Key subphenotypes of bipolar disorder are differentially associated with polygenic liabilities for bipolar disorder, schizophrenia, and major depressive disorder.

Bipolar disorder (BD) features heterogenous clinical presentation and course of illness. It remains unclear how subphenotypes associate with genetic loadings of BD and related psychiatric disorders. We investigated associations between the subphenotypes and polygenic risk scores (PRS) for BD, schizophrenia, and major depressive disorder (MDD) in two BD cohorts from Sweden (N = 5180) and the UK (N = 2577). Participants were assessed through interviews and medical records for inter-episode remission, psychotic features during mood episodes, global assessment of functioning (GAF, function and symptom burden dimensions), and comorbid anxiety disorders. Meta-analyses based on both cohorts showed that inter-episode remission and GAF-function were positively correlated with BD-PRS but negatively correlated with schizophrenia-PRS (SCZ-PRS) and MDD-PRS. Moreover, BD-PRS was negatively, and MDD-PRS positively, associated with the risk of comorbid anxiety disorders. Finally, SCZ-PRS was positively associated with psychotic symptoms during mood episodes. Assuming a higher PRS of certain psychiatric disorders in cases with a positive family history, we further tested the associations between subphenotypes in index BD people and occurrence of BD, schizophrenia, or MDD in their relatives using Swedish national registries. BD patients with a relative diagnosed with BD had: (1) higher GAF and lower risk of comorbid anxiety than those with a relative diagnosed with schizophrenia or MDD, (2) lower risk of psychotic symptoms than those with a relative diagnosed with schizophrenia. Our findings shed light on the genetic underpinnings of the heterogeneity in clinical manifestations and course of illness in BD, which ultimately provide insights for developing personalized approaches to the diagnosis and treatment.

Mental health prior to and during the COVID-19 pandemic in individuals with bipolar disorder: Insights from prospective longitudinal data.

OBJECTIVES: Many studies have examined the impact of COVID-19 on the mental health of the public, but few have focused on individuals with existing severe mental illness with longitudinal data before and during the pandemic. AIMS: To investigate the impact of the COVID-19 pandemic on the mental health of people with bipolar disorder (BD). METHODS: In an ongoing study of people with BD who used an online mood monitoring tool, True Colours, 356 participants provided weekly data on their mental health. Symptoms of depression, mania, insomnia, and suicidal thoughts were compared in 2019 and 2020. From May 2020, participants also provided weekly data on the effect of the COVID-19 pandemic on anxiety, coping strategies, access to care, and medications. RESULTS: On average, symptoms of depression, mania, insomnia, and suicidal thoughts did not significantly differ in 2020 compared to 2019, but there was evidence of heterogeneity. There were high rates of anxiety about the pandemic and its impact on coping strategies, which increased to over 70% of responders in January 2021. A significant proportion of participants reported difficulty accessing routine care (27%) and medications (21%). CONCLUSIONS: Although mood symptoms did not significantly increase during the pandemic overall, we observed heterogeneity among our BD sample and other impacted areas. Individuals' unique histories and psychosocial circumstances are key and should be explored in future qualitative studies. The significant impacts of the pandemic may take time to manifest, particularly among those who are socioeconomically disadvantaged, highlighting the need for further long-term prospective studies.

The influence of borderline personality traits on clinical outcomes in bipolar disorder.

OBJECTIVES: Systematic reviews suggest comorbid borderline personality disorder is present in approximately 20% of individuals who have bipolar disorder, but current diagnostic systems demonstrate a move towards dimensional rather than categorical approaches to classifying personality pathology. We aimed to examine the presence and severity of borderline personality traits in bipolar I and bipolar II disorder, and to explore associations between the presence/severity of borderline personality traits and clinical outcomes in bipolar disorder. METHODS: Borderline personality traits were measured in 1447 individuals with DSM-IV bipolar disorder (1008 bipolar I disorder and 439 bipolar II disorder) using the Borderline Evaluation of Severity over Time (BEST) questionnaire. Lifetime clinical outcomes were assessed via Schedules for Clinical Assessment in Neuropsychiatry (SCAN) semi-structured interview and clinical case notes. RESULTS: Borderline personality traits were common in both bipolar disorder groups, with 86.2% participants reporting at least one trait. These included traits that overlap with (eg mood instability) and those that are distinct from the symptoms of bipolar disorder (eg fear of abandonment). Borderline personality traits were significantly more frequent and more severe in bipolar II disorder compared to bipolar I disorder. More severe borderline traits, and even the presence of a single borderline personality trait, were significantly associated with younger age of bipolar disorder onset and higher prevalence of lifetime alcohol misuse in both bipolar disorder groups. CONCLUSIONS: The presence of comorbid borderline personality traits should be considered in the management of all patients with bipolar disorder irrespective of whether criteria for a categorical borderline personality disorder diagnosis are met.

Migraine associated with early onset postpartum depression in women with major depressive disorder.

Major depressive disorder (MDD) and migraine are both more common among women than men. Women's reproductive years are associated with increased susceptibility to recurrence of both conditions, suggesting a potential role of sex hormones in aetiology. We examined associations between comorbid migraine and clinical features of MDD in women, including relationships with lifetime reproductive events such as childbirth. Lifetime clinical characteristics and reproductive events in a well-characterised sample of 222 UK women with recurrent MDD, with (n = 98) and without (n = 124) migraine were compared. Women had all been recruited as part of a UK-based ongoing programme of research into the genetic and non-genetic determinants of mood disorders. Multivariate analysis showed a specific association between the lifetime presence of migraine and postpartum depression (PPD) within 6 weeks of delivery (OR = 2.555; 95% CI: 1.037-6.295, p = 0.041). This association did not extend to a broader definition of PPD with onset up to 6 months postpartum. All other factors included in the analysis were not significantly associated with the presence of migraine: family history of depression, younger age at depression onset, history of suicide attempt and severe premenstrual syndrome symptoms. The finding that women with MDD and comorbid migraine may be particularly sensitive to hormonal changes early in the postpartum period leads to aetiological hypotheses and suggests this group may be useful for future studies attempting to characterise PPD and MDD phenotypes. The refinement of such phenotypes has implications for individualising risk and treatment and for future biological and genetic studies.

Explaining why childhood abuse is a risk factor for poorer clinical course in bipolar disorder: a path analysis of 923 people with bipolar I disorder.

BACKGROUND: Childhood abuse is a risk factor for poorer illness course in bipolar disorder, but the reasons why are unclear. Trait-like features such as affective instability and impulsivity could be part of the explanation. We aimed to examine whether childhood abuse was associated with clinical features of bipolar disorder, and whether associations were mediated by affective instability or impulsivity. METHODS: We analysed data from 923 people with bipolar I disorder recruited by the Bipolar Disorder Research Network. Adjusted associations between childhood abuse, affective instability and impulsivity and eight clinical variables were analysed. A path analysis examined the direct and indirect links between childhood abuse and clinical features with affective instability and impulsivity as mediators. RESULTS: Affective instability significantly mediated the association between childhood abuse and earlier age of onset [effect estimate (θ)/standard error (SE): 2.49], number of depressive (θ/SE: 2.08) and manic episodes/illness year (θ/SE: 1.32), anxiety disorders (θ/SE: 1.98) and rapid cycling (θ/SE: 2.25). Impulsivity significantly mediated the association between childhood abuse and manic episodes/illness year (θ/SE: 1.79), anxiety disorders (θ/SE: 1.59), rapid cycling (θ/SE: 1.809), suicidal behaviour (θ/SE: 2.12) and substance misuse (θ/SE: 3.09). Measures of path analysis fit indicated an excellent fit to the data. CONCLUSIONS: Affective instability and impulsivity are likely part of the mechanism of why childhood abuse increases risk of poorer clinical course in bipolar disorder, with each showing some selectivity in pathways. They are potential novel targets for intervention to improve outcome in bipolar disorder.

Patterns and clinical correlates of lifetime alcohol consumption in women and men with bipolar disorder: Findings from the UK Bipolar Disorder Research Network.

OBJECTIVES: Despite previous literature on comorbid alcohol use disorders (AUDs) in bipolar disorder (BD), little is known about patterns of alcohol use more widely in this population. We have examined lifetime heaviest average weekly alcohol consumption levels in a large well-characterised UK sample including lifetime clinical correlates of increasing levels of alcohol use. METHODS: Participants were 1203 women and 673 men with bipolar I disorder interviewed by semi-structured interview who had consumed alcohol regularly at any point in their life. RESULTS: Over half of both women (52.3%) and men (73.6%) had regularly consumed over double the current UK recommended guideline for alcohol consumption. In women and men increasing levels of lifetime alcohol consumption were significantly associated with the presence of suicide attempts (women: OR 1.82, P < .001; men: OR 1.48, P = .005) and rapid cycling (women: OR 1.89, P < .001; men: OR 1.88, P < .001). In women only, increasing levels of alcohol consumption were significantly associated with more episodes of depression (OR 1.35, P < .001) and mania (OR 1.30, P < .004) per illness year, less impairment in functioning during the worst episode of mania (OR 1.02, P < .001), fewer psychiatric admissions (OR 0.51, P < .001), comorbid panic disorder (OR 2.16, P < .001) and eating disorder (OR 2.37, P < .001). CONCLUSIONS: Our results highlight the clinical importance of obtaining detailed information on levels of alcohol consumption among patients with BD. Increased levels of alcohol use, not necessarily reaching criteria for AUD, may be helpful in predicting BD illness course, in particular eating disorders comorbidity in women.

International Consortium on the Genetics of Electroconvulsive Therapy and Severe Depressive Disorders (Gen-ECT-ic).

Recent genome-wide association studies have demonstrated that the genetic burden associated with depression correlates with depression severity. Therefore, conducting genetic studies of patients at the most severe end of the depressive disorder spectrum, those with treatment-resistant depression and who are prescribed electroconvulsive therapy (ECT), could lead to a better understanding of the genetic underpinnings of depression. Despite ECT being one of the most effective forms of treatment for severe depressive disorders, it is usually placed at the end of treatment algorithms of current guidelines. This is perhaps because ECT has controlled risk and logistical demands including use of general anaesthesia and muscle relaxants and side-effects such as short-term memory impairment. Better understanding of the genetics and biology of ECT response and of cognitive side-effects could lead to more personalized treatment decisions. To enhance the understanding of the genomics of severe depression and ECT response, researchers and ECT providers from around the world and from various depression or ECT networks, but not limited to, such as the Psychiatric Genomics Consortium, the Clinical Alliance and Research in ECT, and the National Network of Depression Centers have formed the Genetics of ECT International Consortium (Gen-ECT-ic). Gen-ECT-ic will organize the largest clinical and genetic collection to date to study the genomics of severe depressive disorders and response to ECT, aiming for 30,000 patients worldwide using a GWAS approach. At this stage it will be the largest genomic study on treatment response in depression. Retrospective data abstraction and prospective data collection will be facilitated by a uniform data collection approach that is flexible and will incorporate data from many clinical practices. Gen-ECT-ic invites all ECT providers and researchers to join its efforts.

Agitated depression in bipolar disorder.

OBJECTIVES: It has been suggested that agitated depression (AD) is a common, severe feature in bipolar disorder. We aimed to estimate the prevalence of AD and investigate whether presence of AD was associated with episodic and lifetime clinical features in a large well-characterized bipolar disorder sample. METHOD: The prevalence of agitation, based on semi-structured interview and medical case-notes, in the most severe depressive episode was estimated in 2925 individuals with DSM-IV bipolar disorder recruited into the UK Bipolar Disorder Research Network. Predictors of agitation were ascertained using symptoms within the same episode and lifetime clinical features using multivariate models. RESULTS: 32.3% (n = 946) experienced agitation during the worst depressive episode. Within the same episode, significant predictors of presence of agitation were: insomnia (OR 2.119, P < 0.001), poor concentration (OR 1.966, P = 0.027), decreased libido (OR 1.960, P < 0.001), suicidal ideation (OR 1.861, P < 0.001), slowed activity (OR 1.504, P = 0.001), and poor appetite (OR 1.297, P = 0.029). Over the lifetime illness course, co-morbid panic disorder (OR 2.000, P < 0.001), suicide attempt (OR 1.399, P = 0.007), and dysphoric mania (OR 1.354, P = 0.017) were significantly associated with AD. CONCLUSIONS: Agitation accompanied bipolar depression in at least one-third of cases in our sample and was associated with concurrent somatic depressive symptoms, which are also common features of mixed manic states. Furthermore, AD in our sample was associated with lifetime experience of mixed mania, in addition to severe lifetime illness course including comorbid panic disorder and suicidal behavior. Our results have implications for the diagnosis and treatment of agitated features in bipolar depression.

Stratification of the risk of bipolar disorder recurrences in pregnancy and postpartum.

BACKGROUND: Pregnancy and childbirth are a period of high risk for women with bipolar disorder and involve difficult decisions particularly about continuing or stopping medications.AimsTo explore what clinical predictors may help to individualise the risk of perinatal recurrence in women with bipolar disorder. METHOD: Information was gathered retrospectively by semi-structured interview, questionnaires and case-note review from 887 women with bipolar disorder who have had children. Clinical predictors were selected using backwards stepwise logistic regression, conditional permutation random forests and reinforcement learning trees. RESULTS: Previous perinatal history of affective psychosis or depression was the most significant predictor of a perinatal recurrence (odds ratio (OR) = 8.5, 95% CI 5.04-14.82 and OR = 3.6, 95% CI 2.55-5.07 respectively) but even parous women with bipolar disorder without a previous perinatal mood episode were at risk following a subsequent pregnancy, with 7% developing postpartum psychosis. CONCLUSIONS: Previous perinatal history of affective psychosis or depression is the most important predictor of perinatal recurrence in women with bipolar disorder and can be used to individualise risk assessments.Declaration of interestNone.

Genotype-phenotype correlations in Darier disease: A focus on the neuropsychiatric phenotype.

Darier disease (DD) is an autosomal dominant skin disorder caused by mutations in ATP2A2 encoding the sarco/endoplasmic reticulum Ca2+ ATPase Isoform 2 (SERCA2). Evidence of a population-level association between DD and psychiatric disorders suggests that mutations in ATP2A2 may have pleiotropic effects on the brain as well as skin. Evidence of genotype-phenotype relationships between ATP2A2 mutations and neuropsychiatric phenotypes would further support this suggestion. We investigated genotype-phenotype correlations between lifetime neuropsychiatric features and ATP2A2 mutation type (dichotomized into likely gene disrupting [LGD] or protein altering) in 75 unrelated individuals with DD. We also looked for evidence of clustering of mutations within SERCA2 according to neuropsychiatric features. Combining our data with the existing literature, the rate of LGD mutations was found to be significantly higher among DD cases/families with bipolar disorder, schizophrenia, or affective psychosis (p = .011). We also found a significant relationship between mutations located in the S4-M4 region of the protein and the presence of a severe neuropsychiatric phenotype (p = .032). Our findings add support to the hypothesis that Darier-causing mutations in ATP2A2 confer susceptibility to neuropsychiatric dysfunction, in particular severe psychiatric illness. This, together with evidence from research on common polymorphisms confirms ATP2A2 as a gene at which variation influences susceptibility to major psychiatric illness.

A data-driven investigation of relationships between bipolar psychotic symptoms and schizophrenia genome-wide significant genetic loci.

The etiologies of bipolar disorder (BD) and schizophrenia include a large number of common risk alleles, many of which are shared across the disorders. BD is clinically heterogeneous and it has been postulated that the pattern of symptoms is in part determined by the particular risk alleles carried, and in particular, that risk alleles also confer liability to schizophrenia influence psychotic symptoms in those with BD. To investigate links between psychotic symptoms in BD and schizophrenia risk alleles we employed a data-driven approach in a genotyped and deeply phenotyped sample of subjects with BD. We used sparse canonical correlation analysis (sCCA) (Witten, Tibshirani, & Hastie, ) to analyze 30 psychotic symptoms, assessed with the OPerational CRITeria checklist, and 82 independent genome-wide significant single nucleotide polymorphisms (SNPs) identified by the Schizophrenia Working group of the Psychiatric Genomics Consortium for which we had data in our BD sample (3,903 subjects). As a secondary analysis, we applied sCCA to larger groups of SNPs, and also to groups of symptoms defined according to a published factor analyses of schizophrenia. sCCA analysis based on individual psychotic symptoms revealed a significant association (p = .033), with the largest weights attributed to a variant on chromosome 3 (rs11411529), chr3:180594593, build 37) and delusions of influence, bizarre behavior and grandiose delusions. sCCA analysis using the same set of SNPs supported association with the same SNP and the group of symptoms defined "factor 3" (p = .012). A significant association was also observed to the "factor 3" phenotype group when we included a greater number of SNPs that were less stringently associated with schizophrenia; although other SNPs contributed to the significant multivariate association result, the greatest weight remained assigned to rs11411529. Our results suggest that the canonical correlation is a useful tool to explore phenotype-genotype relationships. To the best of our knowledge, this is the first study to apply this approach to complex, polygenic psychiatric traits. The sparse canonical correlation approach offers the potential to include a larger number of fine-grained systematic descriptors, and to include genetic markers associated with other disorders that are genetically correlated with BD.

Sleep loss as a trigger of mood episodes in bipolar disorder: individual differences based on diagnostic subtype and gender.

BackgroundSleep loss may trigger mood episodes in people with bipolar disorder but individual differences could influence vulnerability to this trigger.AimsTo determine whether bipolar subtype (bipolar disorder type I (BP-I) or II (BD-II)) and gender were associated with vulnerability to the sleep loss trigger.MethodDuring a semi-structured interview, 3140 individuals (68% women) with bipolar disorder (66% BD-I) reported whether sleep loss had triggered episodes of high or low mood. DSM-IV diagnosis of bipolar subtype was derived from case notes and interview data.ResultsSleep loss triggering episodes of high mood was associated with female gender (odds ratio (OR) = 1.43, 95% CI 1.17-1.75, P < 0.001) and BD-I subtype (OR = 2.81, 95% CI 2.26-3.50, P < 0.001). Analyses on sleep loss triggering low mood were not significant following adjustment for confounders.ConclusionsGender and bipolar subtype may increase vulnerability to high mood following sleep deprivation. This should be considered in situations where patients encounter sleep disruption, such as shift work and international travel.

Genome-wide association study identifies SESTD1 as a novel risk gene for lithium-responsive bipolar disorder.

Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.

Collaborative genome-wide association analysis supports a role for ANK3 and CACNA1C in bipolar disorder.

To identify susceptibility loci for bipolar disorder, we tested 1.8 million variants in 4,387 cases and 6,209 controls and identified a region of strong association (rs10994336, P = 9.1 x 10(-9)) in ANK3 (ankyrin G). We also found further support for the previously reported CACNA1C (alpha 1C subunit of the L-type voltage-gated calcium channel; combined P = 7.0 x 10(-8), rs1006737). Our results suggest that ion channelopathies may be involved in the pathogenesis of bipolar disorder.

Genome-wide significant locus for Research Diagnostic Criteria Schizoaffective Disorder Bipolar type.

Studies have suggested that Research Diagnostic Criteria for Schizoaffective Disorder Bipolar type (RDC-SABP) might identify a more genetically homogenous subgroup of bipolar disorder. Aiming to identify loci associated with RDC-SABP, we have performed a replication study using independent RDC-SABP cases (n = 144) and controls (n = 6,559), focusing on the 10 loci that reached a p-value <10-5 for RDC-SABP in the Wellcome Trust Case Control Consortium (WTCCC) bipolar disorder sample. Combining the WTCCC and replication datasets by meta-analysis (combined RDC-SABP, n = 423, controls, n = 9,494), we observed genome-wide significant association at one SNP, rs2352974, located within the intron of the gene TRAIP on chromosome 3p21.31 (p-value, 4.37 × 10-8 ). This locus did not reach genome-wide significance in bipolar disorder or schizophrenia large Psychiatric Genomic Consortium datasets, suggesting that it may represent a relatively specific genetic risk for the bipolar subtype of schizoaffective disorder.

Adverse childhood events and psychosis in bipolar affective disorder.

BACKGROUND: There has been increasing interest in the association between childhood trauma and psychosis. Proposals for potential mechanisms involved include affective dysregulation and cognitive appraisals of threat. AIMS: To establish if, within bipolar disorder, childhood events show a significant association with psychosis, and in particular with symptoms driven by dysregulation of mood or with a persecutory content. METHOD: Data on lifetime-ever presence of psychotic symptoms were determined by detailed structured interview with case-note review (n = 2019). Childhood events were recorded using a self-report questionnaire and case-note information. RESULTS: There was no relationship between childhood events, or childhood abuse, and psychosis per se. Childhood events were not associated with an increased risk of persecutory or other delusions. Significant associations were found between childhood abuse and auditory hallucinations, strongest between sexual abuse and mood congruent or abusive voices. These relationships remain significant even after controlling for lifetime-ever cannabis misuse. CONCLUSIONS: Within affective disorder, the relationship between childhood events and psychosis appears to be relatively symptom-specific. It is possible that the pathways leading to psychotic symptoms differ, with delusions and non-hallucinatory symptoms being influenced less by childhood or early environmental experience.

Gambling problems in bipolar disorder in the UK: prevalence and distribution.

BACKGROUND: North American studies show bipolar disorder is associated with elevated rates of problem gambling; however, little is known about rates in the different presentations of bipolar illness. AIMS: To determine the prevalence and distribution of problem gambling in people with bipolar disorder in the UK. METHOD: The Problem Gambling Severity Index was used to measure gambling problems in 635 participants with bipolar disorder. RESULTS: Moderate to severe gambling problems were four times higher in people with bipolar disorder than in the general population, and were associated with type 2 disorder (OR = 1.74, P = 0.036), history of suicidal ideation or attempt (OR = 3.44, P = 0.02) and rapid cycling (OR = 2.63, P = 0.008). CONCLUSIONS: Approximately 1 in 10 patients with bipolar disorder may be at moderate to severe risk of problem gambling, possibly associated with suicidal behaviour and a rapid cycling course. Elevated rates of gambling problems in type 2 disorder highlight the probable significance of modest but unstable mood disturbance in the development and maintenance of such problems.

Bipolar disorder, miscarriage, and termination.

OBJECTIVES: To compare rates of bipolar episodes following miscarriage and termination with those occurring in the postpartum period. METHODS: Information in relation to pregnancy and childbirth was gathered retrospectively for 1,283 women with broadly defined bipolar disorder by interview and case-notes review. RESULTS: Rates of mania or affective psychosis were significantly higher after full-term delivery than after termination (p < 0.001) or miscarriage (p < 0.001). Rates of non-psychotic major depression were similar following full-term deliveries, miscarriages (p = 0.362), and terminations (p = 0.301). CONCLUSIONS: While women with bipolar disorder and their clinicians should be aware of the possible onset of depression in the weeks following miscarriage or termination, episodes of mania or affective psychosis are less common in comparison with the high rates observed in the postpartum period.

Comorbid medical illness in bipolar disorder.

BACKGROUND: Individuals with a mental health disorder appear to be at increased risk of medical illness. AIMS: To examine rates of medical illnesses in patients with bipolar disorder (n = 1720) and to examine the clinical course of the bipolar illness according to lifetime medical illness burden. METHOD: Participants recruited within the UK were asked about the lifetime occurrence of 20 medical illnesses, interviewed using the Schedules for Clinical Assessment in Neuropsychiatry (SCAN) and diagnosed according to DSM-IV criteria. RESULTS: We found significantly increased rates of several medical illnesses in our bipolar sample. A high medical illness burden was associated with a history of anxiety disorder, rapid cycling mood episodes, suicide attempts and mood episodes with a typically acute onset. CONCLUSIONS: Bipolar disorder is associated with high rates of medical illness. This comorbidity needs to be taken into account by services in order to improve outcomes for patients with bipolar disorder and also in research investigating the aetiology of affective disorder where shared biological pathways may play a role.

Association of Occupational Dysfunction and Hospital Admissions With Different Polygenic Profiles in Bipolar Disorder.

OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.