represents a foundational contribution to the science of non-conscious behavioral regulation. This preprint provides a comprehensive analysis of the set phenomenon, revisiting its core premise as a holistic, pre-conscious state that arises from the interaction of a subject's need and the objective situation. We systematically examine the classical haptic methodology and its modern modifications, including visual, computerized, and cross-modal paradigms. The analysis confirms the diagnostic power of set parameters, linking individual differences in set strength and lability to cognitive rigidity or flexibility. Furthermore, we integrate classical theory with contemporary neuroscience, framing set within the predictive coding framework and identifying its neurophysiological substrates in a distributed network including the basal ganglia, prefrontal cortex, and sensory association cortices. The preprint concludes by highlighting the paradigm's significant potential as a quantitative diagnostic tool and proposes future research directions, including the exploration of its neurochemical bases and its role in social cognition.

Abstract: Background: Suicidal ideation (SI) represents a clinical challenge in patients with treat-ment-resistant depression (TRD), and the management of this condition would be as rap-id and effective as possible. Intranasal Esketamine has shown promise in patients with TRD due to its rapid onset of action on both SI and depressive symptoms. Since this med-ication has been recently approved, real-world data on its efficacy remains scarce, and lit-tle is known about which patients are most likely to benefit from this approach. Aims: This study aimed 1) to evaluate the efficacy of intranasal Esketamine on SI and depressive symptoms and 2) to find potential predictors of clinical response. Methods: Patients with TRD who received intranasal Esketamine were included in the study. Clinical evaluations and psychometric assessments were made at baseline (T0) and at five subsequent time points (one week [T1], one month [T2], two months [T3], three months [T4], and six months [T5]). SI was assessed using the Columbia Suicide Severity Rating Scale (C-SSRS), and depressive symptoms were evaluated using the Montgomery–Åsberg Depression Rating Scale (MADRS). Furthermore, socio-demographic, clinical, and pharmacological data were collected. Results: Eighty patients diagnosed with TRD were enrolled. Suicidal ideation (C-SSRS items 1–5) decreased from 1.56 ± 1.65 at baseline to 0.78 ± 1.28 at T1 and 0.12 ± 0.52 at T5 (all p < .001). MADRS fell from 31.81 ± 7.94 to 23.62 ± 9.08 and 10.19 ± 7.33 at the same time points (all p < .001). By T1, 68.4% achieved SI response on the C-SSRS. MADRS response rate increased from 16.7% at T1 to an overall response of 62.5% at T5. Male sex predicted lower odds of early response on the C-SSRS (OR = 0.21, p = .031); no other baseline variable was significant as a predictor. Conclusions: Intranasal Esketa-mine has been shown to be effective in the rapid reduction and lysis of SI in patients with TRD. Male gender was found as a negative predictor of response, suggesting the im-portance of considering gender differences during treatment planning.

Abstract: Background/Objectives Oral health-related quality of life (OHRQoL) may influence mental health outcomes, yet longitudinal evidence on its association with depression remains limited. This study aimed to examine whether oral health status and OHRQoL are associated with the development of depression among adults in Japan. Methods We analyzed data from the Japan COVID-19 and Society Internet Survey (JACSIS), conducted in 2022 and 2023. A total of 15,068 participants aged ≥20 years without depression at baseline were included. Depression onset was identified by self-reported measures between the two survey waves. Logistic regression models estimated odds ratios (ORs) and 95% confidence intervals (CIs) for depression development in relation to OHRQoL and oral health status, adjusting for sociodemographic and behavioral factors. Results During follow-up, 218 participants (1.45%) developed depression. Poorer OHRQoL was significantly associated with development of depression (OR: 1.018; 95% CI: 1.001–1.036; p = 0.039). Additional risk factors included younger age (OR: 0.974; 95% CI: 0.964–0.985), participation in hobbies and cultural activities (OR: 2.224; 95% CI: 1.498–3.302), habitual use of sleeping pills or anxiolytics (current use OR: 3.512; 95% CI: 2.267–5.442), increased loneliness (OR: 1.217; 95% CI: 1.140–1.299), lower life satisfaction (OR: 0.900; 95% CI: 0.836–0.969), and poor self-rated health (OR: 2.921; 95% CI: 1.810–4.715). Conclusions Impaired OHRQoL was associated with depression development, potentially through psychosocial mechanisms. Maintaining good oral health and OHRQoL may help prevent depression, highlighting the need for integrated oral and mental health strategies in clinical practice.