Nils Eiel Steen

• Vai, Benedetta; Cazzella, Tommaso; Monopoli, Camilla; Bravi, Beatrice; Kontogianni, Anastasia & Wessa, Celine [Show all 42 contributors for this article] (2026). A Delphi-method-based consensus for clinical domains and assessment of the inflammatory subtype of major depressive disorder from the ASPIRE study. Brain, Behavior, and Immunity. ISSN 0889-1591. 138. doi: 10.1016/j.bbi.2026.106957.
• Wachtelaer, Eva; Trippaers, Chloë; Andreassen, Ole; Johansen, Ingrid Torp; Steen, Nils Eiel & Ask, Helga [Show all 11 contributors for this article] (2026). Post-infection mental illness: Mapping pathways of vulnerability and resilience in VIRAL-MInds. Brain, Behavior, and Immunity. ISSN 0889-1591. 134. doi: 10.1016/j.bbi.2026.106291. Full text in Research Archive
• Mlakar, Vid; Forti, Marta Di; Halff, Els F.; Srivastava, Deepak P.; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Show all 13 contributors for this article] (2026). Health behaviours and telomere biology in severe mental disorders. Translational Psychiatry. 16(1). doi: 10.1038/s41398-026-04362-2. Full text in Research Archive Show summary

  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.

• Rødevand, Linn Nilsen; Rahman, Mohammad Zillur; Jaholkowski, Piotr Pawel; Parker, Nadine; Valdimarsdóttir, Unnur Anna & Smeland, Olav Bjerkehagen [Show all 14 contributors for this article] (2026). Evidence for overlapping genetic architecture between lifestyle factors and severe mental disorders with different patterns across diagnoses. EBioMedicine. 128. doi: 10.1016/j.ebiom.2026.106304. Full text in Research Archive
• Slapø, Nora Berz; Jørgensen, Kjetil Nordbø; Nerland, Stener; Mørch-Johnsen, Lynn Egeland; Pettersen, Johanne Hagen & Roelfs, Daniel [Show all 23 contributors for this article] (2026). Relationship between N100 amplitude and T1w/T2w-ratio in the auditory cortex in schizophrenia spectrum disorders. Schizophrenia. doi: 10.1038/s41537-025-00715-w. Full text in Research Archive Show summary

  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.

• Zannadeh, Hiba; Aas, Monica; Sampath, Vishnu Priya; Andreassen, Ole; Steen, Nils Eiel & Jørgensen, Kjetil Nordbø [Show all 8 contributors for this article] (2026). Chemical element profiling in hair of bipolar disorder patients and healthy controls. Frontiers in Physiology. 16. doi: 10.3389/fphys.2025.1759047. Full text in Research Archive
• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Løberg, Else-Marie; Steen, Vidar Martin; Steen, Nils Eiel & Andreassen, Ole [Show all 13 contributors for this article] (2026). Neural and vascular cellular adhesion molecules are associated with cognitive function in patients with schizophrenia-spectrum disorders: A longitudinal study. Schizophrenia Research. ISSN 0920-9964. 290, p. 34–41. doi: 10.1016/j.schres.2026.01.021. Full text in Research Archive Show summary

  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.

• Nerland, Stener; Barth, Claudia; Jørgensen, Kjetil Nordbø; Bakke, Laura Anne Wortinger; Castro-Fornieles, Josefina & Díaz-Caneja, Covadonga M. [Show all 44 contributors for this article] (2026). Cerebral cortical alterations in adolescent early-onset psychosis: a surface-based morphometry mega-analysis. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-026-03641-0. Full text in Research Archive Show summary

  Abstract 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.

• Wiström, Erik David; Fuhrer, Julian; Shadrin, Alexey; Fominykh, Vera; O'Connell, Kevin Sean & Jaholkowski, Piotr Pawel [Show all 17 contributors for this article] (2026). Dissecting the genetic relationship between severe mental disorders and autoimmune diseases. Brain, Behavior, and Immunity. ISSN 0889-1591. 133. doi: 10.1016/j.bbi.2025.106249. Full text in Research Archive Show summary

  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.

• Kim, Milin; Leonardsen, Esten H.; Rutherford, Saige; Selbæk, Geir; Persson, Karin & Steen, Nils Eiel [Show all 16 contributors for this article] (2025). Mapping Cerebellar Morphology in 15q11.2 CNV Carriers Using Normative Modeling. medRxiv. doi: 10.1101/2025.05.28.25328353. Full text in Research Archive Show summary

  Abstract Copy number variations (CNVs) at the 15q11.2 locus of the human genome have been associated with altered brain structure and increased risk for neurodevelopmental and neuropsychiatric disorders. The cerebellum is increasingly seen as a crucial brain region for neurodevelopmental conditions, yet the effects of 15q11.2 CNVs on cerebellar morphology remain largely unclear. Importantly, 15q11.2 CNVs shows reduced or incomplete penetrance (meaning that not all CNV carriers are affected) and variable expressivity (meaning that symptoms may differ between individuals with the same genetic alteration). Thus, there is a need to not only assess group differences, but also to quantify anatomical variability at the individual level. Here, we address these issues using normative models of brain anatomy trained on large datasets (n > 52k, age range: 3-85) to assess both group and individual-level deviations in cerebellar anatomy in carriers of 15q11.2 deletions (n = 120, mean [SD] age= 64.95 [7.58]) and duplications (n = 149, mean [SD] age=64.31 [7.21]), compared to non-carriers (n = 19,028, mean [SD] age=64.31 [7.58]). Group-level case-control analyses revealed significantly smaller total and regional cerebellar volumes in both deletion and duplication carriers, though with small effect sizes. Individual-level deviation analyses, capturing pronounced alterations in specific individuals, revealed a heterogeneous pattern among carriers. Overall, our findings suggest that CNVs at the 15q11.2 locus exert modest and highly individualized effects on cerebellar morphology.

• Engchuan, Worrawat; Shanta, Omar; Kumar, Kuldeep; MacDonald, Jeffrey R.; Thiruvahindrapuram, Bhooma & Hamdan, Omar [Show all 250 contributors for this article] (2025). Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects. medRxiv. doi: 10.1101/2025.07.11.25331381. Full text in Research Archive Show summary

  Abstract Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality.

• Mlakar, Vid; Forti, Marta Di; Halff, Els F.; Srivastava, Deepak P.; Akkouh, Ibrahim Ahmed & Djurovic, Srdjan [Show all 13 contributors for this article] (2025). Coffee intake is associated with telomere length in severe mental disorders. BMJ Mental Health. 28(1). doi: 10.1136/bmjment-2025-301700. Full text in Research Archive
• Calkova, Tereza; Vaskinn, Anja; Mørch-Johnsen, Lynn Egeland; Smelror, Runar; Jørgensen, Kjetil Nordbø & Wortinger, Laura Anne [Show all 18 contributors for this article] (2025). Early versus adult onset of schizophrenia: an examination of premorbid and current IQ. Schizophrenia Research: Cognition. 43, p. 100397–100397. doi: 10.1016/j.scog.2025.100397. Full text in Research Archive Show summary

  Background Cognitive deficits are core findings in schizophrenia, but whether the severity of impairments is related to the age of onset remains unclear. We hypothesized that early onset schizophrenia (EOS; onset before age 19) is associated with lower IQ compared to adult-onset schizophrenia (AOS; onset from age 19). Methods We included 99 adult patients with EOS (age of onset: 15.3 ± 2.8 years), 282 adult patients with AOS (age of onset: 26.5 ± 7.4 years), and 863 adult healthy controls (HC). We assessed current IQ with Wechsler Abbreviated Scale of Intelligence (WASI) and estimated premorbid IQ with National Adult Reading Test (NART). Results Both patient groups had lower current IQ than HC ( p < 0.001). Full-scale ( p = 0.004), performance ( p = 0.003) and verbal ( p = 0.011) current IQ were significantly lower in EOS than in AOS, with 5 IQ units difference for all three measures. EOS and AOS did not differ in premorbid IQ, but EOS showed a steeper IQ decline from premorbid levels than AOS (11.4 vs. 8 IQ units, respectively, p = 0.013). Conclusion EOS had lower current IQ than AOS, but did not differ in premorbid IQ, suggesting a larger decline from premorbid IQ levels. This could imply different neurodevelopmental processes underlying cognitive dysfunction related to age of onset in schizophrenia, underscoring the necessity for further inquiry into the mechanisms driving this decline and strategies for its prevention.

• Smeland, Olav B.; Kutrolli, Gleda; Bahrami, Shahram; Fominykh, Vera; Parker, Nadine & Fuhrer, Julian [Show all 21 contributors for this article] (2025). A genome-wide analysis of the shared genetic risk architecture of complex neurological and psychiatric disorders. Nature Neuroscience. ISSN 1097-6256. 28(12), p. 2439–2450. doi: 10.1038/s41593-025-02090-2. Full text in Research Archive Show summary

  Although neurological and psychiatric disorders have historically been considered to reflect distinct pathogenic entities, recent findings suggest shared pathophysiological mechanisms. However, the extent to which these heritable disorders share genetic influences remains unclear. Here we performed a comprehensive analysis of genome-wide association study data, involving nearly 1 million cases across ten neurological diseases and ten psychiatric disorders, to compare their common genetic signal and biological associations. Using complementary statistical tools, we demonstrate that a large set of common genetic variants impacts the risk of multiple neurological and psychiatric disorders, even in the absence of genetic correlations. Furthermore, genome-wide association studies on psychiatric disorders consistently implicate neuronal biology, whereas neurological diseases are associated with diverse neurobiological processes. Together, this study elucidates the genetic relationship between complex neurological and psychiatric disorders, indicating a larger degree of genetic pleiotropy than previously recognized. The findings have implications for disease classification, precision medicine and clinical practice.

• Ormerod, Monica Bettina E. Greenwood; Sheikh, Mashhood Ahmed; Ueland, Thor; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Show all 15 contributors for this article] (2025). Minor immunomodulatory effects of psychotropics suggested in severe mental disorders: Associations of antipsychotics with beta defensin 2, antidepressants with C-reactive protein, and mood stabilizers with soluble interleukin 2 receptor. European psychiatry. ISSN 0924-9338. 68(1). doi: 10.1192/j.eurpsy.2025.10104. Full text in Research Archive Show summary

  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.

• Kreis, Isabel; Wold, Kristin Fjelnseth; Åsbø, Gina; Flaaten, Camilla Bärthel; Engen, Magnus Johan & Lyngstad, Siv Hege [Show all 13 contributors for this article] (2025). Recent cannabis use affects the association between baseline immune markers and long-term outcomes in psychosis. Translational Psychiatry. 15(1). doi: 10.1038/s41398-025-03498-x. Full text in Research Archive Show summary

  Aberrant levels of blood markers reflecting inflammation and immune system activation have been implicated in psychotic disorders and linked to psychotic symptom severity. However, their predictive value for the long-term course of psychotic symptoms as well as the potential confounding and moderating role of cannabis use remain underexplored. We tested if baseline levels of immune markers previously linked to psychotic symptoms or treatment response (CRP, IL-1RA, sIL-2R, sTNFR1, sgp130) predicted 10-year outcomes in a first-episode psychosis sample (N = 320), and whether associations were moderated by baseline cannabis use. We assessed psychiatric (re)admissions and number of psychotic episodes during each year of the follow-up period, as well as change in positive psychotic symptom severity from baseline. Apart from sTNFR1, none of the immune markers significantly predicted psychosis outcomes independently of cannabis use. Baseline sTNFR1 was linked to lower risk of both (re)admissions and psychotic episodes, with an increasingly negative association over time. The statistical effects of CRP, IL-1RA, and sgp130 were all dependent on cannabis use. Specifically, negative (CRP, IL-1RA) or positive associations (sgp130) with psychiatric (re)admission risk or psychotic episode risk were observed in cannabis users only. Similarly, sgp130 was negatively associated with symptom change in cannabis users only. Some of these associations varied by follow-up year of the measured outcome (sgp130, IL-1RA). These findings challenge the prognostic and etiological significance of baseline immune markers for the course of positive psychotic symptoms and emphasize the importance of accounting for cannabis use.

• Lunding, Synve Hoffart; Kreis, Isabel; Rødevand, Linn; Aas, Monica; Werner, Maren Caroline Frogner & Johansen, Ingrid Torp [Show all 16 contributors for this article] (2025). Self-harming behavior linked to earlier onset of cardiovascular disease in severe mental disorders. European psychiatry. ISSN 0924-9338. 68(1). doi: 10.1192/j.eurpsy.2025.10106. Full text in Research Archive Show summary

  Background People with severe mental disorders (SMDs) have about 15 years shorter life expectancy than the general population. Cardiovascular disease (CVD) is among the leading causes of premature mortality and shares genetic underpinnings with SMDs. We investigated the link between clinical traits in SMDs and time to the first CVD diagnosis. Methods The study included 1,627 well-characterized participants with schizophrenia spectrum (SCZ, N  = 998) and bipolar spectrum disorders (BDs, N  = 629), and a reference group of 1,201 healthy controls. CVD diagnoses were obtained from two Norwegian national registries (covering both primary and specialist health care) for the period of 2006–2020. Applying Cox proportional hazard models, we investigated associations between SMD clinical traits and time to first CVD diagnosis in SMD participants, adjusting for age, sex, diagnosis, and tobacco use. Results Among individuals with SMD, recurring self-harming behavior (SHB) was associated with a shorter time to first CVD diagnosis ( p  = .029) relative to those without SHB. In the subgroup with SHB and a history of attempted suicide(s), more suicide attempts were associated with shorter time to first CVD diagnosis ( p  = .041). Significant associations of time to first CVD diagnosis with age at SMD onset and comorbid substance use disorder were not demonstrated. Conclusions SHB and a history of suicide attempts in individuals with SMD seem to be associated with earlier CVD onset, and may improve the prediction of CVD, in addition to standard cardiovascular risk factors.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Nerland, Stener; Ueland, Thor & Wortinger, Laura Anne [Show all 13 contributors for this article] (2025). Toxoplasma gondii associated with psychotic symptom load and cortisol in severe mental illness. Schizophrenia. 11(80). doi: 10.1038/s41537-025-00630-0. Full text in Research Archive Show summary

  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.

• Ormerod, Monica Bettina E. Greenwood; Ueland, Thor; Aas, Monica; Hjell, Gabriela; Rødevand, Linn & Sæther, Linn Sofie [Show all 16 contributors for this article] (2025). Limited evidence of association between dysregulated immune marker levels and telomere length in severe mental disorders. Acta Neuropsychiatrica. ISSN 0924-2708. 37. doi: 10.1017/neu.2024.62. Full text in Research Archive Show summary

  Objective: Accelerated ageing indexed by telomere attrition is suggested in schizophrenia spectrum- (SCZ) and bipolar disorders (BD). While inflammation may promote telomere shortening, few studies have investigated the association between telomere length (TL) and markers of immune activation and inflammation in severe mental disorders. Methods: Leucocyte TL defined as telomere template/amount of single-copy gene template (T/S ratio), was determined in participants with SCZ (N = 301) or BD (N = 211) and a healthy control group (HC, N = 378). TL was analysed with linear regressions for associations with levels of 12 immune markers linked to SCZ or BD. Adjustments were made for a broad range of potential confounding variables. TL was measured by quantitative polymerase chain reaction (qPCR) and the immune markers were measured by enzyme immunoassays. Results: A positive association between levels of soluble tumour necrosis factor receptor 1A (sTNF-R1) and TL in SCZ (β = 0.191, p = 0.012) was observed. Plasma levels of the other immune markers were not significantly associated with TL in the BD, SCZ or HC groups. Conclusion: There was limited evidence of association between immune markers and TL in SCZ and BD. The results provide little support for involvement of immune dysregulation, as reflected by current systemic markers, in telomere attrition-related accelerated ageing in severe mental disorders.

• Wiström, Erik David; O'Connell, Kevin Sean; Koch, Elise; Jaholkowski, Piotr Pawel; Hindley, Guy & Steen, Nils Eiel [Show all 14 contributors for this article] (2025). The genetic overlap between major depressive disorder, white blood cell counts and interleukin 6. Journal of Affective Disorders Reports. 20, p. 1–10. doi: 10.1016/j.jadr.2025.100889. Full text in Research Archive Show summary

  Background: Immune dysregulation may contribute to the pathophysiology of major depressive disorder (MDD). Here we aimed to identify genetic architecture jointly associated with MDD, white blood cell (WBC) count and interleukin 6 (IL-6) levels. Methods: Using genome-wide association studies summary statistics on MDD (330,173 cases and 727,595 controls), WBC counts (nmax = 563,946) and IL-6 (n = 52,654), we performed linkage disequilibrium (LD) score regression, bivariate causal mixture model (MiXeR), conjunctional false discovery rate (conjFDR) and Mendelian randomization (MR) analyses. Additionally, we used an independent MDD dataset (9,582 cases and 84,670 controls) from the Norwegian Mother, Father and Child Cohort Study for polygenic risk score (PRS) analyses. Findings: We found a significant positive genetic correlation (rg = 0.22) between MDD and IL-6. MiXeR estimates indicated substantial differences in the polygenicity of MDD (13.7K variants), WBC subgroups (0.8K-1.8K variants), and IL-6 (0.2K variants), with 10.1 %-31.4 % of the variants influencing WBC subgroups overlapping with MDD. We identified MDD risk loci shared with basophils (8), eosinophils (17), lymphocytes (23), monocytes (14), neutrophils (20), and total WBC counts (20), as well as two loci shared between MDD and IL-6, at conjFDR <0.05. PRS analysis showed a weak, but significantly increased risk for MDD dependent on monocyte count. Limitations: The analyses only included European ancestry samples, and the causal genes associated with the identified genetic loci were not experimentally validated. Conclusions: MDD shares genetic underpinnings with immune system components, which implicates immune-mediated pathways in the pathophysiology of MDD. However, this connection may only be relevant for a minority of patients.

• Kim, Milin; Sharma, Nitin; Leonardsen, Esten Høyland; Rutherford, Saige; Selbæk, Geir & Persson, Karin Ester Torun [Show all 19 contributors for this article] (2025). Predicting Mental and Neurological Illnesses Based on Cerebellar Normative Features. Biological Psychiatry: Global Open Science. 5(5), p. 1–11. doi: 10.1016/j.bpsgos.2025.100541. Full text in Research Archive
• Pentz, Atle Bråthen; Exposito, Veronica; Jole, Oda van; Nerland, Stener; Melle, Ingrid & Steen, Nils Eiel [Show all 13 contributors for this article] (2025). Auditory MMN is associated with the volume of thalamic higher order nuclei in individuals with psychotic disorders and healthy controls. Schizophrenia Research. ISSN 0920-9964. 276, p. 222–233. doi: 10.1016/j.schres.2025.01.031. Full text in Research Archive Show summary

  Objective Predictive coding is a theoretical framework that integrates models of brain dysconnectivity and psychopathology in psychosis. Thalamocortical dysconnectivity as well as reduced thalamic volumes have been reported in psychotic disorders. However, the role of the thalamus in predictive coding is not clear. We examined the relationship between magnetic resonance imaging (MRI)- based thalamic nuclei volumes and mismatch negativity (MMN), a purported index of prediction error signaling known to be impaired in psychosis. Methods We obtained MRI and MMN using a roving paradigm from individuals with SCZ spectrum disorder (SSD, n = 60) or bipolar disorder (BD, n = 69) and HC (n = 252). We segmented volumes of 25 thalamic nuclei bilaterally and tested their associations with MMN amplitude using linear models while covarying for age, sex, diagnosis, and intracranial volumes (ICV). Results We did not find group differences in thalamic volumes that could account for differences in MMN, neither did we find significant volume × diagnosis interactions on MMN for any of the 25 nuclei examined. Across the whole sample, significant positive associations were found between MMN amplitude and the volumes of several higher-order thalamic nuclei, including the mediodorsal medial and lateral nuclei, anterior and medial pulvinar, nucleus reuniens, as well as the lateral geniculate nucleus. Conclusion The results demonstrate a positive association between MMN amplitude and volumes of thalamic association nuclei in patients with psychotic disorders and HC. These findings may suggest a modulatory role of the thalamus in prediction error signaling.

• Meer, Dennis van der; Rahman, Mohammad Zillur; Ottas, Aigar; Parekh, Pravesh; Kutrolli, Gleda & Stinson, Sara Elizabeth [Show all 37 contributors for this article] (2025). Pleiotropic and sex-specific genetic mechanisms of circulating metabolic markers. Nature Communications. 16(1). doi: 10.1038/s41467-025-60058-z. Full text in Research Archive Show summary

  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.

• Inova, Amina; Birkenæs, Viktoria; Quintana, Daniel; Ormerod, Monica Bettina E. Greenwood; Ueland, Torill & Ueland, Thor [Show all 10 contributors for this article] (2024). Cortisol and C-reactive protein (CRP) regulation in severe mental disorders. Psychoneuroendocrinology. ISSN 0306-4530. 172. doi: 10.1016/j.psyneuen.2024.107272. Full text in Research Archive Show summary

  Background People with schizophrenia (SZ) and bipolar disorder (BD) show abnormalities in the biological stress system and low-grade inflammation. However, whether the hypothalamic-pituitary-adrenal (HPA) axis-immune regulation is disrupted in SZ and BD, is yet to be determined. Methods Cortisol and C-reactive protein (CRP) were measured in blood samples collected at or before 10 am in participants with SZ (N = 257), BD (N = 153), and healthy controls (N = 40). Cortisol/CRP ratio was calculated as an indicator of the balance between HPA axis activity and inflammatory activity, called HPA axis-immune regulation. Global functioning and symptom levels were obtained using the Global Assessment of Functioning (GAF) Scale and Positive and Negative Syndrome Scale (PANSS). Standardized neuropsychological tests were used to assess cognitive function. All analyses were adjusted for demographic variables (age and sex) and the time of blood sampling. Results Participants with a SZ or BD diagnosis had lower cortisol/CRP ratios (F=5.93, p = 0.003) compared to healthy controls. The difference was no longer statistically significant (p > 0.1) when BMI was added as a covariate to the model. Within patients, those on psychotropic treatment (n = 337) had lower cortisol/CRP ratio than those not taking psychotropic agents (n = 59) (F=4.72, p = 0.03). Compared to HC, only patients on regular psychotropic agents had lower cortisol/CRP ratio (p = 0.02). Within the SZ group, lower cortisol/CRP ratio was associated with having poorer general functioning as measured by GAF (ß=-0.18, p = 0.01), and more severe negative and general symptomatology as measured by PANSS (ß=0.19, p = 0.007 and ß=0.18, p = 0.01, respectively). In SZ, lower cortisol/CRP ratio was also associated with poorer verbal memory, learning, and processing speed (ß=-0.20 p = 0.007, ß=-0.19 p = 0.01, ß=-0.25, p > 0.001, respectively). No associations were observed between cortisol/CRP ratio and clinical and cognitive functioning in the BD group. Conclusion These findings may indicate HPA axis-immune dysregulation in SZ. Our study further indicates that disrupted HPA axis-immune regulation in people with SZ and BD is associated with psychotropic treatment and fat mass, highlighting the clinical importance of weight control and regular psychotropic treatment follow-ups within this group.

• Pentz, Atle Bråthen; O'Connell, Kevin Sean; Jole, Oda van; Timpe, Clara Marie Fides; Slapø, Nora Berz & Melle, Ingrid [Show all 14 contributors for this article] (2024). Mismatch negativity and polygenic risk scores for schizophrenia and bipolar disorder. Schizophrenia Research. ISSN 0920-9964. 264, p. 314–326. doi: 10.1016/j.schres.2024.01.013. Full text in Research Archive Show summary

  Objective: Auditory mismatch negativity (MMN) impairment is a candidate endophenotype in psychotic disorders, yet the genetic underpinnings remain to be clarified. Here, we examined the relationships between auditory MMN and polygenic risk scores (PRS) for individuals with psychotic disorders, including schizophrenia spectrum disorders (SSD) and bipolar disorder (BD) and in healthy controls (HC). Methods: Genotyped and clinically well-characterized individuals with psychotic disorders (n = 102), including SSD (n = 43) and BD (n = 59), and HC (n = 397) underwent a roving MMN paradigm. In addition MMN, we measured the memory traces of the repetition positivity (RP) and the deviant negativity (DN), which is believed to reflect prediction encoding and prediction error signals, respectively. SCZ and BD PRS were computed using summary statistics from the latest genome-wide association studies. The relationships between the MMN, RP, and DN and the PRSs were assessed with linear regressions. Results: We found no significant association between the SCZ or BD PRS and grand average MMN in the psychotic disorders group or in the HCs group (all p > 0.05). SCZ PRS and BD PRS were negatively associated with RP in the psychotic disorders group (β = 0.46, t = 2.86, p = 0.005 and β = 0.29, t = 0.21, p = 0.034, respectively). No significant associations were found between DN and PRS. Conclusion: These findings suggest that genetic variants associated with SCZ and BD may be associated with MMN subcomponents linked to predictive coding among patients with psychotic disorders. Larger studies are needed to confirm these findings and further elucidate the genetic underpinnings of MMN impairment in psychotic disorders.

• Sartorius, Alina Marie; Rokicki, Jaroslav; Birkeland, Siri; Bettella, Francesco; Barth, Claudia & Lange, Ann-Marie Glasø de [Show all 17 contributors for this article] (2024). An evolutionary timeline of the oxytocin signaling pathway. Communications Biology. 7(1). doi: 10.1038/s42003-024-06094-9. Full text in Research Archive Show summary

  Oxytocin is a neuropeptide associated with both psychological and somatic processes like parturition and social bonding. Although oxytocin homologs have been identified in many species, the evolutionary timeline of the entire oxytocin signaling gene pathway has yet to be described. Using protein sequence similarity searches, microsynteny, and phylostratigraphy, we assigned the genes supporting the oxytocin pathway to different phylostrata based on when we found they likely arose in evolution. We show that the majority (64%) of genes in the pathway are ‘modern’. Most of the modern genes evolved around the emergence of vertebrates or jawed vertebrates (540 - 530 million years ago, ‘mya’), including OXTR, OXT and CD38. Of those, 45% were under positive selection at some point during vertebrate evolution. We also found that 18% of the genes in the oxytocin pathway are ‘ancient’, meaning their emergence dates back to cellular organisms and opisthokonta (3500–1100 mya). The remaining genes (18%) that evolved after ancient and before modern genes were classified as ‘medium-aged’. Functional analyses revealed that, in humans, medium-aged oxytocin pathway genes are highly expressed in contractile organs, while modern genes in the oxytocin pathway are primarily expressed in the brain and muscle tissue.

• Mlakar, Vid; Akkouh, Ibrahim Ahmed; Halff, Els F.; Srivastava, Deepak P.; Birkenæs, Viktoria & Ueland, Torill [Show all 12 contributors for this article] (2024). Telomere biology and its maintenance in schizophrenia spectrum disorders: Exploring links to cognition. Schizophrenia Research. ISSN 0920-9964. 272, p. 89–95. doi: 10.1016/j.schres.2024.08.011. Full text in Research Archive Show summary

  Objective Contemporary research suggests reduced telomere length in schizophrenia spectrum disorders (SZ) compared to age-adjusted non-affected individuals. However, the role of telomere maintenance and telomere repair in SZ is poorly understood as well as the involvement of telomere biology in cognitive abnormalities in SZ. Methods The study consisted of 758 participants (SZ [n = 357] and healthy controls, HC [n = 401]) collected as part of the Norwegian TOP study. Participants were assessed with standardized neuropsychological tests measuring five cognitive domains. Leucocyte telomere length (TL) was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio), used to estimate the mean telomere length. Telomerase activity was assessed by the expression levels of the Telomerase Reverse Transcriptase (TERT) and Telomerase RNA Component (TERC) genes. To assess telomere maintenance and telomere repair we calculated the telomerase expression to TL ratio (TERT/TL and TERC/TL respectively). Results Patients had reduced TERT (F = 5.03, p = 0.03), but not TERC expression (F = 1.04, p = 0.31), and higher TERT/TL (F = 6.68, p = 0.01) and TERC/TL (F = 6.71, p = 0.01), adjusted for age, sex, and ethnicity. No statistically significant association was observed between any of the telomere biology markers and the cognitive domains (p > 0.05). Conclusion Our study shows changes in TERT expression and telomere maintenance and telomere repair in SZ compared HC. However, the role of telomere biology in the mechanism underlying cognitive impairment in psychosis seems limited.

• Andreou, Dimitrios; Steen, Nils Eiel; Mørch-Johnsen, Lynn Egeland; Jørgensen, Kjetil Nordbø; Wortinger, Laura Anne & Barth, Claudia [Show all 19 contributors for this article] (2024). Toxoplasma gondii infection associated with inflammasome activation and neuronal injury. Scientific Reports. 14(1). doi: 10.1038/s41598-024-55887-9. Full text in Research Archive Show summary

  Toxoplasma gondii (TOXO) infection typically results in chronic latency due to its ability to form cysts in the brain and other organs. Latent toxoplasmosis could promote innate immune responses and impact brain function. A large body of evidence has linked TOXO infection to severe mental illness (SMI). We hypothesized that TOXO immunoglobulin G (IgG) seropositivity, reflecting previous infection and current latency, is associated with increased circulating neuron-specific enolase (NSE), a marker of brain damage, and interleukin-18 (IL-18), an innate immune marker, mainly in SMI. We included 735 patients with SMI (schizophrenia or bipolar spectrum) (mean age 32 years, 47% women), and 518 healthy controls (HC) (mean age 33 years, 43% women). TOXO IgG, expressed as seropositivity/seronegativity, NSE and IL-18 were measured with immunoassays. We searched for main and interaction effects of TOXO, patient/control status and sex on NSE and IL-18. In the whole sample as well as among patients and HC separately, IL-18 and NSE concentrations were positively correlated (p < 0.001). TOXO seropositive participants had significantly higher NSE (3713 vs. 2200 pg/ml, p < 0.001) and IL-18 levels (1068 vs. 674 pg/ml, p < 0.001) than seronegative participants, and evaluation within patients and HC separately showed similar results. Post-hoc analysis on cytomegalovirus and herpes simplex virus 1 IgG status showed no associations with NSE or IL-18 which may suggest TOXO specificity. These results may indicate ongoing inflammasome activation and neuronal injury in people with TOXO infections unrelated to diagnosis.

• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Show all 18 contributors for this article] (2024). Dissecting the Shared Genetic Architecture of Common Epilepsies With Cortical Brain Morphology. Neurology: Genetics. 10(3). doi: 10.1212/NXG.0000000000200143. Full text in Research Archive Show summary

  Background and Objectives: Epilepsies are associated with differences in cortical thickness (TH) and surface area (SA). However, the mechanisms underlying these relationships remain elusive. We investigated the extent to which these phenotypes share genetic influences. Methods: We analyzed genome-wide association study data on common epilepsies (n = 69,995) and TH and SA (n = 32,877) using Gaussian mixture modeling MiXeR and conjunctional false discovery rate (conjFDR) analysis to quantify their shared genetic architecture and identify overlapping loci. We biologically interrogated the loci using a variety of resources and validated in independent samples. Results: The epilepsies (2.4 k–2.9 k variants) were more polygenic than both SA (1.8 k variants) and TH (1.3 k variants). Despite absent genome-wide genetic correlations, there was a substantial genetic overlap between SA and genetic generalized epilepsy (GGE) (1.1 k), all epilepsies (1.1 k), and juvenile myoclonic epilepsy (JME) (0.7 k), as well as between TH and GGE (0.8 k), all epilepsies (0.7 k), and JME (0.8 k), estimated with MiXeR. Furthermore, conjFDR analysis identified 15 GGE loci jointly associated with SA and 15 with TH, 3 loci shared between SA and childhood absence epilepsy, and 6 loci overlapping between SA and JME. 23 loci were novel for epilepsies and 11 for cortical morphology. We observed a high degree of sign concordance in the independent samples. Discussion: Our findings show extensive genetic overlap between generalized epilepsies and cortical morphology, indicating a complex genetic relationship with mixed-effect directions. The results suggest that shared genetic influences may contribute to cortical abnormalities in epilepsies.

• Szabo, Attila; O'Connell, Kevin Sean; Akkouh, Ibrahim Ahmed; Ueland, Thor; Sønderby, Ida Elken & Hope, Sigrun [Show all 16 contributors for this article] (2024). Elevated levels of peripheral and central nervous system immune markers reflect innate immune dysregulation in autism spectrum disorder. Psychiatry Research. ISSN 0165-1781. 342. doi: 10.1016/j.psychres.2024.116245. Full text in Research Archive Show summary

  Background Evidence suggests dysregulated immune functions in the pathophysiology of Autism spectrum disorder (ASD), although specific immune mechanisms are yet to be identified. Methods We assessed circulating levels of 25 immune/neuroinflammatory markers in a large ASD sample (n = 151) and matched controls (n = 72) using linear models. In addition, we performed global brain transcriptomics analyses of relevant immune-related genes. We also assessed the expression and function of factors and pathway elements of the inflammasome system in peripheral blood mononuclear cells (PBMC) isolated from ASD and controls using in vitro methods. Results We found higher circulating levels of IL-18 and adhesion factors (ICAM-1, MADCAM1) in individuals with ASD relative to controls. Consistent with this, brain levels of ICAM1 mRNA were also higher in ASD compared to controls. Furthermore, we found higher expression/activity of Caspase-1 and the inflammasome sensor NLRP3 in PBMCs in ASD, both at baseline and following inflammatory challenge. This corresponded with higher levels of secreted IL-18, IL-1β, and IL-8, as well as increased expression of adhesion factors following inflammasome activation in ASD PBMC cultures. Inhibition of the NLRP3-inflammasome rescued the observed immune phenotype in ASD in vitro. Conclusion Our results suggest a role for inflammasome dysregulation in ASD pathophysiology.

• Sæther, Linn Sofie; Szabo, Attila; Akkouh, Ibrahim Ahmed; Haatveit, Beathe; Mohn, Christine & Vaskinn, Anja [Show all 14 contributors for this article] (2024). Cognitive and inflammatory heterogeneity in severe mental illness: Translating findings from blood to brain. Brain, Behavior, and Immunity. ISSN 0889-1591. 118, p. 287–299. doi: 10.1016/j.bbi.2024.03.014. Full text in Research Archive Show summary

  Recent findings link cognitive impairment and inflammatory-immune dysregulation in schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, heterogeneity and translation between the periphery and central (blood-to-brain) mechanisms remains a challenge. Starting with a large SZ, BD and healthy control cohort (n = 1235), we aimed to i) identify candidate peripheral markers (n = 25) associated with cognitive domains (n = 9) and elucidate heterogenous immune-cognitive patterns, ii) evaluate the regulation of candidate markers using human induced pluripotent stem cell (iPSC)-derived astrocytes and neural progenitor cells (n = 10), and iii) evaluate candidate marker messenger RNA expression in leukocytes using microarray in available data from a subsample of the main cohort (n = 776), and in available RNA-sequencing deconvolution analysis of postmortem brain samples (n = 474) from the CommonMind Consortium (CMC). We identified transdiagnostic subgroups based on covariance between cognitive domains (measures of speed and verbal learning) and peripheral markers reflecting inflammatory response (CRP, sTNFR1, YKL-40), innate immune activation (MIF) and extracellular matrix remodelling (YKL-40, CatS). Of the candidate markers there was considerable variance in secretion of YKL-40 in iPSC-derived astrocytes and neural progenitor cells in SZ compared to HC. Further, we provide evidence of dysregulated RNA expression of genes encoding YKL-40 and related signalling pathways in a high neuroinflammatory subgroup in the postmortem brain samples. Our findings suggest a relationship between peripheral inflammatory-immune activity and cognitive impairment, and highlight YKL-40 as a potential marker of cognitive functioning in a subgroup of individuals with severe mental illness.

• Frei, Oleksandr; Hindley, Guy; Shadrin, Alexey; Meer, Dennis van der; Akdeniz, Bayram Cevdet & Hagen, Espen [Show all 50 contributors for this article] (2024). Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nature Genetics. ISSN 1061-4036. 56(6), p. 1310–1318. doi: 10.1038/s41588-024-01771-1. Full text in Research Archive
• Koch, Elise Mirjam; Kämpe, Anders; Alver, Maris; Sigurðarson, Sindri; Einarsson, Guðmundur & Partanen, Juulia [Show all 21 contributors for this article] (2024). Polygenic liability for antipsychotic dosage and polypharmacy - a real-world registry and biobank study. Neuropsychopharmacology. ISSN 0893-133X. 49, p. 1113–1119. doi: 10.1038/s41386-023-01792-0. Full text in Research Archive
• Kim, Milin; Leonardsen, Esten Høyland; Rutherford, Saige; Selbæk, Geir; Persson, Karin Ester Torun & Steen, Nils Eiel [Show all 15 contributors for this article] (2024). Mapping cerebellar anatomical heterogeneity in mental and neurological illnesses. Nature Mental Health. 2(10), p. 1196–1207. doi: 10.1038/s44220-024-00297-z. Full text in Research Archive Show summary

  The cerebellum is linked to motor coordination, cognitive and affective processing, in addition to a wide range of clinical illnesses. To enable robust quantification of individual cerebellar anatomy relative to population norms, we mapped the normative development and aging of the cerebellum across the lifespan using brain scans of >54,000 participants. We estimated normative models at voxel-wise spatial precision, enabling integration with cerebellar atlases. Applying the normative models in independent samples revealed substantial heterogeneity within five clinical illnesses: autism spectrum disorder, mild cognitive impairment, Alzheimer disease, bipolar disorder, and schizophrenia. Notably, individuals with autism spectrum disorder and mild cognitive impairment exhibited increased positive and negative extreme deviations in cerebellar anatomy, while those with schizophrenia and Alzheimer disease showed predominantly negative deviations. Finally, extreme deviations were associated with cognitive scores. Ou

• Karadag, Naz; Hagen, Espen; Shadrin, Alexey; Meer, Dennis van der; O'Connell, Kevin Sean & Rahman, Mohammad Zillur [Show all 19 contributors for this article] (2024). Unraveling the shared genetics of common epilepsies and general cognitive ability. Seizure. ISSN 1059-1311. 122, p. 105–112. doi: 10.1016/j.seizure.2024.09.016. Full text in Research Archive Show summary

  Purpose Cognitive impairment is prevalent among individuals with epilepsy, and increasing evidence indicates that genetic factors can underlie this relationship. However, the extent to which epilepsy subtypes differ in their genetic relationship with cognitive function, and information about the specific genetic variants involved remain largely unknown. Methods We investigated the genetic relationship between epilepsies and general cognitive ability (COG) using complementary statistical tools, including linkage disequilibrium score (LDSC) regression, MiXeR and conjunctional false discovery rate (conjFDR). We analyzed genome-wide association study data on COG (n = 269,867) and common epilepsies (n = 27,559 cases, 42,436 controls), including the broad phenotypes ‘all epilepsy’, focal epilepsies and genetic generalized epilepsies (GGE), as well as specific subtypes. We functionally annotated the identified loci using several biological resources and validated the results in independent samples. Results Using MiXeR, COG (11.2k variants) was estimated to be almost four times more polygenic than ‘all epilepsy’, GGE, juvenile myoclonic epilepsy (JME), and childhood absence epilepsy (CAE) (2.5k – 2.9k variants). The other epilepsy phenotypes were insufficiently powered for MiXeR analysis. We quantified extensive genetic overlap between COG and epilepsy types, but with varying negative genetic correlations (-0.23 to -0.04). COG was estimated to share 2.9k variants with both GGE and ‘all epilepsy’, and 2.3k variants with both JME and CAE. Using conjFDR, we identified 66 distinct loci shared between COG and epilepsies, including novel associations for GGE (27), ‘all epilepsy’ (5), JME (5) and CAE (5). The implicated genes were significantly expressed in multiple brain regions. The results were validated in independent samples (COG: p = 3.62 × 10–7; ‘all epilepsy’: p = 2.58 × 10–3). Conclusion Our study further dissects the substantial genetic basis shared between epilepsies and COG and identifies novel shared loci. An improved understanding of the genetic relationship between epilepsies and COG may lead to the development of novel comorbidity-targeted epilepsy treatments.

• Johansen, Ingrid Torp; Steen, Nils Eiel; Rødevand, Linn; Lunding, Synve Hoffart; Hjell, Gabriela & Ormerod, Monica Bettina E. Greenwood [Show all 11 contributors for this article] (2024). Sex differences in autonomic adverse effects related to antipsychotic treatment and associated hormone profiles. Schizophrenia. 10. doi: 10.1038/s41537-023-00430-4. Full text in Research Archive Show summary

  Autonomic adverse effects of antipsychotic drugs (APs) cause clinical challenges, but few studies have investigated sex differences and their underlying biological pathways. Sex-specific regulation of relevant hormones could be involved. We investigated sex differences in autonomic adverse effects related to olanzapine, quetiapine, risperidone, and aripiprazole, and the role of hormones related to APs. Patients with severe mental disorders (N = 1318) were included and grouped based on AP monotherapy: olanzapine (N = 364), quetiapine (N = 211), risperidone (N = 102), aripiprazole (N = 138), and no AP (N = 503). Autonomic symptoms from the Udvalg for Kliniske Undersøgelser (UKU) side effect scale was analyzed with logistic regression, adjusting for age, diagnosis, and polypharmacy. Further, we analyzed associations between autonomic symptoms and hormones related to APs. We found associations between autonomic adverse effects and APs, with sex-specific risk for palpitations/tachycardia associated with hormonal changes related to APs. Results showed increased salivation associated with aripiprazole, reduced salivation with quetiapine, and nausea/vomiting and palpitations/tachycardia with olanzapine, and higher risk of nausea/vomiting, diarrhea, constipation, polyuria/polydipsia, and palpitations/tachycardia in females. Significant sex x AP interaction was found for palpitations/tachycardia, with higher risk in risperidone-treated males, which was associated with different hormone profiles of prolactin, cortisol, and insulin. Our findings implicate a role of several hormones in the sex-specific autonomic adverse effects related to APs.

• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Steen, Vidar Martin; Andreassen, Ole A.; Steen, Nils Eiel & Ueland, Thor [Show all 12 contributors for this article] (2024). Cellular adhesion molecules in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders. Schizophrenia Research. ISSN 0920-9964. 267, p. 223–229. doi: 10.1016/j.schres.2024.03.029. Full text in Research Archive Show summary

  Background Endothelial inflammation may be involved in the pathogenesis of schizophrenia, and cellular adhesion molecules (CAMs) on endothelial cells may facilitate leukocyte binding and transendothelial migration of cells and inflammatory factors. The aim of the present study was to assess levels of soluble cellular adhesion molecules, including intercellular adhesion molecule (ICAM)-1, vascular adhesion molecule (VCAM)-1, mucosal addressin cell adhesion molecule (MADCAM), junctional adhesion molecule (JAM-A) and neural cadherin (N-CAD) in patients with schizophrenia compared to healthy controls. Methods The study population consists of 138 patients with schizophrenia-spectrum disorder, of whom 54 were drug-naïve, compared to 317 general population controls. The potential confounders age, gender, smoking and body mass index (BMI) were adjusted for in linear regression models. Results The total patient group showed significantly higher levels of ICAM-1 (p < 0.001) and VCAM-1 (p < 0.001) compared to controls. Previously medicated patients showed higher ICAM-1 levels compared to drug-naïve patients (p = 0.042) and controls (p < 0.001), and elevated VCAM-1 levels compared to controls (p < 0.001). Drug-naive patients had elevated levels of VCAM-1 (p = 0.031) compared to controls. Conclusions In our study, patients with schizophrenia – including the drug-naïve – have higher levels of soluble CAMs compared to healthy controls. These findings suggest activation of the endothelial system as in inflammation.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Ueland, Thor; Wortinger, Laura Anne & Mørch-Johnsen, Lynn Egeland [Show all 11 contributors for this article] (2024). Increased Herpes simplex virus 1, Toxoplasma gondii and Cytomegalovirus antibody concentrations in severe mental illness. Translational Psychiatry. 14(1). doi: 10.1038/s41398-024-03198-y. Full text in Research Archive Show summary

  Infections with Cytomegalovirus (CMV), Herpes simplex virus 1 (HSV1) and Toxoplasma gondii (TG) have been implicated in severe mental illness. All three pathogens have high seroprevalence in the human population, are neurotropic and establish a persistent infection. We hypothesized that exposed (seropositive) patients with severe mental illness would show higher immunoglobulin G (IgG) concentrations than exposed healthy controls (HC). We included 765 patients with severe mental illness (schizophrenia n = 515, bipolar disorder n = 250) and 541 HC. CMV, HSV1 and TG IgG seropositivity and concentrations were measured with immunoassays (seropositivity: CMV, n = 447 patients vs. 296 HC; HSV1, n = 355 vs. 238; and TG, n = 159 vs. 126). Among seropositive participants, patients had higher HSV1 (p < 0.001) and TG (p = 0.003) IgG concentrations than HC. Stratifying by diagnosis, both schizophrenia (p = 0.001) and bipolar disorder (p = 0.001) had higher HSV1 IgG concentrations, while schizophrenia only had higher TG (p = 0.009) and CMV (p = 0.045) IgG concentrations than HC. In SZ, higher HSV1 IgG concentrations were associated with higher psychotic (p = 0.030) and manic (p = 0.008) symptom scores, but only among CMV- or TG-infected patients which suggests synergistic effects. Among all participants, HSV1 IgG concentrations were inversely associated with interleukin-18 (p < 0.001) and positively associated with high-sensitivity C-reactive protein (p = 0.002) and B cell-activating factor (p = 0.004), possibly indicating T cell exhaustion, enhanced inflammation, and increased B-cell response, respectively. Patients with severe mental illness exhibit a heightened immune system response to HSV1, TG, and CMV infections suggesting immune system dysfunction and/or a more severe infection. For HSV1, higher IgG concentrations were linked to a greater clinical burden.

• Sæther, Linn Sofie; Ueland, Thor; Haatveit, Beathe; Vaskinn, Anja; Flaaten, Camilla Bärthel & Mohn, Hanne Christine [Show all 12 contributors for this article] (2024). Longitudinal course of inflammatory-cognitive subgroups across first treatment severe mental illness and healthy controls. Psychological Medicine. ISSN 0033-2917. 54, p. 3519–3529. doi: 10.1017/S003329172400206X. Full text in Research Archive Show summary

  Background - While inflammation is associated with cognitive impairment in severe mental illnesses (SMI), there is substantial heterogeneity and evidence of transdiagnostic subgroups across schizophrenia (SZ) and bipolar (BD) spectrum disorders. There is however, limited knowledge about the longitudinal course of this relationship.<p> <p>Methods - Systemic inflammation (C-Reactive Protein, CRP) and cognition (nine cognitive domains) was measured from baseline to 1 year follow-up in first treatment SZ and BD (n = 221), and healthy controls (HC, n = 220). Linear mixed models were used to evaluate longitudinal changes separately in CRP and cognitive domains specific to diagnostic status (SZ, BD, HC). Hierarchical clustering was applied on the entire sample to investigate the longitudinal course of transdiagnostic inflammatory-cognitive subgroups.<p> <p>Results - There were no case-control differences or change in CRP from baseline to follow-up. We confirm previous observations of case-control differences in cognition at both time-points and domain specific stability/improvement over time regardless of diagnostic status. We identified transdiagnostic inflammatory-cognitive subgroups at baseline with differing demographics and clinical severity. Despite improvement in cognition, symptoms and functioning, the higher inflammation – lower cognition subgroup (75% SZ; 48% BD; 38% HC) had sustained inflammation and lower cognition, more symptoms, and lower functioning (SMI only) at follow-up. This was in comparison to a lower inflammation – higher cognition subgroup (25% SZ, 52% BD, 62% HC), where SMI participants showed cognitive functioning at HC level with a positive clinical course.<p> <p>Conclusions - Our findings support heterogenous and transdiagnostic inflammatory-cognitive subgroups that are stable over time, and may benefit from targeted interventions.

• Steen, Nils Eiel; Rahman, Zillur; Szabo, Attila; Hindley, Guy; Parker, Nadine & Cheng, Weiqiu [Show all 20 contributors for this article] (2023). Shared Genetic Loci Between Schizophrenia and White Blood Cell Counts Suggest Genetically Determined Systemic Immune Abnormalities. Schizophrenia Bulletin. ISSN 0586-7614. 49(5), p. 1345–1354. doi: 10.1093/schbul/sbad082. Full text in Research Archive Show summary

  Background: Immune mechanisms are indicated in schizophrenia (SCZ). Recent genome-wide association studies (GWAS) have identified genetic variants associated with SCZ and immune-related phenotypes. Here, we use cutting edge statistical tools to identify shared genetic variants between SCZ and white blood cell (WBC) counts and further understand the role of the immune system in SCZ. Study Design: GWAS results from SCZ (patients, n = 53 386; controls, n = 77 258) and WBC counts (n = 56 3085) were analyzed. We applied linkage disequilibrium score regression, the conditional false discovery rate method and the bivariate causal mixture model for analyses of genetic associations and overlap, and 2 sample Mendelian randomization to estimate causal effects. Study Results: The polygenicity for SCZ was 7.5 times higher than for WBC count and constituted 32%–59% of WBC count genetic loci. While there was a significant but weak positive genetic correlation between SCZ and lymphocytes (rg = 0.05), the conditional false discovery rate method identified 383 shared genetic loci (53% concordant effect directions), with shared variants encompassing all investigated WBC subtypes: lymphocytes, n = 215 (56% concordant); neutrophils, n = 158 (49% concordant); monocytes, n = 146 (47% concordant); eosinophils, n = 135 (56% concordant); and basophils, n = 64 (53% concordant). A few causal effects were suggested, but consensus was lacking across different Mendelian randomization methods. Functional analyses indicated cellular functioning and regulation of translation as overlapping mechanisms. Conclusions: Our results suggest that genetic factors involved in WBC counts are associated with the risk of SCZ, indicating a role of immune mechanisms in subgroups of SCZ with potential for stratification of patients for immune targeted treatment.

• Rødevand, Linn Nilsen; Rahman, Zillur; Hindley, Guy Frederick Lanyon; Smeland, Olav Bjerkehagen; Frei, Oleksandr & Filiz, Tahir Tekin [Show all 15 contributors for this article] (2023). Characterizing the Shared Genetic Underpinnings of Schizophrenia and Cardiovascular Disease Risk Factors. American Journal of Psychiatry. ISSN 0002-953X. 180(11), p. 815–826. doi: 10.1176/APPI.AJP.20220660. Full text in Research Archive
• Aas, Monica; Andreassen, Ole; Gjerstad, Johannes; Rødevand, Linn; Hjell, Gabriela & Johansen, Ingrid Torp [Show all 12 contributors for this article] (2023). Expression of ANK3 moderates the association between childhood trauma and affective traits in severe mental disorders. Scientific Reports. 13:13845, p. 1–9. doi: 10.1038/s41598-023-40310-6. Full text in Research Archive Show summary

  Exposure to early life trauma increases the risk of psychopathology later in life. Here we investigated if ANK3 mRNA levels influence the relationship between childhood trauma experiences and clinical characteristics in mental disorders. A sample of 174 patients with bipolar disorder and 291 patients with schizophrenia spectrum disorder were included. Patients were diagnosed using the Structured Clinical Interview for DSM-IV, and childhood trauma was assessed using the childhood trauma questionnaire. Age at illness onset and number of psychotic and affective episodes were assessed from interview and medical records. Current depressive symptoms were measured using the calgary depression scale for schizophrenia and the inventory for depressive symptomatology. ANK3 expression was analyzed in whole blood using the Illumina HumanHT-12 v4 Expression BeadChip. Analyses were carried out with the Process adjusted for confounders. Within the total sample, patients with both high ANK3 expression and with the most severe childhood sexual abuse had more manic/hypomanic episodes and an earlier age at onset of the first episode. ANK3 mRNA levels also moderated the relationship between emotional neglect and manic/hypomanic episodes. Our results suggest that ANK3 expression levels moderate the association between specific types of childhood trauma and affective traits in mental disorders.

• Hjell, Gabriela; Rokicki, Jaroslav; Szabo, Attila; Holst, Rene; Tesli, Natalia & Bell, Christina [Show all 19 contributors for this article] (2023). Impulsivity across severe mental disorders: a cross-sectional study of immune markers and psychopharmacotherapy. BMC Psychiatry. 23(1). doi: 10.1186/s12888-023-05154-4. Full text in Research Archive Show summary

  Background Impulsivity is a transdiagnostic feature linked to severe clinical expression and a potential target for psychopharmacological strategies. Biological underpinnings are largely unknown, but involvement of immune dysregulation has been indicated, and the effects of psychopharmacological agents vary. We investigated if impulsivity was associated with circulating immune marker levels and with a range of psychopharmacological treatment regimens in severe mental disorders. Methods Impulsivity was assessed in a sample (N = 657) of patients with schizophrenia or schizophreniform disorder (SCZ) (N = 116) or bipolar disorder (BD) (N = 159) and healthy participants (N = 382) using the Barratt Impulsiveness Scale (BIS-11) questionnaire. Plasma levels of systemic immune markers (RANTES, IL-1RA, IL-18, IL-18BP, sTNFR-1) were measured by enzyme immunoassays. Patients underwent thorough clinical assessment, including evaluation of psychotropic medication. Associations were assessed using linear regressions. Results Impulsivity was positively associated with SCZ (p < 0.001) and BD (p < 0.001) diagnosis and negatively associated with age (p < 0.05), but not significantly associated with any of the circulating immune markers independently of diagnostic status. Among patients, impulsivity was negatively associated with lithium treatment (p = 0.003) and positively associated with antidepressant treatment (p = 0.011) after controlling for diagnosis, psychotropic co-medications, manic symptoms, and depressive symptoms. Conclusions We report elevated impulsivity across SCZ and BD but no associations to systemic immune dysregulation based on the current immune marker selection. The present study reveals associations between impulsivity in severe mental disorders and treatment with lithium and antidepressants, with opposite directions. Future studies are warranted to determine the causal directionality of the observed associations with psychopharmacotherapy.

• Hiller, John Kim; Jangmo, Andreas; Tesli, Martin Steen; Jaholkowski, Piotr Pawel; Hoseth, Eva Zsuzsanna & Steen, Nils Eiel [Show all 7 contributors for this article] (2023). Lipid Biomarker Research in Bipolar Disorder: A Scoping Review of Trends, Challenges, and Future Directions. Biological Psychiatry: Global Open Science. 3(4), p. 594–604. doi: 10.1016/j.bpsgos.2023.07.004. Full text in Research Archive Show summary

  Bipolar disorder (BD) is a disabling disorder with heterogeneous symptom profiles and trajectories. Like many other neuropsychiatric disorders, clinical decision making related to diagnoses and choice of treatment is based on clinical assessments alone, and risk prediction for treatment success or resistance at an individual level remains sparse. An enormous effort to add biological markers to this risk prediction is ongoing. The role of lipids in normal brain functioning is well established, and several hypotheses about the role of lipids in the pathogenesis of neuropsychiatric disorders, including BD, have been made. The frequent comorbidity between neuropsychiatric disorders and cardiovascular disease, the genetic overlap of risk genes for severe mental disorders and genes involved in lipid regulation, and the lipid-altering effects of antipsychotics and mood stabilizers indicate that lipids could hold promise as biomarkers for neuropsychiatric disorders, including BD. To date, reviews of lipid biomarkers in schizophrenia and major depression have noted caveats for future investigations, while reviews of lipid biomarker research in BD is missing. In the current scoping review, we present a comprehensive overview of trends in previous research on lipid biomarkers in BD. The current literature varies greatly in the phenotypes investigated and study designs, leading to divergent findings. Small sample size; potential confounders related to physical activity, nutritional status, and medication use; and cross-sectional designs were frequently reported limitations. Future research may benefit from pivoting toward utilization of newer laboratory techniques such as lipidomics, but consistent use of study methods across cohorts is also needed.

• Karadag, Naz; Shadrin, Alexey; O'Connell, Kevin Sean; Hindley, Guy Frederick Lanyon; Rahman, Zillur & Parker, Nadine [Show all 18 contributors for this article] (2023). Identification of novel genomic risk loci shared between common epilepsies and psychiatric disorders. Brain. ISSN 0006-8950. 146(8), p. 3392–3403. doi: 10.1093/brain/awad038. Full text in Research Archive Show summary

  Psychiatric disorders and common epilepsies are heritable disorders with a high comorbidity and overlapping symptoms. However, the causative mechanisms underlying this relationship are poorly understood. Here we aimed to identify overlapping genetic loci between epilepsy and psychiatric disorders to gain a better understanding of their comorbidity and shared clinical features. We analysed genome-wide association study data for all epilepsies (n = 44 889), genetic generalized epilepsy (n = 33 446), focal epilepsy (n = 39 348), schizophrenia (n = 77 096), bipolar disorder (n = 406 405), depression (n = 500 199), attention deficit hyperactivity disorder (n = 53 293) and autism spectrum disorder (n = 46 350). First, we applied the MiXeR tool to estimate the total number of causal variants influencing the disorders. Next, we used the conjunctional false discovery rate statistical framework to improve power to discover shared genomic loci. Additionally, we assessed the validity of the findings in independent cohorts, and functionally characterized the identified loci. The epilepsy phenotypes were considerably less polygenic (1.0 K to 3.4 K causal variants) than the psychiatric disorders (5.6 K to 13.9 K causal variants), with focal epilepsy being the least polygenic (1.0 K variants), and depression having the highest polygenicity (13.9 K variants). We observed cross-trait genetic enrichment between genetic generalized epilepsy and all psychiatric disorders and between all epilepsies and schizophrenia and depression. Using conjunctional false discovery rate analysis, we identified 40 distinct loci jointly associated with epilepsies and psychiatric disorders at conjunctional false discovery rate <0.05, four of which were associated with all epilepsies and 39 with genetic generalized epilepsy. Most epilepsy risk loci were shared with schizophrenia (n = 31). Among the identified loci, 32 were novel for genetic generalized epilepsy, and two were novel for all epilepsies. There was a mixture of concordant and discordant allelic effects in the shared loci. The sign concordance of the identified variants was highly consistent between the discovery and independent datasets for all disorders, supporting the validity of the findings. Gene-set analysis for the shared loci between schizophrenia and genetic generalized epilepsy implicated biological processes related to cell cycle regulation, protein phosphatase activity, and membrane and vesicle function; the gene-set analyses for the other loci were underpowered. The extensive genetic overlap with mixed effect directions between psychiatric disorders and common epilepsies demonstrates a complex genetic relationship between these disorders, in line with their bi-directional relationship, and indicates that overlapping genetic risk may contribute to shared pathophysiological and clinical features between epilepsy and psychiatric disorders.

• Meer, Dennis van der; Cheng, Weiqiu; Rokicki, Jaroslav; Fernandez-Cabello, Sara; Shadrin, Alexey & Smeland, Olav Bjerkehagen [Show all 19 contributors for this article] (2023). Clustering Schizophrenia Genes by Their Temporal Expression Patterns Aids Functional Interpretation. Schizophrenia Bulletin. ISSN 0586-7614. 50(2), p. 327–338. doi: 10.1093/schbul/sbad140. Full text in Research Archive Show summary

  Background Schizophrenia is a highly heritable brain disorder with a typical symptom onset in early adulthood. The 2-hit hypothesis posits that schizophrenia results from differential early neurodevelopment, predisposing an individual, followed by a disruption of later brain maturational processes that trigger the onset of symptoms. Study design We applied hierarchical clustering to transcription levels of 345 genes previously linked to schizophrenia, derived from cortical tissue samples from 56 donors across the lifespan. We subsequently calculated clustered-specific polygenic risk scores for 743 individuals with schizophrenia and 743 sex- and age-matched healthy controls. Study results Clustering revealed a set of 183 genes that was significantly upregulated prenatally and downregulated postnatally and 162 genes that showed the opposite pattern. The prenatally upregulated set of genes was functionally annotated to fundamental cell cycle processes, while the postnatally upregulated set was associated with the immune system and neuronal communication. We found an interaction between the 2 scores; higher prenatal polygenic risk showed a stronger association with schizophrenia diagnosis at higher levels of postnatal polygenic risk. Importantly, this finding was replicated in an independent clinical cohort of 3233 individuals. Conclusions We provide genetics-based evidence that schizophrenia is shaped by disruptions of separable biological processes acting at distinct phases of neurodevelopment. The modeling of genetic risk factors that moderate each other’s effect, informed by the timing of their expression, will aid in a better understanding of the development of schizophrenia.

• Parker, Nadine; Cheng, Weiqiu; Hindley, Guy; O'Connell, Kevin Sean; Karthikeyan, Sandeep & Holen, Børge [Show all 19 contributors for this article] (2023). Genetic Overlap Between Global Cortical Brain Structure, C-Reactive Protein, and White Blood Cell Counts. Biological Psychiatry. ISSN 0006-3223. 95(1). doi: 10.1016/j.biopsych.2023.06.008. Full text in Research Archive Show summary

  Background For many brain disorders, a subset of patients jointly exhibit alterations in cortical brain structure and elevated levels of circulating immune markers. This may be driven in part by shared genetic architecture. Therefore, we investigated the phenotypic and genetic associations linking global cortical surface area and thickness with blood immune markers (i.e., white blood cell counts and plasma C-reactive protein levels). Methods Linear regression was used to assess phenotypic associations in 30,823 UK Biobank participants. Genome-wide and local genetic correlations were assessed using linkage disequilibrium score regression and local analysis of covariance annotation. The number of shared trait-influencing genetic variants was estimated using MiXeR. Shared genetic architecture was assessed using a conjunctional false discovery rate framework, and mapped genes were included in gene-set enrichment analyses. Results Cortical structure and blood immune markers exhibited predominantly inverse phenotypic associations. There were modest genome-wide genetic correlations, the strongest of which were for C-reactive protein levels (rg_surface_area = −0.13, false discovery rate–corrected p = 4.17 × 10−3; rg_thickness = −0.13, false discovery rate–corrected p = 4.00 × 10−2). Meanwhile, local genetic correlations showed a mosaic of positive and negative associations. White blood cells shared on average 46.24% and 38.64% of trait-influencing genetic variants with surface area and thickness, respectively. Additionally, surface area shared 55 unique loci with the blood immune markers while thickness shared 15. Overall, monocyte count exhibited the largest genetic overlap with cortical brain structure. A series of gene enrichment analyses implicated neuronal-, astrocytic-, and schizophrenia-associated genes. Conclusions The findings indicate shared genetic underpinnings for cortical brain structure and blood immune markers, with implications for neurodevelopment and understanding the etiology of brain-related disorders.

• Lunding, Synve Hoffart; Ueland, Torill; Aas, Monica; Høegh, Margrethe Collier; Werner, Maren Caroline Frogner & Rødevand, Linn [Show all 16 contributors for this article] (2023). Tobacco smoking related to childhood trauma mediated by cognitive control and impulsiveness in severe mental disorders. Schizophrenia Research. ISSN 0920-9964. 261, p. 236–244. doi: 10.1016/j.schres.2023.09.041. Full text in Research Archive Show summary

  Background People with severe mental disorders (SMDs) show an increased prevalence of tobacco smoking compared to the general population. Tobacco smoking and other adult adverse health behaviors have been associated with traumatic experiences in childhood. In the present study we investigated the relationship between childhood trauma and tobacco smoking in people with SMDs, including the possible mediating role of cognitive- and personality characteristics, i.e. cognitive control, impulsiveness, affective lability and self-esteem. Methods Enrolled in the study were 871 participants with schizophrenia (SCZ, N = 484) and bipolar (BD, N = 387) spectrum disorders. We assessed tobacco smoking behavior (yes/no and amount), and history of childhood trauma with the Childhood Trauma Questionnaire. Data on cognitive control, impulsiveness, affective lability, and self-esteem were available in subsamples. We performed linear and logistic regressions, and conducted mediation analyses in PROCESS. All analyses were as standard adjusted for age, sex, and diagnostic group. Results Experience of one or more subtypes of childhood trauma was significantly associated with smoking tobacco in SMDs (p = 0.002). There were no significant associations between childhood trauma and amount of tobacco smoking. Cognitive control and impulsiveness were significant mediators between childhood trauma and tobacco smoking. Conclusions These findings indicate the experience of childhood trauma as a predisposing factor for tobacco smoking in SMDs. Cognitive control and impulsiveness were suggested as mediating mechanisms, indicating the importance of considering inhibition related self-regulatory aspects in efforts to improve health behavior in individuals with SMDs and childhood trauma.

• Slapø, Nora Berz; Nerland, Stener; Jørgensen, Kjetil Nordbø; Mørch-Johnsen, Lynn Egeland; Pettersen, Johanne Hagen & Roelfs, Daniel [Show all 22 contributors for this article] (2023). Auditory Cortex Thickness Is Associated With N100 Amplitude in Schizophrenia Spectrum Disorders. Schizophrenia Bulletin Open. 4(1). doi: 10.1093/schizbullopen/sgad015. Full text in Research Archive Show summary

  Background and Hypothesis: The auditory cortex (AC) may play a central role in the pathophysiology of schizophrenia and auditory hallucinations (AH). Previous schizophrenia studies report thinner AC and impaired AC function, as indicated by decreased N100 amplitude of the auditory evoked potential. However, whether these structural and functional alterations link to AH in schizophrenia remain poorly understood. Study Design: Patients with a schizophrenia spectrum disorder (SCZspect), including patients with a lifetime experience of AH (AH+), without (AH−), and healthy controls underwent magnetic resonance imaging (39 SCZ spect, 22 AH+, 17 AH−, and 146 HC) and electroencephalography (33 SCZ spect, 17 AH+, 16 AH−, and 144 HC). Cortical thickness of the primary (AC1, Heschl’s gyrus) and secondary (AC2, Heschl’s sulcus, and the planum temporale) AC was compared between SCZ spect and controls and between AH+, AH−, and controls. To examine if the association between AC thickness and N100 amplitude differed between groups, we used regression models with interaction terms. Study Results: N100 amplitude was nominally smaller in SCZ spect (P = .03, d = 0.42) and in AH− (P = .020, d = 0.61), while AC2 was nominally thinner in AH+ (P = .02, d = 0.53) compared with controls. AC1 thickness was positively associated with N100 amplitude in SCZspect (t = 2.56, P = .016) and AH− (t= 3.18, P = .008), while AC2 thickness was positively associated with N100 amplitude in SCZspect (t = 2.37, P = .024) and in AH+ (t = 2.68, P = .019). Conclusions: The novel indings of positive associations between AC thickness and N100 amplitude in SCZ spect, suggest that a common neural substrate may underlie AC thickness and N100 amplitude alterations.

• Pentz, Atle Bråthen; Timpe, Clara Marie Fides; Normann, Elizabeth Marie; Slapø, Nora Berz; Melle, Ingrid & Lagerberg, Trine Vik [Show all 13 contributors for this article] (2023). Mismatch negativity in schizophrenia spectrum and bipolar disorders: Group and sex differences and associations with symptom severity. Schizophrenia Research. ISSN 0920-9964. 261, p. 80–93. doi: 10.1016/j.schres.2023.09.012. Full text in Research Archive Show summary

  Objective Research increasingly implicates glutamatergic dysfunction in the pathophysiologies of psychotic disorders. Auditory mismatch negativity (MMN) is an electroencephalography (EEG) waveform linked to glutamatergic neurotransmission and is consistently attenuated in schizophrenia (SCZ). MMN consists of two subcomponents, the repetition positivity (RP) and deviant negativity (DN) possibly reflecting different neural mechanisms. However, whether MMN reduction is present across different psychotic disorders, linked to distinct symptom clusters, or related to sex remain to be clarified. Methods Four hundred participants including healthy controls (HCs; n = 296) and individuals with SCZ (n = 39), bipolar disorder (BD) BD typeI (n = 35), or BD type II (n = 30) underwent a roving MMN paradigm and clinical evaluation. MMN, RP and DN as well their memory traces were recorded at the FCZ electrode. Analyses of variance and linear regression models were used both transdiagnostically and within clinical groups. Results MMN was reduced in SCZ compared to BD (p = 0.006, d = 0.55) and to HCs (p < 0.001, d = 0.63). There was a significant group × sex interaction (p < 0.003) and the MMN impairment was only detected in males with SCZ. MMN amplitude correlated positively with Positive and Negative Syndrome Scale total score and negatively with Global Assessment of Functioning Scale score. The deviant negativity was impaired in males with SCZ. No group differences in memory trace indices of the MMN, DN, or RP. Conclusion MMN was attenuated in SCZ and correlated with greater severity of psychotic symptoms and lower level of functioning. Our results may indicate sex-dependent differences of glutamatergic function in SCZ.

• O'Connell, Kevin Sean; Koch, Elise; Lenk, Hasan Cagin; Akkouh, Ibrahim Ahmed; Hindley, Guy Frederick Lanyon & Jaholkowski, Piotr Pawel [Show all 16 contributors for this article] (2023). Polygenic overlap with body-mass index improves prediction of treatment-resistant schizophrenia. Psychiatry Research. ISSN 0165-1781. 325. doi: 10.1016/j.psychres.2023.115217. Full text in Research Archive Show summary

  Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR <0.01, suggesting a role of MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

• Mlakar, Vid; Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Ormerod, Monica Bettina E. Greenwood; Quintana, Daniel & Ueland, Torill [Show all 13 contributors for this article] (2023). Telomere length and verbal learning in bipolar disorders. Journal of Affective Disorders. ISSN 0165-0327. 339, p. 555–560. doi: 10.1016/j.jad.2023.07.087. Full text in Research Archive Show summary

  Introduction: Recent studies indicate accelerated ageing processes, shorter telomere length and poorer cognitive functioning in patients with bipolar disorder. The neurobiology underlying cognitive function in bipolar disorder is yet to be established. We anticipated that accelerated ageing as indicated by shortened telomere length, would be associated with reduced cognitive performance in bipolar disorder, particularly for ageing sensitive functions such as memory and learning. Methods: The study consisted of 647 participants (bipolar disorder [n =246] and healthy controls [n =401]). All participants underwent a standardized neuropsychological test battery, including working memory, executive functioning, processing speed, verbal learning, and verbal memory. Leucocyte telomere length was measured via blood and determined by quantitative real-time Polymerase Chain Reaction (qPCR) providing a telomere to single copy ratio (T/S ratio). The T/S ratio was used as an estimate of the mean telomere length of each participant. All analyses were adjusted for medication, Daily Defined Dose (DDD), chronological age, sex, and ethnicity. Results: Patients had shorter telomere lengths than healthy controls (Cohen’s d =0.11, p =0.01). Within patients’ , a positive association was observed for verbal learning and telomere length (β =0.14, p =0.025), along with a trend for verbal memory and telomere length (β =0.11, p =0.07). No other associations were observed for telomere length and cognitive functioning in the patient or the control group (p > 0.1). Conclusion: Our study may suggest poorer brain health in bipolar disorder as indexed by shorter telomere length and reduced learning correlates. However, the role of telomere length on cognitive functioning in bipolar disorder seems limited.

• Villar, Jonelle Marie Dickow; Stavrum, Anne-Kristin Støbakk; Spindola, Leticia Maria Nery; Torsvik, Anja; Bjella, Thomas & Steen, Nils Eiel [Show all 10 contributors for this article] (2023). Differences in white blood cell proportions between schizophrenia cases and controls are influenced by medication and variations in time of day. Translational Psychiatry. 13(1). doi: 10.1038/s41398-023-02507-1. Full text in Research Archive Show summary

  Cases with schizophrenia (SCZ) and healthy controls show differences in white blood cell (WBC) counts and blood inflammation markers. Here, we investigate whether time of blood draw and treatment with psychiatric medications are related to differences in estimated WBC proportions between SCZ cases and controls. DNA methylation data from whole blood was used to estimate proportions of six subtypes of WBCs in SCZ patients (n = 333) and healthy controls (n = 396). We tested the association of case-control status with estimated cell-type proportions and the neutrophil-to-lymphocyte ratio (NLR) in 4 models: with/without adjusting for time of blood draw, and then compared results from blood samples drawn during a 12-h (07:00–19:00) or 7-h (07:00-14:00) period. We also investigated WBC proportions in a subgroup of medication-free patients (n = 51). Neutrophil proportions were significantly higher in SCZ cases (mean=54.1%) vs. controls (mean=51.1%; p = <0.001), and CD8+T lymphocyte proportions were lower in SCZ cases (mean=12.1%) vs. controls (mean=13.2%; p = 0.001). The effect sizes in the 12-h sample (07:00–19:00) showed a significant difference between SCZ vs. controls for neutrophils, CD4+T, CD8+T, and B-cells, which remained significant after adjusting for time of blood draw. In the samples matched for time of blood draw during 07.00–14.00, we also observed an association with neutrophils, CD4+T, CD8+T, and B-cells that was unaffected by further adjustment for time of blood draw. In the medication-free patients, we observed differences that remained significant in neutrophils (p = 0.01) and CD4+T (p = 0.01) after adjusting for time of day. The association of SCZ with NLR was significant in all models (range: p < 0.001 to p = 0.03) in both medicated and unmedicated patients. In conclusion, controlling for pharmacological treatment and circadian cycling of WBC is necessary for unbiased estimates in case-control studies. Nevertheless, the association of WBC with SCZ remains, even after adjusting for the time of day.

• Reponen, Elina Johanna; Ueland, Thor; Rokicki, Jaroslav; Bettella, Francesco; Aas, Monica & Werner, Maren Caroline Frogner [Show all 10 contributors for this article] (2023). Polygenic risk for schizophrenia and bipolar disorder in relation to cardiovascular biomarkers. European Archives of Psychiatry and Clinical Neuroscience. ISSN 0940-1334. doi: 10.1007/s00406-023-01591-0. Full text in Research Archive Show summary

  Individuals with schizophrenia and bipolar disorder are at an increased risk of cardiovascular disease (CVD), and a range of biomarkers related to CVD risk have been found to be abnormal in these patients. Common genetic factors are a putative underlying mechanism, alongside lifestyle factors and antipsychotic medication. However, the extent to which the altered CVD biomarkers are related to genetic factors involved in schizophrenia and bipolar disorder is unknown. In a sample including 699 patients with schizophrenia, 391 with bipolar disorder, and 822 healthy controls, we evaluated 8 CVD risk biomarkers, including BMI, and fasting plasma levels of CVD biomarkers from a subsample. Polygenic risk scores (PGRS) were obtained from genome-wide associations studies (GWAS) of schizophrenia and bipolar disorder from the Psychiatric Genomics Consortium. The CVD biomarkers were used as outcome variables in linear regression models including schizophrenia and bipolar disorder PGRS as predictors, age, sex, diagnostic category, batch and 10 principal components as covariates, controlling for multiple testing by Bonferroni correction for the number of independent tests. Bipolar disorder PGRS was significantly (p = 0.03) negatively associated with BMI after multiple testing correction, and schizophrenia PGRS was nominally negatively associated with BMI. There were no other significant associations between bipolar or schizophrenia PGRS, and other investigated CVD biomarkers. Despite a range of abnormal CVD risk biomarkers in psychotic disorders, we only found a significant negative association between bipolar disorder PGRS and BMI. This has previously been shown for schizophrenia PGRS and BMI, and warrants further exploration.

• Torsvik, Anja; Brattbakk, Hans-Richard; Trentani, Andrea; Holdhus, Rita; Stansberg, Christine & Bartz-Johannessen, Christoffer [Show all 12 contributors for this article] (2023). Patients with schizophrenia and bipolar disorder display a similar global gene expression signature in whole blood that reflects elevated proportion of immature neutrophil cells with association to lipid changes. Translational Psychiatry. 13. doi: 10.1038/s41398-023-02442-1. Full text in Research Archive Show summary

  Schizophrenia (SCZ) and bipolar disorder (BD) share clinical characteristics, genetic susceptibility, and immune alterations. We aimed to identify differential transcriptional patterns in peripheral blood cells of patients with SCZ or BD versus healthy controls (HC). We analyzed microarray-based global gene expression data in whole blood from a cohort of SCZ (N = 329), BD (N = 203) and HC (N = 189). In total, 65 genes were significantly differentially expressed in SCZ and 125 in BD, as compared to HC, with similar ratio of up- and downregulated genes in both disorders. Among the top differentially expressed genes, we found an innate immunity signature that was shared between SCZ and BD, consisting of a cluster of upregulated genes (e.g., OLFM4, ELANE, BPI and MPO) that indicate an increased fraction of immature neutrophils. Several of these genes displayed sex differences in the expression pattern, and post-hoc analysis demonstrated a positive correlation with triglyceride and a negative correlation with HDL cholesterol. We found that many of the downregulated genes in SCZ and BD were associated with smoking. These findings of neutrophil granulocyte-associated transcriptome signatures in both SCZ and BD point at altered innate immunity pathways with association to lipid changes and potential for clinical translation.

• Cheng, Weiqiu; Parker, Nadine; Karadag, Naz; Koch, Elise; Hindley, Guy Frederick Lanyon & Icick, Romain [Show all 22 contributors for this article] (2023). The relationship between cannabis use, schizophrenia, and bipolar disorder: a genetically informed study. The Lancet Psychiatry. ISSN 2215-0374. 10(6), p. 441–451. doi: 10.1016/S2215-0366(23)00143-8. Full text in Research Archive Show summary

  Background The relationship between psychotic disorders and cannabis use is heavily debated. Shared underlying genetic risk is one potential explanation. We investigated the genetic association between psychotic disorders (schizophrenia and bipolar disorder) and cannabis phenotypes (lifetime cannabis use and cannabis use disorder). Methods We used genome-wide association summary statistics from individuals with European ancestry from the Psychiatric Genomics Consortium, UK Biobank, and International Cannabis Consortium. We estimated heritability, polygenicity, and discoverability of each phenotype. We performed genome-wide and local genetic correlations. Shared loci were identified and mapped to genes, which were tested for functional enrichment. Shared genetic liabilities to psychotic disorders and cannabis phenotypes were explored using causal analyses and polygenic scores, using the Norwegian Thematically Organized Psychosis cohort. Findings Psychotic disorders were more heritable than cannabis phenotypes and more polygenic than cannabis use disorder. We observed positive genome-wide genetic correlations between psychotic disorders and cannabis phenotypes (range 0·22–0·35) with a mixture of positive and negative local genetic correlations. Three to 27 shared loci were identified for the psychotic disorder and cannabis phenotype pairs. Enrichment of mapped genes implicated neuronal and olfactory cells as well as drug–gene targets for nicotine, alcohol, and duloxetine. Psychotic disorders showed a causal effect on cannabis phenotypes, and lifetime cannabis use had a causal effect on bipolar disorder. Of 2181 European participants from the Norwegian Thematically Organized Psychosis cohort applied in polygenic risk score analyses, 1060 (48·6%) were females and 1121 (51·4%) were males (mean age 33·1 years [SD 11·8]). 400 participants had bipolar disorder, 697 had schizophrenia, and 1044 were healthy controls. Within this sample, polygenic scores for cannabis phenotypes predicted psychotic disorders independently and improved prediction beyond the polygenic score for the psychotic disorders. Interpretation A subgroup of individuals might have a high genetic risk of developing a psychotic disorder and using cannabis. This finding supports public health efforts to reduce cannabis use, particularly in individuals at high risk or patients with psychotic disorders. Identified shared loci and their functional implications could facilitate development of novel treatments.

• Sæther, Linn Sofie; Ueland, Thor; Haatveit, Beathe; Maglanoc, Luigi; Szabo, Attila & Djurovic, Srdjan [Show all 15 contributors for this article] (2022). Inflammation and cognition in severe mental illness: patterns of covariation and subgroups. Molecular Psychiatry. ISSN 1359-4184. 8, p. 1284–1292. doi: 10.1038/s41380-022-01924-w. Full text in Research Archive Show summary

  A potential relationship between dysregulation of immune/inflammatory pathways and cognitive impairment has been suggested in severe mental illnesses (SMI), such as schizophrenia (SZ) and bipolar (BD) spectrum disorders. However, multivariate relationships between peripheral inflammatory/immune-related markers and cognitive domains are unclear, and many studies do not account for inter-individual variance in both cognitive functioning and inflammatory/immune status. This study aimed to investigate covariance patterns between inflammatory/immune-related markers and cognitive domains and further elucidate heterogeneity in a large SMI and healthy control (HC) cohort (SZ = 343, BD = 289, HC = 770). We applied canonical correlation analysis (CCA) to identify modes of maximum covariation between a comprehensive selection of cognitive domains and inflammatory/immune markers. We found that poor verbal learning and psychomotor processing speed was associated with higher levels of interleukin-18 system cytokines and beta defensin 2, reflecting enhanced activation of innate immunity, a pattern augmented in SMI compared to HC. Applying hierarchical clustering on covariance patterns identified by the CCA revealed a high cognition—low immune dysregulation subgroup with predominantly HC (24% SZ, 45% BD, 74% HC) and a low cognition—high immune dysregulation subgroup predominantly consisting of SMI patients (76% SZ, 55% BD, 26% HC). These subgroups differed in IQ, years of education, age, CRP, BMI (all groups), level of functioning, symptoms and defined daily dose (DDD) of antipsychotics (SMI cohort). Our findings suggest a link between cognitive impairment and innate immune dysregulation in a subset of individuals with severe mental illness.

• Werner, Maren Caroline Frogner; Wirgenes, Katrine Verena; Shadrin, Alexey; Lunding, Synve Hoffart; Rødevand, Linn & Hjell, Gabriela [Show all 15 contributors for this article] (2022). Immune marker levels in severe mental disorders: associations with polygenic risk scores of related mental phenotypes and psoriasis. Translational Psychiatry. 12(1). doi: 10.1038/s41398-022-01811-6. Full text in Research Archive Show summary

  Several lines of evidence implicate immune abnormalities in the pathophysiology of severe mental disorders (SMD) and comorbid mental disorders. Here, we use the data from genome-wide association studies (GWAS) of autoimmune diseases and mental phenotypes associated with SMD to disentangle genetic susceptibilities of immune abnormalities in SMD. We included 1004 patients with SMD and 947 healthy controls (HC) and measured plasma levels of IL-1Ra, sIL-2R, gp130, sTNFR-1, IL-18, APRIL, and ICAM-1. Polygenic risk scores (PRS) of six autoimmune disorders, CRP, and 10 SMD-related mental phenotypes were calculated from GWAS. General linear models were applied to assess the association of PRS with immune marker abnormalities. We found negative associations between PRS of educational attainment and IL-1Ra (P = 0.01) and IL-18 (P = 0.01). There were nominal positive associations between PRS of psoriasis and sgp130 (P = 0.02) and PRS of anxiety and IL-18 (P = 0.03), and nominal negative associations between PRS of anxiety and sIL-2R (P = 0.02) and PRS of educational attainment and sIL-2R (P = 0.03). Associations explained minor amounts of the immune marker plasma-level difference between SMD and HC. Different PRS and immune marker associations in the SMD group compared to HC were shown for PRS of extraversion and IL-1Ra ([interaction effect (IE), P = 0.002), and nominally for PRS of openness and IL-1Ra (IE, P = 0.02) and sTNFR-1 (IE, P = 0.04). Our findings indicate polygenic susceptibilities to immune abnormalities in SMD involving genetic overlap with SMD-related mental phenotypes and psoriasis. Associations might suggest immune genetic factors of SMD subgroups characterized by autoimmune or specific mental features.

• Icick, Romain; Melle, Ingrid; Etain, Bruno; Høegh, Margrethe Collier; Gard, Sébastien & Aminoff, Sofie Ragnhild [Show all 15 contributors for this article] (2022). Preventive Medication Patterns in Bipolar Disorder and Their Relationship With Comorbid Substance Use Disorders in a Cross-National Observational Study. Frontiers in Psychiatry. 13. doi: 10.3389/fpsyt.2022.813256. Full text in Research Archive Show summary

  Objective The potential role of sub-optimal pharmacological treatment in the poorer outcomes observed in bipolar disorder (BD) with vs. without comorbid substance use disorders (SUDs) is not known. Thus, we investigated whether patients with BD and comorbid SUD had different medication regimens than those with BD alone, in samples from France and Norway, focusing on compliance to international guidelines. Methods Seven hundred and seventy patients from France and Norway with reliably ascertained BD I or II (68% BD-I) were included. Medication information was obtained from patients and hospital records, and preventive treatment was categorized according to compliance to guidelines. We used Bayesian and regression analyses to investigate associations between SUD comorbidity and medication. In the Norwegian subsample, we also investigated association with lack of medication. Results Comorbid SUDs were as follows: current tobacco smoking, 26%, alcohol use disorder (AUD), 16%; cannabis use disorder (CUD), 10%; other SUDs, 5%. Compliance to guidelines for preventive medication was lacking in 8%, partial in 44%, and complete in 48% of the sample. Compliance to guidelines was not different in BD with and without SUD comorbidity, as was supported by Bayesian analyses (highest Bayes Factor = 0.16). Cross national differences in treatment regimens led us to conduct country-specific adjusted regression analyses, showing that (1) CUD was associated with increased antipsychotics use in France (OR = 2.4, 95% CI = 1.4–3.9, p = 0.001), (2) current tobacco smoking was associated with increased anti-epileptics use in Norway (OR = 4.4, 95% CI = 1.9–11, p &amp;lt; 0.001), and (3) AUD was associated with decreased likelihood of being medicated in Norway (OR = 1.2, 95% CI = 1.04–1.3, p = 0.038). Conclusion SUD comorbidity in BD was overall not associated with different pharmacological treatment in our sample, and not related to the level of compliance to guidelines. We found country-specific associations between comorbid SUDs and specific medications that warrant further studies.

• Jensen, Søren Beck; Sheikh, Mashhood Ahmed; Akkouh, Ibrahim Ahmed; Szabo, Attila; O'Connell, Kevin Sean & Lekva, Tove [Show all 23 contributors for this article] (2022). Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness. Schizophrenia Bulletin. ISSN 0586-7614. 49(3), p. 635–645. doi: 10.1093/schbul/sbac191. Full text in Research Archive Show summary

  Abstract Background and Hypothesis Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI. Study Design We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation. Study Results Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4. Conclusions Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.

• Sheikh, Mashhood Ahmed; O'Connell, Kevin Sean; Lekva, Tove; Szabo, Attila; Akkouh, Ibrahim Ahmed & Osete, Jordi Requena [Show all 31 contributors for this article] (2022). Systemic cell adhesion molecules in severe mental illness: Potential role of intercellular CAM-1 in linking peripheral and neuroinflammation. Biological Psychiatry. ISSN 0006-3223. 93, p. 187–196. doi: 10.1016/j.biopsych.2022.06.029. Full text in Research Archive Show summary

  Background Cell adhesion molecules (CAMs) orchestrate leukocyte trafficking and could link peripheral and neuroinflammation in patients with severe mental illness (SMI), by promoting inflammatory and immune-mediated responses and mediating signals across blood-brain barrier. We hypothesized that CAMs would be dysregulated in SMI and evaluated plasma levels of different vascular and neural CAMs. Dysregulated CAMs in plasma were further evaluated in vivo in leukocytes and brain tissue and in vitro in induced pluripotent stem cells. Methods We compared plasma soluble levels of different vascular (VCAM-1, ICAM-1, P-SEL) and neural (JAM-A, NCAD) CAMs in circulating leukocytes in a large SMI sample of schizophrenia (SCZ) spectrum disorder (n = 895) and affective disorder (n = 737) and healthy control participants (n = 1070) controlling for age, sex, body mass index, C-reactive protein, and freezer storage time. We also evaluated messenger RNA expression of ICAM1 and related genes encoding ICAM-1 receptors in leukocytes using microarray (n = 842) and in available RNA sequencing data from the CommonMind Consortium (CMC) in postmortem samples from the dorsolateral prefrontal cortex (n = 474). The regulation of soluble ICAM-1 in induced pluripotent stem cell–derived neurons and astrocytes was assessed in patients with SCZ and healthy control participants (n = 8 of each). Results Our major findings were 1) increased soluble ICAM-1 in patients with SMI compared with healthy control participants; 2) increased ITGB2 messenger RNA, encoding the beta chain of the ICAM-1 receptor, in circulating leukocytes from patients with SMI and increased prefrontal cortex messenger RNA expression of ICAM1 in SCZ; and 3) enhanced soluble ICAM-1 release in induced pluripotent stem cell–derived neurons from patients with SCZ. Conclusions Our results support a systemic and cerebral dysregulation of soluble ICAM-1 expression in SMI and especially in patients with SCZ.

• Rokicki, Jaroslav; Kaufmann, Tobias; Lange, Ann-Marie Glasø de; Meer, Dennis van der; Bahrami, Shahram & Sartorius, Alina [Show all 14 contributors for this article] (2022). Oxytocin receptor expression patterns in the human brain across development. Neuropsychopharmacology. ISSN 0893-133X. doi: 10.1038/s41386-022-01305-5. Full text in Research Archive
• Johansen, Ingrid Torp; Steen, Nils Eiel; Rødevand, Linn; Werner, Maren Caroline Frogner; Lunding, Synve Hoffart & Hjell, Gabriela [Show all 12 contributors for this article] (2022). Sex-specific associations between metabolic hormones, severe mental disorders and antipsychotic treatment. Psychoneuroendocrinology. ISSN 0306-4530. 146. doi: 10.1016/j.psyneuen.2022.105927. Full text in Research Archive
• Winterton, Adriano; Bettella, Francesco; Beck, Dani; Gurholt, Tiril Pedersen; Steen, Nils Eiel & Rødevand, Linn Nilsen [Show all 9 contributors for this article] (2022). The oxytocin signalling gene pathway contributes to the association between loneliness and cardiometabolic health. Psychoneuroendocrinology. ISSN 0306-4530. 144. doi: 10.1016/j.psyneuen.2022.105875. Full text in Research Archive Show summary

  Increasing evidence has shown adverse effects of loneliness on cardiometabolic health. The neuromodulator and hormone oxytocin has traditionally been linked with social cognition and behaviour. However, recent implications of the oxytocin system in energy metabolism and the overrepresentation of metabolic issues in psychiatric illness suggests that oxytocin may represent a mechanism bridging mental and somatic traits. To clarify the role of the oxytocin signalling system in the link between cardiometabolic risk factors and loneliness, we calculated the contribution of single nucleotide polymorphisms (SNPs) in the oxytocin signalling pathway gene-set (154 genes) to the polygenic architecture of loneliness and body mass index (BMI). We investigated the associations of these oxytocin signalling pathway polygenic scores with body composition measured using body magnetic resonance imaging (MRI), bone mineral density (BMD), haematological markers, and blood pressure in a sample of just under half a million adults from the UK Biobank (BMD subsample n = 274,457; body MRI subsample n = 9796). Our analysis revealed significant associations of the oxytocin signalling pathway polygenic score for BMI with abdominal subcutaneous fat tissue, HDL cholesterol, lipoprotein(a), triglycerides, and BMD. We also found an association between the oxytocin signalling pathway polygenic score for loneliness and apolipoprotein A1, the major protein component of HDL. Altogether, these results provide additional evidence for the oxytocin signalling pathway’s role in energy metabolism, lipid homoeostasis, and bone density, and support oxytocin’s complex pleiotropic effects.

• Trubetskoy, Vassily; Pardiñas, Antonio F.; Qi, Ting; Panagiotaropoulou, Georgia; Awasthi, Swapnil & Bigdeli, Tim B. [Show all 434 contributors for this article] (2022). Mapping genomic loci implicates genes and synaptic biology in schizophrenia. Nature. ISSN 0028-0836. 604(7906), p. 502–508. doi: 10.1038/s41586-022-04434-5. Full text in Research Archive Show summary

  Schizophrenia has a heritability of 60–80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies.

• Hjell, Gabriela; Szabo, Attila; Mørch-Johnsen, Lynn Egeland; Holst, Rene; Tesli, Natalia & Bell, Christina [Show all 18 contributors for this article] (2022). Interleukin-18 signaling system links to agitation in severe mental disorders. Psychoneuroendocrinology. ISSN 0306-4530. 140:105721, p. 1–8. doi: 10.1016/j.psyneuen.2022.105721. Full text in Research Archive Show summary

  Objective Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. Methods Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)‐18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. Results Agitation was positively associated with IL-18BP (β = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (β = 0.06, t = 1.27, p = 0.20), IL-18 (β = 0.05, t = 1.25, p = 0.21), IL-18R1 (β = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. Conclusion Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.

• Ormerod, Monica Bettina E. Greenwood; Ueland, Thor; Werner, Maren Caroline Frogner; Hjell, Gabriela; Rødevand, Linn Nilsen & Sæther, Linn Sofie [Show all 14 contributors for this article] (2022). Composite immune marker scores associated with severe mental disorders and illness course. Brain, Behavior, and Immunity - Health (BBI - Health). 24. doi: 10.1016/j.bbih.2022.100483. Full text in Research Archive Show summary

  Background Low-grade inflammation has been implicated in the pathophysiology of severe mental disorders (SMDs) and a link between immune activation and clinical characteristics is suggested. However, few studies have investigated how patterns across immune markers are related to diagnosis and illness course. Methods A total of 948 participants with a diagnosis of schizophrenia (SCZ, N = 602) or bipolar (BD, N = 346) spectrum disorder, and 814 healthy controls (HC) were included. Twenty-five immune markers comprising cell adhesion molecules (CAMs), interleukin (IL)-18-system factors, defensins, chemokines and other markers, related to neuroinflammation, blood-brain barrier (BBB) function, inflammasome activation and immune cell orchestration were analyzed. Eight immune principal component (PC) scores were constructed by PC Analysis (PCA) and applied in general linear models with diagnosis and illness course characteristics. Results Three PC scores were significantly associated with a SCZ and/or BD diagnosis (HC reference), with largest, however small, effect sizes of scores based on CAMs, BBB markers and defensins (p < 0.001, partial η2 = 0.02–0.03). Number of psychotic episodes per year in SCZ was associated with a PC score based on IL-18 system markers and the potential neuroprotective cytokine A proliferation-inducing ligand (p = 0.006, partial η2 = 0.071). Conclusion Analyses of composite immune markers scores identified specific patterns suggesting CAMs-mediated BBB dysregulation pathways associated with SMDs and interrelated pro-inflammatory and neuronal integrity processes associated with severity of illness course. This suggests a complex pattern of immune pathways involved in SMDs and SCZ illness course.

• Beck, Dani; Lange, Ann-Marie Glasø de; Alnæs, Dag; Maximov, Ivan; Pedersen, Mads Lund & Leinhard, Olof Dahlqvist [Show all 20 contributors for this article] (2022). Adipose tissue distribution from body MRI is associated with cross-sectional and longitudinal brain age in adults. NeuroImage: Clinical. 33. doi: 10.1016/j.nicl.2022.102949. Full text in Research Archive Show summary

  There is an intimate body-brain connection in ageing, and obesity is a key risk factor for poor cardiometabolic health and neurodegenerative conditions. Although research has demonstrated deleterious effects of obesity on brain structure and function, the majority of studies have used conventional measures such as waist-to-hip ratio, waist circumference, and body mass index. While sensitive to gross features of body composition, such global anthropometric features fail to describe regional differences in body fat distribution and composition. The sample consisted of baseline brain magnetic resonance imaging (MRI) acquired from 790 healthy participants aged 18–94 years (mean ± standard deviation (SD) at baseline: 46.8 ± 16.3), and follow-up brain MRI collected from 272 of those individuals (two time-points with 19.7 months interval, on average (min = 9.8, max = 35.6). Of the 790 included participants, cross-sectional body MRI data was available from a subgroup of 286 participants, with age range 19–86 (mean = 57.6, SD = 15.6). Adopting a mixed cross-sectional and longitudinal design, we investigated cross-sectional body magnetic resonance imaging measures of adipose tissue distribution in relation to longitudinal brain structure using MRI-based morphometry (T1) and diffusion tensor imaging (DTI). We estimated tissue-specific brain age at two time points and performed Bayesian multilevel modelling to investigate the associations between adipose measures at follow-up and brain age gap (BAG) – the difference between actual age and the prediction of the brain’s biological age – at baseline and follow-up. We also tested for interactions between BAG and both time and age on each adipose measure. The results showed credible associations between T1-based BAG and liver fat, muscle fat infiltration (MFI), and weight-to-muscle ratio (WMR), indicating older-appearing brains in people with higher measures of adipose tissue. Longitudinal evidence supported interaction effects between time and MFI and WMR on T1-based BAG, indicating accelerated ageing over the course of the study period in people with higher measures of adipose tissue. The results show that specific measures of fat distribution are associated with brain ageing and that different compartments of adipose tissue may be differentially linked with increased brain ageing, with potential to identify key processes involved in age-related transdiagnostic disease processes.

• Aas, Monica; Ueland, Torill; Lagerberg, Trine Vik; Melle, Ingrid; Aminoff, Sofie Ragnhild & Høegh, Margrethe Collier [Show all 10 contributors for this article] (2022). Retrospectively assessed childhood trauma experiences are associated with illness severity in mental disorders adjusted for symptom state. Psychiatry Research. ISSN 0165-1781. 320. doi: 10.1016/j.psychres.2022.115045. Full text in Research Archive Show summary

  Converging evidence suggests that childhood trauma is a causal factor in schizophrenia (SZ) and in bipolar disorders (BD). Here, we investigated whether retrospective reports are associated with severity of illness, independent of current symptom state in a large sample of participants with SZ or BD. We included 1260 individuals (SZ [n = 461], BD [n = 352]), and healthy controls; HC [n = 447]) recruited from the same catchment area. A history of childhood trauma was obtained with the Childhood Trauma Questionnaire (CTQ). Diagnosis and episodes were obtained with the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I). Clinical symptoms (state) were assessed with the Positive and Negative Syndrome scale (PANSS), the Calgary Depression Scale (CDSS). Trait related illness characteristics were assessed with age at illness onset, number of episodes, and lifetime suicide attempts. Patients who reported multiple types of childhood trauma experiences had significantly more severe illness course including an earlier illness onset, more mood episodes, and increased risk of at least one suicide attempt, also after adjusting for current symptom state. Retrospective assessed childhood trauma experiences are associated with illness severity in mental disorders adjusted for symptom state. Our results strengthen the role of childhood trauma in development of psychopathology.

• Werner, Maren Caroline Frogner; Wirgenes, Katrine Verena; Shadrin, Alexey; Lunding, Synve Hoffart; Rødevand, Linn & Hjell, Gabriela [Show all 15 contributors for this article] (2022). Limited association between infections, autoimmune disease and genetic risk and immune activation in severe mental disorders. Progress in Neuro-psychopharmacology and Biological Psychiatry. ISSN 0278-5846. 116. doi: 10.1016/j.pnpbp.2022.110511. Full text in Research Archive Show summary

  Background Low-grade inflammation may be part of the underlying mechanism of schizophrenia and bipolar disorder. We investigated if genetic susceptibility, infections or autoimmunity could explain the immune activation. Methods Seven immune markers were selected based on indicated associations to severe mental disorders (IL-1Ra, sIL-2R, IL-18, sgp130, sTNFR-1, APRIL, ICAM-1) and measured in plasma of patients with schizophrenia (SCZ, N = 732) and bipolar spectrum disorders (BD, N = 460) and healthy controls (HC, N = 938). Information on rate of infections and autoimmune diseases were obtained from Norwegian national health registries for a twelve-year period. Polygenic risk scores (PRS) of SCZ and BD were calculated from genome-wide association studies. Analysis of covariance were used to test effects of infection rate, autoimmune disease and PRS on differences in immune markers between patients and HC. Results Infection rate differed between all groups (BD > HC > SCZ, all p < 0.001) whereas autoimmune disease was more frequent in BD compared to SCZ (p = 0.004) and HC (p = 0.003). sIL-2R was positively associated with autoimmune disease (p = 0.001) and negatively associated with PRS of SCZ (p = 0.006) across SCZ and HC; however, associations represented only small changes in the difference of sIL-2R levels between SCZ and HC. Conclusion There were few significant associations between rate of infections, autoimmune disease or PRS and altered immune markers in SCZ and BD, and the detected associations represented only small changes in the immune aberrations. The findings suggest that most of the low-grade inflammation in SCZ and BD is explained by other factors than the underlying PRS, autoimmunity and infection rates.

• Gjerde, Priyanthi Borgen; Steen, Synne Wollen; Vedal, Trude Seselie Jahr; Steen, Nils Eiel; Reponen, Elina Johanna & Andreassen, Ole [Show all 8 contributors for this article] (2022). Lifetime cannabis use Is not associated with negative beliefs about medication in patients with first treatment psychosis. Frontiers in Psychiatry. 13. doi: 10.3389/fpsyt.2022.824051. Full text in Research Archive Show summary

  Objective: Cannabis use is common among patients with psychosis, and along with negative beliefs about medication, it has been found to predict poor adherence to antipsychotic drug treatment. Such lack of adherence to antipsychotic drug treatment increases the risk of poor clinical outcomes and relapse in patients with first treatment for psychosis (FTP). However, to date, it is unclear whether cannabis use may be related to negative perceptions about antipsychotic drug treatment. Methods: A cross-sectional sample of 265 FTP patients with schizophrenia spectrum disorder underwent extensive clinical assessments. Three measures of cannabis use were obtained: lifetime, current and meeting diagnostic criteria for abuse or addiction. For the primary analyses we focused on lifetime cannabis use. The Beliefs about Medication Questionnaire (BMQ) was employed to assess the patients' specific concerns and perceptions of antipsychotic medications, as well as general beliefs about pharmacotherapy. The relationship between lifetime cannabis use and BMQ scores was investigated with general linear model (GLM) analyses, controlling for age and sex. Results: Patients with lifetime use of cannabis ≥10 times were more likely to be male, younger at the age of onset of psychosis and with higher levels of alcohol use and daily tobacco smoking, as compared to the non-users (p < 0.05). Neither lifetime use of cannabis, current use nor a cannabis abuse diagnosis was associated with negative beliefs about medicines as measured by the BMQ questionnaire. Conclusion: Use of cannabis is not linked to negative perceptions about antipsychotic medicines in patients with FTP. Other reasons for poor compliance to antipsychotic drug treatment in cannabis users need to be further investigated.

• Johansen, Ingrid Torp; Steen, Nils Eiel; Haram, Marit; Rødevand, Linn; Werner, Maren Caroline Frogner & Lunding, Synve Hoffart [Show all 13 contributors for this article] (2022). Sex differences in antipsychotic-related triglyceride levels are associated with metabolic hormone differences in patients with severe mental disorders. Schizophrenia Research. ISSN 0920-9964. 243, p. 55–63. doi: 10.1016/j.schres.2022.02.015. Full text in Research Archive Show summary

  Background Adverse effects of antipsychotics (AP) contribute to cardiovascular disease (CVD) risk in patients with severe mental disorders (SMD). We investigated sex differences in AP-related CVD risk factors and the role of metabolic hormones. Methods Patients with SMD (N = 1791) receiving AP with different CVD risk were recruited and grouped into olanzapine and/or clozapine (N = 532), other APs (N = 744) or no use of APs (N = 515). Associations between CVD risk factor (total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), body mass index (BMI), glucose, blood pressure), sex and AP groups were tested in multiple linear regression with interactions, controlling for diagnostic group, lifestyle factors, polypharmacy, age and ethnicity. Next, we tested associations between sex differences in AP-related CVD risk factors and metabolic regulatory hormones. Results AP groups and male sex were significantly associated with higher levels of LDL-C, TG and BMI, and lower levels of HDL-C. Significant interaction between AP groups and sex were found for TG (p = 0.017), with larger increase in males. Serum adiponectin, insulin, cortisol, leptin, testosterone, free thyroxine and thyroid-stimulating hormone (TSH) were associated with TG levels (all p ≤ 0.001), and a significant interaction with sex for insulin (p = 0.005), cortisol (p = 0.016), leptin (p < 0.001) and TSH (p = 0.001). Conclusions We found more severe AP-related CVD risk factors in male patients with SMD. The male-dependent increase in TG levels was associated with leptin, insulin, cortisol and TSH levels. Clinicians treating patients with SMD should be aware of increased vulnerability for AP-related lipid abnormalities in males.

• Birkenæs, Viktoria; Elvsåshagen, Torbjørn; Westlye, Lars Tjelta; Høegh, Margrethe Collier; Haram, Marit & Werner, Maren Caroline Frogner [Show all 14 contributors for this article] (2021). Telomeres are shorter and associated with number of suicide attempts in affective disorders. Journal of Affective Disorders. ISSN 0165-0327. 295, p. 1032–1039. doi: 10.1016/j.jad.2021.08.135. Full text in Research Archive
• Bahrami, Shahram; Shadrin, Alexey A.; Frei, Oleksandr; O`Connell, Kevin; Bettella, Francesco & Krull, Florian [Show all 15 contributors for this article] (2021). Genetic loci shared between major depression and intelligence with mixed directions of effect. Nature Human Behaviour. p. 1–9. doi: 10.1038/s41562-020-01031-2. Full text in Research Archive
• Wiström, Erik David; O'Connell, Kevin Sean; Karadag, Naz; Bahrami, Shahram; Hindley, Guy Frederick Lanyon & Lin, Aihua [Show all 14 contributors for this article] (2021). Genome-wide analysis reveals genetic overlap between alcohol use behaviours, schizophrenia and bipolar disorder and identifies novel shared risk loci. Addiction. ISSN 0965-2140. 117(3). doi: 10.1111/add.15680. Full text in Research Archive Show summary

  Background and aim Schizophrenia (SCZ) and bipolar disorder (BD) have a high comorbidity of alcohol use disorder (AUD), and both comorbid AUD and excessive alcohol consumption (AC) have been linked to greater illness severity. We aimed to identify genomic loci jointly associated with SCZ, BD, AUD and AC to gain further insights into their shared genetic architecture. Design We analysed summary data (P values and Z scores) from genome-wide association studies (GWAS) using conjunctional false discovery rate (conjFDR) analysis, which increases power to discover shared genomic loci. We functionally characterized the identified loci using publicly available biological resources. Setting AUD and AC data provided by the Million Veteran Program, derived from the United States Department of Veterans Affairs Healthcare System. SCZ and BD data provided by the Psychiatric Genomics Consortium, based on cohorts from countries in Europe, North America and Australia. Participants AUD (34 658 cases, 167 346 controls), AC (n = 200 680), SCZ (31 013 cases and 38 918 controls), BD (20 352 cases and 31 358 controls). All participants were of European ancestry. Measurements Genomic loci shared between alcohol traits, SCZ and BD at conjFDR <0.05. Findings Conditional Q-Q plots showed single-nucleotide polymorphism (SNP) enrichment for both alcohol traits across different levels of significance with SCZ and BD, and vice versa. Using conjFDR analysis we leveraged this genetic enrichment and identified several loci shared between SCZ and AUD (n = 28) and AC (n = 24), BD and AUD (n = 2) and AC (n = 8) at conjFDR <0.05. Among these loci, 24 are novel for AUD, 15 are novel for AC, three are novel for SCZ and one is novel for BD. There was a mixture of same and opposite effect directions among the shared loci. Conclusions Alcohol use disorder and alcohol consumption share genomic loci with the psychiatric disorders schizophrenia and bipolar disorder with a mixed pattern of effect directions, indicating a complex genetic relationship between the phenotypes.

• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Chu, Yunhan; Shadrin, Alexey A. & O'Connell, Kevin Sean [Show all 14 contributors for this article] (2021). Extensive bidirectional genetic overlap between bipolar disorder and cardiovascular disease phenotypes. Translational Psychiatry. 11. doi: 10.1038/s41398-021-01527-z. Full text in Research Archive Show summary

  Patients with bipolar disorder (BIP) have a high risk of cardiovascular disease (CVD), despite considerable individual variation. The mechanisms underlying comorbid CVD in BIP remain largely unknown. We investigated polygenic overlap between BIP and CVD phenotypes, including CVD risk factors and coronary artery disease (CAD). We analyzed large genome-wide association studies of BIP (n = 51,710) and CVD phenotypes (n = 159,208–795,640), using bivariate causal mixture model (MiXeR), which estimates the total amount of shared genetic variants, and conjunctional false discovery rate (FDR), which identifies specific overlapping loci. MiXeR revealed polygenic overlap between BIP and body mass index (BMI) (82%), diastolic and systolic blood pressure (20–22%) and CAD (11%) despite insignificant genetic correlations. Using conjunctional FDR < 0.05, we identified 129 shared loci between BIP and CVD phenotypes, mainly BMI (n = 69), systolic (n = 53), and diastolic (n = 53) blood pressure, of which 22 are novel BIP loci. There was a pattern of mixed effect directions of the shared loci between BIP and CVD phenotypes. Functional analyses indicated that the shared loci are linked to brain-expressed genes and involved in neurodevelopment, lipid metabolism, chromatin assembly/disassembly and intracellular processes. Altogether, the study revealed extensive polygenic overlap between BIP and comorbid CVD, implicating shared molecular genetic mechanisms. The mixed effect directions of the shared loci suggest variation in genetic susceptibility to CVD across BIP subgroups, which may underlie the heterogeneity of CVD comorbidity in BIP patients. The findings suggest more focus on targeted lifestyle interventions and personalized pharmacological treatment to reduce CVD comorbidity in BIP.

• Szabo, Attila; O'Connell, Kevin Sean; Ueland, Thor; Sheikh, Mashhood Ahmed; Agartz, Ingrid & Andreou, Dimitrios [Show all 31 contributors for this article] (2021). Increased circulating IL-18 levels in severe mental disorders indicate systemic inflammasome activation. Brain, Behavior, and Immunity. ISSN 0889-1591. 99, p. 299–306. doi: 10.1016/j.bbi.2021.10.017. Full text in Research Archive Show summary

  Background Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) that are part of a psychosis continuum, and dysregulated innate immune responses have been suggested to be involved in their pathophysiology. However, disease-specific immune mechanisms in SMI are not known yet. Recently, dyslipidemia has been linked to systemic inflammasome activation, and elevated atherogenic lipid ratios have been shown to correlate with circulating levels of inflammatory biomarkers in SMI. It is, however, not yet known if increased systemic cholesterol load leads to inflammasome activation in these patients. Methods We tested the hypothesis that patients with SCZ and BD display higher circulating levels compared to healthy individuals of key members of the IL-18 system using a large patient cohort (n = 1632; including 737 SCZ and 895 BD), and healthy controls (CTRL; n = 1070). In addition, we assessed associations with coronary artery disease risk factors in SMI, focusing on relevant inflammasome-related, neuroendocrine, and lipid markers. Results We report higher baseline levels of circulating IL-18 system components (IL-18, IL-18BPA, IL-18R1), and increased expression of inflammasome-related genes (NLRP3 and NLRC4) in the blood of patients relative to CTRL. We demonstrate a cholesterol dyslipidemia pattern in psychotic disorders, and report correlations between levels of blood cholesterol types and the expression of inflammasome system elements in SMI. Conclusions Based on these results, we suggest a role for inflammasome activation/dysregulation in SMI. Our findings further the understanding of possible underlying inflammatory mechanisms and may expose important therapeutic targets in SMI.

• Rødevand, Linn; Bahrami, Shahram; Frei, Oleksandr; Lin, Aihua; Gani, Osman & Shadrin, Alexey A. [Show all 18 contributors for this article] (2021). Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms. Translational Psychiatry. 11(1). doi: 10.1038/s41398-020-01142-4. Full text in Research Archive Show summary

  Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.

• Reponen, Elina Johanna; Tesli, Martin Steen; Dieset, Ingrid; Steen, Nils Eiel; Vedal, Trude Seselie Jahr & Szabo, Attila [Show all 12 contributors for this article] (2021). Adiponectin Is Related to Cardiovascular Risk in Severe Mental Illness Independent of Antipsychotic Treatment. Frontiers in Psychiatry. 12. doi: 10.3389/fpsyt.2021.623192. Full text in Research Archive Show summary

  Background: Schizophrenia (SCZ) and bipolar disorder (BD) are severe mental illnesses (SMI) associated with elevated cardiovascular disease (CVD) risk, including obesity. Leptin and adiponectin are secreted by adipose tissue, with pro- and anti-inflammatory properties, respectively. The second generation antipsychotics (AP) olanzapine, clozapine, and quetiapine have been associated with high leptin levels in SMI. However, the link between inflammatory dysregulation of leptin and adiponectin and CVD risk in SMI, and how this risk is influenced by body mass and AP medication, is still not completely understood. We investigated herein if leptin, adiponectin or their ratio (L/A ratio) could predict increased CVD risk in SCZ, BD, and in subgroups according to use of antipsychotic (AP) treatment, independent of other cardio-metabolic risk factors.<p> <p>Methods: We measured fasting plasma levels of leptin and adiponectin, and calculated the L/A ratio in n = 1,092 patients with SCZ and BD, in subgroups according to AP treatment, and in n = 176 healthy controls (HC). Differences in the levels of adipokines and L/A between groups were examined in multivariate analysis of covariance, and the correlations between adipokines and body mass index (BMI) with linear regression. CVD risk was defined by total cholesterol/high-density lipoprotein (TC/HDL) and triglyceride/HDL (TG/HDL) ratios. The adipokines and L/A ratios ability to discriminate individuals with TG/HDL and TC/HDL ratios above threshold levels was explored by ROC analysis, and we investigated the possible influence of other cardio-metabolic risk factors on the association in logistic regression analyses.<p> <p>Results: We observed higher leptin levels and L/A ratios in SMI compared with HC but found no differences in adiponectin. Both adipokines were highly correlated with BMI. The low adiponectin levels showed a fair discrimination in ROC analysis of individuals with CVD risk, with AUC between 0.7 and 0.8 for both TC/HDL and TG/HDL, in all groups examined regardless of diagnosis or AP treatment. Adiponectin remained significantly associated with an elevated TC/HDL and TG/HDL ratio in SMI, also after further adjustment with other cardio-metabolic risk factors.<p> <p>Conclusions: Adiponectin is not dysregulated in SMI but is associated with CVD risk regardless of AP treatment regime.

• Aas, Monica; Ueland, Torill; Mørch, Ragni Helene; Laskemoen, Jannicke Fjæra; Lunding, Synve Hoffart & Reponen, Elina Johanna [Show all 11 contributors for this article] (2021). Physical activity and childhood trauma experiences in patients with schizophrenia or bipolar disorders. World Journal of Biological Psychiatry. ISSN 1562-2975. 22(8), p. 637–645. doi: 10.1080/15622975.2021.1907707. Full text in Research Archive Show summary

  Background Physical activity promotes resilience and reduces stress. Here we aimed to clarify the impact of physical activity and childhood trauma experiences on current mood and cognitive function in patients with schizophrenia (SZ) or bipolar disorders (BD). Methods Three-hundred-and-six patients with DSM-IV schizophrenia (SZ) or bipolar disorder (BD) were included in the study. Diagnoses were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Physical activity was measured as hours spent on any regular physical activity per week. All patients underwent a neuropsychological test battery. History of Childhood trauma was assessed using the Childhood Trauma Questionnaire and mood symptoms were assessed with the Inventory of Depressive Symptoms. Results Patients with childhood trauma who were physically inactive (˂90 min per week) had the most severe clinical profile, characterised by the highest depressive symptoms (p ˂ 0.001) and lowest performance on working memory tasks (p ˂ 0.001). Among patients with childhood trauma, those who were physically active (≥90 min per week) had better working memory performance than physically inactive patients (p = 0.02). Discussion A history of childhood trauma was associated with poorer working memory and more depressive symptoms only in patients who were physically inactive, suggesting a possible protective factor of physical activity in severe mental disorder.

• Valstad, Mathias; Roelfs, Daniel; Slapø, Nora Berz; Timpe, Clara Marie Fides; Rai, Ahsan & Matziorinis, Anna Maria [Show all 24 contributors for this article] (2021). Evidence for Reduced Long-Term Potentiation-Like Visual Cortical Plasticity in Schizophrenia and Bipolar Disorder. Schizophrenia Bulletin. ISSN 0586-7614. 47(6), p. 1751–1760. doi: 10.1093/schbul/sbab049. Full text in Research Archive Show summary

  Several lines of research suggest that impairments in long-term potentiation (LTP)-like synaptic plasticity might be a key pathophysiological mechanism in schizophrenia (SZ) and bipolar disorder type I (BDI) and II (BDII). Using modulations of visually evoked potentials (VEP) of the electroencephalogram, impaired LTP-like visual cortical plasticity has been implicated in patients with BDII, while there has been conflicting evidence in SZ, a lack of research in BDI, and mixed results regarding associations with symptom severity, mood states, and medication. We measured the VEP of patients with SZ spectrum disorders (n = 31), BDI (n = 34), BDII (n = 33), and other BD spectrum disorders (n = 2), and age-matched healthy control (HC) participants (n = 200) before and after prolonged visual stimulation. Compared to HCs, modulation of VEP component N1b, but not C1 or P1, was impaired both in patients within the SZ spectrum (χ 2 = 35.1, P = 3.1 × 10−9) and BD spectrum (χ 2 = 7.0, P = 8.2 × 10−3), including BDI (χ 2 = 6.4, P = .012), but not BDII (χ 2 = 2.2, P = .14). N1b modulation was also more severely impaired in SZ spectrum than BD spectrum patients (χ 2 = 14.2, P = 1.7 × 10−4). N1b modulation was not significantly associated with Positive and Negative Syndrome Scale (PANSS) negative or positive symptoms scores, number of psychotic episodes, Montgomery and Åsberg Depression Rating Scale (MADRS) scores, or Young Mania Rating Scale (YMRS) scores after multiple comparison correction, although a nominal association was observed between N1b modulation and PANSS negative symptoms scores among SZ spectrum patients. These results suggest that LTP-like plasticity is impaired in SZ and BD. Adding to previous genetic, pharmacological, and electrophysiological evidence, these results implicate aberrant synaptic plasticity as a mechanism underlying SZ and BD.

• Bigseth, Therese Torgersen; Fredriksen, Mats; Egeland, Jens; Andersen, Eivind; Andreassen, Ole Andreas & Bang-Kittilsen, Gry [Show all 15 contributors for this article] (2021). Elevated levels of soluble urokinase plasminogen activator receptor as a low-grade inflammation marker in schizophrenia: A case-control study. Schizophrenia Research. ISSN 0920-9964. 228, p. 190–192. doi: 10.1016/j.schres.2020.11.051. Full text in Research Archive
• Gurholt, Tiril Pedersen; Kaufmann, Tobias; Frei, Oleksandr; Alnæs, Dag; Haukvik, Unn Kristin H. & Meer, Dennis van der [Show all 17 contributors for this article] (2021). Population-based body–brain mapping links brain morphology with anthropometrics and body composition. Translational Psychiatry. doi: 10.1038/s41398-021-01414-7. Full text in Research Archive Show summary

  Abstract Understanding complex body–brain processes and the interplay between adipose tissue and brain health is important for understanding comorbidity between psychiatric and cardiometabolic disorders. We investigated associations between brain structure and anthropometric and body composition measures using brain magnetic resonance imaging (MRI; n  = 24,728) and body MRI ( n  = 4973) of generally healthy participants in the UK Biobank. We derived regional and global measures of brain morphometry using FreeSurfer and tested their association with (i) anthropometric measures, and (ii) adipose and muscle tissue measured from body MRI. We identified several significant associations with small effect sizes. Anthropometric measures showed negative, nonlinear, associations with cerebellar/cortical gray matter, and brain stem structures, and positive associations with ventricular volumes. Subcortical structures exhibited mixed effect directionality, with strongest positive association for accumbens. Adipose tissue measures, including liver fat and muscle fat infiltration, were negatively associated with cortical/cerebellum structures, while total thigh muscle volume was positively associated with brain stem and accumbens. Regional investigations of cortical area, thickness, and volume indicated widespread and largely negative associations with anthropometric and adipose tissue measures, with an opposite pattern for thigh muscle volume. Self-reported diabetes, hypertension, or hypercholesterolemia were associated with brain structure. The findings provide new insight into physiological body–brain associations suggestive of shared mechanisms between cardiometabolic risk factors and brain health. Whereas the causality needs to be determined, the observed patterns of body–brain relationships provide a foundation for understanding the underlying mechanisms linking psychiatric disorders with obesity and cardiovascular disease, with potential for the development of new prevention strategies.

• Lunding, Synve Hoffart; Simonsen, Carmen Elisabeth; Aas, Monica; Rødevand, Linn; Werner, Maren Caroline Frogner & Laskemoen, Jannicke Fjæra [Show all 13 contributors for this article] (2021). Childhood trauma and cardiometabolic risk in severe mental disorders: The mediating role of cognitive control. European psychiatry. ISSN 0924-9338. 64(1). doi: 10.1192/j.eurpsy.2021.14. Full text in Research Archive Show summary

  Background Cardiometabolic risk is increased in severe mental disorders (SMDs), and there appears to be a relationship between childhood trauma and cardiometabolic risk, possibly related to adverse health behavior. The current study examined the association between childhood trauma and serum lipids and adiposity in SMDs and the potential mediating role of cognitive and personality characteristics. Methods Participants with schizophrenia and bipolar spectrum disorders (N = 819) were included, cardiometabolic risk factors (serum lipids, body mass index, and waist circumference) were measured, and history of childhood trauma was assessed by the Childhood Trauma Questionnaire. Cognitive and personality characteristics were available in subsamples, with assessments of cognitive control, impulsiveness, self-esteem, and affective lability. Linear regressions and mediation analyses with Hayes’ PROCESS were performed, adjusting for age, sex, antipsychotic agent propensity of metabolic side-effect, and diagnostic group. Results Experience of three or more subtypes of childhood trauma was positively associated with waist circumference in patients with SMDs (p = 0.014). There were no other significant associations between trauma variables and lipid or adiposity measures in the total sample. Cognitive control was a significant mediator between experience of one or two subtypes of childhood trauma and waist circumference. Conclusions The results indicate childhood trauma as a predisposing factor for increased waist circumference in individuals with SMDs. Poorer cognitive control, suggestive of adverse health behavior, might be a mediating factor of the association, and the findings indicate the potential importance of increased focus on these factors in prevention and treatment regimens targeting cardiometabolic health.

• Beck, Dani; Lange, Ann-Marie G. de; Pedersen, Mads L.; Alnæs, Dag; Maximov, Ivan & Voldsbekk, Irene [Show all 18 contributors for this article] (2021). Cardiometabolic risk factors associated with brain age and accelerate brain ageing. Human Brain Mapping. ISSN 1065-9471. p. 1–21. doi: 10.1002/hbm.25680. Full text in Research Archive Show summary

  The structure and integrity of the ageing brain is interchangeably linked to physical health, and cardiometabolic risk factors (CMRs) are associated with dementia and other brain disorders. In this mixed cross-sectional and longitudinal study (interval mean = 19.7 months), including 790 healthy individuals (mean age = 46.7 years, 53% women), we investigated CMRs and health indicators including anthropometric measures, lifestyle factors, and blood biomarkers in relation to brain structure using MRI-based morphometry and diffusion tensor imaging (DTI). We performed tissue specific brain age prediction using machine learning and performed Bayesian multilevel modeling to assess changes in each CMR over time, their respective association with brain age gap (BAG), and their interaction effects with time and age on the tissue-specific BAGs. The results showed credible associations between DTI-based BAG and blood levels of phosphate and mean cell volume (MCV), and between T1-based BAG and systolic blood pressure, smoking, pulse, and C-reactive protein (CRP), indicating older-appearing brains in people with higher cardiometabolic risk (smoking, higher blood pressure and pulse, low-grade inflammation). Longitudinal evidence supported interactions between both BAGs and waist-to-hip ratio (WHR), and between DTI-based BAG and systolic blood pressure and smoking, indicating accelerated ageing in people with higher cardiometabolic risk (smoking, higher blood pressure, and WHR). The results demonstrate that cardiometabolic risk factors are associated with brain ageing. While randomized controlled trials are needed to establish causality, our results indicate that public health initiatives and treatment strategies targeting modifiable cardiometabolic risk factors may also improve risk trajectories and delay brain ageing.

• Osete, Jordi Requena; Akkouh, Ibrahim; Assis, Denis Reis de; Szabo, Attila; Frei, Evgeniia & Hughes, Timothy [Show all 10 contributors for this article] (2021). Lithium increases mitochondrial respiration in iPSC-derived neural precursor cells from lithium responders. Molecular Psychiatry. ISSN 1359-4184. doi: 10.1038/s41380-021-01164-4. Full text in Research Archive Show summary

  Lithium (Li), valproate (VPA) and lamotrigine (LTG) are commonly used to treat bipolar disorder (BD). While their clinical efficacy is well established, the mechanisms of action at the molecular level are still incompletely understood. Here we investigated the molecular effects of Li, LTG and VPA treatment in induced pluripotent stem cell (iPSC)-derived neural precursor cells (NPCs) generated from 3 healthy controls (CTRL), 3 affective disorder Li responsive patients (Li-R) and 3 Li non-treated patients (Li-N) after 6 h and 1 week of exposure. Differential expression (DE) analysis after 6 h of treatment revealed a transcriptional signature that was associated with all three drugs and most significantly enriched for ribosome and oxidative phosphorylation (OXPHOS) pathways. In addition to the shared DE genes, we found that Li exposure was associated with 554 genes uniquely regulated in Li-R NPCs and enriched for spliceosome, OXPHOS and thermogenesis pathways. In-depth analysis of the treatment-associated transcripts uncovered a significant decrease in intron retention rate, suggesting that the beneficial influence of these drugs might partly be related to splicing. We examined the mitochondrial respiratory function of the NPCs by exploring the drugs’ effects on oxygen consumption rate (OCR) and glycolytic rate (ECAR). Li improved OCR levels only in Li-R NPCs by enhancing maximal respiration and reserve capacity, while VPA enhanced maximal respiration and reserve capacity in Li-N NPCs. Overall, our findings further support the involvement of mitochondrial functions in the molecular mechanisms of mood stabilizers and suggest novel mechanisms related to the spliceosome, which warrant further investigation.

• Engh, John; Ueland, Thor; Agartz, Ingrid; Andreou, Dimitrios; Aukrust, Pål & Boye, Birgitte [Show all 27 contributors for this article] (2021). Plasma Levels of the Cytokines B Cell-Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL) in Schizophrenia, Bipolar, and Major Depressive Disorder: A Cross Sectional, Multisite Study. Schizophrenia Bulletin. ISSN 0586-7614. 48(1), p. 37–46. doi: 10.1093/schbul/sbab106. Full text in Research Archive Show summary

  Background Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. Methods We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. Results Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen’s d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). Conclusions These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.

• Bigseth, Therese Torgersen; Engh, John; Egeland, Jens; Andersen, Eivind; Andreassen, Ole & Bang-Kittilsen, Gry [Show all 15 contributors for this article] (2021). Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms. BMC Psychiatry. 21(1), p. 1–10. doi: 10.1186/s12888-021-03522-6. Full text in Research Archive Show summary

  Background There is evidence of increased low grade inflammation (LGI) in schizophrenia patients. However, the inter-individual variation is large and the association with demographic, somatic and psychiatric factors remains unclear. Our aim was to explore whether levels of the novel LGI marker soluble urokinase plasminogen activator receptor (suPAR) were associated with clinical factors in schizophrenia and if such associations were sex-dependent. Method In this observational study a total of 187 participants with schizophrenia (108 males, 79 females) underwent physical examination and assessment with clinical interviews (Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Alcohol Use Disorder Identification Test (AUDIT), and Drug Use Disorder Identification Test (DUDIT)). Blood levels of suPAR, glucose, lipids, and high sensitivity C-reactive protein (hsCRP) were determined and body mass index (BMI) calculated. Multivariable linear regression analyses were used adjusting for confounders, and sex interaction tested in significant variables. Results Adjusting for sex, age, current tobacco smoking and BMI, we found that levels of hsCRP and depressive symptoms (CDSS) were positively associated with levels of suPAR (p < 0.001). The association between suPAR and CDSS score was significant in females (p < 0.001) but not in males. Immune activation measured by hsCRP was not associated with depressive symptoms after adjusting for BMI. Conclusion Our findings indicate that increased suPAR levels are associated with depressive symptoms in females with schizophrenia, suggesting aberrant immune activation in this subgroup. Our results warrant further studies, including longitudinal follow-up of suPAR levels in schizophrenia and experimental studies of mechanisms.

• Fjukstad, Katrine Kveli; Athanasiu, Lavinia; Bahrami, Shahram; O`Connell, Kevin; Meer, Dennis van der & Bettella, Francesco [Show all 11 contributors for this article] (2021). Genetic variants associated with cardiometabolic abnormalities during treatment with selective serotonin reuptake inhibitors: a genome-wide association study. The Pharmacogenomics Journal. ISSN 1470-269X. 21, p. 574–585. doi: 10.1038/s41397-021-00234-8. Full text in Research Archive Show summary

  Selective serotonin reuptake inhibitors (SSRIs) are prescribed both to patients with schizophrenia and bipolar disorder. Previous studies have shown associations between SSRI treatment and cardiometabolic alterations. The aim of the present study was to investigate genetic variants associated with cardiometabolic adverse effects in patients treated with SSRIs in a naturalistic setting, using a genome-wide cross-sectional approach in a genetically homogeneous sample. We included and genotyped 1981 individuals with schizophrenia or bipolar disorder, of whom 1180 had information available on the outcomes low-density lipoprotein cholesterol (LDL-cholesterol), high-density lipoprotein cholesterol (HDL-cholesterol), triglycerides, and body mass index (BMI) and investigated interactions between SNPs and SSRI use (N = 246) by conducting a genome-wide GxE analysis. We report 13 genome-wide significant interaction effects of SNPs and SSRI serum concentrations on LDL-cholesterol, HDL-cholesterol, and BMI, located in four distinct genomic loci. This study provides new insight into the pharmacogenetics of SSRI but warrants replication in independent populations.

• O'Connell, Kevin Sean; Frei, Oleksandr; Bahrami, Shahram; Smeland, Olav Bjerkehagen; Bettella, Francesco & Cheng, Weiqiu [Show all 16 contributors for this article] (2021). Characterizing the Genetic Overlap Between Psychiatric Disorders and Sleep-Related Phenotypes. Biological Psychiatry. ISSN 0006-3223. 90(9), p. 1–11. doi: 10.1016/j.biopsych.2021.07.007. Full text in Research Archive Show summary

  Background: A range of sleep disturbances are commonly experienced by patients with psychiatric disorders, and genome-wide genetic analyses have shown some significant genetic correlations between these traits. Here, we applied novel statistical genetic methodologies to better characterize the potential shared genetic architecture between sleep-related phenotypes and psychiatric disorders. Methods: Using the MiXeR method, which can estimate polygenic overlap beyond genetic correlation, the shared genetic architecture between major psychiatric disorders (bipolar disorder [N = 51,710], depression [N = 480,359], and schizophrenia [N = 77,096]) and sleep-related phenotypes (chronotype [N = 449,734], insomnia [N = 386,533] and sleep duration [N = 446,118]) were quantified on the basis of genetic summary statistics. Furthermore, the conditional/conjunctional false discovery rate framework was used to identify specific shared loci between these phenotypes, for which positional and functional annotation were conducted with FUMA. Results: Extensive genetic overlap between the sleep-related phenotypes and bipolar disorder (63%–77%), depression (76%–79%), and schizophrenia (64%–79%) was identified, with moderate levels of congruence between most investigated traits (47%–58%). Specific shared loci were identified for all bivariate analyses, and a subset of 70 credible genes were mapped to these shared loci. Conclusions: The current results provide evidence for substantial polygenic overlap between psychiatric disorders and sleep-related phenotypes, beyond genetic correlation (|rg| = 0.02 to 0.42). Moderate congruency within the shared genetic components suggests a complex genetic relationship and potential subgroups with higher or lower genetic concordance. This work provides new insights and understanding of the shared genetic etiology of sleep-related phenotypes and psychiatric disorders and highlights new opportunities and avenues for future investigation.

• Krull, Florian; Akkouh, Ibrahim Ahmed; Hughes, Timothy; Bettella, Francesco; Athanasiu, Lavinia & Smeland, Olav Bjerkehagen [Show all 12 contributors for this article] (2021). Dose-dependent transcriptional effects of lithium and adverse effect burden in a psychiatric cohort. Progress in Neuro-psychopharmacology and Biological Psychiatry. ISSN 0278-5846. 112. doi: 10.1016/j.pnpbp.2021.110408. Full text in Research Archive Show summary

  Lithium is the first-line treatment for bipolar disorder (BD), but there is a large variation in response rate and adverse effects. Although the molecular effects of lithium have been studied extensively, the specific mechanisms of action remain unclear. In particular, the molecular changes underlying lithium adverse effects are little known. Multiple linear regression analyses of lithium serum concentrations and global gene expression levels in whole blood were carried out using a large case-control sample (n = 1450). Self-reported adverse effects of lithium were assessed with the “Udvalg for Kliniske Undersøgelser” (UKU) adverse effect rating scale, and regression analysis was used to identify significant associations between lithium-related genes and six of the most common adverse effects. Serum concentrations of lithium were significantly associated with the expression levels of 52 genes (FDR < 0.01), largely replicating previous results. We found 32 up-regulated genes and 20 down-regulated genes in lithium users compared to non-users. The down-regulated gene set was enriched for several processes related to the translational machinery. Two adverse effects were significantly associated (p < 0.01) with three or more lithium-associated genes: tremor (FAM13A-AS1, FAR2, ITGAX, RWDD1, and STARD10) and xerostomia (ANKRD13A, FAR2, RPS8, and RWDD1). The adverse effect association with the largest effect was between CAMK1D expression and nausea/vomiting. These results suggest putative transcriptional mechanisms that may predict lithium adverse effects, and could thus have a large potential for informing clinical practice.

• Andreou, Dimitrios; Steen, Nils Eiel; Jørgensen, Kjetil Nordbø; Smelror, Runar; Wedervang-Resell, Kirsten & Nerland, Stener [Show all 25 contributors for this article] (2021). Lower circulating neuron-specific enolase concentrations in adults and adolescents with severe mental illness. Psychological Medicine. ISSN 0033-2917. p. 1–10. doi: 10.1017/S0033291721003056. Full text in Research Archive Show summary

  Background Both neurodegenerative and neurodevelopmental abnormalities have been suggested to be part of the etiopathology of severe mental illness (SMI). Neuron-specific enolase (NSE), mainly located in the neuronal cytoplasm, may indicate the process as it is upregulated after neuronal injury while a switch from non-neuronal enolase to NSE occurs during neuronal maturation. Methods We included 1132 adult patients with SMI [schizophrenia (SZ) or bipolar spectrum disorders], 903 adult healthy controls (HC), 32 adolescent patients with SMI and 67 adolescent HC. Plasma NSE concentrations were measured by enzyme immunoassay. For 842 adults and 85 adolescents, we used total grey matter volume (TGMV) based on T1-weighted magnetic resonance images processed in FreeSurfer v6.0. We explored NSE case-control differences in adults and adolescents separately. To investigate whether putative case-control differences in NSE were TGMV-dependent we controlled for TGMV. Results We found significantly lower NSE concentrations in both adult (p < 0.001) and adolescent patients with SMI (p = 0.007) compared to HC. The results remained significant after controlling for TGMV. Among adults, both patients with SZ spectrum (p < 0.001) and bipolar spectrum disorders (p = 0.005) had lower NSE than HC. In both patient subgroups, lower NSE levels were associated with increased symptom severity. Among adults (p < 0.001) and adolescents (p = 0.040), females had lower NSE concentrations than males. Conclusion We found lower NSE concentrations in adult and adolescent patients with SMI compared to HC. The results suggest the lack of progressive neuronal injury, and may reflect abnormal neuronal maturation. This provides further support of a neurodevelopmental rather than a neurodegenerative mechanism in SMI.

• Gjerde, Priyanthi Borgen; Simonsen, Carmen Elisabeth; Lagerberg, Trine V.; Steen, Nils Eiel; Andreassen, Ole A. & Steen, Vidar M. [Show all 7 contributors for this article] (2021). Sex-Specific Effect of Serum Lipids and Body Mass Index on Psychotic Symptoms, a Cross-Sectional Study of First-Episode Psychosis Patients. Frontiers in Psychiatry. 12. doi: 10.3389/fpsyt.2021.723158. Full text in Research Archive Show summary

  Background: Schizophrenia is a disorder with considerable heterogeneity in course and outcomes, which is in part related to the patients' sex. Studies report a link between serum lipids, body mass index (BMI), and therapeutic response. However, the role of sex in these relationships is poorly understood. In a cross-sectional sample of first-episode psychosis (FEP) patients, we investigated if the relationship between serum lipid levels (total cholesterol, HDL-C, LDL-C, and triglycerides), BMI, and symptoms differs between the sexes. Methods: We included 435 FEP patients (males: N = 283, 65%) from the ongoing Thematically Organized Psychosis (TOP) study. Data on clinical status, antipsychotics, lifestyle, serum lipid levels, and BMI were obtained. The Positive and Negative Syndrome Scale (PANSS) and the Calgary Depression Scale for Schizophrenia (CDSS) were used to assess psychotic and depressive symptoms. General linear models were employed to examine the relationship between metabolic variables and symptomatology. Results: We observed a female-specific association between serum HDL-C levels and negative symptoms (B = −2.24, p = 0.03) and between triglycerides levels (B = 1.48, p = 0.04) and BMI (B = 0.27, p = 0.001) with depressive symptoms. When controlling for BMI, only the association between serum HDL-C levels and negative symptoms remained significant. Moreover, the HDL-C and BMI associations remained significant after controlling for demography, lifestyle, and illness-related factors. Conclusion: We found a relationship between metabolic factors and psychiatric symptoms in FEP patients that was sex-dependent.

• Hindley, Guy Frederick Lanyon; Bahrami, Shahram; Steen, Nils Eiel; O'Connell, Kevin Sean; Frei, Oleksandr & Shadrin, Alexey [Show all 13 contributors for this article] (2021). Characterising the shared genetic determinants of bipolar disorder, schizophrenia and risk-taking. Translational Psychiatry. 11:466, p. 1–10. doi: 10.1038/s41398-021-01576-4. Full text in Research Archive Show summary

  Increased risk-taking is a central component of bipolar disorder (BIP) and is implicated in schizophrenia (SCZ). Risky behaviours, including smoking and alcohol use, are overrepresented in both disorders and associated with poor health outcomes. Positive genetic correlations are reported but an improved understanding of the shared genetic architecture between risk phenotypes and psychiatric disorders may provide insights into underlying neurobiological mechanisms. We aimed to characterise the genetic overlap between risk phenotypes and SCZ, and BIP by estimating the total number of shared variants using the bivariate causal mixture model and identifying shared genomic loci using the conjunctional false discovery rate method. Summary statistics from genome wide association studies of SCZ, BIP, risk-taking and risky behaviours were acquired (n = 82,315–466,751). Genomic loci were functionally annotated using FUMA. Of 8.6–8.7 K variants predicted to influence BIP, 6.6 K and 7.4 K were predicted to influence risk-taking and risky behaviours, respectively. Similarly, of 10.2–10.3 K variants influencing SCZ, 9.6 and 8.8 K were predicted to influence risk-taking and risky behaviours, respectively. We identified 192 loci jointly associated with SCZ and risk phenotypes and 206 associated with BIP and risk phenotypes, of which 68 were common to both risk-taking and risky behaviours and 124 were novel to SCZ or BIP. Functional annotation implicated differential expression in multiple cortical and sub-cortical regions. In conclusion, we report extensive polygenic overlap between risk phenotypes and BIP and SCZ, identify specific loci contributing to this shared risk and highlight biologically plausible mechanisms that may underlie risk-taking in severe psychiatric disorders.

• Winterton, Adriano; Bettella, Francesco; Lange, Ann-Marie Glasø de; Haram, Marit; Steen, Nils Eiel & Westlye, Lars Tjelta [Show all 8 contributors for this article] (2021). Oxytocin-pathway polygenic scores for severe mental disorders and metabolic phenotypes in the UK Biobank. Translational Psychiatry. doi: 10.1038/s41398-021-01725-9. Full text in Research Archive Show summary

  Abstract Oxytocin is a neuromodulator and hormone that is typically associated with social cognition and behavior. In light of its purported effects on social cognition and behavior, research has investigated its potential as a treatment for psychiatric illnesses characterized by social dysfunction, such as schizophrenia and bipolar disorder. While the results of these trials have been mixed, more recent evidence suggests that the oxytocin system is also linked with cardiometabolic conditions for which individuals with severe mental disorders are at a higher risk for developing. To investigate whether the oxytocin system has a pleiotropic effect on the etiology of severe mental illness and cardiometabolic conditions, we explored oxytocin’s role in the shared genetic liability of schizophrenia, bipolar disorder, type-2 diabetes, and several phenotypes linked with cardiovascular disease and type 2 diabetes risk using a polygenic pathway-specific approach. Analysis of a large sample with about 480,000 individuals (UK Biobank) revealed statistically significant associations across the range of phenotypes analyzed. By comparing these effects to those of polygenic scores calculated from 100 random gene sets, we also demonstrated the specificity of many of these significant results. Altogether, our results suggest that the shared effect of oxytocin-system dysfunction could help partially explain the co-occurrence of social and cardiometabolic dysfunction in severe mental illnesses.

• Akkouh, Ibrahim; Ueland, Thor; Hansson, Lars; Inderhaug, Elin; Hughes, Timothy & Steen, Nils Eiel [Show all 10 contributors for this article] (2020). Decreased IL-1β-induced CCL20 response in human iPSC-astrocytes in schizophrenia: Potential attenuating effects on recruitment of regulatory T cells. Brain, Behavior, and Immunity. ISSN 0889-1591. 87, p. 634–644. doi: 10.1016/j.bbi.2020.02.008. Full text in Research Archive Show summary

  Schizophrenia (SCZ) is a severe mental disorder with a high heritability. Although its pathophysiology is mainly unknown, dysregulated immune activation and inflammation have recently emerged as possible candidates in the underlying mechanisms of SCZ. Previous studies suggest that aberrant inflammasome activation, glia dysregulation, and brain inflammation may be involved in the pathophysiology of the disorder. Here, we studied the effects of inflammatory modulation on human induced pluripotent stem cell (iPSC)-derived astrocytes generated from SCZ patients and healthy controls (CTRL). Inflammasome activation was mimicked by short-term IL-1β exposure, and gene expression were measured with high-coverage RNA-Seq to ensure a global characterization of the transcriptional effects of the treatment. IL-1β exposure modulated several pathways involved in innate immune responses, cell cycle regulation, and metabolism in both SCZ and CTRL astrocytes. Significant differences were found in the expression of HILPDA and CCL20 genes, both of which had reduced up-regulation upon IL-1β treatment in SCZ astrocytes compared to CTRL astrocytes. CCL20 data were further validated and confirmed using qPCR, ELISA, and regulatory T lymphocyte (Treg) migration assays. Additionally, we found significantly decreased mRNA expression of the Treg-specific marker FOXP3 in the blood of a large cohort of SCZ patients (n = 484) compared to CTRL (n = 472). Since CCL20 is a specific chemoattractant for CD4+CD25+CCR6+ Tregs, which are crucially involved in anti-inflammatory responses during brain (auto)inflammation, our results imply a plausible role for an altered astroglia-CCL20-CCR6-Treg axis in SCZ pathophysiology.

• Winterton, Adriano; Rødevand, Linn; Westlye, Lars Tjelta; Steen, Nils Eiel; Andreassen, Ole Andreas & Quintana, Daniel (2020). Associations of loneliness and social isolation with cardiovascular and metabolic health: A systematic review and meta-analysis protocol. Systematic Reviews. 9(1). doi: 10.1186/s13643-020-01369-8. Full text in Research Archive Show summary

  Background A growing number of studies suggest that social isolation and loneliness are associated with premature mortality and are more prevalent among people with mental illness than in the general population, outlining many potential paths to disease still to be elucidated. The purpose of this meta-analysis is to examine the relationship between loneliness, social isolation, and established cardiovascular/metabolic risk factors and disorders, especially in severe mental illness, and to account for potential heterogeneity in the literature. Methods/design Studies that report measures of loneliness and/or social isolation along with cardiovascular/metabolic risk factors will be identified. PubMed, EMBASE (through Ovid SP), Scopus, and PsycINFO (through Ovid SP) will be searched, along with citation lists of retrieved articles and the Cochrane Database of Systematic Reviews. Grey literature will be searched using Google Scholar. Data will be extracted from eligible studies for a random effects meta-analysis. For each study, a summary effect size, heterogeneity, risk of bias, publication bias, and the effect of categorical and continuous moderator variables will be determined. Discussion This proposed systematic review and meta-analysis will identify and synthesise evidence to determine if there is an association between loneliness, social isolation, and cardiovascular/metabolic risk factors, with a special focus on severe mental illnesses. The results will help determine links and promising avenues of further research. Systematic review registration PROSPERO CRD42018111911

• Hope, Sigrun; Nærland, Terje; Høyland, Anne Lise; Torske, Tonje; Malt, Eva & Abrahamsen, Tore G [Show all 16 contributors for this article] (2020). Higher vitamin B12 levels in neurodevelopmental disorders than in healthy controls and schizophrenia A comparison among participants between 2 and 53 years. The FASEB Journal. ISSN 0892-6638. 34(6), p. 8114–8124. doi: 10.1096/fj.201900855RRR. Full text in Research Archive Show summary

  Recent studies suggest that both high and low levels of vitamin B12 (vitB12) may have negative health impacts. We measured VitB12 in patients with the Neurodevelopmental disorders (ND) (n = 222), comprised of Autism Spectrum Disorders, specific Developmental disorders, and Intellectual Disability (aged 2‐53 years), schizophrenia (n = 401), and healthy controls (HC) (n = 483). Age‐and gender‐adjusted vitB12 z‐scores were calculated by comparisons with a reference population (n = 76 148). We found higher vitB12 in ND (median 420 pmol/L, mean z‐score: 0.30) than in HC (316 pmol/L, z‐score: 0.06, P < .01) and schizophrenia (306 pmol/L, z‐score: −0.02, P < .001), which was significant after adjusting for age, gender, vitB12 supplement, folate, hemoglobin, leukocytes, liver, and kidney function (P < .02). In ND, 20% (n = 44) had vitB12 above 650 pmol/L, and 1% (n = 3) had below 150 pmol/L (common reference limits). In 6.3% (n = 14) of ND, vitB12 was above 2SD of mean in the age‐and gender‐adjusted reference population, which was more frequent than in HC (n = 8, 1.6%), OR: 4.0, P = .001. Low vitB12 was equally frequent as in HC, and vitB12 z‐scores were equal across the age groups. To conclude, vitB12 was higher in ND than in HC and schizophrenia, suggesting a specific feature of ND, which warrants further studies to investigate the underlying mechanisms.

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• Funderud, Cecilie Klem; Fjeldstad, Anette; Agartz, Ingrid; Steen, Nils Eiel; Andreassen, Ole & Aas, Monica [Show all 7 contributors for this article] (2024). The Role of IL-18 and Childhood Trauma in Early-Onset Psychosis. Full text in Research Archive
• Gjerde, Kristian Varden; Bartz-Johannessen, Christoffer; Løberg, Else-Marie; Steen, Vidar Martin; Steen, Nils Eiel & Andreassen, Ole [Show all 12 contributors for this article] (2024). Cellular adhesion molecules and cognition in drug-naïve and previously medicated patients with schizophrenia-spectrum disorders: A longitudinal study. Full text in Research Archive

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