Molecular Psychiatry[JOURNAL]
Sun
100 papers
Diagnostic and sex effects on frontostriatal brain wiring structural organization in early psychosis affective subjects compared to healthy controls.
Levitt JJ, Zhang F, Vangel M … +14 more , Nestor PG, Rathi Y, Cetin-Karayumak S, Kubicki M, Pasternak O, Coleman MJ, Lewandowski KE, Holt DJ, Keshavan M, Bouix S, Öngür D, Breier A, Shenton ME, O'Donnell LJ
Mol Psychiatry · 2026 Jul · PMID 42401715 · Publisher ↗
BACKGROUND: Brain connectivity abnormalities may underlie affective psychosis which may be influenced by sex. Using diffusion magnetic resonance imaging (dMRI) tractography, we assessed frontostriatal brain wiring connec...
BACKGROUND: Brain connectivity abnormalities may underlie affective psychosis which may be influenced by sex. Using diffusion magnetic resonance imaging (dMRI) tractography, we assessed frontostriatal brain wiring connectivity patterns in 46 early psychosis affective and 56 healthy control young adult, male and female participants. METHODS: We collected harmonized whole brain tractography dMRI data from three sites and applied our novel fiber clustering methodology to identify 17 white matter fiber clusters connecting the frontal cortex and caudate per hemisphere in each group. By comparing cortical and caudate inter-cluster endpoint distances between groups, we assessed their patterns of frontostriatal connectivity. RESULTS: 1) In both males and females in early affective psychosis and healthy controls, bilaterally, the frontal cortex to caudate wiring pattern deviated from a topographic organization. 2) in a right hemisphere frontal pole fiber cluster, independent of sex, we found a significant interaction effect of diagnosis on the connectivity pattern between frontal cortex and caudate, (p = 0.013); 3) in a left hemisphere inferior frontal gyrus, pars triangularis, fiber cluster, we found sex influenced the significant interaction effect of diagnosis on the connectivity pattern between frontal cortex and caudate, (p = 0.0085), with the effect much greater in females (p < 0.00001) than in males (p = 0.97); and, 4) post-hoc tests showed a significant effect of diagnosis on the pattern of frontal cortex to caudate connectivity in specific subregions (ps ≤0.04). CONCLUSIONS: Importantly, while the frontostriatal wiring pattern in both early affective psychosis and healthy controls deviated from a topographic organization, we found in a right hemisphere fiber cluster, independent of sex, that a significant interaction effect of diagnosis was observed on the frontal cortex to caudate connectivity pattern, whereas, in a left hemisphere fiber cluster, the effect of diagnosis on connectivity pattern was influenced by sex, showing the importance of the role of sex in brain wiring patterns in early affective psychosis.
Effects of family genetic risk scores and environmental factors on risk of schizophrenia and bipolar disorder.
Robinson N, Ploner A, Ohlsson H … +3 more , Lichtenstein P, Kendler KS, Bergen SE
Mol Psychiatry · 2026 Jul · PMID 42399416 · Publisher ↗
Both genetic and environmental risk factors contribute to the development of schizophrenia (SCZ) and bipolar disorder (BD), but simultaneous investigation of how these factors influence risk has not yet been comprehensiv...
Both genetic and environmental risk factors contribute to the development of schizophrenia (SCZ) and bipolar disorder (BD), but simultaneous investigation of how these factors influence risk has not yet been comprehensively examined in a large population. Therefore, we aimed to investigate and quantify how a multi-generational index of aggregated genetic risk (family genetic risk scores, FGRS) and environmental exposures jointly contribute to risk for SCZ and BD, and whether these relationships differ between the disorders. We conducted a Swedish register-based matched nested case-control study with 3057 SCZ and 15,029 BD cases diagnosed 1988-2013. We used conditional logistic regression to determine individual and joint effects of established environmental risk factors including adverse childhood experiences (ACEs), substance use, adverse perinatal factors, childhood infections, urban birth and longest residence, and FGRS (quintiles) for SCZ and BD and risk of SCZ/BD. We also estimated population attributable fractions (PAFs) for environmental exposures. FGRS were associated with incremental increases in SCZ and BD, with highest risk observed for the highest quintile (SCZ IRR 9.63, 95% CI 7.17-12.94; BD IRR 6.30, 95% CI 5.80-6.84). FGRS and most environmental exposures were independently associated with risk of SCZ and BD. The greatest PAFs were observed for substance use (SCZ 18.3%; BD 13.2%) and ACEs (SCZ 14.1%; BD 19.8%). FGRS are associated with increased risk for SCZ and BD and were largely independent from environmental risk factors. Potentially modifiable factors, ACEs and substance use, accounted for a moderate proportion of all cases and were particularly impactful for BD (PAF 19.8, 95% CI 18.4, 21.2) and SCZ (PAF 18.3, 95% CI 17.6-19.0), respectively.
Mitochondrial-inflammation crosstalk in major depressive disorder: molecular mechanisms and therapeutic implications.
Wang Y, Li JT, Zhu LL … +3 more , Wu YK, Su YA, Si TM
Mol Psychiatry · 2026 Jul · PMID 42399415 · Publisher ↗
Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondri...
Despite its high prevalence, the precise mechanisms underlying major depressive disorder (MDD) remain incompletely understood. Growing evidence identifies mitochondrial dysfunction, including abnormalities in mitochondrial DNA, impaired bioenergetics, disrupted quality control, and redox imbalance, as a central pathological feature of MDD. Beyond deficits in energy production, mitochondria function as upstream regulators of neuroinflammation. Mitochondria derived damage associated molecular patterns and excessive reactive oxygen species activate innate immune signaling, while inflammatory challenges in turn compromise mitochondrial integrity. This bidirectional and self-reinforcing interaction between mitochondrial dysfunction and inflammation may contribute to disease onset, progression, and clinical heterogeneity. Preclinical and clinical studies indicate that conventional antidepressants gradually restore mitochondrial function while suppressing oxidative and inflammatory stress, whereas rapid-acting agents such as ketamine induce acute metabolic reprogramming and mitophagy, enabling swift functional recovery. Mechanistically distinct interventions, including mitochondria targeted antioxidants, metabolic modulators, and psychedelic compounds, further highlight the therapeutic potential of targeting mitochondrial pathways. By integrating current evidence, this review delineates mitochondrial-inflammation crosstalk in MDD and supports mitochondrial regulation as a promising target for novel antidepressant strategies.
Copy number variant scores are associated with cerebrovascular pathology in aging.
Du JN, Tio ES, Bennett DA … +5 more , Schneider JA, Sevim Bayrak C, Alexander-Bloch A, Zhang B, Felsky D
Mol Psychiatry · 2026 Jul · PMID 42399414 · Publisher ↗
Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in older adults, with specific genomic copy number variants (CNVs) implicated in its pathology. However, the aggregate burden of genome-wide CNVs...
Late-onset Alzheimer's disease (LOAD) is the most common cause of dementia in older adults, with specific genomic copy number variants (CNVs) implicated in its pathology. However, the aggregate burden of genome-wide CNVs in dementia and age-related neuropathologies is uncharacterized. This study investigated the association between genome-wide CNV scores (CNV-S) and dementia, as well as LOAD-related neuropathologies, in 1011 elderly participants (mean age 88.06) from two ongoing US-based longitudinal clinical-pathological cohort studies who were initially dementia-free and consented to brain donation upon death. Participants exhibited varying cognitive statuses at death (429 dementia, 258 mild cognitive impairment, 324 cognitively normal). We evaluated effects of (1) eight individual-level CNV-S based on gene loss intolerance and dosage sensitivity; (2) a single nucleotide polymorphism (SNP)-based LOAD polygenic score (PGS-LOAD) calculated using Bayesian continuous shrinkage; and (3) covariates (age, sex, and education). Outcomes included cognitive scores across 19 tests, clinical diagnoses of Alzheimer's disease or mild cognitive impairment, and four LOAD-related neuropathologies assessed postmortem. Analyses identified 4867 CNVs (3918 deletions, 949 duplications) mapped to 3211 genes. Higher deletion CNV-S were significantly associated with increased cerebrovascular pathologies (pLI: β = 0.14, 95% CI [0.08, 0.21]; LOEUF: β = 0.14, 95% CI [0.08, 0.20]; pHI: β = 0.15, 95% CI [0.08, 0.21]; binarized pHI: β = 0.14, 95% CI [0.08, 0.21]). Models predicting cerebral atherosclerosis that included deletion CNV-S significantly outperformed models based on only PGS-LOAD (R increase: 0.02). These findings suggest that genome-wide CNV burden, particularly deletions in dosage-sensitive genes, contributes to cerebrovascular pathology in aging. CNV-S may augment existing LOAD genetic risk models by capturing vascular pathways distinct from traditional SNP-based risk.
Opposite molecular sex correlations in tauopathy paralleled by motor and cognitive efficacy of davunetide in women.
Shapira G, Blatt J, Guz LS … +2 more , Shomron N, Gozes I
Mol Psychiatry · 2026 Jul · PMID 42399413 · Publisher ↗
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Her...
Progressive supranuclear palsy (PSP) is a fatal tauopathy presenting an unmet medical need. Davunetide, targeting tauopathy, has been previously tested in PSP, which, when separated by sex, implied efficacy in women. Here, efficacy was evaluated using longitudinal data (52 weeks) and applying for the first time, the US Food and Drug Administration (FDA) -recommended 10-item PSP Rating Scale (PSPRS-10) compared to the 28-item PSPRS (primary endpoint). Time-, sex-, and treatment-related effects were analyzed using linear mixed-effects models including the FDA-recommended Mixed Models for Repeated Measures (MMRM). Cognitive evaluations used the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Clinical analyses at the individual level accentuated the impact of the 10 PSPRS chosen items and revealed a significant treatment effect favoring women when accounting for time, sex, and treatment interactions (P = 0.0005). Motor measurements were highlighted. RBANS analyses demonstrated women's significant improvements in total raw score, letter-number sequencing, and language scores. Correlating cerebrospinal fluid (CSF) phosphorylated Tau/Tau with functional outcomes revealed significance with p-Tau/Tau ratio and grasping/imitative/utilizing behavior (assessing involuntary actions in PSPRS-28). This correlation was opposite in direction between females (r = 0.77; P = 0.006) and males (r = -0.62; P = 0.075), with sex difference showing a P = 0.0002 value. Similar results were obtained for language. Predicting the final PSPRS score (week 52), addressing all clinical measures, a clear woman-treatment-specific pattern in outcome importance was discovered, highlighting significance for the primary endpoint Schwab and England Activity of Daily Living (SEADL) scale, and stressing the necessity for sex-specific medicine with davunetide as a lead compound.
Identification of hub genes involved in early-onset schizophrenia: from genetic susceptibility to predicted regulated gene expression.
Jen Y, Yu SL, Hsiao PC … +17 more , Kuo PH, Liu CM, Liu CC, Hwang TJ, Hsieh MH, Chien YL, Lin YT, Huang H, Feng YA, Hsiao CK, Lin YF, Faraone SV, Neale B, Glatt SJ, Tsuang MT, Hwu HG, Chen WJ
Mol Psychiatry · 2026 Jul · PMID 42399412 · Publisher ↗
Despite high heritability, much of the genetic architecture of schizophrenia (SZ) remains unexplained, and early-onset SZ may represent a more genetically homogeneous subtype. We examined genetically regulated expression...
Despite high heritability, much of the genetic architecture of schizophrenia (SZ) remains unexplained, and early-onset SZ may represent a more genetically homogeneous subtype. We examined genetically regulated expression risk scores (GeRS) to identify gene networks associated with early-onset SZ and characterize their biological functions. Using genotype data from patients in multiplex families (223 early-onset and 372 late-onset) and simplex families (matched for sex and onset age), SZ-GeRS were estimated based on single-nucleotide polymorphism (SNP)-expression prediction models derived from two transcriptomic reference panels (dorsolateral prefrontal cortex tissue from individuals with psychiatric disorders and brain cortex tissue from the general population). Panel-specific GeRS were constructed using transcriptome-wide association studies (TWAS)-derived effect sizes and integrated using a fixed-effects meta-analytic framework. Module-based SZ-GeRS were constructed by aggregating genes within empirically derived co-expression clusters, followed by network analysis to identify hub genes and functional mapping to infer biological context. Among 13 co-expression modules, meta-analysis identified a significant association between early-onset SZ and Module 10 GeRS (M10-GeRS: adjusted odds ratio [aOR] = 1.22, 95%CI = 1.07-1.40). Hub genes prioritized by complementary network approaches also showed significant associations. Functional enrichment analyses indicated predominant involvement of excitatory neuronal processes and immune-related pathways. Sensitivity analyses using a variance-calibrated TWAS approach to account for polygenicity-driven inflation attenuated gene-level signals but did not materially alter module-level associations, with M10-GeRS remaining robustly associated with early-onset SZ. These findings highlight gene regulatory networks linking genetic susceptibility to molecular mechanisms in early-onset SZ and may inform risk stratification and targeted interventions.
Exercise-induced brain changes in cannabis use disorder: a longitudinal MRI study of a 12-week supervised HIIT program.
Maleki S, Richardson K, Hughes S … +10 more , Kayayan E, Syeda W, Coxon JP, Solowij N, Lubman DI, Lorenzetti V, Caeyenberghs K, Segrave RA, Suo C, Yücel M
Mol Psychiatry · 2026 Jul · PMID 42393253 · Publisher ↗
OBJECTIVE: Cannabis use disorder (CUD) is highly relapsing and has been associated with structural brain alterations (e.g., white matter and cortical thickness) in pathways and regions critical for a healthy brain. The d...
OBJECTIVE: Cannabis use disorder (CUD) is highly relapsing and has been associated with structural brain alterations (e.g., white matter and cortical thickness) in pathways and regions critical for a healthy brain. The development of non-abstinence-based interventions is essential for restoring structural alterations in CUD. Physical exercise, particularly aerobic exercise, may promote neuroplastic changes in brain structure. METHODS: In this novel randomised, single-blind, comparator-controlled trial, we recruited 59 individuals with CUD (76% classified with severe CUD; median age = 25 years, 22% female, without requiring abstinence during intervention). They were randomly allocated to receive 12-weeks of 45 min, three times/week of either: (i) High Intensity Interval Training (HIIT) aimed to achieve 80% of participants' maximum heart rate (above the lactate release threshold); or (ii) active control Strength and Resistance training (S&R). The main outcome was brain structural organisation (fractional anisotropy and cortical thickness) measured via advanced diffusion and anatomical MRI scans conducted before and after 12 weeks. RESULTS: The HIIT group showed significant increases in FA in the left uncinate fasciculus (p = 0.012) and cortical thickness in the right pars opercularis of the inferior frontal gyrus (p = 0.016), revealed by time-by-group interaction. These exercise-induced changes in white matter and cortical thickness significantly correlated with total hours spent with heart rates > 80% (r = 0.32, p = 0.027 and r = 0.41, p = 0.001) and the time spent above the lactate release threshold (r = 0.27, p = 0.061 and r = 0.40, p = 0.004). CONCLUSION: Overall, a 12-week HIIT exercise intervention, without requiring abstinence from cannabis consumption, can enhance brain plasticity.
Shared and specific associations of amygdala nuclei volumes with PTSD symptom domains and childhood trauma: An ENIGMA-PGC PTSD mega-analysis.
Mufford MS, van der Meer D, Baird CL … +105 more , Sun D, LaBar KS, Ramesar R, Hussain A, Abdallah CG, Andrew E, Averill CL, Baker JT, Baugh LA, Blackford JU, Bomyea J, Bryant RA, Ching CRK, Choi K, Cotton AS, Daniels JK, Davenport ND, Davidson RJ, De Bellis MD, Dennis EL, Densmore M, deRoon-Cassini TA, Disner SG, du Plessis S, Etkin A, Fani N, Fercho KA, Fitzgerald J, Geuze E, Gordon EM, Grupe DW, Harpaz-Rotem I, Russel CC, Herzog JI, Hofmann D, Hudson AR, Ipser J, Jahanshad N, Jovanovic T, Kaufman ML, Koch SBJ, Koerte IK, Korgaonkar MS, Krystal JH, Lanius R, Larson C, Lebois LAM, Levy I, Li G, Liberzon I, Logue MW, Magnotta VA, Manthey A, Maron-Katz A, May G, McLaughlin KA, Mueller SC, Nawijn L, Nelson SM, Neria Y, Neufeld RWJ, Nitschke JB, O'Leary EN, Olatunji BO, Olff M, Olson EA, Peverill M, Phan KL, Pineda E, Ressler KJ, Rosso IM, Salminen LE, Meltzer K, Schmahl C, Seedat S, Sharp CA, Shenton ME, Sierk A, Simons RM, Simons JS, Sponheim SR, Stein MB, Stevens JS, Straube T, Suarez-Jimenez B, Théberge J, Thomopolous SI, van der Wee NJA, van der Werff SJA, van Erp TGM, van Rooij SJH, van Zuiden M, Veltman DJ, Vermeiren RRJM, Walter H, Wang X, Wang L, Xie H, Zhu X, Zhu Y, Thompson PM, Andreassen OA, Stein DJ, Morey RA, Dalvie S
Mol Psychiatry · 2026 Jul · PMID 42393252 · Publisher ↗
Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it...
Posttraumatic stress disorder (PTSD) is a psychiatric condition that may develop after trauma exposure. PTSD is characterized by considerable clinical heterogeneity. The amygdala's key role in fear conditioning makes it an important focus for investigating the neurobiology of PTSD. However, associations between amygdala volume and PTSD have been inconsistent. The amygdala consists of functionally distinct nuclei. Specific associations between amygdala nuclei volumes and PTSD may account for previous discrepancies between PTSD and whole amygdala volume. This study investigates the associations between amygdala nuclei volumes, PTSD diagnosis, severity, symptom cluster scores, age of onset and childhood trauma. Individuals with a PTSD diagnosis (n = 771) and controls (n = 1 081, 72% trauma-exposed) were sourced from the Enhancing Neuro-Imaging Genetics through Meta-Analysis and Psychiatric Genomics Consortium (mean age = 32.4 years, (SD = 13 years), 60% male). Nine amygdala nuclei volumes were compared to PTSD diagnosis, age of onset, overall severity, symptom cluster scores (re-experiencing, arousal, and avoidance/emotional numbing), and childhood trauma subscales. Analyses were performed using ordinary least-squares regression, corrected for age, sex, intracranial volume, and whole amygdala volume. PTSD diagnosis was not significantly associated with amygdala nuclei volumes. PTSD severity scores were associated with smaller right lateral nucleus volume (β = -0.26, p = 0.01). Smaller right lateral nucleus volume was also associated with re-experiencing (β = -1.01, p = 0.04) and arousal (β = -0.9, p = 0.04), smaller left paralaminar nucleus volume was associated with re-experiencing (β = -0.1, p = 0.04), smaller left corticoamygdaloid transition area volume was associated with avoidance (β = -0.31, p = 0.02). Larger left and right central nucleus volumes were significantly associated with childhood physical abuse (β = 0.24, p = 9 × 10) and neglect (β = 0.29, p = 0.04), respectively. Differences in select amygdala nuclei volumes among adults are associated with PTSD severity, symptom cluster scores, and childhood physical abuse and neglect. These findings demonstrate nuclei-specific patterns consistent with their functional roles in fear learning and expression.
Cross-ancestry pleiotropic analysis of imaging-derived phenotypes enhances risk stratification of depression.
Feng Y, Guo X, Huang P … +3 more , Jia N, Hu S, Yang S
Mol Psychiatry · 2026 Jul · PMID 42387104 · Publisher ↗
Depression arises from dynamic interactions among genetic predisposition, brain alterations, and environmental stressors. Despite genome-wide association studies (GWAS) identifying risk loci, the mechanisms translating g...
Depression arises from dynamic interactions among genetic predisposition, brain alterations, and environmental stressors. Despite genome-wide association studies (GWAS) identifying risk loci, the mechanisms translating genetic variation into brain changes remain elusive. Imaging-derived phenotypes (IDPs) were the intermediate traits linking genetic architecture to neural circuit dysfunction. Here, we collected large-scale GWAS summary statistics of depression and IDPs across European (EUR; N = 1,293,933 and 33,224, respectively) and East Asian (EAS; N = 82,874 and 7058, respectively). In the multiple-trait analysis between depression and IDPs, we clarified their genetic correlation through MTAG, identified the pleiotropic single nucleotide variants (SNVs) and genes with functional insight, and established the causal relationship through Mendelian randomization via TwoSampleMR in EUR and EAS ancestry, respectively. To discern the heterogeneous genetic drivers, we selected independent SNVs from the multiple-trait analyses to perform unsupervised clustering. Six clusters delineated distinct biological pathways for metabolic regulation, neurotransmitter dynamics, and neuroimmune interactions, with tissue/cell type specificity through MAGMA. Finally, we dissected relationships between depression and polygenic risk score, IDPs, and modifiable lifestyle factors, and introduced a machine learning framework to refine risk stratification (N = 16,166). Our study advanced the understanding of the multiscale etiology of depression while providing dynamic depression risk stratification for precision prevention.
Shared genetic architecture of schizophrenia and Alzheimer's disease and related dementias implicates 16p11.2 and lifespan brain vulnerability.
Chen Y, Cheng L, Wang Q … +5 more , Liu Q, Li W, Wang C, Lv L, Yue W
Mol Psychiatry · 2026 Jul · PMID 42387103 · Publisher ↗
Epidemiological and clinical observations linking schizophrenia (SCZ) to increased dementia risk, together with the occurrence of psychosis in Alzheimer's disease and related dementias (ADRD), suggest that shared genetic...
Epidemiological and clinical observations linking schizophrenia (SCZ) to increased dementia risk, together with the occurrence of psychosis in Alzheimer's disease and related dementias (ADRD), suggest that shared genetic liabilities may contribute to their co-occurrence. Leveraging large-scale genome-wide association study summary statistics for SCZ (53,386 cases and 77,258 controls) and ADRD (111,326 cases and 677,663 controls), we systematically investigated their shared genetic architecture and potential biological mechanisms. We identified three significant local genetic correlations (P < 2.0 × 10⁻⁵) and cross-trait polygenic enrichment between SCZ and ADRD, with 39 genomic loci jointly associated at conjunctional false discovery rate (conjFDR) < 0.05. Fifteen high-confidence genes (CNIH4, CD302, PCGF3, TFR2, EPHX2, SNX32, EFEMP2, CTSW, ASPHD1, TAOK2, INO80E, DOC2A, MAPK3, KANSL1, and XPNPEP3) were consistently prioritized across positional, expression quantitative trait locus, and chromatin-interaction mapping. Tissue- and cell-type enrichment analyses highlighted cerebellar tissues and ependymal-cell-related signals, while pathway analyses implicated synaptic signaling, axonal growth, and presynaptic structural organization. At the locus level, colocalization and transcriptome-wide association analyses converged on 16p11.2, prioritizing INO80E, YPEL3, SLX1B, and TMEM219. Developmental trajectory modeling further revealed region- and stage-specific expression divergence of prioritized 16p11.2 genes, with prominent differences spanning childhood and adulthood. Brain-wide association analysis linked the 16p11.2 lead variant rs9932702 to cortical gray-white contrast (β = -0.062, P = 7.5 × 10⁻¹⁵), a neuroimaging phenotype related to gray-white boundary microstructure and myelination. Finally, bidirectional Mendelian randomization supported a modest directional association between genetic liability to SCZ and increased ADRD risk, but not the reverse direction. Collectively, these findings provide convergent genetic, regulatory, transcriptomic, developmental, and imaging evidence for partial shared liability between SCZ and ADRD, highlighting 16p11.2 and biological processes related to neurodevelopment, synaptic and axonal organization, myelination-related microstructure, and later-life brain vulnerability.
The neurodevelopmental spectrum: phenotypic architecture, etiology, predictive utility, and specificity across development.
Michelini G, Liao W, Lu SD … +6 more , Caserini C, Eley TC, Ronald A, Wilson S, Malanchini M, Rimfeld K
Mol Psychiatry · 2026 Jul · PMID 42387102 · Publisher ↗
Neurodevelopmental conditions are highly heritable, heterogeneous, and frequently co-occur. Transdiagnostic dimensional approaches have advanced understanding and classification of psychiatric disorders, but have largely...
Neurodevelopmental conditions are highly heritable, heterogeneous, and frequently co-occur. Transdiagnostic dimensional approaches have advanced understanding and classification of psychiatric disorders, but have largely omitted neurodevelopmental conditions. Using longitudinal data for >10,000 children from the Twins Early Development Study, we investigated the structure of a transdiagnostic "neurodevelopmental spectrum" across development, its etiology, its ability to predict functional outcomes, and the specificity of these associations. Hierarchical exploratory factor modeling of a broad set of traits/symptoms delineated a neurodevelopmental spectrum encompassing neurodevelopmental traits at ages 7, 12, and 16. This spectrum emerged as a distinct dimension alongside separable dimensions of internalizing, externalizing, and psychosis symptoms. The neurodevelopmental spectrum was highly heritable across development in twin analyses (h = 0.60-0.82) and predicted by polygenic scores (PGS) for neurodevelopmental, cognitive, and educational phenotypes (R up to 2.30% in single-PGS analyses, 3.36% in multi-PGS analyses). Perinatal and early developmental factors (e.g., low birth weight, language delays) were also associated with this spectrum (R up to 8.65%). Individual differences in the neurodevelopmental spectrum predicted cognitive and educational outcomes both concurrently and longitudinally (R up to 20.61%), largely due to overlapping genetic effects. Associations with predictors and outcomes remained largely unchanged after adjusting for internalizing, externalizing, and psychosis dimensions, indicating they were specific to the neurodevelopmental spectrum and not attributable to shared variance with other co-occurring symptoms. Our novel results on the phenotypic architecture, etiological validity, predictive utility, and specificity of the neurodevelopmental spectrum across development support its integration into transdiagnostic frameworks, with important implications for advancing research, psychiatric classification, and clinical care.
Towards ecological psychiatry: The herbicide glyphosate disrupts behavior through microbiota-gut-brain axis.
Matsuzaki R, Valderrama B, Tofani GSS … +5 more , Cagun SC, Fitzgerald P, Clarke G, Gunnigle E, Cryan JF
Mol Psychiatry · 2026 Jun · PMID 42380611 · Publisher ↗
Planetary and human health including mental health are closely interrelated. Increasing evidence also points to a role for the microbiota-gut-brain axis in maintaining optimum mental health. Emerging evidence raises conc...
Planetary and human health including mental health are closely interrelated. Increasing evidence also points to a role for the microbiota-gut-brain axis in maintaining optimum mental health. Emerging evidence raises concerns about the unintended toxicity of environmental exposure to xenobiotics, any substance foreign to the body, on the brain and behavior. Glyphosate is one of the most widely used active ingredients for herbicides for both agricultural and domestic applications. However, investigations on the effects of glyphosate at regulatory reference dose exposures on this axis are currently neglected.Adult male and female mice were exposed to regulatory reference doses of glyphosate via drinking water for 7 weeks to assess its impact on gut microbiota composition, gut barrier function, physiology and behaviors including social interaction, anxiety, cognition, and the stress response. To establish causality, we conducted a microbiota transplantation examining whether behavioral phenotypes were phenocopied in naïve animals.Regulatory reference dose glyphosate exposure primarily affected male mice, leading to impaired social novelty preference and increased anxiety-like behavior, whereas females exhibited a reduction in locomotor activity without other robust behavioral alterations. Transcriptomic analysis of the amygdala revealed gene expression changes consistent with observed behavioral deficits in males. Importantly, microbiota transfer from glyphosate-exposed donors selectively reproduced the social impairments in recipient mice, establishing the role of the glyphosate-remodeled microbiota in modifying social behavior.These findings underscore the importance of evaluating ecologically relevant regulatory reference dose pesticide exposure and provide evidence that glyphosate impacts the microbiota-gut-brain axis to modify behavior. It further supports the concept that xenobiotics in the environment can impact mental health processes and further validates the concept of ecological psychiatry.
BDNF-DT and BDNF-AS-DT: novel genes in the BDNF locus.
Bach SV, Punzi G, Smith NE … +12 more , Mukherjee S, Shin JH, Chen Q, Pertea G, Collado-Torres L, Maynard KR, Page SC, Kleinman JE, Hyde TM, Weinberger DR, Martinowich K, Ursini G
Mol Psychiatry · 2026 Jun · PMID 42380610 · Publisher ↗
Divergent transcription from bidirectional promoters is frequently observed in eukaryotic genomes, but the biological relevance of divergent RNA transcripts (DT) is unknown. We identified and characterized BDNF-DT, a nov...
Divergent transcription from bidirectional promoters is frequently observed in eukaryotic genomes, but the biological relevance of divergent RNA transcripts (DT) is unknown. We identified and characterized BDNF-DT, a novel DT gene, and BDNF-AS-DT, a novel readthrough gene, in the locus containing BDNF, a gene with key roles in neuronal development, differentiation, and synaptic plasticity. BDNF-DT is independent from the known BDNF antisense (BDNF-AS), and its expression is developmentally regulated and positively correlated with BDNF in human postmortem dorsolateral prefrontal cortex (DLPFC). BDNF-DT and BDNF-AS-DT expression increase after induced depolarization, but the temporal dynamics follow expression of BDNF, suggesting a regulatory role. Moreover, CRISPR-mediated upregulation of BDNF in human neural progenitor cells drives BDNF-DT expression. Finally, BDNF-DT shows higher expression in DLPFC from patients diagnosed with schizophrenia compared to neurotypical controls, and genetically predicted lower expression of the BDNF-AS-DT readthrough transcript is associated with schizophrenia and with the schizophrenia-associated C allele of the rs6265 single-nucleotide polymorphism. These findings identify BDNF-DT and BDNF-AS-DT as novel, low-abundance genes that show coordinated expression with BDNF and association with schizophrenia risk, though their biological significance requires further validation given detection limitations and the need to establish causal roles.
Serotonergic SLC10A4 regulates extracellular serotonin levels and antidepressant responsiveness.
Caixeta FV, Lundberg S, Balasubramanian A … +6 more , van Gelder C, Mercer E, Lou G, Jonsson J, Konradsson-Geuken Å, Kullander K
Mol Psychiatry · 2026 Jun · PMID 42380609 · Publisher ↗
Solute carrier family member 10A4 (SLC10A4) is an orphan transporter selectively expressed in aminergic cells, where it localizes to synaptic vesicles and has been implicated in aminergic neurotransmission. Although cons...
Solute carrier family member 10A4 (SLC10A4) is an orphan transporter selectively expressed in aminergic cells, where it localizes to synaptic vesicles and has been implicated in aminergic neurotransmission. Although constitutive knockout studies have suggested a role for SLC10A4 in monoamine and acetylcholine homeostasis, interpretation has been limited by developmental compensation and lack of cell-type specificity. Here, we employed a tamoxifen-inducible CreERT2-lox system to selectively delete Slc10a4 in serotonergic neurons of young adult mice (8-10 weeks), enabling assessment of its function in mature serotonergic circuits. Adult serotonergic deletion of SLC10A4 resulted in a marked reduction of baseline extracellular serotonin levels in the medial prefrontal cortex, as measured by in vivo microdialysis. Notably, the ability of the selective serotonin reuptake inhibitor fluoxetine to elevate extracellular serotonin was strongly attenuated. These neurochemical deficits were accompanied by increased anxiety-like behavior across multiple behavioral paradigms and a blunted antidepressant-like response to fluoxetine in the forced swim test, while locomotor activity and motor coordination remained intact. These findings show that SLC10A4 is required for normal extracellular serotonin availability and antidepressant responsiveness in the adult brain. Together, our results identify SLC10A4 as a novel critical regulator of serotonergic neurotransmission and suggest that presynaptic monoamine handling represents an important and previously underappreciated determinant of affective behavior and treatment efficacy.
TranDep: a transcriptomics atlas of depression.
Zhong X, Gui S, Wang D … +14 more , He Y, Chen X, Chen Y, Chen X, Jiang Y, Qiao R, Ren Y, Zhang H, Tan Q, Wang W, Khaitovich P, Pu J, Liu Y, Xie P
Mol Psychiatry · 2026 Jun · PMID 42380608 · Publisher ↗
Depression is a severe mental illness that poses substantial burdens on public health. Given that depression research is still challenged by its multifaceted pathogenesis, depicting the depression associated genetic regu...
Depression is a severe mental illness that poses substantial burdens on public health. Given that depression research is still challenged by its multifaceted pathogenesis, depicting the depression associated genetic regulatory networks is essential for understanding its mechanism, optimizing diagnosis, and developing targeted therapies. However, a comprehensive panoramic view of transcriptional alterations in depression remains lacking. By leveraging the available transcriptomic studies from the National Center for Biotechnology Information (NCBI), China National Center for Bioinformatics (CNCB), European Bioinformatics Institute (EBI), and our laboratory, we compiled an extensive set of depression related datasets, encompassing 4 species, 31 types of brain and peripheral tissues, 35 categories of antidepressant interventions, and 6391 samples. Furthermore, a unified pipeline for raw data preprocessing and differential expression analysis was employed to identify differentially expressed genes (DEGs). A total of 631882 molecules entries were obtained, including 190366 entries from humans, 6612 from non-human primates, 332780 from mice, and 102124 from rats. Additionally, 15 single-cell and single-nucleus transcriptomic datasets, including 164 samples, and 78536 molecular entries were also included. Notably, we developed the TranDep database ( http://www.depression-atlas.cn/ ) for the depression research community, which provided a user-friendly web interface for browsing, and searching these molecules. To demonstrate the utility of TranDep, a case study was presented to identify robust DEGs, and explore its biological functions in the prefrontal cortex of patients with depression. Overall, TranDep is a comprehensive cross-species resource developed to provide a transcriptional atlas of depression, which may shed light on the identification and validation of diagnostic and therapeutic markers for depression.
Effects of cannabidiol on anxiety- and depressive-like behaviors and cognition: a systematic review and meta-analysis of preclinical studies.
Jantsch J, Wickert F, Fraga GF … +3 more , de Fraga LS, Durán-Carabali LE, Guedes RP
Mol Psychiatry · 2026 Jun · PMID 42380607 · Publisher ↗
BACKGROUND: Cannabidiol (CBD) has emerged as a promising neuroprotective compound, with potential benefits for cognitive and emotional behaviors. However, the consistency of its effects across preclinical models remains...
BACKGROUND: Cannabidiol (CBD) has emerged as a promising neuroprotective compound, with potential benefits for cognitive and emotional behaviors. However, the consistency of its effects across preclinical models remains uncertain. METHODS: We conducted a systematic review and meta-analysis of 123 animal studies assessing the impact of CBD on anxiety-like and depressive-like behaviors, as well as cognition. RESULTS: CBD consistently reduced anxiety- and depressive-like behaviors, with moderate effect sizes observed in paradigms such as the elevated plus maze, novelty suppressed feeding, forced swim, sucrose preference, and tail suspension test. Cognitive effects were more heterogeneous: CBD improved performance in adverse, discriminatory, and working memory tasks, while effects were small or inconsistent in hippocampus-dependent spatial memory tests. Subgroup analyses revealed that CBD's efficacy often depended on the type of behavioral test and the presence of underlying pathologies. Mechanistic evidence implicates serotonergic signaling (notably 5-HT1A receptors), endocannabinoid modulation, anti-inflammatory and neurotrophic pathways, as well as mitochondrial and synaptic plasticity processes, as contributors to these behavioral outcomes. Risk of bias assessment indicated moderate to high quality across studies, confirming the robustness of the findings. CONCLUSIONS: Overall, our results indicate that CBD reduces anxiety-like and depressive-like behaviors and improves cognitive performance across a variety of preclinical models. While these findings support its therapeutic potential and provide a rationale for guiding translational research, clinical evidence in humans is still limited and inconclusive, underscoring the need for further research.
Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder.
Ter Kuile AR, Mitchell BL, Lee SH … +32 more , Morneau-Vaillancourt G, Skelton M, Coleman JRI, Davies HL, Mundy J, Peel AJ, Hübel C, Davies MR, Fürtjes AE, Ahmad Z, Lin Y, Adey BN, McGregor T, Palmos A, Zvrskovec J, Hotopf M, Kalsi G, Smith DJ, Veale D, Walters JTR, Armour C, Hirsch CR, McIntosh AM, Wray NR, Medland SE, Byrne EM, Martin NG, Kingston N, Bradley JR, NIHR BioResource, Breen G, Eley TC
Mol Psychiatry · 2026 Jun · PMID 42374129 · Publisher ↗
Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxie...
Twin studies reveal high genetic overlap between anxiety disorders and depression, contributing to the internalising spectrum. Some genetic specificity for fear-based anxiety disorders (fear), distinct from general anxiety and depression (distress), has also emerged. Limited datasets with detailed phenotyping across anxiety disorders have restricted most genome-wide association studies (GWAS) to "any anxiety diagnosis". Additional genome-wide evidence to discern genetic differences between fear and distress is required. We conducted GWAS meta-analyses of fear (panic, agoraphobia, specific phobia, social anxiety disorder) and generalised anxiety disorder (GAD), measured using brief single-item and detailed symptom-based diagnoses from three datasets. We explored two control group criteria: phenotype-specific (fear/GAD) or broader anxiety/depression screening. We identified one independent genome-wide significant locus and three gene-level associations with fear (up to 35,523 N; 157,447 N). Four genome-wide significant loci and three gene-level associations were identified for GAD (up to 60,879 N; 117,064 N). The genetic correlation between fear and GAD was significantly different from unity only when excluding a depression-enriched dataset and using phenotype-specific control screening (r = 0.87; P = 9.32 × 10). Most complex traits had statistically similar genetic correlations with fear and GAD, including depression. Exceptions included general cognitive ability, educational attainment, and coronary artery disease, showing statistically stronger genetic correlations with fear than GAD, while bipolar disorder type I, anorexia nervosa, and neuroticism displayed the opposite pattern. Our findings partially support a distress-fear genetic distinction, but show stronger evidence for an overarching genetic liability to internalising psychopathology driving comorbidity across anxiety disorders and depression.
Cannabis use and glutamate across the psychosis spectrum: in vivo evidence from 7T proton magnetic resonance spectroscopy.
Roalf DR, Moore TM, Stifelman J … +17 more , Pecsok MK, Atkins A, Baller EB, Calkins ME, De Biasi M, Kohler CG, Mastracchio C, Mordy A, Robinson H, Reddy R, Nanga RPR, Ruparel K, Rush-Goebel S, Wolf DH, Gur RC, Gur RE, Scott JC
Mol Psychiatry · 2026 Jun · PMID 42374128 · Publisher ↗
Cannabis use is linked to elevated psychosis risk, yet the neurobiological mechanisms that couple use to symptom expression remain unclear. Because glutamatergic dysregulation has been implicated in both cannabis effects...
Cannabis use is linked to elevated psychosis risk, yet the neurobiological mechanisms that couple use to symptom expression remain unclear. Because glutamatergic dysregulation has been implicated in both cannabis effects and psychosis vulnerability, we examined whether brain glutamate relates to dimensional psychosis symptoms as a function of cannabis use across the psychosis spectrum. Seventy-nine participants-typically developing controls, clinical high-risk individuals, and patients with psychosis-completed dimensional clinical assessments, detailed cannabis use surveys, urine toxicology, and ultra-high-field 7T magnetic resonance spectroscopy (HMRS) of the anterior cingulate cortex (ACC). Linear models assessed the main and interactive effects of ACC glutamate and cannabis use on psychopathology symptoms. Self-reported cannabis use showed good concordance with urine toxicology, with strongest agreement among frequent users. Both lower ACC glutamate and higher cannabis use were independently associated with positive and negative psychosis symptoms. Notably, lower glutamate levels were associated with higher positive symptoms in cannabis users but not cannabis non-users. Exploratory analyses suggested interactions for depressive and manic symptoms, indicating that glutamatergic abnormalities may amplify the overall severity of cannabis-related symptoms. Sensitivity analyses revealed lower ACC glutamate in psychosis patients-especially cannabis users-highlighting diagnostic group differences and reinforcing the link between cannabis exposure and glutamatergic dysfunction. These findings implicate ACC glutamatergic dysfunction as a transdiagnostic correlate of symptom burden, particularly in those with psychosis who are cannabis users. Glutamate-targeted interventions and longitudinal designs will be needed to examine causal pathways linking cannabis exposure to psychosis-relevant outcomes.
Subtyping OCD based on individual symptom networks: subtype-specific neural dynamics and morphometric similarity linked to molecular profiles.
Yuan D, Wang X, Fan J … +8 more , Zhang Y, Xiao C, Gao F, Liu Q, Han Y, Tan C, Situ W, Zhu X
Mol Psychiatry · 2026 Jun · PMID 42365100 · Publisher ↗
Obsessive-compulsive disorder (OCD) is clinically heterogeneous, posing challenges for diagnosis and treatment. Individual symptom network-based subtyping could provide the framework for characterizing this heterogeneity...
Obsessive-compulsive disorder (OCD) is clinically heterogeneous, posing challenges for diagnosis and treatment. Individual symptom network-based subtyping could provide the framework for characterizing this heterogeneity. This study developed an individualized symptom network (ISN)-based subtyping framework, leveraging a healthy control dataset (n = 3227) to model the normative symptom network. Based on the prominence of obsessive-compulsive (OC) symptoms within ISN (Expected Influence within ISN, EI), three OCD subtypes were identified in the discovery cohort (n = 238). Subtype 1 (39.50%) characterized by checking/obsessing, subtype 2 (6.30%) by ordering/washing and subtype 3 (54.20%) by hoarding, validated in another dataset (n = 79), the follow-up data from the discovery cohort (n = 109) and a subsample of the discovery cohort assessed using other OC symptom scale (n = 83). Nuroimaging analysis revealed distinct brain dynamics and morphometric similarity: subtype 1 exhibited more frequent transitions from the activated visual to frontoparietal control networks and higher morphometric similarity within the default mode network (DMN) compared to subtype 3. Subtype 2 exhibited increased regional intrinsic activity in the inferior frontal gyrus (opercular part) and the postcentral gyrus, with the lowest transitions from the activated somatomotor to the ventral attention networks. Subtype 1 also exhibited significantly higher morphometric similarity within the DMN and its connections to the dorsal/ventral attention networks compared to subtypes 2 and 3. Moreover, these neural features are associated with symptoms. Neurotransmitter-related subtype-specific dynamics to GABAa and μ-opioid, while transcriptomic analyses associated subtype-specific morphometric similarity with IL-1β and TNF-α. Together, biologically grounded 3 OCD subtypes based on EI exhibit replicability across time, samples and assessment scales and offer an individual framework for decoding OCD heterogeneity.
Atrophy in preclinical Alzheimer's disease maps to a network that predicts longitudinal decline.
Lee S, Baratono SR, Ha J … +12 more , Burt GT, Palm ST, Drew WJ, Zide BS, Chiulli NM, Lariviere S, Zhang S, Yeo BTT, Fox MD, Sperling RA, Donovan NJ, Siddiqi SH
Mol Psychiatry · 2026 Jun · PMID 42362770 · Publisher ↗
Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localiz...
Brain atrophy may precede cognitive and functional impairment in Alzheimer's disease (AD), but at this "preclinical" stage, it remains unclear whether atrophy localizes to specific brain networks and whether such localization is associated with clinical outcomes. We investigated cortical thickness in 1778 cognitively unimpaired (CU) older adults with amyloid-β (Aβ) PET from the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) and LEARN (Longitudinal Evaluation of Amyloid Risk and Neurodegeneration) studies, with a subset (N = 445) with tau PET. We estimated the networks disrupted by each individual's cortical thinning using a large normative connectome database (N = 1000), and tested whether this preclinical AD atrophy network is associated with clinical manifestations and longitudinal cognitive (PACC) and functional (CDR) trajectories. Distinct networks connected to atrophy patterns were associated with Aβ and regional tau in CU older adults. These networks were similar to a previously published atrophy network for AD dementia (Aβ: r = 0.817, P = 0.006; tau: r = 0.712, P = 0.046). Atrophy connectivity to this preclinical AD network was associated with higher Aβ and tau, independent of total cortical atrophy, and cross-sectionally with lower cognition, greater subjective cognitive decline, and increased anxiety; longitudinally, it predicted faster cognitive and functional decline over ~5 years. After tau adjustment, the functional-decline effect was preserved while the cognitive-slope effect was largely attenuated. Atrophy in preclinical AD localizes to a network resembling AD dementia, and is independently associated with AD pathologies, clinical outcomes, and longitudinal decline. Network-level neurodegeneration is detectable and clinically informative in preclinical AD, supporting future network-based research and therapeutic development.
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