Molecular Psychiatry[JOURNAL]
Sun
200 papers
Dynamic brain connectivity patterns induced by oxytocin: An fMRI Co-Activation pattern analysis study.
Klugah-Brown B, Li Y, Wu H … +5 more , Yang Z, Hagan AT, Agoalikum E, Wang P, Biswal BB
Mol Psychiatry · 2026 Mar · PMID 41876708 · Publisher ↗
Oxytocin (OT) is a neuropeptide widely implicated in emotional regulation and social cognition. However, its effects on dynamic brain connectivity remain poorly understood. In this study, we applied co-activation pattern...
Oxytocin (OT) is a neuropeptide widely implicated in emotional regulation and social cognition. However, its effects on dynamic brain connectivity remain poorly understood. In this study, we applied co-activation pattern (CAP) analysis to resting-state fMRI data to examine how a single intranasal dose of OT modulates whole-brain functional dynamics. Participants included healthy young (18-31 years) and older (63-81 years) adults, with analyses conducted at both the group level and across age subgroups. OT significantly altered temporal properties of brain states, including increased frequency, in-degree, and out-degree in multiple CAPs, indicating enhanced network flexibility and switching. Notably, OT modulated states involving the amygdala, medial prefrontal cortex, and salience network, regions critical for emotion regulation, and increased self-transition probabilities, suggesting greater within-state stability. Age-stratified analysis revealed differential sensitivity: young adults exhibited more pronounced modulation and greater dynamic flexibility, while older adults showed more sustained engagement with emotion-related states. Importantly, only in the elderly OT and combined young subgroups did time spent in these states significantly correlate with cognitive performance on the Digit Symbol Substitution Test, suggesting that OT-enhanced engagement in these networks supports compensatory mechanisms during aging. No such correlations were found in young participants or in either age group under placebo, highlighting the specificity of oxytocin's functional relevance in older adults. Meta-analytic decoding using Neurosynth confirmed that OT-modulated regions are closely associated with emotion, memory, and social cognition. These findings demonstrate that OT shapes transient brain dynamics in age- and function-specific ways. CAP analysis provides a powerful approach for capturing such neuromodulatory effects.
Anesthetics as emerging therapeutics for post-traumatic stress disorder (PTSD): bridging bench and bedside.
Mei X, Wu H, Yuan T … +6 more , Samsom JN, Ying S, Liu X, Xu T, Liu F, Shen Y
Mol Psychiatry · 2026 Mar · PMID 41876707 · Publisher ↗
Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that develops in the months and years following exposure to severe trauma. Despite growing research, there remain gaps in understanding the full path...
Post-traumatic stress disorder (PTSD) is a severe psychiatric disorder that develops in the months and years following exposure to severe trauma. Despite growing research, there remain gaps in understanding the full pathophysiology of PTSD, so that treatments are not universally effective, contributing to a significant public health burden. Therefore, it is necessary to explore novel therapeutic approaches. Anesthetics have recently been shown as a novel therapeutic agent with promising results in the treatment of PTSD. This review summarizes key mechanisms of anesthetics, including N-methyl-D-aspartate (NMDA) receptor antagonists, α2-adrenergic receptor agonists, Gamma-Aminobutyric Acid (GABA)-A Receptor-related anesthetics and opioids, and their translational potential to treatment of PTSD.
Neuroanatomy reflects individual variability in impulsivity in youth.
Dhamala E, Christensen E, Hanson JL … +8 more , Ricard JA, Arcaro N, Bhola S, Wiersch L, Brosch K, Yeo BTT, Holmes AJ, Yip SW
Mol Psychiatry · 2026 Mar · PMID 41876706 · Publisher ↗
Individual differences in neural circuits underlying emotional regulation, motivation, and decision-making are implicated in many psychiatric illnesses. Interindividual variability in these circuits may manifest, at leas...
Individual differences in neural circuits underlying emotional regulation, motivation, and decision-making are implicated in many psychiatric illnesses. Interindividual variability in these circuits may manifest, at least in part, as individual differences in impulsivity. Impulsivity reflects a tendency towards rapid, unplanned reactions to internal or external stimuli without considering potential negative consequences, coupled with difficulty inhibiting responses. Here, we use multivariate machine learning approaches (brain-based predictive models) to explore the neural bases of impulsivity. We consider multiple impulsivity measures, neuroanatomical features (cortical thickness, surface area, and gray matter volume, as well as non-cortical gray matter volume), and sexes (females and males) in a large sample of youth from the Adolescent Brain Cognitive Development (ABCD) Study at baseline (n = 8630), two-year follow-up (n = 5998), four-year follow-up (n = 4844), and six-year follow-up (n = 3100). Using brain-based predictive models, we demonstrate that regional variations in cortical thickness, surface area, and gray matter volume significantly predict self-reported impulsivity measures, with associations varying across impulsivity dimensions and developmental timepoints. Impulsivity broadly maps onto default mode, limbic, ventral attention, and visual networks, as well as cerebellar and brain stem structures. While many relationships are stable across sexes and developmental time points, others exhibit sex effects and dynamic changes. These results suggest that neuroanatomy is linked to self-reported impulsivity in youth and highlight the complexity of these relationships across measures, features, sexes, and time points. This work also emphasizes the importance of adopting a multivariate and sex-specific approach in neuroimaging and behavioral research.
A genome-wide investigation of depression among individuals with and without irritability.
St-Pierre J, Jang J, Nagy C … +5 more , Fiori L, Turecki G, Dupuis J, Bhatnagar SR, Orri M
Mol Psychiatry · 2026 Mar · PMID 41872521 · Publisher ↗
Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aime...
Individuals presenting with both depression and irritability may constitute a different group of individuals with respect to those presenting without irritability, but their biological differences remain unknown. We aimed to identify genetic variants associated with depression among individuals with and without irritability, highlight biological pathways, and test for genetic associations with other traits. We conducted a genome-wide association study (GWAS) using data from the UK Biobank (N = 487,409). We identified a group of individuals presenting with depression and reporting never having experienced irritability (depression without irritability, n = 35,857, 11.8%), and another with depression and reporting having experienced irritability (depression with irritability, n = 23,613, 8.1%) and compared them to controls with no depression or irritability (n = 268,012). The GWAS of depression without irritability identified 2 SNPs which reached genome-wide significance (P < 5×10; rs72795440 and rs1233494). The GWAS of depression with irritability (N = 292,485) identified 3 SNPs reaching genome-wide significance (rs2815748, rs102275, and rs7227069). When comparing SNPs between depression phenotypes, 15 SNPs had significantly different effect sizes. Patterns of genetic correlation with 44 complex traits were overall similar between the 2 depression phenotypes, with the highest genetic overlap observed with anxiety for depression without irritability (r = .77) and neuroticism for depression with irritability (r = .76). This study shed light into common and distinct biological factors characterizing depression among individuals with and without irritability and contribute to better understanding the genetic architecture of depression to potentially inform treatment and personalized medicine.
Uncoupling memory impairments from autism-associated behaviors in Chd2 deficient mice.
Yoon SH, Hunt RF
Mol Psychiatry · 2026 Mar · PMID 41872520 · Publisher ↗
Mutations in the chromatin remodeler, CHD2, are strongly associated with moderate to severe intellectual disability, autism and epilepsy, but the direct contribution of CHD2 mutations to clinical phenotypes is poorly und...
Mutations in the chromatin remodeler, CHD2, are strongly associated with moderate to severe intellectual disability, autism and epilepsy, but the direct contribution of CHD2 mutations to clinical phenotypes is poorly understood. We report developmental and sex-specific behavioral changes in mice carrying a heterozygous mutation in Chd2. Notably, Chd2 mutants display a range of abnormal behaviors including impairments in multiple forms of memory and social interaction. Memory impairments and memory-relevant transcriptional changes observed in Chd2 mice are largely recapitulated in both sexes by conditional Chd2 in adulthood. However, deficits in social behaviors and neuromodulatory system genes remain largely unaffected in conditional mutants. Reductions in interneuron density were identified throughout the brain of Chd2 mice, and the GABA positive allosteric modulator, L-838,417, was effective in treating abnormal social behavior. Our results suggest a postdevelopmental role for Chd2 in memory whereas neuropsychiatric conditions may be driven by more complex circuit mechanisms involving sexually dimorphic disruptions in brain development.
Global lifetime prevalence of schizophrenia: A systematic review and meta-analysis.
Zhang S, Chen Y, Zhang L … +7 more , Yang X, Dong J, Lu M, Zhou N, Feng Y, Zhang Y, Zhou Y
Mol Psychiatry · 2026 Mar · PMID 41872519 · Publisher ↗
BACKGROUND: Currently, studies on the lifetime prevalence of schizophrenia in the general population have not been updated or limited to a single country or region. The lifetime prevalence of schizophrenia may differ in...
BACKGROUND: Currently, studies on the lifetime prevalence of schizophrenia in the general population have not been updated or limited to a single country or region. The lifetime prevalence of schizophrenia may differ in other populations with certain relevant influencing factors or conditions. Globally, there is a lack of meta-analyses focusing on the lifetime prevalence of schizophrenia in specific populations. This study aims to determine the lifetime prevalence of schizophrenia in the general population, homeless populations, offenders, populations with comorbid mental disorders, populations with comorbid physical illnesses, populations at high genetic risk, populations exposed to stress, low-income populations, and indigenous populations, and to identify relevant factors. METHODS: Meta-analysis was used to estimate the combined lifetime prevalence of schizophrenia in the general population and eight other groups. To explore the sources of heterogeneity and identify factors associated with changes in prevalence, we conducted subgroup analyses of the general population, the homeless population, and the criminal population, examining geographic regions, sociodemographic factors, and methodological characteristics. Meta-regression in the general population examined the relationship between schizophrenia and mean age, publication year, and bias risk. RESULTS: 109 articles were included. Among them, 60 reported results from a sample of 20,910,871 individuals from the general population across 24 countries, 21 involved 6,605 individuals from the homeless population in 11 countries, there were 36 studies involving seven different population groups. The lifetime prevalence of schizophrenia is 0.62% (95% CI [0.51%-0.76%]) in the general population and 10.02% (95% CI [7.38%-13.47%]) in the homeless populations. Asia has the lowest lifetime prevalence of schizophrenia in both the general population and the homeless population, at 0.47% (95% CI [0.35%-0.64%]) and 4.68% (95% CI [2.11%-10.07%]). CONCLUSIONS: Findings indicate that schizophrenia is more prevalent in special populations than in the general population. Understanding and addressing the risk factors contributing to elevated prevalence in vulnerable populations is essential for developing targeted prevention strategies and improving early intervention efforts.
Interventions for negative symptoms in schizophrenia: efficacy and clinical interpretability in a meta-analysis of 451 randomized controlled trials.
Damiani S, Stefanelli R, Fortea L … +22 more , D'Imperio A, Calò M, Casarini F, Crippa A, Esposito CM, Leggi R, Orlandi M, Patron S, Peviani A, Piccolo A, Provenzani U, Santilli F, Spallarossa C, Papanastasiou E, Cella M, Patel R, Solmi M, Galderisi S, Leucht S, Stahl D, Radua J, Fusar-Poli P
Mol Psychiatry · 2026 Mar · PMID 41872518 · Publisher ↗
Negative symptoms (avolition, anhedonia, asociality, blunted affect, and alogia) are among the most disabling features of schizophrenia spectrum disorders. In the absence of treatment consensus guidelines, this PRISMA-co...
Negative symptoms (avolition, anhedonia, asociality, blunted affect, and alogia) are among the most disabling features of schizophrenia spectrum disorders. In the absence of treatment consensus guidelines, this PRISMA-compliant meta-analysis (PROSPERO: CRD42024613967) evaluated efficacy and clinical significance of interventions targeting this dimension. Web of Science/PsycInfo databases were searched from inception to December 2024. Five categories (antipsychotics, other pharmacological agents, brain stimulation, psychosocial, and lifestyle interventions) were analyzed across short/middle/long follow-up times. Categories were divided into 27 subcategories (e.g., 'other pharmacological agents' divided in 14 subcategories including antidepressants, antibiotics, immunomodulators) regardless of follow-up, assessing evidence with GRADE criteria. The primary outcome was the change in negative symptom severity, measured with validated scales (PANSS/SANS/BPRS/CAINS/BNSS) as standardized mean differences (SMD). A clinically meaningful SMD threshold was estimated from the regression between SMD and one-point reductions on the Clinical Global Impression-Severity (CGI-S) scale. This study meta-analyzed 451 trials (n = 42566). The clinically meaningful threshold, obtained from 122 trials reporting CGI-S, was SMD ≥ 0.457. In 214 high-quality studies (n = 19746), 2 category-by-follow-up combinations and 16 subcategories showed significant improvements. Clinically meaningful SMDs for subcategories were antibiotics (0.95; CI: 0.18-1.71; moderate-GRADE), integrated psychosocial interventions (0.93; CI: 0.53-1.33; very-low-GRADE), antidepressants (0.76; CI: 0.33-1.19; moderate-GRADE), physical activity (0.68; CI: 0.39-0.96; very-low-GRADE), transcranial current stimulation (0.52; CI: 0.17-0.86; low-GRADE), and immunomodulators (0.47; CI: 0.26-0.67; high-GRADE), typically as adjuncts to antipsychotics. Heterogeneity was the main limitation. While selected interventions may yield meaningful improvements, more rigorous designs are needed to identify reliable, personalized and scalable treatment options.
BDNF restores impaired long-term potentiation of GABAergic synapses induced by chronic ethanol exposure in the VTA and attenuates reward-seeking behavior.
Xiong JW, Dou MY, Wang Y … +11 more , Zeng T, Qi X, Wei JN, Shi XW, Cui DD, Dai HZ, Du CY, Xu XM, Wang XF, Zhu X, Guan Y
Mol Psychiatry · 2026 Jul · PMID 41872517 · Full text
Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic interm...
Cellular and synaptic plasticity in ventral tegmental area (VTA) play a key role in alcohol use disorder (AUD). Here, we first delineated the in vivo dynamics of dopamine (DA) neuron activity in VTA during chronic intermittent ethanol exposure: initial sensitization was followed by a phase of attenuated and dysregulated response upon the first high-concentration exposure, culminating in stable hyper-responsiveness. Chronic ethanol exposure impaired long-term potentiation of GABAergic synapses (LTP) on VTA DA neurons by reducing presynaptic GABA release, and induced lower levels of brain-derived neurotrophic factor (BDNF) expression in VTA. The impaired LTP recovered after 7 days of withdrawal, in parallel with a restoration of BDNF expression in the VTA. Using a combination of pharmacological and region-specific genetic knockdown approaches, we demonstrate that BDNF signaling through its receptor TrkB is both necessary and sufficient for LTP induction. Crucially, in VTA slices from chronic ethanol-exposed mice, BDNF application rescued the impaired LTP. In vivo, microinjection of BDNF into the VTA rapidly restored the hyperactive state of DA neuron activity induced by ethanol consumption (6 mice per group), an effect that was mimicked by the GABA receptor agonist muscimol and blocked by co-administration of either the TrkB antagonist K252a or the GABA receptor antagonist Gabazine. Furthermore, BDNF microinjection significantly attenuated cue-driven ethanol-seeking behavior (reducing the progressive ratio breakpoint by 52%; 6 mice per group), an effect depending on TrkB activation. Together, our findings reveal that chronic ethanol exposure impairs GABAergic plasticity via BDNF-TrkB signaling, while BDNF restores the impaired LTP and dynamics of DA neuron activity, and attenuates ethanol seeking, identifying a novel therapeutic target for AUD.
Paradoxical role of the mesocorticolimbic Netrin1-DCC pathway in social competition and vulnerability to methamphetamine abuse during adolescence.
Xu W, Zhong J, Ding L … +12 more , Jing H, Chen X, Pan T, Zhang B, Zhou R, Xu L, He J, Liu H, Liu T, Lu Z, Chen W, Zhu Y
Mol Psychiatry · 2026 Mar · PMID 41872516 · Publisher ↗
Social competition exerts a diverse set of influences on neural development and behavior during adolescence and yet the precise underlying molecular mechanisms remain poorly understood. Here, we demonstrate that individu...
Social competition exerts a diverse set of influences on neural development and behavior during adolescence and yet the precise underlying molecular mechanisms remain poorly understood. Here, we demonstrate that individual rodents that rank lower in social hierarchies are more vulnerable to drug abuse. Proteomic analysis revealed a crucial role of the mesocorticolimbic netrin-1/DCC/UNC5 pathway within the nucleus accumbens (NAc) in mediating the impact of social competition. We found that mice with a conditional knockout of the deleted in colorectal cancer (DCC) gene in dopamine neurons were more likely to achieve higher social rank but exhibited increased drug-seeking behaviors. Following dopamine fiber immunostaining, these outcomes were attributed to ectopic mesolimbic dopamine fibers, which enhanced risk-taking behavior in winners that had DCC knockout. Collectively, our work elucidates a molecular mechanism through which social competition influences adolescent brain development and behavior, particularly in relation to drug susceptibility.
NADPH oxidase-1 suppression prolongs the antidepressant-like effect of ketamine.
Nakajima W, Arisawa T, Jitsuki S … +15 more , Yamanoue T, Fujikawa K, Hara M, Sano A, Takada Y, Iai R, Kimura K, Suzuki M, Hatano M, Syed SA, Yajima A, Nagata M, Yatomi T, Abe H, Takahashi T
Mol Psychiatry · 2026 Jul · PMID 41872515 · Full text
Subanesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, produce rapid and robust antidepressant effects in patients with treatment-resistant depression (TRD). However, after a...
Subanesthetic doses of ketamine, a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist, produce rapid and robust antidepressant effects in patients with treatment-resistant depression (TRD). However, after a single administration, the therapeutic benefit is short-lived, and strategies to maintain its efficacy remain unclear. This study focused on the glutamate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), whose activation is known to be a key effector for the action of ketamine. Thus, we developed a novel positive allosteric modulator of AMPAR (K-4) with potential antidepressant-like effects. In Wistar Kyoto rats, a model of TRD, K-4 produced a more sustained antidepressant-like effect than ketamine. Bulk RNA sequencing analysis revealed that K-4-treated rats showed lower expression of NADPH-oxidase-1 (NOX-1) in the medial prefrontal cortex (mPFC) than in ketamine-treated rats. Furthermore, simultaneous administration of a NOX-1 inhibitor with ketamine prolonged the antidepressant-like effect and reduced burst firing in the lateral habenula (LHb). Similarly, short hairpin RNA knockdown of NOX-1 in the mPFC sustained the antidepressant-like effects of ketamine and suppressed LHb bursting activity. These results indicate that NOX-1 suppression prolongs the antidepressant-like effect of ketamine and represents a promising target for maintenance strategies in TRD.
Identifying genetic contributions of 6q21 loci and PPAR pathway to antipsychotic-induced metabolic syndrome: a Sex-Stratified Multi-Omics study.
Zhao G, Sun Y, Lu Z … +11 more , Kang Z, Yu T, Zhang Y, Sun J, Guo J, Feng X, Yuan R, Zhu Y, Yang Y, Cui M, Yue W
Mol Psychiatry · 2026 Jul · PMID 41865124 · Publisher ↗
Antipsychotics-induced metabolic syndrome (APs-induced MetS) is a common side-effect of antipsychotics, significantly increasing the risk of cardiovascular diseases and mortality. However, the genetic risk factors underl...
Antipsychotics-induced metabolic syndrome (APs-induced MetS) is a common side-effect of antipsychotics, significantly increasing the risk of cardiovascular diseases and mortality. However, the genetic risk factors underlying APs-induced MetS remain poorly understood. Thus, we conducted a sex-stratified genome-wide association study (GWAS) in 3067 patients from Schizophrenia In Non-Occidental participants (SINO) trial, and significant results were validated in an independent cohort (all samples = 200) and proteomic data. Post-GWAS analyses were used to further explore the genetic mechanisms involved in APs-induced MetS. Multi-omics prediction incorporating both polygenic risk and proteomic markers was conducted. After quality control, 1956 patients (965 males, 991 females) were included. We identified significant genetic variants (rs73762168; P = 1.77 × 10) on chromosome 6q21, associated with three highly linked genes, NR2E1, SNX3 and AFG1L/LACE1, which were correlated with APs-induced MetS in male patients. Top SNP genotype was validated in independent cohort, showing associations with increased weight and waist circumference. Enrichment analyses across genetic and proteomic data consistently highlighted the PPAR signaling pathway involved in oxidative stress and fatty acid metabolism as a key contributor to APs-induced MetS development. Proteomic analyses confirmed baseline SNX3 protein levels associated with weight gain (P = 0.03) and increased waist circumference (P = 8.87 × 10) following six-week antipsychotic treatment. The multi-omics prediction (R = 0.18) yielded better prediction of APs-induced metabolic side effects than using either marker alone(R = 0.13 or 0.07). This study provides novel genetic insights into the development of APs-induced MetS, particularly in males. The identified genetic variants and pathways offer potential targets for early risk prediction and personalized treatment strategies.
Comprehensive single-cell transcriptomic atlas of microglia in Alzheimer's disease mouse models.
Liu P, Sun T, Yang J … +14 more , Li H, Min W, Zhou X, Xiong R, Wu J, Huang Y, Li Y, Yuan M, Zhang J, Tan X, Song X, Zhang H, Wong ML, Zheng P
Mol Psychiatry · 2026 Jul · PMID 41865123 · Publisher ↗
Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a com...
Microglia are central mediators of neuroinflammation in Alzheimer's disease (AD), yet conserved microglial states and activation trajectories across AD mouse models remain incompletely defined. Here, we constructed a comprehensive Mouse Microglia Atlas (MoMicA) to resolve conserved subtypes, delineate dynamic trajectories, and identify key regulators associated with AD pathology. We integrated ten single-cell and single-nucleus RNA-sequencing datasets from major AD mouse models, yielding 84,764 microglia for harmonized clustering, co-expression network analysis, and pseudotime inference, complemented by immune staining. Across models, AD was characterized by contraction of homeostatic microglia and marked expansion of DAM. MoMicA further delineated refined homeostatic and disease-associated subpopulations, including different homeostatic microglia subclusters and a stepwise progression from homeostatic microglia through activated response and pre-disease-associated states to disease-associated microglia. Network analysis highlighted lipid metabolism and inflammation as dominant AD-related programs and identified Fabp5 as a central hub gene within a DAM-associated lipid module. Multiplex immunofluorescence confirmed that Fabp5 is induced in Clec7a-positive DAM around amyloid plaques in two amyloidosis models. MoMicA therefore provides a valuable resource for dissecting the mechanistic roles of microglia in the onset and progression of AD.
Large-scale proteomic analyses before depression diagnosis reveal novel pathophysiological insights.
Cheng B, Cheng S, Pan C … +6 more , Wei W, Feng J, Qi X, Zhao B, Wen Y, Zhang F
Mol Psychiatry · 2026 Jul · PMID 41862570 · Publisher ↗
BACKGROUND: The early pathophysiology of depression is poorly understood. We elucidated the decadal temporal evolution of plasma proteomic alterations before depression diagnosis and evaluated their associations with com...
BACKGROUND: The early pathophysiology of depression is poorly understood. We elucidated the decadal temporal evolution of plasma proteomic alterations before depression diagnosis and evaluated their associations with comorbid conditions and neuroanatomical changes. METHODS: This study analyzed 31,114 depression-free participants and identified 1555 incident depression cases after a median follow-up of 7.8 years. Cox regression was used to identify depression-associated proteins, adjusting for sociodemographic, lifestyle, and genetic factors. Subsequent analyses of depression-related proteins included exome-wide association analysis (EWAS), temporal change modeling of pre-diagnostic protein dynamics via LOESS regression, association analyses with eight comorbid conditions and 58 regional brain volumes, and LightGBM-based predictive modeling. RESULT: We found 64 depression-related proteins, with PIGR, HAVCR2, and IL4R validated in EWAS. For example, PIGR exhibited risk effects for depression (HR = 1.26, 95%CI: 1.13-1.40) and comorbid conditions, particularly diabetes (HR = 2.34, 95%CI: 2.12-2.58). Temporal profiling identified three protein clusters: one (cell-matrix adhesion) characterized by initial stability and subsequent decline, another (including PIGR and HAVCR2) characterized by MAPK cascade activation, and the third characterized by increased apoptosis and immune response. Neuroimaging correlations confirmed that elevated PIGR levels were associated with reduced volume in the bilateral ventral diencephalon (β = -0.062--0.061). A predictive model combined proteins and clinical features, achieving superior accuracy in depression prediction after 15 years (area under the curve = 0.74). Our findings reveal early peripheral pathophysiological changes in depression, suggesting a progression that may involve early apoptotic processes, an intermediate inflammatory phase, and later proteolytic dysregulation. CONCLUSION: These insights hold significant potential for developing early biomarkers and precision therapies.
Peripheral immune-redox signatures associate with cortical network alterations in anhedonic depression.
Liang S, Tan ZL, Ding J … +6 more , Dai Y, Xu Y, Ma J, Song XM, Yeo BTT, Li T
Mol Psychiatry · 2026 Jul · PMID 41862569 · Publisher ↗
Anhedonia is a core feature of major depressive disorder (MDD), yet links between peripheral molecular signatures and cortical network architecture remain poorly defined. We enrolled 210 participants, including 56 unmedi...
Anhedonia is a core feature of major depressive disorder (MDD), yet links between peripheral molecular signatures and cortical network architecture remain poorly defined. We enrolled 210 participants, including 56 unmedicated MDD patients with high-anhedonia (HA), 61 with low-anhedonia (LA), and 93 healthy controls (HC). Morphometric similarity networks (MSNs) from structural MRI were compared between HA and LA. MSNs index individual-level network organization by quantifying inter-regional morphometric similarity. Regional MSN patterns were linked to Allen Human Brain Atlas using Spearman correlations with spin tests and a multi-K stability screen. Whole-blood RNA-seq (n = 199) was integrated with MSN features via sparse partial least squares-canonical correlation (sPLS-C), with key blood analyses repeated after leukocyte-composition adjustment. Gene Ontology over-representation and MAGMA gene-level analyses provided pathway context. HA showed greater MSN integration than LA, particularly within default-mode and somatomotor networks. MSN maps were negatively correlated with dopamine-transporter and kappa-opioid-receptor densities. Imaging-derived gene associations were enriched for regulation of Toll-like-receptor-3 signaling. In blood, sPLS-C revealed coupling between MSN features and a transcriptomic signature enriched for T-cell activation/differentiation and lymphocyte-apoptosis pathways. After composition adjustment, the pre-specified blood signature did not differ between HA and LA, indicating that between-group differences were largely composition-driven. As supportive genetic context, over-representation on MAGMA FDR-significant genes suggested protocadherin-mediated homophilic adhesion. Peripheral immune-redox pathway enrichment aligns with anhedonia-related cortical network alterations, whereas between-group blood differences are chiefly composition-driven. Adjusting for blood-cell composition is essential, this multimodal framework nominates immune-modulatory/redox targets and synaptic-adhesion biology for precision stratification and intervention.
Elevated pre-supplementary motor area activity during reward expectancy: An impulsivity-related neural marker of vulnerability to bipolar and externalizing disorders.
Raeder R, Arora M, Bertocci M … +9 more , Chase HW, Skeba AS, Bebko G, Aslam HA, Graur S, Benjamin O, Wang Y, Stiffler R, Phillips ML
Mol Psychiatry · 2026 Jul · PMID 41857398 · Full text
Mania/hypomania is pathognomonic of bipolar disorder (BD), yet early identification remains challenging. Impulsivity is a key feature of mania/hypomania and of externalizing disorders that may predispose to BD, but neura...
Mania/hypomania is pathognomonic of bipolar disorder (BD), yet early identification remains challenging. Impulsivity is a key feature of mania/hypomania and of externalizing disorders that may predispose to BD, but neural markers of impulsivity-related risk remain unknown. This study aimed to identify reward expectancy (RE)-related neural correlates of impulsivity facets, test moderation by current affective/anxiety symptoms, and determine whether such markers differentiate BD and/or externalizing disorders from low impulsivity individuals. Two independent BD-risk samples aged 18-30 years, including individuals with prior externalizing disorder diagnoses but not BD, were recruited; a euthymic BD group was also recruited. Impulsivity facets were assessed via Behavioral Activation System (BAS) and UPPS-P scales. Whole-brain regressions identified neural correlates of impulsivity facets during RE. Linear models tested replication and current affective/anxiety symptom moderation. ANCOVA compared neural activity among BD, externalizing, and non-BD/externalizing impulsivity tertile groups. Whole-brain regressions revealed a positive association between BAS Fun Seeking and pre-supplementary motor area (pre-SMA) activity (p = 0.003, k = 167), which replicated when depressive symptoms were covaried (discovery: β = 2.73, p < 0.001; replication: β = 0.88, p = 0.036; combined: β = 1.49, p < 0.001). A significant pre-SMA × depression interaction (β = -0.08, p = 0.037) indicated depressive symptoms attenuated the pre-SMA-Fun Seeking association. Group comparisons revealed greater pre-SMA activity in high-Fun Seeking (p < 0.001) and externalizing disorder groups (p = 0.039) versus low-Fun Seeking, with similar trends observed in BD once individuals taking medications, particularly benzodiazepines (p = 0.012), were excluded. Pre-SMA hyperactivity during RE is a robust neural correlate of BAS Fun Seeking, moderated by depression severity. This pattern represents a trait-linked neural marker of impulsivity associated with vulnerability to BD and externalizing disorders, informing early risk identification and intervention.
Mechanistic insights into cannabidiol-mediated TrkB activation via FRS2 interaction in attenuating Alzheimer's disease pathology and cognitive impairment.
Liu J, Peng F, Li P … +7 more , Yao C, Jin S, Wu G, Zhang T, Liang Q, Wang X, Du X
Mol Psychiatry · 2026 Jul · PMID 41857397 · Publisher ↗
Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotecti...
Alzheimer's disease (AD) is characterized by progressive synaptic failure, neuroinflammation, amyloid and tau pathology, yet effective disease-modifying therapies remain limited. Cannabidiol (CBD) has shown neuroprotective potential in AD, but its direct molecular targets and signaling mechanisms remain unclear. Here, we demonstrate that CBD ameliorates cognitive and emotional deficits in 3×Tg-AD mice by restoring synaptic integrity and plasticity. At the mechanistic level, CBD activated TrkB signaling independently of BDNF, leading to suppression of tau hyperphosphorylation via the PI3K/AKT/GSK3β pathway and attenuation of neuroinflammation and amyloid pathology through inhibition of the JAK2/STAT3/SOCS1 axis. Using isothermal shift assays combined with biophysical binding analyses, we identified FRS2, a core adaptor protein of TrkB, as a direct molecular target of CBD. Molecular dynamics simulations further revealed that CBD stabilizes the FRS2-TrkB interface, thereby facilitating TrkB activation. Importantly, genetic knockdown of FRS2 abolished CBD-induced TrkB signaling and its downstream neuroprotective effects in both cellular and in vivo AD models. Together, these findings identify FRS2 as a critical signaling node mediating BDNF-independent TrkB activation by CBD and establish a mechanistic framework linking CBD to disease-modifying pathways in AD.
Autism spectrum disorder across the lifespan: Dynamic symptom trajectories and multidimensional support framework.
Wang Y, Lv R, Jiang Z … +10 more , Liu Y, Zhang J, Zhao Z, Liu Y, Zheng Y, Liu B, Clauw D, Sun J, Lu L, Yin Q
Mol Psychiatry · 2026 Jul · PMID 41851340 · Publisher ↗
Autism Spectrum Disorder (ASD) is a complex and highly heterogeneous neurodevelopmental condition, typically emerging in early childhood and persisting throughout life. Its core symptoms-social communication deficits and...
Autism Spectrum Disorder (ASD) is a complex and highly heterogeneous neurodevelopmental condition, typically emerging in early childhood and persisting throughout life. Its core symptoms-social communication deficits and restricted, repetitive sensory-motor patterns-exhibit dynamic trajectories across developmental stages, with distinct challenges arising at different ages. While substantial research efforts have been dedicated to pediatric ASD, the scientific focus remains comparatively limited for adult and geriatric populations, leaving their distinct needs less comprehensively addressed. This review begins with a concise overview of the epidemiology and etiology of ASD. We then examine age-dependent symptom evolution and associated challenges across the lifespan, from childhood to advanced age. Finally, we propose a stage-specific, individualized life-course support framework, outlining tailored strategies for distinct developmental phases. This framework transcends symptomatic management to empower functional resilience across the life trajectory, offering a roadmap for research and practice to serve the entire autism spectrum.
Cross-ancestry genetic architecture reveals shared biological pathways of major psychiatric disorders.
Feng Y, Jia N, Huang P … +2 more , Hu S, Yang S
Mol Psychiatry · 2026 Jul · PMID 41844800 · Publisher ↗
Psychiatric disorders, including bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), share substantial genetic overlap. We conducted a cross-ancestry multivariate genome-wide association stud...
Psychiatric disorders, including bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ), share substantial genetic overlap. We conducted a cross-ancestry multivariate genome-wide association study (GWAS) integrating European and East Asian populations to uncover shared genetic underpinnings. Our analyses identified 403 loci associated with shared polygenic liability to psychiatric disorders, including 88 novel regions. Cross-ancestry fine-mapping highlighted robust shared signals, notably at VRK2 (rs7596038), consistently significant across ancestries. Gene prioritization revealed 90 high-confidence candidate genes enriched in neurodevelopmental pathways. Single-nucleus RNA sequencing implicated excitatory neurons and astrocytes as key cellular contexts, emphasizing NCAM1-FGFR1 and NEGR1-NEGR1 signaling pathways. Mendelian randomization analyses provided causal evidence linking shared genetic liability to structural brain alterations, particularly in regions crucial for emotion and cognition. Polygenic risk scores derived from shared genetic liability substantially enhanced predictive accuracy for BD and SCZ, demonstrating strong trans-ancestry validity. These results advance understanding of shared genetic architecture in psychiatric disorders, highlighting potential therapeutic targets and emphasizing the critical importance of diverse ancestry studies in precision psychiatry.
Altered frontal and occipital cortical microstructure in obsessive-compulsive disorder - a multisite mega-analysis.
Thorsen AL, Brecke V, Alnæs D … +31 more , Mataix-Cols D, Kwon JS, Menchon JM, Abe Y, Sakai Y, Phillips ML, Hansen B, Hoexter M, Reddy J, Benedetti F, Brennan BP, Cheng Y, Denys D, Hirano Y, Koch K, Nakao T, Nurmi EL, Simpson HB, Piras F, Tolin DF, Stern ER, Wang Z, Buitelaar J, Morgado P, Beucke JC, Lochner C, Stein DJ, ENIGMA-OCD Working Group, OCD Brain Imaging Consortium, van den Heuvel OA, Ousdal OT
Mol Psychiatry · 2026 Jul · PMID 41833995 · Full text
Alterations in cortical morphology have consistently been reported in obsessive-compulsive disorder (OCD). However, the microstructural properties of the cortex in OCD, including intracortical myelination, remain far les...
Alterations in cortical morphology have consistently been reported in obsessive-compulsive disorder (OCD). However, the microstructural properties of the cortex in OCD, including intracortical myelination, remain far less explored. The contrast between signal intensity in gray and subjacent white matter from T1-weighted magnetic resonance imaging (MRI), i.e. the gray/white matter contrast (GWC), is linked to intracortical myelination and may offer novel insights into the cortical microstructure of OCD. Here, we compared multivariate patterns of GWC defined from an independent component analysis between 454 adults with OCD and 394 healthy controls from eight international sites. To contextualize GWC results with the macrostructure of gray matter in OCD, we also investigated the association between GWC and each individual's similarity with the pattern of gray matter morphology derived from ENIGMA-OCD using the Regional Vulnerability Index (RVI). Finally, we investigated the association of GWC with demographic and clinical characteristics of participants with OCD. Individuals with OCD showed significantly higher GWC in occipital and frontal regions relative to healthy controls. Moreover, OCD individuals had elevated OCD RVI, and individuals with a higher OCD RVI showed widespread higher GWC across the cortex. Finally, sexual/religious symptoms in OCD individuals were associated with higher GWC in frontal regions. In conclusion, we present new evidence of cortical microstructural alterations in OCD, with microstructural alterations relating to both the gray matter macrostructure and the clinical presentation of the disorder.
Multivariate relationships between social cognitive performance and functional connectivity during task and rest across schizophrenia spectrum disorders and healthy controls.
Oliver LD, Yu JC, Hawco C … +12 more , Calarco N, Tan V, Moxon-Emre I, Tang SX, Gold JM, Foussias G, DeRosse P, Argyelan M, Buchanan RW, Malhotra AK, Voineskos AN, and the SPINS Group
Mol Psychiatry · 2026 Jul · PMID 41820637 · Publisher ↗
Social cognitive deficits are common and impact functional outcomes in people with schizophrenia spectrum disorders (SSDs). Functional brain networks during task and rest show complex relationships with cognition. We aim...
Social cognitive deficits are common and impact functional outcomes in people with schizophrenia spectrum disorders (SSDs). Functional brain networks during task and rest show complex relationships with cognition. We aimed to identify relationships between social and non-social cognitive performance and functional connectivity during social processing and at rest across individuals with SSDs and healthy controls. Adults (N = 352; 195 SSDs, 157 controls) completed functional magnetic resonance imaging (fMRI) during the Empathic Accuracy (EA) task and rest, and cognitive assessments. Partial least squares correlation was used to identify latent dimensions (LDs) capturing multivariate relationships between functional connectivity and cognitive measures, evaluated using permutation testing, bootstrapping, and cross-validation. Two significant EA LDs were identified, explaining 73.6 and 9.1% of the variance. EA LD1 captured an association between better performance across cognitive measures and positive connectivity across networks implicated in processing dynamic multimodal and social stimuli. EA LD2 reflected an association between worse EA task performance and stronger positive connectivity between networks implicated in language and social processing. One significant resting-state LD was identified, explaining 85.6% of the variance and capturing an association between better overall cognition and visual, somatomotor, and subcortical connectivity, driven more by the SSD group. Overlapping and divergent connectivity patterns appear to covary with cognitive performance during social processing versus rest across SSDs and healthy controls. Our results support the value of task-based fMRI to identify dimensional functional connectivity patterns associated with particular social cognitive abilities, whereas resting-state connectivity may reflect broader relationships with cognition.
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