Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Identifying genetic differences between bipolar disorder and major depression through multiple GWAS.

Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.

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.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Specificity of polygenic signatures across symptom dimensions in bipolar disorder: an analysis of UK Bipolar Disorder Research Network data.

BACKGROUND: Current definitions and clinical heterogeneity in bipolar disorder are major concerns as they obstruct aetiological research and impede drug development. Therefore, stratification of bipolar disorder is a high priority. To inform stratification, our analysis aimed to examine the patterns and relationships between polygenic liability for bipolar disorder, major depressive disorder (MDD), and schizophrenia with multidimensional symptom representations of bipolar disorder. METHODS: In this analysis, data from the UK Bipolar Disorder Research Network (BDRN) were assessed with the Operational Checklist for Psychotic Disorders. Individuals with bipolar disorder as defined in DSM-IV, of European ancestry (self-reported), aged 18 years or older at time of interview, living in the UK, and registered with the BDRN were eligible for inclusion. Psychopathological variables obtained via interview by trained research psychologists or psychiatrists and psychiatric case notes were used to identify statistically distinct symptom dimensions, calibrated with exploratory factor analysis and validated with confirmatory factor analysis (CFA). CFA was extended to include three polygenic risk scores (PRSs) indexing liability for bipolar disorder, MDD, and schizophrenia in a multiple indicator multiple cause (MIMIC) structural equation model to estimate PRS relationships with symptom dimensions. FINDINGS: Of 4198 individuals potentially eligible for inclusion, 4148 (2804 [67·6%] female individuals and 1344 [32·4%] male individuals) with a mean age at interview of 45 years (SD 12·03) were available for analysis. Three reliable dimensions (mania, depression, and psychosis) were identified. The MIMIC model fitted the data well (root mean square error of approximation 0·021, 90% CI 0·019-0·023; comparative fit index 0·99) and suggests statistically distinct symptom dimensions also have distinct polygenic profiles. The PRS for MDD was strongly associated with the depression dimension (standardised ß 0·125, 95% CI 0·080-0·171) and the PRS for schizophrenia was strongly associated with the psychosis dimension (0·108, 0·082-0·175). For the mania dimension, the PRS for bipolar disorder was weakly associated (0·050, 0·002-0·097). INTERPRETATION: Our findings support the hypothesis that genetic heterogeneity underpins clinical heterogeneity, suggesting that different symptom dimensions within bipolar disorder have partly distinct causes. Furthermore, our results suggest that a specific symptom dimension has a similar cause regardless of the primary psychiatric diagnosis, supporting the use of symptom dimensions in precision psychiatry. FUNDING: Wellcome Trust and UK Medical Research Council.

Borderline personality traits are differently associated with postpartum psychosis and postpartum depression episodes in women with bipolar disorder.

BACKGROUND: Women with bipolar disorder have approximately 40 %-50 % chance of having a perinatal bipolar recurrence. Knowing the factors associated will be beneficial for the prediction and prevention of episodes. We aim to establish if borderline personality disorder traits, as measured by the BEST (Borderline Evaluation of Severity over Time) scale, are associated with perinatal psychiatric outcomes. METHODS: We recruited women with bipolar disorder as part of the BDRN (Bipolar Disorder Research Network) study. Women were interviewed and we collected their demographic and clinical information. Participants subsequently completed the BEST questionnaire. We analysed the association of BEST scores with lifetime presence/absence of perinatal bipolar relapse and, employing multinomial logistic regression, with different subtypes of perinatal outcomes: postpartum psychosis; postpartum depression, and other episodes. RESULTS: In our sample of 807, although there was no significant association between the BEST total score and perinatal episodes as a whole (adjustedOR 1.01 CI95% [0.99, 1.03], p = 0.204), we found significant differing associations with different subtypes of episodes. Women scoring highly on BEST were less likely to experience a postpartum psychotic episode (RRR 0.96 CI95% [0.94, 0.99], p = 0.005) but more likely to experience a non-psychotic depressive episode (RRR 1.03 CI95% [1.01, 1.05], p = 0.007) than no relapse. LIMITATIONS: This study is limited by its cross-sectional design and self-report nature of BEST. CONCLUSIONS: In women with bipolar disorder, borderline traits differentiate the risk of postpartum depression and postpartum psychosis, emphasise the importance of considering risk factors for these perinatal episodes separately, and may help individualise the risk for women in the perinatal period.

User perspectives on long-term remote active electronic self-monitoring of mood symptoms in bipolar spectrum disorders.

BACKGROUND: User feedback is crucial in the development of electronic self-monitoring tools for bipolar spectrum disorders (BSD). Previous studies have examined user experiences in small samples self-monitoring over relatively short time periods. We aimed to explore the experiences of a large sample of individuals with BSD engaged in long-term remote active electronic self-monitoring. METHODS: An online survey, containing closed and open questions, was sent to participants with BSD enrolled on the Bipolar Disorder Research Network (BDRN) True Colours mood-monitoring system. Questions related to experiences of using True Colours, including viewing mood graphs, and sharing data with healthcare professionals (HCPs) and/or family/friends. RESULTS: Response rate was 62.7 % (n = 362). 88.4 % reported finding using True Colours helpful. Commonly reported benefits were having a visual record of mood changes, patterns/triggers and identifying early warning signs. Limitations included questions not being comprehensive or revealing anything new. One third had shared their graphs, with 89.9 % finding it helpful to share with HCPs and 78.7 % helpful to share with family/friends. Perceived benefits included aiding communication and limitations included lack of interest/understanding from others. LIMITATIONS: Responder bias may be present. Findings may not be generalisable to all research cohorts. CONCLUSIONS: The majority of participants valued long-term self-monitoring. Personalisation and ease of use were important. A potential challenge is continued use when mood is long-term stable, highlighting the need for measures to be sensitive to small changes. Sharing self-monitoring data with HCPs may enhance communication of the lived experience of those with BSD. Future research should examine HCPs' perspectives.

Genetic Liabilities Differentiating Bipolar Disorder, Schizophrenia, and Major Depressive Disorder, and Phenotypic Heterogeneity in Bipolar Disorder.

Importance: Understanding the origins of clinical heterogeneity in bipolar disorder (BD) will inform new approaches to stratification and studies of underlying mechanisms. Objective: To identify components of genetic liability that are shared between BD, schizophrenia, and major depressive disorder (MDD) and those that differentiate each disorder from the others and to examine associations between heterogeneity for key BD symptoms and each component. Design, Setting, and Participants: Using data from the Bipolar Disorder Research Network in the United Kingdom, components of liability were identified by applying genomic structural equation modeling to genome-wide association studies of schizophrenia, BD, and MDD. Polygenic risk scores (PRS) representing each component were tested for association with symptoms in an independent BD data set. Adults with DSM-IV BD or schizoaffective disorder, bipolar type, were included. Data were collected from January 2000 to December 2013, and data were analyzed from June 2020 to February 2022. Main Outcomes and Measures: PRS representing the components of liability were tested for association with mania and depression, psychosis, and mood incongruence of psychosis in participants with BD, measured using the Bipolar Affective Disorder Dimensional Scale. Results: Of 4429 included participants, 3012 (68.0%) were female, and the mean (SD) age was 46.2 (12.3) years. Mania and psychosis were associated with the shared liability component (mania ß = 0.29; 95% CI, 0.23-0.34; P = 3.04 × 10-25; psychosis ß = 0.05; 95% CI, 0.04-0.07; P = 2.33 × 10-13) and the components that differentiate each of schizophrenia (mania ß = 0.08; 95% CI, 0.03-0.14; P = .002; psychosis ß = 0.03; 95% CI, 0.01-0.04; P = 1.0 × 10-4) and BD (mania ß = 0.14; 95% CI, 0.09-0.20; P = 1.99 × 10-7; psychosis ß = 0.02; 95% CI, 0.01-0.03; P = .006) from the other disorders. The BD differentiating component was associated with mania independently of effects on psychosis (ß = 0.14; 95% CI, 0.08-0.20; P = 4.32 × 10-6) but not with psychosis independently of mania. Conversely, the schizophrenia differentiating component was associated with psychosis independently of effects on mania (ß = 0.01; 95% CI, 0.003-0.03; P = .02), but not with mania independently of psychosis. Mood incongruence of psychosis was associated only with the schizophrenia differentiating component (ß = 0.03; 95% CI, 0.01-0.05; P = .005). Depression was associated with higher MDD differentiating component (ß = 0.07; 95% CI, 0.01-0.12; P = .01) but lower BD differentiating component (ß = -0.11; 95% CI, -0.17 to -0.06; P = 7.06 × 10-5). Conclusions and Relevance: In this study of BD, clinical heterogeneity reflected the burden of liability to BD and the contribution of alleles that have differentiating effects on risk for other disorders; mania, psychosis, and depression were associated with the components of genetic liability differentiating BD, MDD, and schizophrenia, respectively. Understanding the basis of this etiological heterogeneity will be critical for identifying the different pathophysiological processes underlying BD, stratifying patients, and developing precision therapeutics.

Psychosocial markers of age at onset in bipolar disorder: a machine learning approach.

BACKGROUND: Bipolar disorder is a chronic and severe mental health disorder. Early stratification of individuals into subgroups based on age at onset (AAO) has the potential to inform diagnosis and early intervention. Yet, the psychosocial predictors associated with AAO are unknown. AIMS: We aim to identify psychosocial factors associated with bipolar disorder AAO. METHOD: Using data from the Bipolar Disorder Research Network UK, we employed least absolute shrinkage and selection operator regression to identify psychosocial factors associated with bipolar disorder AAO. Twenty-eight factors were entered into our model, with AAO as our outcome measure. RESULTS: We included 1022 participants with bipolar disorder (µ = 23.0, s.d. ± 9.86) in our model. Six variables predicted an earlier AAO: childhood abuse (ß = -0.2855), regular cannabis use in the year before onset (ß = -0.2765), death of a close family friend or relative in the 6 months before onset (ß = -0.2435), family history of suicide (ß = -0.1385), schizotypal personality traits (ß = -0.1055) and irritable temperament (ß = -0.0685). Five predicted a later AAO: the average number of alcohol units consumed per week in the year before onset (ß = 0.1385); birth of a child in the 6 months before onset (ß = 0.2755); death of parent, partner, child or sibling in the 6 months before onset (ß = 0.3125); seeking work without success for 1 month or more in the 6 months before onset (ß = 0.3505) and a major financial crisis in the 6 months before onset (ß = 0.4575). CONCLUSIONS: The identified predictor variables have the potential to help stratify high-risk individuals into likely AAO groups, to inform treatment provision and early intervention.

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.

Post-partum psychosis and its association with bipolar disorder in the UK: a case-control study using polygenic risk scores.

BACKGROUND: For more than 150 years, controversy over the status of post-partum psychosis has hindered research and caused considerable confusion for clinicians and women, with potentially negative consequences. We aimed to explore the hypothesis that genetic vulnerability differs between women with first-onset post-partum psychosis and those with bipolar disorder more generally. METHODS: In this case-control study on first-onset post-partum psychosis and bipolar disorder in the UK, we included 203 women with first-onset post-partum psychosis (defined as a manic, mixed, or psychotic depression episode within 6 weeks of delivery without a psychiatric history) and 1225 parous women with a history of bipolar disorder. Information on women with bipolar disorder was obtained from the Bipolar Disorder Research Network database, and participants were recruited through screening community mental health teams across the UK and via the media and patient support organisations. All were assessed using a semistructured face-to-face psychiatric interview and psychiatric case note review. 2809 women from the general population were recruited via the national UK Blood Services and the 1958 Birth Cohort (UK National Child Development Study) as controls and matched to cases according to genetic ancestry. All self-reported their ethnicity as White and were recruited from across the UK. Polygenic risk scores (PRSs) were generated from discovery genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Logistic regression was used to model the effect of each PRS on diagnosis, and the RRs and ORs presented were adjusted for ten principal components of genetic variation to account for population stratification. FINDINGS: 203 women with first-onset post-partum psychosis (median age at interview: 46 years [IQR 37-55]) and 1225 women with bipolar disorder (49 years [41-58]) were recruited between September, 1991, and May, 2013, as well as 2809 controls. Women with first-onset post-partum psychosis had similar bipolar disorder and schizophrenia PRSs to women with bipolar disorder, which were significantly higher than those of controls. When compared with controls, women with first-onset post-partum psychosis had an adjusted relative risk ratio (RR) for bipolar disorder PRSs of 1·71 (95% CI 1·56-1·86, p<0·0001) and for schizophrenia PRSs of 1·82 (1·66-1·97, p<0·0001). The effect sizes were similar when comparing women with bipolar disorder to controls (adjusted RR 1·77 [1·69-1·84], p<0·0001 for bipolar disorder PRSs; 2·00 (1·92-2·08), p<0·0001 for schizophrenia PRSs). Although women with bipolar disorder also had higher major depression PRSs than did controls (1·24 [1·17-1·31], p<0·0001), women with first-onset post-partum psychosis did not differ from controls in their polygenic liability to major depression (0·97 (0·82-1·11), p=0·63). INTERPRETATION: Our study supports the recognition of first-onset post-partum psychosis as a separate nosological entity within the bipolar disorder spectrum both in research and clinical settings. FUNDING: Wellcome Trust and Medical Research Council.

Mood episodes in pregnancy and risk of postpartum recurrence in bipolar disorder: The Bipolar Disorder Research Network Pregnancy Study.

BACKGROUND: Women with bipolar disorder (BD) are at high risk of mania/psychosis following childbirth. The risk factors for these episodes remain poorly understood and prospective studies are rare. Here, we examine whether mood episodes occurring within pregnancy predict postpartum recurrence in women with BD using a prospective design. METHOD: 128 women with DSM-5 BD were followed from week 12 of pregnancy (baseline) to 12-weeks postpartum. Semi-structured interviews, supplemented by clinician questionnaires and case-note review, assessed lifetime psychiatric history at baseline, and perinatal psychopathology at two follow-up assessments: third-trimester of pregnancy and 12-weeks postpartum. RESULTS: Postpartum follow-up data were obtained for 124/128 (97%) women [98 bipolar I disorder/schizoaffective-BD (BD-I/SA-BD group) and 26 bipolar II disorder/other specified BD and related disorder (BD-II/BD-OS group)]. Perinatal recurrence was high in both diagnostic groups (57% and 62% respectively). Women with BD-I/SA-BD were significantly more likely to experience mania/psychosis within 6 weeks postpartum (23%, n=22/96) compared to those with BD-II/BD-NOS (4%, n=1/25; p=0.042). In BD-I/SA-BD, mania/psychosis in pregnancy significantly elevated risk of mania/psychosis postpartum compared to remaining well (RR 7.0, p<0.001) and experiencing non-psychotic depression in pregnancy (RR 3.18, p=0.023) Limitations: Predominantly United Kingdom White sample and limited BD-II/BD-OS sample size. CONCLUSIONS: Women with BD are at high risk of recurrence during pregnancy and the postpartum. Over and above risk conferred by a history of BD-I/SA-BD, mania/psychosis during pregnancy further increased risk of postpartum mania/psychosis in this high-risk group. These data may have important implications for prediction and management of severe postpartum recurrence of BD.

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.

Phenomenology, Epidemiology and Aetiology of Postpartum Psychosis: A Review.

Postpartum psychoses are a severe form of postnatal mood disorders, affecting 1-2 in every 1000 deliveries. These episodes typically present as acute mania or depression with psychosis within the first few weeks of childbirth, which, as life-threatening psychiatric emergencies, can have a significant adverse impact on the mother, baby and wider family. The nosological status of postpartum psychosis remains contentious; however, evidence indicates most episodes to be manifestations of bipolar disorder and a vulnerability to a puerperal trigger. While childbirth appears to be a potent trigger of severe mood disorders, the precise mechanisms by which postpartum psychosis occurs are poorly understood. This review examines the current evidence with respect to potential aetiology and childbirth-related triggers of postpartum psychosis. Findings to date have implicated neurobiological factors, such as hormones, immunological dysregulation, circadian rhythm disruption and genetics, to be important in the pathogenesis of this disorder. Prediction models, informed by prospective cohort studies of high-risk women, are required to identify those at greatest risk of postpartum psychosis.

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.

Have I argued with my family this week?": What questions do those with lived experience choose to monitor their bipolar disorder?

BACKGROUND: Electronic self-report mood monitoring tools for individuals with bipolar disorder (BD) are rapidly emerging and predominately employ predefined symptom-based questions. Allowing individuals to additionally choose what they monitor in relation to their BD offers the unique opportunity to capture and gain a deeper insight into patient priorities in this context. METHODS: In addition to monitoring mood symptoms with two standardised self-rated questionnaires, 308 individuals with BD participating in the Bipolar Disorder Research Network True Colours electronic mood-monitoring tool for research chose to create and complete additional personalised questions. A content analysis approach was used to analyse the content of these questions. RESULTS: 35 categories were created based on the personalised questions with the most common being physical activity and exercise, anxiety and panic, sleep and coping/stress levels. The categories were grouped into six overarching themes 1) mental health; 2) behaviour and level of functioning; 3) physical wellbeing; 4) health behaviours; 5) active self-management; and, 6) interpersonal. LIMITATIONS: The average age of the sample was around 50 years meaning our findings may not be generalisable to younger individuals with BD. CONCLUSIONS: Aspects of BD important to patients in relation to longitudinal monitoring extend well beyond mood symptoms, highlighting the limitations of solely relying on standardised questions/mood rating scales based on symptoms primarily used for diagnosis. Additional symptoms and aspects of life not necessarily useful diagnostically for BD may be more important for individuals themselves to monitor and have more meaning in capturing their own experience of changes in BD severity.

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.

Symptom profile of postpartum and non-postpartum manic episodes in bipolar I disorder: a within-subjects study.

The relationship of postpartum mania to episodes of mania occurring outside the perinatal period among women with bipolar disorder remains controversial. Previous studies have used between-subjects designs to compare the clinical presentations of these episodes meaning the differences, in part, may reflect between-group differences. To overcome this we have undertaken within-subject comparisons of the symptom profile of postpartum and non-postpartum manic episodes in 50 women with DSM-IV bipolar I disorder. For each woman detailed symptom information on a postpartum episode of mania and a comparison non-postpartum manic episode was collected. The occurrence of manic, psychotic and depressive symptoms in these episodes were compared. Postpartum manic episodes had a significantly higher incidence of perplexity and excessive self-reproach. Classic manic symptoms, specifically pressured speech and increased sociability, were significantly less frequent in postpartum manic episodes. Overall there were significantly fewer manic symptoms and significantly more depressive symptoms in the postpartum episodes than in the non-postpartum episodes. The mixed presentation of postpartum manic episodes suggests childbirth may act as a pathoplastic trigger in women with bipolar disorder. The differences in symptom profiles suggests further research is warranted into whether differences in treatment response exist among women experiencing postpartum and non-postpartum manic episodes.

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.

Comparison of Genetic Liability for Sleep Traits Among Individuals With Bipolar Disorder I or II and Control Participants.

Importance: Insomnia, hypersomnia, and an evening chronotype are common in individuals with bipolar disorder (BD), but whether this reflects shared genetic liability is unclear. Stratifying by BD subtypes could elucidate this association and inform sleep and BD research. Objective: To assess whether polygenic risk scores (PRSs) for sleep traits are associated with BD subtypes I and II. Design, Setting, and Participants: This case-control study was conducted in the United Kingdom and Sweden with participants with BD and control participants. Multinomial regression was used to assess whether PRSs for insomnia, daytime sleepiness, sleep duration, and chronotype are associated with BD subtypes compared with control participants. Affected individuals were recruited from the Bipolar Disorder Research Network. Control participants were recruited from the 1958 British Birth Cohort and the UK Blood Service. Analyses were repeated in an independent Swedish sample from August 2018 to July 2019. All participants were of European ancestry. Exposures: Standardized PRSs derived using alleles from genome-wide association studies of insomnia, sleep duration, daytime sleepiness, and chronotype. These were adjusted for the first 10 population principal components, genotyping platforms, and sex. Main Outcomes and Measures: Association of PRSs with BD subtypes, determined by semistructured psychiatric interview and case notes. Results: The main analysis included 4672 participants with BD (3132 female participants [67.0%]; 3404 with BD-I [72.9%]) and 5714 control participants (2812 female participants [49.2%]). Insomnia PRS was associated with increased risk of BD-II (relative risk [RR], 1.14 [95% CI, 1.07-1.21]; P = 8.26 × 10-5) but not BD-I (RR, 0.98 [95% CI, 0.94-1.03]; P = .409) relative to control participants. Sleep-duration PRS was associated with BD-I (RR, 1.10 [95% CI, 1.06-1.15]; P = 1.13 × 10-5) but not BD-II (RR, 0.99 [95% CI, 0.93-1.06]; P = .818). Associations between (1) insomnia PRS and BD-II and (2) sleep-duration PRS and BD-I were replicated in the Swedish sample of 4366 individuals with BD (2697 female participants [61.8%]; 2627 with BD-I [60.2%]) and 6091 control participants (3767 female participants [61.8%]). Chronotype and daytime-sleepiness PRS were not associated with BD subtypes. Conclusions and Relevance: Per this analysis, BD subtypes differ in genetic liability to insomnia and hypersomnia, providing further evidence that the distinction between BD-I and BD-II has genetic validity. This distinction will be crucial in selecting participants for future research on the role of sleep disturbance in BD.