The kynurenine pathway (KP) has emerged as a key mediator of inflammation and synaptic plasticity, which play a significant role in the pathophysiology of chronic stress (CS). CS, in turn, is a major environmental factor in the development of psychiatric disorders. Despite growing evidence linking the KP to psychiatric disorders, the mechanisms underlying its alterations under CS remain poorly understood. To address this gap, we conducted the first comprehensive meta-analysis of preclinical rodent studies. Our goal was to systematically evaluate, within controlled experimental paradigms: (1) how, to what extent, and in which brain regions CS affects the KP; (2) which neurochemical pathways are most impacted by CS. We searched PubMed/MEDLINE, EMBASE, Scopus for preclinical studies until 06/27/2025. We performed a systematic review and meta-analysis following a pre-determined protocol (PROSPERO:CRD42023459414), considering KP metabolites and enzymes as outcomes (Standardized Mean Difference=SMD). SYRCLE/CAMARADES tools assessed quality and risk-of-bias. 59 studies entered the meta-analyses. CS proved to increase hippocampal and cortical overall concentrations of kynurenine (SMD=1.71,95 %C.I.[0.99,2.42], p < 0.01,I=91.3 %,k = 23,n = 508; SMD=1.54,95 %C.I.[1.08,2.01],p < 0.01,I=57.77 %,k = 16,n = 247), as well as kynurenine/tryptophan ratio and quinolinic acid. KYNA concentrations decreased in the hippocampus and cortex. KP enzyme expression/activity, including Indoleamine-2,3-Dioxygenase, Tryptophan-2,3-Dioxygenase, Kynurenine-3-Monoxygenase, increased. These findings support a shift of tryptophan metabolism towards the KP following CS. Particularly, the increase in neurotoxic quinolinic acid (NMDAR-agonist) and decrease in KYNA (NMDA-antagonist) may disrupt the neuroprotection/excitotoxic neuronal balance, influencing neuroplasticity. The KP may play a key role in the pathophysiology of CS-associated behaviors, and could serve to highlight potential targets for novel therapeutic strategies, specifically for treatment resistance.

Antipsychotic-induced weight gain (AiWG) is a common, burdensome adverse effect. Switching to antipsychotics with lower metabolic risks, such as aripiprazole, is recommended, but long-term data is limited. Long-acting injectables (LAIs) may offer metabolic benefits over oral formulations, yet evidence is inconsistent. We compared long-term effects of switching to aripiprazole versus paliperidone on bodyweight, considering administration route and smoking. To that end, we analyzed data from 241 participants (mean age = 31.0; 32 % female) in the European Long-acting Antipsychotics in Schizophrenia Trial (EULAST), a multicentre, open-label, randomized trial. Participants received aripiprazole (n = 119) or paliperidone (n = 122), orally or as LAIs. Bodyweight was assessed over 18 months. Secondary outcomes included changes in BMI and cardiometabolic parameters. Both groups showed progressive weight gain: over 18 months, body weight increased by 4.7 kgs (95 % CI 3.0-6.5). Weight gain was 4.5 kgs with aripiprazole (95 % CI 2.1-7.0) and 4.9 kgs with paliperidone (95 % CI 2.3-7.4). Clinically significant weight gain (≥5 %) occurred in 41.1 % and 58.7 % of users, respectively (NNH = 5; p = 0.06). Weight gain was more pronounced among participants receiving LAIs (difference of 5.57 kgs; 95 % CI: 0.8-10.4; p = 0.02). Smoking was associated with greater weight gain (+2.3 kgs; 95 % CI: 0.9-3.6; p = 0.001). In conclusion, switching to aripiprazole or paliperidone did not prevent AiWG and LAIs showed no metabolic advantage relative to oral counterparts. The association between smoking and increased weight gain suggests smoking may represent a modifiable risk factor, warranting further investigation of smoking cessation as a potential intervention in AiWG management.

Studying DNA methylation (DNAm) can provide insights into gene-regulatory mechanisms underlying attention-deficit/hyperactivity disorder (ADHD). While most DNAm studies were performed in bulk tissue, this study used statistical deconvolution to identify cell type-specific DNAm profiles, from five major blood cell types, associated with childhood ADHD symptoms. We performed meta-analyses of methylome-wide association studies (MWAS) for ADHD symptoms (age=4-16 years) in peripheral blood collected during childhood and in cord blood. The investigated cohorts included seven array-based methylation datasets assaying up to 450 K CpGs from the Pregnancy And Childhood Epigenetics Consortium (N=2 934 peripheral blood; N=2 546 cord blood) and a sequencing-based methylation dataset assaying nearly all 28 million CpGs in blood from the Great Smoky Mountain Study (GSMS; N=583). The meta-analyses resulted in methylome-wide significant (FDR<0.05) ADHD associations in CD8T cells (RPL31P11 and KCNJ5) for peripheral blood, and, in cord blood, in monocytes (PDE6B), CD8T cells (KCNA3 and HAND2), and NK cells (KIFC1). Notably, several significant sites detected in peripheral blood (RPL31P11 and KCNJ5) were also detected in cord blood. Furthermore, extended MWAS of all sites available for GSMS detected 69 and 17 additional CpGs in monocytes and granulocytes, respectively. In this first cell type-specific MWAS for ADHD, we identified DNAm associations for ADHD symptoms; some associations were seen in both peripheral blood and cord blood, suggesting potential susceptibility markers for increased ADHD risk. These findings show that cell type-specific analyses and sequencing-based approaches can increase insights into the epigenetic patterns associated with ADHD symptoms in childhood.

The integration of psychedelic therapies into European healthcare is a nuanced process that involves not only obtaining European Medicines Agency (EMA) approval but also successfully navigating Health Technology Assessment (HTA) evaluations across member states. After EMA approval, which focuses on the safety, efficacy, and quality of the therapeutic, HTA agencies assess these therapies for their "added therapeutic value," considering factors like cost-effectiveness, clinical outcomes, and overall societal impact. Each country's HTA, including the UK's National Institute for Health and Care Excellence (NICE), Germany's Institute for Quality and Efficiency in Health Care (IQWiG), and France's Haute Autorité de Santé (HAS), plays a pivotal role in determining reimbursement and access to these treatments. An added challenge is that HTA bodies in Europe often require active comparator studies rather than just placebo controls to establish a treatment's advantage over existing standard of care - a particular hurdle for psychedelic-assisted therapies, where controlled trials against active comparators are almost completely lacking. Furthermore, psychedelics are typically integrated with psychotherapy, adding complexity to HTA evaluations, as few frameworks currently assess the value of combination therapies within healthcare systems. Creating a standardized HTA approach or a unified European guideline for such novel treatments could promote equitable access across countries, helping to overcome the discrepancies in market access and patient reach across Europe.

Serotonergic psychedelics and 3,4-methylendioxtmethamphetamine (MDMA) are promising treatments for mental disorders with a continuously evolving evidence base. We searched Pubmed/Scopus/clinical trial registries up to 08july2025 for double-blind randomized controlled trials (RCTs) testing MDMA or serotonergic psychedelics in patients with mental disorders. Primary outcomes were change in disease-specific symptoms and all-cause discontinuation. Standardized mean differences (SMD) and relative risk (RR) were estimated using random-effects meta-analysis. Risk of bias (RoB) was assessed with Cochrane's RoB-tool version 2 and certainty of evidence with GRADE. The review is maintained as living systematic review (https://ebipsyche-database.org/). We included 30 RCTs (1480 participants; female=45.8 %; with psychological support=83.3 %; high RoB=83.3 %). In post-traumatic stress disorder (PTSD), MDMA reduced PTSD symptoms compared to any control (k = 11; SMD=-0.85 [-1.09; -0.60]; I=0 %; GRADE=low). In major depressive disorder (MDD), psilocybin/ayahuasca/LSD reduced depressive symptoms (k = 8; SMD=-0.62 [-0.97; -0.28]; I=55 %; GRADE=very low). In anxiety disorders, both MDMA and serotonergic psychedelics reduced anxiety symptoms (SMD=-1.18 [-2.04; -0.32]; I=0 %; k = 2; GRADE=low and SMD=-0.88 [-1.70; -0.06]; I=54 %;k = 5; GRADE=very low). In alcohol use disorder, neither psilocybin nor LSD reduced abstinence rates (k = 6; RR=1.42 [0.89; 2.26]; I=7 %; GRADE=very low). In attention-deficit hyperactivity disorder (ADHD), LSD did not reduce ADHD symptoms (k = 1; SMD=0.22 [-0.32; 0.76]; GRADE=very low). Moderate certainty in evidence was only found for MDMA on PTSD symptoms when compared to placebo. MDMA/serotonergic psychedelics were not associated with higher risk of all-cause discontinuation (RR=0.74 [0.32; 1.72]; RR=0.81 [0.56; 1.15]). Overall, MDMA/serotonergic psychedelics are promising for the treatment of PTSD, MDD, and anxiety disorders with moderate to large effect sizes. Pragmatic trials, long-term, head-to-head trials exploring the role of psychological support, aiming to identify predictors of response, and accounting for expectancy and functional unblinding are needed. Studies addressing these limitations will likely be required for regulatory approval of psychedelic drugs.

Exposure to childhood maltreatment (CM) is a crucial risk factor for affective disorders and schizophrenia, which are linked to structural brain network alterations. We hypothesized a significant association between CM and brain structural connectivity in a transdiagnostic sample. Participants included patients with major depressive disorder (n = 827), bipolar disorder (n = 134), schizophrenia spectrum disorders (n = 118), and healthy controls (n = 932) aged 18-65 from the Marburg-Muenster Affective Disorders Cohort Study. Structural brain networks were reconstructed from structural and diffusion-weighted MRI. CM was assessed using the Childhood Trauma Questionnaire (CTQ) based on established cut-offs. Analyses of covariance investigated the main effect of CM and the interaction of diagnosis and CM on global network metrics. In addition, network-based statistic (NBS) analyses were performed to identify the underlying subnetworks. History of CM was positively associated with the number of connections (p=0.01; CM: 95 %-CI=[533.9; 540.6], No CM: 95 %-CI=[529.1; 535.0]), normalized (p=0.02; CM: 95 %-CI=[0.860; 0.863], No CM: 95 %-CI=[0.857; 0.860]) and non-normalized network efficiency (p=0.01; CM: 95 %-CI=[0.405; 0.407], No CM: 95 %-CI=[0.403; 0.405]) and negatively associated with normalized network clustering (p=0.045; CM: 95 %-CI=[4.976; 5.065], No CM: 95 %-CI=[5.100; 5.150]). There were no significant interaction effects of CM and diagnosis. NBS analyses revealed a large network of edges, in which individuals with CM exhibited higher structural connectivity compared to those without, which persisted after correcting for diagnosis. These findings indicate a connectome signature of CM, marked by hyperconnectivity, across major mental disorders and in healthy individuals, suggesting that CM affects connectome architecture independent of present psychiatric diagnoses.

Presence or absence of recent stress preceding emergence of depressive symptoms may play a distinctive role in determining underlying etiological processes, explaining part of the significant heterogeneity characteristic of depression. Separately studying genetic associations of depressive symptoms appearing following, or independently of stress may help disentangle the genetic background of distinct depression subtypes in a general population sample. We included UK Biobank data (application number 1602) of nearly 120,000 subjects, and conducted three separate genome-wide analyses focusing on current depressive symptoms in three groups based on level of stress exposure in the past two years and analysed results from the aspect of neurobiological relationships between genetic variation and brain function. GWAS results were evaluated on SNP and gene-set levels. Heritability estimation revealed 10.4 %, 8.8 % and 5.1 % heritability in major-stress, minor-stress and no-stress groups, respectively. In the no-stress group 22, in the minor-stress group 22, and in the major-stress group 14 SNPs with suggestive significance were identified, with notable differences in the specific genes and processes implicated in the three groups. In the no-stress group marked association with long non-coding and micro-RNA emerged whereas in the major-stress group results implicate involvement of circadian genes and immunological pathways. Our findings reveal marked differences in the genetic underpinnings of depressive symptoms following exposure to different levels of recent stress, arguing that etiological heterogeneity of depression should be considered in both research and clinical applications, and pave the way of distinguishing between subtypes of depression based on the etiological contribution of stress.

Evidence has underscored clinical significance of subjective quality of life (SQoL) as a key therapeutic goal for early psychosis. However, the patterns, predictors and outcomes of SQoL trajectories over long-term follow-up in early psychosis have not been explored. We conducted a 12-year follow-up of the randomized-controlled-trial on extended early intervention for first-episode psychosis with an aim to identify distinct trajectories of the SQoL, their baseline predictors and relationships with 12-year outcomes. Premorbid adjustment, illness characteristics, symptom severity, functioning, and treatment profiles were assessed. Latent growth mixture modeling was employed to derive SQoL trajectories based on 36-Item Short Form Health Survey (SF-36) mental-health component summary scores over 12-year follow-up. Participants who completed SF-36 at three or more time points, including baseline, and 1-, 2-, 3- and 12-year follow-up, were included in the analysis, resulting in 144 patients. Our results identified three distinct trajectories, including high-stable class (36.8 %, n = 53), moderate-improving class (40.3 %, n = 58) and low-stable class (22.9 %, n = 33). Patients in high-stable class had less severe depressive symptoms at baseline than those in moderate-improving class, and less severe positive, negative and depressive symptoms at baseline compared to patients in low-stable class. Additionally, patients with high-stable trajectory exhibited higher rate of personal recovery and lower depressive symptom severity at 12-year follow-up relative to patients with low-stable trajectory. In conclusion, approximately one-fourths of patients displayed consistently poor SQoL over 12 years. Depressive symptoms represent a major determinant of SQoL trajectories, indicating the need to optimize treatment for depression in early psychosis to enhance SQoL outcome.

Structural and functional default mode network (DMN) alterations are common in neuropsychiatric disorders and may contribute transdiagnostically to social dysfunction. Normative modelling enables assessment of DMN alterations at the individual level. This study investigates whether individual deviations in cortical thickness, surface area, and between-network functional connectivity of the DMN differ between schizophrenia (SZ), major depressive disorder (MDD), Alzheimer's disease (AD), and healthy controls (HC), and whether these deviations transdiagnostically relate to social dysfunction. Social dysfunction was assessed using a composite score from the Social Functioning Scale and De Jong-Gierveld Loneliness scale. Structural MRI data was collected for 329 participants (SZ=86, MDD=44, AD=82, HC=117) and resting-state fMRI data for 317 participants. Individual deviation scores of DMN integrity were computed by adapting existing normative models of cortical thickness (N = 58,836), surface area (N = 43,524), and between-network functional connectivity (N = 21,515). Extreme deviations were quantified using a z-threshold of ±1.96. DMN deviation scores were not transdiagnostically associated with social dysfunction across the sample (ps>0.05). AD patients had more extreme negative deviations in DMN cortical thickness than all other groups (ps<0.0001; z = -4.14 to -6.34) and fewer extreme positive deviations in DMN surface area relative to SZ and HC (ps<0.05; z = 2.10 to 2.71). For between-network functional connectivity of the DMN, AD and SZ patients had more extreme negative deviations than MDD and HC (ps<0.05; z = -2.09 to -3.54). To conclude, normative modelling reveals differences in individual deviations of DMN integrity between neuropsychiatric groups, but these deviations do not transdiagnostically relate to social dysfunction.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), currently used for metabolic conditions, have demonstrated potential antidepressant effects via neuromodulatory pathways. This systematic review aims to provide evidence on the antidepressant effects of GLP-1 RAs and elucidate their underlying mechanism of action.