Molecular Psychiatry[JOURNAL]
Sun
200 papers
The role of microRNAs in executive functions: a comprehensive review and bioinformatics analysis of human and animal studies.
Navarro-Flores A, Krüger DM, Kaurani L … +3 more , Fischer A, Schulze TG, Heilbronner U
Mol Psychiatry · 2026 May · PMID 42062542 · Publisher ↗
Executive functions (EFs) are meta-cognitive abilities that orchestrate goal-directed behavior (i.e., set-shifting, working memory, and inhibitory control). Despite their strong genetic composition, the development of EF...
Executive functions (EFs) are meta-cognitive abilities that orchestrate goal-directed behavior (i.e., set-shifting, working memory, and inhibitory control). Despite their strong genetic composition, the development of EFs is shaped by environmental exposures - as maternal distress, perinatal hypoxia, household dysfunction, neglection - which have varying degrees of impact depending on the duration or severity of the exposure, sensitive neurodevelopmental periods, and individual resiliency. Furthermore, they are negatively affected by aging and psychiatric, neurologic, and inflammatory diseases. MicroRNA dysregulation interferes with normal brain development and function and has been associated with various neuropsychiatric disorders; however, its effects on EFs remain unclear. Therefore, in this review we focus on the evidence regarding microRNA changes and their effects on EFs. We performed a systematic search from inception until October 2023 of four databases of human and animal studies. The results are presented narratively. Moreover, we conducted a bioinformatics analysis using experimental mRNA targets of the candidate microRNAs, as well as assessed the risk of bias of the included studies. We found 46 studies (23 in humans, 22 in animals, and one in both). The studies evaluated mild cognitive impairment, psychiatric disorders, and healthy aging. Gene mutations in MIR137 were associated with decreased EF performance, whereas MIR885 gene methylation was associated with increased executive functioning. Mutations in the genes of enzymes relevant for microRNA biosynthesis also impacted EFs. In the revised literature, the microRNAs that were consistently reported as dysregulated in two or more samples in relation to variations in EFs were miR-148a-3p for humans; miR-155, miR-30e, and miR-384-5p for rodents; and miR-132, miR-146a-5p, miR-148-3p, miR-181a-5p, miR-190b, miR-31, miR-501-3p, and miR-9-5p for both humans and rodents. The suggested regulatory pathways behind EFs included changes in neurogenesis, neurodevelopment, and synaptic plasticity/signaling. Changes in the various steps of microRNA biogenesis - such as mutations in the genes coding for microRNAs, reduced availability of relevant processing enzymes, or dysregulation of microRNA expression - are potentially associated with changes in EFs. Future research is required to better understand these associations in relation to developmental stage, diagnosis, disease severity, and the degree of the microRNA dysregulation.
Adeno-Associated virus-based approaches for mitochondrial diseases: advances and challenges.
Corrà S, Balmaceda V, Viscomi C
Mol Psychiatry · 2026 Apr · PMID 42056225 · Publisher ↗
Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy...
Mitochondrial diseases, caused by mutations in either mitochondrial or nuclear DNA, are highly complex genetic disorders characterized by faulty oxidative phosphorylation. Adeno-associated virus (AAV)-based gene therapy with its broad and customizable tissue tropism achieved through natural and engineered serotypes offers a highly effective platform for delivering therapeutic genes to affected tissues. However, the intricate genetics and biology of mitochondria present unique challenges for the development of AAV-based therapies. While gene replacement therapy remains a viable strategy for correcting nuclear gene defects, mutations in mtDNA require specialized approaches, such as mitochondrially targeted, RNA-free base editors and nucleases capable of precise editing within the mitochondrial genome. As an alternative, allotopic expression, which involves expressing mitochondrial genes from the nuclear genome, is currently being evaluated in clinical trials but remains controversial, due to issues related to mitochondrial import and functional integration in the respiratory complexes. The clinical translation of AAV-mediated therapies for mitochondrial diseases still confronts several interrelated challenges, including efficient targeting of multiple affected organs, scalable and cost-effective vector manufacturing, and minimizing vector-associated toxicity. By integrating advanced genome editing technologies with sophisticated vector engineering and delivery strategies, AAV-based gene therapy stands as a transformative approach for addressing the broad and heterogeneous spectrum of primary mitochondrial disorders. Continued progress in overcoming current biological and technical barriers will be essential to realize the full therapeutic potential of AAVs.
Polysubstance use disorders among US adults.
Han B, Volkow ND, Jones CM … +7 more , Dowell D, Baldwin G, Einstein EB, Subramaniam GA, Olsen Y, Blanco C, Compton WM
Mol Psychiatry · 2026 Apr · PMID 42056224 · Publisher ↗
Polysubstance use disorders ( ≥ 2 substance use disorders (SUDs)) are associated with high morbidity and mortality. We analyzed data from 92,233 adult participants in the 2022-2023 US National Surveys on Drug Use and Hea...
Polysubstance use disorders ( ≥ 2 substance use disorders (SUDs)) are associated with high morbidity and mortality. We analyzed data from 92,233 adult participants in the 2022-2023 US National Surveys on Drug Use and Health to estimate past-year prevalence of polysubstance use disorders and to examine their associations with age of substance use initiation. Multivariable logistic regression and Poisson regression were applied. Age- and sex-adjusted past-year prevalence of 2 SUDs was 19.2-44.9% (95% CIs=11.1-62.3%) among adults with any SUD. Age- and sex-adjusted past-year prevalence of ≥3 SUDs ranged from 16.4% (95% CI = 14.3-18.6%) among adults with cannabis use disorder, to 32.4-44.7% (95% CIs=29.1-51.3%) among those with opioid use disorder or prescription stimulant or tranquilizer/sedative use disorder, and up to 48.2-72.0% (95% CIs=39.4-81.7%) among those with methamphetamine, cocaine, or hallucinogen use disorder. Overall, compared to adults who initiated substance use before age 18, the number of SUDs was 73-83% lower for those who initiated at age ≥21 (range of incidence density ratios (IDRs)=0.17-0.27, 95% CIs=0.12-0.31). Specifically, compared with corresponding adult counterparts who initiated before age 18, the number of moderate-severe SUDs was 32% lower among those initiating alcohol at ages 21-29 (IDR = 0.68, 95% CI = 0.57-0.83), 21% lower among those initiating cannabis at ages 21-29 (IDR = 0.79, 95% CI = 0.69-0.90), and 45-62% lower (IDRs=0.38-0.55, 95% CIs=0.31-0.76) among adults who never initiated alcohol, cannabis, or nicotine use. The elevated prevalence of polysubstance use disorders associated with early initiation of substance use underscores the critical need for evidence-based strategies to prevent alcohol, cannabis, and nicotine consumption before age 21.
Cognitive impairment preceding the onset of the first psychosis episode in schizophrenia.
Reichenberg A, Kahn RS
Mol Psychiatry · 2026 Apr · PMID 42050012 · Publisher ↗
Adults with schizophrenia exhibit substantial and widespread cognitive impairment, with subtle cognitive deficits already apparent in childhood and adolescence - many years prior to the onset of psychosis. Here, we focus...
Adults with schizophrenia exhibit substantial and widespread cognitive impairment, with subtle cognitive deficits already apparent in childhood and adolescence - many years prior to the onset of psychosis. Here, we focus on evidence from population-based research highlighting findings specific to cognitive impairment (as indexed by IQ) that precedes the onset of schizophrenia. We illustrate that (i) cognitive impairment worsens from early childhood onwards through to the onset of psychosis; (ii) this early and progressive cognitive impairment is rarely present in other psychotic disorders. At the same time, (iii) early cognitive impairment is not universal in schizophrenia; and (iv) a substantial role for genes affecting both schizophrenia and early life cognitive impairment has not been unequivocally proven. We suggest that a subgroup of patients with schizophrenia is characterized by progressive premorbid cognitive impairment. This group is developmentally distinguishable from the rest of patients with psychoses. Future studies should focus on understanding the (possibly unique) etiology in this neurodevelopmental subgroup of schizophrenia patients.
Exosomes in depression: mechanistic insights, diagnostic potential, and therapeutic opportunities.
Wang F, Yang J, Wang G
Mol Psychiatry · 2026 Apr · PMID 42050011 · Publisher ↗
Exosomes are increasingly recognized as critical mediators of intercellular communication within the central nervous system and along the brain-periphery axis, with emerging relevance to the pathophysiology of depression...
Exosomes are increasingly recognized as critical mediators of intercellular communication within the central nervous system and along the brain-periphery axis, with emerging relevance to the pathophysiology of depression. These nanoscale extracellular vesicles transport bioactive cargo-including microRNAs (miRNAs), proteins, lipids, and metabolites-that can modulate neuroinflammatory signaling, synaptic remodeling, hypothalamic-pituitary-adrenal (HPA) axis dynamics, and gut-brain communication. Converging evidence from human and preclinical studies suggests that alterations in circulating and brain-derived exosomal cargo are associated with major depressive disorder (MDD) and secondary depression following neurological insults such as traumatic brain injury (TBI), implicating shared inflammatory and synaptic pathways alongside distinct etiological drivers. Circulating neuron-enriched exosomes carrying miRNAs such as miR-16 and miR-124 have been proposed as minimally invasive biomarkers reflecting brain-relevant molecular alterations. However, most human data remain cross-sectional and associative, with limited longitudinal replication and incomplete validation of cellular origin. Therapeutically, mesenchymal stem cell (MSC)-derived exosomes demonstrate antidepressant-like effects in rodent models through modulation of microglial activation, enhancement of synaptic plasticity, and attenuation of neuroinflammatory cascades. Engineered exosomes further offer a potential platform for targeted delivery of anti-inflammatory or neuroplasticity-enhancing cargo. Induced pluripotent stem cell (iPSC)-derived exosomes represent a potentially scalable and standardizable therapeutic platform. Despite this promise, substantial barriers impede clinical translation. Isolation workflows-including ultracentrifugation, size-exclusion chromatography, and immunoaffinity capture-vary in yield, purity, and reproducibility, complicating cross-cohort comparability. Moreover, definitive attribution of vesicle origin in peripheral biofluids remains technically constrained, and standardized reporting frameworks are inconsistently applied. Advances in multi-omics profiling, high-throughput sequencing, mass spectrometry, and spatially resolved molecular analyses may improve mechanistic resolution and biomarker robustness. Collectively, exosome research in depression resides at an early but rapidly evolving translational stage. Rigorous methodological standardization, longitudinal cohort validation, and mechanistic dissection across primary and injury-related depression will be essential to determine whether exosome-based diagnostics and therapeutics can fulfill their potential within precision psychiatry.
Alzheimer's disease-like brain pattern biomarker: capturing risks and predicting disease onset.
Kochunov P, Gao S, Salminen LE … +16 more , Jahanshad N, Nir TM, Thompson PM, Du X, Adhikari BM, Kochunov A, Cassidy R, Ma Y, Chiappelli J, Ament S, Pan Y, Chen S, Shuldiner AR, Mitchell BD, Soares LJ, Hong LE
Mol Psychiatry · 2026 Apr · PMID 42045435 · Publisher ↗
Preventing Alzheimer's disease (AD) requires early-warning biomarkers. We developed a Regional Vulnerability Index (RVI) that quantifies individual brain similarity to AD patients' expected brain deficit patterns. We cal...
Preventing Alzheimer's disease (AD) requires early-warning biomarkers. We developed a Regional Vulnerability Index (RVI) that quantifies individual brain similarity to AD patients' expected brain deficit patterns. We calculated regional effect sizes to establish brain deficit patterns in amyloid-positive AD cases compared to amyloid-negative healthy controls. RVI-AD was calculated as a linear index of individual similarity to this established brain pattern in AD. We demonstrated RVI-AD elevation associated with risk factors in 335 participants (mean age: 49 ± 13 years) in the Amish Connectome Project, followed by an independent sample consisting of 26,010 participants (mean age: 64 ± 7 years) from the UK Biobank. Genetic and cardiovascular risks were evaluated using APOE-e4 genotype and Framingham Cardiovascular Risk Scores (FCVRS), respectively. Additionally, we assessed the risk of converting from MCI to dementia in N = 1932 participants (mean age: ~74) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Healthy participants with the APOE-e4 allele had significantly elevated RVI-AD indices (p = 0.03 and 2·10, for ACP and UKBB samples respectively). FCVRS significantly contributed to higher RVI-AD in an interaction with APOE-e4-specific manner (p = 2·10 and 7·10 for ACP and UKBB samples respectively). In ADNI cohort, RVI-AD significantly predicted conversion from MCI to dementia in the next decade, particularly in the first three years (AUC = 70-74%, OR = 2.16, 95% CI = 1.8-2.6, p < 10). In healthy individuals, the RVI-AD detected the insidious impact of APOE-ε4 and cardiovascular risks in otherwise normally aging cohorts. Elevated RVI-AD also predicted conversion to dementia within ten years in the older, high-risk cohort. Further development of this brain-pattern similarity-based approach may yield a noninvasive, clinically accessible biomarker to aid early detection of the subtle to more imminent effects of AD risks.
Astrocytic connexin 43 hemichannel dysregulation drives prefrontal circuit dysfunction and schizophrenia-like behaviors.
Wang L, Xu K, Liao Y … +10 more , Luo Y, Fang Y, Zhang X, Wang J, Li K, Zhou D, Liu S, Chen W, Wang L, Tang J
Mol Psychiatry · 2026 Apr · PMID 42045434 · Publisher ↗
Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and...
Schizophrenia (SCZ) is hypothesized to arise from neural circuit dysfunction, but the role of non-neuronal cells remains poorly defined. While astrocytic connexin 43 (Cx43) facilitates both gap junction (GJ) coupling and hemichannel (HC)-mediated gliotransmitter release, its specific role in SCZ remains unclear. Here, we report elevated Cx43 expression in the prefrontal cortex of individuals with SCZ and investigate its functional relevance in an MK801-induced mouse model. In this model, medial prefrontal cortex (mPFC) Cx43 upregulation was associated with enhanced HC activity without affecting GJ coupling. Pharmacological blockade of Cx43 HC with TAT-Gap19 rescued SCZ-like behavioral and synaptic alterations, whereas astrocyte-specific Cx43 overexpression (Cx43 OE) in the mPFC of naive mice recapitulated behavioral abnormalities. Mechanistically, increased HC activity was linked to excessive astrocytic glutamate release, which was directly visualized using ex vivo two-photon imaging with an astrocyte-specific glutamate sensor and normalized by TAT-Gap19. Together, our results integrate human expression data with experimental evidence to implicate astrocytic Cx43 HC dysregulation in prefrontal circuit dysfunction relevant to SCZ and suggest that glial HC signaling warrants further investigation in SCZ pathophysiology.
Gut microbiome alterations are sex-dependently associated with brain abnormalities in a mouse model of Neurofibromatosis type I.
Reisinger SN, Kong G, van de Garde N … +8 more , Muhammad A, Adithya P, Lu D, Kiridena P, Gubert C, Dabscheck G, Payne JM, Hannan AJ
Mol Psychiatry · 2026 Apr · PMID 42045433 · Publisher ↗
Neurofibromatosis type 1 (NF1) is a genetic condition presenting with variable symptomatology, however most individuals will demonstrate cognitive and behavioural difficulties, including autism. Using a heterozygous germ...
Neurofibromatosis type 1 (NF1) is a genetic condition presenting with variable symptomatology, however most individuals will demonstrate cognitive and behavioural difficulties, including autism. Using a heterozygous germline knockout mouse model of NF1 (Nf1 +/-), we performed in-depth behavioural evaluations encompassing learning and memory, stereotypy, social interaction, anxiety- and depression-like behaviour. Anatomical and functional studies of the brain and gastrointestinal tract were followed by the first investigation of gut microbiota composition (via full-length 16S rRNA sequencing) in a Nf1 +/- mouse model. The cognitive and autism-like behavioural phenotype seen in Nf1 +/- mice was accompanied by a striking increase in relative brain size which is highly relevant to clinical NF1. Furthermore, brain size was correlated with behaviour, supporting a potential mechanistic link. Nf1 +/- mice showed significant alterations in gut microbiota composition vs. Nf1 +/+ wild-type controls, with males additionally showing significant changes to species abundance of the Clostridium and Blautia genera, and the Lachnospiraceae family, findings which partially overlap with those in preclinical and clinical autism. Composition of associated functional pathways was not globally altered, however +/- mice showed significant changes in a pyrimidine deoxynucleotide biosynthesis pathway. In male Nf1 +/- mice, we also identified a genotype-specific host-microbial signature, pointing towards a mechanistic link between gut microbiome composition and brain size. These findings significantly expand our understanding of brain and behavioural abnormalities in this preclinical model of NF1 and, importantly, have uncovered the gut microbiome as a highly promising new area of research and a potential therapeutic target for these symptom clusters.
Blood-derived microRNA signatures associated with hippocampal structure and atrophy rate: findings from the Rhineland Study.
Melas K, Talevi V, Imtiaz MA … +5 more , Krüger DM, Pena-Centeno T, Fischer A, Aziz NA, Breteler MMB
Mol Psychiatry · 2026 Apr · PMID 42032299 · Publisher ↗
MicroRNAs (miRNAs) have been linked to brain disorders, but their relations with hippocampal structure and atrophy remain unexplored. As the hippocampus is pivotal for cognition and dementia, understanding these relation...
MicroRNAs (miRNAs) have been linked to brain disorders, but their relations with hippocampal structure and atrophy remain unexplored. As the hippocampus is pivotal for cognition and dementia, understanding these relations and their specificity for the hippocampus would elucidate miRNA involvement in brain health and neurodegeneration. Here, using population-based data, we cross-sectionally and longitudinally examined the associations of blood-derived miRNAs with left and right hippocampal volume, hippocampal asymmetry, and total brain volume. Expression of miRNAs and their putative target genes was measured at study baseline in whole blood using RNA sequencing. Brain imaging measures were examined at baseline and re-examined 4.60-8.02 years later using 3 T MRI. We investigated miRNA associations with imaging measures cross-sectionally using linear regression and longitudinally using linear mixed-effect models. Cross-sectionally, six miRNAs (miR-199a-3p, miR-199b-3p, miR-155-5p, miR-146a-5p, miR-6859-5p, miR-505-5p) were associated exclusively with left hippocampal volume. Longitudinally, another five miRNAs (miR-361-3p, miR-4473, miR-381-3p, miR-543, miR-370-3p) were associated with left hippocampal, right hippocampal, and total brain atrophy rates. Twenty-one miRNAs were exclusively associated with total brain atrophy rate. In whole blood, miRNAs identified in the cross-sectional analysis targeted genes related to brain development, memory, and synapse assembly. MiRNAs from the longitudinal analysis targeted genes related to axonal and dendritic growth. Several identified miRNAs were previously linked to neurodegeneration. Especially miR-146a-5p and miR-370-3p have been consistently linked to dementia and could be investigated as presymptomatic blood-based biomarkers. The brain-specific functions and interactions with target genes of identified miRNAs could be further investigated to develop therapeutic strategies against neurodegeneration.
Multiomics analysis identifies VPA-induced changes in neural progenitor cells, ventricular-like regions, and cellular microenvironment in dorsal forebrain organoids.
Yentür Z, Branco L, Sarieva K … +10 more , Andreeva D, Kagermeier T, Kulka C, Jarboui MA, Colombo F, Diaz F, Collignon P, Becker K, Selhuber-Unkel C, Mayer S
Mol Psychiatry · 2026 Apr · PMID 42032298 · Publisher ↗
Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neur...
Pharmaceutical agents, such as antiepileptic medications, can cross fetal barriers and affect the developing brain. Prenatal exposure to the antiepileptic drug valproate (VPA) is associated with an increased risk of neurodevelopmental disorders, including congenital malformations and autism spectrum disorder. In animal models and neural organoids, VPA has been shown to alter signaling pathways, such as Wnt pathway, providing insights into VPA-induced neurodevelopmental defects. Here, we exposed dorsal forebrain organoids to VPA for 30 days and examined effects at the tissue, cellular, and molecular level. VPA treatment disrupted ventricular-like regions, indicating defects in cell-cell and cell-matrix interactions. Transcriptomics analysis confirmed altered expression of extracellular matrix (ECM) genes and single cell RNA sequencing analysis identified genes involved in microenvironment sensing, such as cellular mechanosensing and Hippo-YAP/TAZ signaling pathway. Finally, proteomics analysis corroborated that VPA alters the microenvironment of the human dorsal forebrain organoids by disrupting the secretion of ECM proteins. Altogether, our study suggests that VPA-treated dorsal forebrain organoids serve as a model to investigate the role of extracellular processes in brain development and to understand how their disruptions might contribute to neurodevelopmental disorders.
Neuroendocrine signature of ME/CFS: Meta-analytic evidence for bioactive cortisol deficit and exaggerated feedback sensitivity.
Woo TW, Choi YJ, Kim JY … +2 more , Lee JS, Son CG
Mol Psychiatry · 2026 Apr · PMID 42026257 · Publisher ↗
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and...
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a major clinical challenge as a complex multisystemic disorder with no well-established pathophysiological mechanism, characterized by persistent fatigue and post-exertional malaise, along with unrefreshing sleep, cognitive impairment, and impaired stress recovery. Despite decades of investigation into the hypothalamic-pituitary-adrenal (HPA) axis, a definitive neuroendocrine hallmark has remained elusive due to inconsistent findings across various cortisol matrices. Therefore, this systematic review and meta-analysis aimed to provide an integrated understanding of HPA-axis regulation in ME/CFS. We identified 46 case-control studies (comprising 46 independent datasets, including 12 pharmacological challenge studies), involving 1388 ME/CFS patients (71.9% female; mean age 37.3 ± 6.2 years) and 1349 matched healthy controls. Meta-analyses showed lower salivary cortisol at awakening and in the morning. Reductions were also observed in 24-h urinary cortisol and hair cortisol. In pharmacological challenge tests, patients exhibited impaired cortisol release in response to adrenocorticotropic hormone (ACTH) stimulation and exaggerated suppression following glucocorticoid administration. Collectively, these alterations indicate reduced free cortisol availability and enhanced HPA-axis negative feedback sensitivity, consistent with a hyporeactive endocrine state in ME/CFS. This neuroendocrine hypo-reactivity may underlie hallmark clinical features such as unrefreshing sleep, post-exertional malaise, and severe fatigue, as well as cognitive slowing, emotional blunting, and diminished stress resilience frequently observed in ME/CFS and related functional disorders. Integrating neuroendocrine and psychological perspectives may help clarify mechanisms of chronic stress maladaptation and inform psychobiological interventions for fatigue syndromes.
IL-15 receptor alpha deficiency triggers depressive-like behaviors via enhanced microglial synapse pruning.
Tang Y, Huang Y, Pan J … +19 more , Li C, Yang J, Tan X, Hu K, Wen L, Xie P, Liu Y, Xu H, Cao S, Zhang J, Li Y, Liu P, Yuan M, Song X, Wu J, He Y, Wong ML, Licinio J, Zheng P
Mol Psychiatry · 2026 Apr · PMID 42020719 · Publisher ↗
Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely...
Major Depressive Disorder (MDD) is a serious mental illness, and neuroinflammation is increasingly recognized as a contributor to its pathogenesis; however, the underlying cellular and molecular mechanisms remain largely unknown. In this study, we performed single-nucleus RNA sequencing to profile prefrontal cortex transcriptomics in interleukin-15 receptor subunit alpha knockout (Il15ra) mice displaying depressive-like behaviors. Il15ra mice exhibited cell-type-specific transcriptomic alterations, particularly affecting synapse assembly. Co-expression network analysis identified two gene clusters predominantly linked to synaptic pathways in microglia, excitatory neurons, and interneurons, suggesting dysregulated neuron-microglial interactions in depression. Morphological analysis revealed microglial activation and synapse remodeling driven by enhanced neuron-microglia communication via the CX3CL1/CX3CR1 signaling pathway. Pharmacological inhibition of CX3CL1/CX3CR1 signaling using a CX3CR1 antagonist reversed depressive-like behaviors and microglia-mediated excessive synapse pruning caused by IL-15RA deficiency. Collectively, these findings demonstrate that IL-15RA deficiency contributes to depression onset by modulating microglia-mediated synaptic remodeling, highlighting a targetable neuroimmune pathway for therapeutic interventions in MDD.
Cell-type-specific genetic architecture reveals neuronal and immune contributions to neuropsychiatric disorders.
Wang X, Luo L, Chang S … +1 more , Yang L
Mol Psychiatry · 2026 Apr · PMID 42020718 · Publisher ↗
Neuropsychiatric disorders exhibit complex polygenic architectures, yet the cell-type-specific mechanisms underlying most risk loci remain unclear. Here, we integrate single-cell expression quantitative trait locus (sc-e...
Neuropsychiatric disorders exhibit complex polygenic architectures, yet the cell-type-specific mechanisms underlying most risk loci remain unclear. Here, we integrate single-cell expression quantitative trait locus (sc-eQTL) data from brain and blood tissues with genome-wide association studies (GWAS) of six neuropsychiatric disorders (schizophrenia (SCZ), Parkinson's disease (PD), bipolar disorder (BP), major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and autism spectrum disorder (ASD)) to systematically identify putative causal genes at cellular resolution. Employing summary-data-based Mendelian randomization (SMR) across diverse neuronal and immune cell types, we discovered 345 cell-type-specific risk genes for various diseases, including both replicated candidates (such as MAPT in astrocytes for SCZ and PD and FLOT1 in excitatory neurons and inhibitory neurons for SCZ, BP and MDD) and novel associations (such as APTX in microglia for SCZ). Cross-disorder analyses revealed shared pathways in synaptic function and immune regulation. In contrast, disease-specific and tissue-specific patterns were observed across different disorders. Strikingly, we found that brain-derived risk genes exhibited significantly higher cell-type specificity than those identified in blood, underscoring the more focused cellular context of genetic effects in the central nervous system. Our findings suggest that neuropsychiatric disorders arise from a combination of neuronal dysfunction and immune system dysregulation. The study demonstrates how cell-type-specific mapping uncovers etiological mechanisms obscured in bulk-tissue analyses, proving novel information for clarifying the biological mechanism of gene expression implicated in the development of the six neuropsychiatric disorders.
Re-evaluating the effectiveness of ultrabrief pulse ECT: the potential role of (In)appropriate seizure threshold titration.
Meijer JR, Baeken C, De Witte S … +1 more , van Exel E
Mol Psychiatry · 2026 Apr · PMID 42014470 · Publisher ↗
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Multimodal microglial and kynurenine pathway alterations across the affective-psychosis spectrum: a systematic review of patterns, heterogeneity, and dimensional implications.
Nussbaumer M, Guest PC, Schiltz K … +9 more , Dudeck L, Asl LS, Meyer-Lotz G, Dobrowolny H, Leucht S, Bernstein HG, Nickl-Jockschat T, Fernandes BS, Steiner J
Mol Psychiatry · 2026 Apr · PMID 42014469 · Publisher ↗
Immune dysregulation is implicated in patient subgroups in major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ), but the role of microglia across affective and psychotic illnesses remains unclea...
Immune dysregulation is implicated in patient subgroups in major depressive disorder (MDD), bipolar disorder (BD) and schizophrenia (SCZ), but the role of microglia across affective and psychotic illnesses remains unclear. We propose an integrative framework linking systemic immune drivers to microglia-related circuit engagement, cellular phenotype, and kynurenine pathway (KP) branch balance. We systematically reviewed human TSPO-PET, cerebrospinal fluid (CSF) KP metabolite, and postmortem microglial and KP studies. Quantitative synthesis focused on MDD versus SCZ. BD was integrated descriptively due to limited data. MDD showed the most reproducible in vivo signal, with increased TSPO binding in frontolimbic regions (cingulate cortex, hippocampus, prefrontal cortex), and had lower heterogeneity and higher precision than SCZ. Postmortem MDD findings were largely null for diagnosis-level increases in microglial density or classical activation markers, but suggested subtle homeostatic shifts. KP findings were localized and regionally dissociated, including cingulate QUIN-related microglial signals and reduced hippocampal QUIN immunoreactivity in single cohorts. BD evidence was sparse as TSPO-PET comprised a single study reporting hippocampal increases, and postmortem microglial markers were mostly unchanged at the diagnosis level, with suicide or psychosis stratification revealing subgroup effects. Also, BD KP data suggested anterior cingulate upstream activation with a psychosis-linked downstream signal (reduced prefrontal KMO) in a subgroup. In SCZ, TSPO-PET findings were heterogeneous with small decreases or no change, and postmortem studies indicated either activation-marker increases or loss of homeostatic microglial signatures. In addition, the most consistent biochemical signal in SCZ was a shift toward the KYNA branch (increased CSF KYNA and cortical KYNA), consistent with KP-linked glutamatergic dysregulation. Overall, microglia-related alterations appear better explained by biological subgroups and symptom dimensions than by categorical diagnoses, motivating future transdiagnostic studies with dimensional phenotyping, subgroup stratification, longitudinal designs, and microglia-specific biomarkers. Limitations include the limited cellular specificity of TSPO-PET, small sample sizes, and postmortem studies focusing on few cortical/limbic regions rather than whole-brain coverage.
Shared and disorder-specific prenatal and perinatal risk factors for neurodevelopmental disorders: a nationwide cohort study.
Peyre H, Rios P, Botton J … +6 more , Herlemont P, Olié V, Miranda S, Zureik M, Weill A, Dray-Spira R
Mol Psychiatry · 2026 Apr · PMID 42014468 · Publisher ↗
Neurodevelopmental disorders (NDDs) are common, frequently co-occur, and impose a substantial burden, yet the extent to which early-life risk factors differ across the spectrum of NDDs remains unclear. Using the EPI-MERE...
Neurodevelopmental disorders (NDDs) are common, frequently co-occur, and impose a substantial burden, yet the extent to which early-life risk factors differ across the spectrum of NDDs remains unclear. Using the EPI-MERES register, derived from the French National Health Data System, we conducted a nationwide cohort study of all 6.8 million children born in France between 2010 and 2018, followed until September 2024. We investigated prenatal and perinatal risk factors, including gestational age, small for gestational age (SGA), neonatal hypoxia, congenital malformations, parental age, maternal alcohol and tobacco exposure, maternal obesity, and socioeconomic disadvantage, in relation to five major NDDs: communication disorders, specific learning disorders, attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and intellectual disability (ID). Models were estimated both with and without adjustment for co-occurring NDDs. Overall, 506,505 children (7.5%) were identified with at least one NDD over a median follow-up of 9.6 years. Co-occurrence was frequent, especially for ID (54.5%), ASD (52.2%), and ADHD (34.9%). In models not adjusted for NDD co-occurrence, several factors were common across disorders, including male sex, prematurity, SGA, congenital malformations, maternal obesity, prenatal alcohol and tobacco exposure, and young maternal age. In addition, some exposures showed disorder-specific associations, most notably with ID: extreme prematurity, SGA, congenital malformations, neonatal hypoxia, and advanced parental age. After adjustment for co-occurring NDDs, several associations were attenuated, indicating that some risk factors contribute simultaneously to multiple disorders; for example, the male predominance in ID and the association of extreme prematurity with ASD were substantially reduced. These findings delineate shared and disorder-specific prenatal and perinatal risk profiles and emphasize the importance of considering co-occurring diagnoses in understanding etiological pathways and informing early prevention strategies.
Genetic overlap and shared risk loci between autism spectrum disorder and cardiometabolic traits.
Muntané G, Shadrin A, Guardiola-Ripoll M … +5 more , O'Connell KS, Frei O, Naerland T, Vilella E, Andreassen OA
Mol Psychiatry · 2026 Apr · PMID 42009985 · Publisher ↗
Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 2% of the global population. Beyond core symptoms such as social communication deficits and repetitive behaviors, individuals with ASD are at inc...
Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 2% of the global population. Beyond core symptoms such as social communication deficits and repetitive behaviors, individuals with ASD are at increased risk of cardiometabolic comorbidities, including obesity, diabetes, and cardiovascular disease. Here, we investigate the shared genetic architecture between ASD and cardiometabolic traits using large genome-wide association studies datasets and advanced statistical approaches: the bivariate causal mixture (MiXeR) model and pleiotropy-informed conditional false discovery rate (pleioFDR). Our results show significant polygenic overlap between ASD and several cardiometabolic phenotypes, despite almost negligible genetic correlation between the traits. Specifically, we observed positive genetic correlations within the shared component for ASD and metabolic traits, such as body mass index (rg=0.03), type 2 diabetes (rg=0.23), and total cholesterol (rg=0.78). In contrast, negative correlations emerged between ASD and cardiovascular traits, including diastolic and systolic blood pressure (rg = -0,22, for both), pulse pressure (rg = -0.25), and coronary artery disease (rg = -0.90). Finally, we identified 100 shared loci between ASD and cardiometabolic traits, mapping to 124 genes and suggesting shared biological mechanisms underlying these phenotypes and pointing to potential therapeutic targets. Shared loci between ASD and metabolic traits predominantly showed concordant effects, whereas those overlapping with cardiovascular traits-particularly blood pressure-related traits-tended to exhibit discordant effects. Together, these findings deepen our understanding of the biological connections between ASD and cardiometabolic comorbidities and may help inform more personalized strategies for managing ASD and its associated long-term health risks.
Single-cell transcriptomics of human brain disorders.
Arbabi K, Carito G, Luquez T … +1 more , Wainberg M
Mol Psychiatry · 2026 Apr · PMID 42009984 · Publisher ↗
Brain disease is ultimately a disease of its constituent cells, and single-cell genomics has recently begun to illuminate the cellular pathologies underlying human brain disorders. In this review, we synthesize the key b...
Brain disease is ultimately a disease of its constituent cells, and single-cell genomics has recently begun to illuminate the cellular pathologies underlying human brain disorders. In this review, we synthesize the key biological insights from recent single-cell studies of post-mortem human brain tissue across a range of neurological and psychiatric conditions. Organized by major central nervous system cell type, we detail the depletion of vulnerable cellular populations, the emergence of disease-associated states, the dysregulation of gene expression programs, and the interplay between these changes and genetic risk factors. Collectively, these studies mark a turning point in brain disease research, providing the first comprehensive maps of how neurological and psychiatric disorders manifest across the cellular landscape of the human brain.
Multiscale characterization of cortical signatures in positive and negative schizotypy: a worldwide ENIGMA study.
Kirschner M, Hodzic-Santor B, Kennedy L … +69 more , Hansen JY, Antoniades M, Nenadić I, Kircher T, Krug A, Meller T, Dannlowski U, Grotegerd D, Flinkenflügel K, Meinert S, Borgers T, Goltermann J, Hahn T, Böhnlein J, Leehr EJ, Barkhau C, Fornito A, Arnatkeviciute A, Bellgrove MA, Tiego J, DeRosse P, Green M, Quidé Y, Pantelis C, Chan RCK, Wang Y, Ettinger U, Debbané M, Derome M, Gaser C, Besteher B, Diederen K, Spencer TJ, Houenou J, Pomarol-Clotet E, Salvador R, Rössler W, Smigielski L, Kumari V, Premkumar P, Park HRP, Wiebels K, Jansen I, Gilleen J, Allen P, Marsman JB, Lebedeva I, Tomyshev A, Fett AK, Sommer I, Koops S, Grant P, Ferrari A, Wan B, Bègue I, Hernaus D, Jalbrzikowski M, Paquola C, Larivière S, Bernhardt B, Valk SL, Misic B, van Erp TGM, Turner JA, Thompson PM, Aleman A, Dagher A, Kaiser S, Modinos G
Mol Psychiatry · 2026 Apr · PMID 42000906 · Publisher ↗
Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization...
Positive and negative schizotypy reflect distinct patterns of subclinical traits in the general population associated with neurodevelopmental and schizophrenia-spectrum pathologies. Yet, a comprehensive characterization of the unique and shared neuroanatomical signatures of these schizotypy dimensions is lacking. Leveraging 3D brain MRI data from 2730 unmedicated healthy individuals, we identified neuroanatomical profiles of positive and negative schizotypy and systematically compared them with disorder-specific, microarchitectural, neurotransmitter-level, and connectome measures. Positive and negative schizotypy were associated with distinct cortical signatures, of predominantly thinner frontal and thicker paralimbic cortical areas, respectively. These cortical signatures of positive and negative schizotypy were differentially linked to brain-wide cortical patterns of schizophrenia-spectrum (clinical high-risk for psychosis, schizophrenia) and neurodevelopmental conditions (ADHD, autism spectrum disorder and 22q11.2 deletion syndrome). Additionally, the positive and negative schizotypy-related cortical profiles mapped onto different local attributes of gene expression, cortical myelination, D1, and histamine receptor distributions. Network models further showed that positive and negative schizotypy cortical signatures were spatially associated with cortical hubs, suggesting that highly interconnected regions are more vulnerable to the morphological differences associated with both schizotypy dimensions. Finally, predominantly sensorimotor-to-association and paralimbic areas emerged as epicenters with connectivity profiles significantly linked to the schizotypy-related cortical patterns. Collectively, this study identified cortical signatures of positive and negative schizotypy traits that are embedded along multiple scales of cortical organization and neuropsychiatric pathologies. Our work yields novel insights into how neurobiology and brain architecture may guide neuroanatomical vulnerability and resilience to psychopathology in the general population.
GLP-1 receptor agonists and risk of suicide or suicide attempts - A nationwide cohort and self-controlled case series study.
Stanislaus C, Winther-Jensen M, Stanislaus S … +3 more , Osler M, Coello K, Vinberg M
Mol Psychiatry · 2026 Apr · PMID 42000905 · Publisher ↗
The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have raised concerns about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicide or suicide attempt...
The European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) have raised concerns about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and suicide or suicide attempts. We conducted two new-user, active comparator cohort studies. The GLP1-RAs vs sodium-glucose cotransporter-2 (SGLT-2) inhibitors cohort included new users of GLP-1 RAs (n = 83,464) or SGLT-2 inhibitors (n = 78,366), and the GLP1-RAs vs dipeptidyl peptidase-4 (DPP-4) inhibitors cohort included new users of GLP-1 RAs (n = 108,322) or DPP-4 inhibitors (n = 55,411). We also employed a self-controlled case series design to compare suicide, or suicide attempts before and after GLP-1 RA treatment initiation across three time periods. In the cohort analyses patients who initiated GLP-1 RAs did not differ in the hazard ratio (HR) for suicide or suicide attempts from SGLT-2 inhibitor users (HR: 0.93; 95% CI: 0.57-1.52), and GLP-1 RA users had a lower risk of suicide or suicide attempts compared with DPP-4 inhibitor users (HR: 0.58; 95% CI: 0.37-0.91). In the self-controlled case series design, use of GLP-1 RAs was associated with a lower incidence rate ratio (IRR) of suicide or suicide attempts one year after treatment initiation (IRR: 0.45; 95% CI: 0.10-0.50) and 13-24 months after treatment initiation compared with pretreatment. This study showed that use of GLP-1 RAs was not associated with increased incidence of suicide or suicide attempts in either the active comparator new-user design or in the self-controlled case series design.
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