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.

A case-control study of filicide/infanticide in 90 mothers.

This study aims to explore the clinical and socio-demographic characteristics of 30 women who committed filicide and compare them to those of 60 postpartum women who did not commit filicide, including 30 with severe postpartum mental illness and 30 without a known history of psychiatric disorders. Clinical assessment included a face-to-face interview with the Structured Clinical Interviews for DSM-IV Axis I and Axis II Disorders. Information on socio-economic, medical, and personal factors was collected using the Clinical Interview for DSM-IV and organized in a clinical vignette and OPCRIT ratings. Consensus best-estimate diagnoses were made according to DSM-V criteria. Inference was conducted using Fisher's exact test for categorical variables and Mann-Whitney U rank test for continuous variables. Family history of violent death, psychotic symptoms (OR 8.3; CI 95% 2.26-36.13), severe insomnia (9.8; 2.28-61.75), and a schizophrenia spectrum or bipolar diathesis (4.8; 1.22-23.86) were associated with history of filicide. Rates of history of sexual abuse in childhood were higher in both the filicide and the severe postpartum mental illness groups compared to healthy controls (6.7; 1.25-70.46 and 7.8; 1.47; 80.47 respectively). Conversely, we did not observe any difference in the rates of history of sexual abuse in adulthood across groups. The lack of adequate postpartum psychiatric care was an important precipitating factor in many cases of infanticide and even late filicide. This study underscores the need for increasing awareness by health care professionals and the wider society of the complex dynamics and psychiatric risks associated with motherhood.

Postpartum psychosis: a public involvement perspective across three continents.

Postpartum psychosis is a psychiatric emergency that is currently not represented in diagnostic systems, to the detriment of people with lived experience. Engaging with stakeholders offers an important avenue to improve clinical practice and make research more impactful, by providing perspectives based on first-hand, expert experience. There is a paucity of reports on stakeholders' engagement in psychiatry. Activities have thus far been limited to Western countries and there are few reports on postpartum psychosis. We report the results of public involvement activities (in the form of discussion groups) with key stakeholders in India, Malawi and the UK. These discussions centred around the clinical picture of postpartum psychosis and the terminologies used to describe these episodes. Seven major areas were highlighted: how postpartum psychosis is handled within services, common symptoms and characteristics, impact of episode, barriers to care, non-medical approaches, terminology and research areas of interest. According to the discussions, postpartum psychosis presents similarly across countries, although there are differences in access to services, approaches to mental health and terminologies used within and across countries. With this understanding comes the foundation for cross-cultural assessment, service improvement and a stakeholder-informed research agenda.

Genetic association of FMRP targets with psychiatric disorders.

Genes encoding the mRNA targets of fragile X mental retardation protein (FMRP) are enriched for genetic association with psychiatric disorders. However, many FMRP targets possess functions that are themselves genetically associated with psychiatric disorders, including synaptic transmission and plasticity, making it unclear whether the genetic risk is truly related to binding by FMRP or is alternatively mediated by the sampling of genes better characterised by another trait or functional annotation. Using published common variant, rare coding variant and copy number variant data, we examined the relationship between FMRP binding and genetic association with schizophrenia, major depressive disorder and bipolar disorder. High-confidence targets of FMRP, derived from studies of multiple tissue types, were enriched for common schizophrenia risk alleles, as well as rare loss-of-function and de novo nonsynonymous variants in schizophrenia cases. Similarly, through common variation, FMRP targets were associated with major depressive disorder, and we present novel evidence of association with bipolar disorder. These relationships could not be explained by other functional annotations known to be associated with psychiatric disorders, including those related to synaptic structure and function. This study reinforces the evidence that targeting by FMRP captures a subpopulation of genes enriched for genetic association with a range of psychiatric disorders.

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.

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.

Progesterone and plasma metabolites in women with and in those without premenstrual dysphoric disorder.

BACKGROUND: The molecular mechanisms underpinning the progesterone-triggering mood symptoms in women with premenstrual dysphoric disorder (PMDD) are unknown. Cell metabolism is a potential source of variability. Very little is known about the effect of progesterone sensitivity on the metabolome. In this study, we aimed to characterize the effects of progesterone on the global metabolic profile and explore the differences between women with PMDD and controls. METHODS: Plasma was obtained from 12 women with prospectively confirmed PMDD and 25 controls under two hormone conditions: (1) gonadal suppression induced by leuprolide acetate (3.75 mg IM monthly) and (2) add-back phase with leuprolide and progesterone (200 mg twice daily by vaginal suppository). The global metabolic profile was obtained using liquid and gas chromatography followed by mass spectrometry. Differences between groups and time points were tested using repeated measures analysis of variance. The false discovery rate was calculated to account for multiple testing. RESULTS: Amino acids and their derivatives represented 78% (28/36) of the known compounds that were found in significantly lower plasma concentrations after progesterone administration than during gonadal suppression. The concentration of tyrosine was nominally significantly decreased after progesterone add-back in controls, but not in cases (P = 0.02). CONCLUSION: Plasma levels of some amino acids are decreased in response to progesterone. Albeit preliminary, evidence further suggests that progesterone has a different effect on the metabolic profiles of women with PMDD compared to controls. Further research is needed to replicate our findings in a larger sample and to identify the unknown compounds, especially those differentially expressed.

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.

HPA axis reactivity to pharmacologic and psychological stressors in euthymic women with histories of postpartum versus major depression.

It is unclear whether women with a history of postpartum depression (PPD) have residual, abnormal hypothalamic-pituitary-adrenal (HPA) axis reactivity, as has been reported in major depression (MDD). Further unclear is whether the abnormalities in HPA axis reactivity associated with MDD represent a stable, underlying predisposition or a state-dependent phenomenon. This study sought the following: (1) to determine if euthymic postpartum women with a history of depression have an abnormal HPA axis reactivity to pharmacologic and psychological challenges and (2) to compare HPA reactivity in women with histories of PPD versus MDD. As a secondary objective, we wanted to determine the influence of trauma history on HPA axis function. Forty-five parous (12-24 months postpartum), euthymic women with history of MDD (n = 15), PPD (n = 15), and controls (n = 15) completed pharmacologic (dexamethasone/corticotropin-releasing hormone (CRH) test [DEX/CRH]) and psychological (Trier social stress test [TSST]) challenges during the luteal phase. Outcome measures were cortisol and adrenocorticotropic hormone (ACTH) response after DEX/CRH, and blood pressure, heart rate, epinephrine, norepinephrine, and cortisol response during the TSST. All groups had robust cortisol and ACTH response to DEX/CRH and cortisol response to TSST. Groups did not differ significantly in cortisol or ACTH response to DEX/CRH or in blood pressure, heart rate, epinephrine, norepinephrine, or cortisol response to TSST. Cortisol/ACTH ratio did not differ significantly between groups. Trauma history was associated with decreased cortisol response to DEX/CRH in women with histories of MDD, which was not significant after correction (F 8,125, p = 0.02, Greenhouse-Geisser corrected p = 0.11). Currently euthymic women with histories of MDD or PPD did not demonstrate residual abnormal stress responsivity following administration of either a pharmacologic or psychological stressor.

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.

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.

Is Postpartum Depression a Distinct Disorder?

The nosology of postpartum depression (PPD) is controversial. We review the evidence and arguments for and against the recognition of PPD as a distinct disorder and discuss the etiopathogenic and diagnostic validity of PPD as a distinct disorder, including its utility and indications for further research. Although multiple epidemiological and clinical studies have found that depression is more common following childbirth than at other times in a woman's life, there is conflicting evidence for the validity of PPD as a distinct disorder. PPD is likely to be a complex phenotype, encompassing several disorders with different disease pathways. It is plausible that for a sub-group of vulnerable women, childbirth triggers episodes of depression. However, even within this group, the mechanisms underpinning the mood disturbances are likely complex and heterogeneous. The distinction between depression occurring in the perinatal period and depression at other times is important for both research and clinical practice. Research should differentiate between episodes that begin during pregnancy and postpartum, as the pathogenetic factors involved may differ and require specialized treatment.