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At least 19 recordsLinked to original sources
PubMed2026

Prader-Willi syndrome as a neurogenetic model for psychosis and obsessive-compulsive disorder: A review of clinical, behavioral, and biological insights.

Prader-Willi syndrome (PWS) is a complex neurodevelopmental disorder classically defined by hyperphagia and obesity. However, its profound psychiatric phenotype offers a unique genetic framework for understanding major mental illnesses. This review positions PWS as a potentially informative biological model for psychosis and obsessive-compulsive disorder (OCD), bridging the gap between 15q11-q13 imprinting defects and neural circuit dysfunction. We synthesize evidence demonstrating that psychosis in PWS is not a uniform trait but is disproportionately linked to the maternal uniparental disomy (mUPD) subtype. This genotype-phenotype correlation suggests that overexpression of maternally imprinted genes and loss of paternal expression disrupt cortical excitatory-inhibitory balance, resembling the "schizophrenia-bipolar" genomic architecture. Furthermore, synthesized evidence characterizes the repetitive, ritualistic behaviors in PWS not merely as behavioral challenges, but as a developmentally arrested OCD-spectrum phenotype driven by distinct serotonergic-oxytocinergic imbalances and hypothalamic-limbic dysconnectivity. Mechanistic insights from preclinical models of MAGEL2, SNORD116, and NDN deficiency are integrated with clinical findings to highlight shared neurobiological substrates. Finally, we outline a roadmap for precision psychiatry in PWS, emphasizing the necessity of pharmacogenomics in antipsychotic management and the potential of targeted circuit-based therapeutics. By deconstructing the psychiatric comorbidities of PWS, we provide a framework for translating genomic architecture into mechanistic understanding and targeted treatment for complex neuropsychiatric disorders.

15q11-q13↗
PubMed2026

Functional neuroimaging subtypes of obsessive-compulsive disorder: A systematic review and meta-analysis.

Obsessive-compulsive disorder (OCD) exhibits substantial clinical heterogeneity that may reflect underlying neurobiological diversity. Neuroimaging-based subtyping may advance precision psychiatry by identifying biologically distinct subgroups with differential treatment responses. This study systematically synthesized evidence from functional neuroimaging subtyping studies in OCD to identify reproducible neurobiological subtypes, characterize their clinical profiles, and establish a consensus-based classification framework. We reviewed 40 original studies employing machine learning, clustering, normative modeling, or classification approaches, encompassing approximately 8,150 patients. Consensus clustering identified three reproducible neurobiological subtypes. The Limbic-Hyperactive subtype, comprising approximately 40% of patients, exhibited amygdala and insula hyperconnectivity, elevated anxiety levels, predominant contamination and washing symptoms, and favorable response to cognitive-behavioral therapy. The Fronto-Striatal-Hypoconnected subtype, comprising approximately 35% of patients, demonstrated reduced orbitofrontal-striatal connectivity, cognitive inflexibility, predominant checking and ordering symptoms, and a favorable response to selective serotonin reuptake inhibitors. The Global-Disrupted subtype, comprising approximately 25% of patients, exhibited widespread connectivity disruption, greater symptom severity, and poor treatment response. Support vector machine classification achieved 81.5% accuracy for subtype assignment, though classification of OCD versus healthy controls showed limited generalizability in multisite settings (AUC 0.567-0.673). These findings support a neuroimaging-based framework for personalized treatment selection but require prospective validation.

Humans↗
PubMed2026

Machine learning-assisted plasma PEA proteomics enables differential diagnosis of melancholic depression and bipolar disorder.

Differentiating bipolar disorder (BD) from major depressive disorder (MDD) remains a critical unmet need in psychiatry due to overlapping clinical presentations and the absence of reliable biological markers. In this study, we assessed the capacity of multivariate machine learning models to accurately differentiate BD from MDD with melancholic features using plasma proteomic profiles obtained via Proximity Extension Assay (PEA) technology. A total of 67 participants were included (23 BD, 20 MDD, and 24 HC), and plasma protein expression was assessed using the Olink Target 96 Neurology panel. Differential proteomic analysis revealed distinct disorder-specific expression patterns, identifying 21 differentially expressed proteins in BD versus MDD, 18 in BD versus healthy controls, and 7 in MDD versus healthy controls. Using a stepwise feature reduction strategy, machine learning models were trained on three feature sets comprising all proteins, the top 20 most informative proteins, and the top 5 most beneficial proteins, and evaluated across BD-MDD, BD-HC, and MDD-HC classification tasks using five algorithms. For BD-MDD discrimination, the Random Forest model achieved the highest performance when trained on the top 5 protein set (LXN, HAGH, MATN3, PLXNB1, and CTSC), yielding an AUC of 0.905, with similarly strong performance observed using the top 20 protein set. Feature importance analysis highlighted proteins involved in neurodevelopmental processes, immune regulation, and extracellular matrix organization. Overall, these findings demonstrate that integrating plasma proteomics with machine learning enables robust differentiation between BD and MDD with melancholic features, supporting the development of scalable and biologically informed diagnostic tools for precision psychiatry.

Bipolar disorder↗
PubMed2026

Distinct depressive-like behavioural phenotypes in mice exhibit unique patterns of transcriptional perturbations across habenular cell subtypes.

Major depressive disorder (MDD) is characterized by substantial heterogeneity, which hinders attempts to associate distinct symptoms with specific neural mechanisms. The lateral habenula (LHb) is a key brain region involved in negative affect and reward processing, but the molecular changes in the LHb that lead to mood disorders remain unclear. Here, we combined chronic social defeat stress (CSDS), behavioural phenotyping, and single-cell RNA sequencing to examine cell-type and subregion-specific transcriptional changes in the mouse habenula. Mice were classified into behavioural phenotypes reflecting social avoidance, anhedonia, passive coping, resilience, or susceptibility. We identified nine major habenular cell classes and found distinct phenotype-associated transcriptional signatures across both neurons and glia. Distinct transcriptional signatures were observed in LHb neurons of susceptible animals and in oligodendrocytes of resilient animals. Subregional analysis revealed that the oval-medial LHb accounted for most stress-related transcriptional changes, while the HbX subregion displayed a unique molecular signature associated with passive coping behaviour. These findings highlight the cellular heterogeneity of stress responses within the habenula and will pave the way for identifying potential targets for precision psychiatry approaches in depression.

Journal Article↗
PubMed2026

Recall-by-genotype of neurodevelopmental disorder copy number variants in a multi-ancestry, healthcare-system biobank.

Clinical biobanks linking electronic health records (EHRs) with genotype data enable the study of genomic risk factors in real-world populations. However, recall-by-genotype (RbG) of psychiatric risk variants in diverse healthcare-system biobanks remains scarce. Leveraging BioMe, a multi-ancestry biobank within the Mount Sinai Health System, we recalled carriers of rare copy number variants (CNVs) that confer increased risk for neurodevelopmental disorders (NDDs) to establish empirical benchmarks for RbG implementation. We recontacted 892 participants: 335 NDD CNV carriers, 217 individuals with schizophrenia without NDD CNVs, and 340 neurotypical controls without NDD CNVs. Participants completed clinical and cognitive assessments. Overall, 18% of recontacted participants responded to recruitment, and 8% completed the study: 30 NDD CNV carriers, 20 individuals with schizophrenia, and 23 controls. The mean age was 48.8 years, 66% were female, and self-reported ancestry was 37% African, 34% Hispanic, and 26% European. Seventy percent of NDD CNV carriers had at least one neuropsychiatric or developmental condition, including mood or anxiety disorders (40%). Among 22 NDD CNV carriers at loci implicated in impaired cognition, performance was lower than controls on Digit Span Backward (β = -1.76, FDR = 0.04) and Digit Span Sequencing (β = -2.01, FDR = 0.04). NDD CNV carriers also outperformed the schizophrenia group on verbal learning (β = 4.5, FDR = 0.05). Recall of individuals-including those with psychiatric illness-yielded phenotypes not captured in EHRs and provides empirical benchmarks relevant to RbG implementation and precision psychiatry in diverse healthcare systems.

Journal Article↗
PubMed2026

Research agenda to advance anhedonia assessment, understanding and treatment: an ECNP-GALENOS expert meeting report.

Anhedonia, broadly defined as a reduced ability to experience interest or pleasure, represents an important transdiagnostic neuropsychiatric symptom dimension which may benefit from targeted diagnostics and treatments. Different lines of research have proposed that it comprises multiple facets, including deficits in anticipatory ('wanting') and consummatory ('liking') reward processing as well as reward learning and affects different aspects of life (eg, social, physical, cognitive). Certain facets-more specifically anticipation, motivation and reward learning-likely involve blunted phasic dopaminergic signalling. However, recent meta-analytical evidence of human depression studies indicates that prodopaminergic antidepressants produce relatively small improvements in anhedonia symptoms and suggest that mechanisms beyond dopamine likely contribute to anhedonia. This stimulated an expert meeting to review the literature and define priorities for future research in anhedonia. A central key priority is developing a translational biologically-informed nomenclature and consensus that solves the current mismatch between constructs, paradigms and measures, and mechanisms, which separates discrete reward-related processes such as effort allocation, reward learning and anticipatory interest versus consummatory pleasure. Clinical research priorities are improved multimodal measurement tools, integrating neurobiological frameworks (eg, neuroimaging, electrophysiology and liquid biomarkers capturing dopaminergic, glutamatergic, opioid and immunometabolic pathways) and transdiagnostic studies across neuropsychiatric disorders and developmental stages. Innovative trial designs that explicitly target anhedonic phenotypes as a primary outcome and test mechanism-based interventions are also needed. Translational research recommendations include back-translation strategies that begin with patient-relevant phenotypes followed by the development of comparable human and animal tasks that target reward-related processes, such as effort allocation, reward learning and anticipatory interest versus consummatory pleasure, improve cross-species behavioural paradigms and enhance methodological rigour and reproducibility. Collectively, these recommendations will help refine the conceptualisation of anhedonia and advance its role within precision psychiatry as a mechanistically grounded target across multiple disorders.

Humans↗
PubMed2026

Personalised Nutraceutical Treatment Guided by MTHFR Genotype in Mental Health: A Retrospective Cohort Study.

BACKGROUND & AIMS: One-carbon metabolism plays a central role in neurotransmitter synthesis, methylation capacity, and neurobiological resilience. Variants in the methylenetetrahydrofolate reductase (MTHFR) gene can reduce enzymatic activity, affecting folate- and methionine-cycle functions and potentially influencing biological pathways relevant to mood and anxiety disorders. Personalised nutraceutical treatment strategies, particularly those addressing methylation capacity through targeted B-vitamin, folate, and adjunctive metabolic interventions are increasingly implemented in integrative clinical practice, yet evidence regarding their clinical outcomes remains limited. METHODS: We conducted a retrospective cohort study of 50 adults attending an integrative general practice clinic for anxiety and/or depression. All received personalised nutraceutical treatment informed by clinical assessment, laboratory testing and, for 37/50 patients, MTHFR genotyping. Psychological distress was measured using the Kessler-10 (K10) scale at baseline and approximately three months later. Secondary analyses evaluated whether outcomes differed by MTHFR genotype, whether specific supplements (e.g., L-methylfolate and SAMe) were associated with greater improvement, whether biomarker changes correlated with symptom change, and the safety/tolerability profile. RESULTS: Across the full cohort, mean K10 scores significantly decreased by four points over the treatment period, with 72% of patients showing clinical improvement. Reductions in psychological distress were seen across all MTHFR genotypes, including individuals with homozygous variant genotypes. Supplement-specific analyses showed improvement among those receiving methylfolate or SAMe, although the differences were not statistically significant. Following nutraceutical treatment, biomarker analyses demonstrated significant increases in serum vitamin B12 and modest reductions in homocysteine, but biomarker shifts did not correlate strongly with K10 change. No serious adverse events or clinically significant abnormalities in liver or renal function were identified. CONCLUSIONS: In this real-world primary care cohort, personalised nutraceutical treatment, grounded in one-carbon metabolism support and applied alongside usual care, was associated with clinically meaningful reductions in psychological distress. Outcomes were comparable across MTHFR genotypes when treatments were appropriately tailored, suggesting that genotype and biomarker-informed nutraceutical strategies may mitigate potential metabolic disadvantages. These findings support further controlled research into precision nutraceutical psychiatry for anxiety and depression. Secondary analyses of genotype subgroup, specific supplements, and biomarker-outcome associations are reported alongside Benjamini-Hochberg FDR-adjusted p-values and should be interpreted as hypothesis-generating.

Humans↗
PubMed2026

Genetic and epigenetic determinants of cytochrome P450 activity in psychopharmacology: from pharmacogenetics to functional pharmacogenomics.

Classical pharmacogenetics has explained interindividual variability in psychotropic drug response primarily through inherited polymorphisms in cytochrome P450 enzymes. This framework successfully identified extreme metabolizer phenotypes and informed genotype-guided dosing recommendations. However, genotype-based predictions frequently correlate more strongly with pharmacokinetic parameters than with clinical outcomes. Patients sharing similar CYP genotypes often exhibit divergent therapeutic trajectories, while metabolic phenotypes may change during treatment without corresponding alterations in DNA sequence. These observations suggest the existence of a genotype-phenotype gap mediated by regulatory processes not captured by genotyping alone. Evidence from epigenetic regulation, environmental modulation of pharmacogene expression, and phenoconversion indicates that metabolic capacity is better understood as a dynamic functional state rather than a fixed inherited trait. This review examines the role of these mechanisms in psychiatric pharmacotherapy and explores the implications of shifting the predictive focus of precision medicine from static genotype to functional state.

Humans↗
PubMed2025

Genome-wide methylation biomarkers and biological aging in patients with bipolar disorder characterized for lithium response.

BACKGROUND: Epigenetic mechanisms might play a role in modulating susceptibility to bipolar disorder (BD) and response to lithium, the mainstay treatment for BD. Additionally, individuals with BD experience accelerated biological aging. METHODS: We compared blood DNA methylation profiles measured with EPIC v.2.0 arrays between patients with BD (33 lithium responders and 31 nonresponders) and nonpsychiatric controls (n = 32), as well as based on long-term lithium response. In addition, we compared cellular aging between these groups using epigenetic age, pace of aging, and, for the first time, transcriptional age acceleration based on bulk RNA sequencing in 93 patients and 56 controls. RESULTS: We identified 191 differentially methylated positions (DMPs) and 8 differentially methylated regions between patients with BD and controls, located in genes enriched for "Postsynaptic Density" (odds ratio = 6.81, p = 0.001). No DMP was significantly associated with lithium response after multiple testing correction. Patients showed a significantly higher biological age acceleration than controls based on two epigenetic clocks (GrimAge, Mann-Whitney U = 551, p = 0.0009; GrimAge2: U = 477, p = 9.0E-05) and pace of aging (DunedinPACE, t = 3.01, p = 0.003), but not on transcriptional age. While we observed no significant difference in epigenetic aging based on lithium response, lithium responders showed lower epigenetic acceleration using all clocks, with a trend observed using the PhenoAge clock (t = 1.97, p = 0.053). CONCLUSIONS: Our findings point to methylation patterns characterizing BD and support the hypothesis of accelerated cellular aging in BD.

Humans↗
PubMed2026

Precision medicine in mental health: applications, challenges, and recommendations.

Mental disorders represent a major and growing public health challenge in Europe and worldwide, characterised by marked clinical, biological, and functional heterogeneity, that limits the effectiveness of current diagnostic and therapeutic approaches. In recent years, advances in precision medicine have initiated a paradigm shift in psychiatry, offering new opportunities to improve prevention, prediction, diagnosis, treatment selection, and long-term management by integrating biological, psychological, social, and environmental information.This EPA Guidance Paper provides an overview of the current state of precision medicine in mental health and outlines its potential clinical, scientific, and policy implications. We review key advances in genomics, epigenetics, neuroimaging, transcriptomics, digital technologies, and artificial intelligence, highlighting their relevance across the full clinical pathway, from risk prediction and early detection to treatment personalisation and monitoring. We also examine major barriers to implementation, including limited biomarker validation, insufficient representativeness of research populations, ethical and regulatory challenges, data protection concerns, and inequalities in access across healthcare systems.Based on the available evidence, we propose strategic recommendations to support the responsible and equitable integration of precision approaches into mental health care in Europe. These include strengthening translational research, promoting multidisciplinary collaboration, updating regulatory and ethical frameworks, enhancing professional training, and prioritising mental health within national and European research and health agendas. By addressing these challenges, precision psychiatry has the potential to contribute to more effective, person-centred, and sustainable mental health care, while supporting innovation, reducing stigma, and improving outcomes for patients and society.

Humans↗
PubMed1978

Epidemiology of mental disorders: emerging trends in the United States.

Psychiatric epidemiology in the United States currently is being influenced by developments in genetics, psychopharmacology, neurobiology, and particularly psychopathology after the heavy influences of the social sciences during the post-World War II period. The integration of recent scientific developments in psychiatry, with the methodological precision that characterized the earlier studies of the 50s and 60s promises to provide new knowledge on the epidemiology of mental disorders in the community, which will have important implications both for professional practices in medicine and public health and for public policy in the planning of mental health services, training, and research.

Epidemiologic Methods↗
PubMed2025

Precision Genomics: A Reality Having Universal Impact in a New Era of Psychiatry - Lessons Learned, Past and Present.

Addiction neuroscience explores the complex interplay between genetic, neurobiological, environmental, and socio-spiritual factors underlying substance and behavioral addictions. Over the past three decades, research in this domain has identified critical molecular and epigenetic mechanisms-particularly those affecting dopaminergic signaling and reward pathways-that contribute to both vulnerability and resilience to addictive behaviors. Central to this understanding is the concept of reward deficiency syndrome (RDS), first introduced by Kenneth Blum, which posits that hypodopaminergic functioning predisposes individuals to seek maladaptive rewards. Advances in neurogenetics, including the identification of key polymorphisms such as the DRD2 A1 allele, have paved the way for precision tools like the genetic addiction risk severity (GARS®) test. This test, alongside pro-dopaminergic nutraceutical interventions like KB220, demonstrates the potential for early detection and individualized treatment of "pre-addiction" risk states. Despite ongoing reliance on opioids for opioid use disorder (OUD), emerging paradigms advocate for dopamine homeostasis through non-addictive, integrative approaches. Furthermore, the integration of whole genome sequencing data can be used for Genome-Wide Association Studies (GWAS), multi-omics, and machine learning into clinical practice holds promise for advancing personalized medicine in addiction treatment. As the field progresses, addressing health equity and improving genomic representation across populations remain critical goals. This evolving framework underscores the importance of leveraging genomic insights to prevent, predict, and personalize interventions for addiction and mental illness at scale.

Disorder↗
PubMed2025

Whole genome sequence-based association analysis of African American individuals with bipolar disorder and schizophrenia.

In studies of individuals of primarily European genetic ancestry, common and low-frequency variants and rare coding variants have been found to be associated with the risk of bipolar disorder (BD) and schizophrenia (SZ). However, less is known for individuals of other genetic ancestries or the role of rare non-coding variants in BD and SZ risk. We performed whole genome sequencing of African American individuals: 1,598 with BD, 3,295 with SZ, and 2,651 unaffected controls (InPSYght study). We increased power by incorporating 14,812 jointly called psychiatrically unscreened ancestry-matched controls from the Trans-Omics for Precision Medicine (TOPMed) Program for a total of 17,463 controls. To identify variants and sets of variants associated with BD and/or SZ, we performed single-variant tests, gene-based tests for singleton protein truncating variants, and rare and low-frequency variant annotation-based tests with conservation and universal chromatin states and sliding windows. We found suggestive evidence of BD association with single-variants on chromosome 18 and of lower BD risk associated with rare and low-frequency variants on chromosome 11 in a region with multiple BD GWAS loci, using a sliding window approach. We also found that chromatin and conservation state tests can be used to detect differential calling of variants in controls sequenced at different centers and to assess the effectiveness of sequencing metric covariate adjustments. Our findings reinforce the need for continued whole genome sequencing in additional samples of African American individuals and more comprehensive functional annotation of non-coding variants.

Journal Article↗
PubMed1979

On the professional socialization of black residents in psychiatry.

Residents in psychiatry, in addition to acquiring technical knowledge and skills, undergo the process of professional socialization during which they assimilate the values, attitudes, and normative behavior of their professional group. The socialization of any group of trainees is fostered by the clarity and precision of a socialization structure and by the visibility and contribution of certain specific agents of socialization. The authors outline the areas of this process that create problems for black residents in psychiatry and suggest alternatives to the present experience encountered in most training programs.

Black or African American↗
PubMed1978

Psychiatric decision-making by medical students.

Analysis of medical students' formulations and replies to clinical problems indicates difficulty in deciding on the nature and organization of treatment. A programme describing a problem-solving approach was devised, and students taught in this way were shown to be significantly more able to formulate organized treatment plans with more precise aims. It is suggested that problem-solving methods are likely to be much more effective than conventional teaching of psychiatry.

Decision Making↗
PubMed1977

[The two languages of psychiatry (author's transl)].

Psychiatrists still use two languages, that of the "Geisteswissenschaften" (humanities) and that of the sciences. This has often led to a disregard of the differences between understanding and explanation, to a "Sprachverwirrung" (linguistic confusion), or to taking either understanding or explanation as absolute which leads to the formation of closed, ideology-like systems. As a result of the continued necessity for methodological pluralism, it is precisely by observing methodological limitations, that we have the current possibilities for bringing the "Geisteswissenschaften" (humanities) and the sciences, psychology and physiology closer to each other.

Germany, West↗
PubMed2025

Genetics of Anorexia Nervosa: Translation to Future Personalized Therapies.

Anorexia nervosa (AN) is a debilitating and often refractory eating disorder that is unique among psychiatric disorders insofar as nutrition is key to recovery. Treatment options and efficacy are limited with no approved medications for AN. Genetic studies are clarifying the etiology of AN, with the goal of eventually informing the development of innovative personalized pharmacologic, nutritional, microbial, and behavioral interventions. We present the current state of genome-wide and epigenome-wide association studies, gut microbiome research, and functional genomics investigations and discuss translating this knowledge into clinical practice.

Humans↗