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OBJECTIVE: Associations were examined between six psychiatric diagnoses in parents and a broad range of psychiatric and nonpsychiatric outcomes in their offspring. METHODS: All individuals born in Sweden between 1970 and 2000 were linked to their biological parents (N=3,286,293) through Swedish national registers. A matched cohort design, with stratified Cox regression and conditional logistic regression analyses, was used examine associations between six psychiatric diagnoses in the parents and 32 outcomes in their offspring. All children, including those exposed and those not exposed to parents with psychiatric diagnoses, were followed from their date of birth to the date of emigration from Sweden, death, or December 31, 2013, when the offspring were 14-44 years old. RESULTS: In terms of absolute risk, most children who had parents with psychiatric diagnoses were not diagnosed in specialist care themselves, and the proportion of offspring having any of the 16 types of psychiatric conditions ranged from 22.17% (of offspring exposed to parental depression) to 25.05% (of offspring exposed to parental drug-related disorder) at the end of follow-up. Nevertheless, in terms of relative risk, exposure to any of the six parental psychiatric diagnoses increased probabilities of the 32 outcomes among the offspring, with hazard ratios that ranged from 1.03 to 8.46 for time-to-event outcomes and odds ratios that ranged from 1.29 to 3.36 for binary outcomes. Some specificities were observed for parental diagnoses of psychosis and substance-related disorders, which more strongly predicted psychotic-like and externalizing-related outcomes, respectively, in the offspring. CONCLUSIONS: The intergenerational transmission of parental psychiatric conditions appeared largely transdiagnostic and extended to nonpsychiatric outcomes in offspring. Given the broad spectrum of associations with the outcomes, service providers (e.g., psychiatrists, teachers, and social workers) should consider clients' broader psychiatric family history when predicting prognosis and planning interventions or treatment.
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Filho de Pais com Deficiência , Transtornos Mentais , Sistema de Registros , Humanos , Suécia/epidemiologia , Feminino , Transtornos Mentais/epidemiologia , Transtornos Mentais/psicologia , Filho de Pais com Deficiência/psicologia , Filho de Pais com Deficiência/estatística & dados numéricos , Masculino , Adulto , Adolescente , Adulto Jovem , Pais/psicologiaRESUMO
Importance: Electroconvulsive therapy (ECT), wherein a generalized epileptic seizure is induced, is a treatment for major depressive disorder (MDD). Currently, it is unclear whether there is an association between seizure length and treatment outcome. Objective: To explore the association between seizure duration, potential confounding variables, and ECT treatment outcome. Design, Setting, and Participants: This population-based cohort study obtained data from the Swedish National Quality Register for ECT. Patients treated for unipolar MDD with unilateral electrode placement between January 1, 2012, and December 31, 2019, were included. The electroencephalographic (EEG) seizure duration from the first ECT treatment session for each patient was used for analysis. Data analyses were performed between March 2021 and May 2024. Main Outcomes and Measures: The primary outcome was remission, defined as a cutoff score of less than 10 points on the self-assessment version of the Montgomery-Åsberg Depression Rating Scale within 1 week after ECT. Multivariate logistic regression analysis was performed to calculate odds ratios (ORs) between different seizure duration groups. Furthermore, the associations between concomitant use of pharmacological treatments, seizure duration, and remission rate were explored. Results: Among the 6998 patients included, 4229 (60.4%) were female and the mean (SD) age was 55.2 (18.6) years. Overall, 2749 patients (39.3%) achieved remission after ECT. Patients with EEG seizure duration of 60 to 69 seconds had the highest remission rates compared with patients with seizure duration of less than 20 seconds (OR, 2.17; 95% CI, 1.63-2.88; P < .001). Anticonvulsant medications were associated with shorter seizure duration (eg, lamotrigine: ß coefficient [SE], -6.02 [1.08]; P < .001) and lower remission rates (eg, lamotrigine: adjusted OR, 0.67; 95% CI, 0.53-0.84; P < .001). Conclusions and Relevance: This study found an association between seizure length and remission from MDD. Use of anticonvulsant medication during ECT was associated with shorter seizure duration and lower remission rates after ECT.
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Transtorno Depressivo Maior , Eletroconvulsoterapia , Convulsões , Humanos , Eletroconvulsoterapia/métodos , Feminino , Transtorno Depressivo Maior/terapia , Masculino , Pessoa de Meia-Idade , Convulsões/terapia , Adulto , Idoso , Resultado do Tratamento , Suécia , Eletroencefalografia , Estudos de Coortes , Fatores de Tempo , Sistema de RegistrosRESUMO
The diagnostic criteria of bipolar disorder (BD) have changed over time. To test if these changes are reflected in the polygenic profile in BD, we studied the association between first BD diagnosis year (during 1972-2016) and polygenic scores (PGS) for psychiatric disorders in BD patients (N = 3,818). We found significant associations between diagnosis year and PGS for BD, depression, and attention deficit hyperactivity disorder (ADHD). The PGS remained largely stable over time in BD type 1, while changes were observed in BD type 2. These findings bear significance not only for genetic research but also for clinical practise, as shifts in patient characteristics can influence treatment response.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno Bipolar , Herança Multifatorial , Sistema de Registros , Humanos , Transtorno Bipolar/genética , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/epidemiologia , Masculino , Feminino , Herança Multifatorial/genética , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Pessoa de Meia-Idade , Adulto Jovem , AdolescenteRESUMO
Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.
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Transtorno Bipolar , Imageamento por Ressonância Magnética , Obesidade , Análise de Componente Principal , Humanos , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/patologia , Adulto , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Análise por Conglomerados , Adulto Jovem , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
OBJECTIVE: Many but not all persons with bipolar disorder require hospital care because of severe mood episodes. Likewise, some but not all patients experience long-term occupational dysfunction that extends beyond acute mood episodes. It is not known whether these dissimilar outcomes of bipolar disorder are driven by different polygenic profiles. Here, polygenic scores (PGSs) for major psychiatric disorders and educational attainment were assessed for associations with occupational functioning and psychiatric hospital admissions in bipolar disorder. METHODS: A total of 4,782 patients with bipolar disorder and 2,963 control subjects were genotyped and linked to Swedish national registers. Longitudinal measures from at least 10 years of registry data were used to derive percentage of years without employment, percentage of years with long-term sick leave, and mean number of psychiatric hospital admissions per year. Ordinal regression was used to test associations between outcomes and PGSs for bipolar disorder, schizophrenia, major depressive disorder, attention deficit hyperactivity disorder (ADHD), and educational attainment. Replication analyses of hospital admissions were conducted with data from the Bipolar Disorder Research Network cohort (N=4,219). RESULTS: Long-term sick leave and unemployment in bipolar disorder were significantly associated with PGSs for schizophrenia, ADHD, major depressive disorder, and educational attainment, but not with the PGS for bipolar disorder. By contrast, the number of hospital admissions per year was associated with higher PGSs for bipolar disorder and schizophrenia, but not with the other PGSs. CONCLUSIONS: Bipolar disorder severity (indexed by hospital admissions) was associated with a different polygenic profile than long-term occupational dysfunction. These findings have clinical implications, suggesting that mitigating occupational dysfunction requires interventions other than those deployed to prevent mood episodes.
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Transtorno Bipolar , Transtorno Depressivo Maior , Herança Multifatorial , Sistema de Registros , Licença Médica , Humanos , Transtorno Bipolar/genética , Transtorno Bipolar/epidemiologia , Masculino , Feminino , Herança Multifatorial/genética , Adulto , Suécia/epidemiologia , Licença Médica/estatística & dados numéricos , Pessoa de Meia-Idade , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/epidemiologia , Hospitalização/estatística & dados numéricos , Escolaridade , Desemprego/estatística & dados numéricos , Esquizofrenia/genética , Esquizofrenia/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Estudos Longitudinais , Estudos de Casos e ControlesRESUMO
OBJECTIVE: To determine whether the rates of readmissions and suicide vary in psychotic unipolar depression based on whether patients receive maintenance electroconvulsive therapy (M-ECT) following the initial series of ECT, and to examine if there is an age-dependent association. METHODS: We used Swedish national registries to identify hospitalized patients with psychotic unipolar depression, treated 2008-2019 who received ECT during their hospital stay. The patients who received subsequent M-ECT within 14 days after discharge were compared with those who did not. The primary composite outcome was time to readmission due to a psychiatric disorder, suicide attempt, or suicide within 2 years from discharge. Data were analyzed using Cox regression adjusted for previous psychiatric admissions, age, sex, comorbidity, and pharmacological treatment. We also conducted a within-individual analysis using the sign-test, with patients having ≥1 hospital episode followed by M-ECT and ≥1 hospital episode without M-ECT. RESULTS: A total of 1873 patients were included, of which 130 received M-ECT. There was no statistically significant group difference regarding the primary outcome in the whole sample. However, when stratified by age, there was a significant difference in favor of M-ECT for patients >65 years (adjusted hazard ratio 0.55, 95% confidence interval 0.35-0.87). The within-individual analysis, including 46 patients, significantly favored M-ECT. CONCLUSION: M-ECT was not associated with a differential risk of the composite of readmission and suicide in psychotic depression. Among patients >65 years, M-ECT was significantly associated with a decreased risk of the outcome. The possibility of residual confounding cannot be excluded.
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Eletroconvulsoterapia , Readmissão do Paciente , Sistema de Registros , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Suécia/epidemiologia , Readmissão do Paciente/estatística & dados numéricos , Adulto , Tentativa de Suicídio/estatística & dados numéricos , Transtornos Psicóticos/terapia , Transtornos Psicóticos/epidemiologia , Fatores Etários , Idoso de 80 Anos ou maisRESUMO
OBJECTIVE: The majority of patients hospitalized for treatment of a manic episode are readmitted within 2 years despite maintenance treatment. Electroconvulsive therapy (ECT) has been associated with lower rehospitalization rates in some psychiatric conditions, but its association with readmission after a manic episode has not been investigated. Therefore, the aim of this study was to determine whether the time to readmission in patients with mania treated with ECT was longer than in patients not treated with ECT and whether there were subgroups of patients that benefited more. METHODS: This was a nationwide register-based, observational study. All patients diagnosed with bipolar disorder, manic episode, admitted to any hospital in Sweden between 2012 and 2021 were included. Patients contributed data to the study for every admission. All admissions were followed up until psychiatric readmission, death, or the end of the study (December 31, 2021). Association between ECT and time to readmission was analyzed. A paired samples model was performed for 377 patients with at least two admissions for mania, treated with ECT at one admission and without ECT at the other admission. Times to readmission were analyzed. RESULTS: A total of 12,337 admissions were included; mean (SD) age 47.7 (17.2), 5443 (44.1%) men. Readmission rate within 1 year was 54.6%. ECT was administered in 902 (7.3%) admissions. Within 30 days after admission, 182 out of 894 (20.4%) patients treated with ECT versus 2105 out of 11,305 (18.6%) patients treated without ECT were readmitted. There was no association between ECT and time to readmission (aHR 1.00, 95% CI 0.86-1.16, p = 0.992) in the model with all admissions. The paired samples model included 754 admissions (377 patients), mean (SD) age during admission without ECT was 45.6 (16.5), and with ECT 46.6 (16.4), 147 (39.0%) were men. In that model, readmission rate within 30 days for treatment with ECT was 19.0%, and for treatments without ECT, 24.1% (aHR 0.75, 95% CI 0.55-1.02, p = 0.067). CONCLUSION: Readmission rates after inpatient treatment of mania were high. ECT was not significantly associated with longer time to readmission, but there was a trend toward a protective effect of ECT when admissions with and without ECT were compared within the same patients.
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Transtorno Bipolar , Eletroconvulsoterapia , Readmissão do Paciente , Humanos , Eletroconvulsoterapia/estatística & dados numéricos , Readmissão do Paciente/estatística & dados numéricos , Masculino , Feminino , Transtorno Bipolar/terapia , Pessoa de Meia-Idade , Adulto , Suécia/epidemiologia , Sistema de Registros , Fatores de Tempo , Idoso , Mania/terapiaAssuntos
Disforia de Gênero , Puberdade , Humanos , Disforia de Gênero/psicologia , Criança , Feminino , Puberdade/psicologia , Masculino , Adolescente , Supressão da PuberdadeRESUMO
BACKGROUND: Offspring of parents with bipolar disorder have increased risks of their own psychopathology. However, a large-scale survey of psychiatric, somatic, and adverse social outcomes up to adulthood, which could aid in prioritizing and tailoring prevention, is lacking. It also remains to clarify how risks are modified by other parental factors. METHODS: Swedish population registers were linked to compare offspring having (N = 24,788) and not having (N = 247,880) a parent with bipolar disorder with respect to psychiatric diagnoses and psychotropic medication, birth-related and somatic conditions, social outcomes, accidents, suicide attempts, and mortality. Individuals were followed until age 18. We estimated the influence of lifetime parental psychiatric comorbidity, bipolar disorder subtype, and sex on outcomes. RESULTS: Children of parents with bipolar disorder had 2-3 times higher risks of all psychiatric diagnoses, except for bipolar disorder, for which the risk was 11-fold. Significantly increased risks were also found for several somatic conditions, low school grades, criminal behavior, victimization, accidents, and suicidal behavior. Adjusting for lifetime parental psychiatric comorbidity attenuated most associations. Offspring of a parent with bipolar disorder type 2 had statistically significantly higher risks of attention deficit hyperactivity disorder, respiratory tract conditions, and accidents compared with offspring of a parent with bipolar disorder type 1. Offspring of mothers with bipolar disorder had higher risks of several psychiatric diagnoses, respiratory tract conditions, low school grades, and accidents compared with offspring of fathers with bipolar disorder. Having two parents with bipolar disorder entailed the highest risks of psychiatric outcomes in offspring. CONCLUSIONS: Early intervention and family support are particularly warranted for the offspring of a parent with bipolar disorder in the presence of lifetime parental psychiatric comorbidity, when the parent has bipolar disorder type 2, or when the mother or both parents have bipolar disorder.
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To date, four genome-wide association studies (GWAS) of obsessive-compulsive disorder (OCD) have been published, reporting a high single-nucleotide polymorphism (SNP)-heritability of 28% but finding only one significant SNP. A substantial increase in sample size will likely lead to further identification of SNPs, genes, and biological pathways mediating the susceptibility to OCD. We conducted a GWAS meta-analysis with a 2-3-fold increase in case sample size (OCD cases: N = 37,015, controls: N = 948,616) compared to the last OCD GWAS, including six previously published cohorts (OCGAS, IOCDF-GC, IOCDF-GC-trio, NORDiC-nor, NORDiC-swe, and iPSYCH) and unpublished self-report data from 23andMe Inc. We explored the genetic architecture of OCD by conducting gene-based tests, tissue and celltype enrichment analyses, and estimating heritability and genetic correlations with 74 phenotypes. To examine a potential heterogeneity in our data, we conducted multivariable GWASs with MTAG. We found support for 15 independent genome-wide significant loci (14 new) and 79 protein-coding genes. Tissue enrichment analyses implicate multiple cortical regions, the amygdala, and hypothalamus, while cell type analyses yielded 12 cell types linked to OCD (all neurons). The SNP-based heritability of OCD was estimated to be 0.08. Using MTAG we found evidence for specific genetic underpinnings characteristic of different cohort-ascertainment and identified additional significant SNPs. OCD was genetically correlated with 40 disorders or traits-positively with all psychiatric disorders and negatively with BMI, age at first birth and multiple autoimmune diseases. The GWAS meta-analysis identified several biologically informative genes as important contributors to the aetiology of OCD. Overall, we have begun laying the groundwork through which the biology of OCD will be understood and described.
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Background: Accurate diagnosis of bipolar disorder (BD) is difficult in clinical practice, with an average delay between symptom onset and diagnosis of about 7 years. A key reason is that the first manic episode is often preceded by a depressive one, making it difficult to distinguish BD from unipolar major depressive disorder (MDD). Aims: Here, we use genome-wide association analyses (GWAS) to identify differential genetic factors and to develop predictors based on polygenic risk scores that may aid early differential diagnosis. Methods: Based on individual genotypes from case-control cohorts of BD and MDD shared through the Psychiatric Genomics Consortium, we compile case-case-control cohorts, applying a careful merging and quality control procedure. In a resulting cohort of 51,149 individuals (15,532 BD cases, 12,920 MDD cases and 22,697 controls), we perform a variety of GWAS and polygenic risk scores (PRS) analyses. Results: While our GWAS is not well-powered to identify genome-wide significant loci, we find significant SNP-heritability and demonstrate the ability of the resulting PRS to distinguish BD from MDD, including BD cases with depressive onset. We replicate our PRS findings, but not signals of individual loci in an independent Danish cohort (iPSYCH 2015 case-cohort study, N=25,966). We observe strong genetic correlation between our case-case GWAS and that of case-control BD. Conclusions: We find that MDD and BD, including BD with a depressive onset, are genetically distinct. Further, our findings support the hypothesis that Controls - MDD - BD primarily lie on a continuum of genetic risk. Future studies with larger and richer samples will likely yield a better understanding of these findings and enable the development of better genetic predictors distinguishing BD and, importantly, BD with depressive onset from MDD.
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Recent evidence has implicated complement component (C) 4A in excessive elimination of synapses in schizophrenia. C4A is believed to contribute to physiological synapse removal through signaling within the C1q initiated classical activation axis of the complement system. So far, a potential involvement of C1q in the pathophysiology of schizophrenia remains unclear. In this study, we first utilized large-scale gene expression datasets (n = 586 patients with schizophrenia and n = 986 controls) to observe lower C1QA mRNA expression in prefrontal cortex tissue of individuals with schizophrenia (P = 4.8x10-05), while C1QA seeded co-expression networks displayed no enrichment for schizophrenia risk variants beyond C4A. We then used targeted liquid chromatography-mass spectrometry (LS-MS) to measure cerebrospinal fluid (CSF) levels of C1qA in 113 individuals with first-episode psychosis (FEP), among which 66 individuals was later diagnosed with schizophrenia, and 87 healthy controls. CSF concentrations of C1qA were lower in individuals diagnosed with FEP (P = 0.0001), also after removing subjects with a short-term prescription of an antipsychotic agent (P = 0.0005). We conclude that C1q mRNA and protein levels are lower in schizophrenia and that further experimental studies are needed to understand the functional implications.
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Antipsicóticos , Transtornos Psicóticos , Esquizofrenia , Humanos , Complemento C1q , Antipsicóticos/uso terapêutico , RNA MensageiroRESUMO
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.
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BACKGROUND: Angioedema is a rare but potentially life-threatening adverse drug reaction in patients receiving angiotensin-converting enzyme inhibitors (ACEis). Research suggests that susceptibility to ACEi-induced angioedema (ACEi-AE) involves both genetic and nongenetic risk factors. Genome- and exome-wide studies of ACEi-AE have identified the first genetic risk loci. However, understanding of the underlying pathophysiology remains limited. OBJECTIVE: We sought to identify further genetic factors of ACEi-AE to eventually gain a deeper understanding of its pathophysiology. METHODS: By combining data from 8 cohorts, a genome-wide association study meta-analysis was performed in more than 1000 European patients with ACEi-AE. Secondary bioinformatic analyses were conducted to fine-map associated loci, identify relevant genes and pathways, and assess the genetic overlap between ACEi-AE and other traits. Finally, an exploratory cross-ancestry analysis was performed to assess shared genetic factors in European and African-American patients with ACEi-AE. RESULTS: Three genome-wide significant risk loci were identified. One of these, located on chromosome 20q11.22, has not been implicated previously in ACEi-AE. Integrative secondary analyses highlighted previously reported genes (BDKRB2 [bradykinin receptor B2] and F5 [coagulation factor 5]) as well as biologically plausible novel candidate genes (PROCR [protein C receptor] and EDEM2 [endoplasmic reticulum degradation enhancing alpha-mannosidase like protein 2]). Lead variants at the risk loci were found with similar effect sizes and directions in an African-American cohort. CONCLUSIONS: The present results contributed to a deeper understanding of the pathophysiology of ACEi-AE by (1) providing further evidence for the involvement of bradykinin signaling and coagulation pathways and (2) suggesting, for the first time, the involvement of the fibrinolysis pathway in this adverse drug reaction. An exploratory cross-ancestry comparison implicated the relevance of the associated risk loci across diverse ancestries.
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Angioedema , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Estudo de Associação Genômica Ampla , Angioedema/induzido quimicamente , Angioedema/genética , BradicininaRESUMO
Current genetic research on obsessive-compulsive disorder (OCD) supports contributions to risk specifically from common single nucleotide variants (SNVs), along with rare coding SNVs and small insertion-deletions (indels). The contribution to OCD risk from large, rare copy number variants (CNVs), however, has not been formally assessed at a similar scale. Here we describe an analysis of rare CNVs called from genotype array data in 2,248 deeply phenotyped OCD cases and 3,608 unaffected controls from Sweden and Norway. We found that in general cases carry an elevated burden of large (>30kb, at least 15 probes) CNVs (OR=1.12, P=1.77×10-3). The excess rate of these CNVs in cases versus controls was around 0.07 (95% CI 0.02-0.11, P=2.58×10-3). This signal was largely driven by CNVs overlapping protein-coding regions (OR=1.19, P=3.08×10-4), particularly deletions impacting loss-of-function intolerant genes (pLI>0.995, OR=4.12, P=2.54×10-5). We did not identify any specific locus where CNV burden was associated with OCD case status at genome-wide significance, but we noted non-random recurrence of CNV deletions in cases (permutation P = 2.60×10-3). In cases where sufficient clinical data were available (n=1612) we found that carriers of neurodevelopmental duplications were more likely to have comorbid autism (P<0.001), and that carriers of deletions overlapping neurodevelopmental genes had lower treatment response (P=0.02). The results demonstrate a contribution of large, rare CNVs to OCD risk, and suggest that studies of rare coding variation in OCD would have increased power to identify risk genes if this class of variation were incorporated into formal tests.
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Importance: Antidepressants are increasingly prescribed to pediatric patients with unipolar depression, but little is known about the risk of treatment-emergent mania. Previous research suggests pediatric patients may be particularly vulnerable to this adverse outcome. Objective: To estimate whether pediatric patients treated with antidepressants have an increased incidence of mania/hypomania compared with patients not treated with antidepressants and to identify patient characteristics associated with the risk of mania/hypomania. Design, Setting, and Participants: In a cohort study applying the target trial emulation framework, nationwide inpatient and outpatient care in Sweden from July 1, 2006, to December 31, 2019, was evaluated. Follow-up was conducted for 12 and 52 weeks after treatment initiation, with administrative follow-up ending December 31, 2020. Data were analyzed between May 1, 2022, and June 28, 2023. Individuals aged 4 to 17 years with a diagnosis of depression, but without a prior diagnosis of mania/hypomania, bipolar disorder, or psychosis or treatment with mood stabilizer (lithium, valproate, or carbamazepine), prescriptions were included. Exposures: The treatment group included patients who initiated any antidepressant medication within 90 days of diagnosis. The control group included patients who did not initiate antidepressants within 90 days. Main Outcomes and Measures: Diagnosis of mania/hypomania or initiation of mood stabilizer therapy. Incidences were estimated with Kaplan-Meier estimator, and inverse probability of treatment weighting was used to adjust for group differences at baseline. Results: The cohort included 43â¯677 patients (28 885 [66%] girls); 24â¯573 in the treatment group and 19â¯104 in the control group. The median age was 15 (IQR, 14-16) years. The outcome occurred in 96 individuals by 12 weeks and in 291 by 52 weeks. The cumulative incidence of mania was 0.26% (95% CI, 0.19%-0.33%) in the treatment group and 0.20% (95% CI, 0.13%-0.27%) in the control group at 12 weeks, with a risk difference of 0.06% (95% CI, -0.04% to 0.16%). At 52 weeks, the cumulative incidence was 0.79% (95% CI, 0.68%-0.91%) in the treatment group and 0.52% (95% CI, 0.40%-0.63%) in the control group (risk difference, 0.28%; 95% CI, 0.12%-0.44%). Hospitalizations, parental bipolar disorder, and use of antipsychotics and antiepileptics were the most important predictors of mania/hypomania by 12 weeks. Conclusion: This cohort study found no evidence of treatment-emergent mania/hypomania by 12 weeks in children and adolescents. This corresponds to the time frame for antidepressants to exert their psychotropic effect. A small risk difference was found only with longer follow-up. Certain patient characteristics were associated with mania/hypomania, which warrants clinical attention.
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Antipsicóticos , Transtorno Depressivo , Feminino , Humanos , Adolescente , Criança , Masculino , Mania , Estudos de Coortes , Depressão , Antidepressivos/efeitos adversos , Transtorno Depressivo/tratamento farmacológico , Transtorno Depressivo/epidemiologia , Antipsicóticos/uso terapêuticoRESUMO
OBJECTIVE: The aims of this study were to investigate secular trends and distribution of body mass index (BMI) among individuals with bipolar disorders and the general population between 2008 and 2019. METHODS: Data were from the Swedish National Quality Register for Bipolar Disorder, where 24,423 adults with bipolar disorders were identified, and from the national Swedish Living Conditions Surveys, where 77,485 adults from the general population were identified. Quantile regression was used to compare the 15th, 50th, and 85th percentiles of BMI across age and study years. RESULTS: The study sample included 22,127 individuals with bipolar disorders (mean age, 48 years; 63% women) and 71,894 individuals from the general population (mean age, 52 years; 51% women). BMI percentiles were higher among individuals with bipolar disorders. At the 50th percentile, the BMI group differences were 1.1 (95% CI=0.8-1.14) for men and 1.8 (95% CI=1.5-2.1) for women. The gap was widest at the 85th BMI percentile: men, 2.3 (95% CI=1.8-2.8); women, 4.1 (95% CI=3.7-4.6). BMI increased over time in both study groups, but more in the group with bipolar disorders. The changes per decade in mean BMI were 0.4 (95% CI=0.3-0.5) among men in the general population, 1.1 (95% CI=0.7-1.4) among men with bipolar disorders, 0.6 (95% CI=0.5-0.7) among women in the general population, and 1.4 (95% CI=1.1-1.7) among women with bipolar disorders. Women with bipolar disorders had the highest prevalence and the greatest rate of increase of obesity. In 2019, the obesity prevalence was 33% among women and 29% among men with bipolar disorders, compared with 13% and 15%, respectively, among women and men in the general population. CONCLUSIONS: Adults with bipolar disorders had a higher BMI and a higher prevalence of obesity than the general population, indicating a higher cardiometabolic risk. Annually, BMI increased more in the group with bipolar disorders than in the general population, particularly among women and among those with high BMI.
Assuntos
Transtorno Bipolar , Adulto , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Índice de Massa Corporal , Transtorno Bipolar/epidemiologia , Obesidade/epidemiologia , Prevalência , Suécia/epidemiologiaRESUMO
The genetic overlap between schizophrenia (SZ) and bipolar disorder (BD) is substantial. Polygenic risk scores have been shown to dissect different symptom dimensions within and across these two disorders. Here, we focused on the most strongly associated SZ risk locus located in the extended MHC region, which is largely explained by copy numbers of the gene coding for complement component 4A (C4A). First, we utilized existing brain tissue collections (N = 1,202 samples) and observed no altered C4A expression in BD samples. The generated C4A seeded co-expression networks displayed no genetic enrichment for BD. To study if genetically predicted C4A expression discriminates between subphenotypes of BD, we applied C4A expression scores to symptom dimensions in a total of 4,739 BD cases with deep phenotypic data. We identified a significant association between C4A expression and psychotic mood episodes in BD type 1 (BDI). No significant association was observed between C4A expression and the occurrence of non-affective psychotic episodes in BDI, the psychosis dimensions in the total BD sample, or any other subphenotype of BD. Overall, these results points to a distinct role of C4A in BD that is restricted to vulnerability for developing psychotic symptoms during mood episodes in BDI.