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.

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.

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.

Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder.

Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3-2.8, one-sided p = 6.0 × 10-4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ.

Characterisation of age and polarity at onset in bipolar disorder.

BACKGROUND: Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS: To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD: Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS: Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (ß = -0.34 years, s.e. = 0.08), major depression (ß = -0.34 years, s.e. = 0.08), schizophrenia (ß = -0.39 years, s.e. = 0.08), and educational attainment (ß = -0.31 years, s.e. = 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. CONCLUSIONS: AAO and PAO are associated with indicators of bipolar disorder 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.

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.

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.

Adverse childhood experiences and postpartum depression in bipolar disorder.

BACKGROUND: Women are particularly vulnerable to recurrence of bipolar disorder (BD) following childbirth. Risk of postpartum psychosis (PP) is especially high, but postpartum depression (PPD) is also common. Adverse childhood experiences (ACEs) have not been associated with PP, but have been associated with PPD in non-bipolar samples. The relationship between ACEs and PPD within BD remains to be investigated. Here, we examined this association in a large, well-defined sample of women with BD. METHODS: Participants were 575 parous women with DSM-IV BD. Lifetime psychopathology, including perinatal, was assessed via semi-structured interview and case-notes. ACEs, assessed via self-report and case-notes, were compared between women with lifetime PPD (n = 368) and those without a lifetime history of perinatal mood episodes (n = 207). RESULTS: In univariate analysis exposure to 3 or more ACEs, and to childhood abuse specifically, was significantly associated with PPD (p = 0.026 and 0.041 respectively), but this did not remain significant after adjusting for lifetime number of episodes of depression and parity. Post-hoc analysis revealed more frequent episodes of depression to be associated with both a history of 3 or more ACEs and of childhood abuse. LIMITATIONS: Limited range of ACEs assessed and potential recall bias. CONCLUSIONS: Increased frequency of ACEs and particularly childhood abuse was associated with more frequent lifetime episodes of depression, but not specifically episodes with postpartum onset. Understanding factors that mediate the pathway between ACEs and PPD in BD has implications for risk prediction of PPD.

Polygenic risk for circulating reproductive hormone levels and their influence on hippocampal volume and depression susceptibility.

Altered reproductive hormone levels have been associated with the pathophysiology of depressive disorders and this risk may be imparted by their modulatory effect upon hippocampal structure and function. Currently it is unclear whether altered levels of reproductive hormones are causally associated with hippocampal volume reductions and the risk of depressive disorders. Here, we utilize genome-wide association study (GWAS) summary statistics from a GWAS focusing on reproductive hormones, consisting of 2913 individuals. Using this data, we generated polygenic risk scores (PRS) for estradiol, progesterone, prolactin and testosterone in the European RADIANT cohort consisting of 176 postpartum depression (PPD) cases (100% female, mean age: 41.6 years old), 2772 major depressive disorder (MDD) cases (68.6% female, mean age: 46.9 years old) and 1588 control participants (62.5% female, mean age: 42.4 years old), for which there was also a neuroimaging subset of 111 individuals (60.4% female, mean age: 50.0 years old). Only the best-fit PRS for estradiol showed a significant negative association with hippocampal volume, as well as many of its individual subfields; including the molecular layer and granule cell layer of the dentate gyrus, subiculum, CA1, CA2/3 and CA4 regions. Interestingly, several of these subfields are implicated in adult hippocampal neurogenesis. When we tested the same estradiol PRS for association with case-control status for PPD or MDD there was no significant relationship observed. Here, we provide evidence that genetic risk for higher plasma estradiol is negatively associated with hippocampal volume, but this does not translate into an increased risk of MDD or PPD. This work suggests that the relationship between reproductive hormones, the hippocampus, and depression is complex, and that there may not be a clear-cut pathway for etiology or risk moderation.

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.

Genome-wide Burden of Rare Short Deletions Is Enriched in Major Depressive Disorder in Four Cohorts.

BACKGROUND: Major depressive disorder (MDD) is moderately heritable, with a high prevalence and a presumed high heterogeneity. Copy number variants (CNVs) could contribute to the heritable component of risk, but the two previous genome-wide association studies of rare CNVs did not report significant findings. METHODS: In this meta-analysis of four cohorts (5780 patients and 6626 control subjects), we analyzed the association of MDD to 1) genome-wide burden of rare deletions and duplications, partitioned by length (<100 kb or >100 kb) and other characteristics, and 2) individual rare exonic CNVs and CNV regions. RESULTS: Patients with MDD carried significantly more short deletions than control subjects (p = .0059) but not long deletions or short or long duplications. The confidence interval for long deletions overlapped with that for short deletions, but long deletions were 70% less frequent genome-wide, reducing the power to detect increased burden. The increased burden of short deletions was primarily in intergenic regions. Short deletions in cases were also modestly enriched for high-confidence enhancer regions. No individual CNV achieved thresholds for suggestive or significant association after genome-wide correction. p values < .01 were observed for 15q11.2 duplications (TUBGCP5, CYFIP1, NIPA1, and NIPA2), deletions in or near PRKN or MSR1, and exonic duplications of ATG5. CONCLUSIONS: The increased burden of short deletions in patients with MDD suggests that rare CNVs increase the risk of MDD by disrupting regulatory regions. Results for longer deletions were less clear, but no large effects were observed for long multigenic CNVs (as seen in schizophrenia and autism). Further studies with larger sample sizes are warranted.