Risk Of Major Depressive Disorder Research Articles

Dissecting the genetic overlap between severe mental disorders and markers of cellular aging: Identification of pleiotropic genes and druggable targets.

Patients with severe mental disorders such as bipolar disorder (BD), schizophrenia (SCZ) and major depressive disorder (MDD) show a substantial reduction in life expectancy, increased incidence of comorbid medical conditions commonly observed with advanced age and alterations of aging hallmarks. While severe mental disorders are heritable, the extent to which genetic predisposition might contribute to accelerated cellular aging is not known. We used bivariate causal mixture models to quantify the trait-specific and shared architecture of mental disorders and 2 aging hallmarks (leukocyte telomere length [LTL] and mitochondrial DNA copy number), and the conjunctional false discovery rate methodto detect shared genetic loci. We integrated gene expression data from brain regions from GTEx and used different tools to functionally annotate identified loci and investigate their druggability. Aging hallmarks showed low polygenicity compared with severe mental disorders. We observed a significant negative global genetic correlation between MDD and LTL (rg = -0.14, p = 6.5E-10), and no significant results for other severe mental disorders or for mtDNA-cn. However, conditional QQ plots and bivariate causal mixture models pointed to significant pleiotropy among all severe mental disorders and aging hallmarks. We identified genetic variants significantly shared between LTL and BD (n = 17), SCZ (n = 55) or MDD (n = 19), or mtDNA-cn and BD (n = 4), SCZ (n = 12) or MDD (n = 1), with mixed direction of effects. The exonic rs7909129 variant in the SORCS3 gene, encoding a member of the retromer complex involved in protein trafficking and intracellular/intercellular signaling, was associated with shorter LTL and increased predisposition to all severe mental disorders. Genetic variants underlying risk of SCZ or MDD and shorter LTL modulate expression of several druggable genes in different brain regions. Genistein, a phytoestrogen with anti-inflammatory and antioxidant effects, was an upstream regulator of 2 genes modulated by variants associated with risk of MDD and shorter LTL. While our results suggest that shared heritability might play a limited role in contributing to accelerated cellular aging in severe mental disorders, we identified shared genetic determinants and prioritized different druggable targets and compounds.

Acute Stress Increases Striatal Connectivity With Cortical Regions Enriched for μ and κ Opioid Receptors

BackgroundUnderstanding the neurobiological effects of stress is critical for addressing the etiology of major depressive disorder (MDD). Using a dimensional approach involving individuals with differing degree of MDD risk, we investigated 1) the effects of acute stress on cortico-cortical and subcortical-cortical functional connectivity (FC) and 2) how such effects are related to gene expression and receptor maps. MethodsAcross 115 participants (37 control, 39 remitted MDD, 39 current MDD), we evaluated the effects of stress on FC during the Montreal Imaging Stress Task. Using partial least squares regression, we investigated genes whose expression in the Allen Human Brain Atlas was associated with anatomical patterns of stress-related FC change. Finally, we correlated stress-related FC change maps with opioid and GABAA (gamma-aminobutyric acid A) receptor distribution maps derived from positron emission tomography. ResultsResults revealed robust effects of stress on global cortical connectivity, with increased global FC in frontoparietal and attentional networks and decreased global FC in the medial default mode network. Moreover, robust increases emerged in FC of the caudate, putamen, and amygdala with regions from the ventral attention/salience network, frontoparietal network, and motor networks. Such regions showed preferential expression of genes involved in cell-to-cell signaling (OPRM1, OPRK1, SST, GABRA3, GABRA5), similar to previous genetic MDD studies. ConclusionsAcute stress altered global cortical connectivity and increased striatal connectivity with cortical regions that express genes that have previously been associated with imaging abnormalities in MDD and are rich in μ and κ opioid receptors. These findings point to overlapping circuitry underlying stress response, reward, and MDD.

Influence of PCDH9 (rs9540720) and narcissistic personality traits on the incidence of major depressive disorder in Chinese first-year university students: findings from a 2-year cohort study.

Objective: The objective of this study was to explore the influence of the polymorphism of the protocadherin 9 (PCDH9) gene and the narcissistic personality trait (NPT) on the risk of major depressive disorder (MDD) in Chinese first-year university students. Methods: A 2-year cohort study was conducted among Chinese first-year university students who were enrolled in 2018 from two universities in Shandong Province, China. The snapshot technique was used to detect the genotypes of PCDH9 (rs9540720). The Chinese version of the Composite International Diagnostic Interview was used for the MDD assessment. The NPTs were measured by 11 items based on DSM-IV. Patient Health Questionnaire-9 and the Beck Anxiety Inventory were used to assess depressive and anxiety symptoms, respectively. Logistic regression modeling was carried out to examine the relationship between rs9540720, NPTs, and the incidence of MDD. Results: A total of 5,327 students participated in the baseline and follow-up studies and provided their blood samples. PCDH9 (rs9540720) (ORGG+GA = 2.33, 95% CI: 1.35-4.02) and NPTs (OR5-9 = 2.26, 95% CI: 1.40-3.64) increased the risk of MDD onset. There was no multiplicative interaction between NPTs and Rs9540720 (OR = 1.51, 95% CI: 0.30-7.63). Furthermore, there was no additive interaction between them (RERI = 2.40, 95% CI: -0.82-5.62; AP = 0.47, 95% CI: -0.04-0.97; and S = 2.37, 95% CI: 0.54-10.33). Conclusion: PCDH9 (rs9540720) and more NPTs are the risk factors for the incidence of MDD in Chinese first-year university students.

Social zeitgeber and sleep loss as risk factors for suicide in American Indian adolescents.

American Indians / Alaska Natives (AI/AN) bear a high burden of suicide, the reasons for which are not completely understood, and rates can vary by tribal group and location. This article aims to identify circumstances reported by a community group of American Indian adolescent participants to be associated with their depression and/or suicide. American Indian adolescents (n = 360) were recruited from contiguous reservations and were assessed with a semi-structured diagnostic interview. Twenty percent of the adolescents reported suicidal thoughts (ideation, plans), an additional 8% reported a history of suicide attempts, and three deaths due to suicide were reported. Suicidal behaviors and major depressive disorder (MDD) co-occurred and were more common among female adolescents. The distressing events that adolescents most often reported were: death in the family, family disruption, peer relationship problems, and school problems. All of these events were significantly associated with suicidal behaviors, however those with suicidal acts were more likely to report death in the family. Those with MDD but no suicidal behaviors were more likely to report disruptions in the family. Disruptions in falling asleep were also associated with suicidal behaviors and having experienced a death in the family. Disruptions in important relationships, particularly through death or divorce, may be interpreted as a loss or disruption in "social zeitgebers" that may in turn disturb biological rhythms, such as sleep, thus potentially increase the risk for MDD and/or suicide. Prevention programs aimed at ameliorating the impact of disruptions in important relationships may potentially reduce suicidal behaviors in AI/AN adolescents.

Genetic evidence strengthens the bidirectional connection between oral health status and psychiatric disorders: A two-sample Mendelian randomization study

BackgroundObservational studies cannot accurately infer the causal associations between oral health status and psychiatric disorders. MethodsWe conducted univariate and multivariate Mendelian randomization (MR) analyses using single nucleotide polymorphisms (SNPs) associated with eight oral health statuses (periodontitis, DMFS, Nteeth, toothache, loose teeth, painful gums, bleeding gums, and mouth ulcers) and four psychiatric disorders (Schizophrenia, Major Depressive Disorder (MDD), anxiety and stress-related disorder (ASRD), and Bipolar Disorder (BIP)) as instrumental variables. Genetic data were sourced from the Gene-lifestyle interactions in dental endpoints (GLIDE), UK Biobank, Psychiatric Genomics Consortium (PGC), and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH). The inverse variance-weighted (IVW) approach, supported by a comprehensive sensitivity analysis, was employed. ResultsGenetically predicted mouth ulcers were significantly linked to higher MDD (OR = 2.17, 95 % CI: 1.33‐–3.54, P< 0.01) and BIP risks (OR = 2.25, 95 % CI: 1.22–4.15, P = 0.01). BIP heightened bleeding gums risk (OR = 1.01, 95 % CI: 1.00–1.01, P < 0.01). These associations were adjusted for smoking status and alcohol consumption. Painful gums were significantly associated with MDD risk (OR = 96.48, 95 % CI: 2.66–3495.28, P = 0.01), while MDD raised periodontitis risk (OR = 2.15, 95 % CI: 1.24–3.75, P = 0.01), both confounded by smoking and alcohol. Relatively small effects between several variables, while others could not withstand correction for multiple tests. LimitationsThe sample size and limitation to European populations limits the study generalizability. ConclusionsThis study provide evidence of possible causal relationships between several oral health conditions and mental illness. Focusing on oral health and valuing mental health are important for each other and overall health.

Relationship between biological rhythm dysregulation and suicidal ideation in patients with major depressive disorder

BackgroundAlthough the disturbance of circadian rhythms represents a significant clinical feature of major depressive disorder (MDD), the relationship between biological rhythm disturbances and the severity of suicidal ideation in individuals with MDD remains unclear. We aimed to explore the characteristics of different biological rhythm dimensions in MDD and their association with the severity of depressive symptoms and suicidal ideation.MethodsA total of 50 MDD patients and 50 healthy controls were recruited and their general information was collected. The severity of depressive symptoms was assessed with the 17-item Hamilton Depression Rating Scale (HDRS17). The intensity of suicidal ideation was evaluated with the Beck Scale for Suicide Ideation (BSS). The Chinese version of the Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) scale was utilized to assess the participants’ biological rhythm dysregulation. Multiple logistic regression analysis was conducted to explore the relationship between biological rhythm and the risk of MDD. Multiple linear regression analysis was performed in the MDD group to investigate the relationship between different biological rhythm dimensions and suicide ideation.ResultsSignificant differences were observed between the MDD group and the control group in total BRIAN score (Z=-5.41, P < 0.001) as well as scores for each dimension. After adjusting for confounding factors, multiple logistic regression analysis revealed a significant association between total BRIAN score and the presence of MDD (OR = 1.20, 95% CI = 1.10–1.29, P < 0.001), as well as between scores in different BRIAN dimensions and the presence of MDD (activity: OR = 1.47, 95% CI = 1.24–1.74, P < 0.001; sleep: OR = 1.52, 95% CI = 1.28–1.79, P < 0.001; social: OR = 1.80, 95% CI = 1.32–2.46, P < 0.001; eating pattern: OR = 1.34, 95% CI = 1.12–1.60, P = 0.001). In patients with MDD, linear regression analysis demonstrated a positive relationship between BSS scores and BRIAN eating pattern scores (β = 0.34, P = 0.022), even after adjusting for demographic factors and the severity of depression.ConclusionsPatients with MDD exhibited significantly higher levels of dysregulation in all four biological rhythm dimensions compared to healthy controls and the degree of dysregulation was associated with the severity of depression. More importantly, dysregulation of eating pattern may increase the intensity of suicidal ideation in MDD, thus elevating the risk of suicide.

Investigation of peripheral inflammatory biomarkers in association with suicide risk in major depressive disorder.

Suicide is the most severe complication of major depressive disorder (MDD). Novel research assumes the role of immunological dysregulation in the background - several studies have reported alterations in the number of inflammatory cells related to both MDD and suicidality. There are currently no objective, routinely measured parameters to indicate suicidal vulnerability. However, altered inflammatory cell numbers and ratios have been proposed as potential biomarkers of suicide risk (SR). The present research aims to examine changes of these values related to increased SR in MDD as an assumed inflammatory state. We investigated laboratory parameters of psychiatric in-patients diagnosed with MDD (n = 101) retrospectively. Individuals with recent suicide attempt (SA) (n = 22) and with past SA (n = 19) represented the high SR group. MDD patients with no history of SA (n = 60) composed the intermediate SR group. We compared the number of neutrophil granulocytes, monocytes, lymphocytes, platelets, white blood cell count (WBC), neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), red blood cell distribution width (RDW) and erythrocyte sedimentation rate (ESR). Furthermore, we evaluated alterations of these parameters related to antidepressant (AD) and antipsychotic (AP) treatment, which have been proved to have anti-inflammatory effects. We found a significant increase in neutrophil granulocyte count, NLR, monocyte count, MLR, WBC and ESR in patients with recent SA compared to patients with no history of SA. Moreover, there was a significant elevation in monocyte count, MLR, ESR and RDW in patients with high SR compared to patients with intermediate SR. AD treatment resulted in a significant decrease in neutrophil granulocyte count and NLR, however, it did not affect monocyte count and MLR. Assuming immunological mechanisms in the background of MDD and suicidality, our findings support the role of NLR as a biomarker of acute SR, though its alterations may be masked by possible anti-inflammatory effects of AD treatment in the long term. However, MLR, a marker exhibiting changes which are not attenuated by pharmacotherapy, may be a possible indicator of both acute and long-term suicidal vulnerability.

Association between alopecia areata, anxiety, and depression: Insights from a bidirectional two-sample Mendelian randomization study

BackgroundAs research progresses, there has been growing interest in the association between Alopecia areata (AA) and anxiety, as well as depression. However, there have been limited reports on the genetic variation level of AA in relation to mental disorders. MethodWe performed large-scale Two sample Mendelian randomization (MR) analyses to examine whether there is a association between AA with anxiety and depression. The data utilized for AA analysis were sourced from the FinnGen release 9 databases, including 682 cases and 361,822 controls. Summary statistics for major depression disorder (MDD) were obtained from a genome-wide meta-analysis dataset, incorporating 170,756 cases and 329,443 controls. The anxiety disorder data was conducted by the Anxiety Neuro Genetics Study Consortium, including 5580 cases and 11,730 controls. We employed four distinct approaches, including MR-Egger, weighted median, random-effect inverse variance weighted (IVW), and weighted mode, to conduct the MR analysis. ResultsGenetic liability to AA was associated with an increased risk of Major depression disorder (MDD) and anxiety demonstrated an odds ratio (OR) of 1.01 (βivw = 0.011, PIVW = 0.023) and OR of 1.16 (βivw = 0.150, PIVW = 0.002). Upon conducting the Bonferroni correction, the P-values were 0.046 and 0.004, respectively. For reverse analysis, we observed no significant association between anxiety and MDD with the risk of AA. ConclusionsOur research unveil a unidirectional causal association whereby AA exerts a risk effect against MDD and anxiety, which serves as a valuable complement to prior meta-analyses, enriching the existing body of knowledge on the subject matter.

Association between serum and urinary environmental metal levels and major depressive disorder: a study based on logistic regression and quantile regression.

Major depressive disorder (MDD) is a prevalent mental disorder globally. Increasing evidence suggests that Environmental Metal (EM) play a crucial role in MDD. Therefore, this study investigated the roles of barium (Ba), cesium (Cs), nickel (Ni), manganese (Mn), lead (Pb), mercury (Hg), cadmium (Cd), and tin (Sn) in the etiology of MDD. The study included 72 MDD patients and 75 healthy controls (HCs) from the Second People's Hospital of Zhumadian, China. Inductively coupled plasma mass spectrometer (ICP-MS) measured the metal levels in serum and urine samples from both groups. Significant differences in serum and urine levels of EMs were observed between MDD patients and HCs. After adjusting for age, gender, and BMI, logistic regression and quantile regression models revealed significant associations between EMs and MDD. In serum samples, higher Sn levels (OR = 1.22, p = 0.044) increased MDD risk, whereas higher Cs levels (OR = 0.02, p < 0.001), Cd (OR = 0.06, p = 0.047), and Mn (OR = 0.54, p = 0.016) decreased MDD risk. In urine samples, higher Ba levels (OR = 0.94, p = 0.015), Ni (OR = 0.87, p = 0.0024), Sn (OR = 1.62, p < 0.001), and Mn (OR = 0.77, p = 0.037) were significantly associated with MDD. Sn significantly positively predicted HAMD-24 scores at the 0.50 and 0.75 quantiles (β = 0.96, p = 0.018; β = 1.25, p = 0.008) as did Pb (β = 5.15, p = 0.001; β = 4.19, p = 0.004). Ba positively predicted depressive symptoms across all quantiles (all p < 0.05). Hg positively predicted HAMD-24 scores at the 0.50 quantile (β = 9.20, p = 0.050). These findings underscore EMs' importance in depression, aiding in targeted interventions for varying degrees of depression and necessitating future studies to clarify causality and mechanisms.

The long-term spatio-temporal trends in burden and attributable risk factors of major depressive disorder at global, regional and national levels during 1990-2019: a systematic analysis for GBD 2019.

Caused by multiple risk factors, heavy burden of major depressive disorder (MDD) poses serious challenges to public health worldwide over the past 30 years. Yet the burden and attributable risk factors of MDD were not systematically known. We aimed to reveal the long-term spatio-temporal trends in the burden and attributable risk factors of MDD at global, regional and national levels during 1990-2019. We obtained MDD and attributable risk factors data from Global Burden of Disease Study 2019. We used joinpoint regression model to assess the temporal trend in MDD burden, and age-period-cohort model to measure the effects of age, period and birth cohort on MDD incidence rate. We utilized population attributable fractions (PAFs) to estimate the specific proportions of MDD burden attributed to given risk factors. During 1990-2019, the global number of MDD incident cases, prevalent cases and disability-adjusted life years (DALYs) increased by 59.10%, 59.57% and 58.57%, respectively. Whereas the global age-standardized incidence rate (ASIR), age-standardized prevalence rate (ASPR) and age-standardized DALYs rate (ASDR) of MDD decreased during 1990-2019. The ASIR, ASPR and ASDR in women were 1.62, 1.62 and 1.60 times as that in men in 2019, respectively. The highest age-specific incidence, prevalence and DALYs rate occurred at the age of 60-64 in women, and at the age of 75-84 in men, but the maximum increasing trends in these age-specific rates occurred at the age of 5-9. Population living during 2000-2004 had higher risk of MDD. MDD burden varied by socio-demographic index (SDI), regions and nations. In 2019, low-SDI region, Central sub-Saharan Africa and Uganda had the highest ASIR, ASPR and ASDR. The global PAFs of intimate partner violence (IPV), childhood sexual abuse (CSA) and bullying victimization (BV) were 8.43%, 5.46% and 4.86% in 2019, respectively. Over the past 30 years, the global ASIR, ASPR and ASDR of MDD had decreased trends, while the burden of MDD was still serious, and multiple disparities in MDD burden remarkably existed. Women, elderly and populations living during 2000-2004 and in low-SDI regions, had more severe burden of MDD. Children were more susceptible to MDD. Up to 18.75% of global MDD burden would be eliminated through early preventing against IPV, CSA and BV. Tailored strategies-and-measures in different regions and demographic groups based on findings in this studywould be urgently needed to eliminate the impacts of modifiable risk factors on MDD, and then mitigate the burden of MDD.

Higher atherogenic index of plasma is associated with increased major depressive disorder: insights from a nationally representative study.

Emerging studies reveal a shared pathophysiological underpinning for metabolic problems and mental illnesses. The present study aimed to determine the association between atherogenic index of plasma (AIP) and the incidence of major depressive disorder (MDD). 7,951 subjects of US adults were collected from the National Health and Nutrition Examination Survey (NHANES) 2005-2018. MDD was evaluated through the Patient Health Questionnaire (PHQ-9). Multivariate logistic regression, sensitivity analysis, and spline smoothing plot method were used to identify the relationship between AIP and MDD. The cut-off point was calculated using recursive partitioning analysis when segmenting effects emerged. The area under the receiver operating characteristic (ROC) curve (AUC) and Hosmer-Lemeshow test were conducted to evaluate the performance of AIP in identifying MDD. Subgroup analyses and interaction tests were used to explore whether the association was stable in different populations. A positive correlation between AIP and PHQ-9 score and MDD was both observed in 7,951 subjects included in the study, with a significant threshold of -0.42 determined using recursive partitioning analysis. In the fully adjusted model, a positive association between AIP and PHQ-9 score and MDD was observed (β=0.46, 95% CI 0.14~0.78; OR=1.42, 95% CI 1.04~1.93). Individuals in the highest AIP quartile had a 0.39-unit higher PHQ-9 score (β=0.39, 95% CI 0.12~0.66) and a significantly 33% greater risk of MDD than those in the lowest AIP quartile (OR=1.33, 95% CI 1.02~1.73). Spline smoothing plot analysis further confirmed the positive and non-linear association between AIP and PHQ-9 and MDD. ROC analysis (AUC=0.771) and the Hosmer-Lemeshow test (χ2 = 14.239, P=0.076) suggested an excellent performance and goodness-of-fit of the relatively optimal model. DCA and CIC analysis also revealed a favorable overall net benefit and clinical impact of the model. Subgroup analyses and interaction tests revealed that the association between AIP and PHQ-9 score and MDD remained consistent across different subgroups and was not modified by other covariates, and this positive correlation was more pronounced in those with diabetes or hypertension. An elevated AIP is linked to a higher chance of MDD, especially in those with diabetes or hypertension. Resolving dyslipidemia and managing comorbidities may help reduce the likelihood of developing MDD.

Genetic evidence suggests a genetic association between major depressive disorder and reduced cortical gray matter volume: A Mendelian randomization study and mediation analysis

BackgroundSeveral studies have suggested an association between major depressive disorder (MDD) and abnormal brain structure. However, it is unclear whether MDD affects cortical gray matter volume, a common indicator of cognitive function. We aimed to determine whether MDD was associated with decreased cortical gray matter volume (GMV) through a Mendelian randomization (MR) study. MethodsWe obtained summary genetic data from a study conducted by the Psychiatric Genomics Consortium, which recruited a total of 480,359 participants (135,458 cases and 344,901 controls). Genetic tools—single nucleotide polymorphisms (SNPs)—of MDD were extracted from the study and their effects on gray matter volumes of the cortex and total brain were evaluated in a large cohort from the UK Biobank (n = 8427). The effects of the SNPs were pooled using inverse variance weighted (IVW) analysis and further tested in several sensitivity analyses. We tested whether C-reactive protein (CRP) levels and interleukin-6 signaling were the mediators of the effects using a multivariate MR model. ResultsThirty-three SNPs were identified and adopted as genetic tools for predicting MDD. IVW analysis showed that MDD was associated with lower overall GMV (beta value −0.106, 95%CI -0.188 to −0.023, p = 0.011) in the frontal pole (left frontal pole, −0.152, 95%CI -0.177 to −0.127, p = 0.013; right frontal pole, −0.133, 95%CI -0.253 to −0.013, p = 0.028). Multivariate and mediation analysis showed that interleukin-6 was an important mediator of GMV reduction. Reverse causality analysis found no evidence that total GMV affected the risk of MDD, but showed that increased left precuneus cortex volume and left posterior cingulate cortex volume were associated with increased risk of MDD. LimitationsPotential pleiotropic effects and overestimation of real-world effects. Key assumptions for MR analysis may not be satisfactorily met. ConclusionMDD was associated with a reduced GMV, and interleukin-6 might be a mediator of GMV reduction.

Common and distinct neural correlates of emotional processing in individuals at familial risk for major depressive disorder and bipolar disorder: A comparative meta-analysis

Individuals at familial risk for mood disorders exhibit deficits in emotional processing and associated brain dysfunction prior to illness onset. However, such brain-behavior abnormalities related to familial predisposition remain poorly understood. To investigate robust abnormal functional activation patterns during emotional processing in unaffected at-risk relatives of patients with major depressive disorder (UAR-MDD) and bipolar disorder (UAR-BD), we performed a meta-analysis of task-based functional magnetic resonance imaging studies using Seed-based d Mapping (SDM) toolbox. Common and distinct patterns of abnormal functional activation between UAR-MDD and UAR-BD were detected via conjunction and differential analyses. A total of 17 studies comparing 481 UAR and 670 healthy controls (HC) were included. Compared with HC, UAR-MDD exhibited hyperactivation in the parahippocampal gyrus, amygdala and cerebellum, while UAR-BD exhibited parahippocampal hyperactivation and hypoactivation in the striatum and middle occipital gyrus (MOG). Conjunction analysis revealed shared hyperactivated PHG in both groups. Differential analysis indicated that the activation patterns of amygdala and MOG significantly differed between UAR-MDD and UAR-BD. These findings provide novel insights into common and distinct neural phenotypes for familial risk and associated risk mechanisms in MDD and BD, which may have implications in guiding precise prevention strategies tailored to the family context.

The Kessler Psychological Distress Scale in Australian adolescents: Analysis of the second Australian Child and Adolescent Survey of Mental Health and Wellbeing.

The 10-item Kessler Psychological Distress Scale (K10) is used to screen adolescents for mental disorders in Australian clinical practice; however, there are no Australian adolescent normative data. Data were drawn from a nationally representative sample (N = 2964) of Australian adolescents (11-17 years). This study had three aims: (1) to examine concurrent validity between the K10 and Strengths and Difficulties Questionnaire (SDQ) emotional symptoms subscale, (2) to establish normative Australian adolescent K10 data and (3) to determine optimal K10 cut-off scores for screening for major depressive disorder (MDD) via receiver operator characteristic curve analysis and stratum-specific likelihood ratios. The K10 and SDQ emotional symptoms scales were moderately correlated (rs = 0.63, p < 0.001). Older female adolescents reported higher total K10 scores compared with younger female adolescents (15-17 years: M = 20.2, standard error [SE] = 0.3; 11-14 years: M = 16.8, SE = 0.3) and male adolescents (11-14 years: M = 16.6, SE = 0.2; 15-17 years: M = 16.0, SE=0.2). K10 scores to optimally discriminate those with and without MDD varied by age and sex and had low specificities. Stratum-specific likelihood ratios indicated adolescents with a K10 score of ≥30 will have a 12.9 (95% confidence interval = [10.2, 16.2]) increased likelihood of MDD. The K10 has utility for assessing psychological distress in health care and epidemiological research in Australian adolescents. Adolescents with K10 scores in the 'very high' range are at increased risk of MDD. Further assessment of these young people is indicated to identify those with or at risk of developing MDD.

Peripheral immunity and risk of incident brain disorders: a prospective cohort study of 161,968 participants

Whether peripheral immunity prospectively influences brain health remains controversial. This study aims to investigate the longitudinal associations between peripheral immunity markers with incident brain disorders. A total of 161,968 eligible participants from the UK Biobank were included. We investigated the linear and non-linear effects of peripheral immunity markers including differential leukocytes counts, their derived ratios and C-reactive protein (CRP) on the risk of dementia, Parkinson’s disease (PD), stroke, schizophrenia, bipolar affective disorder (BPAD), major depressive disorder (MDD) and anxiety, using Cox proportional hazard models and restricted cubic spline models. Linear regression models were used to explore potential mechanisms driven by brain structures. During a median follow-up of 9.66 years, 16,241 participants developed brain disorders. Individuals with elevated innate immunity markers including neutrophils, monocytes, platelets, neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII) had an increased risk of brain disorders. Among these markers, neutrophils exhibited the most significant correlation with risk of dementia (hazard ratio 1.08, 95% confidence interval 1.04–1.12), stroke (HR 1.06, 95% CI 1.03–1.09), MDD (HR 1.13, 95% CI 1.10–1.16) and anxiety (HR 1.07, 95% CI 1.04–1.10). Subgroup analysis revealed age-specific and sex-specific associations between innate immunity markers with risk of dementia and MDD. Neuroimaging analysis highlighted the associations between peripheral immunity markers and alterations in multiple cortical, subcortical regions and white matter tracts, typically implicated in dementia and psychiatric disorders. These findings support the hypothesis that neuroinflammation is important to the etiology of various brain disorders, offering new insights into their potential therapeutic approaches.

Gender differences in the association between cardiovascular diseases and major depressive disorder among older adults in India.

Despite the global disease burden associated with the co-occurrence of cardiovascular diseases (CVDs) and depression, depression remains underdiagnosed and undertreated in the CVD population, especially among older adults in India. As such, this study examines (1) the association between single and multiple CVDs and major depressive disorder among older Indians; (2) whether this association is mediated by older adults' self-rated health and functional limitations; and (3) whether these associations vary for older men and women. Data come from the 2017-18 wave 1 of the Longitudinal Ageing Study in India. Multivariable logistic regression is used to explore the association between CVDs and major depressive disorder among older men and women. The Karlson-Holm-Breen (KHB) method is used to examine the mediation effects of self-rated health and functional difficulties in the observed associations. Overall, 5.08% of the older adults had multiple CVDs. Older women (9.71%) had a higher prevalence of major depressive disorder compared to men (7.50%). Multiple CVDs were associated with greater odds of major depressive disorder after adjusting the potential covariates (adjusted odds ratio [AOR]: 1.49; 95% confidence interval [CI]: 1.10-2.00). Older men with multiple CVDs had a greater risk of major depressive disorder (AOR: 1.64; 95% CI: 1.05-2.57) relative to women with CVDs (AOR: 1.39; 95% CI: 0.93-2.08). The association between multiple CVDs and depression was mediated by self-rated health (34.03% for men vs. 34.55% for women), ADL difficulty (22.25% vs. 15.42%), and IADL difficulty (22.90% vs. 19.10%). One in five older Indians with multiple CVDs reports major depressive disorder, which is three times more common than the prevalence of depressive disorder in older adults without CVDs. This association is attenuated by self-rated health and functional limitations. Moreover, these associations are more pronounced in older men relative to older women. These findings depart from prior inferences that men with CVDs are less psychologically distressed than their female counterparts. Moreover, the findings underscore the importance of gender-specific approaches to interventions and therapeutics for CVD-related mental health.

The impact of genetic risk for schizophrenia on eating disorder clinical presentations

A growing body of literature recognizes associations between eating disorders (EDs) and schizophrenia and suggests that familial liability to schizophrenia in individuals with anorexia nervosa (AN) reveals distinct patterns of clinical outcomes. To further investigate the influence of schizophrenia genetic liability among individuals with EDs, we evaluated the associations between schizophrenia polygenic risk scores (PRS) and clinical presentations of individuals with EDs including their overall health condition and ED-related symptoms. Using data from two previous studies of the genetics of EDs comprising 3,573 Anorexia Nervosa Genetics Initiative (ANGI) cases and 696 Binge Eating Genetics Initiative (BEGIN) cases born after 1973 and linked to the Swedish National Patient Register, we examined the association of schizophrenia PRS on ED clinical features, psychiatric comorbidities, and somatic and mental health burden. Among ANGI cases, higher schizophrenia PRS was statistically significantly associated with higher risk of major depressive disorder (MDD) measured by hazard ratio (HR) with 95% confidence interval (CI) (HR [95% CI]: 1.07 [1.02, 1.13]) and substance abuse disorder (SUD) (HR [95% CI]: 1.14 [1.03, 1.25]) after applying multiple testing correction. Additionally, higher schizophrenia PRS was associated with decreased clinical impairment assessment scores (−0.56, 95% CI: [−1.04, −0.08]) at the conventional significance level (p < 0.05). Further, in BEGIN cases, higher schizophrenia PRS was statistically significantly associated with earlier age at first ED symptom (−0.35 year, 95% CI: [−0.64, −0.06]), higher ED symptom scores (0.16, 95% CI: [0.04, 0.29]), higher risk of MDD (HR [95% CI]: 1.18 [1.04, 1.34]) and SUD (HR [95% CI]: 1.36 [1.07, 1.73]). Similar, but attenuated, patterns held in the subgroup of exclusively AN vs other eating disorder (OED) cases. These results suggest a similar pattern of influence of schizophrenia PRS for AN and OED cases in terms of psychiatric comorbidities, but a different pattern in terms of ED-related clinical features. The disparity of the effect of schizophrenia PRS on AN vs OED merits further investigation.

Psychiatric and substance use disorders among adults over age 50 who use cannabis: A matched cohort study using electronic health record data

IntroductionAdults over age 50 increasingly use cannabis, but few studies have examined co-occurring psychiatric and substance use disorders (SUDs) in this population. The current study utilized electronic health record (EHR) data to compare adults age 50 + with ICD-10 cannabis codes (cases) and matched controls on common psychiatric and SUDs from 2016 to 2020. MethodPatients age 50 + from an integrated healthcare system in Hawai’i were identified using ICD-10 codes for cannabis (use, abuse, and dependence) from 2016 to 2018. In a matched cohort design, we selected non-cannabis-using controls (matched on sex and age) from the EHR (n = 275) and compared them to cases (patients with an ICD-10 cannabis code; n = 275) on depressive and anxiety disorders and SUDs (i.e., tobacco, opioid, and alcohol use disorders) over a two-year follow-up period. ResultsParticipants were 62.8 years (SD = 7.3) old on average; and were White (47.8 %), Asian American (24.4 %), Native Hawaiian or Pacific Islander (19.3 %), or Unknown (8.5 %) race/ethnicity. Conditional multiple logistic regression was used to estimate odds ratios comparing cases vs controls. Participants with an ICD-10 cannabis code had a significantly greater risk of major depressive disorder (OR = 10.68, p < 0.0001) and any anxiety disorder (OR = 6.45, p < 0.0001), as well as specific anxiety or trauma-related disorders (e.g., generalized anxiety disorder, PTSD) and SUDs (ORs 2.72 – 16.00, p < 0.01 for all). ConclusionsOver a two-year period, diverse adults age 50 + in Hawai’i with ICD-10 cannabis codes experienced higher rates of subsequent psychiatric and SUDs compared to controls. These findings can guide efforts to inform older adults about possible cannabis-related risks.

Impact of painful physical symptoms on first-episode major depressive disorder in adults with subthreshold depressive symptoms: A prospective cohort study

ObjectiveTo investigate the impact of baseline painful physical symptoms (PPS) on subsequent first-episode major depressive disorder (MDD) in adults with subthreshold depressive symptoms, including subgroup analyses to assess whether the associations differ in individuals with and without physical diseases. MethodsA total of 2343 adults with subthreshold depressive symptoms were recruited at 34 primary health care centers. PPS were measured at baseline. First-episode MDD during follow-up was diagnosed by professional psychiatrists using the Mini-International Neuropsychiatric Interview. ResultsBaseline PPS showed independent impacts on first-episode MDD in adults with subthreshold depressive symptoms without physical diseases, but not in those with physical diseases. A non-linear association (P < 0.001) was observed between PPS burden and the risk of first-episode MDD. The HRs for first-episode MDD exhibited a rapidly increasing trend between PPS burden scores of 10–16, and maintained consistently high when scores exceeded 16. The analyses for specific PPS revealed that headache, neck pain, and heart or chest pain were independently associated with first-episode MDD in participants without physical diseases, the HRs were 1.57 (1.15–2.36), 1.53 (1.02–2.30), and 1.69 (1.14–2.50), respectively. Further network analysis demonstrated that heart or chest pain serves as a bridge symptom among the seven specific PPS and first-episode MDD in those without physical diseases. ConclusionPPS burden and heart or chest pain may be significant indicators for first-episode MDD in adults with subthreshold depressive symptoms without physical diseases. Future studies should investigate whether interventions targeting PPS can prevent episode MDD in this subthreshold population.

Resting-State Functional Connectivity of the Anterior Cingulate Cortex Among Persons With Mood Disorders and Suicidal Behaviors.

To assess whether anterior cingulate cortex (ACC) abnormalities contribute to suicide risk in major depressive disorder and bipolar disorder, the investigators compared resting-state functional connectivity (rsFC) of ACC subdivisions between individuals with major depressive or bipolar disorder with and without a lifetime history of suicidal behavior. Forty-two inpatients with and 26 inpatients without a history of suicidal behavior (SB+ and SB-, respectively) associated with major depressive or bipolar disorder and 40 healthy control (HC) participants underwent rsFC neuroimaging. RsFC of the subgenual, perigenual, rostral, dorsal, and caudal subdivisions of the ACC was calculated. Possible confounders, such as psychosis and severity of depression, were controlled for, seed-to-voxel and post hoc region of interest (ROI)-to-ROI analyses were performed, and the accuracy of rsFC in classifying suicidal behavior was studied. Compared with individuals in the SB- and HC groups, patients in the SB+ group had higher rsFC between the left rostral and right dorsal ACC seeds and visual cortex clusters. Conversely, rsFC between the left rostral and right dorsal ACC seeds and cingulate and frontal clusters was lower in the SB+ group than in the HC group. Left rostral ACC to left Brodmann's area 18 connectivity showed up to 75% discriminative accuracy in distinguishing SB+ from SB- patients. A history of suicidal behavior among individuals with major depressive disorder or bipolar disorder was associated with altered rsFC of the rostral and caudal ACC, regions involved in conflict detection and error monitoring. Replication of these findings is needed to further explore the involvement of the ACC in the neurobiology of suicidal behavior and suicidal ideation.