Transl Psychiatry [JOURNAL]
Sun
200 papers
Abnormal left prefrontal N100 and its relationship with fronto-limbic metabolism in major depressive disorder.
Lin SW, Wang YF, Lin HC … +8 more , Juan CH, Yang BH, Romorodi R, Noda Y, Cheng CM, Jeng JS, Bai YM, Li CT
Transl Psychiatry · 2026 Jun · PMID 42236682 · Publisher ↗
Dysfunction within inhibitory GABAergic systems is implicated in the pathophysiology of major depressive disorder (MDD). The N100, a transcranial magnetic stimulation-evoked potential (TEP), reflects inhibitory neural pr...
Dysfunction within inhibitory GABAergic systems is implicated in the pathophysiology of major depressive disorder (MDD). The N100, a transcranial magnetic stimulation-evoked potential (TEP), reflects inhibitory neural processes mediated by GABA-B receptors. Yet, the relationship between the N100, stress levels, and cerebral glucose metabolism in MDD remains under-investigated. We sought to elucidate the fundamental processes of frontal inhibitory function by examining the left prefrontal N100 in patients with MDD and healthy controls (HCs). Sixty-six patients with MDD and 20 HCs were recruited; the N100 component was derived from single-pulse TEPs targeting the left dorsolateral prefrontal cortex. Patients were stratified into low-severity (score ≤ 16) and high-severity (score ≥17) groups based on the 17-item Hamilton Depression Rating Scale (HDRS-17). Cerebral metabolic activity was estimated using 18F-FDG PET standardized uptake values (SUVs). N100 amplitudes were significantly greater in the low-severity depression group compared to HCs (p = 0.002) and exhibited a positive correlation with daily life stress exclusively in HCs (r = 0.653, p = 0.002). In the MDD group, higher N100 amplitudes were associated with increased SUVs in the prefrontal cortex (p = 0.037) and inversely correlated with SUVs in the right middle temporal cortex, right inferior parietal cortex, and middle cingulum (SVC-corrected p < 0.05). Furthermore, N100 amplitudes correlated positively with the number of treatment failures specifically in the non-treatment-resistant depression (nTRD) subgroup. These data indicate that the N100 is significantly associated with depression severity and may represent a dynamic, compensatory neurophysiological mechanism aiming to restore the excitatory/inhibitory balance in response to aberrant fronto-limbic metabolism.
Glutamate- and GABA-targeted drugs for Cc-occurring bipolar and alcohol use disorders: a randomized, double-blind, placebo-controlled, crossover study of N-acetylcysteine, gabapentin, and placebo.
Prisciandaro JJ, Mellick WH, Hix S … +3 more , Brand K, Tolliver BK, Anton RF
Transl Psychiatry · 2026 Jun · PMID 42236678 · Publisher ↗
Forty percent of people with bipolar disorder (BD) develop alcohol use disorder (AUD), with co-occurring AUD substantially worsening the course of BD. Though efficacious treatments remain elusive, frontal glutamate and G...
Forty percent of people with bipolar disorder (BD) develop alcohol use disorder (AUD), with co-occurring AUD substantially worsening the course of BD. Though efficacious treatments remain elusive, frontal glutamate and GABA dysregulation represent promising targets for intervention. This study evaluated the ability of two adjunctive medications, N-acetylcysteine (NAC) and gabapentin, to modulate glutamate and GABA (primary) and to reduce heavy drinking and depressive symptoms (exploratory) in people with BD + AUD. Fifty-four individuals meeting DSM-5 criteria for BD + AUD were enrolled in a randomized, double-blind, placebo-controlled, crossover study, with 3, 1-week conditions (NAC, gabapentin, placebo). Medication effects on dorsal anterior cingulate cortex (dACC) glutamate+glutamine (Glx) and GABA levels, via proton MR spectroscopy, and percent heavy drinking days (%HDD) and depressive symptoms were evaluated with linear mixed models. Forty-nine participants (M[SD] age=41.0[12.2], 51% female, 74% white) provided 121-131 posttreatment-MRI scans, depending on analysis. Medications were well-tolerated, and adherence was excellent. DACC Glx (F = 4.76, p = 0.012) but not GABA (F = 0.96, p = 0.388) levels significantly differed across conditions, with only NAC (M[SD] = 21.50[2.55]) demonstrating significantly different(lower) glutamate levels relative to placebo (M[SD] = 22.59[2.56]; p = 0.003; SMD = 0.43). %HDD (F = 3.90, p = 0.025) also significantly differed across conditions, again with only NAC (M[SD] = 31.86[4.60]) demonstrating significantly different(lower) %HDD relative to placebo (M[SD] = 40.94[4.55]; p = 0.015; SMD = 0.33), though neither NAC (p = 0.128) nor gabapentin (p = 0.228) differed from placebo on depressive symptoms. These results support the development of mechanistic clinical trials targeting glutamatergic dysfunction in people with BD + AUD. Trial Registration: https://clinicaltrials.gov/study/NCT03220776.
Male Sapap3 knockout mice show threat bias under conflict during platform-mediated avoidance task: effects of extinction with response prevention and implications for obsessive compulsive disorder.
Manning EE, Crummy EA, Pierson JL … +4 more , LaPalombara Z, Li X, Manikandan S, Ahmari SE
Transl Psychiatry · 2026 Jun · PMID 42236491 · Publisher ↗
Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive thoughts (obsessions) and repetitive rituals aimed at avoiding aversive outcomes (compulsions), which interferes with patients'...
Obsessive compulsive disorder (OCD) typically involves cycling between symptoms of intrusive thoughts (obsessions) and repetitive rituals aimed at avoiding aversive outcomes (compulsions), which interferes with patients' lives. This relationship between obsessions and compulsions highlights a potential role of impaired threat processing and avoidance in OCD symptoms. Platform mediated avoidance (PMA) has proven to be a useful rodent paradigm to examine avoidance neurobiology and OCD-relevant constructs, such as exposure with response prevention (ERP) and persistent avoidance. However, the ERP protocol has only been used in rats, and studies in OCD-relevant transgenic mouse models may shed further light on neural mechanisms relevant to the disorder. To address this gap, we tested male Sapap3 knockout (KO) mice, a leading preclinical model in OCD research, using PMA with ERP. We examined avoidance acquisition, expression, and extinction, as well as reward-seeking under motivational conflict, in separate cohorts conditioned using high or low intensity shock. Sapap3-KOs exhibited heightened suppression of lever pressing for rewards and elevated freezing during a warning tone signaling impending footshocks, suggesting greater threat sensitivity under motivational conflict. Avoidance responding was acquired more slowly and extinguished more robustly following ERP in Sapap3-KOs trained with lower-intensity shock only. c-Fos expression showed preliminary evidence for decreased activity of medial orbitofrontal cortex (mOFC) in KOs, which may mediate post-ERP reduction of threat responses. Together these findings suggest that mOFC changes may contribute to therapeutic effects in OCD, and that dysfunction in mOFC may contribute to increased influence of threats (vs rewards) over action selection in OCD.
Plasma short-chain fatty acid concentrations in social anxiety disorder and changes after cognitive behavioral therapy.
Cai W, Stiernborg M, Wolthon A … +5 more , Landberg R, Manzouri A, Furmark T, Lavebratt C, Månsson KNT
Transl Psychiatry · 2026 Jun · PMID 42236485 · Full text
Emerging evidence indicates that the gut microbiota are linked to variation in social behavior and anxiety, with short-chain fatty acids (SCFAs) proposed as key microbial metabolites that may mediate microbiota-brain com...
Emerging evidence indicates that the gut microbiota are linked to variation in social behavior and anxiety, with short-chain fatty acids (SCFAs) proposed as key microbial metabolites that may mediate microbiota-brain communication. Cognitive behavioral therapy (CBT) is an effective treatment for social anxiety disorder (SAD), but it remains unclear whether gut microbiota changes following treatment. In this longitudinal study, 46 individuals with SAD underwent nine weeks of internet-delivered CBT. Plasma concentrations of nine SCFAs were measured using liquid chromatography-mass spectrometry: twice at pre-treatment, once at post-treatment and once at a 36-month follow-up in patients, with > 80% data completeness. Healthy controls (n = 42) underwent two SCFA assessments 11 weeks apart. Generalized additive mixed models were used to assess longitudinal changes with CBT, linear mixed models for patient-control differences, and intraclass correlation coefficients for test-retest reliability. CBT led to significant reductions in social anxiety symptoms, and effects were sustained at 36 months follow-up. Plasma concentrations of butyric, isobutyric, propionic, and valeric acids increased after CBT, with trajectories predominantly explained by time rather than individual variability. Before CBT, isobutyric acid was statistically significantly lower in SAD patients, relative to healthy controls. These findings provide initial evidence that sustained therapeutic benefits of CBT may be linked to alterations in circulating microbial metabolites, as indexed by lower isobutyric acid in SAD patients at pre-treatment, and increases in isobutyric, butyric, propionic and valeric acids after therapy. Lifestyle factors were not assessed but may have contributed to the observed long-term metabolic changes.
Translational pathways of oxytocin therapy in schizophrenia: bridging negative symptom domains and neural mechanisms.
Ji L, Wang X, Li Y … +5 more , Zhao W, Du X, Gao Y, Li J, Liu S
Transl Psychiatry · 2026 Jun · PMID 42236472 · Publisher ↗
Negative symptoms of schizophrenia, characterized by motivational deficits, diminished hedonic experience, and impaired affective expression, remain a major therapeutic challenge. Oxytocin, a neuropeptide with central ne...
Negative symptoms of schizophrenia, characterized by motivational deficits, diminished hedonic experience, and impaired affective expression, remain a major therapeutic challenge. Oxytocin, a neuropeptide with central nervous system activity, has emerged as a promising therapeutic target due to the close alignment of its functions with the pathophysiological mechanisms underlying negative symptoms. Based in the dimensional model of negative symptoms, this review systematically synthesizes advances in understanding the physiological functions of the oxytocin system and its therapeutic potential for negative symptoms in schizophrenia, with a focus on its multi-target neural mechanisms. Oxytocin exerts its effects through coordinated modulation of multiple neural circuits: enhancing mesolimbic dopamine pathway function to improve social reward processing and facilitating motivation via the prefrontal-striatal circuit, while stabilizing the amygdala-prefrontal emotional circuit and modulating the sensorimotor integration network and prefrontal motor pathway to ameliorate affective expression deficits. Current evidence highlights the therapeutic potential of oxytocin; however, clinical findings demonstrate marked heterogeneity, suggesting that its translation still requires overcoming multiple challenges. Future research should integrate genetic, neuroimaging, and behavioral paradigms to identify oxytocin-sensitive subtypes, optimize administration strategies, and coordinate behavioral interventions, thereby advancing the translation of oxytocin toward precision psychiatry in schizophrenia.
Dup15q model mice exhibit impaired gastrointestinal motility and a constipation-like phenotype, alleviated by prucalopride.
Balasuriya GK, Tamada K, Nomura J … +2 more , Cirillo C, Takumi T
Transl Psychiatry · 2026 Jun · PMID 42230559 · Publisher ↗
Chromosome 15q duplication syndrome (Dup15q) is a neurodevelopmental disorder linked to autism spectrum disorder (ASD), involving increased copies of the 15q11.2-q13 region. About 80% of individuals with Dup15q experienc...
Chromosome 15q duplication syndrome (Dup15q) is a neurodevelopmental disorder linked to autism spectrum disorder (ASD), involving increased copies of the 15q11.2-q13 region. About 80% of individuals with Dup15q experience gastrointestinal (GI) dysfunction, including constipation. The duplicated region encodes GABA receptor A subunits, affecting GABAergic signalling, while reduced serotonin (5-HT) levels impair neuronal activity and social behaviour in a mouse model of Dup15q (15q dup). Given that both GABA and serotonin are expressed in the enteric nervous system (ENS), this study investigates gastrointestinal dysfunction in a Dup15q mouse model and the potential role of Prucalopride (pre-existing 5-HT4 receptor agonist). Colon RNA extracts were analysed for GABA receptor subunit and serotonin-associated gene expression using quantitative PCR. Total GI transit was assessed by Carmine red dye gavage. Ex vivo colonic motility was analysed via video imaging. The GABA receptor A antagonist Bicuculline was used to assess GABAergic signalling. Prucalopride, a 5-HT4 receptor (5HT4R) agonist, was administered for six days, and its effects on GI transit and social interaction were evaluated. 15q dup mice exhibited elevated GABA receptor gene expression and reduced Tph2 and Htr4 expression in the colon. Total GI transit was delayed, and ex vivo colonic motility was slower and less extensive. Bicuculline further impaired colonic contractions, indicating enhanced GABAergic sensitivity. Prucalopride restored GI transit delays and improved social interaction, as evidenced by increased contact duration in social tests. 15q dup mice exhibit constipation-like gastrointestinal dysfunction, and prucalopride alleviated their delayed transit and improved social behaviour. These findings highlight a potential avenue for symptom-focused intervention in this model.
Myo-inositol concentration in the medial prefrontal cortex is associated with changes in brain white matter microstructure in early psychosis.
Pavan T, Wang Q, Alemán-Gómez Y … +10 more , Jenni R, Cleusix M, Alameda L, Q Do K, Conus P, Hagmann P, Steullet P, Klauser P, Xin L, Jelescu I
Transl Psychiatry · 2026 Jun · PMID 42230558 · Publisher ↗
Recent research highlights the critical role of white matter (WM) alterations in psychosis and schizophrenia (SZ), reporting volumetric and structural brain changes in affected individuals. In this study, we explored the...
Recent research highlights the critical role of white matter (WM) alterations in psychosis and schizophrenia (SZ), reporting volumetric and structural brain changes in affected individuals. In this study, we explored the role of astroglia in SZ, which is believed to play a role in white matter integrity. We investigated for the first time the associations between advanced diffusion Magnetic Resonance Imaging (dMRI) measures of WM microstructure and Magnetic Resonance Spectroscopy (MRS)-derived glial markers in 30 subjects with early psychosis (EP, mean age 24 ± 6) versus 49 healthy controls (HC, mean age 25 ± 6). We focused on two metabolites involved in glia: myo-Inositol (myo-Ins) and total Choline (tCho), measured in the medial prefrontal cortex (mPFC), relating them to quantitative dMRI metrics derived from Diffusion Kurtosis Imaging (DKI) and WM Tract Integrity-Watson (WMTI-W) biophysical model, including mean diffusivity and kurtosis, axonal water fraction and extra-axonal diffusivities in the whole white matter. Our findings reveal a difference between EP and HC in WM diffusivities, specifically in the extra-axonal parallel direction, but not in MRS metabolites. However, we found that the mPFC myo-Ins concentrations in EP are exclusively and strongly associated with proximal WM microstructure features, in the form of a positive correlation with axonal water fraction, a proxy for axonal density, and a negative correlation with extra-axonal parallel diffusivity, suggesting the white matter alterations could be linked to astrocytic changes in early psychosis.
Constipation is associated with an increased risk of depression: A systematic review and meta-analysis of observational studies.
Ren ZY, Guo ZY, Diao Q … +3 more , Hashimoto K, Yang JJ, Zhang GF
Transl Psychiatry · 2026 Jun · PMID 42230550 · Publisher ↗
BACKGROUND: Constipation is a prevalent functional gastrointestinal disorder that impairs quality of life and is frequently accompanied by psychological distress. Emerging evidence suggests a potential association betwee...
BACKGROUND: Constipation is a prevalent functional gastrointestinal disorder that impairs quality of life and is frequently accompanied by psychological distress. Emerging evidence suggests a potential association between constipation and depression, possibly mediated by gut-brain axis dysfunction; however, epidemiological findings remain inconsistent. METHODS: We conducted a systematic review and meta-analysis of observational studies examining the association between constipation and depression in the general population. PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to October 1, 2025. Random-effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity, prediction intervals, subgroup analyses, sensitivity analyses, and publication bias were assessed. RESULTS: Eighteen studies involving 730,263 participants were included. Constipation was significantly associated with an increased risk of depression (OR = 2.08, 95% CI: 1.84-2.34), with substantial heterogeneity (I² = 92.6%). The association remained robust across sensitivity analyses. Stronger associations were observed in adolescents, in studies conducted in Asia and North America, in smaller studies, and in those using self-reported depression measures. Prediction interval analyses indicated a consistently positive association across diverse populations. CONCLUSIONS: This meta-analysis provides robust evidence that constipation is associated with a significantly increased risk of depression. These findings highlight the importance of integrated gastrointestinal and mental health care, particularly for younger individuals with chronic constipation, and support further prospective and mechanistic studies targeting the gut-brain axis.
An integrative mendelian randomisation and drug mechanism framework for target prioritisation and therapeutic repurposing in major depression.
Ter Kuile AR, Finan C, Chopade S … +7 more , van Vugt M, Hukerikar N, Barral S, Stringaris A, Schmidt AF, Kuchenbaecker K, Pingault JB
Transl Psychiatry · 2026 Jun · PMID 42230543 · Publisher ↗
Major depression (MD) treatments have limited efficacy and target few mechanisms, highlighting the need for innovative drug discovery. Drugs targeting genetically supported proteins are 2.6 times more likely to succeed i...
Major depression (MD) treatments have limited efficacy and target few mechanisms, highlighting the need for innovative drug discovery. Drugs targeting genetically supported proteins are 2.6 times more likely to succeed in drug development. Here, we use genetic methods to identify and prioritise MD drug targets, leveraging genome-wide association study (GWAS) summary statistics from >525,000 MD cases. We derived exposure data from 10 datasets measuring protein quantitative trait loci (pQTLs) and gene expression levels (eQTLs) in blood, cerebrospinal fluid, and brain tissues. We performed cis-Mendelian randomisation (MR) on 3469 druggable targets (genes encoding proteins targeted by existing compounds or experimentally predicted to be druggable). To strengthen causal inference, we implemented robust MR estimators, colocalisation, external replication, and assessed directional consistency across tissues. We integrated cis-MR effect directions with drug mechanisms and clinical annotations to infer potential therapeutic effects. Validation analyses showed that 82% of drugs approved for depression/anxiety had ≥1 significant MR target, compared to 51% for compounds in clinical trials. For repurposing, we prioritised 54 targets of compounds developed for other conditions with estimated beneficial effects on MD (e.g., an inhibitor for a risk-increasing target). Ten high-priority targets of brain-penetrating compounds included ACE and NISCH (cardiovascular drugs), NDUFA2, NDUFB6, and NDUFS1 (metformin), CDK4, NTRK3, and MET (oncology inhibitors), and GLS and NOS2 (enzyme inhibitors). We found genetic evidence for established and novel MD targets across the drug development pipeline. Novel targets point to mechanisms beyond monoaminergic systems, most with approved drugs for other conditions, offering immediate repurposing opportunities.
Sex-specific associations of depression with inflammatory markers: a systematic review and meta-analysis.
Szabo YZ, Nishimi K, Smirnova M … +7 more , Niles A, Lerche AS, Tsai HA, Afroz S, Huey N, Mathur M, O'Donovan A
Transl Psychiatry · 2026 Jun · PMID 42230540 · Publisher ↗
INTRODUCTION: Converging evidence implicates elevated inflammation in the pathophysiology of depression and its medical comorbidities. Despite known sex differences in both inflammatory activity and depression, a dedicat...
INTRODUCTION: Converging evidence implicates elevated inflammation in the pathophysiology of depression and its medical comorbidities. Despite known sex differences in both inflammatory activity and depression, a dedicated large-scale review of these differences is lacking. METHODS: We conducted a sex-stratified systematic review and meta-analysis of studies examining associations between depression and blood-based inflammatory markers in adult humans. Searches of PubMed, PsycINFO, and Scopus, and reference treeing, yielded 124 eligible papers including data from 423,421 participants (53% female). Analyses focused on depression and inflammatory markers C-reactive protein (CRP), interleukin (IL)-6, tumor necrosis factor (TNF)-α, IL-1β, and fibrinogen. Sex-stratified meta-analyses and meta regressions for the effects of sex were conducted, separately for cross-sectional and longitudinal designs. RESULTS: Cross-sectionally, depression was modestly associated with higher levels of all markers combined in both females (Cohen's d = 0.06, 95% CI [0.03-0.10]) and males (Cohen's d = 0.14, 95% CI [0.09-0.19]). Depression was associated with elevated IL-6 in females, and elevated CRP and IL-6 in males. Longitudinally, elevated IL-6 was associated with subsequent depression among females and elevated CRP was associated with depression in males, whereas depression was not associated with subsequent inflammation in either sex. CONCLUSION: Overall, results indicated modest associations between depression and elevated inflammation in both sexes, with slightly stronger associations in males. Associations between specific inflammatory markers (i.e., IL-6 in females and CRP in males) and subsequent depression differed by sex. These findings highlight the cross-sex relevance of inflammation in depression, and subtle sex differences in directionality and specific markers.
Shared genetic architecture and pathways linking major depressive disorder and autoimmune thyroid disease: insights from common and rare variants.
Liu S, Zeng Y, Xiao L … +13 more , Wu Y, Hou C, Yang H, Wei M, Tang Y, Huang Y, Liu Y, Ma Q, Yin Y, Zhang M, Chen Y, Song H, Wang Q
Transl Psychiatry · 2026 Jun · PMID 42225622 · Publisher ↗
Major depressive disorder (MDD) and autoimmune thyroid disease (AITD) frequently co-occur, yet the genetic factors underlying their comorbidity remain unclear. We performed a population-matched cohort study from the UK B...
Major depressive disorder (MDD) and autoimmune thyroid disease (AITD) frequently co-occur, yet the genetic factors underlying their comorbidity remain unclear. We performed a population-matched cohort study from the UK Biobank to evaluate the phenotypic association between MDD and AITD. Genetic correlation, causal relationships, and pleiotropic loci/genes shared between the diseases were assessed based on common variants using genome-wide association study (GWAS) summary statistics, complemented by individual-level validation through polygenic risk score analysis. We additionally performed an exome-wide association analysis using the UK Biobank 450k whole-exome sequencing (WES) release to identify disease-specific risk genes from rare variants. Findings from common and rare variants were integrated and subjected to pathway enrichment, protein-protein interaction (PPI) and transcription factor (TF) analyses to locate functional modules. In the cohort study, MDD and AITD were associated with a 2.8-fold increased risk of developing the other condition. We confirmed a modest but statistically significant positive genetic correlation (r = 0.14, P = 2.96 × 10) and confirmed the absence of a direct causal relationship. Integrative pleiotropy analyses identified 14 pleiotropic loci mapped to 58 shared genes. Gene ontology, TF enrichment and PPI analyses of disease-specific and shared genes revealed that the genetic signals converge on shared modules involving T-cell receptor signaling, thyroid hormone metabolic process and neurodegeneration, prioritized by key immune-inflammatory and neuro-developmental regulators. Our findings provide a molecular framework for MDD-AITD comorbidity, highlighting specific pathways as potential targets for integrated therapeutic strategies.
Nociceptin/orphanin FQ receptor agonism attenuates behavioral and neural responses to conditioned aversive stimuli.
Hur KH, Pizzagalli DA, Stover J … +2 more , Cayetano K, Kohut SJ
Transl Psychiatry · 2026 May · PMID 42218133 · Publisher ↗
The nociceptin/orphanin FQ peptide (NOP) receptor has emerged as a promising anxiolytic target, as its activation has been shown to reduce anxiety-related behaviors in rodents. However, the mechanisms underlying these ef...
The nociceptin/orphanin FQ peptide (NOP) receptor has emerged as a promising anxiolytic target, as its activation has been shown to reduce anxiety-related behaviors in rodents. However, the mechanisms underlying these effects are not well understood. Here, we investigated the effects of the selective NOP receptor agonist SCH-221510 (0.01-0.1 mg/kg, IM) on behavioral and neural responses to aversive stimuli in squirrel monkeys (n = 3). Subjects underwent Pavlovian fear conditioning, wherein a visual conditioned stimulus (CS) was paired with the presentation of an aversive stimulus. Event-related functional magnetic resonance imaging (fMRI) was conducted in awake subjects to evaluate CS-evoked neural responses. Behavioral and neural responses to the CS were assessed across three experimental phases: pre-conditioning (Pre-C), post-conditioning (Post-C), and Post-C with SCH-221510 administration. In behavioral assessments, CS presentation during Post-C elicited a robust suppression of ongoing operant responding, which was absent during Pre-C and significantly attenuated by SCH-221510 treatment (0.1 mg/kg). fMRI results revealed that, relative to Pre-C, CS presentation during Post-C was associated with increased BOLD activity in brain regions previously implicated in fear processing (e.g., amygdala), expression and regulation (e.g., prefrontal cortex; PFC), as well as sensory integration (e.g., visual cortex). Critically, SCH-221510 (0.1 mg/kg) administration significantly attenuated CS-induced neural activation in these regions. Furthermore, resting-state functional connectivity analysis revealed that SCH-221510 administration decreased connectivity between PFC and amygdala, while enhancing connectivity among PFC subregions. Collectively, these findings suggest that NOP receptor agonism may attenuate conditioned responses to aversive stimuli by modulating functional interactions within a PFC-amygdala circuit.
MIR1255A regulates pathways critical for brain development, risk genes for depression and neurodevelopmental disorders.
Feng Y, Wigg KG, Barr CL
Transl Psychiatry · 2026 May · PMID 42218122 · Publisher ↗
Multiple lines of evidence implicate microRNAs (miRNAs) in major depressive disorder (MDD), including the location of miRNAs genes (MIRs) within genomic regions identified by genome wide association studies (GWAS). To in...
Multiple lines of evidence implicate microRNAs (miRNAs) in major depressive disorder (MDD), including the location of miRNAs genes (MIRs) within genomic regions identified by genome wide association studies (GWAS). To investigate the role of MIRs in the genetic risk for MDD, we identified all associated single nucleotide polymorphism (SNPs) that were expression quantitative loci (eQTLs) for MIRs in brain tissues. Our analyses identified four MIRs having associated eQTLs in the credible SNP set (variants near a genetic association signal predicted to include causal variants). Based on pathway analyses of the predicted targets, we selected MIR1255A for functional studies and overexpressed it in human neural precursor cells (NPCs) to identify target genes in neural cells. Transcriptome analyses of the transfected cells identified 343 differentially expressed (DE) genes at an adjusted p (FDR) <0.05 and an additional 276 DE genes at adjusted p < 0.1 (total 619 genes). Of these, 14 genes were supported as genetic risk genes by fine mapping by GWAS (representation factor 1.8, p < 0.025), with additional genes implicated in risk from biological studies (altered expression or serum levels in individuals with MDD, animal models). Notably, 157 DE genes were implicated in neurodevelopmental disorders (representation factor 1.5, p < 3.31E-07). Gene set enrichment analyses of DE genes revealed the top categories as neurogenesis, generation of neurons, regulation of cell differentiation and neuron development. These findings support MIR1255A as regulator of processes critical for neurodevelopment and a contributor to genetic risk for depression.
Emotion regulation impairment across psychiatric disorders: a systematic review and meta-analysis.
Sloan ME, Stellern J, Xiao KB … +9 more , Germeyer A, Gill K, Laputsina V, Mulsant BH, Ngoy A, Nguyen M, Tang VM, Sanches M, Gowin JL
Transl Psychiatry · 2026 May · PMID 42215453 · Publisher ↗
Psychiatric disorders are among the leading contributors to the global burden of disease. Impaired emotion regulation has been hypothesized to be a transdiagnostic feature of psychiatric disorders, but this has not been...
Psychiatric disorders are among the leading contributors to the global burden of disease. Impaired emotion regulation has been hypothesized to be a transdiagnostic feature of psychiatric disorders, but this has not been proven across all classes of psychopathology. We sought to systematically review and meta-analyze emotion regulation impairment across major psychiatric disorders to determine if impairment is truly transdiagnostic. Selected studies compared healthy controls and individuals with a psychiatric disorder. Emotion regulation was assessed by the Difficulties in Emotion Regulation Scale (DERS), the Emotion Regulation Questionnaire (ERQ), and two other scales. Differences between cases and controls were estimated using Hedges' g for each disorder and scale. 188 studies were included, representing 563 case-control comparisons across 15 diagnoses with 11,201 cases and 9609 controls. For the DERS, case-control differences were large and significant for all 12 disorders analyzed, with effect sizes ranging from 0.94 (95% CI: 0.67-1.21) for bipolar disorder to 2.55 (95% CI: 2.28-2.83) for borderline personality disorder (BPD); BPD had a significantly larger case-control effect size than most other disorders. For the ERQ, use of cognitive reappraisal (an adaptive form of emotion regulation) was reduced in all disorders except panic disorder and use of expressive suppression (a maladaptive form of emotion regulation) was greater in all disorders except ADHD and OCD. Overall, individuals with major psychiatric disorders demonstrated reduced capacity to regulate their emotions across diagnoses and measures, suggesting that interventions which improve emotion regulation could be beneficial to prevent or treat many psychiatric disorders.
Differences in how NMDA antagonists modulate negative affective biases in male rats may serve as a predictor of clinical efficacy in major depressive disorder.
Hinchcliffe JK, Kamenish K, Bartlett J … +3 more , Arban R, Hengerer B, Robinson ESJ
Transl Psychiatry · 2026 May · PMID 42215446 · Publisher ↗
Affective biases shape cognitive and emotional behaviour and are important in major depressive disorder (MDD). Modulation of affective biases by the NMDA antagonist, ketamine, may underlie its antidepressant effects but...
Affective biases shape cognitive and emotional behaviour and are important in major depressive disorder (MDD). Modulation of affective biases by the NMDA antagonist, ketamine, may underlie its antidepressant effects but not all NMDA antagonists are efficacious. Some studies suggest ketamine's efficacy involves non-NMDA mechanisms e.g. via its active metabolite HNK (2R, 6R)-hydroxynorketamine), but an alternative hypothesis is that pharmacodynamic differences relating to ion trapping and/or affinity may be relevant. This study used a rat model of affective biases to investigate how different NMDA antagonists influence retrieval of a negatively biased memory, both acutely (<60 min) and ~24 h post-treatment. We compared compounds tested clinically (lanicemine, memantine, CP101,606), reference antagonists with different pharmacodynamic profiles (phencyclidine, PCP; ephenidine), and HNK. PCP, lanicemine, and ephenidine but not CP101,606 acutely attenuated negative biases. At 24 h, these effects were sustained for CP101,606 and ephenidine with a trend towards inducing a positive bias. Lanicemine's effects were sustained only at high doses and PCP and memantine had no effects. HNK looked like ketamine but only at doses higher than those achieved through metabolism of the effective ketamine dose. These findings suggest that sustained modulation of affective biases, particularly when the treatment facilitates re-learning with a more positive affective valence, correlates with therapeutic efficacy. Based on preliminary findings using reference NMDA antagonists, differences in antidepressant efficacy may relate to ion trapping properties. Very high or very low ion trapping appear less effective than intermediate compounds like ketamine and ephenidine or subunit-selective antagonists like CP101,606.
Lac-Phe elicits anxiolytic-like effects associated with monoaminergic signaling in mice.
Suzuki S, Chiba K, Kanzaki H … +10 more , Takahashi H, Yamazaki Y, Takahashi N, Naoi M, Kise R, Inoue A, Tsuzuki K, Seto Y, Nakamura TJ, Kaneko K
Transl Psychiatry · 2026 May · PMID 42215433 · Publisher ↗
Anxiety disorders are a growing public health concern in modern societies burdened with chronic stress and diminishing work motivation, imposing a substantial disease burden across all age groups. Lactoyl-phenylalanine (...
Anxiety disorders are a growing public health concern in modern societies burdened with chronic stress and diminishing work motivation, imposing a substantial disease burden across all age groups. Lactoyl-phenylalanine (Lac-Phe), an endogenous metabolite produced during exercise and found in fermented foods, has recently gained attention for its metabolic regulatory functions, yet its potential anxiolytic effects remain unclear. In this study, we report that Lac-Phe administration elicits anxiolytic-like behavior in mice. Oral administration of Lac-Phe significantly increased open-arm exploration in the elevated plus maze (EPM), indicating anxiolytic-like activity. Similar behavioral effects were observed following intraperitoneal and intracerebroventricular administration in the EPM and the novelty-suppressed feeding test. Pharmacological blockade experiments indicated that dopamine D1 and serotonin 5-HT1A receptor signaling contribute to Lac-Phe-induced anxiolytic-like effects. Consistently, intraperitoneal administration of Lac-Phe increased dopamine tissue content in the hypothalamus and striatum and reduced hippocampal IL-1β and IL-6 mRNA expression. Together, these results suggest that Lac-Phe exerts anxiolytic-like effects, potentially involving monoaminergic signaling in the brain, and support further investigation of Lac-Phe as a food-derived metabolite in the context of stress- and anxiety-related outcomes.
Plasma Glial Fibrillary Acidic Protein (GFAP) shows age-dependent associations with externalizing psychopathology and atypical brain connectivity.
Niveditha BS, Holla B, Subramanian S … +35 more , Gagana N, Bhargavi KM, Sharma E, Mahadevan J, Purushottam M, Viswanath B, Benegal V, Arunachal G, Heron J, Hickman M, Basu D, Subodh BN, Singh L, Singh R, Kumaran K, Kuriyan R, Kurpad SS, Kartik K, Kalyanram K, Desrivieres S, Barker G, Papadopoulos Orfanos D, Toledano MB, Murthy P, Vaidya N, Krishnaveni G, Schumann G, Sharma KK, Bhaskarapillai B, Thennarasu K, Kashyap R, Bharath RD, Chakrabarti A, Chetan GK, Srinivas Bharath MM
Transl Psychiatry · 2026 May · PMID 42215432 · Publisher ↗
Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pat...
Externalizing disorders are common neurodevelopmental conditions, yet their underlying biology is not fully understood. Integrating peripheral biomarkers with brain imaging offers a powerful approach to elucidate the pathophysiology of these disorders. This study aimed to investigate the association between indicators of glial activation (glial fibrillary acidic protein; GFAP) and axonal injury (neurofilament light chain; NfL) in plasma with functional brain connectivity, and externalizing psychopathology (EXT) in a neurodevelopmental cohort. Towards this, a cross-sectional study was conducted with 144 participants selected from the Indian cVEDA cohort and balanced into EXT and healthy control (HC) groups using Mahalanobis distance matching. Plasma GFAP and NfL were quantified using Simoa technology. Resting-state fMRI data were used to generate between-network connectivity deviation scores via normative modelling. We used Gamma General Linear Models (Gamma GLMs) to test for an age-by-EXT interaction on GFAP/ NfL levels and sparse partial least squares (sPLS) regression to identify connectivity features that correlated with them. We found a significant age-by-EXT interaction for GFAP (p = 0.002), where EXT was associated with higher GFAP levels only in younger participants (<14 years). No significant effects were found for NfL. The sPLS analysis identified a significant five-feature brain connectivity signature that correlated with GFAP levels. This pattern was characterized by atypically strong connectivity between sensorimotor-limbic and attention-default mode networks, and weaker-than-expected connectivity within the default mode network. In conclusion, our findings identify a strong association between plasma GFAP and EXT in youth in an age dependent manner, suggesting a key role for glial activation in the early pathophysiology of these disorders. This process is linked to a specific, multivariate pattern of brain dysconnectivity, providing a potential neurobiological signature that warrants further investigation.
Multimodal phenotypic classification of generalized anxiety and panic using structural MRI data and psychosocial factors: machine learning results from the German National Cohort (NAKO) study.
Gutzeit J, Weiß M, Kuhn T … +30 more , Klinger-König J, Streit F, Jockwitz C, Brandes B, Wright MN, Friedrich CM, Woeckel M, Mikolajczyk R, Keil T, Castell S, Betker P, Schlett CL, Bärnighausen TW, Bamberg F, Günther M, Hirsch JG, Pischon T, Niendorf T, Leitzmann MF, Bohmann P, Wirkner K, Krist L, Wang Y, Berger K, Walther S, Grabe HJ, Deckert J, Caspers S, Hein G, Erhardt-Lehmann A
Transl Psychiatry · 2026 May · PMID 42209472 · Full text
Anxiety disorders are common and impairing mental health conditions. Using data from 26,378 adults in the German National Cohort Study (NAKO), we investigated psychosocial and neuroimaging predictors of generalized anxie...
Anxiety disorders are common and impairing mental health conditions. Using data from 26,378 adults in the German National Cohort Study (NAKO), we investigated psychosocial and neuroimaging predictors of generalized anxiety disorder (GAD) symptoms and panic attacks. We conducted machine-learning analyses of 246 regions of interest from whole-brain imaging data in combination with psychosocial variables. Neuroimaging data alone showed suboptimal classification performance, whereas psychosocial variables alone - particularly depressive symptoms, stress, and childhood trauma - achieved the strongest discrimination for GAD symptoms and panic attacks. Adding neuroimaging features to psychosocial models modestly improved unbalanced accuracy and specificity by reducing false-positive classifications, indicating a conditional and complementary contribution of neuroanatomical information. Within the multivariate models, features from anxiety-related circuits, including the amygdala and superior parietal lobule, were consistently selected. Overall, these findings suggest that psychosocial factors dominate classification of anxiety outcomes, while structural MRI measures may provide complementary information within multimodal frameworks aimed at refining classification and supporting the development of individualized risk profiles to guide tailored therapeutic and preventive strategies.
Enhancing anandamide signalling through fatty acid amide hydrolase inhibition: An update on the pharmacological strategy for treating psychiatric disorders.
Couttas TA, Hoffmann AE, Jieu B … +4 more , Golla FR, Shepherd CE, Leweke FM, Rohleder C
Transl Psychiatry · 2026 May · PMID 42209468 · Full text
Endocannabinoids (eCBs) are lipid-derived neuromodulators that regulate numerous neurophysiological processes by modulating synaptic transmission. Synthesised on demand in response to increased postsynaptic intracellular...
Endocannabinoids (eCBs) are lipid-derived neuromodulators that regulate numerous neurophysiological processes by modulating synaptic transmission. Synthesised on demand in response to increased postsynaptic intracellular calcium or activation of postsynaptic G-protein coupled receptors, eCBs are rapidly degraded, resulting in transient, tightly regulated signalling. Dysregulation in the endocannabinoid system (ECS), including altered peripheral and central eCB concentrations and/or cannabinoid-1 receptor (CBR) expression, has been observed across psychiatric syndromes, including major depressive disorder, psychotic disorders, and post-traumatic stress disorder (PTSD). These associations have prompted growing interest in pharmacological strategies targeting the ECS. Though medical cannabis is increasingly prescribed for psychiatric symptoms, its clinical use remains controversial due to limited high-quality evidence, psychotropic side effects, and regulatory constraints. An alternative is to enhance the signalling of a principal eCB, anandamide (AEA), potentially offering more physiologically constrained CBR engagement, by inhibiting fatty acid amide hydrolase (FAAH), the main enzyme degrading AEA and its congener, N-acylethanolamines (NAE), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). This review consolidates recent clinical evidence for FAAH inhibitors, examining their influence on AEA, safety and efficacy in ameliorating symptoms across a range of psychiatric conditions, including depression, anxiety, PTSD, and cannabis use disorder (CUD). Presently, only two compounds, PF-04457845 (JZP150) and JNJ-42165279, have progressed to Phase II trials, demonstrating modest clinical benefit in CUD, with no efficacy in PTSD or osteoarthritis pain. Herein, we discuss emerging insights, safety considerations, broader mechanistic implications, and future directions for FAAH-targeted therapeutics, advocating for a precision medicine approach to realise their potential in the treatment of psychiatric disorders.
Arousal shapes motivation: an integrative framework for understanding motivational deficits.
Thurn L, Culbreth AJ, Hernaus D
Transl Psychiatry · 2026 May · PMID 42209459 · Publisher ↗
Motivational deficits are a core feature of psychiatric disorders like major depressive disorder and schizophrenia, contributing significantly to reduced levels of daily functioning and quality of life. While most mechan...
Motivational deficits are a core feature of psychiatric disorders like major depressive disorder and schizophrenia, contributing significantly to reduced levels of daily functioning and quality of life. While most mechanistic frameworks of motivational impairments emphasize difficulties in accurately representing the value of goals - typically linked to dysfunction in dopamine-mediated reward systems - emerging evidence suggests that these models may be incomplete. In particular, dysfunctional modulation of arousal states may play a critical and underappreciated role by impairing the mobilization of cognitive and physiological resources required for goal-directed behavior in individuals with motivational deficits. Here, we aim to bridge the gap between arousal and valuation processes by offering an initial proposal for an integrative framework capable of explaining how motivational deficits may arise from their maladaptive interactions. We do this by first outlining how arousal systems support motivated behavior at a neural and cognitive level in healthy individuals, followed by highlighting converging evidence of arousal dysregulation in individuals with mood and psychotic disorders. Based on this work, we extend existing frameworks of motivated behavior by integrating arousal dynamics in order to outline how disruptions in the dynamic modulation of arousal can directly interfere with the formation and updating of value representations. We also offer recommendations for experimental and computational approaches that are needed to further clarify the role of arousal dynamics in healthy and clinical populations. A causal exploration of these mechanisms could lead to a more fine-grained understanding of disrupted processes of motivated behavior across transdiagnostic dimensions of psychopathology.
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