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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BackgroundDepression and obesity are highly prevalent, and major impacts on public health frequently co-occur. Recently, we reported that having depression moderates the effect of the FTO gene, suggesting its implication in the association between depression and obesity.AimsTo confirm these findings by investigating the FTO polymorphism rs9939609 in new cohorts, and subsequently in a meta-analysis.MethodThe sample consists of 6902 individuals with depression and 6799 controls from three replication cohorts and two original discovery cohorts. Linear regression models were performed to test for association between rs9939609 and body mass index (BMI), and for the interaction between rs9939609 and depression status for an effect on BMI. Fixed and random effects meta-analyses were performed using METASOFT.ResultsIn the replication cohorts, we observed a significant interaction between FTO, BMI and depression with fixed effects meta-analysis (β = 0.12, P = 2.7 × 10-4) and with the Han/Eskin random effects method (P = 1.4 × 10-7) but not with traditional random effects (β = 0.1, P = 0.35). When combined with the discovery cohorts, random effects meta-analysis also supports the interaction (β = 0.12, P = 0.027) being highly significant based on the Han/Eskin model (P = 6.9 × 10-8). On average, carriers of the risk allele who have depression have a 2.2% higher BMI for each risk allele, over and above the main effect of FTOConclusionsThis meta-analysis provides additional support for a significant interaction between FTO, depression and BMI, indicating that depression increases the effect of FTO on BMI. The findings provide a useful starting point in understanding the biological mechanism involved in the association between obesity and depression. [ABSTRACT FROM AUTHOR]

Background: The relative contribution of demographic, lifestyle and medication factors to the association between affective disorders and cardiometabolic diseases is poorly understood.Aims: To assess the relationship between cardiometabolic disease and features of depresion and bipolar disorder within a large population sample.Method: Cross-sectional study of 145 991 UK Biobank participants: multivariate analyses of associations between features of depression or bipolar disorder and five cardiometabolic outcomes, adjusting for confounding factors.Results: There were significant associations between mood disorder features and 'any cardiovascular disease' (depression odds ratio (OR) = 1.15, 95% CI 1.12-1.19; bipolar OR = 1.28, 95% CI 1.14-1.43) and with hypertension (depression OR = 1.15, 95% CI 1.13-1.18; bipolar OR = 1.26, 95% CI 1.12-1.42). Individuals with features of mood disorder taking psychotropic medication were significantly more likely than controls not on psychotropics to report myocardial infarction (depression OR = 1.47, 95% CI 1.24-1.73; bipolar OR = 2.23, 95% CI 1.53-3.57) and stroke (depression OR = 2.46, 95% CI 2.10-2.80; bipolar OR = 2.31, 95% CI 1.39-3.85).Conclusions: Associations between features of depression or bipolar disorder and cardiovascular disease outcomes were statistically independent of demographic, lifestyle and medication confounders. Psychotropic medication may also be a risk factor for cardiometabolic disease in individuals without a clear history of mood disorder. [ABSTRACT FROM AUTHOR]

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

Objectives Darier disease is an autosomal dominant skin disorder caused by mutations in the ATPase, Ca++ transporting, cardiac muscle, slow twitch 2 ( ATP2A2) gene and previously reported to cosegregate with bipolar disorder and schizophrenia in occasional pedigrees. It is, however, unknown whether these associations exist also in the general population, and the objective of this study was to examine this question. Methods We compared a national sample of individuals with Darier disease and their first-degree relatives with matched unexposed individuals from the general population and their first-degree relatives, respectively. To examine risks for bipolar disorder and schizophrenia, risk ratios and 95% confidence intervals ( CIs) were estimated using conditional logistic regressions. Results Individuals with Darier disease had a 4.3 times higher risk of being diagnosed with bipolar disorder (95% CI: 2.6-7.3) and a 2.3 times higher risk of being diagnosed with schizophrenia (95% CI: 1.1-5.2) than matched individuals from the general population. Relatives of individuals with Darier disease had a 1.6 times higher risk of having bipolar disorder (95% CI: 1.1-2.5) than relatives of matched individuals from the general population, but no increased risk of schizophrenia (risk ratio = 0.8, 95% CI: 0.4-1.8). Conclusions The association between Darier disease and bipolar disorder is manifest also in the population, and our data suggest that genetic variability within the ATP2A2 gene that causes Darier disease also confers susceptibility for bipolar disorder. The Darier-causing mutations merit additional attention in molecular genetic research on bipolar disorder. [ABSTRACT FROM AUTHOR]

Background: Obesity is strongly associated with major depressive disorder (MDD) and various other diseases. Genome-wide association studies have identified multiple risk loci robustly associated with body mass index (BMI). In this study, we aimed to investigate whether a genetic risk score (GRS) combining multiple BMI risk loci might have utility in prediction of obesity in patients with MDD. Methods: Linear and logistic regression models were conducted to predict BMI and obesity, respectively, in three independent large case-control studies of major depression (Radiant, GSK-Munich, PsyCoLaus). The analyses were first performed in the whole sample and then separately in depressed cases and controls. An unweighted GRS was calculated by summation of the number of risk alleles. A weighted GRS was calculated as the sum of risk alleles at each locus multiplied by their effect sizes. Receiver operating characteristic (ROC) analysis was used to compare the discriminatory ability of predictors of obesity. Results: In the discovery phase, a total of 2,521 participants (1,895 depressed patients and 626 controls) were included from the Radiant study. Both unweighted and weighted GRS were highly associated with BMI (P <0.001) but explained only a modest amount of variance. Adding 'traditional' risk factors to GRS significantly improved the predictive ability with the area under the curve (AUC) in the ROC analysis, increasing from 0.58 to 0.66 (95% CI, 0.62-0.68; χ² = 27.68; P <0.0001). Although there was no formal evidence of interaction between depression status and GRS, there was further improvement in AUC in the ROC analysis when depression status was added to the model (AUC = 0.71; 95% CI, 0.68-0.73; χ² = 28.64; P <0.0001). We further found that the GRS accounted for more variance of BMI in depressed patients than in healthy controls. Again, GRS discriminated obesity better in depressed patients compared to healthy controls. We later replicated these analyses in two independent samples (GSK-Munich and PsyCoLaus) and found similar results. Conclusions: A GRS proved to be a highly significant predictor of obesity in people with MDD but accounted for only modest amount of variance. Nevertheless, as more risk loci are identified, combining a GRS approach with information on non-genetic risk factors could become a useful strategy in identifying MDD patients at higher risk of developing obesity. [ABSTRACT FROM AUTHOR]

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

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. [ABSTRACT FROM AUTHOR]

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

Background Obesity has been shown to be associated with depression and it has been suggested that higher body mass index (BMl) increases the risk of depression and other common mental disorders. However, the causal relationship remains unclear and Mendelian randomisation, a form of instrumental variable analysis, has recently been employed to attempt to resolve this issue. Aims To investigate whether higher BMl increases the risk of major depression. Method Two instrumental variable analyses were conducted to test the causal relationship between obesity and major depression in RADIANT, a large case-control study of major depression. We used a single nucleotide polymorphism (SNP) in FTO and a genetic risk score (GRS) based on 32 SNPs with well-established associations with BMl. Results Linear regression analysis, as expected, showed that individuals carrying more risk alleles of FTO or having higher score of GRS had a higher BMl. Probit regression suggested that higher BMl is associated with increased risk of major depression. However, our two instrumental variable analyses did not support a causal relationship between higher BMl and major depression (FTO genotype: coefficient -0.03, 95% Cl -0.18 to 0.13, P = 0.73; GRS: coefficient -0.02, 95% Cl -0.11 to 0.07, P = 0.62). Conclusions Our instrumental variable analyses did not support a causal relationship between higher BMl and major depression. The positive associations of higher BMl with major depression in probit regression analyses might be explained by reverse causality and/or residual confounding. [ABSTRACT FROM AUTHOR]

Background Previous studies on the association between adiposity and mood disorder have produced contradictory results, and few have used measurements other than body mass index (BMI). We examined the association between probable major depression and several measurements of adiposity: BMI, waist circumference (WC), waist-hip-ratio (WHR), and body fat percentage (BF%). Methods We conducted a cross-sectional study using baseline data on the sub-group of UK Biobank participants who were assessed for mood disorder. Multivariate logistic regression models were used, adjusting for potential confounders including: demographic and life-style factors, comorbidity and psychotropic medication. Results Of the 140,564 eligible participants, evidence of probable major depression was reported by 30,145 (21.5%). The fully adjusted odds ratios (OR) for obese participants were 1.16 (95% confidence interval (CI) 1.12, 1.20) using BMI, 1.15 (95% CI 1.11, 1.19) using WC, 1.09 (95% CI 1.05, 1.13) using WHR and 1.18 (95% CI 1.12, 1.25) using BF% (all p < 0.001). There was a significant interaction between adiposity and gender (p = 0.001). Overweight women were at increased risk of depression with a dose response relationship across the overweight (25.0-29.9 kg/m²), obese I (30.0-34.9 kg/m²), II (35.0-39.9 kg/m²) and III (≥40.0 kg/m²) categories; fully adjusted ORs 1.14, 1.20, 1.29 and 1.48, respectively (all p < 0.001). In contrast, only obese III men had significantly increased risk of depression (OR 1.29, 95% CI 1.08, 1.54, p = 0.006). Conclusion Adiposity was associated with probable major depression, irrespective of the measurement used. The association was stronger in women than men. Physicians managing overweight and obese women should be alert to this increased risk. [ABSTRACT FROM AUTHOR]

Background Obesity is known to increase the risk of many diseases and reduce overall quality of life. This study examines the relationship with self-reported health (SRH) and happiness. Methods We conducted a cross-sectional study of the 163 066 UK Biobank participants who completed the happiness rating. The association between adiposity and SRH and happiness was examined using logistic regression. SRH was defined as good (excellent, good), or poor (fair, poor). Self-reported happiness was defined as happy (extremely, very, moderately) or unhappy (moderately, very, extremely). Results Poor health was reported by 44 457 (27.3%) participants. The adjusted ORs for poor health were 3.86, 2.92, 2.60 and 6.41 for the highest, compared with lowest, deciles of Body Mass Index, waist circumference, waist to hip ratio and body fat percent, respectively. The associations were stronger in men (p<0.001). Overall, 7511 (4.6%) participants felt unhappy, and only class III obese participants were more likely to feel unhappy (adjusted OR 1.33, 95% CI 1.15 to 1.53, p<0.001) but the associations differed by sex (p<0.001). Among women, there was a significant association between unhappiness and all levels of obesity. By contrast, only class III obese men had significantly increased risk and overweight and class I obese men were less likely to be unhappy. Conclusions Obesity impacts adversely on happiness as well as health, but the association with unhappiness disappeared after adjustment for self-reported health, indicating this may be mediated by health. Compared with obese men, obese women are less likely to report poor health, but more likely to feel unhappy. [ABSTRACT FROM AUTHOR]

Background Disruption in the parent-child relationship is a commonly hypothesized risk factor through which maternal depression may increase risk for offspring psychopathology. However, maternal depression is commonly accompanied by other psychopathology, including antisocial behaviour. Few studies have examined the role of co-occurring psychopathology in depressed mothers. Using a longitudinal study of offspring of mothers with recurrent depression, we aimed to test whether maternal warmth/hostility mediated links between maternal depression severity and child outcomes, and how far direct and indirect pathways were robust to controls for co-occurring maternal antisocial behaviour. Methods Mothers with a history of recurrent major depressive disorder and their adolescent offspring (9-17 years at baseline) were assessed three times between 2007 and 2010. Mothers completed questionnaires assessing their own depression severity and antisocial behaviour at Time 1 (T1). The parent-child relationship was assessed using parent-rated questionnaire and interviewer-rated 5-min speech sample at Time 2 (T2). Offspring symptoms of depression and disruptive behaviours were assessed using the Child and Adolescent Psychiatric Assessment at Time 3 (T3). Results Maternal hostility and warmth, respectively, mediated the association between maternal depression severity and risk for offspring psychopathology. However, the effects were attenuated when maternal antisocial behaviour was included in the analysis. In tests of the full theoretical model, maternal antisocial behaviour predicted both maternal hostility and low warmth, maternal hostility predicted offspring disruptive behaviour disorder symptoms, but not depression, and maternal warmth was not associated with either child outcome. Conclusions Parenting interventions aimed at reducing hostility may be beneficial for preventing or reducing adolescent disruptive behaviours in offspring of depressed mothers, especially when depressed mothers report co-occurring antisocial behaviour. [ABSTRACT FROM AUTHOR]

Objectives. Co-morbidity between depression and anxiety disorders is common. In this study we define a quantitative measure of anxiety by summating four anxiety items from the SCAN interview in a large collection of major depression (MDD) cases to identify genes contributing to this complex phenotype. Methods. A total of 1522 MDD cases dichotomised according to those with at least one anxiety item scored ( n = 1080) and those without anxiety ( n = 442) were analysed, and also compared to 1588 healthy controls at a genome-wide level, to identify genes that may contribute to anxiety in MDD. Results. For the quantitative trait, suggestive evidence of association was detected for two SNPs, and for the dichotomous anxiety present/absent ratings for three SNPs at genome-wide level. In the genome-wide analysis of MDD cases with co-morbid anxiety and healthy controls, two SNPs attained P values of < 5 × 10-6. Analysing candidate genes, P values ≤ 0.0005 were found with three SNPs for the quantitative trait and three SNPs for the dichotomous trait. Conclusions. This study provides an initial genome-wide assessment of possible genetic contribution to anxiety in MDD. Although suggestive evidence of association was found for several SNPs, our findings suggest that there are no common variants strongly associated with anxious depression. [ABSTRACT FROM AUTHOR]

Objectives Large, rare chromosomal copy number variants ( CNVs) have been shown to increase the risk for schizophrenia and other neuropsychiatric disorders including autism, attention-deficit hyperactivity disorder, learning difficulties, and epilepsy. Their role in bipolar disorder ( BD) is less clear. There are no reports of an increase in large, rare CNVs in BD in general, but some have reported an increase in early-onset cases. We previously found that the rate of such CNVs in individuals with BD was not increased, even in early-onset cases. Our aim here was to examine the rate of large rare CNVs in BD in comparison with a new large independent reference sample from the same country. Methods We studied the CNVs in a case-control sample consisting of 1,650 BD cases (reported previously) and 10,259 reference individuals without a known psychiatric disorder who took part in the original Wellcome Trust Case Control Consortium ( WTCCC) study. The 10,259 reference individuals were affected with six non-psychiatric disorders (coronary artery disease, types 1 and 2 diabetes, hypertension, Crohn's disease, and rheumatoid arthritis). Affymetrix 500K array genotyping data were used to call the CNVs. Results The rate of CNVs > 100 kb was not statistically different between cases and controls. The rate of very large (defined as > 1 Mb) and rare (< 1%) CNVs was significantly lower in patients with BD compared with the reference group. CNV loci associated with schizophrenia were not enriched in BD and, in fact, cases of BD had the lowest number of such CNVs compared with any of the WTCCC cohorts; this finding held even for the early-onset BD cases. Conclusions Schizophrenia and BD differ with respect to CNV burden and association with specific CNVs. Our findings support the hypothesis that BD is etiologically distinct from schizophrenia with respect to large, rare CNVs and the accompanying associated neurodevelopmental abnormalities. [ABSTRACT FROM AUTHOR]

Neuroscience studies into psychiatric disorders generally rely on disease definitions that are based on the influential Diagnostic and Statistical Manual of Mental Disorders (DSM), the fifth edition of which (DSM-5) was released earlier this year. Designed as a purely diagnostic tool, the DSM considers different disorders as distinct entities. However, boundaries between disorders are often not as strict as the DSM suggests. To provide an alternative framework for research into psychiatric disorders, the US National Institute of Mental Health (NIMH) has recently introduced its Research Domain Criteria (RDoC) project. In the RDoC, five 'domains' each reflect a brain system in which functioning is impaired, to different degrees, in different psychiatric conditions. Nature Reviews Neuroscience asked six leading investigators for their thoughts on how DSM-5 and the RDoC will influence neuroscience research into psychiatric disorders. [ABSTRACT FROM AUTHOR]

Objectives: UK Biobank is a landmark cohort of over 500,000 participants which will be used to investigate genetic and non-genetic risk factors for a wide range of adverse health outcomes. This is the first study to systematically assess the prevalence and validity of proposed criteria for probable mood disorders within the cohort (major depression and bipolar disorder). Methods: This was a descriptive epidemiological study of 172,751 individuals assessed for a lifetime history of mood disorder in relation to a range of demographic, social, lifestyle, personality and health-related factors. The main outcomes were prevalence of a probable lifetime (single) episode of major depression, probable recurrent major depressive disorder (moderate), probable recurrent major depressive disorder (severe), probable bipolar disorder and no history of mood disorder (comparison group). Outcomes were compared on age, gender, ethnicity, socioeconomic status, educational attainment, functioning, self-reported health status, current depressive symptoms, neuroticism score, smoking status and alcohol use. Results: Prevalence rates for probable single lifetime episode of major depression (6.4%), probable recurrent major depression (moderate) (12.2%), probable recurrent major depression (severe) (7.2%) and probable bipolar disorder (1.3%) were comparable to those found in other population studies. The proposed diagnostic criteria have promising validity, with a gradient in evidence from no mood disorder through major depression and probable bipolar disorder in terms of gender distribution, socioeconomic status, self-reported health rating, current depressive symptoms and smoking. Significance: The validity of our proposed criteria for probable major depression and probable bipolar disorder within this cohort are supported by these cross-sectional analyses. Our findings are likely to prove useful as a framework for a wide range of future genetic and non-genetic studies. [ABSTRACT FROM AUTHOR]

Background: There is recent evidence of some degree of shared genetic susceptibility between adult schizophrenia and childhood attention-deficit hyperactivity disorder (ADHD) for rare chromosomal variants.Aims: To determine whether there is overlap between common alleles conferring risk of schizophrenia in adults with those that do so for ADHD in children.Method: We used recently published Psychiatric Genome-wide Association Study (GWAS) Consortium (PGC) adult schizophrenia data to define alleles over-represented in people with schizophrenia and tested whether those alleles were more common in 727 children with ADHD than in 2067 controls.Results: Schizophrenia risk alleles discriminated ADHD cases from controls (P = 1.04 × 10(-4), R(2) = 0.45%); stronger discrimination was given by alleles that were risk alleles for both adult schizophrenia and adult bipolar disorder (also derived from a PGC data-set) (P = 9.98 × 10(-6), R(2) = 0.59%).Conclusions: This increasing evidence for a small, but significant, shared genetic susceptibility between adult schizophrenia and childhood ADHD highlights the importance of research work across traditional diagnostic boundaries. [ABSTRACT FROM AUTHOR]

Objectives Women who experience postpartum psychosis ( PP) seek guidance on further pregnancies and risk of illness; however, empirical data are limited. This study describes reproductive and mental health outcomes in women diagnosed with PP and examines clinical risk factors as predictors of further illness. Methods A retrospective cohort design was used; 116 women who experienced episodes of mania or depression with psychotic features within six weeks of childbirth were recruited. All subjects underwent clinical diagnostic interviews and medical case notes were reviewed. Results Only 33% of women had an antecedent history, of which 34% had bipolar disorder and 55% unipolar depression. Only 58% of those with PP in their first pregnancy had a subsequent pregnancy, and 18% of marriages ended following the PP episode. Clinical presentation at the time of initial episode did not influence the timing of the onset of symptoms, treatment, or recovery. Although 86% of patients received treatment within 30 days of onset, 26% of women reported ongoing symptoms at a year after delivery. The recurrence rate of PP was 54.4%; a longer duration of the index episode (p < 0.05) and longer latency between the index PP and next pregnancy predicted a subsequent PP. The rate of subsequent non-puerperal episodes was 69%, and all these episodes were bipolar. Conclusions Postpartum psychosis is difficult to predict in women with no antecedent history and is associated with a high rate of subsequent puerperal and non-puerperal illness. Risk of further illness needs to be conveyed in order to allow fully informed decisions to be made regarding future pregnancies. [ABSTRACT FROM AUTHOR]

Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets.Objective: To identify SCZ susceptibility genes.Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1,085,772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs.Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases.Patients: We included 11,185 cases and 10,768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families.Main Outcomes and Measures: Case-control status for SCZ.Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P < 2.20 x 10(-16) and 93% in subjects of European ancestry only (P < 2.20 < 10(-16)). Our results supported the major histocompatibility complex region showing a3.7-fold overall enrichment of replication values of P < .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P = 2.53 x 10(-10)) and NOTCH4 (P = 3.16 x 10(-7)) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 x 10(-7)), AS3MT (P = 9.01 x 10(-7)), CNNM2 (P = 6.07 = 10(-7)), and NT5C2(P = 4.09 x 10(-7)). To explore the many small effects, we performed pathway analyses. The most significant pathways involved neuronal function (axonal guidance, neuronal systems, and L1 cell adhesion molecule interaction)and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse).Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets. [ABSTRACT FROM AUTHOR]

Importance: Schizophrenia (SCZ) is a devastating psychiatric condition. Identifying the specific genetic variants and pathways that increase susceptibility to SCZ is critical to improve disease understanding and address the urgent need for new drug targets. Objective: To identify SCZ susceptibility genes. Design: We integrated results from a meta-analysis of 18 genome-wide association studies (GWAS) involving 1 085 772 single-nucleotide polymorphisms (SNPs) and 6 databases that showed significant informativeness for SCZ. The 9380 most promising SNPs were then specifically genotyped in an independent family-based replication study that, after quality control, consisted of 8107 SNPs. Setting: Linkage meta-analysis, brain transcriptome meta-analysis, candidate gene database, OMIM, relevant mouse studies, and expression quantitative trait locus databases. Patients: We included 11185 cases and 10 768 control subjects from 6 databases and, after quality control 6298 individuals (including 3286 cases) from 1811 nuclear families. Main Outcomes and Measures: Case-control status for SCZ. Results: Replication results showed a highly significant enrichment of SNPs with small P values. Of the SNPs with replication values of P<.01, the proportion of SNPs that had the same direction of effects as in the GWAS meta-analysis was 89% in the combined ancestry group (sign test, P<2.20 X 10-16) and 93% in subjects of European ancestry only (P< 2.20 X 10-16). Our results supported the major histocompatibility complex region showing a 3.7-fold overall enrichment of replication values of P< .01 in subjects from European ancestry. We replicated SNPs in TCF4 (P=2.53 X 10-10) and NOTCH4 (P=3.16X 10~7) that are among the most robust SCZ findings. More novel findings included POM121L2 (P = 3.51 X 10-7), AS3MT (P=9.01 X 10-7), CNNM2 (P=6.07 X 10-7), and NT5C2 (P=4.09 X 10-7). To explore the many small effects, we performed pathway analyses. The most significant path-ways involved neuronal function (axonal guidance, neuronal systems, and LI cell adhesion molecule interaction) and the immune system (antigen processing, cell adhesion molecules relevant to T cells, and translocation to immunological synapse). Conclusions and Relevance: We replicated novel SCZ disease genes and pathogenic pathways. Better understanding the molecular and biological mechanisms involved with schizophrenia may improve disease management and may identify new drug targets. [ABSTRACT FROM AUTHOR]

Background: Offspring of mothers with depression are at heightened risk of psychiatric disorder. Many mothers with depression have comorbid psychopathology. How these co-occurring problems affect child outcomes has rarely been considered.Aims: To consider whether the overall burden of co-occurring psychopathology in mothers with recurrent depression predicts new-onset psychopathology in offspring.Method: Mothers with recurrent depression and their adolescent offspring (9-17 years at baseline) were assessed in 2007 and on two further occasions up to 2011. Mothers completed questionnaires assessing depression severity, anxiety, alcohol problems and antisocial behaviour. Psychiatric disorder in offspring was assessed using the Child and Adolescent Psychiatric Assessment.Results: The number of co-occurring problems in mothers (0, 1 or 2+) predicted new-onset offspring disorder (odds ratio (OR) = 1.80, 95% CI 1.17-2.77, P = 0.007). Rates varied from 15.7 to 34.8% depending on the number of co-occurring clinical problems. This remained significant after controlling for maternal depression severity (OR = 1.73, 95% CI 1.03-2.89, P = 0.040).Conclusions: The burden of co-occurring psychopathology among mothers with recurrent depression indexes increased risk of future onset of psychiatric disorder for offspring. This knowledge can be used in targeting preventive measures in children at high risk of psychiatric disorder. [ABSTRACT FROM AUTHOR]

This report is of a round-table discussion held in Cardiff in September 2009 for Cesagen, a research centre within the Genomics Network of the UK’s Economic and Social Research Council. The meeting was arranged to explore ideas as to the likely future course of human genomics. The achievements of genomics research were reviewed, and the likely constraints on the pace of future progress were explored. New knowledge is transforming biology and our understanding of evolution and human disease. The difficulties we face now concern the interpretation rather than the generation of new sequence data. Our understanding of gene-environment interaction is held back by our current primitive tools for measuring environmental factors, and in addition, there may be fundamental constraints on what can be known about these complex interactions. [ABSTRACT FROM AUTHOR]

Doublecortin and calmodulin like kinase 1 (DCLK1) is implicated in synaptic plasticity and neurodevelopment. Genetic variants in DCLK1 are associated with cognitive traits, specifically verbal memory and general cognition. We investigated the role of DCLK1 variants in three psychiatric disorders that have neuro-cognitive dysfunctions: schizophrenia (SCZ), bipolar affective disorder (BP) and attention deficit/hyperactivity disorder (ADHD). We mined six genome wide association studies (GWASs) that were available publically or through collaboration; three for BP, two for SCZ and one for ADHD. We also genotyped the DCLK1 region in additional samples of cases with SCZ, BP or ADHD and controls that had not been wholegenome typed. In total, 9895 subjects were analysed, including 5308 normal controls and 4,587 patients (1,125 with SCZ, 2,496 with BP and 966 with ADHD). Several DCLK1 variants were associated with disease phenotypes in the different samples. The main effect was observed for rs7989807 in intron 3, which was strongly associated with SCZ alone and even more so when cases with SCZ and ADHD were combined (P-value = 4×10-5 and 4×10-6, respectively). Associations were also observed with additional markers in intron 3 (combination of SCZ, ADHD and BP), intron 19 (SCZ+BP) and the 39UTR (SCZ+BP). Our results suggest that genetic variants in DCLK1 are associated with SCZ and, to a lesser extent, with ADHD and BP. Interestingly the association is strongest when SCZ and ADHD are considered together, suggesting common genetic susceptibility. Given that DCLK1 variants were previously found to be associated with cognitive traits, these results are consistent with the role of DCLK1 in neurodevelopment and synaptic plasticity. [ABSTRACT FROM AUTHOR]

ABSTRACT Aims Depressive symptomatology can increase risk of development of alcohol problems in young people. Tension reduction and family interactional theories may explain the relationship between depression and problematic alcohol use in youth. This study addresses the nature of the longitudinal relationship between these two behaviours. The available literature is currently inconclusive about whether there are gender differences in these relationships; this is also examined. Design The association between childhood depressive behaviours and adolescence problematic alcohol use was examined using ordered logistic regression models. Evidence of gender differences and the impact of relevant covariates on these relations were examined. Missing data were imputed using a Multiple Imputation by Chained Equation (MICE) approach. Settings The Avon Longitudinal Study of Parents and Children (ALSPAC), a large UK population-based birth cohort. Participants A total of 4220 British boys and girls. Measurements Depressive symptomatology was assessed in childhood (mean age = 10.6, SD = 0.2) using the Short Mood and Feelings Questionnaire (SMFQ). Problematic alcohol use was assessed from several questions queried in adolescence (mean age = 13.8, SD = 0.2). Findings Childhood depressive symptoms were associated with increased risk of problematic alcohol use in early adolescence for girls [odds ratio (OR) = 1.14, P = 0.016] but not boys. This association for girls weakened (OR = 1.12, P = 0.058) when a priori selected covariates were taken into account, particularly the family and greater social environment. Conclusions Problematic alcohol use in girls (but not boys) is associated with prior depressive symptoms. This association may be attributable to several family and social environment factors, suggesting that a family interactional theoretical model may explain these findings. [ABSTRACT FROM AUTHOR]

The Asylum Journal, first published in 1853, is now, as the British Journal of Psychiatry, in its 200th volume. It has changed greatly in its breadth and scope, but its core values and concerns--professional respect, removal of stigma, delivery of care, understanding of pathology, and informed treatment--have remained at its heart throughout. We predict some changes for the future, but not dramatic ones, and conclude that the impinging advances of science will elucidate and refine, but not remove, the need for a journal that is proud to represent psychiatry or, in the words of John Bucknill, its first editor, 'to render prominent its characteristics and to stamp it as a specialty'. [ABSTRACT FROM AUTHOR]

We conducted a combined genome-wide association study (GWAS) of 7,481 individuals with bipolar disorder (cases) and 9,250 controls as part of the Psychiatric GWAS Consortium. Our replication study tested 34 SNPs in 4,496 independent cases with bipolar disorder and 42,422 independent controls and found that 18 of 34 SNPs had P < 0.05, with 31 of 34 SNPs having signals with the same direction of effect (P = 3.8 × 10?7). An analysis of all 11,974 bipolar disorder cases and 51,792 controls confirmed genome-wide significant evidence of association for CACNA1C and identified a new intronic variant in ODZ4. We identified a pathway comprised of subunits of calcium channels enriched in bipolar disorder association intervals. Finally, a combined GWAS analysis of schizophrenia and bipolar disorder yielded strong association evidence for SNPs in CACNA1C and in the region of NEK4-ITIH1-ITIH3-ITIH4. Our replication results imply that increasing sample sizes in bipolar disorder will confirm many additional loci. [ABSTRACT FROM AUTHOR]

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Smith DJ, Griffiths E, Poole R, di Florio A, Barnes E, Kelly MJ, Craddock N, Hood K, Simpson S. Beating Bipolar: exploratory trial of a novel internet-based psychoeducational treatment for bipolar disorder. Bipolar Disord 2011: 13: 571-577. © 2011 The Authors. Journal compilation © 2011 John Wiley & Sons A/S. Objectives: Psychoeducational approaches are promising interventions for the long-term management of bipolar disorder. In consultation with professionals, patients, and their families we have developed a novel web-based psychoeducational intervention for bipolar disorder called Beating Bipolar. We undertook a preliminary exploratory randomized trial to examine efficacy, feasibility and acceptability. Methods: This was an exploratory randomized controlled trial of Beating Bipolar (current controlled trials registration number: ISRCTN81375447). The control arm was treatment-as-usual and the a priori primary outcome measure was quality of life [measured by the brief World Health Organization Quality of Life (WHOQOL-BREF) scale]. Secondary outcomes included psychosocial functioning, insight, depressive and manic symptoms and relapse, and use of healthcare resources. Fifty participants were randomized to either the Beating Bipolar intervention plus treatment-as-usual or just treatment-as-usual. The intervention was delivered over a four-month period and outcomes were assessed six months later. Results: There was no significant difference between the intervention and control groups on the primary outcome measure (total WHOQOL-BREF score) but there was a modest improvement within the psychological subsection of the WHOQOL-BREF for the intervention group relative to the control group. There were no significant differences between the groups on any of the secondary outcome measures. Conclusions: Beating Bipolar is potentially a safe and engaging intervention which can be delivered remotely to large numbers of patients with bipolar disorder at relatively low cost. It may have a modest effect on psychological quality of life. Further work is required to establish the impact of this intervention on insight, knowledge, treatment adherence, self-efficacy and self-management skills. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study was to find loci for major depression via linkage analysis of a large sibling pair sample. Method: The authors conducted a genome-wide linkage analysis of 839 families consisting of 971 affected sibling pairs with severe recurrent major depression, comprising waves I and II of the Depression Network Study cohort. In addition to examining affected status, linkage analyses in the full data set were performed using diagnoses restricted by impairment severity, and association mapping of hits in a large case-control data set was attempted. Results: The authors identified genomewide significant linkage to chromosome 3p25-26 when the diagnoses were restricted by severity, which was a maximum LOD score of 4.0 centered at the linkage marker D3S1515. The linkage signal identified was genome-wide significant after correction for the multiple phenotypes tested, although subsequent association mapping of the region in a genome-wide association study of a U.K. depression sample did not provide significant results. Conclusions: The authors report a genome-wide significant locus for depression that implicates genes that are highly plausible for involvement in the etiology of recurrent depression. Despite the fact that association mapping in the region was negative, the linkage finding was replicated by another group who found genome-wide-significant linkage for depression in the same region. This suggests that 3p25-26 is a new locus for severe recurrent depression. This represents the first report of a genome-wide significant locus for depression that also has an independent genome-wide significant replication. [ABSTRACT FROM AUTHOR]

Background: Bipolar disorder is complex and can be difficult to diagnose. It is often misdiagnosed as recurrent major depressive disorder.Aims: We had three main aims. To estimate the proportion of primary care patients with a working diagnosis of unipolar depression who satisfy DSM-IV criteria for bipolar disorder. To test two screening instruments for bipolar disorder (the Hypomania Checklist (HCL-32) and Bipolar Spectrum Diagnostic Scale (BSDS)) within a primary care sample. To assess whether individuals with major depressive disorder with subthreshold manic symptoms differ from those individuals with major depressive disorder but with no or little history of manic symptoms in terms of clinical course, psychosocial functioning and quality of life.Method: Two-phase screening study in primary care.Results: Three estimates of the prevalence of undiagnosed bipolar disorder were obtained: 21.6%, 9.6% and 3.3%. The HCL-32 and BSDS questionnaires had quite low positive predictive values (50.0 and 30.1% respectively). Participants with major depressive disorder and with a history of subthreshold manic symptoms differed from those participants with no or little history of manic symptoms on several clinical features and on measures of both psychosocial functioning and quality of life.Conclusions: Between 3.3 and 21.6% of primary care patients with unipolar depression may have an undiagnosed bipolar disorder. The HCL-32 and BSDS screening questionnaires may be more useful for detecting broader definitions of bipolar disorder than DSM-IV-defined bipolar disorder. Subdiagnostic features of bipolar disorder are relatively common in primary care patients with unipolar depression and are associated with a more morbid course of illness. Future classifications of recurrent depression should include dimensional measures of bipolar symptoms. [ABSTRACT FROM AUTHOR]

Background: Suicidal behaviour can be conceptualised as a continuum from suicidal ideation, to suicidal attempts to completed suicide. In this study we identify genes contributing to suicidal behaviour in the depression study RADIANT. Methodology/Principal Findings: A quantitative suicidality score was composed of two items from the SCAN interview. In addition, the 251 depression cases with a history of serious suicide attempts were classified to form a discrete trait. The quantitative trait was correlated with younger onset of depression and number of episodes of depression, but not with gender. A genome-wide association study of 2,023 depression cases was performed to identify genes that may contribute to suicidal behaviour. Two Munich depression studies were used as replication cohorts to test the most strongly associated SNPs. No SNP was associated at genome-wide significance level. For the quantitative trait, evidence of association was detected at GFRA1, a receptor for the neurotrophin GDRA (p = 2e-06). For the discrete trait of suicide attempt, SNPs in KIAA1244 and RGS18 attained p-values of <5e-6. None of these SNPs showed evidence for replication in the additional cohorts tested. Candidate gene analysis provided some support for a polymorphism in NTRK2, which was previously associated with suicidality. Conclusions/Significance: This study provides a genome-wide assessment of possible genetic contribution to suicidal behaviour in depression but indicates a genetic architecture of multiple genes with small effects. Large cohorts will be required to dissect this further. [ABSTRACT FROM AUTHOR]

Background: Antidepressants exhibit a variety of pharmacological actions including inhibition of the serotonin and noradrenaline transporters. We wished to investigate whether genetic variation could be used to target or personalise treatment, in a comparison of selective serotonin reuptake inhibitors (SSRIs) with noradrenaline reuptake inhibitors (NARIs).Aims: To test the hypothesis that patients homozygous for the long (insertion) polymorphism of the serotonin transporter (5-HTTLPR) have an increased response to SSRI antidepressants but not to NARI antidepressants.Method: In an individually randomised, parallel-group controlled trial, people meeting criteria for a depressive episode who were referred by their general practitioner were randomised to receive either citalopram (an SSRI) or reboxetine (an NARI). Randomisation was by means of a remote automated system accessed by telephone. The main outcome was depressive symptoms, measured by Beck Depression Inventory (BDI) total score 6 weeks after randomisation. The trial was registered with the International Standard Randomised Controlled Trials Number registry (ISRCTN31345163).Results: Altogether 298 participants were randomised to receive citalopram and 303 were randomised to reboxetine. At 6 weeks follow-up, complete data were available for 258 participants taking citalopram and 262 taking reboxetine. We found no evidence to support an influence of 5-HTTLPR on outcome following antidepressant treatment. The interaction term for BDI score at 6 weeks was 0.50 (95% CI -2.04 to 3.03, P = 0.70), which indicated that responses to the SSRI and NARI were similar irrespective of 5-HTTLPR genotype.Conclusions: It is unlikely that the 5-HTTLPR polymorphism alone will be clinically useful in predicting response to antidepressants in people with depression. [ABSTRACT FROM AUTHOR]