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The response to lithium for the treatment of bipolar disease is variable. This genetic study showed a strong association between variants in GADL1 and response to treatment in Han Chinese patients with bipolar I disease. Bipolar disorder is a disabling mental illness that is characterized by episodes of both elevated or irritable mood and depression. 1 , 2 Currently, lithium is the first-line choice for maintenance treatment of bipolar disorder and reduces the risks of relapse and suicide. 3 – 5 Approximately 80% of patients with bipolar I disorder who are treated with lithium over the long term have at least a partial response, 6 and 30% have an excellent response 7 , 8 with complete remission of symptoms observed in populations of patients of European descent. Clinical predictors of a good response to lithium treatment have been reported, such as age . . .

BackgroundThe genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses.MethodsTo calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives.ResultsThe PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ.ConclusionsThese findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

We assessed whether the risk of various psychotic disorders and non-psychotic bipolar disorder (including mania) varied by migrant status, a region of origin, or age-at-migration, hypothesizing that risk would only be elevated for psychotic disorders. We established a prospective cohort of 1 796 257 Swedish residents born between 1982 and 1996, followed from their 15th birthday, or immigration to Sweden after age 15, until diagnosis, emigration, death, or end of 2011. Cox proportional hazards models were used to model hazard ratios by migration-related factors, adjusted for covariates. All psychotic disorders were elevated among migrants and their children compared with Swedish-born individuals, including schizophrenia and schizoaffective disorder (adjusted hazard ratio [aHR]migrants: 2.20, 95% CI 1.96-2.47; aHRchildren : 2.00, 95% CI 1.79-2.25), affective psychotic disorders (aHRmigrant1.42, 95% CI 1.25-1.63; aHRchildren: 1.22 95% CI 1.07-1.40), and other non-affective psychotic disorders (aHRmigrant: 1.97, 95% CI 1.81-2.14; aHRchildren: 1.68, 95% CI 1.54-1.83). For all psychotic disorders, risks were generally highest in migrants from Africa (i.e. aHRschizophrenia: 5.24, 95% CI 4.26-6.45) and elevated at most ages-of-migration. By contrast, risk of non-psychotic bipolar disorders was lower for migrants (aHR: 0.58, 95% CI 0.52-0.64) overall, and across all ages-of-migration except infancy (aHR: 1.20; 95% CI 1.01-1.42), while risk for their children was similar to the Swedish-born population (aHR: 1.00, 95% CI 0.93-1.08). Increased risk of psychiatric disorders associated with migration and minority status may be specific to psychotic disorders, with exact risk dependent on the region of origin.

To investigate the association of midlife and late-life undiagnosed mood symptoms, especially their comorbidity, with long-term dementia risk among multi-regional and ethnic adults. The prospective study used data from the UK Biobank ( = 142,670; mean follow-up 11.0 years) and three Asian studies ( = 1,610; mean follow-up 4.4 years). Undiagnosed mood symptoms (manic symptoms, depressive symptoms and comorbidity of depressive and manic symptoms) and diagnosed mood disorders (depression, mania and bipolar disorders) were classified. Plasma levels of 168 metabolites were measured. The association between undiagnosed mood symptoms and 12-year dementia (including subtypes) risk and domain-specific cognitive function was examined. The contribution of metabolites in explaining the association between symptom comorbidity and dementia risk was estimated. Undiagnosed mood symptoms were prevalent (11.4% in the UK cohort and 31.2% in Asian cohorts) among 1,462 (1.0%) and 74 (19.4%) participants who developed dementia. Comorbidity of undiagnosed mood symptoms was associated with higher dementia risk (sub-distribution hazard ratios = 9.46; 95% confidence interval = 4.07-21.97), especially Alzheimer's disease, and with worse reasoning ability, poorer numeric memory and metabolic dysfunction. Glucose and total Esterified Cholesterol explained 9.1% of the association between symptom comorbidity and dementia, with most of the contribution being from glucose (6.8%). Comorbidity of undiagnosed mood symptoms was associated with a higher cumulative risk of dementia in the long term. Glucose metabolism could be implicated in the development of mood disorders and dementia. The distinctive pathophysiological mechanism between psychiatric and neurodegenerative disorders warrants further exploration.

Risk for mood and anxiety disorders associated with US-nativity may vary across immigrant groups. Using data from the National Epidemiological Study of Alcohol and Related Conditions (NESARC), we examined the association of lifetime risk for mood and anxiety disorders with US-nativity and age at immigration across seven subgroups of the US population defined by country or region of ancestral origin: Mexico, Puerto-Rico, Cuba, Central and South America, Western Europe, Eastern Europe, and Africa and the Caribbean. Discrete time survival models were used to compare lifetime risk between the US-born, immigrants who arrived in the USA prior to the age of 13 years and immigrants who arrived in the USA at the age of 13 years or older. The association of risk for mood and anxiety disorders with US-nativity varies significantly across ancestral origin groups (p<0.001). Among people from Mexico, Eastern Europe, and Africa or the Caribbean, risk for disorders is lower relative to the US-born among immigrants who arrived at the age of 13 years or higher (odds ratios in the range 0.34-0.49) but not among immigrants who arrived prior to the age of 13 years. There is no association between US-nativity and risk for disorder among people from Western Europe and Puerto Rico. Low risk among immigrants relative to the US-born is limited to groups among whom risk for mood and anxiety disorder is low in immigrants who spent their pre-adolescent years outside of the USA.

Objectives(1) To explore the role of ethnicity in receiving cognitive–behavioural therapy (CBT) for people with psychosis or bipolar disorder while adjusting for differences in risk profiles and symptom severity. (2) To assess whether context of treatment (inpatient vs community) impacts on the relationship between ethnicity and access to CBT.DesignCohort study of case register data from one catchment area (January 2007–July 2017).SettingA large secondary care provider serving an ethnically diverse population in London.ParticipantsData extracted for 30 497 records of people who had diagnoses of bipolar disorder (International Classification of Diseases (ICD) code F30-1) or psychosis (F20–F29 excluding F21). Exclusion criteria were: <15 years old, missing data and not self-defining as belonging to one of the larger ethnic groups. The sample (n=20 010) comprised the following ethnic groups: white British: n=10 393; Black Caribbean: n=5481; Black African: n=2817; Irish: n=570; and ‘South Asian’ people (consisting of Indian, Pakistani and Bangladeshi people): n=749.Outcome assessmentsORs for receipt of CBT (single session or full course) as determined via multivariable logistic regression analyses.ResultsIn models adjusted for risk and severity variables, in comparison with White British people; Black African people were less likely to receive a single session of CBT (OR 0.73, 95% CI 0.66 to 0.82, p<0.001); Black Caribbean people were less likely to receive a minimum of 16-sessions of CBT (OR 0.83, 95% CI 0.71 to 0.98, p=0.03); Black African and Black Caribbean people were significantly less likely to receive CBT while inpatients (respectively, OR 0.76, 95% CI 0.65 to 0.89, p=0.001; OR 0.83, 95% CI 0.73 to 0.94, p=0.003).ConclusionsThis study highlights disparity in receipt of CBT from a large provider of secondary care in London for Black African and Caribbean people and that the context of therapy (inpatient vs community settings) has a relationship with disparity in access to treatment.

To identify bipolar disorder (BD) genetic susceptibility factors, we conducted two genome-wide association (GWA) studies: one involving a sample of individuals of European ancestry (EA; n =1001 cases; n =1033 controls), and one involving a sample of individuals of African ancestry (AA; n =345 cases; n =670 controls). For the EA sample, single-nucleotide polymorphisms (SNPs) with the strongest statistical evidence for association included rs5907577 in an intergenic region at Xq27.1 ( P =1.6 × 10 −6 ) and rs10193871 in NAP5 at 2q21.2 ( P =9.8 × 10 −6 ). For the AA sample, SNPs with the strongest statistical evidence for association included rs2111504 in DPY19L3 at 19q13.11 ( P =1.5 × 10 −6 ) and rs2769605 in NTRK2 at 9q21.33 ( P =4.5 × 10 −5 ). We also investigated whether we could provide support for three regions previously associated with BD, and we showed that the ANK3 region replicates in our sample, along with some support for C15Orf53 ; other evidence implicates BD candidate genes such as SLITRK2 . We also tested the hypothesis that BD susceptibility variants exhibit genetic background-dependent effects. SNPs with the strongest statistical evidence for genetic background effects included rs11208285 in ROR1 at 1p31.3 ( P =1.4 × 10 −6 ), rs4657247 in RGS5 at 1q23.3 ( P =4.1 × 10 −6 ), and rs7078071 in BTBD16 at 10q26.13 ( P =4.5 × 10 −6 ). This study is the first to conduct GWA of BD in individuals of AA and suggests that genetic variations that contribute to BD may vary as a function of ancestry.

Meta-analyses of bipolar disorder (BD) genome-wide association studies (GWAS) have identified several genome-wide significant signals in European-ancestry samples, but so far account for little of the inherited risk. We performed a meta-analysis of ∼750 000 high-quality genetic markers on a combined sample of ∼14 000 subjects of European and Asian-ancestry (phase I). The most significant findings were further tested in an extended sample of ∼17 700 cases and controls (phase II). The results suggest novel association findings near the genes TRANK1 ( LBA1 ), LMAN2L and PTGFR . In phase I, the most significant single nucleotide polymorphism (SNP), rs9834970 near TRANK1 , was significant at the P =2.4 × 10 −11 level, with no heterogeneity. Supportive evidence for prior association findings near ANK3 and a locus on chromosome 3p21.1 was also observed. The phase II results were similar, although the heterogeneity test became significant for several SNPs. On the basis of these results and other established risk loci, we used the method developed by Park et al. to estimate the number, and the effect size distribution, of BD risk loci that could still be found by GWAS methods. We estimate that >63 000 case–control samples would be needed to identify the ∼105 BD risk loci discoverable by GWAS, and that these will together explain <6% of the inherited risk. These results support previous GWAS findings and identify three new candidate genes for BD. Further studies are needed to replicate these findings and may potentially lead to identification of functional variants. Sample size will remain a limiting factor in the discovery of common alleles associated with BD.

We report the first genome-wide association study in 1000 bipolar I patients and 1000 controls, with a replication of the top hits in another 409 cases and 1000 controls in the Han Chinese population. Four regions with most strongly associated single-nucleotide polymorphisms (SNPs) were detected, of which three were not found in previous GWA studies in the Caucasian populations. Among them, SNPs close to specificity protein 8 ( SP8 ) and ST8 α- N -acetyl- neuraminide α-2,8-sialyltransferase ( ST8SIA2 ) are associated with Bipolar I, with P -values of 4.87 × 10 −7 (rs2709736) and 6.05 × 10 −6 (rs8040009), respectively. We have also identified SNPs in potassium channel tetramerization domain containing 12 gene ( KCTD12 ) (rs2073831, P =9.74 × 10 −6 ) and in CACNB2 (Calcium channel, voltage-dependent, β-2 subunit) gene (rs11013860, P =5.15 × 10 −5 ), One SNP nearby the rs1938526 SNP of ANK3 gene and another SNP nearby the SNP rs11720452 in chromosome 3 reported in previous GWA studies also showed suggestive association in this study ( P =6.55 × 10 −5 and P =1.48 × 10 −5 , respectively). This may suggest that there are common and population-specific susceptibility genes for bipolar I disorder.

Background In order to support evidence-based policies for reduction of stigma, a better understanding of its components: ignorance (knowledge), prejudice (attitude) and discrimination (behaviour) is necessary. This study explores public perceptions and quantifies stigma for three chronic mental disorders: autism, schizophrenia and bipolar disorders in France. Methods Survey of 1000 adults selected from an established market research panel. The 21-item questionnaire explored knowledge, attitudes and behaviours toward each disorder. Results Although 95% respondents recognized the names of each disorder fewer than 70% could report specific characteristics and only 33% considered that publically available information was adequate; most respondents identified the media as their main resource. Labeling of conditions in a negative way was frequent (61%) when referring to mental disorders in general, but fell significantly (18%) when linked to an individual with a disorder. Individuals with schizophrenia are assumed to be dangerous; 65% respondents would engage in social distancing from such an individual, versus 29% for bipolar disorders and 7% for autism (p < 0.001). In contrast to other disorders, discrimination against schizophrenia was only partly attenuated in those with familiarity with mental disorders (through personal or family illness). Conclusion This first population-based survey in France shows that attitudes towards bipolar disorders and autism are less prejudicial than towards schizophrenia. However, most public attitudes and behaviours towards different disorders appear to be based on assumptions rather than knowledge or evidence suggesting a generic information or anti-stigma programme is unlikely to be effective.