Search

Objective Apathy is a central predictor of a poor functional outcome in schizophrenia. Schizophrenia polygenic risk scores (PRSs) are used to detect genetic associations to key clinical phenotypes in schizophrenia. We explored the associations between schizophrenia PRS and apathy levels in schizophrenia spectrum disorders (n = 281) and matched healthy controls (n = 298), and further how schizophrenia PRS contributed in predicting apathy when added to premorbid and clinical factors in the patient sample. Method Schizophrenia PRSs were computed for each participant. Apathy was assessed with the Apathy Evaluation Scale. Bivariate correlation analyses were used to investigate associations between schizophrenia PRS and apathy, and between apathy and premorbid and clinical factors. Multiple hierarchical regression analyses were employed to evaluate the contributions of clinical variables and schizophrenia PRS to apathy levels. Results We found no significant associations between schizophrenia PRS and apathy in patients and healthy controls. Several premorbid and clinical characteristics significantly predicted apathy in patients, but schizophrenia PRS did not. Conclusion Since the PRSs are based on common genetic variants, our results do not preclude associations to other types of genetic factors. The results could also indicate that environmentally based biological or psychological factors contribute to apathy levels in schizophrenia.

Background Childhood maltreatment is a well-known risk factor for developing a more severe and complex form of bipolar disorders (BD). However, knowledge is scarce about the interactions between childhood maltreatment and underlying genetic vulnerability on the clinical expression of BD. Method We assigned a BD-polygenic risk score (BD-PRS), calculated from the Psychiatric Genomics Consortium, to each individual in a sample of 402 cases with BD. The lifetime clinical expression of BD was characterized using structured interviews and patients completed the Childhood Trauma Questionnaire (CTQ) to assess the severity of childhood maltreatment. Results Cases who reported more severe childhood maltreatment had a lower BD-PRS (rho = -0.12, P = .01), especially when considering emotional abuse (rho = -0.16, P = .001). An interaction between BD-PRS and childhood maltreatment was observed for the risk of rapid cycling (P = .01). No further interactions between BD-PRS and childhood maltreatment were observed for other clinical characteristics (age at onset, suicide attempts, number of mood episodes, mixed features, substance use disorders and psychotic symptoms). Conclusion Our study is the first to show that less genetic risk may be needed to develop a more unstable form of BD when exposed to childhood maltreatment. Our study supports childhood trauma as an independent risk factor for BD.

Social functioning is impaired in severe mental disorders despite clinical remission, illustrating the need to identify other mechanisms that hinder psychosocial recovery. Affective lability is elevated and associated with an increased clinical burden in psychosis spectrum disorders. We aimed to investigate putative associations between affective lability and social functioning in 293 participants with severe mental disorders (schizophrenia- and bipolar spectrum), and if such an association was independent of well-established predictors of social impairments. The Affective Lability Scale (ALS-SF) was used to measure affective lability covering the dimensions of anxiety-depression, depression-elation and anger. The interpersonal domain of the Social Functioning Scale (SFS) was used to measure social functioning. Correlation analyses were conducted to investigate associations between affective lability and social functioning, followed by a hierarchical multiple regression and follow-up analyses in diagnostic subgroups. Features related to premorbid and clinical characteristics were entered as independent variables together with the ALS-SF scores. We found that higher scores on all ALS-SF subdimensions were significantly associated with lower social functioning (p p = 0.019). Our results indicate that elevated affective lability may have a negative impact on social functioning in severe mental disorders, which warrants further investigation. Clinically, it might be fruitful to target affective lability in severe mental disorders to improve psychosocial outcomes.

BackgroundStudying the phenotypic and genetic characteristics of age and polarity at onset (AAO, PAO) in bipolar disorder (BD) can provide new insights into disease pathology and facilitate the development of screening tools.AimsTo examine the genetic architecture of AAO and PAO and their association with BD disease characteristics.MethodsGenome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (N=12977) and PAO (N=6773) were conducted in BD patients of 34 cohorts and a replication sample (N=2237). The association of onset with disease characteristics was investigated in two of these cohorts.ResultsEarlier AAO was associated with an increased risk of psychotic symptoms, suicidality, and fewer episodes. A depressive onset correlated with lifetime suicidality and a manic onset with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in SNV-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased polygenic scores for autism spectrum disorder (β=-0.34 years, SE=0.08), major depression (β=-0.34 years, SE=0.08), schizophrenia (β=-0.39 years, SE=0.08), and educational attainment (β=-0.31 years, SE=0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.ConclusionsAAO and PAO are associated with indicators of BD severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents, and phenotype definitions introduce significant heterogeneity, affecting analyses.RELEVANCE STATEMENTIn the largest study to systematically characterize age at onset (N=12977) and polarity at onset (N=6773) in bipolar disorder, we describe an association between illness onset characteristics and indicators of severity, confirming their clinical relevance. Our study shows that that early illness onset is associated with genetic liability for a broad range of psychiatric disorders. However, we also highlight systematic differences in age at onset across cohorts, continents, and phenotype definitions. This heterogeneity results in reduced heritability and affects genetic analyses, underscoring the need for the development of standardized phenotype definitions.

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

Background Affective lability is elevated and associated with increased clinical burden in psychosis spectrum disorders. The extent to which the level, structure and dispersion of affective lability varies between the specific disorders included in the psychosis spectrum is however unclear. To have potential value as a treatment target, further characterization of affective lability in these populations is necessary. The main aim of our study was to investigate differences in the architecture of affective lability in different psychosis spectrum disorders, and if putative differences remained when we controlled for current symptom status. Methods Affective lability was measured with The Affective Lability Scale Short Form (ALS-SF) in participants with schizophrenia (SZ, n = 76), bipolar I disorder (BD-I, n = 105), bipolar II disorder (BD-II, n = 68) and a mixed psychosis-affective group (MP, n = 48). Multiple analyses of covariance were conducted to compare the ALS-SF total and subdimension scores of the diagnostic groups, correcting for current psychotic, affective and anxiety symptoms, substance use and sex. Double generalized linear models were performed to compare the dispersion of affective lability in the different groups. Results Overall group differences in affective lability remained significant after adjusting for covariates (p = .001). BD-II had higher affective lability compared to SZ and BD-I (p = .004), with no significant differences between SZ and BD-I. There were no significant differences in the contributions of ALS-SF dimensions to the total affective lability or in dispersion of affective lability between the groups. Conclusions This study provides the construct of affective lability in psychosis spectrum disorders with more granular details that may have implications for research and clinical care. It demonstrates that despite overlap in core symptom profiles, BD-I is more similar to SZ than it is to BD-II concerning affective lability and the BD groups should consequently be studied apart. Further, affective lability appears to be characterized by fluctuations between depressive- and other affective states across different psychosis spectrum disorders, indicating that affective lability may be related to internalizing problems in these disorders. Finally, although the level varies between groups, affective lability is evenly spread and not driven by extremes across psychosis spectrum disorders and should be assessed irrespective of diagnosis.

Background. Despite apparent clinical remission, individuals with psychotic disorders often experience significant impairments across functional domains. Thus, there is a need to search beyond management of core symptoms to optimize treatment outcomes. Affective dysregulation is considered a risk factor for poor clinical and functional outcomes in many mental disorders, but research investigating such features in psychosis, particularly in schizophrenia, is limited. We aimed to investigate the level of affective lability (AL) in participants with schizophrenia- and bipolar spectrum disorders (n = 222) compared to healthy controls (n = 140), as well as clinical correlates of AL in the diagnostic groups. Methods. The Affective Lability Scale (ALS-SF) was used to measure total score of AL and subscores covering the domains of anxiety/depression, depression/elation, and anger. An analysis of covariance was performed to compare the ALS-SF total score between groups, correcting for potential confounders, as well as standard multiple regression analyses for diagnosis-specific investigations of the relationship between AL and demographic and clinical features. Results. Both the schizophrenia- and bipolar spectrum group had significantly higher ALS-SF total score compared to controls (p < 0.001), and no significant differences between the patient groups were found. In the schizophrenia group, current psychotic and depressive symptoms were significantly and independently associated with AL (p = 0.012 and p = 0.024, respectively). Conclusions. The findings indicate that AL is elevated in psychotic disorders and that it transcends diagnostic boundaries. Further research into the causal relationship between psychotic and affective symptoms and AL, as well as its role as a potential therapeutic target in psychosis spectrum disorders, is warranted.

BACKGROUND: Schizophrenia (SZ) and bipolar disorder (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, patients with BD, and healthy control (HC) subjects across 10 cohorts.METHODS: We trained 6 cross-validated models using different combinations of DTI data from 927 HC subjects (18-94 years of age) and applied the models to the test sets including 648 patients with SZ (18-66 years of age), 185 patients with BD (18-64 years of age), and 990 HC subjects (17-68 years of age), estimating the brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.RESULTS: Tenfold cross-validation revealed high accuracy for all models. Compared with HC subjects, the model including all feature sets significantly overestimated the age of patients with SZ (Cohen's d = -20.29) and patients with BD (Cohen's d = 0.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy-based models showed larger group differences than the models based on other DTI-derived metrics.CONCLUSIONS: Brain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

Neurocognitive impairment has been found to be a marked feature in bipolar disorder (BD), also in the early phase of the illness. The longitudinal course of neurocognitive functioning, however, remains sparsely investigated. The aims of the study were to investigate the course of neurocognitive function in BD I, and to what degree neurocognitive change or stability is observed also on the individual level. Forty-two patients and 153 comparable healthy controls were assessed at baseline and one-year follow-up. Compared to the healthy control (HC) group BD I patients perform significantly poorer at both baseline and follow-up across all neurocognitive domains and on most neurocognitive subtests. Neurocognitive impairment remained stable for most patients from baseline to follow-up, both on a group level and when investigating individual trajectories, indicative of a relatively stable course of neurocognitive functioning in the early phase of BD I.

Background Metacognitive factors influence depression, but are largely unexplored in bipolar disorders. We examined i) differences in metacognitive beliefs and thought control strategies between individuals with bipolar disorder and controls, and ii) to what extent clinical characteristics were related to levels of metacognitive beliefs and thought control strategies in bipolar disorder. Method Eighty patients with bipolar disorder were assessed for age at onset of affective disorder, number of affective episodes, symptoms of mania and depression, metacognitive beliefs (MCQ-30) and thought control strategies (TCQ). Control subjects (N = 166) completed MCQ-30 and TCQ. Factors impacting on metacognitive beliefs and thought control strategies were explored with multiple linear regressions. Results Patients with bipolar disorder reported higher levels of unhelpful metacognitive beliefs and thought control strategies than controls. Metacognitive beliefs were mainly influenced by depressive symptoms, and age at onset of affective illness. Thought control strategies were mainly influenced by metacognitive beliefs and age at onset of affective illness. Conclusion Our findings suggest that metacognitive beliefs and control strategies are relevant in bipolar disorder. Depression and age at onset of affective disorder could contribute to metacognitive beliefs in bipolar disorder, and influence the use of thought control strategies. This indicates potential relationships that warrant further investigation for clinical relevance.

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.

BackgroundSchizophrenia (SZ) and bipolar disorders (BD) share substantial neurodevelopmental components affecting brain maturation and architecture. This necessitates a dynamic lifespan perspective in which brain aberrations are inferred from deviations from expected lifespan trajectories. We applied machine learning to diffusion tensor imaging (DTI) indices of white matter structure and organization to estimate and compare brain age between patients with SZ, BD, and healthy controls across 10 cohorts.MethodsWe trained six cross-validated models using different combinations of DTI data from 927 healthy controls (HC, 18-94 years), and applied the models to the test sets including 648 SZ (18-66 years) patients, 185 BD patients (18-64 years), and 990 HC (17-68 years), estimating brain age for each participant. Group differences were assessed using linear models, accounting for age, sex, and scanner. A meta-analytic framework was applied to assess the heterogeneity and generalizability of the results.Results10-fold cross-validation revealed high accuracy for all models. Compared to controls, the model including all feature sets significantly over-estimated the age of patients with SZ (d=-.29) and BD (d=.18), with similar effects for the other models. The meta-analysis converged on the same findings. Fractional anisotropy (FA) based models showed larger group differences than the models based on other DTI-derived metrics.ConclusionsBrain age prediction based on DTI provides informative and robust proxies for brain white matter integrity. Our results further suggest that white matter aberrations in SZ and BD primarily consist of anatomically distributed deviations from expected lifespan trajectories that generalize across cohorts and scanners.

BACKGROUND: Childhood maltreatment is a well-known risk factor for developing a more severe and complex form of bipolar disorders (BD). However, knowledge is scarce about the interactions between childhood maltreatment and underlying genetic vulnerability on the clinical expression of BD. METHODS: We assigned a BD-polygenic risk score (BD-PRS), calculated from the Psychiatric Genomics Consortium, to each individual in a sample of 397 cases with BD. The lifetime clinical expression of BD was characterized using structured interviews and patients completed the Childhood Trauma Questionnaire (CTQ) to assess the severity of Childhood maltreatment. RESULTS: Cases who reported more severe childhood maltreatment had a lower BD-PRS (rho=-0.10, p=0.04). An interaction was observed between BD-PRS and childhood maltreatment on number of mood episodes (p=0.056), whereby low BD-PRS and no childhood maltreatment was associated with having fewer mood episodes (p=0.003). This result was mainly due to an interaction between BD-PRS and childhood maltreatment on major depressive episodes (p=0.01), but not on manic episodes. An interaction between BD-PRS and childhood maltreatment was also identified on the risk of rapid cycling (p=0.0097). No further interactions between BD-PRS and childhood maltreatment were observed for other clinical characteristics (age at onset, suicide attempts, mixed episodes, substance use disorders and psychotic symptoms). DISCUSSION: Less genetic risk may be needed to develop a severe form of BD when exposed to childhood maltreatment, in particular when considering number of major mood episodes and rapid cycling.

Background Sleep disturbances are prevalent in people with psychosis and are related to several negative outcomes. Recent research indicates that sleep disturbances contribute to the development of psychosis and is therefore an important treatment target. Despite this, a study found that sleep problems in people with psychosis were mostly assessed informally and treated with non-recommended interventions. However, it is uncertain whether these findings reflect local practise or rather status quo for how sleep disturbances in the context of psychosis are approached across different treatment sites. We aimed to replicate this study and investigate how sleep disturbances in people with psychosis are viewed, assessed and treated by clinicians across several mental health services, and the clinicians' perceived barriers to sleep treatment. Methods A total of 204 clinicians completed an e-mail survey about sleep problems and psychosis. Results The main findings were highly consistent with previous research; the clinicians found sleep problems in patients with psychosis to be highly prevalent and with negative consequences. However, structured assessments and the use of recommended treatment interventions were rare. This apparent paradox may at least partly be explained by the clinicians' perceived barriers to sleep treatment, including their declared lack of knowledge about sleep assessment and sleep treatment, and beliefs that sleep treatment is (too) demanding in this population. Conclusion Many patients with psychosis across several treatment sites receive less than optimal sleep treatment. Increasing clinicians' knowledge about adequate sleep treatment and its feasibility for patients with psychotic disorders is therefore imperative.

The aim of this study is to investigate the validity of the Norwegian version of the Insight Scale (IS) in large and representative samples of patients with schizophrenia spectrum disorders, bipolar I disorder and bipolar II disorder. A total of 997 participants were included (schizophrenia spectrum disorders: 557; bipolar I disorder: 282; bipolar II disorder: 138). Confirmatory factor analysis was conducted to investigate the construct validity and bivariate correlational analysis was applied to investigate convergent validity. Confirmatory factor analyses indicated a reasonable model fit to the original three-factor subscale structure of the IS in all three diagnostic groups. The IS total score and its subscales correlated significantly with both the insight items in the Young Mania Rating Scale and the Positive and Negative Syndrome Scale in both schizophrenia spectrum disorders and bipolar I disorder. In the bipolar II disorder group, however, the IS subscales correlated poorly with both the observer-rated measures. Our study supports the construct validity of the IS in both schizophrenia spectrum disorder- and bipolar disorder populations. The study also demonstrates that patients’ self-reports of insight correspond to observer-based single item ratings of insight in bipolar I disorder and schizophrenia spectrum disorders.

Objectives: Perceived/experienced stigma and its relationship with clinical outcome were investigated across the first year of treatment in a large sample with first-episode psychosis (FEP). Methods: FEP participants (n = 112) in the TOP study were investigated at baseline and 1-year follow-up. Perceived/experienced stigma was measured with items from the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0), assessing problems because of barriers and hindrances, and living with dignity because of attitudes and actions of others. Clinical outcome included: symptoms, global functioning, self-rated disability and self-rated life satisfaction. Results: In the total sample, 46% perceived/experienced stigma at baseline, which decreased significantly to 32% at 1-year follow-up. Perceived/experienced stigma was present in 1/5 at both time-points (Sustained stigma), in 2/5 at only one time-point (Transient stigma), and in 2/5 it was not present at either time-point (No stigma). Compared to the No stigma group, the Sustained stigma group had significantly higher levels of positive, excited and depressive symptoms and self-rated disability, as well as lower levels of global functioning and life satisfaction at 1 year follow-up, while the Transient stigma group only had poorer functioning and higher self-rated disability. Yet the outcome variables improved across the first year of treatment in all three stigma groups. Conclusion: Perceived/experienced stigma was common in FEP, yet the rate decreased across the first year of treatment. Although there was some clinical improvement across the first year of treatment irrespective of stigma, stigma was related to poorer clinical outcome in a bidirectional manner. This suggests that perceived/experienced stigma is an important target in the early stages of treatment. Keywords: Perceived stigma, Experienced stigma, First-Episode psychosis, Life satisfaction, Symptomatology

Objectives Due to limited research on the association between recurrence of mood episodes and the longitudinal course of neurocognitive functioning in early phase bipolar I disorder (BD I), the impact of recurrence on neurocognition remains unclear. Further, a strong correlation between neurocognitive impairment and functional impairment has been demonstrated. The longitudinal relationship between neurocognitive impairment and functional outcome in relation to recurrence is, however, not established. Methods The current study investigated the longitudinal relationship between neurocognition, recurrence of mood episodes and functional outcome in a sample of first-treatment (FT) BD I patients (N = 42), with and without relapse, during a 1-year follow-up period. The longitudinal course of neurocognitive functioning in the patients was also compared to that of a group of healthy controls (N = 143). Results Compared to both patients with relapse and healthy controls, no-relapse patients showed neurocognitive improvements. The polarity of the relapse episodes was mostly depressive, and for the no-relapse patients, reduction of symptoms was associated with neurocognitive improvement. No-relapse patients showed better global and occupational functioning. Conclusions The current study found different neurocognitive and functional trajectories in FT BD I patients with and without relapse, with differences at follow-up to some degree being mediated by current symptoms. The current findings highlight the importance of treatment focusing on neurocognition and symptom states with the aim of improving functional recovery.

AIMS: The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with first-treatment bipolar I disorder (BD I). METHODS: One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM-IV was used for DSM-IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative Syndrome Scale correspondingly. Cannabis use within the six last months was recorded. RESULTS: After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P CONCLUSIONS: The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I. Language: en

Background Affective dysregulation and psychotic experiences or symptoms often co-occur in the general population as well as in bipolar and psychotic disorders, suggesting a complex interplay. Early trauma is hypothesised to be important for the aetiology of both, and individuals with early traumatic experiences often develop disorders characterised by an admixture of affective and psychotic symptoms. Early emotional abuse seems to be particularly relevant for both disorders. Studies of common factors associated with affective dysregulation and psychosis in bipolar and psychotic disorders could help further theoretical understanding and tailor therapeutic interventions. Metacognitive beliefs – beliefs that outline the importance or consequence of thoughts – have been proposed as one possible common factor. Compared to healthy controls, patients with affective or psychotic disorders hold higher levels of metacognitive beliefs that could be maladaptive. Metacognitive beliefs have been linked to affective and/or psychotic diagnoses and symptoms in these disorders, and to early trauma in general. However, little is known about the specific relationships between symptoms of bipolar/psychotic disorders, early emotional abuse, and metacognitive beliefs. This project had three objectives: (1) to examine the prevalence of metacognitive beliefs in bipolar and psychotic disorders, compared to controls; (2) explore whether illness-related factors were linked to metacognitive beliefs; (3) examine if symptomatic responses (depression or positive symptoms) to early emotional abuse were mediated by metacognitive beliefs. Methods Patients with a bipolar or psychotic disorder, and healthy controls, were included through the on-going Thematically Organised Psychosis (TOP) Study in Oslo, Norway. Analyses included t-tests for group comparisons, regression analyses, and regression based mediation pathway analyses where the indirect effects were tested with bootstrapped confidence intervals. Results Patients with bipolar or psychotic disorders reported higher levels of metacognitive beliefs compared to controls. Metacognitive beliefs were significantly related to depression for all patients. Higher levels of metacognitive beliefs were also related to illness-factors related to a poorer long-term outcome, specifically an earlier age at onset of affective disorder in bipolar disorders, and poorer premorbid social adjustment in psychotic disorders. Metacognitive beliefs significantly mediated the relationship between early emotional abuse and depression. The combination of metacognitive beliefs and depression significantly mediated the relationship between early emotional abuse and positive symptoms. The mediation models explained a moderate amount of the variance in symptoms (R2 = .21 and .29) compared to direct models of early emotional abuse impacting on symptomatic responses directly (R2 = .04 and .03) Discussion Our results show that patients with bipolar or psychotic report higher levels of metacognitive beliefs compared to controls, and that such beliefs relate to current symptoms of depression in both patient groups. Our results also suggest that metacognitive beliefs relate to factors present before or at the onset of illness, which are often linked to a poorer long-term outcome in the disorders. Further, our findings suggest that in regards to early emotional abuse, metacognitive beliefs could play a role in an affective pathway to psychosis. Metacognitive beliefs could thus be relevant treatment targets in regards to depression and positive symptoms in bipolar and psychotic disorders.

Purpose To study social functioning, and its relationship with clinical and neurocognitive variables, in patients having their first treatment contact for a manic episode. Methods A total of 55 first contact mania patients, 34 with a first manic episode (FM) and 21 with previously untreated manic episodes (PM), and 110 healthy control subjects matched for age, sex and education to the patient group, completed the Social Functioning Scale (SFS), a self-reported assessment of social functioning. The patients also completed a broad neuropsychological test battery. Results Both patient groups scored significantly lower on self-rated social functioning compared to healthy controls, with PM patients reporting significantly lower functioning than FM patients. There were no significant correlations between clinical symptoms and social functioning. On a trend level, a reduced SFS score was associated with more cannabis use, higher levels of depression and more depressive episodes as well as an earlier age at onset. There was no significant association between social function and neurocognition. Conclusions Social dysfunction was present in patients with BD at first treatment contact—the main predictors of which being the severity of clinical symptoms.

There is little knowledge about the role of the duration of untreated bipolar (DUB) illness in first-treatment bipolar disorder I (BD I), its association with symptoms at start of first treatment, and development over the first year, and limited knowledge about factors that influence the length of DUB. Substance use has shown to delay identification of primary psychiatric disorders, and while cannabis use is common in BD the role of cannabis in relationship to DUB is unclear. The aim of the present study is to examine the associations between DUB and key clinical outcomes at baseline in BD I, and at one year follow-up, and to evaluate the influence of cannabis use. Patients with first-treatment BD I (N=62) completed comprehensive clinical evaluations, which included both DUB and the number of previous episodes. There were no significant associations between DUB and key clinical outcomes. Longer duration from first manic episode to treatment was associated with risk of starting excessive cannabis use after onset of the bipolar disorder. The main finding is the lack of significant associations between features of previous illness episodes and clinical outcomes. Long duration of untreated mania seems to increase the risk for later cannabis use.

Background The aim of this study was to investigate whether childhood trauma was associated with more severe clinical features in patients with first-episode psychosis, both at the initial assessment and after one year. Methods Ninety-six patients with a first-episode of a DSM-IV diagnosis of psychosis, in addition to 264 healthy controls from the same catchment area, were recruited to the TOP NORMENT study. A history of childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ). Function and symptom severity were measured using the Global Assessment of Functioning (GAF) Scale divided into function (GAF-F) and symptoms (GAF-S), the Positive and Negative Syndrome Scale (PANSS) and the Young Mania Rating Scale (YMRS). All clinical assessments were completed at two time points: At an initial assessment within the first year of initiating treatment for psychosis and after one year. Results Childhood trauma was associated with significantly reduced global functioning and more severe clinical symptoms at both baseline and follow-up, whereas emotional neglect was associated with a significantly reduced improvement rate for global functioning (GAF-F) over the follow-up period. Conclusion Our data indicate that patients with first-episode psychosis who report a history of childhood trauma constitute a subgroup characterized by more severe clinical features over the first year of treatment, as well as slower improvement rates.

Studies suggest altered affect regulation manifested by affective lability in manic/mixed and euthymic states in patients with bipolar disorder (BD). Altered affect regulation may arise from disturbances in interactions between the cognitive and the emotional brain networks. However, the relationship between affective lability and executive function has not previously been studied. Our aim was to investigate affective lability, as measured with the Affective Lability Scale (ALS) in patients with BD (N=32) compared to healthy controls (HC) (N=60), and its relationship to executive functioning. We found significantly higher ALS scores in the BD than in the HC group, indicating a higher degree of affective lability in patients with BD. Sub-sample analysis revealed a significant positive relationship between affective lability and semantic set shifting abilities in BD only. These findings suggest that higher levels of affective lability compared with controls are a trait as well as state dependent in BD, and that disturbed affective lability may arise from an aberrant interaction between cognitive and emotional brain networks.

Hellvin T, Sundet K, Simonsen C, Aminoff SR, Lagerberg TV, Andreassen OA, Melle I. Neurocognitive functioning in patients recently diagnosed with bipolar disorder. Bipolar Disord 2012: 14: 227–238. © 2012 The Authors. Journal compilation © 2012 John Wiley & Sons A/S. Objectives: Cognitive dysfunction in bipolar disorder (BD) is well established in the literature; however, there are few studies of neurocognition in patients early in the course of the illness. In this study we compare neurocognitive function in a cohort of first-contact mania patients with a healthy control group matched for age, gender, and education. Methods: Patients with a first manic episode (FM) (n = 34) or previous untreated manic episodes (PM) (n = 21) were neuropsychologically tested following their first treated manic episode. A total of 110 matched healthy control comparison subjects were also tested. The following cognitive domains were evaluated: verbal and visual learning and memory, attention, processing speed, executive functioning, and IQ. Results were corrected for speed of processing differences and were compared with previously reported results for multiple-episode BD patients. Results: BD patients early in their disease course showed impairments in psychomotor speed, attention, learning and memory, executive functioning, and IQ. When controlling for speed of processing, measures of visuoconstructive reasoning and motor dexterity remained statistically significant. Eighteen percent of FM and 16% of PM patients were found to have clinically significant neurocognitive impairment. No significant relationship between clinical symptoms and neurocognition was found. The first-contact mania patients studied were found to have smaller neurocognitive deficits compared to multiple-episode patients in previous studies. Conclusions: Neurocognitive dysfunction is present in early BD and is clinically significant for a proportion of patients. Our findings also suggest that neurocognitive dysfunction may increase with illness progression.

Both schizophrenia (SCZ) and bipolar disorder (BD) are associated with disturbances in emotion processing. Previous studies suggest that patients with SCZ assess unpleasant pictures as less arousing than healthy controls (HC), while patients with BD assess neutral pictures as more arousing than HC. No previous studies have investigated whether there is a difference in emotional response across all three groups. Our aim was to explore whether there was a difference in the evaluation of valence and in arousal between SCZ, BD and HC for aversive and neutral pictures. We showed 72 pictures (neutral, non-socially aversive and socially aversive) from the International Affective Picture System (IAPS) to 347 subjects. There was a clear interaction effect between the diagnostic group and increasing picture aversiveness for both valence and arousal. There were no significant differences in valence ratings between the different groups or in arousal ratings on any type of stimuli between BD patients and HC. However, SCZ patients reported significantly lower arousal for aversive stimuli, particularly with a social content, when compared to BD patients and HC. This was more pronounced in females. The presence of lifetime psychotic symptoms did not influence emotional responses.

Background Early onset of bipolar disorder (BD) is an important clinical predictor of a more severe course and poorer outcome. A higher proportion of childhood onset BD has been reported in studies from USA compared to Europe. We investigated age at onset of first affective episode in a Norwegian sample and compared it to previous European and US findings. In addition, we examined whether age at onset influenced on time to first treatment, and if patient characteristics related to illness severity influenced age at onset. Methods Two hundred and twenty five BD patients were recruited consecutively mainly from psychiatric out-patient units at three major hospitals in Oslo, Norway, diagnosed using SCID-I and divided into four groups based on age at onset. Results Six percent of the patients had onset in childhood, 32% in adolescence, 43% in young adulthood, and 19% as adults. Average age at onset was 22.8 years (SD 9.4). There was a significantly higher age at onset and a significantly shorter time from onset to first treatment in patients with lifetime hospitalization. Limitation Retrospective information which could be confounded by collection bias. Conclusion Age at onset in our sample resembled previous European studies, but not US- or Norwegian studies. The difference in age at onset seems more related to different definitions of onset, than to hospitalization history. This highlights the importance of improving the research criteria and of using similar criteria to ascertain age at onset.

Background Schizophrenia is a severe mental disorder associated with derogated function across various domains, including perception, language, motor, emotional, and social behavior. Due to its complex symptomatology, schizophrenia is often regarded a disorder of cognitive processes. Yet due to the frequent involvement of sensory and perceptual symptoms, it has been hypothesized that functional disintegration between sensory and cognitive processes mediates the heterogeneous and comprehensive schizophrenia symptomatology. Methods Here, using resting-state functional magnetic resonance imaging in 71 patients and 196 healthy controls, we characterized the standard deviation in BOLD (blood-oxygen-level-dependent) signal amplitude and the functional connectivity across a range of functional brain networks. We investigated connectivity on the edge and node level using network modeling based on independent component analysis and utilized the brain network features in cross-validated classification procedures. Results Both amplitude and connectivity were significantly altered in patients, largely involving sensory networks. Reduced standard deviation in amplitude was observed in a range of visual, sensorimotor, and auditory nodes in patients. The strongest differences in connectivity implicated within-sensorimotor and sensorimotor-thalamic connections. Furthermore, sensory nodes displayed widespread alterations in the connectivity with higher-order nodes. We demonstrated robustness of effects across subjects by significantly classifying diagnostic group on the individual level based on cross-validated multivariate connectivity features. Conclusion Taken together, the findings support the hypothesis of disintegrated sensory and cognitive processes in schizophrenia, and the foci of effects emphasize that targeting the sensory and perceptual domains may be key to enhance our understanding of schizophrenia pathophysiology.

Objectives Explanatory factors for the observed neurocognitive impairment in early-stage bipolar I disorder (BD-I) have received little attention. The current study investigated neurocognitive functioning in first-treatment (FT) BD-I compared to FT schizophrenia (SCZ), and healthy controls (HCs), and the effect of history of psychosis and previous episodes in the two clinical groups. Methods A total of 202 FT patients with BD-I (n = 101) and SCZ spectrum disorder (n = 101), in addition to HCs (n = 101), were included. A comprehensive neurocognitive test battery was used to assess verbal learning and memory, executive functioning, processing speed, and attention and working memory. Neurocognitive functioning and the effect of history of psychosis and number of previous episodes were analyzed using separate multivariate analyses of variance and correlation analysis. Results FT patients with BD-I performed intermediately between FT SCZ spectrum patients and HCs on all measures. Compared to HCs, FT BD-I showed impaired functioning across all neurocognitive domains. No differences in neurocognitive functioning were observed in psychotic versus nonpsychotic FT patients with BD-I. With the exception of an association between number of manic episodes and two measures of executive function in FT BD-I, no associations were found between number of episodes and neurocognitive performance. Conclusions Neurocognitive impairments were present in FT BD-I, and were not explained by history of psychosis or number of previous psychotic or depressive episodes. There were indications that executive function could be associated with number of previous manic episodes.

Bipolar disorder (BD) is a genetically and clinically heterogeneous disorder. Current classifications of BD rely on clinical presentations without any validating biomarkers, making homogenous and valid subtypes warranted. This study aims at investigating whether a BD polygenic risk score (PGRS) can validate BD subtypes including diagnostic sub-categories (BD-I versus BD-II), patients with and without psychotic symptoms, polarity of first presenting episode and age at onset based groups. We also wanted to investigate whether illness severity indicators were associated with a higher polygenic risk for BD.Analyze differences in BD PGRS scores between suggested subtypes of BD and between healthy controls (CTR) and BD in a sample of N=669 (255 BD and 414 CTR).The BD PGRS significantly discriminates between BD and CTR (p0.001). There were no differences in BD PGRS between groups defined by diagnostic sub-categories, presenting polarity and age at onset. Patients with psychotic BD had nominally significantly higher BD PGRS than patients with non-psychotic BD after controlling for diagnostic sub-category (p=0.019). These findings remained trend level significant after Bonferroni corrections (p=0.079).The low explained variance of the current PGRS method could lead to type II errors.There are nominally significant differences in BD PGRS scores between patients with and without psychotic symptoms, indicating that these two forms of BD might represent distinct subtypes of BD based in its polygenic architecture and a division between BD with and without psychotic symptoms could represent a more valid subclassification of BD than current diagnostic sub-categories. If replicated, this finding could affect future research, diagnostics and clinical practice.

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.

Purpose Immigrants have heightened risks of psychotic disorders, and it is proposed that migration influences symptom profiles. The purpose of this study was to investigate if either migration experience and/or visible minority status affected symptom profiles, using a cross-culturally validated five-factor model of the Positive and Negative Syndrome Scale (PANSS), in patients with broadly defined psychotic disorders. Methods PANSS was assessed in a large catchment area based sample of patients with psychotic disorders verified with the Structured Clinical Interview for DSM-IV (n = 1,081). Symptom profiles based on Wallwork et al. five-factor model were compared for Norwegians (73 %), white immigrants (10.5 %), and visible minority groups (16.5 %). Results Visible minorities were significantly younger, had less education, more often a schizophrenia diagnosis and higher PANSS positive, negative and disorganized/concrete factor scores than Norwegians and white immigrants. After controlling for confounders only the items “Delusions” and “Difficulty in abstract thinking” differed between groups. Multivariate analyses indicated that these items were not associated with immigration per se, but rather belonging to a visible minority. Conclusion We found mostly similarities in psychotic symptoms between immigrants and Norwegians when using a cross-culturally validated five-factor model of the PANSS. Immigration did not directly influence psychotic symptom profiles but visible minority groups had higher levels of “Delusions” and “Difficulty in abstract thinking”, both symptoms that are partially context dependent. The final publication is available at Springer.

The aim of this study was to investigate the associations between recent cannabis use, current symptomatology and age at onset of first manic, depressive and psychotic episodes in a large sample with first-treatment bipolar I disorder (BD I).One hundred one patients with first-treatment Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) bipolar I disorder were included as part of the Thematically Organized Psychosis study. The Structural Clinical Interview for DSM-IV was used for DSM-IV diagnosis and identification of episodes of illness. Earlier suicide attempts were recorded. Manic, depressive and psychotic symptoms were rated using the Young Mania Rating Scale, Inventory of Depressive Symptoms and Positive and Negative Syndrome Scale correspondingly. Cannabis use within the six last months was recorded.After controlling for confounders, recent cannabis use was significantly associated with lower age at onset of first manic and psychotic episode, but not with onset of first depressive episode (both P 0.05). Recent use was also associated with more lifetime suicide attempts (P 0.01). No group differences were found on symptom levels.The present study confirms earlier findings of an association between cannabis use and a lower age at onset. Recent cannabis use was also associated with more lifetime suicide attempts. The current findings suggest that recent cannabis use is associated with a more severe course of illness in the early phase of BD I.

This study aimed to investigate associations between a history of childhood trauma and levels of affective lability in bipolar patients compared to controls. Forty-two patients and 14 controls were assessed using the Affective Lability Scale (ALS) and the Childhood Trauma Questionnaire (CTQ). Affective Lability Score was significantly associated with scores on the Childhood Trauma Questionnaire. A multivariate regression model indicated a relationship between childhood trauma scores and differences in affective lability between patients and controls.

Cannabis use seems to play a causal role in the development of psychotic disorders. Recent evidence suggests that it may also precipitate onset in bipolar disorder. We here investigate if there is a dose-response relationship between cannabis use and age at onset in bipolar disorder, and whether there are interactions between cannabis use and illness characteristics (presenting polarity and presence of psychosis). Consecutively recruited patients with a DSM-IV, SCID verified diagnosis of bipolar I, II or NOS disorder (n=324) participated. Two-way ANCOVAS were used to investigate the effect of levels of cannabis use (10 times during one month lifetime,10 times during one month lifetime or a cannabis use disorder) on age at onset, including interaction effects with illness characteristics, while controlling for possible confounders. There was a significant association indicating a dose-response relationship between cannabis use and age at onset, which remained statistically significant after controlling for possible confounders (gender, bipolar subtype, family history of severe mental illness and alcohol or other substance use disorders). There were no interaction effects between cannabis use and presenting polarity or presence of psychosis. Doses of cannabis used may affect the age at onset of bipolar disorder.

Cognitive dysfunction in bipolar disorder (BD) is well established in the literature; however, there are few studies of neurocognition in patients early in the course of the illness. In this study we compare neurocognitive function in a cohort of first-contact mania patients with a healthy control group matched for age, gender, and education.Patients with a first manic episode (FM) (n = 34) or previous untreated manic episodes (PM) (n = 21) were neuropsychologically tested following their first treated manic episode. A total of 110 matched healthy control comparison subjects were also tested. The following cognitive domains were evaluated: verbal and visual learning and memory, attention, processing speed, executive functioning, and IQ. Results were corrected for speed of processing differences and were compared with previously reported results for multiple-episode BD patients.BD patients early in their disease course showed impairments in psychomotor speed, attention, learning and memory, executive functioning, and IQ. When controlling for speed of processing, measures of visuoconstructive reasoning and motor dexterity remained statistically significant. Eighteen percent of FM and 16% of PM patients were found to have clinically significant neurocognitive impairment. No significant relationship between clinical symptoms and neurocognition was found. The first-contact mania patients studied were found to have smaller neurocognitive deficits compared to multiple-episode patients in previous studies.Neurocognitive dysfunction is present in early BD and is clinically significant for a proportion of patients. Our findings also suggest that neurocognitive dysfunction may increase with illness progression.

Objectives Bipolar disorder (BD), over the long term, can manifest a variety of outcomes depending on a number of different conditions. There is a need for further knowledge regarding preventive factors as well as predictors of the disabling course of the disorder. Studies regarding the impact on functional outcome of premorbid and current general intellectual function [intelligence quotient (IQ)] and premorbid functioning in BD patients are sparse. The present study addressed the role of premorbid functioning [assessed with the Premorbid Adjustment Scale (PAS)], intelligence, course of illness, and sociodemographics on occupational outcome in BD. Methods Bipolar disorder patients were recruited consecutively from psychiatric units (outpatient and inpatient) in four major hospitals in Oslo, Norway [(N = 226: 64.4% bipolar I disorder (BD-I); 30.1% bipolar II disorder (BD-II); 5.5% bipolar disorder not otherwise specified (BD-NOS); 38.6% males]. The associations between current IQ, premorbid IQ [assessed using the National Adult Reading Test (NART)], PAS, clinical and sociodemographic characteristics, and receipt of disability benefit were analysed using descriptive statistics and logistic regression analyses. Results The number of hospitalizations for depressive episodes and illness duration was associated with a higher risk of receipt of disability benefit. PAS, premorbid and current IQ, as well as decline in IQ, did not explain the higher risk of receipt of disability benefits. Conclusions Severe clinical course of BD was associated with receipt of disability benefit. Occupational outcome was unrelated to PAS, premorbid and current IQ, as well as decline in IQ. This suggests that the persistence of severe clinical symptoms, rather than global cognitive functioning, determines occupational outcome in BD and emphasizes the protective potential of early and continuous clinical treatment.

Aminoff SR, Hellvin T, Lagerberg TV, Berg AO, Andreassen OA,Melle I. Neurocognitive features in subgroups of bipolar disorder.Bipolar Disord 2013: 15: 272–283. © 2013 John Wiley & Sons A/S.Published by Blackwell Publishing Ltd.Objective: To examine which subgroups of DSM-IV bipolar disorder(BD) [BD type I (BD-I) or BD type II (BD-II), and subgroups based onhistory of psychosis, presenting polarity, and age at onset] differentiatebest regarding neurocognitive measures.Methods: A total of 199 patients with BD were characterized by clinicaland neurocognitive features. The distribution of subgroups in thissample was: BD-I, 64% and BD-II, 36%; 60% had a history ofpsychosis; 57% had depression as the presenting polarity; 61% had anearly onset of BD, 25% had a mid onset, and 14% had a late onset. Weused multivariate regression analyses to assess relationships betweenneurocognitive variables and clinical subgroups.Results: Both BD-I diagnosis and elevated presenting polarity wererelated to impairments in verbal memory, with elevated presentingpolarity explaining more of the variance in this cognitive domain(22.5%). History of psychosis and BD-I diagnosis were both related toimpairment in semantic fluency, with history of psychosis explainingmore of the variance (11.6%).Conclusion: Poor performance in verbal memory appears to beassociated with an elevated presenting polarity, and poor performance insemantic fluency appears to be associated with a lifetime history ofpsychosis.

The aim of the study was to investigate which factors are associated with age at onset in bipolar disorder with a specific focus on excessive alcohol and cannabis use, and the sequence of the onsets of excessive substance use and bipolar disorder. We investigated a naturalistic sample of 151 patients with bipolar I and II disorder receiving psychiatric treatment. Whether the presence of excessive substance use prior to bipolar disorder onset or the type of substance used (alcohol or cannabis) was associated with differences in age at onset was investigated using hierarchical and multiple linear regression analyses, adjusting for potential confounders. Patients with excessive alcohol use had a significantly later onset compared with patients with excessive cannabis use. Excessive general substance use prior to bipolar disorder onset was associated with a later onset. However, excessive cannabis use was associated with an earlier onset whether it preceded or followed bipolar disorder onset, also after adjusting for possible confounders. Excessive use of alcohol or other substances was not independently associated with age at onset in multivariate analyses. Alcohol use was associated with a later onset compared with cannabis use, suggesting different relationships to the onset of bipolar disorder. Lifetime use of cannabis predicted an earlier onset, independent of the sequence of onsets. This indicates that an early onset may increase the risk of cannabis use and that cannabis use may trigger bipolar disorder in vulnerable individuals.