Search Results (313)

Recent years have seen growing medical interest in the influence of crosstalk between the gut microbiota and the endocannabinoidome (eCBome) on inflammation and pain modulation. Growing evidence indicates that gut microbiota can modify the effects of several marketed drugs, including analgesics. Cannabigerol (CBG) is an overlooked phytocannabinoid with a broad pharmacological spectrum and no psychotropic effects, which has anti-inflammatory and antinociceptive properties. This review aims to provide a comprehensive exploration of CBG and its role at the intersection of gut microbiota and eCBome, detailing the pharmacological mechanisms by which it acts as a promising therapeutic agent to modulate chronic inflammation and pain. Our data review suggests that CBG could act on the eCBome by activating CB2, PPARs, TRPV1, TRPA1, and α2-adrenergic receptors, while suppressing cellular and molecular mechanisms of inflammation, such as TNFα, COX-2, iNOS, IL-1β, and IL-6, and increasing antioxidant factors. These receptors and enzymes are distributed across neurons, glial, immune, and epithelial cells, which can also positively modulate gut microbiota and its metabolites, producing neurotransmitters, cytokines, and enzymes that regulate eCBome tone, and generating cannabinoid-mimetic compounds as part of pleiotropic functions. Nevertheless, CBG may exert direct effects on gut microbiota, promoting eubiosis and symbiotic bacteria. Moreover, there are no specific preclinical assays that demonstrate how CBG modulates the bidirectional communication between the gut microbiota and eCBome, addressing the specific mechanism involved in eCBome activation, and determining whether its anti-inflammatory and analgesic effects are dependent on gut microbiota type. Therefore, studies are required to evaluate this hypothesis to achieve translational medicine impact. Full article

Purpose: Delirium is a frequent and serious condition in older patients, associated with severe adverse outcomes and lacking proven pharmacological treatments. Non-pharmacological multicomponent strategies are recommended, and specialized delirium care environments (e.g., delirium room, delirium unit, psychogeriatric unit) have been proposed as a potential strategy to improve the management of delirium in hospitalized older adults. Our objective was to provide the first systematic review and pooled analysis on the subject, synthesizing the characteristics of specialized delirium environments in the care of delirium and their association with clinical outcomes. Methods: A systematic search of MEDLINE, Cochrane, and EMBASE identified studies on patients aged 65 years and older with delirium or related acute confusional states admitted to specialized delirium care environments. Study quality was assessed using Cochrane’s risk of bias tools, and exploratory pooled analyses were conducted when at least three studies reported the same outcome. Results: Nine studies, reported across 15 publications and including 2226 patients, met the inclusion criteria. Interventions were heterogeneous in structure and content, but most combined delirium-oriented staff training, enhanced surveillance, environmental adaptation, and multicomponent non-pharmacological care. Comparator groups were also diverse and included standard wards, earlier versions of specialized care models, indirect admission pathways, and non-delirious controls. The narrative synthesis suggested that specialized delirium care environments were most consistently associated with shorter delirium duration, more favorable discharge outcomes, lower physical restraint use, and better functional recovery, while findings for length of stay, falls, psychotropic drug use, and mortality were less consistent. Exploratory pooled analyses suggested a favorable direction of effect for several outcomes, particularly discharge destination and mortality, but pooled estimates were not statistically significant and should not be interpreted as definitive evidence of efficacy. All included studies were judged to be at a high or critical risk of bias. Conclusions: Specialized delirium care environments appear promising for the management of delirium in hospitalized older adults, particularly for outcomes closely related to day-to-day delirium care. However, the current evidence base is limited by substantial heterogeneity in intervention models, comparator groups, and outcome definitions, as well as by a high risk of bias across studies. These findings support further evaluation of specialized delirium care models, but do not yet allow firm conclusions regarding their effectiveness. Full article

Background/Objectives: Elderly patients (≥65 years) with atopic dermatitis (AD) often carry multimorbidity and face elevated risks with Janus kinase (JAK) inhibitors. Phase III trials included few older adults, and real-world data beyond 12 months remain scarce. We evaluated 36-month efficacy, safety, and drug persistence of upadacitinib 15 mg once daily in 62 Chinese elderly patients. Methods: This retrospective cohort study was conducted at Sir Run Run Shaw Hospital (March 2022-July 2026). All patients received upadacitinib 15 mg once daily. Assessments included Week 4 pruritus Numerical Rating Scale (NRS) response, Eczema Area and Severity Index (EASI) 75/90, and Investigator’s Global Assessment (IGA) 0/1 at Weeks 12 and 24. Drug persistence was estimated with the Kaplan–Meier method (36-month cutoff), and predictors were identified by Cox regression. Results: Median age was 70.0 years, 75.8% were male, and baseline EASI was 34.5, with substantial comorbidity (Charlson Comorbidity Index [CCI] 5.0; psychotropic use 46.8%). Week 4 itch response was 70.8%. EASI 75 reached 75.0% (IGA 0/1 44.4%) at Week 12, rising to 88.0% (64.0%) at Week 24. Persistence declined from 88.7% at Month 3 to 66.1% at Month 6, the steepest drop, reaching 38.7% at Month 36. Treatment-emergent adverse events (TEAEs) occurred in 54.8% and serious adverse events (SAEs) in 8.1%, with herpesvirus infection (21.0%) being the most common event, and there were no adverse event (AE)-related discontinuations, major adverse cardiovascular events (MACE), or venous thromboembolism (VTE). In multivariate analysis, Week 4 itch response predicted longer persistence (hazard ratio [HR] = 0.203, 95% confidence interval [CI]: 0.091-0.452, p < 0.001), while psychotropic medication use predicted shorter persistence (HR = 2.814, 95% CI: 1.237-6.403, p = 0.014). Conclusions: Upadacitinib showed robust efficacy and acceptable safety over 36 months in elderly AD patients. Persistence dropped most sharply between Months 3 and 6. Week 4 itch response and psychotropic medication use independently predicted persistence. A structured Month 3 visit integrating itch reassessment, mental health screening, and dose optimization may improve long-term outcomes. Full article

Background: Migraine is a leading cause of disability worldwide and is frequently associated with psychiatric comorbidities that may influence pain perception and treatment response. Anti-CGRP monoclonal antibodies represent an effective preventive treatment, although response variability remains poorly understood, particularly in patients with complex neuropsychiatric profiles. Case Presentation: We report the case of a 49-year-old woman with migraine with a previously chronic course and psychiatric comorbidity, including bipolar disorder and obsessive–compulsive disorder, treated with galcanezumab. The clinical course was characterized by an “on-off-on” pattern, with marked worsening after treatment discontinuation and subsequent improvement after treatment reintroduction. Results: The patient presented with severe emotional distress (BDI-II = 59; STAI = 77–80), a very high self-reported burden of central sensitization-related symptoms (CSI = 100/100) and reduced performance on cognitive screening measures (MoCA = 19/30; BCSE = 18/58). MMPI-3 findings indicated a high level of self-reported psychological distress; however, substantial elevations in symptom-validity indicators required cautious interpretation of the substantive scales. Conclusions: This case illustrates that complex neuropsychiatric comorbidity and psychotropic polypharmacotherapy did not preclude an apparent clinical benefit from galcanezumab. Treatment discontinuation and reintroduction were temporally associated with worsening and subsequent improvement in headache frequency, although causality cannot be established from a single uncontrolled observation. The case also highlights the potential value of coordinated neurological and psychiatric monitoring in patients with migraine and complex neuropsychiatric profiles. Full article

Background/Objectives: The use of antidepressants and anxiolytics has increased worldwide, raising concerns about treatment patterns, medication safety, and rational use. This study aimed to characterize the frequency, utilization patterns, and safety-related aspects of antidepressant and anxiolytic use among healthcare students and university staff at a Brazilian public university. Methods: A cross-sectional study was conducted between September 2024 and June 2025 using an online questionnaire administered to students and staff at the University of São Paulo, Brazil. Descriptive statistics and multivariable logistic regression were applied to characterize medication utilization patterns and evaluate factors associated with antidepressant and/or anxiolytic use. Results: Among the 300 participants, 167 (55.7%) reported antidepressant and/or anxiolytic use during the previous six months. Most users reported treatment for more than one year (59.9%), anxiety as the primary indication (68.3%), and prescription by a healthcare professional (93.4%). A total of 203 medications were reported, with selective serotonin reuptake inhibitors being the most common pharmacological class (42.4%). Among users, 99 (59.3%) reported at least one self-reported adverse effect, most commonly excessive drowsiness, reduced libido/sexual dysfunction, dry mouth, headache, and nausea. No statistically significant independent associations were identified between antidepressant and/or anxiolytic use and the evaluated sociodemographic characteristics. Conclusions: Antidepressant and anxiolytic use was frequently reported and was characterized by predominantly long-term, professionally prescribed treatment and frequent self-reported adverse effects. These findings may inform institutional strategies to improve access to mental healthcare while promoting the rational and safe use of psychotropic medications within university settings. Full article

Concurrent exposure to analgesic and psychotropic drugs is frequent in patients with pain, psychiatric comorbidity, frailty, or acute-care needs. The clinically important question is whether analgesics and psychotropic drugs act on the same metabolic, transporter, receptor, ion-channel, or cellular stress systems. This narrative mechanistic review discusses those points of contact. CYP-mediated inhibition or induction, phenoconversion, altered parent-to-metabolite ratios, and blood–brain barrier transporter effects can change both systemic and central exposure, particularly through CYP2D6, CYP3A4, CYP2C9, CYP2B6, and P-glycoprotein. Pharmacodynamic toxicity may involve serotonergic excess, opioid and GABAergic effects in respiratory-control networks, hERG/IKr-related loss of repolarization reserve, or dopamine D2 receptor blockade. Non-opioid analgesics and psychotropic background therapy add further pathways involving renal and gastrointestinal vulnerability, hematological toxicity, mitochondrial injury, and altered central nervous system function. At the cellular level, mitochondrial dysfunction, oxidative stress, calcium dysregulation, and endoplasmic reticulum stress are discussed primarily as mechanistic or preclinical contributors unless direct clinical evidence is available. Overall, analgesic–psychotropic co-exposure is presented as a clinically important example of pathway convergence, while pharmacogenomic and computational approaches are interpreted in relation to drug exposure, organ reserve, and patient-specific vulnerability. Full article

Background/Objectives: Electroconvulsive therapy (ECT) remains the most effective biological treatment for treatment-resistant depression. Although its efficacy has been consistently demonstrated, the influence of seizure characteristics and treatment parameters on clinical outcomes in routine practice remains incompletely understood. This study aimed to evaluate the effectiveness of seizure threshold-titrated ECT in patients with treatment-resistant depression and to describe treatment outcomes in relation to seizure expression and technical treatment variables. Methods: We conducted a retrospective naturalistic study at the Department of ECT, Dr. Gh. Preda Clinical Psychiatric Hospital, Sibiu, Romania. Consecutive patients treated with ECT for treatment-resistant depressive episodes between March 2022 and December 2025 were included. Clinical outcomes were assessed before and after treatment using the Montgomery–Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), Mini-Mental State Examination (MMSE), and Global Assessment of Functioning Scale (GAF). Information regarding electrode placement, seizure threshold, seizure duration, the number of ECT sessions, and concomitant psychotropic medication was collected from medical records. Results: Nineteen acute ECT courses were available for outcome analysis. Depressive symptom severity improved significantly following treatment, with median MADRS scores decreasing from 38 (IQR 36–41) to 20 (IQR 9.5–24) (p < 0.001). A clinical response was observed in 57.9% of courses, while 36.8% achieved remission. Similar improvements were noted in self-reported depressive symptoms and overall functioning, with median BDI scores decreasing from 38 to 16 and median GAF scores increasing from 55 to 65. MMSE scores remained stable throughout treatment. Considerable variability was observed in both motor and EEG seizure durations; however, no consistent relationship between seizure duration and antidepressant response was identified. Discussion: The observed outcomes are consistent with previous evidence supporting ECT as an effective intervention for severe depressive illness. Functional improvement accompanied symptom reduction, while no decline in global cognitive performance, as assessed by the MMSE, was observed. In this cohort, seizure duration alone did not appear to provide meaningful information regarding treatment response. Conclusions: Seizure threshold-titrated ECT was associated with substantial clinical improvement in patients with treatment-resistant depressive episodes, accompanied by improved functioning and stable global cognitive performance. These findings support the continued use of individualized ECT protocols in routine clinical practice and highlight the need for further research on neurophysiological predictors of treatment outcome. Full article

Objective: This study examined the association between glycemic status, indexed by HbA1c, and cognitive functioning in individuals with bipolar disorder (BD), recurrent major depressive disorder (rMDD), schizophrenia (SZ), and healthy controls (HCs). Methods: In this cross-sectional study, 215 participants (45 HCs, 64 BD, 62 rMDD, 44 SZ) were assessed. Cognitive performance was evaluated using a comprehensive neuropsychological battery measuring attention, processing speed, memory, executive functions, and social cognition. Sociodemographic characteristics, chlorpromazine-equivalent antipsychotic doses (CEDA), and metabolic variables (body mass index, waist circumference, lipid profile, fasting glucose, and HbA1c) were collected. Group differences, correlation analyses, and multiple regression models were performed. Results: All patient groups showed significantly poorer cognitive performance compared with HCs. HbA1c levels were highest in the SZ group; however, associations between HbA1c and cognitive performance were strongest in the BD group and less consistent in rMDD. In regression analyses, HbA1c was associated with cognitive performance in BD and HCs, with weaker effects in rMDD. CEDA was associated with HbA1c levels and partially attenuated the relationship between HbA1c and cognitive outcomes. Conclusions: HbA1c levels were associated with cognitive performance in non-diabetic individuals, particularly in BD and rMDD. These findings suggest that subclinical variation in glycemic regulation may be relevant to cognitive functioning in psychiatric disorders. Further longitudinal studies are needed to clarify the influence of metabolic factors and psychotropic medication on cognitive outcomes. Full article

Background and Objectives: Although the association between frailty and constipation in older adults has attracted growing attention, evidence linking the Clinical Frailty Scale (CFS) to colonic transit time (CTT) remains scarce. In this retrospective study, we examined this association using colon capsule endoscopy (CCE). Materials and Methods: We enrolled 124 older adults (64 men, 60 women) aged ≥ 65 years (mean age 74.6 ± 5.6) who underwent CCE for colorectal polyp screening at Aishinkai Nakae Hospital, Japan, between January 2014 and July 2024. CTT was determined at the time of CCE, and frailty was assessed with the Japanese version of the CFS. To avoid the oversimplification inherent in a strict dichotomy, participants were analyzed primarily as three ordered categories—Robust (CFS 1–2; n = 73), Intermediate (CFS 3–4; n = 43), and Frail (CFS 5–7; n = 8)—and, for comparability with previous reports, also as a Robust versus Non-robust (CFS 3–7; n = 51) dichotomy. The independent association between CFS and CTT was examined with three complementary multivariable linear regression models (Model 2: CFS continuous; Model 3: CFS three-category ordinal; Model 3b: CFS three-category dummy with Robust as reference), each adjusted for 10 covariates: age, sex, body mass index, type 2 diabetes mellitus, laxative use, anticholinergic drug use, psychotropic drug use, hypothyroidism, smoking history, and history of abdominal surgery. Results: CTT rose stepwise across the three frailty categories (Robust: 132.0 min [IQR 81.0–229.0], 157.9 ± 99.9; Intermediate: 198.0 min [90.5–267.0], 186.1 ± 99.8; Frail: 241.5 min [199.0–320.5], 295.8 ± 181.3; Kruskal–Wallis p = 0.027; Jonckheere–Terpstra P for trend = 0.017); the dichotomous comparison was concordant (median 214.0 vs. 132.0 min; Mann–Whitney U U = 1441.5; p = 0.033). A graded dose–response-like relationship was further supported by Spearman correlation between the CFS score and CTT (ρ = 0.232; p = 0.009). Women had significantly longer CTT than men (median 189 vs. 121 min; p = 0.013), and the three-group trend was significant within the female subgroup (Kruskal–Wallis p = 0.032) but not within men (p = 0.138). In multivariable analysis, CFS remained independently associated with CTT prolongation both as a continuous score (Model 2: β = 36.6 per 1-point increase; 95% CI 17.3 to 56.0; p < 0.001) and as an ordinal three-category predictor (Model 3: β = 52.7 per one-step advance; 95% CI 19.7 to 85.8; p = 0.002). In the dummy-coded specification (Model 3b), the Frail-versus-Robust contrast was markedly significant (β = 155.4 min; 95% CI 71.5 to 239.3; p < 0.001), whereas the Intermediate-versus-Robust contrast was not (β = 27.0; 95% CI −15.5 to 69.5; p = 0.210). Female sex retained independent significance across models (β ≈ 47–49 min; p = 0.016–0.021). The original dichotomous Non-robust versus Robust specification (Model 1) was no longer significant after full adjustment (p = 0.372). Conclusions: Frailty progression, as assessed by the CFS, is independently and monotonically associated with prolonged CTT in older adults, with the effect becoming statistically manifest predominantly at the more advanced end of the frailty spectrum and particularly in women. Although these findings do not establish causality between frailty and constipation—and frailty itself reflects a multifactorial age-related process that may not be fully reversible—CCE-measured CTT provides an objective, radiation-free physiological biomarker of frailty-related bowel dysfunction that may support risk stratification and inform future interventional trials targeting potentially modifiable components of the gut–muscle axis. Full article

Objective: To analyze the evolving epidemiological characteristics of pediatric poisoning from 2019 to 2024 in Southwest China, explore the changing patterns of pediatric poisoning in the post-pandemic era, and provide a reference for poisoning prevention and the development of effective prevention and treatment strategies. Methods: This study included 3923 cases of pediatric poisoning treated at the Emergency Department of West China Second University Hospital, Sichuan University. Clinical data such as gender, age, poisonous substance, and cause of poisoning were described. The chi-square trend test was used to analyze annual changes, and multivariate Poisson regression was employed to identify risk factors for hospitalization and for intentional poisoning in children. Results: The total number of cases increased significantly from 544 in 2019 to 1006 in 2024. A marked “polarization” pattern was observed: among children aged 1–3 years, unintentional ingestion of household chemicals predominated (n = 2332), whereas among adolescents aged 12–14 years, intentional self-poisoning cases surged by 580%, with the toxic agents shifting mainly to psychotropic prescription drugs. From 2019 to 2024, the proportions of intentional poisoning, psychotropic drug poisoning, psychiatric comorbidity, and delayed presentation all increased significantly. Poisson regression indicated that the post-pandemic period, psychiatric comorbidity, and exposure to psychotropic drugs were risk factors for intentional poisoning. Conclusions: Following the COVID-19 pandemic, mental health problems among adolescents have become increasingly prominent, and pediatric poisoning has exhibited a bipolarization pattern. Clinical prevention and control strategies should shift from simple emergency treatment to early intervention, psychological screening, and comprehensive prevention, so as to reduce health damage to children and the societal disease burden. Full article

Background/Objectives: Behavioral and psychological symptoms of dementia (BPSD) are highly prevalent among nursing home residents and represent a major clinical and care-related challenge. These symptoms are frequently associated with increased psychotropic drug use despite limited efficacy and important safety concerns. This study aimed to evaluate longitudinal changes in BPSD and psychotropic drug use following implementation of the “Los Filabres” protocol, a structured person-centered non-pharmacological intervention, in nursing home residents with dementia. Methods: A single-arm longitudinal pre–post observational study was conducted in five nursing homes in Andalusia, Spain, including 204 residents with dementia or cognitive impairment. After staff training, the intervention was implemented over 12 months. Outcomes were assessed at baseline (T0), 6 months (T1) and 12 months (T2) using the Neuropsychiatric Inventory (NPI), including symptom frequency, severity, clinical relevance, and caregiver-related distress. Psychotropic drug use was analyzed according to the Anatomical Therapeutic Chemical classification system. Statistical analyses included Friedman and Cochran’s Q tests, with effect sizes estimated using Cohen’s d and h. The observational nature of the study implies that observed changes may be subject to limitations such as Hawthorne effects. Results: Significant reductions were observed across all global NPI dimensions over time (p < 0.001), including symptom frequency, severity, clinical relevance, and caregiver-related distress. The proportion of participants with at least one clinically relevant symptom decreased from 93.1% at baseline to 35.8% at 12 months (p < 0.001). Significant longitudinal reductions were also observed in psychotropic drug use, with the mean number of psychotropic drugs per participant decreasing from 2.38 to 1.57 (p < 0.001). Reductions were observed in anxiolytic and antipsychotic use, as well as in as-needed prescriptions. Conclusions: The “Los Filabres” protocol was associated with significant longitudinal reductions in BPSD and psychotropic drug use in nursing home residents with dementia. These findings suggest that structured person-centered non-pharmacological interventions based on the identification of unmet needs may help support dementia care and more individualized pharmacological management in long-term care settings. These findings should be interpreted cautiously due to the observational pre–post design and absence of a control group. Full article

Recent evidence reveals that several psychotropic compounds exert significant biological effects on the skin through neurochemical and immunomodulatory pathways. Cannabinoids such as tetrahydrocannabinol (THC) show potent anti-inflammatory, antipruritic, and anti-aging properties when applied topically, and may hold therapeutic potential. Antidepressants, particularly fluoxetine (Prozac), have been shown to regulate the expression of pro-inflammatory cytokines in keratinocytes, suggesting benefits applied in allergic pathologies. Additionally, fluoxetine promotes wound healing and cell regeneration, indicating broader dermatological applications. Psychedelics, acting as serotonin receptor agonists (5-HTR), may influence cellular aging and immune modulation via the serotonergic system. Studies report that 5-HT receptor agonists can prevent UV-induced photocarcinogenesis, while psilocybin has been observed to reduce aging markers in human fibroblasts. Furthermore, recent data suggests that psilocin may alleviate acute itch involving the kynurenine pathway. These findings highlight the emerging relevance of psychoactive compounds in cutaneous biology, bridging neuropharmacology and dermatology toward novel therapeutic strategies. Full article

Background: Kidney disorders are strongly related to metabolic disturbances, including obesity and type 2 diabetes. Excessive intake of sugar and saturated fats promotes lipid accumulation, cellular energy issues and inflammatory responses. Cannabigerol (CBG), a non-psychotropic phytocannabinoid, has recently gained attention for its metabolic, anti-inflammatory and potential protective properties. Methods: The present study investigated the effect of two weeks of CBG administration (last 14 days of the experiment) on fatty acid (FA) composition, FA metabolic pathways and FA transporters in rats subjected to a high-fat high-sucrose diet (HFHS) for 6 weeks. Male Wistar rats were divided into four groups: Control, CBG, HFHS, and HFHS+CBG. Kidney tissue and urine samples were analyzed by gas–liquid chromatography (GLC) for lipid fractions and FA profiles, while protein expression of FA transporters and metabolic enzymes was assessed by immunoblotting. Polysaccharides and collagen fibers were visualized using Periodic Acid-Schiff (PAS) and AZAN staining, respectively. ELISA and colorimetric kits were used to measure urinary albumin and creatinine contents. Results: HFHS feeding altered renal lipid homeostasis, increasing saturated and monounsaturated fatty acids (SFA and MUFA, respectively) levels and affecting desaturation and elongation ratios. CBG supplementation affected renal lipid metabolism by lowering triacylglycerol (TAG) accumulation, restoring polyunsaturated fatty acids (PUFA) in phospholipid (PL) and altering FA ratios, suggesting an improvement in lipid balance. CBG also increased the expression of carnitine palmitoyltransferase 1 (CPT1) and lipoprotein lipase (LPL) and decreased the expression of stearoyl-CoA desaturase 1 (SCD1) and fatty acid synthase (FAS), suggesting a shift toward enhanced FA oxidation and reduced lipogenesis. Conclusions: Overall, CBG exerted good effects on renal lipid metabolism and may mitigate early lipid-mediated injury associated with metabolic kidney disorders. Full article

Background/Objectives: Sex-specific differences in the pharmacokinetics of psychotropic drugs are gaining increasing clinical relevance, but only limited data are currently available on sex-specific effects within genetically defined metabolizer phenotype categories. The objective of this study was to assess genotype-dependent sex differences in the metabolic capacity of the drug-metabolizing enzymes CYP2D6 and CYP2C19. Methods: Statistical analyses were performed using linear mixed-effects models with subject-level random intercepts to account for repeated therapeutic drug monitoring (TDM) measurements. Venlafaxine and risperidone were used as probe drugs to find differences in the metabolic capacity of CYP2D6 and escitalopram for CYP2C19. Pharmacokinetic surrogate parameters were the metabolite-to-parent ratio (MPR) for venlafaxine and risperidone and the dose-corrected serum concentration (CD) for escitalopram. Models included sex, metabolizer phenotype, and their interaction, adjusted for age and creatinine production rate (CPR). Sex-specific differences within phenotype groups were assessed using estimated marginal means. Results: Among venlafaxine samples (N = 117) and risperidone samples (N = 73), no significant sex-specific differences in MPR were observed within CYP2D6 metabolizer groups. For escitalopram samples (N = 51), a significant sex difference was observed among CYP2C19 normal metabolizers (NMs), with higher CD in males compared to females. Conclusions: Exploratory analyses suggested a higher metabolic capacity in CYP2C19 NM females treated with escitalopram. Due to the limited sample size, however, this finding should be considered hypothesis-generating. Future studies in larger samples are needed to corroborate whether sex and other factors modulate the metabolic capacity of CYP2C19, e.g., by epigenetic mechanisms. Full article

Growing evidence indicates that the gut microbiota is not a static ecosystem but a rhythmic metabolic organ whose oscillatory activity is tightly coordinated with host circadian biology. Disruption of this temporal alignment, through irregular diet, sleep disturbance, shift work, or social jet lag, may profoundly alter microbial composition and the production of neuroactive metabolites. These alterations have emerged as potential contributors to the pathophysiology of mood disorders. This review introduces the concept of chrono-metabolic psychiatry, a framework integrating circadian rhythms, gut microbiota dynamics, and host metabolic signaling in the development and course of depressive and bipolar disorders. In this framework, the term “chrono-metabolic” refers to the integration of biological timing, host metabolic regulation, and microbiota-derived metabolic signaling. Chrono-metabolic psychiatry therefore shifts the focus from static dysbiosis or neurotransmitter imbalance alone to the time-dependent interactions among circadian misalignment, microbial rhythmicity, immune regulation, metabolite production, and affective instability. Diurnal fluctuations in short-chain fatty acids, tryptophan–kynurenine metabolites, bile acids, and microbial-derived neurotransmitters interact with clock gene regulation, hypothalamic–pituitary–adrenal axis activity, neuroinflammation, and synaptic plasticity. Chrono-disruption may represent a transdiagnostic vulnerability factor and may confirm the bidirectional relationship between mood instability and microbiota rhythmicity. Emerging therapeutic implications, including chrono-nutrition, time-restricted feeding, targeted probiotic administration (“chronobiotics”), and the microbiota-modulating effects of psychotropic medications are discussed. By shifting from a compositional to a temporal–metabolic perspective, this model highlights the importance of microbial oscillations rather than static dysbiosis alone. Integrating circadian biology into microbiota research may enable metabolomic stratification and pave the way for precision psychiatry approaches grounded in host–microbe metabolic crosstalk. Future longitudinal and time-resolved multi-omics studies are needed to validate this framework and to translate it into clinically actionable interventions. Full article