Background: Depression is commonly perceived as a single underlying disease with a number of potential treatment options. However, patients with major depression differ dramatically in their... Show moreBackground: Depression is commonly perceived as a single underlying disease with a number of potential treatment options. However, patients with major depression differ dramatically in their symptom presentation and comorbidities, e.g. with anxiety disorders. There are also large variations in treatment outcomes and associations of some anxiety comorbidities with poorer prognoses, but limited understanding as to why, and little information to inform the clinical management of depression. There is a need to improve our understanding of depression, incorporating anxiety comorbidity, and consider the association of a wide range of symptoms with treatment outcomes. Method: Individual patient data from six RCTs of depressed patients (total n = 2858) were used to estimate the differential impact symptoms have on outcomes at three post intervention time points using individual items and sum scores. Symptom networks (graphical Gaussian model) were estimated to explore the functional relations among symptoms of depression and anxiety and compare networks for treatment remitters and those with persistent symptoms to identify potential prognostic indicators. Results: Item-level prediction performed similarly to sum scores when predicting outcomes at 3 to 4 months and 6 to 8 months, but outperformed sum scores for 9 to 12 months. Pessimism emerged as the most important predictive symptom (relative to all other symptoms), across these time points. In the network structure at study entry, symptoms clustered into physical symptoms, cognitive symptoms, and anxiety symptoms. Sadness, pessimism, and indecision acted as bridges between communities, with sadness and failure/worthlessness being the most central (i.e. interconnected) symptoms. Connectivity of networks at study entry did not differ for future remitters vs. those with persistent symptoms. Conclusion: The relative importance of specific symptoms in association with outcomes and the interactions within the network highlight the value of transdiagnostic assessment and formulation of symptoms to both treatment and prognosis. We discuss the potential for complementary statistical approaches to improve our understanding of psychopathology. Show less
Background This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data. Methods Individual... Show moreBackground This study aimed to develop, validate and compare the performance of models predicting post-treatment outcomes for depressed adults based on pre-treatment data. Methods Individual patient data from all six eligible randomised controlled trials were used to develop (k = 3, n = 1722) and test (k = 3, n = 918) nine models. Predictors included depressive and anxiety symptoms, social support, life events and alcohol use. Weighted sum scores were developed using coefficient weights derived from network centrality statistics (models 1-3) and factor loadings from a confirmatory factor analysis (model 4). Unweighted sum score models were tested using elastic net regularised (ENR) and ordinary least squares (OLS) regression (models 5 and 6). Individual items were then included in ENR and OLS (models 7 and 8). All models were compared to one another and to a null model (mean post-baseline Beck Depression Inventory Second Edition (BDI-II) score in the training data: model 9). Primary outcome: BDI-II scores at 3-4 months. Results Models 1-7 all outperformed the null model and model 8. Model performance was very similar across models 1-6, meaning that differential weights applied to the baseline sum scores had little impact. Conclusions Any of the modelling techniques (models 1-7) could be used to inform prognostic predictions for depressed adults with differences in the proportions of patients reaching remission based on the predicted severity of depressive symptoms post-treatment. However, the majority of variance in prognosis remained unexplained. It may be necessary to include a broader range of biopsychosocial variables to better adjudicate between competing models, and to derive models with greater clinical utility for treatment-seeking adults with depression. Show less
BACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a... Show moreBACKGROUND: The prevalence of depression is higher in individuals with autoimmune diseases, but the mechanisms underlying the observed comorbidities are unknown. Shared genetic etiology is a plausible explanation for the overlap, and in this study we tested whether genetic variation in the major histocompatibility complex (MHC), which is associated with risk for autoimmune diseases, is also associated with risk for depression.METHODS: We fine-mapped the classical MHC (chr6: 29.6-33.1 Mb), imputing 216 human leukocyte antigen (HLA) alleles and 4 complement component 4 (C4) haplotypes in studies from the Psychiatric Genomics Consortium Major Depressive Disorder Working Group and the UK Biobank. The total sample size was 45,149 depression cases and 86,698 controls. We tested for association between depression status and imputed MHC variants, applying both a region-wide significance threshold (3.9 x 10(-6) ) and a candidate threshold (1.6 x 10(-4) ).RESULTS: No HLA alleles or C4 haplotypes were associated with depression at the region-wide threshold. HLAB*08:01 was associated with modest protection for depression at the candidate threshold for testing in HLA genes in the meta-analysis (odds ratio = 0.98, 95% confidence interval = 0.97-0.99).CONCLUSIONS: We found no evidence that an increased risk for depression was conferred by HLA alleles, which play a major role in the genetic susceptibility to autoimmune diseases, or C4 haplotypes, which are strongly associated with schizophrenia. These results suggest that any HLA or C4 variants associated with depression either are rare or have very modest effect sizes. Show less
Depression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of... Show moreDepression is more frequent among individuals exposed to traumatic events. Both trauma exposure and depression are heritable. However, the relationship between these traits, including the role of genetic risk factors, is complex and poorly understood. When modelling trauma exposure as an environmental influence on depression, both gene-environment correlations and gene-environment interactions have been observed. The UK Biobank concurrently assessed Major Depressive Disorder (MDD) and self-reported lifetime exposure to traumatic events in 126,522 genotyped individuals of European ancestry. We contrasted genetic influences on MDD stratified by reported trauma exposure (final sample size range: 24,094-92,957). The SNP-based heritability of MDD with reported trauma exposure (24%) was greater than MDD without reported trauma exposure (12%). Simulations showed that this is not confounded by the strong, positive genetic correlation observed between MDD and reported trauma exposure. We also observed that the genetic correlation between MDD and waist circumference was only significant in individuals reporting trauma exposure (r(g) = 0.24, p = 1.8 x 10(-7) versus r(g) = -0.05, p = 0.39 in individuals not reporting trauma exposure, difference p = 2.3 x 10(-4)). Our results suggest that the genetic contribution to MDD is greater when reported trauma is present, and that a complex relationship exists between reported trauma exposure, body composition, and MDD. Show less
Choi, K.W.; Chen, C.Y.; Stein, M.B.; Klimentidis, Y.C.; Wang, M.J.; Koenen, K.C.; ... ; Major Depressive Disorder Working 2019
IMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and... Show moreIMPORTANCE Increasing evidence shows that physical activity is associated with reduced risk for depression, pointing to a potential modifiable target for prevention. However, the causality and direction of this association are not clear; physical activity may protect against depression, and/or depression may result in decreased physical activity.OBJECTIVE To examine bidirectional relationships between physical activity and depression using a genetically informed method for assessing potential causal inference.DESIGN, SETTING, AND PARTICIPANTS This 2-sample mendelian randomization (MR) used independent top genetic variants associated with 2 physical activity phenotypes-self- reported (n = 377 234) and objective accelerometer-based (n = 91 084)-and with major depressive disorder (MDD) (n = 143 265) as genetic instruments from the largest available, nonoverlapping genome-wide association studies (GWAS). GWAS were previously conducted in diverse observational cohorts, including the UK Biobank (for physical activity) and participating studies in the Psychiatric Genomics Consortium (for MDD) among adults of European ancestry. Mendelian randomization estimates from each genetic instrument were combined using inverse variance weighted meta-analysis, with alternate methods (eg, weighted median, MR Egger, MR-Pleiotropy Residual Sum and Outlier [PRESSO]) and multiple sensitivity analyses to assess horizontal pleiotropy and remove outliers. Data were analyzed from May 10 through July 31, 2018.MAIN OUTCOMES AND MEASURES MDD and physical activity.RESULTS GWAS summary data were available for a combined sample size of 611 583 adult participants. Mendelian randomization evidence suggested a protective relationship between accelerometer-based activity and MDD (odds ratio [ OR], 0.74 for MDD per 1-SD increase in mean acceleration; 95% CI, 0.59-0.92; P = .006). In contrast, there was no statistically significant relationship between MDD and accelerometer-based activity (beta = -0.08 in mean acceleration per MDD vs control status; 95% CI, -0.47 to 0.32; P = .70). Furthermore, there was no significant relationship between self-reported activity and MDD (OR, 1.28 for MDD per 1-SD increase in metabolic-equivalent minutes of reported moderate-to-vigorous activity; 95% CI, 0.57-3.37; P = .48), or between MDD and self-reported activity (beta = 0.02 per MDD in standardized metabolic-equivalent minutes of reported moderate-to-vigorous activity per MDD vs control status; 95% CI, -0.008 to 0.05; P = .15).CONCLUSIONS AND RELEVANCE Using genetic instruments identified from large-scale GWAS, robust evidence supports a protective relationship between objectively assessed-but not self-reported-physical activity and the risk for MDD. Findings point to the importance of objective measurement of physical activity in epidemiologic studies of mental health and support the hypothesis that enhancing physical activity may be an effective prevention strategy for depression. Show less
Grove, J.; Ripke, S.; Als, T.D.; Mattheisen, M.; Walters, R.K.; Won, H.; ... ; 23andMe Re 2019
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially... Show moreAutism spectrum disorder (ASD) is a highly heritable and heterogeneous group of neurodevelopmental phenotypes diagnosed in more than 1% of children. Common genetic variants contribute substantially to ASD susceptibility, but to date no individual variants have been robustly associated with ASD. With a marked sample-size increase from a unique Danish population resource, we report a genome-wide association meta-analysis of 18,381 individuals with ASD and 27,969 controls that identified five genome-wide-significant loci. Leveraging GWAS results from three phenotypes with significantly overlapping genetic architectures (schizophrenia, major depression, and educational attainment), we identified seven additional loci shared with other traits at equally strict significance levels. Dissecting the polygenic architecture, we found both quantitative and qualitative polygenic heterogeneity across ASD subtypes. These results highlight biological insights, particularly relating to neuronal function and corticogenesis, and establish that GWAS performed at scale will be much more productive in the near term in ASD. Show less
Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by... Show moreStress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 x 10(-6)). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 x 10(-9); total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 x 10(-8); dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 x 10(-8); dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 x 10(-6)). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 x 10(-3)). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions. Show less
AbstractElectroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an... Show moreAbstractElectroconvulsive therapy (ECT) is the treatment of choice for severe and treatment-resistantdepression; disorder severity and unfavorable treatment outcomes are shown to be influencedby an increased genetic burden for major depression (MD). Here, we tested whether ECT assign-ment and response/nonresponse are associated with an increased genetic burden for majordepression (MD) using polygenic risk score (PRS), which summarize the contribution of disease-related common risk variants. Fifty-one psychiatric inpatients suffering from a major depressiveepisode underwent ECT. MD-PRS were calculated for these inpatients and a separatepopulation-based sample (n = 3,547 healthy; n = 426 self-reported depression) based on sum-mary statistics from the Psychiatric Genomics Consortium MDD-working group (Cases:n = 59,851; Controls: n = 113,154). MD-PRS explained a significant proportion of disease statusbetween ECT patients and healthy controls (p = .022, R2 = 1.173%); patients showed higherMD-PRS. MD-PRS in population-based depression self-reporters were intermediate betweenECT patients and controls (n.s.). Significant associations between MD-PRS and ECT response(50% reduction in Hamilton depression rating scale scores) were not observed. Our findings indi-cate that ECT cohorts show an increased genetic burden for MD and are consistent with thehypothesis that treatment-resistant MD patients represent a subgroup with an increased geneticrisk for MD. Larger samples are needed to better substantiate these findings. Show less
Lewis, G.; Ioannidis, K.; Harmelen, A. van; Neufeld, S.; Stochl, J.; Jones, P.B.; Goodyer, I. 2018
BackgroundThere is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic... Show moreBackgroundThere is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic hair development which are controlled by different hormonal pathways. The contributions of pubertal timing (age at onset) and pubertal status (stage of development, irrespective of timing) are also poorly understood. We tested the hypothesis that stage of breast development in female adolescents, controlled largely by increased estradiol, would be more strongly associated with depression than pubic hair development which occurs in both males and females, and is controlled by adrenal androgens. We investigated whether this association was independent of pubertal timing.MethodsROOTS is an ongoing cohort of 1,238 adolescents (54% female) recruited in Cambridgeshire (UK) at age 14.5, and followed-up at ages 16 and 17.5. Depression was assessed using the Mood and Feelings Questionnaire (MFQ) and clinical interview. Breast and pubic hair development were assessed at 14.5, using Tanner rating scales.ResultsFor each increase in Tanner breast stage at 14.5, depressive symptoms increased by 1.4 MFQ points (95% CI 0.6 to 2.3), irrespective of age at onset. Pubic hair status was only associated with depressive symptoms before adjustment for breast status, and was not associated with depression in males. The same pattern was observed longitudinally, and for depression diagnoses.LimitationsWe did not directly measure hormone levels, our findings are observational, and the study had a relatively low response rate.ConclusionsFemales at more advanced stages of breast development are at increased risk of depression, even if their age at pubertal onset is not early. Alongside social and psychological factors, hormones controlling breast but not pubic hair development may contribute to increased incidence of female depression during puberty. Show less
BackgroundThere is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic... Show moreBackgroundThere is an association between puberty and depression, but many things remain poorly understood. When assessing puberty in females, most studies combine indicators of breast and pubic hair development which are controlled by different hormonal pathways. The contributions of pubertal timing (age at onset) and pubertal status (stage of development, irrespective of timing) are also poorly understood. We tested the hypothesis that stage of breast development in female adolescents, controlled largely by increased estradiol, would be more strongly associated with depression than pubic hair development which occurs in both males and females, and is controlled by adrenal androgens. We investigated whether this association was independent of pubertal timing.MethodsROOTS is an ongoing cohort of 1,238 adolescents (54% female) recruited in Cambridgeshire (UK) at age 14.5, and followed-up at ages 16 and 17.5. Depression was assessed using the Mood and Feelings Questionnaire (MFQ) and clinical interview. Breast and pubic hair development were assessed at 14.5, using Tanner rating scales.ResultsFor each increase in Tanner breast stage at 14.5, depressive symptoms increased by 1.4 MFQ points (95% CI 0.6 to 2.3), irrespective of age at onset. Pubic hair status was only associated with depressive symptoms before adjustment for breast status, and was not associated with depression in males. The same pattern was observed longitudinally, and for depression diagnoses.LimitationsWe did not directly measure hormone levels, our findings are observational, and the study had a relatively low response rate.ConclusionsFemales at more advanced stages of breast development are at increased risk of depression, even if their age at pubertal onset is not early. Alongside social and psychological factors, hormones controlling breast but not pubic hair development may contribute to increased incidence of female depression during puberty. Show less
Wray, N.R.; Ripke, S.; Mattheisen, M.; Trzaskowski, M.; Byrne, E.M.; Abdellaoui, A.; ... ; Major Depressive Disorder Working 2018
BackgroundEarly life stress (ELS) consists of child family adversities (CFA: negative experiences that happened within the family environment) and/or peer bullying. ELS plays an important role in... Show moreBackgroundEarly life stress (ELS) consists of child family adversities (CFA: negative experiences that happened within the family environment) and/or peer bullying. ELS plays an important role in the development of adolescent depressive symptoms and clinical disorders. Identifying factors that may reduce depressive symptoms in adolescents with ELS may have important public mental health implications.MethodsWe used structural equation modelling and examined the impact of adolescent friendships and/or family support at age 14 on depressive symptoms at age 17 in adolescents exposed to ELS before age 11. To this end, we used structural equation modelling in a community sample of 771 adolescents (322 boys and 477 girls) from a 3 year longitudinal study. Significant paths in the model were followed-up to test whether social support mediated or moderated the association between ELS and depressive symptoms at age 17.ResultsWe found that adolescent social support in adolescence is negatively associated with subsequent depressive symptoms in boys and girls exposed to ELS. Specifically, we found evidence for two mediational pathways: In the first pathway family support mediated the link between CFA and depressive symptoms at age 17. Specifically, CFA was negatively associated with adolescent family support at age 14, which in turn was negatively associated with depressive symptoms at age 17. In the second pathway we found that adolescent friendships mediated the path between peer bullying and depressive symptoms.Specifically, relational bullying was negatively associated with adolescent friendships at age 14, which in turn were negatively associated with depressive symptoms at age 17. In contrast, we did not find a moderating effect of friendships and family support on the association between CFA and depressive symptoms.ConclusionsFriendships and/or family support in adolescence mediate the relationship between ELS and late adolescent depressive symptoms in boys and girls. Therefore, enhancing affiliate relationships and positive family environments may benefit the mental health of vulnerable youth that have experienced CFA and/or primary school bullying. Show less