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Objectives A consensus definition of clinical recovery in first-episode psychosis (FEP) is required to improve knowledge about recovery rates in this population. To propose criteria for a future consensus definition, this study aims to investigate rates of clinical recovery when using a standard definition (full psychotic symptom remission and adequate functioning for minimum one year) across both affective and nonaffective FEP groups (bipolar spectrum and schizophrenia spectrum disorders). Second, we aim to explore changes in rates when altering the standard definition criteria. Third, to examine the extent to which healthy controls meet the functioning criteria. Study design In total, 142 FEP participants and 117 healthy controls preselected with strict criteria, were re-assessed with structured clinical interviews at 10-year follow-up. Study results A total of 31.7% were in clinical recovery according to the standard definition, with significantly higher recovery rates in bipolar (50.0%) than in schizophrenia spectrum disorders (22.9%). Both groups’ recovery rates decreased equally when extending duration and adding affective symptom remission criteria and increased with looser functioning criteria. In healthy controls, 18.8% did not meet the standard criteria for adequate functioning, decreasing to 4.3% with looser criteria. Conclusions Findings suggest that clinical recovery is common in FEP, although more in bipolar than in schizophrenia spectrum disorders, also when altering the recovery criteria. We call for a future consensus definition of clinical recovery for FEP, and suggest it should include affective symptom remission and more reasonable criteria for functioning that are more in line with the general population.

IntroductionThe Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnostic category “Psychotic disorder not otherwise specified” (PNOS) is seldom investigated, and we lack knowledge about long-term outcomes. We examined long-term symptom severity, global functioning, remission/recovery rates, and diagnostic stability after the first treatment for PNOS.MethodsParticipants with first-treatment PNOS (n = 32) were reassessed with structured interviews after 7 to 10 years. The sample also included narrow schizophrenia spectrum disorders (SSD, n = 94) and psychotic bipolar disorders (PBD, n = 54). Symptomatic remission was defined based on the Remission in Schizophrenia Working Group criteria. Clinical recovery was defined as meeting the criteria for symptomatic remission and having adequate functioning for the last 12 months.ResultsParticipants with baseline PNOS or PBD had lower symptom severity and better global functioning at follow-up than those with SSD. More participants with PNOS and PBD were in symptomatic remission and clinical recovery compared to participants with SSD. Seventeen (53%) PNOS participants retained the diagnosis, while 15 participants were diagnosed with either SSD (22%), affective disorders (19%), or substance-induced psychotic disorders (6%). Those rediagnosed with SSD did not differ from the other PNOS participants regarding baseline clinical characteristics.ConclusionsLong-term outcomes are more favorable in PNOS and PBD than in SSD. Our findings confirm diagnostic instability but also stability for a subgroup of participants with PNOS. However, it is challenging to predict diagnostic outcomes of PNOS based on clinical characteristics at first treatment.

BackgroundIntellectual functioning (IQ) is lower in schizophrenia patients compared to healthy controls, with bipolar patients intermediate between the two. Declines in IQ mark the onset of schizophrenia, while stability is generally found post-onset. There are to date few studies on long-term IQ development in bipolar disorder. This study presents 10-year follow-up data on IQ, including premorbid IQ estimates, to track the developmental course from pre-onset levels to long-term outcomes in both patient groups compared to healthy controls.MethodsWe included 139 participants with schizophrenia, 76 with bipolar disorder and 125 healthy controls. Mixed model analyses were used to estimate developmental slopes for IQ scores from estimated premorbid level (NART IQ) through baseline (WASI IQ) measured within 12 months post-onset, to 10-year follow-up (WASI IQ), with pairwise group comparisons. The best fit was found using a model with a breakpoint at baseline assessment.ResultsOnly the schizophrenia group had significant declines from estimated premorbid to baseline IQ levels compared to controls. When comparing patient groups, schizophrenia patients had steeper declines than the bipolar group. Increases in IQ were found in all groups over the follow-up period.ConclusionsTrajectories of IQ from premorbid level to 10-year follow-up indicated declines from estimated premorbid level to illness onset in both patient groups, followed by increases during the follow-up period. Schizophrenia patients had a steeper decline than bipolar patients. During follow-up, increases indicate developmental improvement for both patient groups, but with a maintained lag compared to healthy controls due to lower premorbid levels.

Personality and cognition are heritable mental traits, and their genetic determinants may be distributed across interconnected brain functions. However, previous studies have employed univariate approaches which reduce complex traits to summary measures. We applied the “pleiotropy-informed” multivariate omnibus statistical test (MOSTest) to genome-wide association studies (GWAS) of 35 item and task-level measures of neuroticism and cognition from the UK Biobank (n=336,993). We identified 431 significant genetic loci and found evidence of abundant pleiotropy across personality and cognitive domains. Functional characterisation implicated genes with significant tissue-specific expression in all tested brain tissues and enriched in brain-specific gene-sets. We conditioned independent GWAS of the Big 5 personality traits and cognition on our multivariate findings, which boosted genetic discovery in other personality traits and improved polygenic prediction. These findings advance our understanding of the polygenic architecture of complex mental traits, indicating a prominence of pleiotropic genetic effects across higher-order domains of mental function.Graphical abstract

BackgroundSchizophrenia (SZ) and bipolar disorder (BD) are heritable, polygenic disorders with shared clinical and genetic components, suggesting a psychosis continuum. Cannabis use is a well-documented environmental risk factor in psychotic disorders. In the current study, we investigated the relationship between SZ genetic load and cannabis use before illness onset in SZ and BD spectrums. Since frequent early cannabis use (age MethodsWe assigned a SZ-polygenic risk score (PGRS) to each individual in our independent sample (N= 381 SZ spectrum cases, 220 BD spectrum cases and 415 healthy controls), calculated from the results of the Psychiatric Genomics Consortium (PGC) SZ case–control study (N= 81 535). SZ-PGRS in patients who used cannabis weekly to daily in the period before first illness episode was compared with that of those who never or infrequently used cannabis.ResultsPatients with weekly to daily cannabis use before illness onset had the highest SZ-PGRS (p= 0.02, Cohen'sd= 0.33). The largest difference was found between patients with daily or weekly cannabis use before illness onset p= 0.003, Cohen'sd= 0.42).ConclusionsOur study supports an association between high SZ-PGRS and frequent cannabis use before illness onset in psychosis continuum disorders.

Cognitive dysfunctions are core features of psychotic disorders with substantial impact on daily functioning. Vitamin D deficiency has been found to be related to cognitive dysfunctions, but the associations between vitamin D deficiency and cognition in persons with a psychotic disorder are largely unknown.This cross-sectional study included 225 patients with a DSM-IV psychotic disorder consecutively recruited from 2003 to 2014 and 159 randomly selected healthy controls, assessed by a cognitive test battery, a clinical protocol (including Structured Clinical Interview for DSM-IV Axis I Disorders and Positive and Negative Syndrome Scale), and a physical examination including vitamin D measurements. Multiple regression models were performed to evaluate the effect of vitamin D deficiency (defined serum 25-hydroxyvitamin D [25(OH)D]25 nmol/L) on key cognitive domains: processing speed, verbal learning, verbal memory, and executive functioning.Vitamin D deficiency was significantly associated with decreased processing speed (ie, Digit Symbol Coding) (t = -2.6, P = .01; total model: adjusted R² = 0.40, F6, 374 = 43.8, P.001) and decreased fluency (ie, verbal fluency) (t = -2.1, P = .04; total model: adjusted R² = 0.35, F6, 373 = 34.2, P.001) when the results were controlled for age, ethnicity, IQ, patient versus control status, and substance or alcohol abuse. Additional analyses indicated that negative symptoms diluted the association between vitamin D deficiency and processing speed (t = -1.72, P = .09) and verbal fluency (t = -1.35, P = .18) in patients.The associations between vitamin D deficiency and processing speed and verbal fluency are good arguments for planning large-scale randomized controlled studies in target populations so conclusions can be made about the potential beneficial effect of vitamin D on cognition in psychotic disorders.

The aim was to gain more knowledge about early clinical recovery in first-episode psychosis (FEP). The interrelationship between symptomatic remission, poor global functioning and neurocognitive impairment was investigated. FEP participants (n =91) from the TOP study were investigated at baseline and 1-year follow-up. Symptomatic remission was defined by internationally standardized criteria. Poor global functioning was defined as GAF-F score ≤60. Neurocognitive impairment was defined as 1.5 standard deviation below healthy controls on a neuropsychological composite score. Finally, early clinical recovery was defined as symptomatic remission during the last 6 months and functional remission (1. GAF-F score ≥61, 2. at least 50% study/employment, and 3. living independently). At 1-year follow-up 26% were in symptomatic remission, predicted by duration of untreated psychosis and baseline positive symptoms. Significantly fewer in the symptomatic remission group had poor global functioning compared to the non-remission group, with no difference in the rate of neurocognitive impairment. Finally, 14% were considered in early clinical recovery. They had the same rate of neurocognitive impairment as the remaining group. These findings imply that symptomatic remission and early clinical recovery can already be identified at 1-year follow-up, and that this is relatively independent of neurocognitive impairment.

BackgroundMany studies have shown associations between a history of childhood trauma and more severe or complex clinical features of bipolar disorders (BD), including suicide attempts and earlier illness onset. However, the psychopathological mechanisms underlying these associations are still unknown. Here, we investigated whether affective lability mediates the relationship between childhood trauma and the severe clinical features of BD.MethodA total of 342 participants with BD were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Diagnostic Interview for Genetic Studies (DIGS) or the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I). Affective lability was measured using the short form of the Affective Lability Scale (ALS-SF). A history of childhood trauma was assessed using the Childhood Trauma Questionnaire (CTQ). Mediation analyses were performed using the SPSSprocessmacro.ResultsUsing the mediation model and covariation for the lifetime number of major mood episodes, affective lability was found to statistically mediate the relationship between childhood trauma experiences and several clinical variables, including suicide attempts, mixed episodes and anxiety disorders. No significant mediation effects were found for rapid cycling or age at onset.ConclusionsOur data suggest that affective lability may represent a psychological dimension that mediates the association between childhood traumatic experiences and the risk of a more severe or complex clinical expression of BD.

Background Suicide attempts (SA) are more frequent in bipolar disorder (BD) than in most other mental disorders. Prevention strategies would benefit from identifying the risk factors of SA recurrence in BD. Substance use disorders (SUD) (including tobacco-related) are strongly associated with both BD and SA, however, their specific role for the recurrence of SA in BD remains inadequately investigated. Thus, we tested if tobacco smoking - with or without other SUDs – was independently associated with recurrent SA in BD. Methods 916 patients from France and Norway with ascertained diagnoses of BD and reliable data about SA and SUD were classified as having no, single, or recurrent (≥2) SA. Five SUD groups were built according to the presence/absence/combination of tobacco, alcohol (AUD) and cannabis use disorders. Multinomial logistic regression was used to identify the correlates of SA recurrence. Results 338 (37%) individuals reported at least one SA, half of whom (173, 51%) reported recurrence. SUD comorbidity was: tobacco smoking only, 397 (43%), tobacco smoking with at least another SUD, 179 (20%). Regression analysis showed that tobacco smoking, both alone and comorbid with AUD, depressive polarity of BD onset and female gender were independently associated with recurrent SA. Limitations Lack of data regarding the relative courses of SA and SUD and cross-national differences in main variables. Conclusion Tobacco smoking with- or without additional SUD can be important risk factors of SA recurrence in BD, which is likely to inform both research and prevention strategies.

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p

Background: Sleep disturbances are prevalent in severe mental disorders but their type and frequency across diagnostic categories has not been investigated in large scale studies. Methods: Participants with Schizophrenia spectrum disorders (SCZ, (N = 617)), Bipolar disorders (BD, (N = 440)), and Healthy Controls (HC, (N = 173)) were included in the study. Sleep disturbances (insomnia, hypersomnia and delayed sleep phase) were identified based on items from the Inventory of Depressive Symptoms – Clinician rated scale. Clinical symptoms were assessed with the Positive and Negative Syndrome scale and level of functioning with the Global assessment of Functioning scale. Results: The rate of any sleep disturbance was 78% in SZ, 69% in BD and 39% in HC. Insomnia was the most frequently reported sleep disturbance across all groups. Both diagnostic groups reported significantly more of any sleep disturbances than HC (P

Autism spectrum disorder (ASD) and other neurodevelopmental disorders (NDs) are behaviorally defined disorders with overlapping clinical features that are often associated with higher-order cognitive dysfunction, particularly executive dysfunction. Our aim was to determine if the polygenic score (PGS) for ASD is associated with parent-reported executive dysfunction in everyday life using the Behavior Rating Inventory of Executive Function (BRIEF). Furthermore, we investigated if PGS for general intelligence (INT) and attention deficit/hyperactivity disorder (ADHD) also correlate with BRIEF. We included 176 children, adolescents and young adults aged 5-22 years with full-scale intelligence quotient (IQ) above 70. All were admitted for clinical assessment of ASD symptoms and 68% obtained an ASD diagnosis. We found a significant difference between low and high ASD PGS groups in the BRIEF behavior regulation index (BRI) (P = 0.015, Cohen's d = 0.69). A linear regression model accounting for age, sex, full-scale IQ, Social Responsiveness Scale (SRS) total score, ASD, ADHD and INT PGS groups as well as genetic principal components, significantly predicted the BRI score; F(11,130) = 8.142, P < 0.001, R2 = 0.41 (unadjusted). Only SRS total (P < 0.001), ASD PGS 0.1 group (P = 0.018), and sex (P = 0.022) made a significant contribution to the model. This suggests that the common ASD risk gene variants have a stronger association to behavioral regulation aspects of executive dysfunction than ADHD risk or INT variants in a clinical sample with ASD symptoms. Autism Res 2020, 13: 207-220. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: People with autism spectrum disorder (ASD) often have difficulties with higher-order cognitive processes that regulate thoughts and actions during goal-directed behavior, also known as executive function (EF). We studied the association between genetics related to ASD and EF and found a relation between high polygenic score (PGS) for ASD and difficulties with behavior regulation aspects of EF in children and adolescents under assessment for ASD. Furthermore, high PGS for general intelligence was related to social problems. National Research Council of Norway. Grant Number: Grant #213694 South‐Eastern Norway Regional Health Authority. Grant Number: Grant #39763 Vestre Viken Hospital Trust. Grant Number: Grant #6903002

Objectives Knowledge about self-rated disability over time in psychotic disorders is limited. How self-rated disability relates to clinician-rated global functioning, self-rated life satisfaction and symptomatology was investigated across the first year of treatment in early psychosis. Methods Participants with first treated episode of psychosis (n = 115) were investigated at baseline and 1-year follow-up. Self-rated Disability was measured with World Health Organization- Disability Assessment Schedule 2.0. Clinician-rated global functioning, self-rated life satisfaction, and symptomatology were measured with appropriate scales. Results Average self-rated disability in first-treated episode of psychosis was high, corresponding with the 10% highest in a general population sample. However, 37% were not disabled at a clinically significant level after one year. Self-rated disability was highest in the two social domains (Getting along with people and Participation in society), but improved significantly from baseline to 1-year. At 1-year follow-up self-rated disability had significant weak to medium correlations with clinician-rated global functioning and positive symptoms, and mainly medium to strong correlations with life satisfaction and depressive symptoms. Yet only baseline depression significantly predicted disability after one year. Conclusion Self-rated disability in first treated episode of psychosis is high, but improves across the first year, indicating signs of early recovery. Moreover, self-rated disability is related, but distinct from clinician-rated global functioning and self-rated life satisfaction, suggesting that self-rated disability should also be assessed in order to more fully describe outcomes in first episode psychosis. The findings highlight the need for specialised treatment of depression and social disability in early psychosis.

Background Individuals with bipolar disorder present with moderate impairments in social cognition during the euthymic state. The impairment extends to theory of mind and to the perception of emotion in faces and voices, but it is unclear if emotion perception from body movements is affected. The main aim of this study was to examine if participants with bipolar disorder perform worse than healthy control participants on a task using point-light displays of human full figures moving in a manner indicative of a basic emotion (angry, happy, sad, fearful, neutral/no emotion). A secondary research question was whether diagnostic subtypes (bipolar I, bipolar II) and history of psychosis impacted on this type of emotion perception. Finally, symptomatic, neurocognitive, and functional correlates of emotion perception from body movements were investigated. Methods Fifty-three individuals with bipolar I (n = 29) or bipolar II (n = 24) disorder, and 84 healthy control participants were assessed for emotion perception from body movements. The bipolar group also underwent clinical, cognitive, and functional assessment. Research questions were analyzed using analyses of variance and bivariate correlations. Results The bipolar disorder group differed significantly from healthy control participants for emotion perception from body movements (Cohen’s d = 0.40). Analyses of variance yielded no effects of sex, diagnostic subtype (bipolar I, bipolar II), or history of psychosis. There was an effect of emotion, indicating that some emotions are easier to recognize. The lack of a significant group × emotion interaction effect points, however, to this being so regardless of the presence of bipolar disorder. Performance was unrelated to manic and depressive symptom load but showed significant associations with neurocognition and functional capacity. Conclusions Individuals with bipolar disorder had a small but significant impairment in the ability to perceive emotions from body movement. The impairment was global, i.e., affecting all emotions and equally present for males and females. The impairment was associated with neurocognition and functional capacity, but not symptom load. Our findings identify pathopsychological factors underlying the functional impairment in bipolar disorder and suggest the consideration of social cognition training as part of the treatment for bipolar disorder.

Background Utilization of diagnostic information from national patient registries rests on the quality of the registered diagnoses. We aimed to investigate the agreement and consistency of diagnoses of psychotic and bipolar disorders in the Norwegian Patient Registry (NPR) compared to structured interview-based diagnoses given as part of a clinical research project. Methods Diagnostic data from NPR were obtained for the period 01.01.2008–31.12.2013 for all patients who had been included in the Thematically Organized Psychosis (TOP) study between 18.10.2002 and 01.09.2014 with a Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) diagnosis of schizophrenia (n = 537), delusional disorder (n = 48), schizoaffective disorder (n = 118) or bipolar disorder (n = 408). Diagnostic agreement between the primary DSM-IV diagnosis in TOP and the International Classification of Diseases, 10th revision (ICD-10) diagnoses in NPR was evaluated using Cohen’s unweighted nominal kappa (κ). Diagnostic consistency was calculated as the proportion of all registered severe mental disorder diagnoses in NPR that were equivalent to the primary diagnosis given in the TOP study. Results The proportion of patients registered with the equivalent ICD-10 diagnosis as the primary DSM-IV diagnosis given in TOP was 84.2% for the schizophrenia group, 68.8% for the delusional disorder group, 76.3% for the schizoaffective disorder group, and 78.4% for the bipolar disorder group. Diagnostic agreement was good for schizophrenia (κ = 0.74) and bipolar disorder (κ = 0.72), fair for schizoaffective disorder (κ = 0.63), and poor for delusional disorder (κ = 0.39). Among patients with DSM-IV schizophrenia, 4.7% were diagnosed with ICD-10 bipolar disorder, and among patients with DSM-IV bipolar disorder, 2.5% were diagnosed with ICD-10 schizophrenia. Diagnostic consistency was 84.9% for schizophrenia, 59.1% for delusional disorder, 65.9% for schizoaffective disorder, and 91.0% for bipolar disorder. Conclusions When compared to research-based diagnoses, clinical diagnoses of schizophrenia and bipolar disorder in the NPR are accurate and consistent, with minimal diagnostic overlap between the two disorders.

OBJECTIVE: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder.METHOD: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density.RESULTS: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001).CONCLUSION: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge.

BACKGROUND: Neurocognitive impairment is a core feature of schizophrenia strongly related to functional outcome. The presence and severity of deficits varies between individuals, with some showing considerably impaired and others relatively intact performance. Tracking the development of cognitive functioning over time and investigating the relationship to other clinical features and outcome, is an important step towards more targeted interventions. Impairments are found in a range of cognitive domains, as well as in both premorbid and current IQ. Premorbid IQ measures are used to investigate decline before and during the course of illness, compared to current IQ. Longitudinal studies generally show stability over time for IQ measures, although few long-term follow-up (fu) studies exist. Thus, this study explored long-term trajectories of premorbid and current IQ, using 10-year fu data. METHODS: The sample consists of 33 patients with schizophrenia-spectrum disorders and 92 healthy controls recruited to the TOP study in Norway. Comprehensive clinical and neurocognitive assessments were conducted at baseline and 10-year fu. Premorbid IQ was measured using WASI and current IQ using NART. Thirty-three patients and 89 controls completed the WASI and 30 patients and 92 controls completed the NART at both time-points. Premorbid IQ was estimated from NART error scores using the Norwegian validated formula correcting for age and years of education. Due to missing data only 28 patients and 83 controls were included in this analysis. More cases are being included consecutively. RESULTS: Mean WASI IQ scores for patients were 104.9 (SD 15.3) at baseline and 108.6 (SD 16.2) at fu. For controls, WASI IQ scores were 115.4 (SD 8.4) at baseline and 118.9 (SD 8.5) at fu. For patients, NART error scores ere 19.2 (SD 10.5) at baseline and 17.0 (SD 9.3) at fu, while controls made 14.8 (SD 7.8) errors at baseline and 14.4 (SD 7.4) at fu. For patients, the mean NART IQ scores were 109.7 (SD6.9) at baseline and 109.7 (SD 6.5) at fu. Controls had scores of 113.6 (SD5.0) and 113.6 (SD 4.5) at respectively baseline and fu. Repeated-measures ANOVA showed that patients scored significantly lower than controls on all measures: WASI IQ, F(1,120) = 24.15, p < 0.000, NART error scores F(1,120) = 4,35, p = 0,039 and NART IQ, F(1,110) = 14.04, p < 0.000. For WASI IQ scores, there was a significant effect of time, F(1,120) = 27.49, p > 0.000), but no time*group interaction. For NART error scores, there was a significant effect of time, F(1,120) = 9.97, p = 0.002, and a time*group interaction, F(1,120) = 4.57, p=0.035). There was no significant main effect of time or time*group interaction for NART IQ scores. DISCUSSION: In line with other studies, lower IQ was found in the schizophrenia-spectrum group, both at baseline and 10-year fu. Results indicate small, but significant improvements in current IQ as measured by the WASI, as well as NART error scores for both groups. Although NART error scores improved slightly more for patients than controls, estimated premorbid IQ from NART scores was stable across time for both groups. These preliminary findings show slight improvement in current IQ, while premorbid IQ shows a high degree of stability across 10 years. Although small increases are found in WASI scores, they support existing literature finding long-term stability in IQ.

Bipolar disorder may emerge during several decades of life. Studies from many countries have reported three peaks in the distribution of the age of onset, occurring at about ages 17, 26, and over 40 (1–5). Differences in the distribution of the age of onset were also reported among countries (6), although only limited data are available from some regions of the world. Patients living in North America generally have a younger age of onset than those living in European countries (6–8). In many studies conducted in the USA, about 60% of patients experience the onset of bipolar disorder before the age of 19 (6, 9–12), as compared to a third or less for many studies in European countries (1, 5, 6, 13–16). Diverse factors may contribute to this variation in the age of onset. There is agreement among researchers that both a patient’s genetic makeup and methodological issues in defining onset contribute to the reported differences, and that the variability in the age of onset reflects the genetic heterogeneity underlying bipolar disorder (1–3, 17). A positive family history is one of the strongest predictors of early onset (18). However, in addition to the genetic component, both the broad variability in the age of onset, and the onset peaks occurring after puberty (19) suggest that non-genetic factors may have considerable influence (20). There is limited understanding of how non-genetic factors, such as socioeconomic status and the physical environment, may impact the expression of bipolar disorder (21). In a recent study, a linear association was detected between the age of onset of schizophrenia and latitude, with a much younger onset occurring in individuals living closer to the equator (22). Latitude is often used as a proxy measure of sunlight, such as in studies of seasonal and geographical variation in affective disorders and suicide (23–28). However, more direct measures of the amount of electromagnetic energy striking the surface of the earth are now available, such as solar insolation (29). Sunlight is the primary synchronizer of circadian rhythmicity in most animals, including humans (30), and disruptions in circadian function may contribute to the pathophysiology of bipolar disorder (31). The purpose of this study was to investigate if the age of onset of bipolar I (BP-I) disorder was associated with sunlight at the location of onset, as measured by solar insolation.

Background In the present study we investigated genetic variants associated with bipolar disorder in a homogenous Norwegian sample, and potential genetic overlap with schizophrenia, using the Affymetrix 6.0 array. Methods We carried out a genome-wide association study (GWAS) by genotyping 620 390 single-nucleotide polymorphisms (SNPs) in a case-control sample of Norwegian origin (the TOP study) including bipolar disorder (n = 194), healthy controls (n = 336) and schizophrenia (n = 230), followed by replication and combined analysis in a genetically concordant Icelandic sample of bipolar disorder (n = 435), and healthy controls (n = 10,258). Results We selected 1000 markers with the lowest P values in the TOP discovery GWAS and tested these (or their surrogates) for association in the Icelandic replication sample. Polymorphisms on 35 loci were confirmed associated with bipolar disorder (nominal P value

Objective Cannabis use disorders (CUD) may influence the course of bipolar disorder (BD), but key confounding factors such as tobacco smoking have not been adequately addressed. This study examined whether CUD was associated with a more severe illness course in tobacco smoking BD patients. Methods A sample of French and Norwegian tobacco smoking patients with BD I and II (N=642) was investigated. DSM-IV diagnoses and other characteristics were obtained through personal interviews using structured questionnaires. The association between CUD and illness course was assessed in regression analyses. Results In bivariate analyses, CUD was associated with earlier BD onset, higher frequency of manic (in BD I) and depressive episodes and hospitalizations per illness year, and a higher occurrence of psychotic episodes. After controlling for potential confounders, the relationships with earlier BD onset (B=−5.60 95% CI=−7.65 to −3.64), and increased rates of manic episodes (OR=1.93, 95% CI: 1.15 to 3.23) and hospitalizations (OR=2.93, 95% CI: 1.85 to 4.64) remained statistically significant. Limitations Despite the multivariate approach, differences between the two samples may lead to spurious findings related to hidden confounders. Substance use and mood episode information was collected retrospectively, and potential birth cohort effects could not be controlled for. Conclusion Studies have found associations between tobacco smoking and poorer outcomes in BD. In this study on tobacco smoking BD patients we report an association between CUD and illness severity, suggesting that CUD exacerbates the disease evolution independently of tobacco smoking. Specific treatment and prevention programs addressing CUD in BD patients are warranted.

Vitamin D deficiency is common among patients with psychotic disorders and could be due to unknown disease mechanisms or contingent factors. However most studies are performed in chronic patients and have often failed to address the influence of ethnicity on vitamin D levels in clinical samples. We investigated serum concentrations of 25-hydroxy vitamin D (S-25 OH D) in first episode patients compared to patients with multi episodes and healthy controls; with a specific focus on differences between visible ethnic minorities and participants from the majority population. A total of 284 participants were included in this cross-sectional study. First episode patients with a DSM-IV psychotic disorder were matched on age, gender and ethnicity to participants from a multi episode patient sample (1:1) and healthy controls (1:2). We did not find any differences between either patient groups or the healthy controls, but participants from visible ethnic minorities had significantly lower S-25 OH D than participants from the majority population. This implies that S-25 OH D should be routinely measured in persons from visible ethnic minorities since low levels are associated with higher levels of depressive symptoms. © 2015. This manuscript version is made available under the CC-BY-NC-ND 4.0 license

Purpose:Two common approaches to identify subgroups of patients with bipolar disorder are clustering methodology (mixture analysis) based on the age of onset, and a birth cohort analysis. This study investigates if a birth cohort effect will influence the results of clustering on the age of onset, using a large, international database.Methods:The database includes 4037 patients with a diagnosis of bipolar I disorder, previously collected at 36 collection sites in 23 countries. Generalized estimating equations (GEE) were used to adjust the data for country median age, and in some models, birth cohort. Model-based clustering (mixture analysis) was then performed on the age of onset data using the residuals. Clinical variables in subgroups were compared.Results:There was a strong birth cohort effect. Without adjusting for the birth cohort, three subgroups were found by clustering. After adjusting for the birth cohort or when considering only those born after 1959, two subgroups were found. With results of either two or three subgroups, the youngest subgroup was more likely to have a family history of mood disorders and a first episode with depressed polarity. However, without adjusting for birth cohort (three subgroups), family history and polarity of the first episode could not be distinguished between the middle and oldest subgroups.Conclusion:These results using international data confirm prior findings using single country data, that there are subgroups of bipolar I disorder based on the age of onset, and that there is a birth cohort effect. Including the birth cohort adjustment altered the number and characteristics of subgroups detected when clustering by age of onset. Further investigation is needed to determine if combining both approaches will identify subgroups that are more useful for research.

BACKGROUND: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association.METHODS: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation.RESULTS: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model.CONCLUSIONS: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

BACKGROUND: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode.METHODS: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations.RESULTS: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California.LIMITATIONS: Recall bias for onset and family history data.CONCLUSIONS: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

Introduction The aim of this study was to investigate the psychometric properties of the original 54 item version (ALS-54) and the short 18 item version (ALS-18) of the Affective Lability Scale (ALS) in patients with bipolar disorders, their first-degree relatives and healthy controls. Internal Consistency and Confirmatory Factor Analysis were performed, comparing clinical and non-clinical group comparisons on ALS scores. Methods A total of 993 participants (patients with bipolar disorders [ n =422], first-degree relatives [ n =201] and controls [ n =370]) were recruited from France and Norway. Diagnosis and clinical characteristics were assessed using the Structured Clinical Interview for DSM-IV Axis I disorders (SCID-I), or the Diagnostic Interview for Genetic Studies (DIGS). Affective lability was measured using the ALS-54 and ALS-18. Results Both ALS-54 and ALS-18 showed high internal consistency, but the subdimensions of both versions were highly inter-correlated. From confirmatory factor analysis both versions revealed acceptable to good model fit. Patients had significantly higher ALS scores compared to controls, with affected first-degree relatives presenting intermediate scores. Conclusion Both the original ALS-54 version and the short ALS-18 version showed good psychometric properties. They also discriminated between patients with a bipolar disorder (high ALS), first degree relatives (intermediate ALS), and healthy controls (low ALS). A high correlation between ALS items for both versions was observed. Our study supports reducing the scale from 54 to 18 items.

Objective Here we investigated a two hit gene environment model in relation to functional genomic factors (BDNF mRNA), and volume of hippocampal subfields in schizophrenia spectrum and bipolar disorders, focusing on both an environmental (childhood trauma) and genetic risk factor (BDNF val66met). Method A total of 323 patients with a broad DSM-IV schizophrenia spectrum disorder or bipolar disorder were consecutively recruited. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire. BDNF DNA and RNA were analyzed using standardized procedures. A subsample of n = 108 underwent MRI scanning, and the FreeSurfer was used to obtain measures of hippocampal subfield. All MRI data were corrected for age and gender, with post-hoc analysis correcting for ICV. Results A history of childhood trauma or being a met carrier of the BDNF val66met was associated with significantly reduced BDNF mRNA level. Additive effects were observed between a history of childhood trauma and BDNF val66met, in the direction of met carriers with high levels of childhood trauma having the lowest BDNF mRNA levels. Lastly, met carriers reporting high levels of childhood trauma (specifically sexual or physical abuse) had significantly reduced hippocampal subfield volumes CA2/3 and CA4 dentate gyrus. Conclusion The current findings demonstrate that the reduced BDNF mRNA levels found in psychosis may be associated with both a history of childhood trauma and BDNF val66met variants. Further, our study supports a two hit model including a history of childhood trauma as well as genetic vulnerability (met carriers of the BDNF val66met) behind reduced volume of hippocampal subfields in psychosis. This was specifically found for areas important for neurogenesis, the CA2/3and the CA4 DG.