5-HTP (Serotonin)

Background: Athletic performance is a multifactorial construct influenced by physiological, biomechanical, and psychological determinants. In recent years, genetic factors have been increasingly recognized as contributors to inter-individual variability in performance. In particular, polymorphisms in genes involved in neurobiological pathways have been associated with cognitive processes relevant to sport performance. However, the distribution of cognition-related genetic variants in elite athletes has not been systematically synthesized. Methods: This meta-analysis aimed to examine the distribution of selected candidate gene polymorphisms previously associated with cognition-related traits in elite athletes compared to control populations. A systematic literature search identified 17 eligible case-control studies investigating allele distributions of COMT rs4680, BDNF rs6265, DRD2 rs1800497, OPRM1 rs1799971, and HTR1A rs6295. Pooled analyses were performed using a fixed-effect model, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. Results: Elite athletes demonstrated a significantly higher frequency of the G allele of COMT rs4680 (OR = 1.11; 95% CI: 1.02-1.21; p = 0.013) and the G allele of BDNF rs6265 (OR = 1.40; 95% CI: 1.10-1.77; p = 0.005) compared to controls. No significant differences were observed for HTR1A rs6295, DRD2 rs1800497, or OPRM1 rs1799971 polymorphisms (p > 0.05). Conclusions: This meta-analysis indicates that certain genetic variants previously associated with cognition-related traits, particularly COMT rs4680 and BDNF rs6265, are more frequently observed in elite athletes. These findings suggest a potential association between cognition-related genetic pathways and elite athletic status. However, as the present analysis is based on genetic distribution rather than direct cognitive assessments, the results should be interpreted within the context of association rather than causation.

INTRODUCTION: The gut-brain axis constitutes a bidirectional network linking the gastrointestinal tract and central nervous system through neural, endocrine, metabolic, and immune pathways. Neurotransmitters play a central role in mediating this crosstalk, serving as intermediates through which the gut microbiota influences brain function. Although important mechanistic advances have been made, research on the neurotransmitter-mediated gut-brain axis remains fragmented across disciplines. This study aimed to provide a comprehensive bibliometric overview of this field. METHODS: We conducted a bibliometric analysis of 788 publications retrieved from Web of Science, Scopus, and PubMed between 2005 and 2025. Using VOSviewer, CiteSpace, and Pajek, we analyzed publication trends, geographic distribution, institutional and author contributions, journal co-citations, and keyword evolution to characterize the knowledge structure and emerging themes of the field. RESULTS: The results revealed three developmental phases: an exploratory phase (2005-2016) with limited output, a developmental phase (2017-2019) with moderate growth, and a rapid expansion phase (2020-2025) marked by exponential increases in publications driven by advances in microbiome and neurotransmitter research. China led in publication volume, while the United States and Ireland served as major hubs of collaboration. University College Cork showed the highest citation impact, with 10,935 citations from 28 publications (average citations per document = 390.54). John F. Cryan, Timothy G. Dinan, and Gerard Clarke were among the leading contributors, with Cryan ranking first in both publication output and citation count. Keyword and thematic analyses identified gut microbiota, serotonin, short-chain fatty acids, depression, and inflammatory bowel disease as core topics, reflecting a shift from mechanistic studies to disease-specific and neurotransmitter-targeted research. Highly cited studies focused on microbial regulation of neurotransmitters, neuroimmune signaling, and their implications for neurodevelopmental and neurodegenerative disorders. DISCUSSION: This study provides the first comprehensive bibliomet

BACKGROUND: Equine emotion and welfare are of increasing concern to the general public, equestrians and researchers. There is growing demand for more objective indicators of specific emotional states, as well as the well-being of horses in a variety of contexts. Such markers may also assist in both the diagnosis and selection of biological therapies within equine behavioral medicine. RESULTS: This scoping review summarizes and appraises the published findings relating to relevant biological measurements from the last two decades. Particular attention is given to methodological, subject-related and context-dependent factors that might affect reference values. The most common biomarkers found were ACTH, cortisol and serotonin. Other biomarkers found, but with fewer reports, were oxytocin, melatonin, dopamine and tryptophan. CONCLUSIONS: We conclude that research on these topics has used diverse methodological approaches which makes their current clinical value hard to determine. This could explain the common recommendation for the need for further research. To create useful, valid and applicable indicators for the study of emotional states in clinical environments, there is a need for both agreed definition of relevant subjective states and greater consensus on the standardized protocols to be used for sample collection, analysis and units of measurement reported. Our findings provide a solid basis for the further development of the assaying of these biomarkers for more routine use in both clinical practice and equine welfare research.

The hypothalamic-pituitary-adrenal axis (HPA axis) is an important part of the stress response. The HPA axis may adapt to the environment in part through epigenetics, including DNA methylation. This pre-registered (OSF), PRISMA-compliant systematic review and meta-analysis aimed to evaluate the level of evidence for an association between DNA methylation and the cortisol response to an acute psychological stressor, a key marker of HPA axis function, in humans. PsycINFO, MEDLINE, Scopus, and Web of Science were searched on the 1st of September 2025 and risk of bias was evaluated using an original rubric. Thirty-nine studies were included, with mixed results. Meta-analyses revealed support for an association between NR3C1 methylation and a stronger cortisol response in infants (r = 0.26, p = .01), but not other age groups (r = -0.01, p = . 85). There was some tentative evidence for an association between SLC6A4 methylation and a weaker cortisol response (r = -0.15, p = .056), but the effect was not significant. There was preliminary (non-meta-analytic) support for LEP, NR3C2, OXTR, and SKA2. The evidence to date must be considered low certainty, due to a combination of small sample sizes, incomplete reporting, substantial methodological and conceptual heterogeneity, a high likelihood of residual confounding, and a reliance on outdated and unreliable candidate gene methods. Given the low certainty of the evidence, it is not yet possible to draw any strong conclusions. Directions for research include a collaborative, protocolised, methylome-wide meta-analysis and a focus on genomic loci that may be more strongly correlated between brain and peripheral tissue. This review received no specific funding.

In severe cases of depression and obsessive-compulsive disorder (OCD), clomipramine is sometimes administered parenterally. This systematic review aimed to investigate whether parenteral clomipramine is superior to oral clomipramine or other treatments, primarily in terms of reducing depressive/OCD symptoms within two weeks (CRD420250654029). Medline, Embase, the Cochrane Library, and PsycInfo were searched for relevant publications. Randomized controlled trials (RCTs) without a high risk of bias formed the primary basis for the conclusions. Meta-analyses were performed when applicable. Certainty of evidence was assessed according to GRADE. The literature search identified 4973 unique publications, whereof 14 RCTs contributed data regarding the question at issue in this systematic review. The evidence synthesis revealed that parenteral clomipramine may not be superior to oral administration in terms of reducing depressive symptoms within two weeks, but a clinically relevant effect cannot be excluded (low certainty of evidence; five RCTs including 70 patients; mean difference of change in Hamilton depression rating scale scores (meta-analysis based on three RCTs): -1.27 (95% confidence interval: -3.09 to 0.54; 2, I2 = 22%). Regarding patients with OCD, no conclusion could be drawn (very low certainty of evidence; two RCTs including 47 patients; meta-analysis not conducted due to heterogeneity). Regarding comparisons with other treatments, the available RCT (depression) did not allow for conclusions, or no RCTs (OCD) were available. Current evidence indicates that parenteral administration of clomipramine may not be favourable compared to oral administration, and RCTs with relevant comparisons such as electroconvulsive therapy and ketamine are lacking.

INTRODUCTION: More than 720 000 individuals die by suicide annually worldwide, making it a major public health concern and a leading cause of death among young people, particularly in Asian populations. Dysregulation of the 5-hydroxytryptamine system has been implicated in suicide risk. The SLC6A4 gene encodes the serotonin transporter, which regulates synaptic 5-hydroxytryptamine levels. Its promoter region contains a 44-base-pair insertion/deletion polymorphism, known as the serotonin-transporter-linked polymorphic region (5-HTTLPR). We examined the association between the 5-HTTLPR polymorphism and suicide death in a Japanese cohort, representing the largest sample from an Asian population to date. METHODS: We included 448 suicide decedents and 361 controls. Genomic DNA was extracted from peripheral blood, and 5-HTTLPR genotypes were determined using PCR. We evaluated genotype- and allele-level associations with suicide. Additionally, we conducted a meta-analysis incorporating previous studies. RESULTS: The distributions of 5-HTTLPR genotypes and alleles differed significantly between suicide decedents and controls (S allele: OR = 1.62, 95% CI = 1.26-2.09, p < 0.001). The associations remained significant in subgroup analyses by sex, age group, and violent methods. Age- and sex-matched analyses yielded consistent results. However, the random-effects meta-analysis did not demonstrate a significant association. CONCLUSION: Our findings indicate a potential association between 5-HTTLPR polymorphisms and suicide death in a Japanese population. Although further research in larger and diverse samples is warranted, these results may contribute to a better understanding of the biological underpinnings of suicide risk. © 2026 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsychopharmacology.

INTRODUCTION: Binge eating disorder (BED) is a common psychiatric condition associated with psychological and cardiometabolic morbidity. Psychotherapy remains a core treatment modality while pharmacologic agents such as lisdexamfetamine, selective-serotonin reuptake inhibitors (SSRIs), and topiramate demonstrate variable efficacy and tolerability. Incretin therapies-specifically glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 RA-originally developed for type 2 diabetes mellitus (T2DM) and obesity, are an emerging therapy of interest for BED due to their effects on satiety, appetite regulation, and reward-driven eating. This systematic review examines current data surrounding the efficacy of incretin therapies in treating BED and discusses potential mechanisms underlying their effects. METHODS: This systematic review was registered with PROSPERO (CRD42024615851) and conducted in accordance with PRISMA 2020 guidelines. Comprehensive searches were performed across MEDLINE, Embase, PsycINFO, Scopus, and Cochrane CENTRAL from inception to December 2024. Eligible studies included human trials evaluating GLP-1 RAs or dual GLP-1/GIP agonists in patients with diagnosed BED or binge eating behaviors. Data were extracted on study design, interventions, eating disorder outcomes, psychiatric symptoms, weight, and cardiometabolic measures. RESULTS: Of 1125 screened records, 12 studies met inclusion criteria. Interventions studied included liraglutide, semaglutide, and dulaglutide, with sample sizes generally < 75 participants. Despite heterogeneity in study design and outcome measures, consistent reductions in binge eating behaviors were observed, reflected by improvements in Binge Eating Scale scores, reductions in binge frequency, and remission rates. GLP-1 RAs were also associated with significant reductions in body weight (-3 to -24 kg), BMI, and improvements in glycemic control among individuals with diabetes. Adverse effects were primarily gastrointestinal, with no new psychiatric safety concerns identified. DISCUSSION: GLP-1 RAs may offer dual therapeutic benefits for BED, reducing binge eating

OBJECTIVE: This network meta-analysis evaluated the efficacy of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists, with or without Dexamethasone (D), for preventing chemotherapy-induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC) who were limited to these regimens. METHODS: Randomized controlled studies (RCTs) were searched in PubMed, Embase, Cochrane and Web of Science from their inception up to January 28, 2026 (a supplementary search was conducted from April 1, 2025, to January 28, 2026), to identify studies on patients who used 5-HT3 receptor antagonists (with or without Dexamethasone) to prevent nausea and vomiting caused by highly emetogenic chemotherapy. A total of 36 randomized controlled trials (reported in 37 articles) enrolling 11,131 patients were included in this analysis. The outcome measures included acute nausea, acute vomiting, acute complete control, delayed nausea, delayed vomiting and delayed complete control. RESULTS: Palonosetron (P) is generally more effective than first-generation 5-HT3 receptor antagonists (1st 5-HT3 antagonists), with a significantly greater advantage over Ondansetron in the delayed phase (such as in delayed vomiting (20 trials/6,347 patients) (RR 1.47, 95% CI [1.03-2.08]). In all phases, adding Dexamethasone to 1st 5-HT3 antagonists significantly improved efficacy compared to using them alone. However, combining Dexamethasone with palonosetron showed no significant advantage over Palonosetron alone in any outcome measure in indirect comparisons. In the delayed phase [such as in delayed vomiting (20 trials/6,347 patients)), Palonosetron + Dexamethasone (P+D) demonstrated statistically significant superiority over both Ondansetron + Dexamethasone (O+D) (RR 1.35, 95% CI [1.14-1.60]) and Granisetron + Dexamethasone (G+D) (RR 1.52, 95% CI [1.22-1.91]). However, in the acute phase, Palonosetron + Dexamethasone showed statistically significant superiority over Ondansetron + Dexamethasone (RR 0.81, 95% CI [0.69-0.96]) only in preventing acute vomiting (23 trials/9096 patients). In contrast, no significant efficacy differences were observed between Palonosetron + Dexamethasone and Tro

The precise regulation of the sleep-wake cycle relies on the coordinated interplay of multiple brain regions, diverse neuronal subtypes, and various neurotransmitter systems. In the neural structures of the midbrain, the ventral tegmental area (VTA) functions as a key neuromodulatory hub. Traditionally, it was thought to regulate reward and motivation primarily; however, recent studies have increasingly established its pivotal role in the sleep-wake rhythm. Based on the VTA's anatomical and cellular heterogeneity, this paper comprehensively summarizes the functional specificity and corresponding circuit mechanisms of dopaminergic (DA), glutamatergic (GLU) and GABAergic (GABA) neurons in sleep-wake regulation. Existing evidence indicates that dopaminergic and glutamatergic neurons jointly form a core arousal-promoting network through their subtype-specific long-range projections. In contrast, GABA neurons facilitate non-rapid eye movement (NREM) sleep and constrain excessive arousal activation via inhibitory projections and local negative feedback loops. Within a unified rhythmic framework, the synergy and counterbalance among these three neuronal subtypes provide a structural basis for the VTA to maintain the stability of sleep-wake states and enable their flexible transition. Furthermore, the interactions between the VTA and other arousal-promoting systems, including orexin, norepinephrine, and serotonin, further expand its functional hierarchy within the whole-brain sleep regulatory network. Meanwhile, circadian modulation of the VTA dopaminergic system maintains sleep-wake and emotional homeostasis. Finally, this paper discusses current limitations in refining neuronal subtypes, causal verification of mechanisms, and clinical translation. It highlights the scientific potential of using the VTA as a target in the management of sleep disorders.

BACKGROUND: Depressive disorders represent a major contributor to the global burden of disease, with persistently rising prevalence rates posing significant challenges to individual quality of life and public health systems. Existing first-line medications such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) typically require 2-4 weeks to take effect, with complete remission rates below 60%. Approximately one-third of patients discontinue treatment within 90 days due to adverse reactions including gastrointestinal discomfort, weight changes, or sexual dysfunction. Consequently, exploring interventions with faster onset and improved tolerability holds significant clinical importance. METHODS: A systematic search of seven databases-PubMed, Embase, Web of Science, Cochrane CENTRAL, CNKI, AMED, and Scopus-identified randomised controlled trials (RCTs) and mechanism studies published between 2010 and 2025. A qualitative synthesis method analysed clinical efficacy and adverse reactions, integrating evidence from metabolomics, epigenetics, and network pharmacology. Botanical drug identification was performed in accordance with ConPhYMP guidelines, with all species names validated taxonomically against the Medicinal Plant Names Services (MPNS) and Plants of the World Online (POWO) databases. RESULTS: Twenty-one RCTs (n = 2,766) and three mechanistic studies were included. Findings indicated that Xiaoyao Formula may exert earlier effects than SSRIs (descriptive trend: 1-2 weeks vs. 2-4 weeks), with comparable or preliminary evidence of superior remission rates and lower residual symptom incidence. Adverse reactions, particularly gastrointestinal discomfort and sleep disturbances, were significantly reduced. No serious adverse events, hepatotoxicity, or clinically significant drug interactions were reported across the evidence base, although systematic adverse event reporting was incomplete in earlier trials. Mechanistic studies suggest a hypothetical sequential pathway-'inflammation precedes neuroplasticity recovery'-involving downregulation of IL-6 and NLRP3 inflammasome, reduced methylation of the BDNF promote

OBJECTIVE: To evaluate the efficacy and safety of Lactiplantibacillus plantarum Z6 (L. plantarum Z6) supplementation in infants with functional constipation (FC) and to explore its effects on gut microbiota composition. STUDY DESIGN: In this randomized, placebo-controlled trial, 100 infants diagnosed with FC were enrolled and allocated to receive either L. plantarum Z6 or placebo. Clinical outcomes, including weekly bowel movement frequency, Bristol stool scale scores, and Wexner constipation scores, were assessed. Serum 5-hydroxytryptamine (5-HT) levels and fecal microbiota profiles were analyzed to evaluate neurogastrointestinal and microbial responses. RESULTS: L. plantarum Z6 supplementation significantly increased weekly bowel movements and Bristol stool scores while reducing Wexner scores (p < 0.05). Serum 5-HT concentrations were elevated, indicating improved gastrointestinal motility. Gut microbiota analysis revealed enhanced α-diversity, higher abundances of Bifidobacterium, Gemmiger, and Lactobacillus, and reduced Streptococcus. Correlation analysis demonstrated a positive association between L. plantarum Z6 intake and Bifidobacterium enrichment, suggesting targeted modulation of beneficial taxa. CONCLUSIONS: L. plantarum Z6 is a safe and effective probiotic intervention for infantile functional constipation. The results highlight its potential to improve bowel function and beneficially reshape the gut microbiota, offering a microbiota-targeted therapeutic strategy for pediatric gastrointestinal disorders. Chinese Clinical Trial Registry ID: ChiCTR2300073079. © 2026 Wiley‐VCH GmbH.

BACKGROUND: Depression is a common psychiatric disorder worldwide, often linked to complications like impaired sexual function. AIM: To determine the effect of the probiotic Lactofem combined with Escitalopram on severity of depression and sexual function in men diagnosed with mild to moderate depression undergoing SSRI treatment. METHODS: In a randomized controlled trial, 240 men with mild to moderate depression were assigned to 2 groups. The intervention group (119 participants) received Lactofem alongside Escitalopram, while the control group (121 participants) received only Escitalopram for 2 months. OUTCOMES: Depression severity was measured by the Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI). Sexual function was assessed using the International Index of Erectile Function (IIEF) questionnaire at baseline and after treatment. RESULTS: Both groups showed significant improvement in depression scores (P < .05). The Lactofem group had a greater reduction in HDRS (6.42 ± 3.45 vs 8.61 ± 4.15, P < .05) and BDI scores (27.63 ± 4.13 vs 30.24 ± 4.51, P < .05). Sexual function improvements were significantly higher in the intervention group across all domains: erectile function, orgasmic function, sexual desire, intercourse satisfaction, and overall satisfaction (all P < .05). CLINICAL IMPLICATIONS: Probiotics such as Lactofem may offer benefits as adjunctive therapy to reduce depression symptoms and improve SSRI-induced sexual dysfunction. STRENGTHS AND LIMITATIONS: Strengths include a rigorous randomized design, validated tools, and large sample size. Limitations are recruitment from a single Iranian clinic with culturally homogenous, married men, absence of placebo, young patient age, and no long-term follow-up. CONCLUSION: Adding Lactofem to Escitalopram treatment significantly reduces depression severity and enhances sexual function in men with mild to moderate depression. CLINICAL TRIAL NUMBER: IRCT20160524028038N14, Registration Date: 2024-05-17. TRIAL REGISTRATION: ClinicalTrials.gov identifier: https://irct.behdasht.gov.ir/trial/67103. © The Author(s) 2026. Published by Oxford University Press on behalf of The International Soci

BACKGROUND: Methamphetamine (MA) addiction is a chronic relapsing disorder that impairs physical health, induces mental distress (e.g., anxiety), and triggers abnormal inflammatory and neurotransmitter responses, all contributing to high relapse rates. Mindfulness and yoga interventions may alleviate psychological distress and improve physical well-being in substance users; however, few studies have systematically investigated their comprehensive effects on physical function, inflammatory markers, neurotransmitter balance, and relapse intention in MA addicts, leaving a gap in non-pharmacological interventions for this population. OBJECTIVE: This randomized controlled trial aimed to investigate the effects of a 24-week yoga intervention integrated with mindfulness components on multiple health outcomes among individuals with methamphetamine use disorder, ncluding physical function (assessed by Functional Movement Screening [FMS], reaction time, sleep quality, subjective fatigue, and creatine kinase [CK]), anxiety, inflammatory response (tumor necrosis factor-α [TNF-α], interleukin-6 [IL-6], and interleukin-10 [IL-10]), heart rate variability (HRV), relapse-related neurotransmitters (dopamine [DA], serotonin [5-HT], and norepinephrine [NE]), and relapse intention. METHODS: Eighty MA addicts meeting DSM-5 criteria were randomly assigned to an experimental group (n = 41; 40-min mindfulness yoga sessions, three times weekly for 24 weeks) or a control group (n = 39; no additional intervention). Assessments were conducted at baseline and post-intervention for all outcomes, with additional measurements at 4 and 12 weeks for fatigue, CK, and inflammatory markers. RESULTS: Following the 24-week intervention, the experimental group demonstrated significant improvements in sleep quality (PSQI score reduced from 14.32 to 8.41), anxiety levels (BAI score decreased), FMS total score (increased from 9.24 to 12.12), and reaction time (improved from 0.59 s to 0.48 s) compared to baseline and controls (p < 0.01). Relapse intention (OCDS score reduced from 29.12 to 18.45) and NE levels significantly decreased, while DA and 5-HT levels significantly increased (p < 0.01). The experim

OBJECTIVES: To observe the effect of auricular thumbtack needle combined with behavioral therapy on anxiety symptoms, clinical symptoms, and peripheral serum 5-hydroxytryptamine (5-HT) content in female patients with mild to moderate overactive bladder (OAB) accompanied by anxiety symptoms. METHODS: A total of 118 female patients with mild to moderate OAB and anxiety symptoms were randomly divided into an experimental group (59 cases, 10 dropouts) and a control group (59 cases, 2 dropouts). In the control group, the behavioral therapy and basic treatment were provided. In the experimental group, auricular thumbtack needle therapy was given in addition to treatments in the control group. The thumbtack needles were applied to the auricular points of heart (CO15), liver (CO12), kidney (CO10), and bladder (CO9). Behavioral therapy was conducted daily, and the thumbtack needles were replaced every 3-4 days, alternating between both ears, for a total of 6 weeks. The following indicators were observed before and after treatment:overactive bladder symptom score (OABSS), Hamilton anxiety scale (HAMA) score, overactive bladder questionnaire (OAB-q) score, Pittsburgh sleep quality index (PSQI) score, Hamilton depression scale (HAMD) score, traditional Chinese medicine (TCM) syndrome score, urodynamic parameters (maximum flow rate [MFR], maximum cystometric capacity [MCC], and residual urine volume [RUV]), nocturia frequency, and serum 5-HT content measured by ELISA. RESULTS: After 2, 4, and 6 weeks of treatment, the scores of OABSS, HAMA, OAB-q, PSQI, HAMD, and TCM syndrome scores in both groups decreased significantly (P<0.05) compared with those before treatment. After 6 weeks of treatment, the nocturia frequency of patients in both groups were lower (P<0.05) than those before treatment, while the MFR, MCC and serum 5-HT contents were all higher (P<0.05) than those before treatment;RUV of the experiment group decreased (P<0.05). Compared with the control group at different time points after treatment, the experimental group showed lower scores of OABSS, HAMA, OAB-q, PSQI, HAMD, TCM syndrome scores as well as reduced nocturia frequency (P<0.05), along with elevated MFR, M

Venlafaxine, a serotonin-norepinephrine reuptake inhibitor, is an antidepressant administered as a racemate of (S)- and (R)-venlafaxine enantiomers, which differ in pharmacological activity. It is extensively metabolized, primarily via CYP2D6, to its major active metabolite, O-desmethylvenlafaxine. Variability in CYP2D6 activity, due to genetic polymorphisms or co-administration with CYP2D6 inhibitors, can potentially alter exposure to both venlafaxine and O-desmethylvenlafaxine. This study aimed to quantify the impact of strong CYP2D6 inhibitor on the pharmacokinetics of venlafaxine and O-desmethylvenlafaxine and to evaluate whether dose adjustment is warranted when exposure to the active compounds is normalized by their relative pharmacodynamic potency. In a two-phase crossover study, 24 subjects received a single oral dose of 150 mg racemic venlafaxine. Following a 2-week washout period, a strong CYP2D6 inhibitor (paroxetine 20 mg) was administered daily for 10 days, with venlafaxine co-administered on the final day. Enantiomer-specific parent-metabolite models were developed using nonlinear mixed-effect modeling. A one-compartment model with first-order absorption, incorporating a first-pass effect, and linear elimination was applied for both enantiomers. CYP2D6 inhibition reduced parent-to-metabolite conversion, with a 2.5-fold greater effect on (R)-venlafaxine compared to (S)-venlafaxine. The co-administration of CYP2D6 inhibitor reduced by ∼8% the potency-adjusted exposure for norepinephrine and serotonin transporters. Although venlafaxine exposure increased under CYP2D6 inhibition, the magnitude of this effect was lower than that observed comparing CYP2D6 phenotypes. Therefore, dosing recommendations for venlafaxine in the presence of CYP2D6 inhibitors should be aligned with those for CYP2D6 intermediate metabolizers, for whom no dose adjustment is recommended. © 2026 American College of Clinical Pharmacology.

OBJECTIVES: To evaluate the effectiveness of magnesium supplementation as an adjunct to fluoxetine therapy for improving depressive symptoms and serum serotonin levels in patients with depression. METHODS: Consecutive patients aged 18 to 45 years who had been prescribed fluoxetine therapy for new-onset or chronic depression were recruited between November 2024 and February 2025 at the outpatient psychiatry clinic of Wahidin Sudirohusodo General Hospital and three affiliated hospitals in Makassar, Indonesia. Participants were randomised in an alternating sequence to receive either fluoxetine 20 mg/day alone or in combination with oral magnesium supplementation 250 mg/day. Outcomes were assessed at baseline and week 6. The severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale (HDRS). Blood samples were collected to measure serum serotonin levels. RESULTS: In total, 32 women and 8 men who received either fluoxetine alone (n = 20) or in combination with magnesium (n = 20) were included in the analysis. Both groups showed significant reductions in HDRS total score from baseline to week 6 (p < 0.001), but changes in serum serotonin level were not significant in either group. The reduction in HDRS total score was greater in the intervention group than in the control group (-6.35 vs -2.80, p < 0.001), particularly in the domains of mood and insomnia. The median reduction in HDRS total score was greater in the intervention group than in the control group (-6 vs -2, p < 0.001). The group effect remained significant (F(1,30) = 33.51, partial η2 = 0.528, p < 0.001) after adjustment for baseline HDRS score and demographic covariates, indicating a large effect size. CONCLUSION: Magnesium supplementation as an adjunct to fluoxetine therapy improves HDRS total score in patients with depression.

PURPOSE: Depression and anxiety negatively impact COPD prognosis, yet evidence for psychopharmacological interventions remains limited. This study evaluated the efficacy and safety of low-dose escitalopram for managing these comorbidities in COPD patients. PATIENTS AND METHODS: In this double-blind, placebo-controlled trial, 150 COPD patients with moderate-to-severe anxiety and/or depression were randomized (1:1) to receive escitalopram (5-10 mg/day) or placebo for 4 weeks, followed by an 11-month observational follow-up without maintenance study medication. Primary endpoints were changes in HAMA-14 and HAMD-17 scores at Month 1. Secondary outcomes included CAT scores, mMRC ratings, and lung function (FEV1% predicted) through Month 12. RESULTS: At Month 1, escitalopram demonstrated significantly greater reductions in HAMA-14 (-9.25 [95% CI -9.67 to -8.82] vs -2.20 [-2.46 to -1.95]) and HAMD-17 (-7.37 [-7.74 to -7.01] vs -1.37 [-1.72 to -1.01]) compared to placebo (p < 0.01). These improvements were sustained at Month 12 (p < 0.01). CAT scores improved significantly more in the escitalopram group (-6.20 [-6.68 to -5.72]) versus placebo (-2.79 [-3.02 to -2.55]) over the 12-month observational period (p < 0.01). No significant differences were observed for mMRC or FEV1% predicted. Adverse events were mild and comparable between groups. CONCLUSION: Short-term treatment with low-dose escitalopram significantly alleviates depression and anxiety in COPD patients. Notably, this brief intervention initiated a sustained positive clinical trajectory over 12 months. Combined with a favorable safety profile, these findings support its potential integration into comprehensive COPD management protocols, pending multicenter validation. TRIAL REGISTRATION: ChiCTR1800017338 (https://www.chictr.org.cn/). Registered 25-July-2018. © 2026 Gao et al.

BACKGROUND: The benefits of acute physical exercise for substance use disorders have received extensive attention, but it is currently unclear whether adding repetitive transcranial magnetic stimulation (rTMS) based on exercise can achieve the superposition of benefits. This study aims to explore the acute effect and potential mechanism of rTMS combined with physical exercise on people with methamphetamine use disorders (MUD), and reveal the differences in effects among different models. METHODS: 64 men with MUD were randomly divided into the physical exercise group (PEG), low-frequency rTMS + physical exercise group (LF rTMS + PEG), high-frequency rTMS + physical exercise group (HF rTMS + PEG), and control group (CG) by an acute experimental study. The PEG was required to complete 35 min of moderate-intensity physical exercise, and the LF- and HF rTMS + PEG were required to complete the 1Hz and 10Hz rTMS tasks of 10 min based on the exercise group, respectively, while the CG only performed the reading task. RESULTS: Three acute interventions not only significantly reduce depression, anxiety, and psychological cravings in people with MUD but also enhance internal inhibition (particularly in the HF rTMS + PEG) and increase the levels of DA, β-EP, and 5-HT in the blood. Meanwhile, these acute effects persisted for up to 60 min post-intervention (except for anxiety), and the HF rTMS + PEG demonstrated relatively stronger sustainability of these effects. Moreover, electrophysiological data revealed that compared to neutral cues, people with MUD exhibited abnormal prefrontal activation (manifested as significantly lower Fz-alpha wave power) when exposed to drug-related cues at baseline. Then all three intervention groups showed significantly increased Fz-alpha wave power during drug-cue tasks immediately after intervention, and both the LF rTMS + PEG and HF rTMS + PEG maintained significantly higher values compared to the CG at 60 min post-intervention. CONCLUSION: A single session of moderate-intensity physical exercise demonstrates acute benefits for both psychological and physiological withdrawal recovery in people with MUD. More importantly, it is essential to co

IMPORTANCE: Seltorexant, a selective orexin-2 receptor (OX2R) antagonist, has demonstrated antidepressant effects in major depressive disorder (MDD), particularly among patients with higher baseline insomnia symptoms. OBJECTIVE: To investigate flexibly dosed seltorexant vs flexibly dosed quetiapine extended release (quetiapine-XR) as adjunctive treatment to a selective serotonin (SSRI) or serotonin-norepinephrine (SNRI) reuptake inhibitor. SETTING: Outpatient. DESIGN: Randomized, active-controlled, multicenter, exploratory phase 2 study with screening (≤4 weeks), double-blind treatment (24 weeks), and post-treatment follow-up (2 weeks) phases. PARTICIPANTS: Patients with MDD and inadequate response to 1-3 SSRIs/SNRIs, including an ongoing SSRI/SNRI, in the current depressive episode. INTERVENTIONS: Flexibly dosed seltorexant (20 or 40 mg) or quetiapine-XR (150 or 300 mg, with 2-day initial dosing of 50 mg) once daily as adjunctive therapy to an SSRI/SNRI. Randomization (1:1) was stratified by baseline Insomnia Severity Index total score (≥15 vs <15). Safety, tolerability, and preliminary efficacy were evaluated. MAIN OUTCOMES AND MEASURES: Primary efficacy endpoint was time to all-cause study drug discontinuation. Secondary efficacy endpoints included change in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Subgroup analyses included MADRS change by mode dose (MD; most frequent daily dose received by a patient during the study). Safety and tolerability also were assessed. RESULTS: Time to all-cause discontinuation (estimated 25th percentile [80% CI]: seltorexant, 62 [38, 83] days vs quetiapine-XR, 42 [35, 61] days; hazard ratio [80% CI]: 0.83 [0.6, 1.2]) and all-cause discontinuation (seltorexant, 41.2% vs quetiapine-XR, 47.1%; 2-sided P = .5355) did not differ significantly between treatment groups. For the seltorexant 20-mg MD group, MADRS total scores consistently improved over time and reductions were numerically greater at weeks 18 and 24 versus the seltorexant 40-mg MD and the combined quetiapine-XR groups, and patients with higher baseline insomnia symptoms had greater improvement in MADRS total score, consistent with prior studies showing

Erratum in Eur Neuropsychopharmacol. 2026 Aug 27;113:113860. doi: 10.1016/j.euroneuro.2026.113860. Optimising patient outcomes in treatment resistant depression (TRD) requires treatments which provide sustained remission, without relapse, and tolerability in the long term. ESCAPE-LTE (NCT04829318) was a phase IV, single-arm, 2-year (104 weeks) long-term extension of ESCAPE-TRD (NCT04338321; 32 weeks), a rater-blinded, randomised, active-controlled trial, which evaluated the safety, tolerability and efficacy of esketamine nasal spray (NS), alongside an ongoing selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor, in patients with TRD. The primary endpoints were the proportion of patients who reported treatment-emergent adverse events (TEAEs) or suicidal ideation and behaviour (using the Columbia-Suicide Severity Rating Scale). Effectiveness was assessed using the Montgomery-Åsberg Depression Rating Scale, Clinical Global Impression-Severity scale, Patient Health Questionnaire-9 and EuroQol 5-Dimension 5-Level questionnaire. Outcomes are reported from ESCAPE-TRD baseline to the end of ESCAPE-LTE (136 weeks of treatment, 138 weeks including safety follow-up). In patients who entered ESCAPE-LTE (N = 183), TEAEs and serious TEAEs were observed in 96.7% and 8.2%, respectively. 98.3% of TEAEs occurring on dosing days resolved same-day; few patients discontinued due to TEAEs during ESCAPE-LTE (3.3%). 151/160 (94.4%) patients who were non-suicidal at baseline remained non-suicidal to the end of ESCAPE-LTE. In the subgroup with remission in ESCAPE-TRD, 79.2% did not relapse or discontinue treatment throughout ESCAPE-LTE; the overall relapse rate for patients achieving remission across both studies was 6.9%. The vast majority of patients with TRD who achieved remission with esketamine NS did not relapse over 136 weeks of treatment; no new safety concerns were identified, and the safety profile was consistent with short-term studies.

BACKGROUND: Optimizing pain control and anesthesia stability is essential for surgical outcomes in dogs. This study evaluated the effects of preoperative tapentadol on anesthesia depth, recovery, and serotonin levels in dogs undergoing elective spaying. METHODS: Sixty-six healthy female dogs were randomly assigned to three groups: standard pain relief, tapentadol alone, or tapentadol combined with standard pain relief. Anesthesia was induced with propofol and maintained with sevoflurane. Intraoperative heart rate, blood pressure, anesthetic depth, postoperative sedation, pain scores, and plasma serotonin concentrations were recorded. RESULTS: Tapentadol-treated dogs showed deeper and more stable anesthesia during surgical stimulation, higher early postoperative sedation that resolved within two hours, and reduced postoperative serotonin levels compared with controls. All analgesic protocols maintained adequate pain control, and biochemical parameters remained within normal limits. CONCLUSIONS: Preoperative tapentadol enhances anesthetic stability, supports smoother early recovery, and modulates serotonin levels in dogs, suggesting benefits for perioperative pain management and overall surgical welfare.

Background/Objective: A substantial proportion of patients with obsessive-compulsive disorder (OCD) does not respond adequately to first-line treatments such as selective serotonin reuptake inhibitors and cognitive-behavioral therapy. OCD has traditionally been conceptualized as a serotonergic disorder. However, emerging evidence suggests that glutamatergic dysfunction plays an important role. Ketamine and esketamine are NMDA receptor antagonists with rapid antidepressant effects and have therefore attracted interest as potential treatments for OCD. This scoping review aims to map and synthesize the existing preclinical and clinical evidence regarding the therapeutic potential of ketamine and esketamine in OCD. Methods: A scoping review methodology based on the Arksey and O'Malley framework and Joanna Briggs Institute guidance was applied. Searches were conducted in PubMed, Scopus, and Web of Science. Studies that examined ketamine or esketamine in OCD populations or relevant experimental models were included. Results: Twenty-one studies met the inclusion criteria, of which five were preclinical studies and sixteen were clinical investigations. Preclinical evidence suggests that ketamine and esketamine improve compulsive-like behaviors. Clinical studies suggest that ketamine can produce rapid reductions in obsessive symptoms, though results remain inconsistent. Most trials evaluated single administrations, while limited evidence suggests that repeated dosing strategies may provide greater clinical benefit. Conclusions: Ketamine and esketamine show promise as rapid acting interventions for OCD, particularly in treatment refractory cases. However, current evidence remains preliminary and heterogeneous. Future research should prioritize adequately powered randomized trials and investigation of repeated administration protocols with longer follow-up periods to determine efficacy and optimal clinical implementation.

Obsessive-compulsive disorder (OCD) is a chronic mental disorder characterized by distressing thoughts and repetitive behaviors that significantly impair daily functioning and quality of life. Many patients fail to achieve sufficient symptom relief with first-line treatments, such as cognitive-behavioral therapy (CBT) or selective serotonin reuptake inhibitors (SSRIs). Dopaminergic dysregulation has been implicated in the pathophysiology of OCD, providing a rationale for pharmacological augmentation strategies. This article presents a narrative review of the evidence regarding the efficacy, safety, and clinical applicability of antipsychotic agents and emerging pharmacological augmentation approaches, including extended-release methylphenidate (MPH-ER), in SSRI-resistant OCD. A literature search was conducted using PubMed, EBSCO, and Embase databases, with an additional search of Google Scholar, focusing on studies examining pharmacological augmentation in treatment-resistant OCD. Overall, the evidence base is limited by small sample sizes, short follow-up durations, heterogeneous response criteria, and a lack of head-to-head comparisons versus CBT augmentation, which constrains the generalizability of conclusions. Dopamine receptor antagonists, particularly risperidone, as well as the partial agonist aripiprazole, remain the most consistently supported augmentation strategies, while olanzapine and quetiapine may be considered in selected cases. Evidence for MPH-ER is currently limited-supported by one small RCT and two recent case series-and may be considered in carefully selected adults with comorbid ADHD or marked executive dysfunction, although larger controlled studies and long-term safety data are required before firm clinical recommendations can be made.

The accumulated ammonia within the recirculating aquaculture systems threaten fish health, while little is known about the influences during early fish ontogeny. Using larval and juvenile yellow catfish (Pelteobagrus fulvidraco) as a model, a comprehensive experiment exposing fish to varying total ammonia nitrogen concentrations (0, 10, 20 mg/L for larvae; 0, 25, 125 mg/L for juveniles) was conducted to evaluate the effects on gill transcriptome and microbiota along with the serotonergic regulation. First, the serotonin (5-HT) signal, which controls oxygen chemoreception and ventilation, was mainly detected in the surface of the body of the larvae, and then shifted to gill filaments of juveniles, showing a transition from cutaneous to branchial respiration. Both larval and juvenile yellow catfish exhibited reduced survival, damaged gill structure, and elevated 5-HT expression after ammonia exposure, as well as upregulated tph1b, slc6a4b, scgn and lama5 expression with the increased ammonia concentration, indicating the effects on respiratory function via serotonergic regulation. Further transcriptome analysis was conducted in juveniles to identify the differentially expressed genes (DEGs) and thus, to illustrate more detailed responses after ammonia exposure; KEGG enrichment analysis of DEGs indicated the coping strategy shifted from metabolic buffering to metabolic elimination via glutamine synthesis with the increased ammonia level. The qRT-PCR experiment also identified the increased expression of genes involved in the urea cycle-such as ass1, asl and glula-with the increased ammonia level. Considering the potential contributary role of microbiome to gill health, 16S sequencing was conducted on the gill in the control and the 125 mg/L ammonia-exposed group. Ammonia exposure at 125 mg/L induced significant variation in Simpson index and a marked decline in β diversity. Notably, the abundance of opportunistic pathogens such as Pseudomonadota increased, while the abundance of Deinococcota and Deinococcus-which were renowned for exceptional stress resistance capacity-decreased after ammonia exposure. Thus ammonia exposure disrupts the transcriptomic and microecol

As a representative next-generation probiotic, Akkermansia muciniphila (A. muciniphila) produces a variety of functional proteins that play critical roles in the prevention and treatment of multiple diseases, including metabolic disorders, inflammatory diseases, neurological disorders, and cancer. This review summarizes the disease-associated proteins of A. muciniphila reported to date, including the outer membrane proteins Amuc_1100 and Amuc_1098, as well as the secreted proteins P9 (Amuc_1631), P5, Amuc_1409, Amuc_1434, and Amuc_2109. These proteins exert their biological effects by activating multiple signaling pathways, such as Toll-like receptor 2 (TLR2), ICAM-2, and Wnt/β-catenin, thereby regulating physiological processes including glucagon-like peptide-1 (GLP-1) secretion, serotonin biosynthesis, lipid metabolism, and intestinal stem cell proliferation. This review provides a theoretical foundation and future perspectives for in-depth research investigation and clinical application of A. muciniphila disease-related proteins.

Glucagon-like peptide-1 (GLP-1) and dual GIP/GLP-1 receptor agonists, originally introduced for the management of type 2 diabetes mellitus and obesity, are increasingly recognized for their broader actions within the central nervous system, with emerging implications in neuropsychiatry and neurodegeneration. This review integrates current preclinical and clinical evidence, emphasizing their pharmacodynamic profile, central receptor distribution, and the molecular pathways linking metabolic signaling to neural function. Evidence suggests that GLP-1 receptor activation across key brain regions involved in energy balance and reward modulates multiple neurotransmitter systems, including dopamine and serotonin, as well as glutamatergic and GABAergic transmission, thereby influencing behavior, affective processes, and cognitive function. In parallel, these agents exhibit neuroprotective properties through improved neuronal insulin sensitivity, attenuation of neuroinflammatory pathways, and support of neuroplasticity, alongside effects on limiting pathological protein aggregation. Dual GIP/GLP-1 agonism may further potentiate these central actions through complementary metabolic and synaptic mechanisms. Although pharmacovigilance data have identified isolated neuropsychiatric adverse events, current clinical evidence does not support a consistent causal association. Collectively, incretin-based therapies represent a promising translational approach at the interface of metabolic and neuropsychiatric disorders, warranting further investigation into their long-term central safety, therapeutic efficacy, and clinical relevance.

The formulation of the gut-brain-microbiota axis (GBA) theory has led to new research directions that have expanded our understanding of the pathogenesis, phenotypic variability, and clinical course of Parkinson's disease (PD). Models of PD pathogenesis, based on the Braak hypothesis, suggest a subtype of the disease in which pathological changes begin in the gut many years before the onset of brain pathology and the manifestation of motor symptoms. Gut microbiota may influence nervous system function along the GBA by influencing intestinal permeability, chronic inflammation, and α-synuclein aggregation. Accumulating evidence suggests that the gut microbiota may also regulate the synthesis and metabolism of neurotransmitters, including dopamine (DA), serotonin (5-HT), acetylcholine (ACh) and γ-aminobutyric acid (GABA), both in the gut and brain, and indirectly stimulate central nervous system activity via the vagus nerve, which receives signals from the enteric nervous system. Research on the effects of microbiota on GBA has paved the way for the identification of novel treatment strategies, including probiotics, prebiotics, synbiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT), aimed at not only symptomatic but also disease-modifying treatment of PD. In this article, we propose a novel approach to GBA as a link between gut microbiota and gut and brain neurotransmitter metabolism in PD. We review the latest research on the gut epithelial barrier. We analyze and summarize the potential of therapeutic interventions targeting gut microbiota and their impact on neurotransmitter regulation in PD.

Biogenic amines are nitrogenous compounds that may occur in foods through plant metabolism, bee enzymatic activity, or microbial decarboxylation. This study evaluated biogenic amines content in monofloral honeys from Algeria and Morocco, integrating compositional analysis, quality indices, and dietary exposure assessment within a toxicological risk characterization framework. Eight amines were quantified by HPLC-FLD, and Estimated Daily Intake (EDI) was calculated under adult and pediatric low- and high-consumption scenarios. Composite indices, including Total Biogenic Amines (TBA), Biogenic Amine Index (BAI), Vasoactive Amine Load (VAL), Potentiation Index (PI), and Quality Index (QI), were determined. Marked intra- and inter-city variability was observed, particularly for serotonin, tryptamine, and tyramine. Algerian Euphorbia orientalis L. samples showed the highest TBA and VAL values. However, histamine concentrations generally remained below 1 mg/kg, and tyramine levels were markedly lower than doses associated with hypertensive effects. Worst-case EDI values were in the order of 10-3-10-4 mg/kg body weight/day, including high-consumption pediatric scenarios. PI values were low, indicating limited synergistic amplification by diamines. Overall, despite botanical and geographical variability, the analyzed honeys exhibit a wide safety margin and based on the applied screening-level assessment, no immediate risk is indicated under the considered scenarios.

Parkinson's disease (PD) is one of the most prevalent and extensively studied neurodegenerative conditions. One of its most challenging clinical manifestations is the emergence of dyskinesias, characterized by involuntary movements that significantly impair patients' quality of life. Meanwhile, boron, as a trace element, and boron-containing compounds have emerged as active modulators of neurotransmitter systems. To evaluate the effect of aryl-boroxazolidones on parkinsonism, the in vitro neurotoxicity of three boroxazolidones was assessed, along with the effects of two of them in mice with parkinsonism induced by MPTP administration. Two novel compounds demonstrated a limitation of parkinsonism, whereas risperidone reduced the beneficial effect of the tested boroxazolidones. The three boroxazolidones did not induce toxicity in neurons or glial cells at concentrations up to 100 µM. In silico analyses support the ability of BCC to act as ligands of dopamine and serotonin receptors. Taken together, these results suggest that the tested boroxazolidones are promising candidate agents, warranting further exploration for the treatment of PD.

Dietary supplementation with tryptophan in sows is a promising strategy for optimizing both performance and animal welfare. In addition to its role in protein synthesis, this essential amino acid is a precursor of serotonin and melatonin, which are bioactive compounds that influence appetite, social behavior, and stress regulation. However, the reported effects on reproductive outcomes and maternal metabolism remain inconsistent. This systematic review evaluated the evidence of tryptophan supplementation as a modulator of behavior and productivity in sows. Searches were conducted in Scopus and Web of Science databases. Experimental peer-reviewed studies that assessed tryptophan supplementation across different physiological phases (gestation and lactation), dietary levels, and environmental contexts were included. This review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, and the protocol was preregistered. Screening and data extraction were performed by two independent reviewers, and the risk of bias was assessed using the SYRCLE's (Systematic Review Center for Laboratory Animal Experimentation) risk of bias tool. Eleven studies met the eligibility criteria of this review. Tryptophan supplementation consistently reduced aggressiveness in group-housing systems and supported piglet survival and growth. However, the effects on reproductive performance and maternal metabolism vary depending on the dose, parity, and environmental conditions. The heterogeneity of the study designs and the absence of a meta-analysis due to data variability were identified as the main limitations. Overall, tryptophan supplementation demonstrated potential benefits for sow welfare and productivity, but the results remained context dependent. Long-term and standardized studies are required to clarify its impact, particularly on reproductive efficiency and maternal physiology. Plain Language Summary: Tryptophan is an amino acid that can be added to sow diets to improve both their behavior and productivity. In addition to its role in protein synthesis, tryptophan serves as a precursor for bioactive compounds into substances that i