Search Results (128)

Background/Objectives: Depression and anxiety disorders exhibit significant clinical heterogeneity, which complicates diagnosis and treatment. This study investigated whether tripartite interactions between biological sex, the serotonin transporter gene promoter region (5-HTTLPR), and brain-derived neurotrophic factor (BDNF) G196A polymorphisms explain specific symptom-level variations. Methods: A community sample of 271 Australian adults was genotyped for common 5-HTTLPR (short/long) and BDNF (G/A) variants. Participants completed self-reported measures of anxiety (SAS), depression subtypes (SDS; clinical content scales), and psychological resilience (CDRISC). Morning salivary cortisol, BMI, and substance use were assessed as potential confounds. Statistical analyses utilised a three-way factorial ANCOVA to test for interactions on raw scores, controlling for age. Significant omnibus interactions were decomposed via planned stratified ANCOVAs within each 5-HTTLPR stratum. Results: The BDNF GA genotype exerted opposite effects on anxiety and anhedonia depending on sex and 5-HTTLPR background. In females, GA was associated with increased symptoms on an ss background, whereas in males, GA was associated with increased symptoms on an ll background. These effects were highly specific to anxiety and anhedonic depression, while depressed mood, cognitive, and somatic subtypes remained unaffected. Findings were independent of cortisol, BMI, smoking, alcohol use, and psychological resilience. Conclusions: The findings reveal a complex, sex-dependent genetic interaction that selectively influences anhedonia and anxiety. They should be interpreted in the context of modest subgroup sizes following genotype stratification and require replication in larger independent cohorts. Nonetheless, this study highlights the value of considering sex-stratified genetic backgrounds and symptom specificity to advance personalised precision medicine in psychiatry. Full article

Background: Major depressive disorder (MDD) affects 332 million people worldwide, yet diagnosis remains reliant on subjective clinical interviews with substantial inter-rater variability. Objective neuroimaging model-attributed regions offer a path toward precision psychiatry, but existing computational approaches often lack clinical interpretability. Methods: We propose HDGNN-Mamba2, a Mamba-based spatiotemporal heterogeneous dynamic graph neural network. A hybrid Mamba2-GNN block with cross-attention fusion is developed to capture individual spatiotemporal contextual features and identify model-attributed regions. A heterogeneous global graph block with dynamic edge updating is constructed, integrating individual brain features with non-imaging phenotypic information (sex, age, education) to extract embeddings through inter-individual relationship modeling. Heterogeneous Graph Supervised Contrastive Learning is integrated to enhance discriminative capacity. Results: Evaluated on 533 subjects from the REST-meta-MDD dataset, HDGNN-Mamba2 achieved 83.88% accuracy, 86.52% sensitivity, and 80.85% specificity in ten-fold cross-validation. The identified model-attributed regions include the anterior cingulate cortex, parahippocampal gyrus, and thalamus. Conclusions: HDGNN-Mamba2 demonstrates competitive performance as an algorithmic framework for MDD classification, offering complementary architectural advantages in spatiotemporal fusion and interpretable region identification. Full article

Background: Personalized precision medicine adapts therapeutic strategies to individual characteristics. In psychiatry, suboptimal outcomes with antipsychotics are often related to adverse drug reactions, poor adherence and therapeutic failure. Pharmacogenetics, particularly CYP2D6 genotyping, can improve clinical outcomes through genotype-guided therapy. This study aimed to design and implement a pharmacogenomic and pharmacokinetic testing program for long-acting injectable (LAI) antipsychotics within the Galician Health Service to enhance personalized psychiatric care. Methods: The pilot program encompasses pharmacogenetic and pharmacokinetic testing. Inclusion criteria were broad, covering patients initiating or receiving LAI antipsychotic therapy, as well as those with prior adverse reactions in order to explore scenarios where pharmacogenetic and/or pharmacokinetic data could help with clinical decisions. Structured workflows, interdisciplinary training and integration of results into the electronic health record supported implementation. A pharmacogenetic panel was specifically designed for psychiatric care, targeting clinically relevant variants in CYP2D6, CYP3A4 and ABCB1. Results: A total of 540 patients were included, with primary testing reasons being clinical follow-up (54.6%) and oral-to-LAI transition (38.5%). The CYP2D6 phenotypes were 55% normal, 34% intermediate, 6.3% poor and 4.3% ultrarapid metabolizers. Atypical metabolism was observed in 6.7% of patients for CYP3A4 and in over half for ABCB1. Plasma drug levels were within the therapeutic range for most patients, though some measurements were above or below expected values. Conclusions: This pilot demonstrates a scalable, evidence-based approach to precision psychiatry for LAI antipsychotics, integrating pharmacogenetic and pharmacokinetic testing into routine care. The framework facilitates genotype-guided decision-making and supports broader adoption of pharmacogenomics in psychiatric practice. Full article

Attention-deficit/hyperactivity disorder (ADHD) is traditionally defined by symptoms of inattention, hyperactivity, and impulsivity. However, growing evidence suggests that this framework incompletely reflects the underlying neurobiology and clinical heterogeneity of the disorder, particularly in females. Current models of dopaminergic neurotransmission propose that ADHD is characterized not by simple dopamine deficiency but by dysregulation of tonic and phasic dopamine signaling. Theoretical models propose that reduced tonic dopamine activity may coexist with enhanced stimulus-dependent phasic responses in ADHD. Whether such signaling differences produce alternating states of underactivation and hyperactivation within the same individual has not been directly demonstrated and constitutes a central hypothesis of the present framework. In this narrative hypothesis paper, I examine evidence linking dopaminergic dysregulation to a broader ADHD phenotype encompassing four functional domains: energy regulation, attention allocation, behavioral activation, and emotional reactivity and awareness. Within these domains, hyperactivity and hypoactivity, inattention and hyperfocus, impulsive responding and difficulty initiating action, and emotional hyperreactivity and alexithymia are treated as potentially related manifestations rather than established psychometric opposites. Neuroimaging studies report alterations in dopamine transporter and receptor availability, while clinical and behavioral studies document associations between ADHD and different, sometimes contrasting manifestations within the proposed domains. Importantly, internally experienced manifestations such as emotional dysregulation, hypoactivity, procrastination, and hyperfocus appear particularly relevant to female presentations of ADHD. I propose that ADHD should be conceptualized as a multidimensional disorder of dopaminergic regulation. This framework may better explain phenotypic diversity, improve identification of underrecognized presentations, and guide future biomarker-driven and precision-medicine approaches to ADHD. Full article

Major depressive disorder (MDD) remains a leading cause of disability; however, monoaminergic models do not fully explain delayed treatment onset, incomplete remission, or rapid responses to glutamatergic interventions. In this study, we proposed a system-level ionic homeostasis framework for MDD. In this model, genetic susceptibility, chronic stress, metabolic burden, and neuroinflammation converge in neuronal and glial ion-channel systems, disrupting calcium, potassium, chloride, and purinergic homeostasis. These disturbances alter intrinsic excitability, synaptic integration, inhibitory tone, glial buffering, and neuron–glia signaling, thereby promoting excitation–inhibition imbalance, impaired plasticity, and corticolimbic network instability. We reviewed the evidence implicating the CACNA1C/Cav1.2, TREK-1, KCNQ, NKCC1/KCC2, HCN, transient receptor potential/acid-sensing ion channels, and glial mediators, including P2X7R, Kir4.1, and AQP4. We also discuss how ketamine-related mechanisms, chloride-restoring strategies, anti-inflammatory ion channel targeting, neuromodulation, EEG biomarkers, and AI/multiomics approaches support mechanism-informed precision therapeutics. MDD could be conceptualized as a distributed failure of ionic homeostasis that links neuroinflammation, E/I imbalance, network instability, and impaired adaptive plasticity. Full article

Background: Major depressive disorder, particularly in its treatment-resistant form, remains a leading cause of global disability. When pharmacotherapy and psychotherapy fail, neuromodulation techniques such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS) are increasingly utilized. However, variability in protocols and outcome reporting continues to generate uncertainty regarding their comparative benefits and safety profiles. Objective: To comprehensively map and synthesize the available evidence on the clinical benefits and adverse effects of ECT and rTMS in adults with major depressive disorder and treatment-resistant depression. Methods: A scoping review was conducted following PRISMA-Sc guidelines and registered in PROSPERO; PubMed–MEDLINE, Scopus, and the Virtual Health Library were searched from inception to October 2022. Observational and experimental studies evaluating ECT and or rTMS in adults with depressive disorders were included. Data were extracted on study design, population characteristics, stimulation parameters, clinical outcomes, and adverse effects. Methodological quality was assessed using National Heart, Lung, and Blood Institute tools. Results: A total of 165 studies comprising 10,701 participants were included. ECT and rTMS were consistently associated with clinically meaningful reductions in depressive symptom severity across heterogeneous protocols. ECT demonstrated the most robust response rates, particularly in treatment-resistant and severe depression, while rTMS showed substantial efficacy with a more favorable safety profile. Adverse effects were more frequent and severe with ECT, including transient cognitive disturbances and cardiovascular complications, whereas rTMS was predominantly associated with mild, self-limited side effects such as headache and scalp discomfort. Considerable heterogeneity in stimulation parameters and diagnostic subgroups was observed across studies. Conclusions: Both ECT and rTMS represent effective neuromodulation strategies for major depressive disorder and treatment-resistant depression. ECT remains the most potent intervention in highly refractory cases, whereas rTMS offers a less invasive alternative with strong tolerability. Standardization of stimulation protocols, biomarker-informed stratification, coadjuvancy analysis, and long-term controlled studies are necessary to refine clinical positioning and advance precision neuromodulation in depression care. Full article

Background/Objectives: Electroconvulsive therapy (ECT) is among the most effective treatments for severe major depression, treatment-resistant depression, psychotic and bipolar depression, catatonia, and selected psychotic disorders. Yet response, remission, seizure adequacy, and cognitive tolerability remain difficult to predict for an individual patient. This review examines whether oral and gut microbial signatures can inform precision ECT as contextual biological markers, rather than as standalone explanations of ECT efficacy. Methods: A structured narrative PubMed/MEDLINE search was conducted on 1 May 2026 and supplemented by targeted manual searches of Crossref, Google Scholar, journal websites, and reference lists updated through 17 May 2026. Evidence was grouped as direct human ECT–microbiome studies, indirect human ECT biomarker studies, preclinical electroconvulsive shock (ECS) studies, and mechanistic microbiome–gut–brain literature. Results: Direct human ECT–microbiome evidence remains very limited and currently consists of two small prospective cohorts with sufficient microbiome data, totaling approximately 25 patients across studies, plus one single-patient case report. In severe or treatment-resistant depression, a pilot oral microbiome study with sufficient microbiological data from 14 patients reported higher pre-treatment oral alpha diversity in responders than in non-responders, without a consistent global oral microbiome shift after ECT. In schizophrenia, a small stool microbiome cohort of 11 patients suggested that baseline Bifidobacterium and Lactobacillus proportions may relate to symptom improvement, although sample size and confounding preclude firm inference. Conclusions: Microbiome-informed precision ECT remains a biologically plausible research direction, but current human evidence supports only cautious evaluation of baseline microbial context as a candidate predictor, not clinical microbiome-guided ECT, mediation, or microbiome-modifying intervention. The strongest current biological bridge comes from inflammatory markers, particularly baseline CRP and IL-6. Preclinical ECS studies support gut inflammatory, motility and vagal mechanisms, but they cannot substitute for human validation. Full article

Precision psychiatry promises a more objective and effective approach to psychiatric care, yet its implementation raises growing ethical challenges as technology advances. This narrative review offers a qualitative synthesis of the ethical issues reported in 62 studies, with emphasis on the practical tensions that arise when core principles conflict. Rather than organising concerns around traditional ethical principles, the review maps them across the main modalities of precision psychiatry, namely genomics, neuroimaging, digital phenotyping, and AI-driven interventions. Four explicit positions are advanced. First, equity must be engineered from the outset rather than assumed. Second, interpretability should outweigh marginal gains in accuracy in a field built on subjective report. Third, stigma is bidirectional and contingent on framing and the availability of meaningful intervention. Fourth, individualised care must demonstrate clinical and economic superiority over standardised approaches. Precision psychiatry is likely to reshape psychiatric practice and the therapeutic relationship itself. Interdisciplinary collaboration, clear guidelines, and continuous ethical vigilance will be essential for responsible adoption and sustained public trust. Full article

The rapid integration of artificial intelligence (AI) into mental healthcare presents opportunities and ethical challenges, particularly for complex conditions like obsessive–compulsive disorder (OCD). In this perspective, we argue for a Dual Imperative: establishing safety architectures for AI-powered therapeutic tools to prevent algorithmic sycophancy (symptom accommodation), while mandating explainable AI (XAI) in prognostic models to ensure clinical auditability. In therapeutics, we propose a Guardian Angel architecture that utilizes patient-specific fear hierarchies and linguistic stance detection to distinguish compulsive reassurance-seeking from legitimate patient questions. This approach transforms potential therapeutic ruptures into opportunities for distress tolerance via the Digital Ulysses Pact, a patient-authorized, algorithmically enforced response prevention protocol. In diagnostics, we address the black box problem in precision psychiatry. We argue that as AI evolves from detection to high-stakes treatment selection, safety and accountability become a prerequisite for clinical application. Although distinct in implementation, these architectures form an integrated framework for aligning therapeutic and diagnostic AI. These architectures are not parallel tracks but a unified ecosystem: A patient’s XAI-audited profile can inform the Guardian Angel’s configuration, while the longitudinal data gathered during therapy enriches diagnostic precision. Grounded in ethical principles and best practices in OCD, this suggests a path toward AI that is auditable in its diagnostic logic, firm in its therapeutic boundaries, and enforceable through emerging regulatory frameworks. Full article

Background/Objectives: Vitamin D is a nutrient-related secosteroid system with endocrine, paracrine, immunological, and neurodevelopmental actions relevant to nutritional psychiatry. Psychiatric research has often treated vitamin D either as a cross-sectional correlate of depression or as a non-specific supplement expected to act across heterogeneous diagnostic categories. This narrative review aimed to develop a more discriminating framework in which vitamin D is considered a lifespan neuroimmune and immunometabolic signal whose psychiatric relevance depends on developmental timing, biological context, and phenotype. Methods: Evidence was integrated from developmental epidemiology, neonatal dried-blood-spot studies, randomized trials, meta-analyses, Mendelian randomization studies, clinical guidelines, and mechanistic neuroscience. The review focuses on prenatal and neonatal 25-hydroxyvitamin D, vitamin D-binding protein, free and bioavailable vitamin D, vitamin D receptor signaling, immune and microglial pathways, neurotransmitter systems, neurotrophic signaling, mitochondrial function, oxidative stress, hypothalamic–pituitary–adrenal-axis regulation, and the gut–microbiota–immune–brain axis. Results: The available evidence does not support vitamin D as a universal treatment for psychiatric disorders. Instead, vitamin D deficiency and altered vitamin D biology appear most relevant in biologically and clinically defined risk states, including neurodevelopmental vulnerability, inflammatory depression, psychosis liability, severe mental illness with nutritional deprivation, metabolic comorbidity, and cognitive frailty. Mechanistic data support plausible links with cytokine biology, the tryptophan–kynurenine pathway, dopaminergic and serotonergic systems, stress regulation, and neuroimmune homeostasis. Conclusions: Vitamin D should be conceptualized in psychiatry as a context-dependent neuroimmune and immunometabolic signal rather than a generic psychotropic intervention. Future studies should prioritize biomarker-enriched, developmentally timed, nutrition-centered models of precision prevention and adjunctive care. Full article

Sex differences are increasingly recognized as key determinants of vulnerability, clinical presentation, and treatment response in depression. Rather than arising from a single mechanism, these differences emerge from the interplay of multiple biological and non-biological factors. Converging evidence points to the hippocampus as a central region where these processes intersect, with adult neurogenesis and astrogliogenesis representing a potential mechanistic link between sex-specific biological factors and behavioral outcomes in depression. In this review, we integrate findings from human studies and preclinical models to examine how sex impacts depression while considering the multiple origins of sexual differentiation in the central nervous system. We discuss the importance of studying sex as a biological variable and acknowledge current limitations in the field. Finally, we highlight how cytogenic processes in the adult hippocampus are modulated in a sex-dependent manner, how their disruption may contribute to the pathophysiology of depression, and their potential role in precision psychiatry. Adult cytogenesis provides a promising target for developing therapeutic strategies aimed at promoting the integration of these cells in neural circuits, which may counterbalance the cellular impairments observed in stress-induced depression, representing a therapeutic avenue for this disorder. 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

Anxiety disorders are disabling and treated with cognitive-behavioral or exposure-based psychotherapy. However, many patients remain symptomatic, fail to remit, relapse, or discontinue treatment. This narrative review examined whether psychotherapy non-response, defined here as persistent clinically significant anxiety symptoms, avoidance, or functional impairment after an apparently adequate psychotherapy trial, may reflect mismatch between therapeutic mechanisms and the dominant processes maintaining anxiety, and aimed to develop a usable taxonomy of mechanistic non-response. This structured narrative review followed SANRA principles. PubMed/MEDLINE, Scopus, PsycINFO, Web of Science, and the Cochrane Library were searched for peer-reviewed literature published from 1 January 2000 to 30 April 2026, including selected earlier landmark studies. Clinical, experimental, neurobiological, psychophysiological, process, and theoretical evidence were synthesized narratively. Psychotherapy mechanisms were organized around inhibitory learning, cognitive reappraisal, attentional modulation, emotion regulation, avoidance reversal, and interpersonal learning. Anxiety maintenance was multilevel, involving threat neurocircuitry, stress-related learning conditions, intolerance of uncertainty, attentional threat capture, safety behaviors, avoidance reinforcement, developmental adversity, and attachment insecurity. Non-response was framed as mismatch between the dominant maintaining process and the therapeutic mechanism expected to modify it. Six failure modes were identified: impaired inhibitory learning, cognitive rigidity/intolerance of uncertainty, stress-related learning impairment, attentional dysregulation, attachment-related barriers, and chronic avoidance dominance. Psychotherapy non-response in adult anxiety disorders should prompt mechanistic reformulation rather than repetition of the same intervention or labeling as treatment resistance. The taxonomy links recognizable failure signatures to mechanism-matched adaptations: redesigned exposure, uncertainty-focused work, attentional interventions, sequencing when arousal or sleep impairs learning, relational repair, and reduction in avoidance contingencies. The narrative review provides a concise clinical taxonomy and practical mechanism-matched adaptations to guide reformulation and treatment redesign after psychotherapy non-response in routine care. The taxonomy supports mechanism-matched reformulation after psychotherapy non-response and requires prospective validation. Full article

Background/Objectives: Gut microbiota dysregulation has been increasingly implicated in the pathophysiology of autism spectrum disorder (ASD), yet clinical responses to standardized probiotic interventions remain inconsistent, likely reflecting substantial inter-individual variability in baseline microbiome composition, host–microbe interactions, immune tone, and metabolic function. Here, we present a pilot implementation of a metagenomics-guided, personalized synbiotic intervention in children with ASD using the Systematic Microbiome Assessment and Reconstruction Therapy (SMART) framework. Methods: Seven children (aged 5–12 years) underwent longitudinal fecal shotgun metagenomic profiling, and dietary habits, food sensitivities, and regional dietary background were recorded as contextual factors potentially influencing microbiome composition and response to intervention. Individualized synbiotic formulations were constructed based on microbial taxonomic composition and inferred functional capacity and iteratively refined over time. Gastrointestinal outcomes were assessed through caregiver-reported clinical observations, whereas behavioral changes were evaluated using standardized instruments. Results: Several participants demonstrated improvements in gastrointestinal symptoms and selected behavioral domains. Notably, in a subset of participants, improvements in gastrointestinal function preceded measurable behavioral changes. Conclusions: Although limited by a small sample size and lack of a control group, these findings provide preliminary evidence supporting the feasibility of implementing a metagenomics-guided personalized synbiotic framework in ASD and generate hypotheses for future investigation. This work presents a preliminary conceptual framework for integrating microbial composition and inferred functional profiling into individualized intervention design and highlights the potential value of microbiome-informed stratification in future studies of treatment response. Larger controlled studies with objective outcome measures are warranted to further evaluate feasibility, reproducibility, and potential clinical utility. Full article

Major depressive disorder (MDD) and anxiety disorders are increasingly understood as conditions involving complex metabolic dysregulation across multiple biological domains. This review aimed to synthesize current clinical and translational evidence on amino acid metabolism, lipid metabolism and short-chain fatty acids (SCFAs) as potential biomarkers, and components of integrative metabolic profiling in these disorders. A structured narrative approach was applied, focusing on studies assessing metabolomic alterations, their clinical correlates and their potential role in patient stratification, and treatment response. The available evidence indicates that amino acid disturbances, particularly within the tryptophan–kynurenine pathway, represent the most consistent and clinically interpretable findings. Lipid-related alterations, especially involving long-chain polyunsaturated fatty acids, provide complementary insights into membrane function, inflammation and neuroplasticity. In contrast, SCFAs appear to function as context-dependent markers rather than robust standalone biomarkers, with their clinical relevance depending on biological matrix, metabolic context and host–microbiota interactions. Importantly, most studies assess individual metabolites rather than integrated metabolic profiles, limiting their interpretability within a metabolomic framework. Overall, current evidence supports a shift toward integrative biomarker models that combine metabolic data with selected molecular and clinical parameters. Future research should focus on standardized, reproducible profiling approaches to enable biologically informed stratification and personalized treatment strategies. Full article