Transl Psychiatry [JOURNAL]
Sun
200 papers
The distinct effects of metabolic syndrome on negative symptoms and on antipsychotic therapy of schizophrenia involve insular volume, functional connectivity, and genetic polymorphisms.
Zhou J, Duan M, Jiang S … +12 more , Huang H, Wen F, Luo Y, Tang Y, He H, Yi Q, Vega MLB, Zhang L, Yao G, Klugah-Brown B, Yao D, Luo C
Transl Psychiatry · 2026 Jul · PMID 42386701 · Publisher ↗
As a prevalent comorbidity in schizophrenia, metabolic syndrome (MetS) exerts complex influences on residual symptoms and therapeutic outcomes of antipsychotic treatment. This study investigates the underlying neuroimagi...
As a prevalent comorbidity in schizophrenia, metabolic syndrome (MetS) exerts complex influences on residual symptoms and therapeutic outcomes of antipsychotic treatment. This study investigates the underlying neuroimaging, physiological and genetic mechanisms. At baseline, 142 participants were categorized into four groups according to diagnoses of schizophrenia and MetS. During follow-up, schizophrenia patients with and without MetS (SCZ-MetS and SCZ-nMetS) underwent 4-week antipsychotic treatment. Functional and structural magnetic resonance images, metabolic indicators and clinical scales were collected to investigate effects of MetS on gray matter volume (GMV), functional connectivity (FC) of schizophrenia patients, and related clinical implications. Using cytochrome P450 2D6 (CYP2D6) polymorphisms and brain-wide gene expression profiles, we explored genetic mechanisms of the therapeutic link between MetS and schizophrenia. SCZ-MetS showed greater insular GMV atrophy and functional dysconnectivity. Indirect effects of fasting blood glucose (FBG) on negative symptoms via insular GMV atrophy were observed. However, during follow-up, we observed group × time interactions on GMV and FC in insula. Increased GMV of the right insula in SCZ-MetS was correlated with the remission rate of positive symptoms. A moderation effect of FBG on this correlation was revealed. Finally, CYP2D6 polymorphisms and gene expression related to antipsychotic-response explained group × time interaction of GMV. Collectively, glucose metabolism, insular volume and FC underlie two distinct effects of MetS on: residual negative symptoms and therapeutic outcomes of positive symptoms in schizophrenia. The genetic mechanisms linking MetS to therapeutic outcomes involve CYP2D6 polymorphisms and the expression of genes related to antipsychotic-response.
Latent subdimensions of anxiety and depression differentially influence exertion of effort in pursuit of reward versus avoidance of threat.
Senta JD, Collins AGE, Dayan P … +1 more , Bishop SJ
Transl Psychiatry · 2026 Jun · PMID 42380135 · Publisher ↗
Anxiety and depression are highly comorbid. Across species, depression-related phenotypes have been linked to reduced willingness to expend effort to pursue rewards. Effortful threat avoidance has been less extensively s...
Anxiety and depression are highly comorbid. Across species, depression-related phenotypes have been linked to reduced willingness to expend effort to pursue rewards. Effortful threat avoidance has been less extensively studied. Here, we used a dimensional model of psychopathology to investigate whether distinct sub-dimensions of depressed and anxious affect differentially impact effortful reward pursuit versus threat avoidance in humans. Hierarchical Bayesian modeling revealed that component decision-making mechanisms underlying effortful reward pursuit were differentially impacted by latent dimensions capturing the depressive symptoms of apathy versus anhedonia. Meanwhile, only the latent dimension tapping worry-related symptoms significantly impacted effortful threat avoidance, increasing willingness to exert effort to avoid threat and reducing sensitivity to threat magnitude.
The cell-type specific interaction based drug repurposing for psychiatric disorders.
Tang Y, Zhou Y, Wei Z … +2 more , Wen Y, Peng C
Transl Psychiatry · 2026 Jun · PMID 42374032 · Publisher ↗
Psychiatric disorders severely challenge the public health, but the development of new psychotropic medications cannot keep pace with clinical needs. The rapid accumulation of single-cell RNA data provides opportunities...
Psychiatric disorders severely challenge the public health, but the development of new psychotropic medications cannot keep pace with clinical needs. The rapid accumulation of single-cell RNA data provides opportunities to develop new computational approaches of drug repurposing. However, there is a lack of dedicated computational tools for psychiatric disorders in this field. In this work, we developed a cell-type specific interaction based computational pipeline scPsyDrug to prioritize the drugs for psychiatric disorders. This tool integrated the single-cell transcriptomics, protein-protein interactions, drug-target interactions and psychiatric risk genes to construct cell type-specific interactions and seed genes for drug prioritization. We first evaluated the scPsyDrug performance using the publicly available single cell RNA datasets derived from the clinical patients, including Major Depressive Disorder, Schizophrenia and Parkinson's disease, in which scPsyDrug covered lots of approved drugs and clinical-trial compounds in the top recommended candidates. We next applied scPsyDrug to Zbtb18 mice, an anxiety-like mouse model, to screen the potential drugs. The scPsyDrug prioritized Forskolin and Chlorpropamide as the top candidates, while the following drug treatment demonstrated that these two compounds could respectively rescue the anxiety-like behaviors in Zbtb18 mice. We also used scPsyDrug to screen herb ingredients, and validated the efficacy of Osthole in rescuing the anxiety-like behaviors in the mouse model. Collectively, the scPsyDrug can be applied to different kinds of psychiatric disorders for drug repurposing, and we also provided experimental evidence for the potential roles of Forskolin, Chlorpropamide and Osthole in anxiety intervention.
Psychotropic drug-induced weight gain and untargeted metabolomics: machine learning-driven results from a prospective cohort study.
Piras M, Magliocco G, Ranjbar S … +13 more , Le Gludic S, Gasser M, Gamma F, Preisig M, Crettol S, Vandenberghe F, Ansermot N, Grandjean C, Dubath C, von Gunten A, Conus P, Thomas A, Eap CB
Transl Psychiatry · 2026 Jun · PMID 42364989 · Publisher ↗
Several psychotropic drugs can induce important weight gain. The present study aims to elucidate the metabolomic fingerprint of this adverse effect. From the Psymetab cohort, 151 follow-ups from 135 patients starting a w...
Several psychotropic drugs can induce important weight gain. The present study aims to elucidate the metabolomic fingerprint of this adverse effect. From the Psymetab cohort, 151 follow-ups from 135 patients starting a weight-inducing psychotropic drug were selected. Untargeted metabolomics analyses were applied to plasma samples collected at treatment baseline and at another time point during the follow-up. Dimension reduction and feature selection approaches such as Minimum-Redundancy/Maximum-Relevance coupled with a bootstrap of 5000 Least Absolute Shrinkage and Selection Operator were applied to select metabolic features associated with weight change per month of treatment. Our selection algorithm identified 56 metabolic features. Out of the 56, 10 were identified, of which 6 were confirmed by standard references. Consistent with previous studies, increases in the intensity changes of glycerophospholipids such as lysophosphatidylcholine (18:2/0:0), and tryptophan metabolites such as acetylkynurenine and 5-hydroxy-L-tryptophan were positively associated with weight change. Moreover, increases in the intensity changes of the amino acids citrulline and N-Acetyl-L-aspartic, and of the xanthine 1-methyluric acid and of the pyrimidine nucleoside uridine were positively associated with weight changes, whereas increases in the intensity changes of the amino acid glutamine and of the steroidal glycoside glycochenodeoxycholic acid 3-glucuronide were negatively associated with the outcome. The present study highlighted novel potential biomarkers for weight change under psychotropic treatment, confirming an alteration in the pathways of glycerophospholipids and tryptophan metabolites. These results emphasise the potential use of metabolomics for clarifying metabolic changes and for defining biomarkers with a prospective use in clinical practice.
The effects of propranolol and corticosterone on susceptibility priming in a mouse model of social defeat stress.
Manganaro A, Zhang JY, Zanni G … +2 more , Fillinger C, Dumitriu D
Transl Psychiatry · 2026 Jun · PMID 42362531 · Publisher ↗
Animal models for stress-related mood disorders aim to mirror the diverse spectrum of stress responses observed in humans, which ultimately determine an individual's susceptibility or capacity to cope effectively with th...
Animal models for stress-related mood disorders aim to mirror the diverse spectrum of stress responses observed in humans, which ultimately determine an individual's susceptibility or capacity to cope effectively with the stressor. The acute social defeat stress (ASDS) protocol allows a rapid phenotypic classification of mice subjected to social stress to interrogate the early neural patterns beyond divergent stress outcomes. Although ASDS alone does not cause chronic depression-like behaviors, it "primes" the mouse to be highly susceptible to a subsequent, subthreshold stress (StSDS). Here, we tested whether pharmacological manipulation shortly before ASDS can counter this susceptibility priming. Specifically, we examined the β-adrenergic receptor antagonist propranolol and the glucocorticoid corticosterone. Male mice received acute intraperitoneal injections of propranolol, corticosterone, or saline prior to ASDS, followed one week later by StSDS and social interaction testing. Propranolol partially prevented the emergence of social avoidance following subsequent StSDS, without modifying the behavioral outcome of ASDS. In contrast, corticosterone administered at different doses, failed to prevent susceptibility priming to later StSDS, disrupting also the typical acute ASDS behavioral profiling at low and medium doses. The results suggest that blocking β-adrenergic signaling during an acute stressor can reduce future stress susceptibility, while underscoring the complex and dose-dependent effects of glucocorticoids on stress responsivity.
The physiological foundation of extinction improvement by tDCS over the ventromedial prefrontal cortex (vmPFC) in healthy humans: an fMRI study.
Chhabra H, Ma Y, Genç E … +2 more , Nitsche MA, Yavari F
Transl Psychiatry · 2026 Jun · PMID 42362528 · Full text
A growing body of research highlights the fear extinction model as a key framework for understanding the pathology of anxiety disorders and developing therapeutic interventions. Functional imaging studies link successful...
A growing body of research highlights the fear extinction model as a key framework for understanding the pathology of anxiety disorders and developing therapeutic interventions. Functional imaging studies link successful extinction recall and reduced amygdala reactivity with ventromedial prefrontal cortex (vmPFC) activity, while dysfunctional vmPFC activity is associated with anxiety pathology. Enhancing vmPFC activity through transcranial direct current stimulation (tDCS) has thus emerged as a promising approach to augment cognitive behavioral therapy (CBT) and therapeutic exposure therapies for anxiety disorders. In this study, anodal tDCS was applied over the vmPFC during the extinction learning phase of a 3-day fear acquisition/extinction paradigm (anodal tDCS: 21, sham tDCS: 23 participants). Skin conductance response (SCR) and Blood Oxygenation Level Dependent (BOLD) brain activity were recorded simultaneously. Healthy participants who received real tDCS showed significantly improved extinction recall compared to the sham tDCS group, as indicated by the SCR. Fear acquisition activated core regions of the fear network, including the anterior cingulate cortex, amygdala, orbitofrontal cortex, and insular cortex. During extinction learning, real tDCS activated both fear and safety networks (particularly the posterior cingulate and middle temporal cortex) during early extinction, while the sham tDCS group showed activity only in the fear network. Furthermore, a decoupling of the vmPFC with fear network regions with real tDCS during extinction was observed, indicating strengthened inhibitory control. These findings suggest that anodal tDCS over the vmPFC promotes early activation of the safety network, enhancing extinction learning and consolidation. This suggests its translational potential as an adjunctive intervention for anxiety disorders.
Multi-ancestry multi-trait analysis reveals shared genetics across major psychiatric disorders and Alzheimer's disease.
Zheng X, Feng H, Ren L … +1 more , Zhang Y
Transl Psychiatry · 2026 Jun · PMID 42362520 · Publisher ↗
The clinical overlap between major psychiatric disorders (MPDs) and Alzheimer's disease (AD) implicates complex shared etiology. Previous studies demonstrated that both diseases are genetically complex and highly heritab...
The clinical overlap between major psychiatric disorders (MPDs) and Alzheimer's disease (AD) implicates complex shared etiology. Previous studies demonstrated that both diseases are genetically complex and highly heritable, suggesting that more endeavors are necessary to be made from the very bottom to understand their genetic basis. With the advance of post-genomic analysis, multi-ancestry meta-analysis allows the generalizability of the genetic architecture across different populations to uncover ancestry-specific variants, while multi-trait analysis enables the discovery of the co-colocalized risk genomic regions across diseases. Therefore, in this study, we leveraged published GWAS summary statistics from European, East Asian, Hispanic and African American populations to report schizophrenia, major depressive disorders, and Alzheimer's disease risk loci and further fine-mapping to credible sets with >95% PP inclusion of the causal variant. We distilled 2871 potential traits from publicly available and found 134 traits significantly genetically correlated with both MPDs and AD using batch LD score regression. We then prioritized the identified loci from multi-ancestry results for cross-trait colocalization analysis to assess shared genetic etiology and further nominated 2 colocalized loci across both conditions, including rs2532240 and rs6504163. In the end, we finalized our analysis by validation and functional inference of the underlying susceptibility genes as well as putative mechanisms using evidence from multiple resources, including FIVEx, Open Targets, and scQTLbase.
The relationship between renin-angiotensin system-modulating medication and depression: a systematic review.
Kulkarni S, Prasad D, Bauermeister S … +1 more , Reinecke A
Transl Psychiatry · 2026 Jun · PMID 42362518 · Publisher ↗
INTRODUCTION: The renin-angiotensin system (RAS) is implicated in stress, inflammation, and reward-related neurobiology, and RAS inhibition shows antidepressant-like effects in preclinical models. Whether angiotensin-con...
INTRODUCTION: The renin-angiotensin system (RAS) is implicated in stress, inflammation, and reward-related neurobiology, and RAS inhibition shows antidepressant-like effects in preclinical models. Whether angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are associated with depression outcomes in adults remains uncertain. METHODS: We searched MEDLINE, Embase, PsycINFO, APA PsycArticles, and AMED from inception to November 2024 for observational studies examining ACEI or ARB exposure and depression outcomes in adults. Risk of bias was assessed with the Quality in Prognosis Studies (QUIPS) tool. Due to methodological heterogeneity, no meta-analysis was performed, and findings were synthesised using structured direction of effect methods, with sensitivity synthesis restricted to studies at low risk of confounding. RESULTS: Fifteen studies involving more than 7 million participants were included. Eight studies reported protective associations between ACEI or ARB exposure and depression outcomes, six found no clear association, and one linked data cohort reported a modest increase in major depressive disorder with angiotensin antagonist monotherapy compared with patients not receiving antihypertensive treatment. Protective associations were more common in large registry cohorts using clinician-coded outcomes, whereas studies using symptom scales or prescription-based proxies were more often null. Among studies with stronger confounding control, findings were mixed. CONCLUSION: Observational evidence suggests a modest protective association between ACEI or ARB exposure and depression outcomes. However, heterogeneity in exposure and outcome definitions, together with residual confounding, limits causal inference. Prospective studies using bias-resistant designs and improved characterisation of incident depression, and better characterisation of drug-specific exposure are needed.
Metabolomic alterations in cord blood improve the prediction of childhood-onset neurodevelopmental disorders.
Girchenko P, Lahti-Pulkkinen M, Ni C … +5 more , Lahti J, Tian L, Airikka A, Kajantie E, Räikkönen K
Transl Psychiatry · 2026 Jun · PMID 42350403 · Publisher ↗
We aimed to identify cord blood metabolic measures associated with childhood-onset neurodevelopmental disorders (NDDs) and to examine whether they improve prediction beyond known early-life risk factors. In a prospective...
We aimed to identify cord blood metabolic measures associated with childhood-onset neurodevelopmental disorders (NDDs) and to examine whether they improve prediction beyond known early-life risk factors. In a prospective study of 858 children followed to a median age of 14.1 years (IQR 13.7-14.8), cord blood levels of 110 metabolic measures were assessed at birth and NDD diagnoses obtained from nationwide register. We identified 12 cord blood metabolic measures together explaining 5.0% of variance in any NDD, seven related to HDL synthesis, concentration and composition, one to concentration of lipoprotein particles, two to fatty acids and two to amino acids; their levels were 0.26-0.36(95%CI: -0.55, -0.06) standard deviations lower in the children who were later diagnosed with any NDD compared to the children with no mental disorders (p-value for overall model including all 12 metabolic measures <0.0001). They were also associated with early-life risk factors of NDDs, and improved the prediction of any NDD over a model that included only sociodemographic, prenatal and birth-related early-life risk factors(AUC = 0.74,95% CI 0.69-0.79; R2 = 16.6%; p < 0.0001 vs. AUC 0.71,95% CI, 0.66-0.76; R2 = 12.2%; p < 0.0001; Likelihood Ratio Test [LRT] p = 0.04). The improvement was more modest when the model additionally included maternal polygenic risk scores for ADHD and ASD (AUC = 0.75,95% CI 0.70-0.80; R2 = 18.3%; p < 0.0001 vs. AUC 0.72,95% CI, 0.67-0.78; R2 = 13.9%; p < 0.0001; LRT p = 0.08). Cord blood metabolic measures predicted NDDs diagnosed from birth through adolescence and improved prediction beyond early-life risk factors, with smaller incremental value when maternal PRSs for ADHD and ASD were included.
Expression patterns of risk genes associated with three evolutionarily relevant syndromes in rhesus macaque and human brains.
Karunakaran KB, Purushottam M, Balakrishnan N … +3 more , Viswanath B, Amemori KI, Jain S
Transl Psychiatry · 2026 Jun · PMID 42350389 · Publisher ↗
Depressive disorder (DD), Alzheimer's disease (AD), and schizophrenia (SZ) are evolutionarily relevant traits that disrupt neural networks supporting affect and cognition. While genome-wide association studies have ident...
Depressive disorder (DD), Alzheimer's disease (AD), and schizophrenia (SZ) are evolutionarily relevant traits that disrupt neural networks supporting affect and cognition. While genome-wide association studies have identified risk-related genes for these diseases, how the expression of these genes compare across species remains unclear. In this study, we examined the spatial and temporal expression of ~2000 disease-associated genes in human and rhesus macaque brains. Distinct cross-species signatures emerged. DD-linked genes showed broad cortical-subcortical expression in humans but were confined to subcortical regions in macaques. The divergent subset was enriched for neuron differentiation, migration, synaptic signalling, and cognition. SZ-linked genes were expressed across cortical-subcortical-cerebellar structures in humans. AD-linked genes showed postnatal cortical-hippocampal macaque expression, and broader cortical-subcortical human expression. Cross-species spatial comparisons revealed a significant negative correlation for DD genes, suggesting a broader spatial distribution of DD-related gene expression in humans, extending to distributed emotion-cognition networks, compared to affective hubs in macaques. SZ genes exhibited a similar, though non-significant, negative trend, while AD genes showed a weak, non-significant correlation, indicating an absence of systematic expression shifts. Together, evolutionary shifts in gene expression may have shaped emotional and cognitive functions in humans, and susceptibility to psychiatric and neurodegenerative disorders.
Comparative efficacy of dual- vs. single-node tACS in amnestic mild cognitive impairment: behavioral and EEG evidence.
Wang L, Li Y, Jiang Y … +7 more , Piao Z, Gu L, Zhu F, Kang A, Su H, Zhang J, Yan T
Transl Psychiatry · 2026 Jun · PMID 42350379 · Publisher ↗
The efficacy of current transcranial stimulation in cognitive disorders is limited by single-node intervention. Recent evidence indicates that amnestic mild cognitive impairment (aMCI) is associated with dysconnectivity...
The efficacy of current transcranial stimulation in cognitive disorders is limited by single-node intervention. Recent evidence indicates that amnestic mild cognitive impairment (aMCI) is associated with dysconnectivity in the frontoparietal network (FPN) and abnormal theta oscillations. Modulating the FPN with theta-frequency stimulation therefore represents a promising intervention for aMCI. We developed a noninvasive transcranial alternating current stimulation (tACS) protocol to modulate long-range theta interactions within the FPN in aMCI patients. Thirty patients with aMCI were randomly assigned to receive 10 sessions (2 mA, 6 Hz, 25 min per session) of either dual-node tACS applied over the right FPN (i.e., the dorsolateral prefrontal cortex, DLPFC, and the posterior parietal cortex, PPC) or single-node tACS over the right DLPFC alone. Participants also undergone EEG recordings during resting state, a 2-back working memory, and an associative memory task before and after intervention. Compared with single-node stimulation, dual-node stimulation produced more significant improvements in global cognition, as measured by Montreal Cognitive Assessment. Dual-node stimulation also enhanced resting-state theta power in dorsolateral and midline prefrontal cortices. Furthermore, dual-node stimulation was superior to single-site stimulation in improving memory performance and network dynamics. Specifically, it enhanced theta-gamma phase-amplitude coupling in right DLPFC during the working memory task and increased right frontal-to-parietal theta-phase synchronization during the associative memory task. This study provides preliminary evidence that dual-node tACS targeted over the FPN may offer behavioral and neurophysiological benefits over single-node stimulation in aMCI. Trial registration: Chinese Clinical Trial Registry, ChiCTR2200058652; Registration Date: 2022-03-13.
Single-nucleus transcriptomic atlas of sexually dimorphic molecular responses to sub-chronic variable stress in the mouse hippocampus.
Liang L, Yuan YP, Chang CL … +2 more , Zhang J, Liang C
Transl Psychiatry · 2026 Jun · PMID 42342683 · Publisher ↗
BACKGROUND: Major depressive disorder (MDD) exhibits a higher prevalence in women, yet the underlying cellular mechanisms for this clinical disparity remain elusive. To investigate sex-specific molecular mechanisms, we p...
BACKGROUND: Major depressive disorder (MDD) exhibits a higher prevalence in women, yet the underlying cellular mechanisms for this clinical disparity remain elusive. To investigate sex-specific molecular mechanisms, we profiled sex-specific molecular responses to sub-chronic stress in the mouse hippocampus at single-nucleus resolution. METHODS: Male and female C57BL/6N mice were exposed to sub-chronic variable stress (SCVS). Anhedonia was assessed via sucrose preference and novelty-suppressed feeding. We employed single-nucleus RNA sequencing (snRNA-seq) to map sex-specific hippocampal responses to sub-chronic variable stress (SCVS) in mice. RESULTS: Female mice displayed significantly exacerbated anhedonia and selective depletion of plasma serotonin (5-HT) following SCVS exposure, contrasting with minimal behavioral changes in males. Single-nucleus RNA sequencing of 31,256 hippocampal cells revealed profound sex-dimorphic transcriptional reprogramming: females exhibited a 3-fold greater number of differentially expressed genes (DEGs) than males with minimal overlap. Key mechanistic findings included: (1) Females exhibited oligodendrocyte-specific upregulation of mitochondrial genes (mt-Atp6, mt-Co3), increasing oxidative stress susceptibility. Concurrently, stress depleted their baseline oligodendrocyte predominance, potentially disrupting hippocampal synchrony underlying anhedonia.; (2) Females exhibit broad Mef2c upregulation, while males show astrocyte/cholinergic neuron NRG-1 upregulation and astrocyte Slc6a11 downregulation; (3) Females display suppressed oxytocin signaling and coordinated dampening of glutamatergic signaling, astrocytic K⁺ buffering, and cell adhesion; males exhibit dysregulated kinase/phosphatase activity. CONCLUSION: This study presents the single-nucleus atlas of hippocampal sexual dimorphism in stress response, identifying oligodendrocyte mitochondrial dysfunction, pan-cellular Mef2c upregulation, and oxytocin suppression as potential female-specific therapeutic targets for depression. Our findings reveal fundamental sex-divergent molecular adaptations to stress, providing a roadmap for novel, sex-stratified treatments for MDD.
Mechanistic insights toward dissociating therapeutic from psychedelic effects: bridging the gap between psychedelic research and mental health care.
Pettorruso M, d'Andrea G, Inserra A … +12 more , Cavallotto C, Censi S, Billard E, Di Stefano A, De Risio L, Tullo MG, D'Addario C, Di Lorenzo G, Wise RG, Sensi SL, Zoratto F, Martinotti G
Transl Psychiatry · 2026 Jun · PMID 42342649 · Publisher ↗
Clinical trials investigating psychedelic compounds for depression and anxiety-related disorders are yielding promising preliminary results. Psychedelics produce profound alterations in brain function-such as suppression...
Clinical trials investigating psychedelic compounds for depression and anxiety-related disorders are yielding promising preliminary results. Psychedelics produce profound alterations in brain function-such as suppression of the default mode network and thalamocortical dysregulation-leading to intense subjective experiences including ego dissolution and mystical-type states.While often described as meaningful or therapeutic, these effects can also be unpredictable or distressing. Because of these effects, which require labor-intensive, potentially cost-challenging preparation, administration, integration sessions, and exclude individuals with psychiatric vulnerabilities (e.g., bipolar disorder, borderline personality disorder, schizophrenia), questions remain about their real-world scalability. Consequently, there is growing interest in the possibility of dissociating the therapeutic benefits of psychedelics from their consciousness-altering effects.In this perspective, we examine emerging clinical and preclinical evidence investigating this scientifically timely and pressing question. Pharmacological strategies such as serotonin 2A receptor (5-HTR) antagonism and the development of "biased" psychedelic analogues or psychedelic-inspired compounds with reduced or null psychedelic potential may represent potential routes through which therapeutic efficacy may be retained even in the absence of psychedelic experiences. Current preclinical data suggest that downstream molecular and network-level mechanisms may mediate therapeutic effects independently of 5-HTR-driven subjective states.Whether these mechanisms can fully substitute for the experiential component of psychedelic therapy remains to be determined. Nonetheless, confirming this dissociation could mark a turning point in psychopharmacology, enabling the development of next-generation psychedelic-inspired treatments that may be more scalable, accessible, and appropriate for a broader range of psychiatric populations.
Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies.
Szlendak R, Bouquier N, Rzońca-Niewczas S … +7 more , Varrault A, Bouschet T, Rudzka-Dybała M, Górka-Skoczylas P, Lory P, Hoffman-Zacharska D, Perroy J
Transl Psychiatry · 2026 Jun · PMID 42342644 · Publisher ↗
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders associated with genetic mutations, including some in GRIN genes encoding NMDA receptor (NMDA-R) subunits. Despite affecting the...
Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders associated with genetic mutations, including some in GRIN genes encoding NMDA receptor (NMDA-R) subunits. Despite affecting the same receptor, each mutation may lead to distinct neurological disorders, emphasizing the necessity of understanding receptor dysfunction to tailor treatments effectively. In a genetic screen of DEEs patients, we identified a de novo pathogenic GRIN2B nonsense mutation, p.Glu839Ter (called GluN2B-E839*), which truncates the C-terminal domain (CTD) of the GluN2B subunit, a poorly characterized region critical for receptor function. This variant was prioritized for functional study due to the limited knowledge about the CTD's role. We fully characterized the clinical presentation of the patient, who displayed intellectual disability, epilepsy, and hyperkinetic behavioral disorders. Molecular and cellular analyses in heterologous systems and patient-derived neurons revealed that GluN2B-E839* subunit assembles correctly with other subunits to form NMDA-Rs but exhibits reduced surface expression, impaired interactions with PSD95, and altered biophysical properties, including reduced current amplitudes, increased magnesium sensitivity, and diminished calcium influx. These dysfunctions likely contribute to impaired synaptic plasticity and DEEs pathophysiology. Our findings highlight the critical role of the GluN2B CTD in NMDA-R function and neuronal signaling and underscore the need for systematic characterization of GRIN variants to improve diagnostic precision and therapeutic targeting for DEEs. This study establishes a robust framework combining complementary experimental approaches with patient-derived preclinical models to link molecular dysfunctions to clinical phenotypes.
Fluoxetine disrupts cholesterol metabolism in endothelial cells via SREBP2 activation.
Oliveira F, Papa C, Hagemann T … +26 more , Schipper R, Geier F, Röxe T, Zulfqar F, Prönnecke C, Schmidt L, Stryhanyuk H, Hoffmann A, Kyselova A, Karantanou C, Buckley Y, Farhan MA, Rodríguez-Aguilera JR, Ambreen S, Yao H, Arif A, Martin HNG, Ebert T, Klöting N, Blüher M, Shahzad K, Boeckel JN, Hagberg CE, Chakaroun R, Bibli SI, Sheikh BN
Transl Psychiatry · 2026 Jun · PMID 42337263 · Full text
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for the treatment of depressive disorders. Recent clinical reports and studies in animal models have suggested that fluoxetine increases t...
Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly prescribed for the treatment of depressive disorders. Recent clinical reports and studies in animal models have suggested that fluoxetine increases the risk of cardiovascular diseases, but the underlying mechanisms remain unknown. Here, we uncover that fluoxetine disrupts lipid and cholesterol metabolism in primary human endothelial cells (ECs). Fluoxetine triggered an upregulation of cholesterol metabolism genes, leading to the accumulation of lipid droplets in ECs. We find higher levels of cholesterol esters, ceramides, sphingolipids and fatty acids in ECs treated with fluoxetine. The disruption of lipid homeostasis was driven by increased cholesterol biosynthesis, as well as low-density lipoprotein (LDL) uptake and transcytosis via the LDL receptor. Fluoxetine accumulated in ECs in the endoplasmic reticulum (ER), caused ER expansion and reduced protein translation, without inducing ER stress markers. Mechanistically, fluoxetine activated the SREBP2 transcription factor in an INSIG-dependent manner. SREBP2 inhibition attenuated the fluoxetine-mediated upregulation of the LDL receptor and lipid accumulation. Our findings reveal that fluoxetine reprograms lipid metabolism and leads to endothelial dysfunction.
Decomposing neuroanatomical heterogeneity in depression: insights from an ENIGMA major depressive disorder working group study in 5146 individuals.
Sempach L, Ulrich S, Bauduin SEEC … +88 more , Bauer J, Benedetti F, Berger K, Besteher B, Bülow R, Connolly CG, Corruble E, Couvy-Duchesne B, Cullen KR, Dannlowski U, Davey CG, Dima D, Dols A, Evans JW, Fu C, Fuentes-Claramonte P, Gonul AS, Gotlib IH, Goya-Maldonado R, Grabe HJ, Groenewold NA, Grotegerd D, Gruber O, Hahn T, Hamilton JP, Han LKM, Harrison BJ, Hatton SN, Hermesdorf M, Hickie IB, Ho TC, Hubbert JM, Jahanshad N, Jamalabadi H, Jamieson AJ, Jurischka C, Jüllig A, Kamishikiryo T, Kircher T, Koopowitz SM, Krämer B, Kraus A, Krieger J, Krug A, Lagopoulos J, Li M, McIntosh A, Meinert S, Melloni EMT, Mwangi B, Nenadic I, Ojha A, Okada G, Oudega ML, Penninx BWJH, Poletti S, Pomarol-Clotet E, Portella MJ, Reneman L, Rodriguez-Cano E, Sacchet M, Salvador R, Schrantee A, Shinzato H, Sim K, Slump TM, Soares JC, Stein DJ, Stein F, Teutenberg L, Thomas-Odenthal F, Thomopoulos SI, van der Wee NJA, van der Werff SJA, Völzke H, Walter M, Whalley HC, Whittle S, Wittfeld K, Wu MJ, Yang TT, Zarate C, Zunta-Soares GB, Thompson PM, Veltman DJ, Pozzi E, Schmaal L, Schmidt A
Transl Psychiatry · 2026 Jun · PMID 42337246 · Publisher ↗
The clinical and biological heterogeneity of major depressive disorder (MDD) may reflect the aggregation of different conditions with distinct pathologies under a single diagnostic label. Neuroanatomical heterogeneity in...
The clinical and biological heterogeneity of major depressive disorder (MDD) may reflect the aggregation of different conditions with distinct pathologies under a single diagnostic label. Neuroanatomical heterogeneity in MDD was examined using a harmonized, age- and sex-matched sample from the ENIGMA MDD consortium (N = 5146; age range: 9-82 years; 64% female). Analyses of global neurostrucutral variability revealed greater cortical thickness heterogeneity in MDD compared with healthy controls (Cohen's d = -0.26). Regionally, increased variability in cortical thickness was most prominent in the cingulate (+6.1 to +6.6% more variation in MDD) and insular (+5.8%) cortices, as well as in the frontal (+5.7 to +6.8%) and temporal (+6.1 to +6.8%) lobes. Heterogeneity in cortical thickness was more pronounced among patients using antidepressant medication (Cohen's d = -0.39). Patient-specific analyses further showed that individuals with markedly increased cortical thickness variability (<5 percentile relative to the normative range) exhibited greater depressive symptom severity than those within the normative range (5-95 percentile; Cohen's d = 0.19-0.36). Overall, the results indicate that neuroanatomical heterogeneity in MDD is primarily expressed in cortical thickness, offering refined insights into the neurobiological complexity of structural alterations associated with depression. These findings could guide future stratification efforts examining whether regionally confined changes in cortical thickness within areas of pronounced variability reflect clinically meaningful patient subgroups.
Transcranial direct current stimulation for perioperative depression in breast cancer surgery: a randomized controlled trial.
Zan W, Zhou M, Qi Y … +6 more , Wang R, Chen J, Zu C, Li X, Zhou T, Wang L
Transl Psychiatry · 2026 Jun · PMID 42336829 · Publisher ↗
IMPORTANCE: Perioperative depression is a psychological disorder prevalent in patients undergoing breast cancer surgery and is primarily characterized by feelings of depression or a lack of interest. There is a paucity o...
IMPORTANCE: Perioperative depression is a psychological disorder prevalent in patients undergoing breast cancer surgery and is primarily characterized by feelings of depression or a lack of interest. There is a paucity of effective interventions for these conditions. Transcranial direct current stimulation (tDCS) has shown potential in the treatment of various depression-related disorders. OBJECTIVE: To investigate the efficacy of tDCS in alleviating perioperative depression in patients undergoing breast cancer surgery. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial was conducted between December 17, 2024, and March 28, 2025, in the Xuzhou Central Hospital. Patients aged 18 years or older undergoing elective breast cancer surgery were randomly assigned to either the active tDCS group or the sham tDCS group. Intention-to-treat data analysis was performed in April 2025. INTERVENTIONS: Patients were randomly assigned to receive 2 sessions of either active tDCS or sham tDCS over the left dorsolateral prefrontal cortex. Interventions were delivered daily, each morning, starting one day prior to surgery and continuing until the fifth postoperative day. Assessments of perioperative depression levels and sleep quality were conducted at baseline, the 5th day and 1st month after surgery. Additionally, the incidence of adverse reactions and postoperative NRS scores were evaluated. MAIN OUTCOMES AND MEASURES: The main outcome was HAMD-17(Hamilton Depression Rating Scale 17 items) scores on days 5 and 1 month after surgery. The secondary outcomes included the following: 1. BDI-13(Beck Depression Inventory 13 items) scores on days 5 and 1 month after surgery. 2. PSQI(Pittsburgh sleep quality index) on days 5 and 1 month after surgery. 3.NRS (Number Rating Scale) scores at rest and active states before surgery and 1-5 days after surgery. 4. Postoperative adverse reactions (end of the operation to the 5th day after the operation). RESULTS: A total of 64 patients were recruited and randomly assigned to the active tDCS group (32 patients) or the sham tDCS group (32 patients). Following the intervention, the active tDCS group showed a HAMD score of 4.67(1.75), which was significantly lower than that of the sham tDCS group's 6.37(2.99) (P = 0.01). The active tDCS group showed significantly lower NRS scores than the sham tDCS group (P < 0.001). The active tDCS group had a PSQI score of 3.57(1.59), which was significantly lower than that of the sham group (4.87(2.37); P = 0.016). Additionally, a significant difference (P = 0.018) was observed in the incidence of postoperative nausea and vomiting between the two groups. CONCLUSIONS AND RELEVANCE: tDCS can accelerate depressive symptoms relief during acute recovery and offer short-term benefits for early postoperative patients. The lack of group difference at 1 month reflects continued improvement in the sham group, not waning of the active effect. tDCS is a nonpharmacological adjunct to accelerate early recovery after breast cancer surgery. TRIAL REGISTRATION: Chinese Clinical Trial Register Identifier: ChiCTR 2500104410.
Regulation of oligodendrocyte metabolism and myelination by acetyl-L-carnitine in a mouse model of post-weaning social isolation.
Yang HJ, Park YH, Kim D … +4 more , Lee A, Park M, Koh E, Lee G
Transl Psychiatry · 2026 Jun · PMID 42331788 · Publisher ↗
Adolescent social stress can impair myelination and increase vulnerability to psychiatric symptoms. We investigated whether acetyl-L-carnitine (ALC), a metabolite linking energy and lipid metabolism, regulates oligodendr...
Adolescent social stress can impair myelination and increase vulnerability to psychiatric symptoms. We investigated whether acetyl-L-carnitine (ALC), a metabolite linking energy and lipid metabolism, regulates oligodendrocyte (OL) myelination and rescues behavioral deficits in a post-weaning social isolation (PWSI) mouse model. In vitro, ALC uptake and conversion through the OCTN2/CrAT axis promoted myelin sheath expansion without affecting OL precursor proliferation or early differentiation. ALC activated ERK signaling, increased histone acetylation, promoted PPARγ nuclear translocation, and selectively enhanced mitochondrial respiration in mature OLs. In vivo, oral ALC supplementation restored social preference and medial prefrontal cortex MBP expression in PWSI mice, whereas cuprizone co-administration abolished these effects, suggesting that the therapeutic effects of ALC are closely associated with its impact on myelination. Lipidomic analysis of the corpus callosum showed that ALC restored PWSI-induced changes in fatty acid chain length and unsaturation. These findings identify ALC as a metabolic regulator that restores social isolation-induced myelin deficits by coordinating myelin protein synthesis, mitochondrial function, and myelin lipid remodeling. ALC may therefore provide a metabolic strategy for targeting myelin-related neurodevelopmental and psychiatric disorders.
taVNS alleviates depressive-like and metabolic dysfunction in T2DD mice with modulation of hypothalamic 5-HT signaling.
Zhang Y, Zhou Q, Zou N … +3 more , Xin C, Rong P, Li S
Transl Psychiatry · 2026 Jun · PMID 42331787 · Publisher ↗
Type 2 diabetes mellitus and depression are mutually reinforcing, yet combined pharmacotherapy is limited by side effects and poor tolerability. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive...
Type 2 diabetes mellitus and depression are mutually reinforcing, yet combined pharmacotherapy is limited by side effects and poor tolerability. Transcutaneous auricular vagus nerve stimulation (taVNS) is a non-invasive neuromodulatory approach with emerging metabolic and antidepressant potential, although its central mechanisms remain unclear. Here, we investigated whether hypothalamic serotonergic signaling is involved in the dual effects of taVNS in a mouse model of type 2 diabetes with depression (T2DD). T2DD was induced in db/db mice by chronic unpredictable mild stress, followed by taVNS intervention (2/15 Hz, 1 mA, 30 min/day for 3 weeks). Behavioral performance, body weight, and fasting blood glucose were assessed, while brain-wide neuronal activity was mapped using fluorescence micro-optical sectioning tomography (fMOST). Hypothalamic 5-HT release was monitored by fiber photometry, and 5-HT content and 5-HT₁A receptor expression were quantified by ELISA and Western blotting. TaVNS significantly reduced body weight and fasting blood glucose, alleviated depression-like behaviors, and improved locomotor activity. Brain-wide mapping revealed state-dependent modulation of neuronal activity, characterized by widespread activation under physiological conditions and suppression of stress-induced hyperactivation in T2DD. Notably, taVNS induced robust hypothalamic 5-HT release, increased long-term 5-HT levels, and upregulated 5-HT₁A receptor expression. Correlation analyses further linked enhanced hypothalamic serotonergic signaling to improved glycemic control and behavioral outcomes. These findings suggest that hypothalamic 5-HT signaling may contribute to the dual metabolic and antidepressant effects of taVNS and highlight its potential as an integrative neuromodulatory intervention for metabolic-psychiatric comorbidity.
Linking electric field directionality to treatment outcome in OCD: Insights from patient-specific tDCS modeling.
Gosez J, Germaneau A, El Houari K … +6 more , Bokam P, Rochette M, Langbour N, Guillevin R, Jaafari N, Harika-Germaneau G
Transl Psychiatry · 2026 Jun · PMID 42331786 · Publisher ↗
Transcranial direct current stimulation (tDCS) is a promising intervention for treatment-resistant obsessive-compulsive disorder (OCD), yet clinical outcomes remain inconsistent. To investigate the neural mechanisms unde...
Transcranial direct current stimulation (tDCS) is a promising intervention for treatment-resistant obsessive-compulsive disorder (OCD), yet clinical outcomes remain inconsistent. To investigate the neural mechanisms underlying therapeutic variability, we conducted a patient-specific finite element (FE) modeling study of electric fields (EF) induced by tDCS in OCD patients. Forty-two patients from a double-blind, randomized clinical trial received active tDCS with the cathode over the pre-supplementary motor area and the anode over the right supraorbital region. Clinical response was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and responders were defined as those achieving ≥35% score reduction. Individual head models were created using SimNIBS, and current density directionality () and magnitude () were analyzed. Voxel-wise comparisons revealed significantly greater depolarization (> 0) in the left anterior prefrontal cortex (BA10) and right frontal eye field (BA 8) associated with a reduction of Y-BOCS. A link between hyperpolarization of right pars orbitalis (BA47) and improvement in symptoms was also found. Notably, no significant findings emerged using EF magnitude (), underscoring the relevance of current directionality in treatment response. To our knowledge, this is the first study to associate directional EF modeling with clinical outcomes in OCD. Our findings highlight the importance of considering both EF direction and anatomical variability when optimizing tDCS protocols. This approach may contribute to more personalized and effective neuromodulation strategies for psychiatric disorders.
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