Major Depressive Disorder Scores Research Articles

The efficacy of zuranolone versus placebo in postpartum depression and major depressive disorder: a systematic review and meta-analysis.

Zuranolone, an oral version of allopregnanolone and neurosteroid, is a novel drug for the treatment of major depressive disorder (MDD) and postpartum depression (PPD). The purpose of this systematic review and meta-analysis was to assess the efficacy of zuranolone in the treatment of MDD and PPD. A systematic search was conducted using EBSCOhost to simultaneously search Academic Search Premier, APA PsycArticles, APA PsycInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, CINAHL Ultimate, and MEDLINE with Full Text. Two independent reviewers screened the articles and completed a full-text review using Covidence. The quality of each study was assessed using the Cochrane Risk of Bias tool for randomized trials (RoB 2). A meta-analysis was then conducted using Review Manager (RevMan v5.4) software. The initial search yielded 127 results, with 6 articles fitting our inclusion and exclusion criteria. All 6 studies, comprising 1707 participants, had an overall low risk of bias. There was a significant decrease in HAM-D scores for MDD at 15days versus placebo (MD - 2.40, 95% CI - 3.07 to - 1.63; p < .001). When pooling data for PDD, there was an overall significant decrease in HAM-D scores at 15days versus placebo (MD - 4.06, 95% CI - 4.25 to - 3.87; p < .001). The results suggest that zuranolone can improve symptoms of PPD at 15days; however, results were not clinically significant for MDD. Future research is needed to evaluate the long-term efficacy of zuranolone in PPD and the treatment efficacy in MDD.

Depression, anxiety, eating problems, and diabulimia risk in adolescents with type 1 diabetes: a case-control study.

Type 1 diabetes (T1D) causes psychological distress, negatively impacting normal childhood activities. Depression, anxiety disorders, and eating problems are commonly observed in this population. The study population consisted of 40 adolescents (22 females and 18 males) who had been diagnosed with T1D and 41 healthy adolescents (21 females and 20 males). The aim of this study was to compare adolescents with T1D to healthy controls in terms of depression, anxiety, and eating problems and subsequently examine the T1D group in relation to the risk of diabetes-specific eating disorders. Eating Attitudes Test (EAT-40), Revised Children's Anxiety and Depression Scale (RCADS), and Diabetes Eating Problem Survey- Revised (DEPS-R) scales were used to compare the case and control groups. The case group exhibited significantly higher scores in EAT-40 total score, RCADS parent form major depressive disorder (MDD), social anxiety disorder (SAD), generalized anxiety disorder (GAD), panic disorder (PD), total anxiety score, total scale scores, RCADS child form MDD, PD, and total scale scores compared to the control group. Individuals at high risk of diabetes-specific eating disorder within the case group demonstrated significantly higher RCADS (child and parent form) MDD scores and RCADS parent form separation anxiety (SA) and total scale scores. Binary logistic regression analysis revealed that the RCADS parent form total scale score could predict DEPS-R. Routine screening of children and adolescents diagnosed with T1D for depression, anxiety, and eating disorder risk may facilitate early detection of possible psychopathologies, allowing for early intervention to address factors that may disrupt treatment adherence. Further longitudinal studies with larger samples are needed to investigate psychopathologies, particularly eating disorders, in children and adolescents with T1D.

Polygenic risk of major depressive disorder as a risk factor for venous thromboembolism.

Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are associated with an increased risk of cardiovascular diseases, including venous thromboembolism (VTE). The reasons for this are complex and include obesity, smoking, and use of hormones and psychotropic medications. Genetic studies have increasingly provided evidence of the shared genetic risk of psychiatric and cardiometabolic illnesses. This study aimed to determine whether a genetic predisposition to MDD, BD, or SCZ is associated with an increased risk of VTE. Genetic correlations using the largest genome-wide genetic meta-analyses summary statistics for MDD, BD, and SCZ (Psychiatric Genetics Consortium) and a recent genome-wide genetic meta-analysis of VTE (INVENT Consortium) demonstrated a positive association between VTE and MDD but not BD or SCZ. The same summary statistics were used to construct polygenic risk scores for MDD, BD, and SCZ in UK Biobank participants of self-reported White British ancestry. These were assessed for impact on self-reported VTE risk (10 786 cases, 285 124 controls), using logistic regression, in sex-specific and sex-combined analyses. We identified significant positive associations between polygenic risk for MDD and the risk of VTE in men, women, and sex-combined analyses, independent of the known risk factors. Secondary analyses demonstrated that this association was not driven by those with lifetime experience of mental illness. Meta-analyses of individual data from 6 additional independent cohorts replicated the sex-combined association. This report provides evidence for shared biological mechanisms leading to MDD and VTE and suggests that, in the absence of genetic data, a family history of MDD might be considered when assessing the risk of VTE.

Attention-Deficit/Hyperactivity Disorder and Major Depressive Disorder: Evidence From Multiple Genetically Informed Designs

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are two highly prevalent disorders that frequently co-occur. Prior evidence from genetic and cohort studies supports an association between ADHD and MDD. However, the direction and mechanisms underlying their association remain unclear. As onset of ADHD occurs in early life, it has been hypothesized that ADHD may cause MDD. MethodsWe examined the association of ADHD with MDD using 3 different genetically informed methods to disentangle causality from confounding: 1) a nationwide longitudinal register-based full sibling comparison (N = 1,018,489) adjusting for shared familial confounding; 2) a prospective co-twin control study comprising 16,477 twins (5084 monozygotic and 11,393 dizygotic); and 3) a two-sample Mendelian randomization analysis using the largest available ADHD (N = 225,534) and MDD (N = 500,199) genome-wide association study summary statistics, adjusting for correlated and uncorrelated horizontal pleiotropy. ResultsSibling and twin comparisons indicated that individuals with ADHD have an increased risk for subsequent development of MDD (hazard ratio = 4.12 [95% CI 3.62–4.69]) after adjusting for shared genetic and familial factors and that ADHD scores endorsed by parents are positively associated with subsequent MDD scores at ages 15 and 18 years (b = 0.07 [95% CI 0.05–0.08] and b = 0.09 [95% CI 0.08–0.11], respectively). Mendelian randomization analyses showed that genetic liability for ADHD is causally related to MDD (odds ratio = 1.15 [95% CI 1.08–1.23]). ConclusionsOur study provides consistent results across 3 different genetically informative approaches, strengthening the hypothesis that ADHD is causally related to MDD.

Decreased functional connectivity in patients with major depressive disorder and a history of childhood traumatization through experiences of abuse

BackgroundChildhood trauma (CT) increases vulnerability for the development of major depressive disorder (MDD). Alterations in resting-state functional connectivity (RSFC) have frequently been reported for MDD. These alterations may be much more prominent in depressive patients with a history of CT. The present study aims to compare RSFC in different brain networks of patients with MDD and CT (MDD+CT) vs. MDD and no CT compared to healthy controls. Methods45 patients (22 with CT) were compared to 23 age-and-gender-matched healthy control subjects. Demographic parameters, severity of MDD, severity of CT and comorbid anxiety disorders were assessed. For assessment of RSFC alterations, a seed-based approach within five well-established RSFC networks was used. ResultsCT in MDD patients predicts severity of comorbid anxiety. A significant decrease in in-between network RSFC-values of MDD patients compared to controls was found in the network pairs of default mode network (DMN) – dorsal attention network (DAN), ventral attention network (VAN) – DMN and DAN – affective network (AN). MDD+CT patients presented more aberrant RSFC than MDD-CT patients. MDD scores predicted the decrease in RSFC for MDD patients. Higher Childhood Trauma Questionnaire (CTQ) scores are linked to reduced functional connectivity (FC) between DMN – DAN. ConclusionsOur study shows reduced RSFC in MDD patients for DMN – DAN, VAN – DMN, DAN – AN and MDD+CT patients presented more aberrant RSFC so that we suspect CT to be a considerable factor in the etiology of MDD. Through dysregulated neural circuits, CT is likely to contribute to a distinct MDD pathophysiology.

Loneliness, internalizing symptoms, and inflammatory markers in adolescent COVID‐19 survivors

BackgroundConcerns about the psychiatric sequelae after COVID‐19 infection have increased as the pandemic spreads worldwide. The increase in self‐isolation during this pandemic period has also revealed the importance of feelings of loneliness. This study aimed to examine the relationship between baseline inflammation levels, internalizing symptoms, and feelings of loneliness in adolescent COVID‐19 survivors in the long term.MethodsA total of 74 adolescents (41 girls, 55.4%, mean age 14.88) and their parents were included in the study. This cross‐sectional study assessed internalizing symptoms via Revised Children's Anxiety and Depression Scale (RCADS) and feelings of loneliness using the UCLA‐loneliness scale. Baseline inflammatory markers at COVID‐19 diagnosis were collected. Logistic regression analysis was used to determine predictors for depression in adolescents.ResultsThe most common disorder was Major Depressive Disorder (MDD) (25.7%), and 33.8% of the adolescents were in the clinical range in at least one internalizing domain. Baseline C‐Reactive Protein (CRP) levels correlated weakly with MDD scores. Loneliness scores correlated with all internalizing symptoms, strong association with MDD scores. Loneliness, anxiety, and parental anxiety were associated with an increased likelihood of MDD. Baseline CRP positivity did not predict MDD in adolescent COVID‐19 survivors.ConclusionsThis study indicates that anxiety, loneliness, and parental anxiety play an important role in adolescents' experience of depressive symptoms after COVID‐19 infection. Thus, screening parental psychopathology and loneliness in COVID‐19 survivors seems to be preventive for adolescent mental health problems.

Comparing personalized brain-based and genetic risk scores for major depressive disorder in large population samples of adults and adolescents.

Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based 'Regional Vulnerability Index' (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N=702, age=59±10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N=3,825, age=10±1; 2-year follow-up N=2,081, age=12±1). MDD-RVIs quantify the correlation of the individual's corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed. In adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (β=0.099-0.281, PFDR=0.001-0.043) than MDD-PRS (β=0.056-0.152, PFDR=0.140-0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (β=0.084-0.086, p=1.38×10-4-4.77×10-4) but not with any MDD-RVIs (β<0.05, p>0.05). Our results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.

Associations between sensory processing and depression in autistic girls

BackgroundAutistic youth often experience depression, which can confound their social interactions as well as contribute to decreased quality of life. One of the possible correlates of depression in these youth is their sensitivity to sensory stimuli, which can be of several kinds, and is often referred to as Sensory Features (SF). MethodsThe association between SF (using the Sensory Profile (SPr)) and Major Depressive Disorder (MDD) (as measured by the Child and Adolescent Symptom Inventory MDD subscale (CASI-D)) was investigated in 53 autistic girls and adolescents aged 6–17 yr, using total MDD scores and also the underlying components of MDD identified via Factor Analysis. Data were collected from the autistic females as well as one of their parents to compare these sources for their association between SF and MDD. ResultsData from the SPr and the CASI-D revealed a significant correlation between SP and total scores from the CASI-D, although that association was not uniform across all four Quadrants of the SPr. Examination of the factor structure of the CASI-D revealed two major components, only one of which (Depressed Mood) was significantly associated with aspects of SPr. The data fitted a model of depression as a behavioural withdrawal from chronic stress as an attempted adaptation to that stress. Only the girls’ own evaluations of their SF made significant contributions to their Depressed Mood. ConclusionsThe link between SF and MDD in these girls may need to be based upon their own evaluations of their SF-related behaviour. Implications for assessment and treatment of SP-related MDD are discussed.

Symptom dimensions of major depression in a large community-based cohort.

Our understanding of major depression is complicated by substantial heterogeneity in disease presentation, which can be disentangled by data-driven analyses of depressive symptom dimensions. We aimed to determine the clinical portrait of such symptom dimensions among individuals in the community. This cross-sectional study consisted of 25 261 self-reported White UK Biobank participants with major depression. Nine questions from the UK Biobank Mental Health Questionnaire encompassing depressive symptoms were decomposed into underlying factors or 'symptom dimensions' via factor analysis, which were then tested for association with psychiatric diagnoses and polygenic risk scores for major depressive disorder (MDD), bipolar disorder and schizophrenia. Replication was performed among 655 self-reported non-White participants, across sexes, and among 7190 individuals with an ICD-10 code for MDD from linked inpatient or primary care records. Four broad symptom dimensions were identified, encompassing negative cognition, functional impairment, insomnia and atypical symptoms. These dimensions replicated across ancestries, sexes and individuals with inpatient or primary care MDD diagnoses, and were also consistent among 43 090 self-reported White participants with undiagnosed self-reported depression. Every dimension was associated with increased risk of nearly every psychiatric diagnosis and polygenic risk score. However, while certain psychiatric diagnoses were disproportionately associated with specific symptom dimensions, the three polygenic risk scores did not show the same specificity of associations. An analysis of questionnaire data from a large community-based cohort reveals four replicable symptom dimensions of depression with distinct clinical, but not genetic, correlates.

Parental incarceration and the mental health of youth in the justice system: The moderating role of neighborhood disorder.

Neighborhood-level characteristics may inform youths’ experience of parental incarceration; however, their precise role has not yet been established. Some empirical evidence indicates that neighborhood disorder compounds the psychological distress of parental incarceration because youth living in disorderly neighborhoods are more likely to be affected by other related stressors. Other theorists suggest that neighborhood disorder mitigates the psychological distress of parental incarceration because the residents of disordered neighborhoods may be more equipped to address the collateral challenges associated with incarceration. Drawing upon secondary data from 1,186 male youth who had been arrested for the first time, the present study empirically tested these competing hypotheses by examining the moderating role of neighborhood disorder in the predictive relationship between parental incarceration and symptoms of generalized anxiety disorder (GAD) and major depressive disorder (MDD). The results indicate that both youth of color and youth living in high levels of neighborhood disorder experience no incremental change in GAD and MDD scores when a parent is incarcerated. However, parental incarceration is associated with significantly higher GAD and MDD scores among White youth in nondisordered neighborhoods. The results speak to the contextual mechanisms that inform youths’ experience of parental incarceration. (PsycInfo Database Record (c) 2021 APA, all rights reserved)

Anxiety and depression in pediatric patients with vitiligo and alopecia areata and their parents: A cross‐sectional controlled study

Alopecia areata (AA) and vitiligo are associated with various psychiatric comorbidities, and the care of a child with AA or vitiligo may be associated with higher anxiety and depression than healthy children. We aimed to identify psychiatric findings in children and adolescent groups with AA and vitiligo and to evaluate the levels of anxiety and depression in their parents. This study included 31 patients with AA and 29 patients with vitiligo, aged seven to 17years, and their parents. Age- and gender-matched 30 controls and their parents were included. The patients and controls completed the Revised Child Anxiety and Depression Scales-Child version (RCADS-C), and their parents completed the parent version (RCADS-P). The parents also completed the Beck Anxiety Inventory (BAI) and Beck Depression Inventory (BDI). In addition, the stressful event history of all cases was noted. Stressful event history was higher in the vitiligo group compared to the AA group, and it was higher in the AA and vitiligo groups compared to the control group. Separation anxiety, generalized anxiety, social phobia, and major depressive disorder (MDD) scores were higher in the AA group than controls according to the RCADS-C. According to the RCADS-P, panic disorder (PD), MDD, and total anxiety scores were higher in the AA group. Only the PD and MDD scores were higher in the vitiligo group than those of the controls based on the RCADS-P. Lastly, no significant difference was observed between the three groups concerning the parents' BAI and BDI scores. Stressful events were more common in pediatric patients with vitiligo than those with AA. Anxiety symptoms were more prevalent in patients with AA than those with vitiligo.

Sex-specific association between infant caudate volumes and a polygenic risk score for major depressive disorder.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

Polygenic prediction of the risk of perinatal depressive symptoms.

Perinatal depression carries adverse effects on maternal health and child development, but genetic underpinnings remain unclear. We investigated the polygenic risk of perinatal depressive symptoms. About 742 women from the prospectivePrediction and Prevention of Pre-eclampsia and Intrauterine Growth Restriction cohort were genotyped and completed the Center for Epidemiologic Studies Depression scale 14 times during the prenatal period and twice up to 12 months postpartum. Polygenic risk scores for major depressive disorder, bipolar disorder, schizophrenia, and cross-disorder were calculated using multiple p-value thresholds. Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder, but not bipolar disorder, were associated with higher prenatal and postpartum depressive symptoms (0.8%-1% increase per one standard deviation increase in polygenic risk scores). Prenatal depressive symptoms accounted for and mediated the associations between the polygenic risk scores and postpartum depressive symptoms (effect size proportions-mediated: 52.2%-88.0%). Further, the polygenic risk scores were associated with 1.24-1.45-fold odds to belong to the group displaying consistently high compared with consistently low depressive symptoms through out the prenatal and postpartum periods. Polygenic risk scores for major depressive disorder, schizophrenia, and cross-disorder in non-perinatal populations generalize to perinatal depressive symptoms and may afford to identify women for timely preventive interventions.

Genetic risk for major depressive disorder and loneliness in sex-specific associations with coronary artery disease

Major depressive disorder (MDD) and loneliness are phenotypically and genetically correlated with coronary artery disease (CAD), but whether these associations are explained by pleiotropic genetic variants or shared comorbidities is unclear. To tease apart these scenarios, we first assessed the medical morbidity pattern associated with genetic risk factors for MDD and loneliness by conducting a phenome-wide association study in 18,385 European-ancestry individuals in the Vanderbilt University Medical Center biobank, BioVU. Polygenic scores for MDD and loneliness were developed for each person using previously published meta-GWAS summary statistics, and were tested for association with 882 clinical diagnoses ascertained via billing codes in electronic health records. We discovered strong associations with heart disease diagnoses, and next embarked on targeted analyses of CAD in 3893 cases and 4197 controls. We found odds ratios of 1.11 (95% CI, 1.04–1.18; P 8.43 × 10−4) and 1.13 (95% CI, 1.07–1.20; P 4.51 × 10−6) per 1-SD increase in the polygenic scores for MDD and loneliness, respectively. Results were similar in patients without psychiatric symptoms, and the increased risk persisted in females even after adjusting for multiple conventional risk factors and a polygenic score for CAD. In a final sensitivity analysis, we statistically adjusted for the genetic correlation between MDD and loneliness and re-computed polygenic scores. The polygenic score unique to loneliness remained associated with CAD (OR 1.09, 95% CI 1.03–1.15; P 0.002), while the polygenic score unique to MDD did not (OR 1.00, 95% CI 0.95–1.06; P 0.97). Our replication sample was the Atherosclerosis Risk in Communities (ARIC) cohort of 7197 European-ancestry participants (1598 incident CAD cases). In ARIC, polygenic scores for MDD and loneliness were associated with hazard ratios of 1.07 (95% CI, 0.99–1.14; P = 0.07) and 1.07 (1.01–1.15; P = 0.03), respectively, and we replicated findings from the BioVU sensitivity analyses. We conclude that genetic risk factors for MDD and loneliness act pleiotropically to increase CAD risk in females.

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

Genetic Risk for Psychiatric Disorders and Telomere Length.

Background: Previous studies have revealed associations between psychiatric disorder diagnosis and shorter telomere length. Here, we attempt to discern whether genetic risk for psychiatric disorders, or use of pharmacological treatments (i.e., antidepressants), predict shorter telomere length and risk for aging-related disease in a United Kingdom population sample.Methods: DNA samples from blood were available from 351 participants who were recruited as part of the South East London Community Health (SELCoH) Study, and for which whole-genome genotype data was available. Leukocyte telomere length was characterized using quantitative polymerase chain reactions. Individualized polygenic risk scores for major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) were calculated using Psychiatric Genomics Consortium summary statistics. We subsequently performed linear models, to discern the impact polygenic risk for psychiatric disorders (an etiological risk factor) and antidepressant use (common pharmacological treatment) have on telomere length, whilst accounting for other lifestyle/health factors (e.g., BMI, smoking).Results: There were no significant associations between polygenic risk for any of the psychiatric disorders tested and telomere length (p > 0.05). Antidepressant use was significantly associated with shorter telomere length and this was independent from a depression diagnosis or current depression severity (p ≤ 0.01). Antidepressant use was also associated with a significantly higher risk of aging-related disease, which was independent from depression diagnosis (p ≤ 0.05).Conclusion: Genetic risk for psychiatric disorders is not associated with shorter telomere length. Further studies are now needed to prospectively characterize if antidepressant use increases risk for aging-related disease and telomere shortening, or whether people who age faster and have aging-related diseases are just more likely to be prescribed antidepressants.

Polygenic risk scores for major depressive disorder and neuroticism as predictors of antidepressant response: Meta-analysis of three treatment cohorts.

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. However, recent genetic advances suggest that Polygenic Risk Scores (PRS) could allow MDD patients to be stratified for antidepressant response. We used PRS for MDD and PRS for neuroticism as putative predictors of antidepressant response within three treatment cohorts: The Genome-based Therapeutic Drugs for Depression (GENDEP) cohort, and 2 sub-cohorts from the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study PRGN-AMPS (total patient number = 760). Results across cohorts were combined via meta-analysis within a random effects model. Overall, PRS for MDD and neuroticism did not significantly predict antidepressant response but there was a consistent direction of effect, whereby greater genetic loading for both MDD (best MDD result, p < 5*10–5 MDD-PRS at 4 weeks, β = -0.019, S.E = 0.008, p = 0.01) and neuroticism (best neuroticism result, p < 0.1 neuroticism-PRS at 8 weeks, β = -0.017, S.E = 0.008, p = 0.03) were associated with less favourable response. We conclude that the PRS approach may offer some promise for treatment stratification in MDD and should now be assessed within larger clinical cohorts.

Association of Whole-Genome and NETRIN1 Signaling Pathway–Derived Polygenic Risk Scores for Major Depressive Disorder and White Matter Microstructure in the UK Biobank

BackgroundMajor depressive disorder is a clinically heterogeneous psychiatric disorder with a polygenic architecture. Genome-wide association studies have identified a number of risk-associated variants across the genome and have reported growing evidence of NETRIN1 pathway involvement. Stratifying disease risk by genetic variation within the NETRIN1 pathway may provide important routes for identification of disease mechanisms by focusing on a specific process, excluding heterogeneous risk-associated variation in other pathways. Here, we sought to investigate whether major depressive disorder polygenic risk scores derived from the NETRIN1 signaling pathway (NETRIN1-PRSs) and the whole genome, excluding NETRIN1 pathway genes (genomic-PRSs), were associated with white matter microstructure. MethodsWe used two diffusion tensor imaging measures, fractional anisotropy (FA) and mean diffusivity (MD), in the most up-to-date UK Biobank neuroimaging data release (FA: n = 6401; MD: n = 6390). ResultsWe found significantly lower FA in the superior longitudinal fasciculus (β = −.035, pcorrected = .029) and significantly higher MD in a global measure of thalamic radiations (β = .029, pcorrected = .021), as well as higher MD in the superior (β = .034, pcorrected = .039) and inferior (β = .029, pcorrected = .043) longitudinal fasciculus and in the anterior (β = .025, pcorrected = .046) and superior (β = .027, pcorrected = .043) thalamic radiation associated with NETRIN1-PRS. Genomic-PRS was also associated with lower FA and higher MD in several tracts. ConclusionsOur findings indicate that variation in the NETRIN1 signaling pathway may confer risk for major depressive disorder through effects on a number of white matter tracts.

Response to therapeutic sleep deprivation: a naturalistic study of clinical and genetic factors and post-treatment depressive symptom trajectory

Research has shown that therapeutic sleep deprivation (SD) has rapid antidepressant effects in the majority of depressed patients. Investigation of factors preceding and accompanying these effects may facilitate the identification of the underlying biological mechanisms. This exploratory study aimed to examine clinical and genetic factors predicting response to SD and determine the impact of SD on illness course. Mood during SD was also assessed via visual analogue scale. Depressed inpatients (n = 78) and healthy controls (n = 15) underwent ~36 h of SD. Response to SD was defined as a score of ≤ 2 on the Clinical Global Impression Scale for Global Improvement. Depressive symptom trajectories were evaluated for up to a month using self/expert ratings. Impact of genetic burden was calculated using polygenic risk scores for major depressive disorder. In total, 72% of patients responded to SD. Responders and non-responders did not differ in baseline self/expert depression symptom ratings, but mood differed. Response was associated with lower age (p = 0.007) and later age at life-time disease onset (p = 0.003). Higher genetic burden of depression was observed in non-responders than healthy controls. Up to a month post SD, depressive symptoms decreased in both patients groups, but more in responders, in whom effects were sustained. The present findings suggest that re-examining SD with a greater focus on biological mechanisms will lead to better understanding of mechanisms of depression.

Predicting loneliness with polygenic scores of social, psychological and psychiatric traits

Loneliness is a heritable trait that accompanies multiple disorders. The association between loneliness and mental health indices may partly be due to inherited biological factors. We constructed polygenic scores for 27 traits related to behavior, cognition and mental health and tested their prediction for self-reported loneliness in a population-based sample of 8798 Dutch individuals. Polygenic scores for major depressive disorder (MDD), schizophrenia and bipolar disorder were significantly associated with loneliness. Of the Big Five personality dimensions, polygenic scores for neuroticism and conscientiousness also significantly predicted loneliness, as did the polygenic scores for subjective well-being, tiredness and self-rated health. When including all polygenic scores simultaneously into one model, only 2 major depression polygenic scores remained as significant predictors of loneliness. When controlling only for these 2 MDD polygenic scores, only neuroticism and schizophrenia remain significant. The total variation explained by all polygenic scores collectively was 1.7%. The association between the propensity to feel lonely and the susceptibility to psychiatric disorders thus pointed to a shared genetic etiology. The predictive power of polygenic scores will increase as the power of the genome-wide association studies on which they are based increases and may lead to clinically useful polygenic scores that can inform on the genetic predisposition to loneliness and mental health.