Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

Background Suicide among youth has increased over past decades and is now among the most common causes of death for adolesecents. Suicidal ideation, the traditional basis of risk assessment, has serious limitations in predicting imminent risk, necessitating novel modes of risk assessment. The Suicide Crisis Syndrome (SCS) is an acute cognitive-affective state that has been shown to be predictive of near-term suicidal thoughts and behavior. It is currently under consideration for inclusion in DSM as a suicide-specific disorder. To date, the SCS has not been tested in adolescents. The present study examines the concurrent validity of the SCS with regard to suicidal ideation using data from an epidemiological study of adolecent health, the Norwegian Young-HUNT3 study. Methods The sample included 8,199 adolescents, aged 13–20, who participated in the Young HUNT3 study, administered between 2006 and 2008 in the Trøndelag district of Norway. Of these, 3,212 respondents answered a question on history of suicidal ideation. The SCS was assessed by a proxy measure (SCS-YHP) derived from the survey items. The association between the SCS-YHP and suicidal ideation was assessed through several logistic regression analyses. Sensitivity analyses were performed to test two additional formats of the SCS-YHP, maintaining the same items but reducing the stringency of the criteria to increase the case rate. Results Concurrent validity was strong for all three formats. Odds ratios ranged from 6.72 to 11.75 and were significant, at minimum, at the .002 level, such that adolescents who were rated as SCS positive, by any of 3 different formats, were approximately 7–12 times more likely to report a history of suicidal ideation. These associations remained significant after controlling for age and sex. Sensitivity and specificity were also high; 67 to 78% for sensitivity and 77–78% for specificity across the three formats, the most stringent format having the strongest sensitivity/specificity. Conclusions As an important first step, this study provides prelmimary evidence of concurrent validity for the Suicide Crisis Syndrome among adolescents. Future research can aim to replicate these findings with a validated measure of the SCS for youth and to test predictive validity to suicidal behavior.

Abstract Background Cardiometabolic diseases are the main causes of death in persons with severe mental illness (SMI), highlighting the need to improve management of cardiovascular risk factors in both primary and specialized health care. The “Healthy Heart Tool” aims at helping health care workers to identify persons at risk, and to initiate proper interventions. Here we investigate if the recommendations in the Healthy Heart Tool are followed one year after implementation and whether implementation of the tool improved cardiometabolic risk factors in SMI. Methods Data from 270 individuals with SMI from six Norwegian hospitals were collected at baseline and at 12 months after implementation of the Healthy Heart Tool throughout the health care services. Changes from baseline to 12 months follow-up were analyzed using chi-square and independent t-tests, whereas implementation effects were analyzed using logistic general linear mixed models. Results After implementing the Healthy Heart Tool, significantly more persons received dietary advice and/or salt restriction advice (75.5% vs. 84.8%, p = 0.035). After controlling for Body Mass Index (BMI) ≥ 30 and sex, there was an odds ratio (OR) of 8.9 (95% CI 1.42–55.77) for receiving dietary advice and/or advice on salt reduction. There was a significant reduction (p = 0.016) in numbers of participants with high levels of total serum cholesterol ≥ 5 mmol/ (54.4% vs. 46.3%). Conclusions Implementing the Healthy Heart Tool can increase awareness of cardiovascular risk factors in patients with SMI. The intervention increased the proportion of individuals who received dietary and salt reduction advice and decreased the proportion of individuals with high cholesterol levels. However, due to the small numbers, these results should be interpreted with caution. Nonetheless, the findings suggest that the Healthy Heart Tool may be an effective means for improving the management of cardiovascular risk factors in individuals with SMI in typical clinical settings. Trial registrations The trial was retrospectively registered in ClinicalTrials.gov 29.01.25, ID NCT 06807242.

Biomarkers for the diagnosis and clinical management of psychiatric disorders are currently lacking. Extracellular vesicles (EVs), lipid membrane-encapsulated vesicles released by cells, hold promise as a source of biomarkers due to their ability to carry molecules that reflect the status of their donor cells and their ubiquitous presence in biofluids. This review examines the literature on EVs in biofluids from psychiatric disorder patients, and discuss how the published studies contribute to our understanding of the pathophysiology of these conditions and to the discovery of potential biomarkers.We analyzed 46 studies on blood-borne EVs; no investigations on cerebrospinal fluid-derived EVs were found. A significant number of studies lacked optimal description of the methodology and/or characterization of the isolated EVs. Moreover, many studies aimed to capture brain-derived EVs, but often capture-proteins with low brain specificity were used. Considering biomarkers, miRNAs were the most investigated molecular type, but based on the studies analyzed it was not possible to identify robust biomarker candidates for the investigated disorders. Additionally, we describe the contribution of EV studies in illuminating the pathophysiology of psychiatric disorders, including research on insulin resistance, inflammation, mitochondrial dysfunction, and the microbiota.We conclude that there is a shortage of studies with detailed methodology description and EV sample characterization in psychiatric research. To exploit the potential of EVs to investigate psychiatric disorders and identify biomarkers more studies and validated protocols using capture proteins with high specificity to brain cells are needed.The review protocol was pre-registered in the PROSPERO database under the registration number CRD42021277534.

Bipolar disorder is a leading contributor to the global burden of disease1. Despite high heritability (60-80%), the majority of the underlying genetic determinants remain unknown2. We analysed data from participants of European, East Asian, African American and Latino ancestries (n = 158,036 cases with bipolar disorder, 2.8 million controls), combining clinical, community and self-reported samples. We identified 298 genome-wide significant loci in the multi-ancestry meta-analysis, a fourfold increase over previous findings3, and identified an ancestry-specific association in the East Asian cohort. Integrating results from fine-mapping and other variant-to-gene mapping approaches identified 36 credible genes in the aetiology of bipolar disorder. Genes prioritized through fine-mapping were enriched for ultra-rare damaging missense and protein-truncating variations in cases with bipolar disorder4, highlighting convergence of common and rare variant signals. We report differences in the genetic architecture of bipolar disorder depending on the source of patient ascertainment and on bipolar disorder subtype (type I or type II). Several analyses implicate specific cell types in the pathophysiology of bipolar disorder, including GABAergic interneurons and medium spiny neurons. Together, these analyses provide additional insights into the genetic architecture and biological underpinnings of bipolar disorder.

Importance:The clinical heterogeneity of bipolar disorder (BD) is a major obstacle to improving diagnosis, predicting patient outcomes, and developing personalized treatments. A genetic approach is needed to deconstruct the disorder and uncover its fundamental biology. Previous genetic studies focusing on broad diagnostic categories have been limited in their ability to parse this complexity. Objective:To test the hypothesis that clinically distinct subphenotypes of BD are associated with different underlying common variant genetic architectures. Design Setting and Participants:This multicenter study included a primary genome-wide association study (GWAS) of up to 23,819 bipolar disorder (BD) cases and 163,839 controls. These results were integrated via multi-trait analysis of GWAS (MTAG) with external summary statistics for BD (59,287 cases; 781,022 controls) and schizophrenia (SCZ; 53,386 cases; 77,258 controls). Sample overlap was statistically accounted for. Main Outcomes and Measures:The primary outcomes were the genetic dimensions underlying BD heterogeneity, differentiated by single nucleotide polymorphism (SNP)-heritability (h 2 SNP ), genetic correlations, genomic loci ( P ≤5×10 -8 ), and functional, cell-type, and gene-expression pathway analyses. Results:We identified four genetically-informed dimensions of BD: Severe Illness, Core Mania, Externalizing/Impulsive Comorbidity, and Internalizing/Affective Comorbidity. The analyses yielded up to 181 subphenotype-associated loci, 53 of which are novel. The Severe Illness Dimension was characterized by a unique neuro-immune signature (a protective association with HLA-DMB , P =2.50×10 -273 ) evident only when leveraging SCZ genetic data. The Internalizing/Affective dimension was associated with neurodevelopmental genes (e.g., DCC ). Notably, the rapid-cycling subphenotype showed a unique signature of strong negative selection, a finding not observed in other subphenotypes. Conclusions and Relevance:The clinical heterogeneity of bipolar disorder appears to be defined by a complex and multi-layered genetic architecture. The presented findings provide an empirical framework that may advance psychiatric nosology beyond its current diagnostic boundaries. These results may also inform future research to identify targets for personalized interventions. The delineation of these genetically-informed dimensions offers specific, biologically-grounded hypotheses for subsequent therapeutic discovery. Establishing such a framework is an essential step toward refining diagnostic criteria and developing more effective, personalized treatments. This work lays the foundation for a transition from a uniform treatment model to the paradigm of precision psychiatry. Key Points:Question: What are the distinct genetic architectures underlying the clinical heterogeneity of bipolar disorder?Findings: In this genetic study of 23,819 bipolar disorder (BD) cases and 163,839 controls, clinical heterogeneity mapped onto four genetically-informed dimensions. A severe illness dimension was defined by a neuro-immune signature ( HLA-DMB ) shared with schizophrenia. An affective comorbidity dimension was distinguished by neurodevelopmental pathways involving axonal guidance ( DCC ). Notably, the rapid-cycling phenotype showed evidence of purifying selection, suggesting influence by rare, highly penetrant alleles. Meaning: These findings provide a data-driven biological framework for bipolar disorder, guiding future research toward patient stratification and targeted therapeutics.

BackgroundThe rate of suicide attempts by patients with bipolar disorder is high. In addition to patient and country specific factors, environmental factors may contribute to suicidal behavior. Sunlight has multiple diverse impacts on human physiology and behavior. Solar insolation is defined as the electromagnetic energy from the sun striking a surface area on earth. We previously found that a large change in solar insolation between the minimum and maximum monthly values was associated with an increased risk of suicide attempts in patients with bipolar I disorder.MethodsThe association between solar insolation and a history of suicide attempts in bipolar disorder was again investigated using an international database with 15% more data and more sites at diverse locations and countries.ResultsData were available from 5641 patients with bipolar I disorder living at a wide range of latitudes in 41 countries in both hemispheres. A large change in solar insolation between the minimum and maximum monthly values was associated with a history of suicide attempts in patients with bipolar I disorder, a replication of our prior analysis. The estimated model also associated state sponsored religion in the onset country, female gender, a history of alcohol or substance abuse, and being part of a younger birth cohort with a history of suicide attempts.ConclusionsA large change between the minimum and maximum monthly values of solar insolation was associated with a history of suicide attempts in bipolar I disorder, replicating our prior research. Physicians should be aware that daylight has wide ranging physiological and psychiatric impacts, and that living with large changes in solar insolation may be associated with an increased suicide risk.

Background and aimsThis study explored the associations between symptoms of the Suicide Crisis Syndrome (SCS) at admission and self-harm and death by suicide post-discharge. The association between clinicians' emotional responses toward inpatients at admission and post-discharge self-harm and suicide death was also explored.MethodsWithin the first 24-h of admission, patients completed a self-report measure of symptoms of SCS, and clinicians reported their emotional responses toward the patients. Follow-up data were obtained from the Norwegian Patient Registry and the Norwegian Cause of Death Registry.ResultsWithin 18 months post-discharge, 44 (12.7%) out of 347 patients had self-harmed, and five patients (1.4%) had died by suicide. At admission, patients who later self-harmed reported higher symptoms of SCS compared to the other patients. Clinicians reported more negative emotional responses toward the self-harm group. In a regression analysis, previous suicidal behavior and a diagnosis of "emotionally unstable personality disorder" (EUPD; F60.3) were associated with increased risk of self-harm post-discharge.ConclusionThe results indicated that patients with post-discharge episodes of self-harm are significantly different from patients who do not self-harm in terms of more intense symptoms of SCS during admission. Clinicians' negative emotional responses may be relevant in the assessment of the risk of post-discharge self-harm.

Perceived usefulness in the clinical setting is important in the implementation of novel constructs and assessments. The suicide crisis syndrome (SCS) has been proposed and validated as a theoretical framework for assessing acute suicide risk, but clinicians' perceptions of the SCS have not yet been examined. In this study, we evaluated perceived utility of the SCS across several provider locations to assess its perceived value as a clinical tool. A sample of 47 practitioners across three sites who had received education about, but no implementation of, the SCS, and a separate sample of 52 practitioners at a site that had systematically implemented the SCS, completed a survey assessing its feasibility, appropriateness, acceptability, incremental helpfulness, and overall clinical utility. In both samples, clinicians reported favorable ratings for feasibility, appropriateness, acceptability, incremental helpfulness, and overall clinical utility. In Sample 1, clinicians with previous experience using the SCS reported significantly higher ratings for all categories except incremental helpfulness than those without prior SCS use. In Sample 2, there were no significant differences in ratings between participants with or without prior use of SCS. Comparison of the two samples found no significant differences in all categories except acceptability, as those in Sample 2 showed significantly higher ratings. Regardless of implementation, clinicians reported generally favorable perceptions of the SCS, and those from the implementation sample reported significantly higher acceptability of its use. This suggests that clinicians may be supportive of the use and implementation of the SCS in clinical settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Major depressive disorder (MDD) is a highly prevalent psychiatric condition associated with significant disability, mortality and economic burden. A large proportion of MDD patients are treated in primary health care in the local community. Attentional Bias Modification (ABM) training in combination with antidepressants could be an effective treatment. Here we test the hypothesis that adding an ABM procedure to regular treatment with antidepressants in primary health care will result in further improvement of symptoms compared to treatment with antidepressants alone (treatment as usual, TAU) and as compared to an active comparison condition.Methods: A total of 246 patients with a diagnosis of MDD will be included in this study. The study is a threearmed pragmatic randomized controlled trial comparing the efficacy of ABM as add-on to treatment with antidepressants in primary care (ABM condition) compared to standard antidepressant treatment (TAU condition). In a third group participants will complete the same schedule of intermediate assessments as the ABM condition in addition to TAU, but no ABM, thus controlling for the non-training-specific aspects of the ABM condition (Antidepressant active comparison group). Discussion: The clinical outcome of this study may help develop easily accessible, low-cost treatment of depression in primary health care. Moreover, the study aims to broaden our knowledge of optimal treatment for patients with a MDD by providing adjunct treatment to facilitate recovery and long-term gain.

Background Giant cell arteritis (GCA) is an autoimmune vasculitis affecting medium- and large-sized arteries. Vascular inflammation may lead to narrowing of the arterial lumen, and acute occlusion may result in vision loss and stroke. The classical symptoms include headache, fever, and jaw claudication. However, there is an increasing recognition of atypical presentations. Case Presentation. We report a case of a 70-year-old woman presenting with fluctuating manic symptoms and confusion, in addition to headache and musculoskeletal pain. After diagnosis of GCA, treatment with corticosteroids gradually improved the somatic symptoms. Conclusion Corticosteroids led to a temporary exacerbation of manic symptoms, which improved after 3 to 4 weeks of continuous treatment, indicating that the symptoms were most likely associated with GCA. The patient manifested with clinical features and a clinical course that has, to our knowledge, not been described or published before. Therefore, GCA may be an underdiagnosed disease in psychiatric populations and should be considered in case of atypical, new-onset psychiatric disorders in the elderly.

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.

Abstract Background Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. Methods Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. Results The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. Conclusion UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Purpose The aim of the present study was to investigate the psychometric validity of the Modular Assessment of Risk for Imminent Suicide (MARIS) questionnaire in relation to recent suicidal ideation and behavior among a sample of patients admitted to an acute psychiatric inpatient department in Norway. Methods The MARIS was completed within the first 24 h after admission by 338 patients and their clinicians. Information on recent suicidal ideation and behavior was extracted from patients' medical charts. Two out of four MARIS modules, the Suicide Trigger Scale Short-Form (STS-SF; modified version), and the Therapist Response Questionnaire Short-Form (TRQ-SF) demonstrated good internal consistency. The relationships between the STS-SF, addressing symptoms of the suicide crisis syndrome, and the TRQ-SF, exploring therapist emotional responses, and recent suicidal ideation was investigated by logistic regression analysis. Results In the logistic regression analysis including pre-selected diagnoses, age, and gender as covariates, both STS-SF and TRQ-SF showed significant associations with recent suicidal ideation (inclusive of suicidal behavior in 27% of the patients with suicidal ideation). Conclusion Both the STS-SF and the TRQ-SF showed concurrent and incremental validity with regard to suicidal ideation. This is the first study showing the cross-cultural validity of the MARIS and supports its clinical utility as a suicide risk assessment tool in inpatient settings. Additionally, this study adds to the literature supporting the value of assessing clinicians' emotional responses to high risk patients.

•Investigating the predictive validity of a novel suicide risk assessment to suicide mortality of discharged patients.•Patients evaluated at high suicide risk at admission had an odds ratio of nine for post-discharge suicide.•Recent suicidal ideation and affective disturbance were associated with being evaluated at high suicide risk.

BackgroundHuman cells and bacteria secrete extracellular vesicles (EV) which play a role in intercellular communication. EV from the host intestinal epithelium are involved in the regulation of bacterial gene expression and growth. Bacterial EV (bactEV) produced in the intestine can pass to various tissues where they deliver biomolecules to many kinds of cells, including neurons. Emerging data indicate that gut microbiota is altered in patients with psychotic disorders. We hypothesized that the amount and content of blood-borne EV from intestinal cells and bactEV in psychotic patients would differ from healthy controls.MethodsWe analyzed for human intestinal proteins by proteomics, for bactEV by metaproteomic analysis, and by measuring the level of lipopolysaccharide (LPS) in blood-borne EV from patients with psychotic disorders (n = 25), tested twice, in the acute phase of psychosis and after improvement, with age- and sex-matched healthy controls (n = 25).ResultsPatients with psychotic disorders had lower LPS levels in their EV compared to healthy controls (p = .027). Metaproteome analyses confirmed LPS finding and identified Firmicutes and Bacteroidetes as dominating phyla. Total amounts of human intestine proteins in EV isolated from blood was lower in patients compared to controls (p = .02).ConclusionsOur results suggest that bactEV and host intestinal EV are decreased in patients with psychosis and that this topic is worthy of further investigation given potential pathophysiological implications. Possible mechanisms involve dysregulation of the gut microbiota by host EV, altered translocation of bactEV to systemic circulation where bactEV can interact with both the brain and the immune system.

Objective: To prospectively investigate the predictive value of diagnosis, suicidal behavior, and subjectively experienced depressed mood for imminent risk of suicide death. Methods: This prospective study included a representative and diagnostically mixed sample of 7,000 acutely hospitalized psychiatric patients between May 2005 and July 2014 in a Norwegian catchment area of 400,000 inhabitants. Suicide deaths were registered at 1 and 2 weeks and at 1, 6, and 12 months following admission. Survival and hazard functions were estimated, and Cox regression was used to estimate the predictive values of suicidal ideation, suicide attempts, a diagnosis of depressive disorder, and severely depressed mood. Assessments were conducted at admission and included ICD-10 diagnosis, clinical interview in the form of the Health of the Nation Outcome Scales, and qualitative assessments of suicidal ideation and suicide attempts during the past week. Results: During 1-year follow-up, 101 patients (1.4%) died by suicide, of whom almost 70% were men. Only severely depressed mood, including inappropriate self-blame and guilt, predicted suicide within the first week after admission (hazard ratio [HR] = 7.3; 95% confidence interval [CI], 1.4-37.1; P =.01). Suicidal ideation predicted death by suicide at 2 weeks (HR = 3.8; 95% CI, 1.2-12.8; P =.02) and all follow-up time points after, whereas a recent suicide attempt predicted suicide from the 1-month followup (HR = 7.3; 95% CI, 2.2-23.7; P <.001) onward. Conclusions: We recommend thoroughly examining severity of depressed mood during assessment of imminent suicide risk.