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Contains fulltext : 290804.pdf (Publisher’s version ) (Closed access) Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84-98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention. 01 februari 2023

Additional file 4: Appendix Text 1: Associations between explored psychiatric symptoms.

Additional file 1: Table A Sensitivity analysis: Associations between depressive symptoms and suPAR, multivariable regression analyses in participants with schizophrenia.

Additional file 5: Appendix Text 2 - Exploration of the relationship between hsCRP and depressive symptoms beyond CDSS sum score.

Additional file 3:. Metabolic risk associated with antipsychotic medication.

Additional file 2: Table B1 Internal reliability of the Norwegian version of the Calgary Depression Scale for Schizophrenia. Table B2 Internal reliability of the Norwegian version of the Calgary Depression Scale for Schizophrenia, by sex.

The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges. Non

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P

Citation: Elisabeth Haug, Merete G. Øie, Ole A. Andreassen, Unni Bratlien, Kristin L. Romm, Paul Møller and Ingrid Melle, The Association between Anomalous Self-experiences, Self-esteem and Depressive Symptoms in First Episode Schizophrenia, Frontiers in Human Neuroscience, 10, (2016). Aim To investigate the relationship between anomalous self-experiences and duration of untreated psychosis in a sample of patients with first episode schizophrenia spectrum disorders. Methods Anomalous self-experiences were assessed by means of the Examination of Anomalous Self-Experience manual in 55 patients referred to their first adequate treatment for schizophrenia. Diagnoses, symptom severity, functioning and childhood trauma were assessed using the Structured Clinical Interview for the Positive and Negative Syndrome Scale, Premorbid Adjustment Scale, Social Functioning Scale and Childhood trauma questionnaire. Substance misuse was measured with the Drug Use Disorder Identification Test, and alcohol use was measured with the Alcohol Use Disorder Identification Test. Duration of untreated psychosis was measured in accordance with a standardized procedure. Results High levels of anomalous self-experiences are significantly associated with longer duration of untreated psychosis, an association which held after correcting for other variables associated with long duration of untreated psychosis. Conclusions The field of early detection in psychosis is in need of additional clinical perspectives to make further progress. Improved understanding and assessment of anomalous self-experiences may help clinicians to detect these important phenomena and provide earlier help, and thus reduce treatment delay. This work was supported by Innlandet Hospital Trust (grant number 150229)

Funding for this study was provided by Innlandet Hospital Trust (grant number 150229) and the Regional Health Authority of South-Eastern Norway (grant numbers, 2006258, 2008058, and 2011085). The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Epidemiological studies suggest a relationship between blood lipids and immune-mediated diseases, but the nature of these associations is not well understood. We used genome-wide association studies (GWAS) to investigate shared single nucleotide polymorphisms (SNPs) between blood lipids and immune-mediated diseases. We analyzed data from GWAS (n~200,000 individuals), applying new False Discovery Rate (FDR) methods, to investigate genetic overlap between blood lipid levels [triglycerides (TG), low density lipoproteins (LDL), high density lipoproteins (HDL)] and a selection of archetypal immune-mediated diseases (Crohn’s disease, ulcerative colitis, rheumatoid arthritis, type 1 diabetes, celiac disease, psoriasis and sarcoidosis). We found significant polygenic pleiotropy between the blood lipids and all the investigated immune-mediated diseases. We discovered several shared risk loci between the immune-mediated diseases and TG (n = 88), LDL (n = 87) and HDL (n = 52). Three-way analyses differentiated the pattern of pleiotropy among the immune-mediated diseases. The new pleiotropic loci increased the number of functional gene network nodes representing blood lipid loci by 40%. Pathway analyses implicated several novel shared mechanisms for immune pathogenesis and lipid biology, including glycosphingolipid synthesis (e.g. FUT2) and intestinal host-microbe interactions (e.g. ATG16L1). We demonstrate a shared genetic basis for blood lipids and immune-mediated diseases independent of environmental factors. Our findings provide novel mechanistic insights into dyslipidemia and immune-mediated diseases and may have implications for therapeutic trials involving lipid-lowering and anti-inflammatory agents. publishedVersion

Objectives Bipolar disorder (BD) is a highly heritable disorder with polygenic inheritance. Among the most consistent findings from functional magnetic imaging (fMRI) studies are limbic hyperactivation and dorsal hypoactivation. However, the relation between reported brain functional abnormalities and underlying genetic risk remains elusive. This is the first cross-sectional study applying a whole-brain explorative approach to investigate potential influence of BD case-control status and polygenic risk on brain activation. Methods A BD polygenic risk score (PGRS) was estimated from the Psychiatric Genomics Consortium BD case-control study, and assigned to each individual in our independent sample (N=85 BD cases and 121 healthy controls (HC)), all of whom participated in an fMRI emotional faces matching paradigm. Potential differences in BOLD response across diagnostic groups were explored at whole-brain level in addition to amygdala as a region of interest. Putative effects of BD PGRS on brain activation were also investigated. Results At whole-brain level, BD cases presented with significantly lower cuneus/precuneus activation than HC during negative face processing (Z-threshold=2.3 as cluster-level correction). The PGRS was associated positively with increased right inferior frontal gyrus (rIFG) activation during negative face processing. For amygdala activation, there were no correlations with diagnostic status or PGRS. Conclusions These findings are in line with previous reports of reduced precuneus and altered rIFG activation in BD. While these results demonstrate the ability of PGRS to reveal underlying genetic risk of altered brain activation in BD, the lack of convergence of effects at diagnostic and PGRS level suggests that this relation is a complex one.

Aim: Lack of insight into illness is frequent in psychotic disorders and seen as part of their primary pathology. The recognition of symptoms as psychotic, and beliefs about treatment alternatives, is also influenced by socio-cultural factors. Here we examined clinical insight into illness and beliefs about psychosis in immigrants in their first episode of psychosis compared to a reference group. Methods: 277 first episode psychosis participants were recruited to this cross-sectional study; 40 first- and 40 second-generation immigrants from Europe, Americas and Oceania (n=37), Asia including Turkey (n=28), or Africa (n=15). The Birchwood Insight Scale was used to measure clinical insight and “The Attitudes and Beliefs about Mental Health Problems”, schizophrenia version to assess socio-cultural beliefs. Results: Immigrants did not differ from the reference sample in clinical insight. After controlling for education level first generation immigrants were less likely to recognize psychotic symptoms (OR 2.9; Wald = 8.977, df 1, p =.003) and viewed hospitalization (OR 5.2; Wald = 20.388, df 1, p =.001) and treatment by a psychiatrist (OR 4.9; Wald = 6.609, df 1, p =.01)) as less beneficial than the reference group. Immigrants from Asia held more alternative explanations (OR 0.3; Wald = 6.567, df 1, p=.010). There were significantly stronger associations between clinical insight and socio-cultural beliefs in the reference group. Conclusions: Socio-cultural beliefs about psychosis in immigrants in first episode psychosis calls for more tailored information to this group, and emphasize the importance of treatment interventions involving both a cultural and personal perspective of insight.

Schizophrenia (SZ) is a psychotic disorder with significant cognitive dysfunction. Abnormal brain activation during cognitive processing has been reported, both in task-positive and task-negative networks. Further, structural cortical and subcortical brain abnormalities have been documented, but little is known about how task-related brain activation is associated with brain anatomy in SZ compared to healthy controls (HC). Utilizing linked independent component analysis (LICA), a data-driven multimodal analysis approach, we investigated structure–function associations in a large sample of SZ (n = 96) and HC (n = 142). We tested for associations between task-positive (fronto-parietal) and task-negative (default-mode) brain networks derived from fMRI activation during an n-back working memory task, and brain structural measures of surface area, cortical thickness, and gray matter volume, and to what extent these associations differed in SZ compared to HC. A significant association (p, Highlights • Linked ICA was used to investigate structure–function relationships from MRI data. • We tested associations between brain structure and working memory-related networks. • A large sample of schizophrenia patients and healthy controls was included. • Task-positive activation was associated with fronto-temporal thickness in patients. • Other associations were moderate and mostly schizophrenia-related.

Background Negative symptoms in schizophrenia have been associated with structural and functional changes in the prefrontal cortex. They often persist after treatment with antipsychotic medication which targets, in particular, the ventral striatum (VS). As schizophrenia has been suggested to arise from dysfunctional connectivity between neural networks, it is possible that residual aberrant striato-cortical connectivity in medicated patients plays a role in enduring negative symptomology. The present study examined the relationship between striato-cortical connectivity and negative symptoms in medicated schizophrenia patients. Methods We manipulated motivation in a perceptual decision-making task during functional magnetic resonance imaging. Comparing healthy controls (n = 21) and medicated patients with schizophrenia (n = 18) we investigated how motivation-mediated changes in VS activation affected functional connectivity with the frontal cortex, and how changes in connectivity strength from the neutral to motivated condition related to negative symptom severity. Results A pattern of aberrant striato-cortical connectivity was observed in the presence of intact VS, but altered left inferior frontal gyrus (IFG) motivation-mediated activation in patients. The more severe the patient's negative symptoms, the less the connectivity strength between the right VS and left IFG changed from the neutral to the motivated condition. Despite aberrant striato-cortical connectivity and altered recruitment of the left IFG among patients, both patients and healthy controls adopted a more liberal response strategy in the motivated compared to the neutral condition. Conclusions The present findings suggest that there is a link between dysfunctional striato-cortical connectivity and negative symptom severity, and offer a possible explanation as to why negative symptoms persist after treatment with antipsychotics.

Background: Aripiprazole is an atypical antipsychotic drug that is characterized by partial dopamine D2 receptor agonism. Its pharmacodynamic profile is proposed to be beneficial in the treatment of cognitive impairment, which is prevalent in psychotic disorders. This study compared brain activation characteristics produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist, during a task targeting executive functioning. Methods: Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo before performing an executive functioning task while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. Results: There was a tendency towards reduced performance in the aripiprazole group compared to the two other groups. The image analysis yielded a strong task-related BOLD-fMRI response within each group. An uncorrected between-group analysis showed that aripiprazole challenge resulted in stronger activation in the frontal and temporal gyri and the putamen compared with haloperidol challenge, but after correcting for multiple testing there was no significant group difference. Conclusion: No significant group differences between aripiprazole and haloperidol in frontal cortical activation were obtained when corrected for multiple comparisons. This study is registered in ClinicalTrials.gov (identifier: 2009-016222-14).

Despite the promise of intranasal oxytocin (OT) for modulating social behavior, recent work has provided mixed results. This may relate to suboptimal drug deposition achieved with conventional nasal sprays, inter-individual differences in nasal physiology and a poor understanding of how intranasal OT is delivered to the brain in humans. Delivering OT using a novel ‘Breath Powered’ nasal device previously shown to enhance deposition in intranasal sites targeted for nose-to-brain transport, we evaluated dose-dependent effects on social cognition, compared response with intravenous (IV) administration of OT, and assessed nasal cavity dimensions using acoustic rhinometry. We adopted a randomized, double-blind, double-dummy, crossover design, with 16 healthy male adults completing four single-dose treatments (intranasal 8 IU (international units) or 24 IU OT, 1 IU OT IV and placebo). The primary outcome was social cognition measured by emotional ratings of facial images. Secondary outcomes included the pharmacokinetics of OT, vasopressin and cortisol in blood and the association between nasal cavity dimensions and emotional ratings. Despite the fact that all the treatments produced similar plasma OT increases compared with placebo, there was a main effect of treatment on anger ratings of emotionally ambiguous faces. Pairwise comparisons revealed decreased ratings after 8 IU OT in comparison to both placebo and 24 IU OT. In addition, there was an inverse relationship between nasal valve dimensions and anger ratings of ambiguous faces after 8-IU OT treatment. These findings provide support for a direct nose-to-brain effect, independent of blood absorption, of low-dose OT delivered from a Breath Powered device.

Data suggest that individuals with schizophrenia (SZ) and superior intelligence can present without specific neurocognitive deficits. However, neurocognitive decrements, defined as worse cognition than expected, have been reported in practically all SZ cases. This study investigated if neurocognitive decrements are present in intellectually superior SZ by comparing the neuropsychological profile of SZ cases with IQ-matched healthy controls (HC) across intellectual levels. Participants with SZ and HCs were stratified into three IQ-groups; intellectually low (IQ 80–95; SZ n = 65 and HC n = 13), intellectually normal (IQ = 100–115; SZ n = 111 and HC n = 115), and intellectually superior (IQ = 120; SZ n = 20 and HC n = 50). A repeated measures multivariate analysis of co-variance compared performance on eight selected neuropsychological tests across IQ-strata and diagnostic group. Differences in clinical characteristics and social functioning in SZ across IQ-strata were investigated with multivariate and univariate analyses of variance. Intellectually superior SZ participants scored within normal limits, but had neurocognitive decrements compared to superior HCs. Decrements were of the same magnitude as in the low and normal IQ-strata. Levels of functional impairments and clinical characteristics in participants with SZ did not differ significantly across IQ-strata. Results indicate that neurocognitive decrements are present in intellectually superior SZ to the same extent as in intellectually low and intellectually normal SZ, supporting the notion that SZ is a neurocognitive disorder. Similar levels of social functional deficits and clinical symptoms suggest similar disease processes in SZ across intellectual level.

Background There is limited knowledge about how environmental factors affect the course of bipolar disorder (BD). Cannabis has been proposed as a potential risk factor for poorer course of illness, but the role of cannabis use has not been studied in a first treatment BD I sample. Methods The present study examines the associations between course of illness in first treatment BD I and continued cannabis use, from baseline to one year follow up. Patients (N = 62) with first treatment DSM-IV BD I were included as part of the Thematically Organized Psychosis study (TOP), and completed interviews and self-report questionnaires at both baseline and follow up. Cannabis use within the last six months at baseline and use between baseline and follow up (“continued use”) was recorded. Results After controlling for confounders, continued cannabis use was significantly associated with elevated mood (YMRS) and inferior global functioning (GAF-F) at follow up. Elevated mood mediated the effect of cannabis use on global functioning. Conclusions These results suggest that cannabis use has clinical implications for the early course of BD by increasing mood level. More focus on reducing cannabis use in clinical settings seems to be useful for improving outcome in early phase of the disorder.