Transl Psychiatry [JOURNAL]
Sun
200 papers
Subanesthetic doses of ketamine to rats and monkeys rapidly increases radioligand binding in brain to phosphodiesterase-4, an indirect marker of cAMP.
Parcon PA, Bardhoshi A, Olsen-Dufour A … +12 more , Cureton R, Jana S, Morse CL, Henter ID, Totis J, Jenson AE, Pamie-George MT, Liow JS, Zoghbi SS, Wu S, Pike VW, Innis RB
Transl Psychiatry · 2026 Apr · PMID 42014381 · Full text
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a robust, rapid-acting antidepressant whose molecular effects have not been fully elucidated. Phosphodiesterase-4 (PDE4), which terminates cyclic adenosine...
The N-methyl-D-aspartate (NMDA) receptor antagonist ketamine is a robust, rapid-acting antidepressant whose molecular effects have not been fully elucidated. Phosphodiesterase-4 (PDE4), which terminates cyclic adenosine monophosphate (cAMP) activity, may underlie antidepressant response. In particular, previous studies found that whole brain binding of the positron emission tomography (PET) radioligand [C](R)-rolipram to PDE4 was decreased in individuals with major depressive disorder; eight weeks of antidepressant treatment rescued this decrease in [C](R)-rolipram binding. This study used [C](R)-rolipram, which targets all PDE4 subtypes, and [F]PF-06445974, which is preferential for PDE4B over PDE4D, to determine whether ketamine infusion could rapidly increase cAMP activity in rats (at 10 mg/kg) and rhesus macaques (at 0.5 mg/kg). Ketamine increased [C](R)-rolipram binding to PDE4 in rats (mean standardized uptake value (SUV) increase=24% ± 14%, range=3%-42%, p = 0.004) and in monkeys (mean distribution volume (V) increase=14% ± 2%, range=12%-16%, p = 0.003). Ketamine also increased [F]PF-06445974 binding in monkeys within one hour of infusion (mean V increase 28% ± 7%, range=16%-37%, p = 0.008). When [C](S)-rolipram, which has no specific binding to PDE4, was used to control for the effects of ketamine on blood flow and radioligand delivery in rats, no consistent effects were observed for ketamine. Collectively, the results suggest that ketamine infusion rapidly increases cAMP activity and may be an underlying mechanism for ketamine's rapid antidepressant effects. These data support a common pathway for cAMP and antidepressant action and suggest that PDE4 inhibition, particularly PDE4B, may be an effective and rapid-acting antidepressant mechanism.
mTOR-driven autophagy-inflammation crosstalk underlies schizophrenia pathophysiology.
Yan L, Wang X, Zhang Y … +5 more , Yan H, Lin Z, Zhang L, Zhang C, Song C
Transl Psychiatry · 2026 Apr · PMID 42010301 · Full text
Schizophrenia (SZ) is characterized by immune dysregulation and decreased autophagy. However, the mechanistic interplay between these two processes remains unclear. This study aimed to explore the relationship between au...
Schizophrenia (SZ) is characterized by immune dysregulation and decreased autophagy. However, the mechanistic interplay between these two processes remains unclear. This study aimed to explore the relationship between autophagy and inflammation in SZ patients and a maternal immune activation (MIA)-induced SZ mouse model. Autophagic activity and inflammatory markers were assessed in peripheral blood mononuclear cells (PBMCs) from SZ patients and healthy controls using flowcytometry, Western blotting, and qPCR. Cytokine modulation experiments were conducted in vitro to determine causal relationships. Behavioral, molecular, and neurochemical analyses were performed in MIA-induced SZ-like mice, with or without mTOR inhibitor rapamycin treatment, to assess the role of mTOR-regulated autophagy in vivo. SZ patients exhibited reduced autophagic-lysosome function in PBMCs, evidenced by decreased monodansylcadaverine-positive cells, Beclin-1, LC3B/LC3A, LAMP1, and cathepsin D, alongside increased p62 levels, accompanied by hyperactivation of the PI3K/AKT/mTOR pathway and ULK1 inhibition. These changes were associated with elevated inflammatory markers, including IL-1β, IL-6, IFN-γ, and NLRP3 inflammasome components (NLRP3, ASC, caspase-1). Pharmacological inhibition of autophagy further amplified inflammatory gene expression in vitro, while IL-10 treatment restored LC3B expression, which suppressed by IL-1β/IL-6. MIA mice showed SZ-like behaviors, reduced hippocampal Beclin-1, glial polarization imbalance, cortical neuroinflammation, and monoaminergic disruptions. Rapamycin-induced mTOR inhibition restored autophagy and reversed these abnormalities. Our findings demonstrated that hyperactivation of mTOR suppressed autophagy, leading to sustained elevation of pro-inflammatory cytokines in SZ. Inhibition of mTOR restored autophagic activity, thereby reducing neuroinflammation and glial pro-inflammatory activation, suggesting autophagy as a promising therapeutic target for SZ.
Diagnostic performance of plasma p-tau217 levels measured with different assays for Alzheimer's disease.
He Y, Du Y, Liu D … +5 more , Che P, Wang Y, Li J, Wang C, Zhang N
Transl Psychiatry · 2026 Apr · PMID 42009653 · Full text
Plasma tau phosphorylated at threonine 217 (p-tau217) has been recommended as a biomarker for the diagnosis of Alzheimer's disease (AD). We evaluated the diagnostic and differential performance of plasma p-tau217 levels...
Plasma tau phosphorylated at threonine 217 (p-tau217) has been recommended as a biomarker for the diagnosis of Alzheimer's disease (AD). We evaluated the diagnostic and differential performance of plasma p-tau217 levels measured with three novel assays in a Chinese population. A total of 233 participants were recruited, including 39 cognitively unimpaired controls (CUCs), 28 individuals with mild cognitive impairment (MCI) due to AD, 57 individuals with AD dementia (ADD), 70 individuals with subcortical ischemic vascular dementia (SIVD), and 39 individuals with frontotemporal lobar degeneration (FTLD). Plasma p-tau217 levels were measured using one assay based on single-molecule techniques (DiSMS), one assay based on digital ELISA (LyMedivh™ AXL), and one assay based on flow cytometry (CBA), as well as a reference assay (ALZpath Simoa). Group differences in plasma p-tau217 levels were assessed using analysis of covariance, and the diagnostic and differential performance of the assays was evaluated via receiver operating characteristic analysis. Partial correlation analysis was used to examine the correlations between the measurements of the three novel assays and those of the reference assay. We found that plasma p-tau217 levels measured with all three novel assays were higher in the ADD group than in the CUC, SIVD, and FTLD groups (all p < 0.05) and effectively discriminated ADD patients from both CUCs and non-AD dementia patients. The diagnostic and differential performances did not significantly differ among the three assays (all p > 0.05). Both the DiSMS and LyMedivh™ AXL assays also revealed elevated plasma p-tau217 levels in the MCI group compared to the CUC group. Moreover, the measurements of the three novel assays demonstrated significant correlations with the ALZpath Simoa measurements (p < 0.01). When using their optimal cutoff values, both the DiSMS and LyMedivh™ AXL assays yielded a specificity of 100% and a sensitivity of 94.4%, and the CBA assay showed a specificity of 100% and a sensitivity of 88.9%. In conclusion, our study demonstrated the diagnostic and differential abilities of plasma p-tau 217 levels measured with three novel assays that can serve as potential alternatives to the currently available testing methods for AD diagnosis.
Associations of oral contraceptives and hormone replacement therapy with incident dementia risk: a population-based cohort study.
Ou YN, Liu X, Gao PY … +5 more , Yang L, Feng JF, Tan L, Yu JT, Song JH
Transl Psychiatry · 2026 Apr · PMID 42000775 · Full text
The relationships between exogenous hormones and dementia, as well as cognitive function in females, remains debated. This study aimed to investigate the associations of exogenous hormone exposure (oral contraceptives [O...
The relationships between exogenous hormones and dementia, as well as cognitive function in females, remains debated. This study aimed to investigate the associations of exogenous hormone exposure (oral contraceptives [OC] and hormone replacement therapy [HRT]) with incident dementia risk, cognitive function and changes in brain structures. Multivariate Cox proportional hazard regression models were used to assess the associations between exogenous hormone exposure and dementia incidence. Linear regression models were employed to explore the relationships of exogenous hormone exposure and cognitive performances. Mediation models were conducted to explore the underlying mechanisms driven by brain structures. A total of 233,896 female participants from the UK Biobank were included. In fully adjusted models, OC use was associated with reduced risks of all-cause dementia (ACD) (HR [95% CI], 0.806 [0.724-0.897]), Alzheimer's disease (AD) (HR [95%CI], 0.767 [0.659-0.893]) and vascular dementia (VaD) (HR [95%CI], 0.735 [0.578-0.934]). HRT was associated with decreased risks of ACD (HR [95%CI], 0.897 [0.811-0.992]) and AD (HR [95%CI], 0.804 [0.696-0.928]). Duration of OC use showed a non-linear (J-shaped) association with the risks of ACD and AD. In addition, brain structures, including the bilateral pallidum and left thalamus proper were identified as potential mediators in the relationships between the duration of OC use and cognitive performance. To summarize, exogenous hormone use is associated with reduced dementia risk and better cognitive function, with pallidum and thalamus possibly mediating the associations.
Divergence of C4A and C4B in first-episode psychosis: Insights from CSF and plasma immune profiling.
Arjmand S, Chaudhary M, Samudyata … +7 more , Piehl F, Pelanis A, Engberg G, Cervenka S, Landén M, Erhardt S, Sellgren CM
Transl Psychiatry · 2026 Apr · PMID 42000733 · Full text
The complement genes C4A and C4B share high sequence similarity yet differ in biological function and disease relevance. C4A, in contrast to C4B, is implicated in synaptic pruning and increased risk for schizophrenia, ho...
The complement genes C4A and C4B share high sequence similarity yet differ in biological function and disease relevance. C4A, in contrast to C4B, is implicated in synaptic pruning and increased risk for schizophrenia, however beyond this their distinct roles within the human brain remain poorly understood. We analyzed cerebrospinal fluid (CSF) levels of C4A, C4B, C1Q, along with 48 inflammation-related proteins, measured in both CSF and plasma, in 90 healthy controls and 113 patients with first-episode psychosis (FEP). In controls, C4A and C4B were positively associated with C1Q (z = 0.41, p < 0.001, and z = 0.48, p < 0.001, respectively), whereas in FEP, the CSF C1Q-C4A association was abolished (z = 0.09, p = 0.40). Across inflammatory markers, C4A levels in controls showed predominantly negative correlations in CSF, while C4B and C1Q exhibited mostly positive correlations. Using permutation tests on directional mean differences, we observed a robust positive directional shift for C4A in FEP (z = 3.81, p < 0.0001), while C4B showed a non-significant negative shift (z = -2.64, p > 0.9). The overall C4A directional shift was largely preserved in plasma, though the structure of complement-protein interactions differed markedly between the biological compartments, CSF and plasma. Together, these findings identify distinct and compartment-specific patterns of immune network interactions for C4A and C4B and suggest that C4A-inflammatory protein relationships are selectively altered in FEP.
Decoding kratom: molecular mechanisms and epigenetic factors in use and dependence.
Misnan E, Hasbullah NZA, Abd Rashid R … +2 more , Mohd Shah A, Sim MS
Transl Psychiatry · 2026 Apr · PMID 41997923 · Full text
Kratom (Mitragyna speciosa) is a traditional Southeast Asian botanical long used for alleviating pain and boosting energy. Its chief bioactive compound, mitragynine (MG), exhibits both opioid-like and stimulant propertie...
Kratom (Mitragyna speciosa) is a traditional Southeast Asian botanical long used for alleviating pain and boosting energy. Its chief bioactive compound, mitragynine (MG), exhibits both opioid-like and stimulant properties and has prompted interest in its potential role in pain management and opioid withdrawal support. However, its safety profile and underlying mechanisms remain incompletely understood. This systematic review critically synthesizes preclinical evidence on kratom's molecular, pharmacological, and epigenetic effects. Guided by PRISMA 2020 criteria, studies indexed in Scopus and Web of Science (2000-2024) were analyzed, focusing on receptor activity, intracellular signaling, and gene regulation in in vitro and in vivo models. Among 20 eligible studies, key findings indicate that kratom alkaloids engage μ-opioid, adrenergic, and serotonergic receptors; modulate dopaminergic and glutamatergic systems; and exert anti-inflammatory and analgesic effects. Under chronic exposure followed by withdrawal, MG was associated with reduced histone acetylation and increased HDAC2 expression, while Rab35 emerged as a potential withdrawal-associated biomarker. MG also inhibited cardiac ion channels and altered CYP450 enzyme expression, highlighting safety concerns related to cardiotoxicity and drug-drug interactions. Despite these mechanistic insights, limitations in pharmacokinetic data, standardized dosing, and long-term safety preclude clinical application. Future research should prioritize controlled human studies, omics-driven biomarker discovery, and evidence-based regulatory evaluation to clarify kratom's therapeutic potential and risk profile.
Cross-Species evidence for hippocampal CACNA1C as a therapeutic target for alcohol use disorder.
Pareek T, Pham LM, O'Donovan SM … +7 more , Zamarripa CA, Allen Iv O, Freeman KB, Platt DM, Grant KA, Pantazopoulos H, Gisabella B
Transl Psychiatry · 2026 Apr · PMID 41997900 · Full text
Context-induced relapse is a major barrier to recovery from alcohol use disorder (AUD). Identifying molecular targets involved in contextual memories associated with alcohol use may serve as novel pharmacotherapies. Our...
Context-induced relapse is a major barrier to recovery from alcohol use disorder (AUD). Identifying molecular targets involved in contextual memories associated with alcohol use may serve as novel pharmacotherapies. Our RNAseq profiling study of the hippocampus from rhesus monkeys with chronic alcohol use identified the voltage-gated calcium channel CACNA1C as a promising therapeutic target. However, data regarding CACNA1C expression in AUD and whether inhibition of CACNA1C can attenuate ethanol contextual memories remains limited. We tested the hypothesis that hippocampal CACNA1C expression is increased in human and nonhuman primates (NHPs) with chronic alcohol use. Further, we used a mouse conditioned place preference (CPP) paradigm to test the hypothesis that Nifedipine, a CACNA1C-selective L-type calcium channel antagonist, can attenuate ethanol-induced CPP. CACNA1C mRNA expression was increased in the hippocampus of subjects with AUD (p < 0.03). Increased densities of CACNA1C neurons (p < 0.01) and glia (p < 0.02) were observed in rhesus monkeys with chronic alcohol use. Ethanol-treated mice spent more time in the ethanol-paired chamber compared to the vehicle animals (p < 0.04), demonstrating ethanol-induced CPP. This effect was attenuated by Nifedipine, as time spent in the ethanol-paired chamber in the ethanol + Nifedipine group was not significantly different from the vehicle group. These findings demonstrate that chronic alcohol use increases CACNA1C expression in the hippocampus across species and that a CACNA1C subtype-selective antagonist reduces ethanol-induced CPP. Together, these results support CACNA1C as a promising therapeutic target for memory dysfunction in AUD.
Correlation between peripheral and central inflammatory and neuronal injury markers in mild cognitive impairment patients: the role of blood-brain barrier status.
Liu QF, Shi CN, Wu XM … +5 more , Hu XY, Gu HW, Yang JJ, Ji MH, Liu QR
Transl Psychiatry · 2026 Apr · PMID 41997897 · Full text
The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state b...
The relationship between peripheral and central biomarkers in mild cognitive impairment (MCI), and the potential role of blood-brain barrier (BBB) dysfunction in this process, remain unclear. MCI, an intermediate state between normal aging and dementia, is characterized by early neuroinflammation and neuronal injury, yet how systemic markers reflect central pathology is poorly understood. In this study, we enrolled 74 participants, including 37 MCI patients and 37 cognitively normal controls. Based on the CSF/serum albumin ratio, subjects were classified into four groups-NC (cognitively normal with intact BBB), NMCI (MCI with intact BBB), BC (cognitively normal with BBB disruption), and BMCI (MCI with BBB disruption)-and further grouped as BBB-intact or BBB-disrupted. Serum and cerebrospinal fluid (CSF) levels of interleukin-4 (IL-4), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), glial fibrillary acidic protein (GFAP), and neurofilament light (Nf-L) were measured using enzyme-linked immunosorbent assay. Spearman correlation analysis was applied to examine peripheral-central associations. No significant correlations were observed in NC or NMCI groups. A moderate serum-CSF GFAP correlation was found in the BC group (r = 0.446, P = 0.033), which became markedly stronger in the BMCI group (r = 0.753, P < 0.001). In the BBB-disrupted group, significant correlations were detected for GFAP (r = 0.652, P < 0.001), IL-4 (r = 0.412, P = 0.003), IL-6 (r = 0.296, P = 0.035), and TNF-α (r = 0.352, P = 0.011), with GFAP showing the strongest association. In contrast, within the BBB-intact group, only serum-CSF IL-6 correlation reached significance (r = 0.469, P = 0.024). These findings suggest that BBB disruption markedly enhances peripheral-central biomarker associations, especially for GFAP, highlighting the regulatory role of BBB integrity in linking systemic inflammation, neuronal injury, and MCI pathophysiology.
Sex-dependent modulation of social distance by lipopolysaccharide-induced inflammation in mice.
Yamamoto M, Hayashi K, Kanayama M … +3 more , Inoue H, Matsushima S, Toda K
Transl Psychiatry · 2026 Apr · PMID 41991521 · Full text
Depression is a major psychiatric disorder, and accumulating evidence indicates that inflammatory processes contribute to its pathophysiology. Peripheral administration of lipopolysaccharide (LPS) reliably induces system...
Depression is a major psychiatric disorder, and accumulating evidence indicates that inflammatory processes contribute to its pathophysiology. Peripheral administration of lipopolysaccharide (LPS) reliably induces systemic inflammation and is widely used to model inflammation-related depression and sickness behavior. However, despite the strong association between social behavior and depressive states, the impact of LPS-induced inflammation on social interactions remains insufficiently understood. Here, we investigated how acute inflammatory responses influence social and non-social behaviors in C57BL/6 J mice following intraperitoneal LPS administration. Immunological analyses using ELISA and flow cytometry revealed marked increases in circulating IL-1β, IL-6, and TNF-α, accompanied by reductions in T cells, B cells, neutrophils, and monocytes. Baseline levels of B cells, neutrophils, and monocytes differed between sexes. Behavioral assessments demonstrated that LPS-treated male mice exhibited increased social contact and reduced social distance in both familiar and unfamiliar dyads, whereas these effects were absent in female pairs. In contrast, LPS induced comparable reductions in body weight, locomotor activity, and fecal output in the open-field test, as well as decreased sucrose preference and overall licking counts in the sucrose preference task, in both sexes. These findings indicate that LPS-induced inflammation modulates social behavior in a sex-dependent manner. Notably, the enhanced social contact observed in male dyads cannot be attributed to weight loss, hypoactivity, altered orofacial movements, or reduced reward sensitivity, as these physiological and motivational impairments were similarly present in both sexes. This study highlights distinct social behavioral consequences of inflammatory activation and advances our understanding of immune-behavior interactions.
Physical-Digital and social-nonsocial extracurricular engagement: differential effects on brain development and psychological outcomes in children.
Tian X, Yang R, Lou J … +7 more , Sun Y, Wang M, Wang Q, Lei W, Li A, Zhang Z, Liu B
Transl Psychiatry · 2026 Apr · PMID 41991511 · Full text
Extracurricular activities shape children's development, yet how the interaction between their modality (digital/physical) and social context (social/non-social) impact mental health and neurodevelopment remains unclear....
Extracurricular activities shape children's development, yet how the interaction between their modality (digital/physical) and social context (social/non-social) impact mental health and neurodevelopment remains unclear. This study examined these relationships and their bidirectionality, as well as mediation by brain structural changes. Using baseline and one-year follow-up data from 8230 children in the Adolescent Brain Cognitive Development Study, we analyzed self-reported screen time for six digital activities (three social, three non-social), caregiver-reported participation in 28 extracurricular activities (11 social, 17 non-social), mental health via the Child Behavior Checklist and Kiddie Schedule for Affective Disorders and Schizophrenia, and gray matter volume using T1-weighted MRI. Distinct interaction patterns between modality and social context emerged. Physical-social activities were linked to fewer psychiatric symptoms, particularly withdrawn/depressed behaviors, and increased frontoparietal gray matter. In contrast, digital non-social activities were associated with higher psychiatric risk, especially rule-breaking behaviors, and reduced temporal gray matter. Physical non-social and digital-social activities demonstrated mixed effects on developmental measures. Longitudinal analyses revealed bidirectional activity-mental health associations, with brain volume changes mediating 3.7-5.0% of these relationships. These findings highlight the interactive role of activity modality and social context in children's development and provide neurobiological evidence informing guidelines for beneficial developmental outcomes.
Suicide risk genes impact evolutionarily conserved survival strategies.
Dustin A, Dwyer DS
Transl Psychiatry · 2026 Apr · PMID 41986315 · Full text
Genome-wide association studies (GWAS) and candidate gene analyses have identified possible suicide risk genes that are highly conserved during evolution and enriched in genes essential for life. However, functional role...
Genome-wide association studies (GWAS) and candidate gene analyses have identified possible suicide risk genes that are highly conserved during evolution and enriched in genes essential for life. However, functional roles for these risk genes have not been confirmed and pathways from risk variant to relevant phenotype to suicidality-related behavior remain unknown, highlighting critical gaps in our knowledge. Here, we report findings from the largest behavioral and mechanistic study of suicide risk genes to date. In Caenorhabditis elegans, mutations in risk gene counterparts caused exaggerated threat evaluation (social feeding) and diminished motivation to seek food, which represent ancient strategies for avoiding harm and ensuring survival (foraging). Genetic variation affected neuropeptide (NPY and TGF-β) function and kinase signaling. Remarkably, the altered behaviors were corrected with drugs that reduce suicidal behavior including antidepressants and clozapine. Taken together, these findings reveal that risk genes predisposing a person to take their life normally promote strategies to survive.
Early life adversity increases striatal dopamine D1 receptor density and promotes social alcohol drinking in mice, especially males.
Anderson LG, Tischer AE, Bock R … +2 more , Michaelides M, Alvarez VA
Transl Psychiatry · 2026 Apr · PMID 41986313 · Full text
The brain's reward-processing circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. Adverse experiences early in life can increase...
The brain's reward-processing circuitry remains sensitive to experience throughout early life and into adulthood, allowing individuals to adapt to their unique environments. Adverse experiences early in life can increase vulnerability to substance use disorders, likely through alterations to this circuitry. Yet, the precise neurobiological mechanisms by which early life adversity acts are incompletely characterized. In this study, we used a limited bedding and nesting (LBN) paradigm as a translationally relevant model of early life adversity in isogenic C57BL/6J mice. After LBN-rearing, we assessed the lasting behavioral and neurobiological impacts of this experience in adulthood. In robust sample sizes, our results validated previous findings of increased risk avoidance, enhanced acute locomotor response to alcohol, and greater voluntary alcohol drinking in socially-housed LBN-reared mice, especially males. Further, using autoradiography, we found LBN-reared mice had increased striatal D1-like receptor binding, skewing D1- to D2-like receptor balance relative to cross-fostered controls. However, after voluntary alcohol drinking, we found a strong downregulation in D1-like, and some D2-like, receptor binding, negating pre-existing differences in striatal dopamine receptor binding. We posit that via both transcriptional and post-transcriptional mechanisms, LBN-rearing upregulates striatal D1-receptor density and alters risk avoidance and acute alcohol stimulation to promote alcohol drinking among adversity-exposed mice. Together, these findings reveal specific neurobiological mechanisms that promote alcohol consumption following early life adversity and suggest complex interactions between early life adversity, sex-related factors, and dopamine receptor regulation in contributing to alcohol use disorder (AUD) vulnerability.
Stress and synaptic density in psychosis and clinical high risk: evidence from [F]SynVesT-1 PET.
Blasco MB, Nisha Aji K, Ramos-Jiménez C … +7 more , Chartrand D, Hsiao CH, Hopewell R, Massarweh G, Cohen J, Rusjan PM, Mizrahi R
Transl Psychiatry · 2026 Apr · PMID 41986308 · Full text
Synaptic dysfunction is implicated in the pathophysiology of schizophrenia, and positron emission tomography (PET) studies demonstrate in vivo reductions in synaptic density across illness stages. Stress is a key modifia...
Synaptic dysfunction is implicated in the pathophysiology of schizophrenia, and positron emission tomography (PET) studies demonstrate in vivo reductions in synaptic density across illness stages. Stress is a key modifiable risk factor, and while animal studies show it disrupts synaptic function, its effects on humans remain unclear. We examined the relationship between stress and synaptic density in individuals with first-episode psychosis (FEP) and those at clinical high risk (CHR). Seventy-eight participants, including 25 FEP, 32 CHR, and 21 healthy controls (HC), underwent 90-min [F]SynVesT-1 PET scans to quantify synaptic density measured as SV2A binding across prioritized brain regions. Stress-related measures included the Hassles and Uplifts Scale and the Trier Inventory for Chronic Stress (TICS). Depressive symptoms were evaluated using the Hamilton Depression Rating Scale (HDRS). Across all participants, greater acute stress was associated with lower [F]SynVesT-1 binding (F = 12.0, p < 0.001), with no significant group interaction (F = 2.44, p = 0.09). Group differences emerged for chronic stress and depressive symptoms (TICS × Group: F = 3.87, p = 0.02; sqHDRS × Group: F = 4.47, p = 0.01). Post hoc analyses revealed that higher chronic stress was associated with lower synaptic density in HC (F = 7.07, p = 0.009) but not in clinical groups. Lower mood symptoms were associated with lower synaptic density in FEP (F = 5.19, p = 0.02) only. These findings indicate that the relationship between stress and synaptic density differs between clinical and healthy groups. The changes in the relationship between stress and synaptic density in FEP may reflect impaired adaptive neuroplasticity, providing a potential mechanism by which stress contributes to psychosis vulnerability.
Effects of a single dose of psilocybin on diet-induced weight loss in obese mice.
Keenan RJ, Haque RT, Jin X … +7 more , Mustafa T, Homman-Ludiye J, Elysee K, Wee ZS, Simonds SE, Foldi CJ, Cowley MA
Transl Psychiatry · 2026 Apr · PMID 41980923 · Full text
Prolonged obesity induces enduring structural changes within neural circuits that contribute to maintaining the body at an elevated/obese body weight. These circuits regulate various mechanisms which can inhibit extreme...
Prolonged obesity induces enduring structural changes within neural circuits that contribute to maintaining the body at an elevated/obese body weight. These circuits regulate various mechanisms which can inhibit extreme or persistent weight loss. Therefore, a potential therapeutic strategy to facilitate weight loss is to promote structural plasticity within the brain. Psychedelic compounds, such as psilocybin, promote neural plasticity caused by a rapid and persistent growth of dendritic spines, which can facilitate the remodelling of neural circuits. Preclinical and clinical studies using psychedelic compounds have demonstrated efficacy for various neuropsychiatric disorders, which are often comorbid with obesity, and share underlying neural mechanisms. Here, we evaluate the effects of a single dose of psilocybin on body weight, food intake and energy expenditure in diet-induced obese (DIO) mice switched onto a low-fat chow. Psilocybin exacerbated diet-induced weight loss over a four-week period in DIO mice and increased the susceptibility for mice to exhibit more profound weight loss. Psilocybin appears to exert these effects predominantly through modulating food intake, with no influence on energy expenditure. No differences were observed in body weight or food intake in DIO mice maintained on a high-fat diet, indicating psilocybin does not necessarily directly promote weight loss or reduce food intake. Rather, it may help facilitate weight loss, provided it is administered in combination with other weight loss promoting interventions. Additional experimentation is required to examine the precise mechanisms involved; however, this data supports further investigation into the use of psychedelic compounds as an adjunct therapy for obesity.
R-loop landscapes in the developing human brain are linked to neural differentiation and cell type-specific transcription.
LaMarca EA, Saito A, Plaza-Jennings A … +16 more , Espeso-Gil S, Hellmich A, Fernando MB, Javidfar B, Liao W, Estill M, Townsley K, Florio A, Ethridge JE, Do C, Tycko B, Shen L, Kamiya A, Tsankova NM, Brennand KJ, Akbarian S
Transl Psychiatry · 2026 Apr · PMID 41974678 · Full text
Here, we construct genome-scale maps of R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in both proliferative and differentiated zones of the human pren...
Here, we construct genome-scale maps of R-loops, three-stranded nucleic acid structures comprised of a DNA/RNA hybrid and a displaced single strand of DNA, in both proliferative and differentiated zones of the human prenatal brain. We show that R-loops are abundant in the progenitor-rich germinal matrix and preferentially form at gene promoters slated for upregulated expression at later stages of differentiation, including numerous neurodevelopmental risk genes. RNase H1-mediated contraction of the genomic R-loop space in neural progenitors shifted differentiation toward the neuronal lineage and was associated with transcriptomic alterations, along with defective functional and structural neuronal connectivity in vivo and in vitro. Therefore, we conclude that R-loops are important for fine-tuning differentiation-sensitive gene expression programs of neural progenitor cells.
Identification of an immune-metabolic biosignature linking depressive symptoms and breast cancer in a clinical population.
Giona L, Collacchi B, Capoccia S … +10 more , Borgi M, Raggi C, Bonucci A, Fabi A, Falcicchio C, Perrone M, Chiarotti F, Ortona E, Berry A, Cirulli F
Transl Psychiatry · 2026 Apr · PMID 41965831 · Full text
Breast cancer (BC) is a leading cause of mortality among women. Comorbidity with mood disorders is a condition either disregarded or underdiagnosed in BC patients, but that might ultimately jeopardize health trajectories...
Breast cancer (BC) is a leading cause of mortality among women. Comorbidity with mood disorders is a condition either disregarded or underdiagnosed in BC patients, but that might ultimately jeopardize health trajectories. This is supported by evidence indicating that the same biological pathways relevant for mood disorders may also underlie tumorigenesis. In this study, we aimed at deriving a reliable biosignature of mental health vulnerability in BC patients. We conducted a cross-sectional study in a population of 44 women diagnosed with BC who underwent surgery before receiving adjuvant chemotherapy. All subjects were scored for symptoms of depression, anxiety and stress; blood samples were used to measure relevant biomarkers of inflammation, energy homeostasis and brain plasticity, while circadian cortisol rhythm was assessed in the saliva. Based on a rigorous statistical approach, we identified a specific immune- metabolic biosignature of depression relying upon each subject's BMI, IL-5 and leptin. Following the validation of the model, we defined a cut-off value to identify those subjects who are at elevated risk of poor prognosis based on our biosignature. This signature holds potential for the timely identification of those individuals for whom depressive symptoms are sustained by a deranged immune-metabolic milieu and might therefore be at higher risk of poorer health outcomes. Our results strengthen the importance of accounting for brain-body communication in cancer and suggest that routine screening for mental health in BC patients should be prioritized in order to put in place tailored intervention strategies to improve health outcomes.
Correlation networks of blood proteins in the neuroimmunology of schizophrenia-replication and extension.
Jeffries CD, Bizon CA, Ford JR … +12 more , Addington J, Bearden CE, Cadenhead K, Cannon TD, Cornblatt B, Keshavan M, Mathalon D, Seidman L, Stone WS, Walker EF, Woods SW, Perkins DO
Transl Psychiatry · 2026 Apr · PMID 41965717 · Full text
The Pearson sample correlation between two biomarkers across a group of individuals can sometimes be much stronger than expected by chance. In the context of psychosis risk, we previously analyzed blood plasma protein da...
The Pearson sample correlation between two biomarkers across a group of individuals can sometimes be much stronger than expected by chance. In the context of psychosis risk, we previously analyzed blood plasma protein data from initial presentations as collected in the North American Prodrome Longitudinal Study 2 (NAPLS2). We found enhanced correlation between proteins SERPINE1 and TIMP1, both promoters of coagulation and inhibitors of remodeling of extracellular matrix (ECM). Participants were unaffected community controls vs. others of clinical high risk. The SERPINE1-TIMP1 correlation was consistently higher in individuals at clinical high risk for psychosis who later converted to a psychotic disorder vs. participants who were nonconverters or unaffected community controls. Here, we extend those findings using data from a larger cohort, the North American Prodrome Longitudinal Study 3 (NAPLS3). Again, the correlation between SERPINE1 and TIMP1 remained higher in psychosis high-risk converters vs. the other groups. In NAPLS3 we added an assay for PLAT (anti-coagulation plasminogen activator strongly inhibited by SERPINE1). Comparing the three NAPLS3 groups we found a decreased correlation between SERPINE1 and PLAT in converters. In summary, the increased correlation of SERPINE1 and TIMP1 in converters is consistent with restricted brain circuit remodeling and increased tendency to coagulation. Rigorous application of permutation testing yielded NAPLS2 vs. NAPLS3 consistency of SERPINE1-TIMP1 correlation patterns with empirical p-value 0.03.
Development and validation of a precision treatment rules for first-line antipsychotic recommendations in first episode psychosis jointly incorporating effectiveness, side effects and patient preferences.
Krakowski K, Oliver D, Arribas M … +5 more , Logeswaran Y, de Micheli A, Patel R, Stahl D, Fusar-Poli P
Transl Psychiatry · 2026 Apr · PMID 41965367 · Full text
Selecting first-line antipsychotic medication for first episode of psychosis patients is a very challenging task requiring the clinicians to empirically weight multiple criteria. Precision treatment rules developed using...
Selecting first-line antipsychotic medication for first episode of psychosis patients is a very challenging task requiring the clinicians to empirically weight multiple criteria. Precision treatment rules developed using health records offer a pragmatic approach to support clinicians' treatment selection, however, they don't incorporate side effects and patient preferences. We used Electronic Health Records from Early Intervention for Psychosis services in South London and the Maudsley NHS Trust and followed the RECORD and TRIPOD + AI guidelines. Precision treatment rules were developed using causal machine learning methods and estimated effectiveness (change of medication, hospitalisation) and side effects (extrapyramidal side effects, hyperprolactinemia, sedation, sexual side effects, and weight gain) using clinical, demographic, symptom and substance use predictors. Patient preferences regarding side effects were incorporated by ranking method. 1709 patients (mean age 26.7 years and 64% male) were included. Aripiprazole was recommended to between 80 and 98% of patients depending on selected patients' preferences. Compared to the observed treatment decisions we estimated that under treatment rules recommendations hyperprolactinemia would be reduced by 4.7 percentage points (pp), sedation by 15.8 pp, sexual side effects by 4.3 pp and weight gain by 15.2 pp with no change in hospitalisation and change of medications outcomes. However, extrapyramidal side effects were estimated to increase by 5.5 pp. This study presents the first precision treatment rules for early psychosis that integrate effectiveness, side effects and patient preferences. Further research using larger data sets, more predictors and treatment options is suggested.
Not only gut feelings: pancreatic hormone, amylin, controls emotionality and sociability, in a sex divergent manner.
Byun S, Sotzen MR, Knappenberger MA … +3 more , Olekanma DI, Bento M, Skibicka KP
Transl Psychiatry · 2026 Apr · PMID 41965364 · Full text
Amylin, a pancreatic peptide hormone, has gained attention for its role in appetite regulation. Its analogues are approved for use in diabetic patients, and it is now under investigation as a potential anti-obesity thera...
Amylin, a pancreatic peptide hormone, has gained attention for its role in appetite regulation. Its analogues are approved for use in diabetic patients, and it is now under investigation as a potential anti-obesity therapeutic. However, despite its clinical use, its effects on emotionality remain poorly understood. Given that many other food intake-modulating substances influence psychiatric functions, here we determined the role of systemic amylin in modulating key aspects of emotionality and sociability in male and female rats. We further evaluated whether the central amygdala (CeA) is sufficient for mediating amylin's actions on emotionality and sociability. Male and female rats received either systemic or intra-CeA amylin. Anxiety-like behavior was evaluated in the elevated plus maze and the acoustic startle response. Systemic and CeA amylin administration induced sex-specific effects on anxiety-like behavior, with both administration routes consistently eliciting anxiolytic responses in males and anxiogenic responses in females. Intra-CeA amylin increased depression-like behavior, evaluated by the forced swim test, in female rats only. Aggressive behavior, investigated by resident-intruder test, was consistently reduced in both sexes, while only systemic, but not intra-CeA, amylin increased social interaction in the sociability test. These findings suggest that amylin modulates emotional and social behaviors in a sex-dependent manner, with the CeA as a sufficient neural substrate to drive these effects of amylin. Considering previous anti-obesity therapeutics have been withdrawn from the market because of emotionality side effects, our results highlight the importance of understanding these effects in both sexes separately for the development of safe amylin-based obesity treatments that minimize psychiatric risks.
Advancing translational research in binge-eating: Integrating insights from clinical practice into animal models.
Dufour R, Shalev U, Booij L
Transl Psychiatry · 2026 Apr · PMID 41965343 · Full text
Binge-eating behaviors are key components of several types of eating disorders, yet their etiology remains unclear. Animal models have provided valuable insights by enabling experimentally controlled investigations of bi...
Binge-eating behaviors are key components of several types of eating disorders, yet their etiology remains unclear. Animal models have provided valuable insights by enabling experimentally controlled investigations of biological, behavioral, and environmental factors contributing to eating disorders. This narrative review examines the clinical relevance of animal models in advancing our understanding of binge-eating-related disorders. We propose five translational priorities focused on clinically-meaningful features of binge eating and their relevance for improving animal-model development: (1) loss of control and compulsivity, (2) negative affect and stress responsivity, (3) developmental timing and sex differences, (4) individual differences and variability, and (5) treatment responsiveness. Various animal models, including food restriction, stress-induced, and addiction-based paradigms, have been developed to study binge eating. Limitations include the inability of animal models to fully capture the psychological and sociocultural dimensions of binge eating, such as the sense of loss of control, stigma, distress, and body-image concerns. While existing models capture key biological and behavioral components of binge eating, closer alignment with clinically defining features, for example, through the inclusion of emotional stressors and varied outcome measures, could improve translational impact. By refining current models to match clinical reality, animal research may continue to enhance our understanding of eating disorders and inform the development of novel treatment approaches.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe