Cortical brain morphology in early-onset psychosis (EOP; age of onset < 19 years) is poorly understood, partly due to recruitment constraints linked to its low incidence. We pooled T1-weighted magnetic resonance imaging (MRI) data from 387 adolescents with EOP (mean age=16.1±1.5; 49.6% female) and 338 healthy controls (CTR; mean age=15.8±1.9, 54.4% female) from nine research sites worldwide. Using harmonized processing protocols with FreeSurfer, we extracted cortical brain metrics from 34 bilateral regions. Univariate regression analysis revealed widespread lower bilateral cortical thickness (left/right hemisphere: d=-0.36/-0.31), surface area (left/right: d=-0.42/-0.41), cortical volume (left/right: d=-0.58/-0.56), and Local Gyrification Index (LGI; left/right: d=-0.39/-0.52) in EOP relative to CTR. Subgroup analyses showed broader and more pronounced case-control differences in early-onset schizophrenia for area, volume, and LGI. We found no associations with antipsychotic medication use, illness duration, age of onset, or positive symptoms. Negative symptoms were related to smaller left lingual volumes (partial r=-0.21; p FDR =0.014) and antidepressant users had smaller area (d=-0.43; p FDR =0.034) and volume (d=-0.50; p FDR =0.003) of the right rostral anterior cingulate compared to non-users. Cortical alterations in EOP showed a similar pattern to those observed in prior studies on adults with schizophrenia (SCZ; r=0.62) and bipolar disorders (BD; r=0.61). However, surface area alterations were overall 1.5 times greater for EOP than adult SCZ and 4.6 times greater than adult BD. In the largest study of its kind, we observed an extensive pattern of cortical alterations in adolescents with psychotic disorders, highlighting the potential impact of aberrant neurodevelopment on cortical morphology in this clinical group.

Most studies assessing the association between infection accumulation and mental disorders focus on hospitalization-based severe infections. However, most infections are more common, and community acquired. This study aimed to evaluate the effects of community-based infection accumulation on risk to develop a mental disorder, and risk factors modulating this association. A nationwide population-based matched cohort study was conducted, utilizing the registries of Clalit Health Services, the largest healthcare organization in Israel. Individuals born between the years 1995–2005 with history of specific infections (n = 35 020) were propensity score matched to an unexposed group with no such history (n = 35 020). These individuals were followed up until 2024 for a mental disorder onset. Serology, nasal and saliva-based tests for cytomegalovirus, herpesviruses, hepatitis, influenza, or toxoplasma gondii starting from birth were identified, and patients were followed for onset of anxiety, depression schizophrenia and bipolar disorders. Individuals with history of infection accumulation demonstrated higher risk to develop a mental disorder, with risk gradually increasing after one (HR, 1.08, 95%CI, 1.01–1.17, p = 0.036), two (HR, 1.19, 95%CI, 1.09–1.30, p < 0.001) and three or more infections (HR, 1.81, 95%CI, 1.32–2.48, p < 0.001) up to first five years post-infection. These associations were stronger in females, individuals of older age and individuals with larger families. The findings suggest that community-based immune challenges might shape vulnerability for mental disorders, and stress the need to consider infection history in future efforts to develop patient-tailored prevention and intervention strategies.

Introduction Bipolar disorder (BD) is a severe psychiatric disorder characterized by shifting of mood patterns from manic to depressive episodes. The molecular mechanisms underlying BD have not been fully elucidated, and research into biomarkers is important for prevention and early intervention. The Na+, K+-ATPase is a metalloprotein that interacts with many chemical elements. It was demonstrated that the interactions of Na+, K+-ATPase with endogenous cardiac steroids is involved in BD. It was hypothesized that these interactions are mimicked by chemical elements which may participate in BD etiology. We have recently demonstrated that the concentration of Aluminum (Al), Boron (B), Cupper (Cu), Potassium (K), Magnesium (Mg) and Vanadium (V) were significantly lower in the pre-frontal cortex of individuals with BD compared with controls. We hypothesized that differences in the levels of chemical elements between BD and healthy controls would also be reflected in scalp hair.MethodsTo test this hypothesis, the levels of 25 chemical elements were determined by Inductively coupled plasma mass spectrometry (ICP-MS) in the scalp hair of 30 individuals with BD and 30 sex- and age-matched controls.ResultsWe found that the levels of Al, Cu, Nickel (Ni) and Thallium (Tl) are elevated in the hair of BD patients compared to controls. In addition, the concentrations of Ni levels in hair samples were correlated with the severity of the mental illness as quantified by the Global Assessment of Functioning Scale.ConclusionAlthough interpretations are tentative due to the limited sample size, our results suggest that changes in chemical elements may be involved either in the etiology of BD or altered due to the disease progression, which needs to be clarified further in larger independent samples.

ABSTRACT Schizophrenia (SCZ) is increasingly linked to neuroimmune dysregulation and impaired synaptic plasticity, yet the cellular mechanisms connecting inflammatory signaling to neural dysfunction remain poorly understood. Using human induced pluripotent stem cell (iPSC)-derived cortical spheroids (hCS) and astrocytes from patients with SCZ and matched controls, we investigated the effects of GABA A receptor modulation on immune signaling and neuroplasticity. Inflammatory stimulation induced robust interferon-responsive transcriptional programs, prominently involving the antiviral effector MX1 and related interferon-stimulated genes. Computational deconvolution and cell type-specific analyses identified astrocytes as key mediators of these responses. Muscimol, a non-classic psychedelic and GABA A receptor agonist, suppressed inflammatory gene expression, reduced secretion of proinflammatory cytokines, and attenuated interferon-associated signaling. In addition, muscimol induced neuroplasticity-associated transcriptional programs, including upregulation of NTRK2 and ELK1 in hCSs, and restored impaired glutamate uptake in iPSC-derived SCZ astrocytes. These effects were blocked by GABA A receptor inhibition, confirming receptor-dependent mechanisms. Proteomic analyses of hCS cultures, and independent human dorsolateral prefrontal cortex datasets revealed baseline dysregulation of GABAergic and neurotrophin signaling in SCZ, supporting translational relevance. Together, these findings demonstrate that GABA A receptor activation by muscimol suppresses inflammatory signaling while promoting neuroplasticity in hCSs, and identify astrocytes as central regulators of interferon-dependent neuroimmune dysfunction in SCZ. These results establish non-classic psychedelic compounds as potential modulators of neuroimmune-plasticity coupling and suggest that targeting astrocyte GABAergic signaling may represent a therapeutic strategy for restoring neural homeostasis in SCZ.

BACKGROUND:Elevated inflammatory biomarkers have been consistently associated with a subset of depressive symptoms, particularly atypical and energy-related features, as well as antidepressant treatment resistance. This evidence has supported the definition of an inflammatory subtype of major depressive disorder (ISMDD), characterized by immune-inflammatory dysregulation and reduced response to first- and second-line antidepressants. However, a lack of consensus on its definition and assessment tools limits research and treatment development. METHODS:Using a Delphi approach, international experts from the ASPIRE consortium (Advanced Stratification of People with Depression based on Inflammation, n = 25) identified ISMDD symptom domains, which were then evaluated by the European College of Neuropsychopharmacology Immuno-Neuropsychiatry Network (INPN-ECNP, n = 12). Using the same consensus structure, the coverage of these domains by depression rating scales was then assessed. People with lived experience (PWLE, n = 11) provided perspectives on the clinical relevance and impact of the emerged symptoms. RESULTS:ASPIRE consensus identified ten ISMDD symptom domains: fatigue/low energy, hypersomnia, increased weight/appetite, cognitive difficulties, lack of motivation, anhedonia, diminished interest, leaden paralysis, psychomotor retardation, and insomnia, with the first five being also confirmed by INPN-ECNP consensus. Except for increased weight/appetite, PWLE identified these domains as negatively affecting quality of life; most of them were also reported as not extensively assessed in clinical care. Among rating scales, the Inventory of Depressive Symptomatology tools, including their Quick versions, were the only instruments covering all or almost all the ISMDD domains. CONCLUSION:These findings support a framework for ISMDD and highlight the importance of symptom assessment to improve clinical evaluation, research, and personalized immunopsychiatric treatment.

BACKGROUND:Severe mental disorders (SMDs) are associated with unhealthy lifestyle, contributing to increased risk of comorbid cardiovascular disease. Genetic factors influence both SMDs and lifestyle behaviours, but their genetic relationships remain unclear. Here, we aimed to unravel the shared genetic architecture of SMDs and lifestyle factors. Additionally, we assessed if genetic propensity to SMDs predicts body mass index (BMI) and lipids through lifestyle factors. METHODS:We analysed genome-wide data on major depression (MD) (N = 480,359), schizophrenia (SCZ) (N = 130,644), bipolar disorder (BIP) (N = 353,889) and self-reported lifestyle factors (N = 266,048-606,820), including food intake, physical activity, sedentary behaviours, and accelerometer-assessed activity from All of Us (N = 30,132) and UK Biobank (N = 91,105) to obtain objective measures for sensitivity analysis. We estimated the shared genetic architecture using bivariate MiXeR. Shared genetic loci were identified using conjunctional false discovery rate and mapped to genes, which were subject to enrichment analyses. We applied structural equation modelling (SEM) to assess if lifestyle mediates the relationship between polygenic risk score for SMDs and BMI and lipids. People with lived experience were involved in the research. FINDINGS:There was extensive genetic overlap between lifestyle factors and SMDs, with different patterns of effects. MD was genetically correlated with less physical activity and more sedentary behaviour. SCZ and BIP displayed opposite patterns with genetic associations with less sedentary behaviour, more physical activity and healthier food intake. This divergent pattern across SMDs was largely consistent using accelerometer-assessed activity. We identified 551 shared loci, implicating biological processes related to neurodevelopment and synaptic and neuronal properties. Further analyses indicated that lifestyle factors partly mediate the relationship between genetic risk for SMDs and BMI and lipids. INTERPRETATION:The results show a genetic propensity towards unhealthier lifestyle behaviours in MD, while SCZ and BIP displayed a divergent pattern. The genetic correlations reflecting mixed effect directions may also imply subgroups with different genetic propensity, which can form the basis for risk stratification and more tailored lifestyle interventions and personalised treatment. FUNDING:Research Council of Norway (grants, 273291, 273446, 300309, 324252, and 326813), South-East Norway Regional Health Authority (grants 2023-031 and 2022-073), NordForsk (University Cooperation Grant 164218, PreciMENT), European Union's Horizon 2020 Research and Innovation Programme (grant 847776, CoMorMent; grant 964874, RealMent), and the National Institutes of Health (grant R01MH125938).

Alterations in telomere length (TL), a marker of cellular ageing, have been reported in individuals with severe mental disorders (SMD). Epidemiological studies of the general population have highlighted that unhealthy lifestyles may exacerbate telomere attrition. However, the impact of lifestyle on TL within the context of SMD remains unexplored. The study consisted of 410 participants (schizophrenia spectrum [n = 225] and affective disorder [n = 185]) collected as part of the Norwegian Thematically Organised Psychosis (TOP) study. Leukocyte TL was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR). Patients provided self-report data on six lifestyle domains including: diet, exercise, smoking, alcohol consumption, substance use, and coffee consumption. A global dichotomised (healthy vs unhealthy) lifestyle variable was created, as well as a health behaviour variable, indicating the level of unhealthy behaviours. Individuals with an unhealthy lifestyle had shorter TL compared to those with a healthy lifestyle (Cohen's d = 0.58, F = 8.62, p = 0.004). A relationship was observed between increasing number of unhealthy behaviours and shorter TL (F = 2.69, p = 0.02), adjusted for age, sex, ethnicity, trauma exposure, medication daily defined dose (DDD), years of education and diagnosis. In terms of base-pair loss, individuals with healthy lifestyles exhibited a roughly 6-year lower biological age, compared to individuals with unhealthy lifestyles. Our study indicates that a healthier lifestyle is associated with longer TL in SMD. This highlights the importance of health behaviours as potential clinical targets for ensuring healthier cellular ageing in psychiatric populations.

BACKGROUND:Schizophrenia patho-etiology may involve endothelial inflammation and blood-brain barrier (BBB) dysregulation with cellular adhesion molecules (CAMs) as important mediators. CAMs are essential for cellular integrity but can show increased levels in inflammation. Cognitive dysfunction precedes and exists independently of psychotic symptoms in schizophrenia patients. CAMs could impact cognition through influence on BBB integrity. To gain insights into disease mechanisms and potential therapeutic targets, we explored the relationship between CAMs protein levels and neurocognitive tests in schizophrenia-spectrum disorders in the BeSt InTro study. METHODS:Seventy-one in- and out-patients underwent CAMs measurements and neuropsychological testing on a minimum of one time point: baseline, 6, 26, or 52 weeks. Cognitive domains included working memory, processing speed, verbal abilities, executive functions, and overall cognition. CAMs analyzed were neural CAMs: junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD); vascular CAMs: intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), and platelet (P)-selectin from fasting blood samples. Linear mixed effects models, adjusted for age, sex, body mass index, smoking, education, and drug naivety, estimated CAMs effect on cognitive outcome measures. RESULTS:N-CAD levels correlated positively with overall cognition (p = 0.002), working memory (p = 0.034), and executive functions (p = 0.0011). ICAM-1 levels correlated positively with overall cognition (p = 0.037). Conversely, JAM-A levels correlated negatively with executive functions (p = 0.021). CONCLUSION:Associations between CAMs (N-CAD, ICAM-1, JAM-A) and neurocognitive tests suggest CAMs may impact cognition in schizophrenia. Contrary to our hypothesis, most associations between CAMs levels and cognitive tests were positive. Future research on mechanisms is mandatory.

Schizophrenia spectrum disorders (SCZspect) are associated with altered function in the auditory cortex (AC), indicated by lower N100 amplitude of the auditory evoked potential (AEP). Although the neural substrate behind lower N100 amplitude remains elusive, myelination in the AC may play a role. This study compared N100 amplitude and magnetic resonance imaging (MRI) T1 weighted and T2 weighted ratio (T1w/T2w-ratio), as a proxy of myelination, in the primary AC (AC1) and secondary AC (AC2) between SCZspect (n = 33, 48% women) and healthy controls (HC, n = 144, 49% women). We also examined the associations between N100 amplitude and T1w/T2w-ratios across groups. We finally explored N100 amplitude and T1w/T2w-ratios and the N100-T1w/T2w-ratio associations between male and female SCZspect and HC. N100 amplitude was significantly lower in male SCZspect compared to male HC (p = 0.01) and nominally lower in SCZspect compared to HC (p = 0.03). However, T1w/T2w-ratios in AC1/AC2 did not differ between groups, and no association was found between N100 amplitude and T1w/T2w-ratio in either group. These findings suggest that sex-specific effects should be considered in SCZspect neurophysiology research. Our results do not support the hypothesis of an association between lower N100 amplitude and lower T1w/T2w-ratio in the AC1/AC2 in SCZspect. More precise assessments of intracortical myelin are needed to understand the relationship between N100 amplitude and cortical myelination in the AC in SCZspect and in healthy controls.

Neuroinflammation and astrocyte dysfunction are associated with schizophrenia. To elucidate the molecular mechanisms involved, we generated induced pluripotent stem cells from 14 schizophrenia patients and 14 healthy controls and differentiated them to human cortical spheroids. Transcriptional profiling revealed overexpression of cilia-related genes in schizophrenia spheroids which was mainly driven by astrocytes. We identified baseline abnormal astrocyte distribution in schizophrenia and show that it is triggered by the pro-inflammatory cytokine macrophage migration inhibitory factor (MIF), primarily secreted by neurons. While treatment with the MIF antagonist ISO-1 attenuated abnormal astrocyte distribution in schizophrenia spheroids and reduced pro-inflammatory cytokines secretion, MIF gene knockout with CRISPR-Cas9 exacerbated astrocyte and cytokines dysregulation in schizophrenia cultures, suggesting that both extremes of elevated and absent MIF lead to impaired astrocyte distribution and that a minimum expression of MIF is required for optimal cell function. Taken together, our results point to a MIF-induced regulation of cortical astroglia in schizophrenia and highlight MIF antagonists as potential novel treatment strategies.

Background Mental and neurological conditions have been linked to structural brain variations. However, aside from dementia, the value of brain structural characteristics derived from brain scans for prediction is relatively low. One reason for this limitation is the clinical and biological heterogeneity inherent to such conditions. Recent studies have implicated aberrations in the cerebellum, a relatively understudied brain region, in these clinical conditions. Methods Here, we used machine learning to test the value of individual deviations from normative cerebellar development across the lifespan (based on trained data from >27,000 participants) for prediction of autism spectrum disorder (ASD) (n = 317), bipolar disorder (n = 238), schizophrenia (SZ) (n = 195), mild cognitive impairment (n = 122), and Alzheimer's disease (n = 116); individuals without diagnoses were matched to the clinical cohorts. We applied several atlases and derived median, variance, and percentages of extreme deviations within each region of interest. Results The results show that lobular and voxelwise cerebellar data can be used to discriminate reference samples from individuals with ASD and SZ with moderate accuracy (the area under the receiver operating characteristic curves ranged from 0.56 to 0.65). Contributions to these predictive models originated from both anterior and posterior regions of the cerebellum. Conclusions Our study highlights the utility of cerebellar normative modeling in predicting ASD and SZ, aided by 4 cerebellar atlases that enhanced the interpretability of the findings.

Toxoplasma gondii (TG) is a prevalent parasite that establishes lifelong latency after primary infection. TG has been linked to severe mental illness (SMI), potentially through dopamine dysregulation in the brain. There is a bidirectional interaction between dopamine and the hypothalamic-pituitary-adrenal axis, where dopamine may influence cortisol regulation and cortisol may affect dopamine release. We hypothesised that TG would be associated with elevated circulatory cortisol levels, increased severity of psychotic symptoms, and structural brain aberrations in SMI. Our study included 765 patients with SMI (515 with schizophrenia spectrum disorders and 250 with bipolar disorders) and 541 healthy controls (HC). TG immunoglobulin G seropositivity and circulatory cortisol concentrations were measured with immunoassays, and T1-weighted MRI scans were processed using FreeSurfer. Psychotic symptom scores were evaluated using the Positive and Negative Syndrome Scale. In SMI, TG seropositivity was associated with higher cortisol levels (p = 0.002), but not in HC. Seropositive patients had lower total psychotic symptom scores (p = 0.006) than seronegative patients, driven by the schizophrenia subgroup (p = 0.002). This effect was observed for positive, negative, and general psychotic symptom scores, but only for patients with an illness duration of 10 years or more. In an exploratory analysis, TG seropositivity was nominally associated with smaller thalamus, nucleus accumbens, and middle temporal volumes in SMI, and with smaller fusiform, parahippocampal, and pars triangularis volumes in HC. In conclusion, TG exposure in SMI was linked to elevated cortisol levels and reduced psychotic symptom scores, suggesting that its impact on SMI may be more complex and context-dependent than previously assumed.

Metabolites in plasma form biosignatures of a range of common complex human diseases. Discovering variants with pleiotropic effects across metabolites can reveal underlying biological mechanisms. We therefore performed uni- and multivariate genome-wide association studies (GWAS) on 249 circulating metabolic markers across 328,006 UK Biobank and Estonian Biobank participants. We investigated rare variation through whole exome sequencing gene burden tests, analysed the role of body mass index through Mendelian randomization, and performed genome-wide interaction analyses with sex. We discovered 15,585 loci summed over the univariate GWAS, with high pleiotropy across markers, linked to a wide range of disorders. Findings from common and rare variant gene tests converged on lipid homeostasis pathways. 31 loci interacted with sex, mapped to genes involved in cholesterol processing. The findings offer insights into the genetic architecture of circulating metabolites, revealing pleiotropic loci, highlighting the role of rare variation, and uncovering sex-specific molecular mechanisms of lipid metabolism.

Rare copy number variants (CNVs) are a key component of the genetic basis of psychiatric conditions, but have not been well characterized for most. We conducted a genome-wide CNV analysis across six diagnostic categories (N = 574,965): autism (ASD), ADHD, bipolar disorder (BD), major depressive disorder (MDD), PTSD, and schizophrenia (SCZ). We identified 35 genome-wide significant associations at 18 loci, including novel associations in SCZ ( SMYD3, USP7 - HAPSTR1 ) and in the combined cross-disorder analysis ( ASTN2 ). Rare CNVs accounted for 1-3% of heritability across diagnoses. In ASD, associations were uniformly positive, consistent with autism having diverse etiologies and clinical presentations. By contrast, CNVs showed a dose-dependent relationship for other diagnoses, including SCZ and PTSD, with reciprocal deletions and duplications having inversely correlated effects and distinct genotype-phenotype relationships. Our findings suggest that genes have effects that are both dose-dependent and pleiotropic, such that a positive influence on one dimension of psychopathology may be accompanied by positive or negative effects on others.

Objective Telomere length (TL) is an indicator of cellular ageing, with patients with severe mental disorders tending to have shorter telomeres than the general population. Coffee consumption may reduce oxidative stress, helping prevent biological ageing processes like telomeric shortening. The UK National Health Service advises limiting caffeine intake to 400 mg/day (4 cups of coffee). However, the role of coffee consumption and TL in psychiatric populations remains unclear. Methods This cross-sectional study included 436 participants (schizophrenia spectrum (n=259) and affective disorders (n=177)) from the Norwegian TOP study. Leucocyte TL was measured via blood using quantitative real-time polymerase chain reaction (qPCR). Patients self-reported coffee consumption, quantified as cups per day (no coffee, 1-2, 3-4, 5+). Results An inverted J-shape was found between TL and coffee intake, peaking at 3-4 cups/day before declining after 4 cups (F=3.29, p=0.02). The largest TL difference was between those drinking the highest recommended dose and non-drinkers (F=6.13, p=0.01). Coffee drinkers within the recommended dose had longer TL, comparable to 5 years younger biological age, adjusted for confounders. Conclusion Coffee intake within the recommended dose is linked to longer telomeres in severe mental disorders, comparable to 5 years younger biological age.

BACKGROUND:Immunomodulatory effects of psychotropic agents used to treat severe mental disorders (SMDs) have been suggested. We investigated associations between immune marker levels and antipsychotic- (AP), antidepressant- (AD), and mood stabilizing agents (MS) use in SMDs. METHODS:We included 1215 participants with SMDs (777 with schizophrenia spectrum disorders and 438 with bipolar disorders). Circulating levels of 45 immune markers were determined by enzyme-immunoassay or immunoturbidimetry and analyzed for associations with use, doses, and serum concentrations of AP, AD, and MS. Extensive adjustments for potential confounders were performed. Immune marker levels of 1008 healthy controls served as a reference. RESULTS:AP use was significantly associated with higher plasma levels of beta defensin 2 (BD-2) (β = 0.094, p = 0.8E-4), AD use with higher serum levels of CRP (β = 0.072, p = 0.8E-3), and MS use with higher plasma levels of soluble interleukin 2 receptor (sIL-2R) (β = 0.063, p = 0.9E-4). These findings were paralleled by positive associations with psychotropic agent dose and serum concentrations: AP dose was associated with BD-2 levels (β = 0.045, p = 2.3E-4), AD dose with CRP levels (β = 0.039, p = 0.001), MS dose with sIL-2R levels (β = 0.048, p = 0.001), and serum concentration of AD was nominally positively associated with CRP (β = 0.072, p = 0.002). CONCLUSIONS:The findings suggest that AP and MS use affect pathways involved in immune homeostasis and inflammatory regulation in individuals with SMDs, while AD use augments low-grade systemic inflammation reflected by CRP.

Severe mental disorders have been linked to immune system dysfunction. While a genetic association between mental disorders and autoimmune diseases has been suggested, their genetic relationship remains incompletely understood. Utilizing a complementary set of statistical analyses, we conducted a comprehensive investigation of the genetic architecture between severe mental disorders (major depression (MD), bipolar disorder (BD), and schizophrenia (SCZ)) and seven autoimmune diseases (autoimmune thyroiditis, celiac disease, inflammatory bowel disease (IBD), multiple sclerosis, psoriasis, rheumatoid arthritis, and type 1 diabetes), involving a total of 667,518 cases from 10 genome-wide association studies. While MD was positively genetically correlated with five autoimmune diseases, BD and SCZ were only positively correlated with IBD, suggesting differences in the genetic signal shared with autoimmunity across these mental disorders. A considerable fraction of genetic variants influencing autoimmune diseases (range 17.1-88.4 %) was estimated to overlap with mental disorders; however, this constitutes only a minor part of genetic variants influencing the more polygenic mental disorders. Finally, we identified 172 genetic loci jointly affecting mental disorders and autoimmune diseases, implicating both lipid metabolism and TNF signaling. In conclusion, MD, BD, and SCZ have a small but distinct genetic overlap with autoimmune diseases, which may inform new possible immune targets for treatment in mental illness.

Objective Alterations in telomere length (TL), a marker of cellular ageing, have been reported in individuals with severe mental disorders (SMD) compared to unaffected peers. Epidemiological studies of the general population have highlighted that unhealthy lifestyles may exacerbate telomere attrition. However, the impact of lifestyle on TL within the context of SMD remains unexplored. Methods The study consisted of 410 participants (schizophrenia spectrum [n = 225] and affective disorder [n = 185]) collected as part of the Norwegian Thematically Organised Psychosis (TOP) study. Leukocyte TL was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR). Patients provided self-report data on six lifestyle domains including: diet, exercise, smoking, alcohol consumption, and substance use. A global dichotomised (healthy vs unhealthy) lifestyle variable was created, as well as a dose-dependent lifestyle variable indicating the level of unhealthy behaviours. Results Individuals with an unhealthy lifestyle had shorter telomere length compared to those with a healthy lifestyle (Cohen’s d = 0.59, F = 9.44, p = 0.002). A dose relationship was observed between increasing number of unhealthy behaviours and shorter TL (F = 2.80, p = 0.02), adjusted for age, sex, ethnicity, trauma exposure, daily defined dose (DDD) of medication, and diagnosis. In terms of base-pair loss, individuals with healthy lifestyles exhibited a roughly 6-year lower biological age, compared to individuals with unhealthy lifestyles. Conclusion Our study indicates that a healthier lifestyle is associated with longer TL in SMD. This highlights the importance of health behaviours as potential clinical targets for ensuring healthier cellular ageing in psychiatric populations.