Journal Of Affective Disorders[JOURNAL]
Sun
200 papers
From polyvictimization to heterogeneous sequelae: Four-wave longitudinal investigation of children's complex PTSD symptom trajectories.
Liang Y, Ni Z, Xu J … +4 more , Xu S, Wei C, Peng Y, Xi J
J Affect Disord · 2026 Jun · PMID 42365931 · Publisher ↗
Complex post-traumatic stress disorder (CPTSD) is clinically associated with chronic and repeated traumatic exposures during childhood, but related research examining trajectories of CPTSD alongside their risk and protec...
Complex post-traumatic stress disorder (CPTSD) is clinically associated with chronic and repeated traumatic exposures during childhood, but related research examining trajectories of CPTSD alongside their risk and protective factors remains critically scarce. This study aims to investigate CPTSD trajectories and identify predictors among de facto unattended children in China. 298 de facto unattended children were assessed at 4 intervals in 2 years on CPTSD symptoms and external (threats and deprivation experiences) and internal associated factors (feelings of loneliness, security, and hope). Parallel process latent growth analysis (PP-LCGA) was used to determine the joint trajectories of PTSD and disturbances in self-organization (DSO) symptoms of CPTSD. Multinomial logistic regression was performed to identify risk and protective factors. The results indicated that PTSD and DSO symptoms develop synchronously overall. Four heterogeneous groups of CPTSD symptoms were identified: low symptoms group (29.87%), moderate symptoms group (47.43%), persistent high symptoms group (12.75%), and delayed deterioration group (11.07%). Additionally, different external factors (threats and deprivation experiences) were detected as important associated factors of different trajectories. As for internal factors, the sense of loneliness emerged as a significant risk factor, whereas the sense of security functioned as a protective factor. The observed concurrent development of PTSD and DSO symptoms lends support to the distinction of CPTSD as an independent diagnostic entity. Our findings call for further attention to experiences of deprivation and the enhancement of children's sense of security, which may strengthen their adaptive capacity, thereby protecting and promoting their mental health.
Peripheral and central inflammatory markers associated with anxiety in epilepsy: A combined biomarker model.
Chen Y, He M, Zhao T … +6 more , Wang N, Sun L, Wang B, Han J, Zhou Y, Han X
J Affect Disord · 2026 Jun · PMID 42365930 · Publisher ↗
BACKGROUND: Anxiety is a common psychiatric comorbidity in epilepsy and is associated with adverse clinical outcomes. Emerging evidence suggests that inflammatory processes may contribute to its pathophysiology; however,...
BACKGROUND: Anxiety is a common psychiatric comorbidity in epilepsy and is associated with adverse clinical outcomes. Emerging evidence suggests that inflammatory processes may contribute to its pathophysiology; however, the relationship between peripheral and central inflammatory markers and anxiety in epilepsy remains unclear. METHODS: This retrospective study included 184 patients with epilepsy, classified into those with anxiety symptoms (EP-A, n = 107) and without anxiety (EP-nA, n = 77) based on the Hamilton Anxiety Rating Scale. Clinical data and inflammatory markers from peripheral blood and cerebrospinal fluid (CSF) were collected. Logistic regression, restricted cubic spline (RCS) analysis, and receiver operating characteristic (ROC) curves were used to identify independent risk factors and evaluate predictive performance. RESULTS: Patients with anxiety symptoms exhibited significantly elevated peripheral inflammatory markers, including platelet count, monocyte count, CRP, CAR, and PLR (all P < 0.05), as well as increased central markers such as CSF white blood cell count, lactate, and IgG index (all P < 0.05). Multivariate analysis identified CAR, PLR, CSF lactate, and IgG index as independent risk factors. RCS analysis demonstrated nonlinear associations for several markers, with risk increasing sharply beyond specific thresholds. The combined model showed good predictive performance (AUC = 0.814), with satisfactory sensitivity and specificity. CONCLUSIONS: Peripheral and central inflammatory markers are associated with anxiety in epilepsy. A combined biomarker model may provide a clinically useful tool for early risk stratification and supports a potential role of neuroinflammation in epilepsy-related anxiety.
Altered thalamic subregional connectivity with default mode and frontoparietal networks in adolescents with depression.
Ji J, Sun H, Liu Y … +3 more , Yu H, Zhang X, Xu C
J Affect Disord · 2026 Jun · PMID 42365929 · Publisher ↗
BACKGROUND: The thalamus plays a pivotal role in the pathophysiology of adolescent depression, with its subregions showing functional heterogeneity. Abnormalities in the default mode (DMN) and frontoparietal networks (FP...
BACKGROUND: The thalamus plays a pivotal role in the pathophysiology of adolescent depression, with its subregions showing functional heterogeneity. Abnormalities in the default mode (DMN) and frontoparietal networks (FPN) are associated with depressive symptoms, and both networks are closely coupled with the thalamus. This study examined, at a finer granularity, functional connectivity (FC) changes between thalamic subregions and these networks in depressed adolescents, aiming to reveal underlying mechanisms and explore their potential as diagnostic biomarkers. METHOD: This study included 64 depressed adolescents and 54 matched healthy controls. All participants underwent functional magnetic resonance imaging. Using thalamic subregions as seeds, we calculated the FC of these seeds with the DMN and FPN. We correlated FC values exhibiting group differences with clinical scores and constructed a machine learning model to evaluate clinical relevance and predictive accuracy. RESULTS: Compared to healthy controls, depressed adolescents exhibited reduced connectivity between the right ventral posterior (VP) thalamus and bilateral anterior cingulate cortex, and between the left VP thalamus and the right supramarginal gyrus (SMG) and inferior parietal lobule. The FC strength between the left VP thalamus and right SMG was negatively correlated with self-esteem. The classifier incorporating these altered FCs demonstrated moderate discriminative ability between the groups, where each feature contributed to the model decision. CONCLUSION: This study identified abnormal FC between thalamic subregions and the DMN and FPN. These alterations may contribute to the onset and progression of adolescent depression and show promise as potential biomarkers, thus providing a more objective basis for clinical diagnosis.
The effect of cumulative trauma load on suicide risk and thoughts in trauma-exposed youth over two years.
Metts A, Creech SK, Leri J … +9 more , Dodd CG, Newport DJ, Shahidullah JD, Rousseau JF, Foshee KL, Richmond RE, Garrett AS, Wagner KD, Nemeroff CB
J Affect Disord · 2026 Jun · PMID 42364662 · Publisher ↗
Trauma exposure has been linked to increased risk for suicide, a leading cause of death among youth. To date, most research identifying trauma as a risk factor for suicidality has been based on cross-sectional studies. T...
Trauma exposure has been linked to increased risk for suicide, a leading cause of death among youth. To date, most research identifying trauma as a risk factor for suicidality has been based on cross-sectional studies. To understand if trauma confers prospective risk for suicidality, this study used two-year longitudinal data from youth with trauma histories enrolled in the Texas Childhood Trauma Research Network. We analyzed data from 2606 youth assessed at baseline, including 1252 with two-year follow-up data. Analyses included youth with and without Criterion A trauma. Linear mixed effect models were estimated to disentangle the effects of trauma on between- and within-subject changes in two dimensions of suicidality, Propensity for Suicide and Suicidal Thoughts. Results demonstrated evidence for small between-person effects of cumulative trauma load and Propensity for Suicide (Posterior Median [Mdn.] = 0.16, SD = 0.03, adjusted p < .001) and Suicidal Thoughts (Mdn. = 0.10, SD = 0.03, adjusted p < .001). Unexpectedly, there was also evidence for a negative within-person effect of cumulative trauma load changes on Propensity for Suicide, with the effect falling below the threshold for a small effect (Mdn. = -0.04, SD = 0.01, adjusted p = .012). Sensitivity analyses indicated that unintentional trauma exposure may have driven the within-person effect, whereas unintentional trauma and interpersonal trauma exposure consistently demonstrated positive between-person effects. These findings demonstrate the long-term impact of trauma exposure on increased risk for suicide and suicidal thoughts in youth. Clinical implications for reducing suicidality risk in trauma-exposed youth are discussed.
Multimodal connectomic signatures of functional rigidity identify bipolar disorder at the individual level.
Zhang X, Liu Y, Xu Y … +5 more , Liang H, Chen G, Yao Z, Fu Y, Yang R
J Affect Disord · 2026 Jun · PMID 42364661 · Publisher ↗
BACKGROUND: Bipolar Disorder (BD) is characterized by severe emotional instability. While traditionally viewed through the lens of anatomical dysconnectivity, it remains unclear how the brain's anatomical scaffold abnorm...
BACKGROUND: Bipolar Disorder (BD) is characterized by severe emotional instability. While traditionally viewed through the lens of anatomical dysconnectivity, it remains unclear how the brain's anatomical scaffold abnormally constrains its functional dynamics to produce such volatile mood states. METHODS: We investigated the multi-modal connectome in 41 BD patients and 40 healthy controls (N=81). A high-fidelity pipeline was employed to robustly reconstruct structural networks. We then applied Graph Signal Processing (GSP) and functional gradient analysis to resting-state fMRI data to quantify structure-function alignment and hierarchical network dynamics. RESULTS: Network-based statistics revealed no NBS-detected macroscale structural disruptions in BD. However, GSP analysis uncovered a profound pathological shift toward "functional rigidity". BD patients exhibited significantly elevated structure-function alignment (hyper-coupling), indicating that functional dynamics are excessively restricted by the underlying anatomical backbone. Furthermore, a multimodal connectomic model demonstrated good performance in distinguishing BD from healthy controls at the individual level (accuracy=74.1%, AUC=0.888, sensitivity=70.7%, specificity=77.5%, permutation p=0.001). SHAP analysis localized the dominant predictors to the prefrontal-limbic emotion-regulation circuit. CONCLUSION: BD is characterized by profound "functional rigidity" rather than sheer anatomical degradation. This excessive structure-function tethering may constitute a candidate inter-episode connectomic signature with preliminary individual-level discrimination potential, offering new insights into the connectomic basis of inter-episode functional dysregulation in BD and motivating prospective validation in independent longitudinal cohorts.
Comorbid impairments of emotional and cognitive functions induced by different sleep deprivation durations.
Shi L, Li F, Shan M … +4 more , Sun S, Yan G, Dong L, Hu H
J Affect Disord · 2026 Jun · PMID 42364660 · Publisher ↗
Sleep deprivation (SD) is a major risk factor for neuropsychiatric disorders and is known to induce comorbid emotional and cognitive impairments; however, the temporal dynamics and underlying mechanistic pathways remain...
Sleep deprivation (SD) is a major risk factor for neuropsychiatric disorders and is known to induce comorbid emotional and cognitive impairments; however, the temporal dynamics and underlying mechanistic pathways remain poorly defined. Here, we established a standardized rotating rod-based SD model using male ICR mice (4-6 weeks old) to systematically investigate the effects of different SD durations. (1, 2, 3, or 7 days) on emotional and cognitive functions and the potential involvement of ferroptosis-related mechanisms. Emotional and cognitive functions were evaluated using a battery of behavioral tests. Hippocampal morphology was assessed by hematoxylin-eosin staining, while hippocampal ferrous iron content, systemic oxidative stress markers including total antioxidant capacity, glutathione, and malondialdehyde, together with ferroptosis-related protein expression were quantified. Our study demonstrated that 1-day SD induced anxiety-like behaviors and a stress-induced hyperactive state, accompanied by mild cognitive deficits. In contrast, prolonged SD (3- and 7-day SD) progressively promoted depressive-like behaviors accompanied by worsening cognitive deficits. Histological analysis revealed duration-dependent neuronal loss and structural damage in the hippocampal CA1 and CA3 regions. Biochemical analyses revealed duration-dependent alterations in hippocampal Fe levels, with marked lipid peroxidation dysregulation emerging after 7-day SD. Western blotting analysis indicated that 7-day SD markedly disrupted hippocampal ferroptosis-related SIRT1/SLC7A11/GPX4 signaling pathways. In conclusion, SD induce duration-dependent comorbid emotional and cognitive dysfunction, accompanied by hippocampal injury and ferroptosis-related alterations. These findings provide preliminary evidence for a potential link between SD-induced neurobehavioral impairments and ferroptosis-related changes, warranting further mechanistic investigation.
Measurement stability and differential domain-specific trajectories of the PHQ-9 in late-life depression: Evidence from a collaborative care trial.
Ndukwe R, Scazufca M, Van de Ven P
J Affect Disord · 2026 Jun · PMID 42364659 · Publisher ↗
BACKGROUND: The Patient Health Questionnaire-9 (PHQ-9) is routinely used to monitor depressive symptoms. However, whether its empirically derived two-factor structure remains stable across repeated assessments in clinica...
BACKGROUND: The Patient Health Questionnaire-9 (PHQ-9) is routinely used to monitor depressive symptoms. However, whether its empirically derived two-factor structure remains stable across repeated assessments in clinically depressed populations is not well established. METHODS: Using item-level data from a secondary analysis of the PROACTIVE cluster-randomised controlled trial (N=558; PHQ-9 ≥10 at baseline; aged ≥60 years), we evaluated longitudinal measurement invariance of an empirically derived two-factor PHQ-9 structure across three assessment points using WLSMV structural equation modelling with multiple imputation. We then modelled domain-specific latent growth trajectories by trial arm and examined within-person temporal dynamics using a random intercept cross-lagged panel model (RI-CLPM). RESULTS: Metric invariance was supported and partial scalar invariance achieved across all three time points, after freeing thresholds for three interpretable items (sleep disturbance, fatigue, and suicidal ideation). The intervention was associated with a steeper improvement in cognitive-affective symptoms but showed no significant effect on somatic symptom trajectories. Within-person somatic deviations at baseline were temporally associated with subsequent cognitive-affective deviations, whereas the reverse was not. CONCLUSIONS: The two-factor structure of the PHQ-9 is metrically stable through clinical recovery in older adults with moderate-to-severe depression. Domain-specific subscores capture differential treatment response and temporal symptom dynamics that total scores conceal, and can be calculated from existing PHQ-9 items at no additional burden. These findings support the routine use of domain-level monitoring in collaborative care programmes serving older adults in low- and middle-income country (LMIC) settings.
Maternal depression and paternity leave-taking in Italy: the mediating role of coparenting and parenting stress.
Filippi B, Mancinelli E
J Affect Disord · 2026 Jun · PMID 42362066 · Publisher ↗
The transition to parenthood represents a vulnerable period for maternal mental health. Although current literature recognizes the benefit of paternity leave-taking on maternal mental health during the post-partum and fa...
The transition to parenthood represents a vulnerable period for maternal mental health. Although current literature recognizes the benefit of paternity leave-taking on maternal mental health during the post-partum and family well-being, empirical evidence on its impact remains limited. The present study aimed to evaluate the association of fathers' paternal leave on maternal mental health outcomes, as mediated by co-parenting and parenting stress. A sample of 346 Italian mothers (Mage = 34.25; SD = 4.45) of infants aged 0-12 months (Childs' age in days M = 144.97; SD = 103.05) completed an online survey assessing fathers' paternity leave uptake, maternal depressive symptoms, parenting stress, and coparenting quality. Results showed that women whose partners took paternity leave reported significantly lower depressive symptoms, lower parenting stress, and higher coparenting quality than those whose partners did not. However, paternity leave-taking was not directly associated with depressive symptoms after accounting for parenting stress and coparenting. Instead, significant indirect effects emerged: paternity leave-taking was associated with higher coparenting quality and lower parenting stress, which in turn were associated with fewer maternal depressive symptoms. Taken together, these findings highlight the positive role of fathers' paternal leave on maternal depressive symptoms during the postpartum period, particularly through increased co-parenting. Policies promoting fathers' leave uptake may therefore represent an important lever for strengthening family well-being during the transition to parenthood.
NKG2A and NKp30 expression in NK cells correlates with preserved white matter and cortical thickness and reduced negative symptoms in psychiatric disorders.
Inuggi A, Altosole T, Escelsior A … +15 more , Damele L, Cilia E, Favilla L, Marenco G, Sterlini B, Uras CRM, Parisi B, Guglielmo R, Pereira Da Silva B, Loiacono F, Fenoglio D, Filaci G, Amore M, Serafini G, Marcenaro E
J Affect Disord · 2026 Jun · PMID 42362065 · Publisher ↗
BACKGROUND AND HYPOTHESIS: Immune dysregulation contributes to the pathophysiology of schizophrenia (SZ) and bipolar disorder (BD), but specific immune alterations remain unclear. Natural killer (NK) cells, regulated by...
BACKGROUND AND HYPOTHESIS: Immune dysregulation contributes to the pathophysiology of schizophrenia (SZ) and bipolar disorder (BD), but specific immune alterations remain unclear. Natural killer (NK) cells, regulated by a balance of activating and inhibitory receptors, are increasingly implicated in neuroimmune interactions. We hypothesized that distinct NK cell receptor expression patterns may identify patient subgroups characterized by preserved brain structure and reduced symptom burden. STUDY DESIGN: We conducted deep immunophenotyping and unsupervised clustering of NK cells from 53 patients (32 BD, 21 SZ) and 25 healthy controls (HC). Frequencies of NK subsets defined by main receptor expression were examined. A subset of 58 participants also underwent MRI to assess cortical thickness and white matter microstructure. Associations between immune profiles, imaging measures and clinical symptoms were tested. STUDY RESULTS: Across clustering models, we consistently identified a patient-specific cluster (PSI) characterized by increased NKG2ANKp30 NK cells and reduced double-negative (NKG2ANKp30) NK cells. This pattern was independent of classical CD56-based maturation. Patients in the PSI cluster showed preserved cortical thickness and white matter integrity compared with patients outside the cluster, who exhibited widespread reductions relative to HC controls. Furthermore, reduced double-negative NK frequencies correlated with lower burden of negative symptoms. CONCLUSIONS: Co-expression of NKp30 and NKG2A defines a meaningful NK cell phenotype associated with immune regulation, preserved brain structure, and improved clinical outcomes in SZ and BD. This profile may represent a marker of immune resilience and neuroimmune homeostasis, with potential implications for early diagnosis, patient stratification, and novel therapeutic strategies.
History of anxiety, depression, and post-traumatic stress disorder diagnoses among midlife and older transfeminine and transmasculine adults in the United States: A cross-sectional analysis within the STRONG cohort.
Cicero EC, Flatt JD, Kaabi O … +9 more , Tangpricha V, Getahun D, McPherson L, Lash TL, Silverberg MJ, Vupputuri S, Perkins M, Barnes LL, Goodman M
J Affect Disord · 2026 Jun · PMID 42362064 · Publisher ↗
INTRODUCTION: Little is known about anxiety, depression, and post-traumatic stress disorder (PTSD) diagnoses among midlife and older transgender adults (aged 45 years and older). METHODS: This analysis used electronic he...
INTRODUCTION: Little is known about anxiety, depression, and post-traumatic stress disorder (PTSD) diagnoses among midlife and older transgender adults (aged 45 years and older). METHODS: This analysis used electronic health record data from the Study of Transition, Outcomes, and Gender, and included transfeminine (TF;n = 3080) and transmasculine (TM;n = 1705) adults aged 45+, along with demographically matched cisgender men (CM) and cisgender women (CW). History of anxiety, depression, and PTSD diagnoses among TF and TM adults and their CM and CW referents was examined. Estimates were calculated overall and stratified by age groups (45-54, 55-64, 65-74, 75+). Analyses were repeated among subgroups (gender-affirming hormone therapy (GAHT) receipt, minoritized ethnoracial status). Adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) were estimated using Poisson regression. RESULTS: aPRs (95% CI) comparing TF to CM were 2.16 (2.08, 2.23) for anxiety, 2.77 (2.66, 2.89) for depression, and 7.11 (6.16, 8.20) for PTSD; corresponding TF versus CW estimates were 1.38 (1.34, 1.42), 1.65 (1.59, 1.71), and 3.27 (2.89, 3.71). Among TM adults, aPRs versus CM were 2.36 (2.26, 2.46) for anxiety, 3.18 (3.02, 3.34) for depression, and 11.12 (9.49, 13.04) for PTSD; corresponding estimates versus CW were 1.49 (1.44, 1.54), 1.80 (1.73, 1.88), and 4.76 (4.20, 5.39). Elevated prevalence was observed across age strata and among those with evidence of GAHT receipt and was more pronounced among individuals from minoritized ethnoracial groups. CONCLUSION: Anxiety, depression, and PTSD prevalence were substantially higher among TF and TM adults than among matched cisgender referents. Mental health disparities were evident across midlife and older adulthood, underscoring the need for interventions and policies that support equitable mental health among transgender adults.
Heterogeneous trajectories of depressive symptoms in the aging process: A sequence analysis within nine-year follow-ups of Chinese cohorts.
Li Y
J Affect Disord · 2026 Jun · PMID 42362063 · Publisher ↗
OBJECTIVE: Depression in later life has increasingly become alarming with the progressive population aging worldwide, but the dynamics of depressive symptoms may vary across individuals in the aging process. This study a...
OBJECTIVE: Depression in later life has increasingly become alarming with the progressive population aging worldwide, but the dynamics of depressive symptoms may vary across individuals in the aging process. This study aims to investigate heterogeneity in trajectories of depressive symptoms among Chinese cohorts as they age and examine demographic and socioeconomic factors associated with different trajectory patterns. METHODS: Using data from the 2011-2020 China Health and Retirement Longitudinal Study (CHARLS), the study employed sequence analysis to address heterogeneity in the trajectories of depressive symptoms for Chinese cohorts aged 45-64 years (n = 6161) in 2011 and conducted multinomial logistic regression to examine factors associated with the trajectory membership. RESULTS: 43% of respondents did not report depressive symptoms over the study period. An additional eight types of trajectories of depressive symptoms were identified among respondents who experienced the emergence, persistence, or remission of depression over time. Better socioeconomic conditions were associated with decreased risks of entering depressive trajectories. Age was not necessarily linked to the presence of depression; yet, age-related events and experiences, such as the loss of spouse, diminishing family connections, and declining physical health, played significant roles in developing and sustaining depressive symptoms as people aged. CONCLUSIONS: Trajectories of depressive symptoms exhibit great heterogeneity across populations entering older ages. While long-term efforts should target socioeconomic inequalities, promoting social connections offers a modifiable pathway to mitigate depressive risk in the aging population.
Impact of amyloid-Beta on the functional hierarchies and clinical outcomes in late-life depression.
Je N, Kang DW, Um YH … +4 more , Kim S, Lim HK, Kim M, Wang SM
J Affect Disord · 2026 Jun · PMID 42362062 · Publisher ↗
Late-life depression (LLD) is characterized by high treatment resistance, particularly in patients with significant cerebral amyloid-beta (Aβ) deposition. However, the underlying mechanisms through which Aβ compromises c...
Late-life depression (LLD) is characterized by high treatment resistance, particularly in patients with significant cerebral amyloid-beta (Aβ) deposition. However, the underlying mechanisms through which Aβ compromises clinical recovery remain poorly understood. We investigated whether Aβ burden drives treatment resistance by inducing hierarchical rigidity in the brain's macroscale functional organization. We analyzed longitudinal resting-state fMRI and amyloid-PET data from 93 LLD patients (44 Aβ+, 49 Aβ-) over a one-year treatment interval. Functional connectivity (FC) gradients were constructed using diffusion map embedding to characterize the sensory-to-transmodal cortical hierarchy. At baseline, Aβ + patients exhibited widespread FC gradient aberrations, primarily within the frontoparietal control and default mode networks, despite equivalent depression severity to Aβ- patients. Following treatment, the Aβ + group showed significantly poorer clinical remission (p < 0.001). Longitudinal analysis revealed a lack of significant group × time interaction, indicating that gradient disorganization in Aβ + LLD remained unresolved. Cerebral Aβ acts as a physiological constraint on the hierarchical plasticity required for antidepressant response. This "hierarchical rigidity" suggests that Aβ anchors the brain in a dysfunctional, compressed state, precluding the adaptive reorganization necessary for recovery. Baseline functional gradients may serve as a potent prognostic marker for identifying amyloid-associated treatment resistance in LLD.
Did COVID-19 change the trajectory of children's internalising symptoms? A meta-analysis of longitudinal studies and moderating factors.
Elgendi MM, Stewart SH, Sherry S … +1 more , Deacon SH
J Affect Disord · 2026 Jun · PMID 42349528 · Publisher ↗
The COVID-19 pandemic disrupted children's and adolescents' daily lives worldwide, raising concerns about changes in internalising symptoms. Prior reviews have documented elevated depression and anxiety symptoms during t...
The COVID-19 pandemic disrupted children's and adolescents' daily lives worldwide, raising concerns about changes in internalising symptoms. Prior reviews have documented elevated depression and anxiety symptoms during the pandemic, but cross-sectional designs have limited conclusions about within-person change and its moderators. To address this gap, we conducted a meta-analysis of longitudinal studies assessing internalising symptoms before and during the COVID-19 pandemic. Eighty peer-reviewed studies (187 effect sizes) contributed data from youth aged 5-17 years across 20 countries. Standardized mean change (SMC) effect sizes were synthesised using random-effects models with robust variance estimation. Guided by Bronfenbrenner's ecological systems theory, we examined moderators spanning individual, family/school, contextual, and temporal domains. Overall, internalising symptoms increased modestly from pre- to peri-pandemic assessments (SMC = 0.32, 95% CI [0.11, 0.53]; multilevel SMC = 0.34, 95% CI [0.15, 0.53]). Effects varied widely across studies (I = 97.9%), indicating highly heterogeneous symptom trajectories, and suggesting that pooled estimates should be interpreted cautiously. Larger increases were observed in studies including parent-report measures and in contexts of full school closures and highly stringent government responses. Age, gender/sex, region, COVID prevalence, and assessment timing were not significant moderators. Although there were larger increases for composite scores across broad internalising and depressive symptoms than for anxiety or stress, there were no statistically robust between-domain differences. Together, these results indicate that internalising symptoms increased modestly during the COVID-19 pandemic, but that youth experiences were highly context-dependent, underscoring the importance of considering ecological conditions-such as school closures and policy responses-when evaluating pandemic-related mental health change.
Role of resilience in modifying the links between genetic propensity for mental disorders and irritability.
Saarinen A, Lyytikäinen LP, Lavonius V … +7 more , Asikainen T, Sormunen E, Kähönen M, Hietala J, Raitakari O, Lehtimäki T, Keltikangas-Järvinen L
J Affect Disord · 2026 Jun · PMID 42349527 · Publisher ↗
AIMS: We examined (1) whether polygenic risk scores for schizophrenia (PRS), major depression (PRS), and posttraumatic stress disorder (PRS) explain irritability between ages 20 and 50 and (2) whether these associations...
AIMS: We examined (1) whether polygenic risk scores for schizophrenia (PRS), major depression (PRS), and posttraumatic stress disorder (PRS) explain irritability between ages 20 and 50 and (2) whether these associations are modified by early psychosocial resilience. METHODS: Participants came from the prospective, population-based Young Finns Study (n = 1272-2212). The most recent available genome-wide association studies were used to calculate PRSs. Irritability was assessed over a 15-year follow-up (participants being 20-50 years old). Early resilience was assessed across five indices: psychological strength, social satisfaction, leisure time activities, responsible health behaviors, and school career. Covariates included early family environment, traumatic experiences, health behaviors, and socioeconomic factors. RESULTS: PRS and PRS showed robust positive associations with irritability, whereas PRS was only modestly associated with higher disposition to behavioral form of irritability and only in earliest adulthood. We did not observe interactions between PRSs and most resilience indices (e.g., psychological strength, social satisfaction). However, school career and leisure time activities had interactions with PRSs, indicating a stronger protective effect against irritability in individuals with higher vs. lower PRSs. PRS and PRS have clearly more robust associations with irritability compared to PRS. CONCLUSIONS: Polygenic liabilities for affective disorders but not schizophrenia are associated with higher irritability trajectories between ages 20 and 50 years. Individuals with higher or lower PRSs appeared to benefit from early resilience indices in a largely similar manner, except for school career and leisure time activities, which seemed to have particularly strong protective effects in individuals with high PRSs.
Big Five personality dimensions and their association with depressive symptom severity over the treatment course.
Berg MC, Richter M, Gruber M … +11 more , Goltermann J, Claaß LV, Herpertz J, Leenings R, Gutfleisch L, Fasshauer JM, Storck M, Blitz R, Dannlowski U, Back M, Opel N
J Affect Disord · 2026 Jun · PMID 42349526 · Publisher ↗
Personality traits and depressive symptoms are closely related, yet their coordinated change during treatment remains insufficiently understood. We examined change in Big Five scores and depression during inpatient care...
Personality traits and depressive symptoms are closely related, yet their coordinated change during treatment remains insufficiently understood. We examined change in Big Five scores and depression during inpatient care and tested whether personality trait expression was associated with symptom-specific depressive change. In this naturalistic study, 334 inpatients with affective or psychotic disorders at a German University Hospital completed Beck Depression Inventory and Big Five Inventory-2-XS across three to five assessments. Coordinated change in depression severity and personality scores was examined using bivariate latent growth models. To capture symptom-level heterogeneity, proportional-odds ordinal mixed-effects models were fitted for each BDI item using average personality scores across treatment as moderators. Depression severity decreased over treatment. Growth models showed coordinated change between depression and several personality trait scores: reductions in Neuroticism and increases in Agreeableness, Conscientiousness, and Extraversion were associated with greater reductions in depression severity. At the symptom level, higher average Neuroticism was associated with slower improvement across a broad range of affective, cognitive, somatic, and functioning-related symptoms. Higher average Agreeableness and Extraversion were associated with faster improvement in selected symptoms, while Openness showed limited symptom-specific associations and Conscientiousness showed no significant moderation effects. Self-reported personality trait scores and depression show coordinated change during inpatient treatment. Symptom-level analyses suggest that depressive symptom trajectories differ according to average personality trait expression across treatment. These findings highlight the potential value of integrating personality assessment with symptom-level monitoring, while underscoring that the observed associations are non-causal and should not be interpreted as baseline prediction.
Differential analysis of CACNA1C polymorphisms among patients with depression and bipolar disorder and exploration of sleep as a mediator.
Xu Z, Guo Y, Shao Y … +7 more , Shen T, Chen L, Chen Z, Chen S, Chen B, Yuan Y, Cai Y
J Affect Disord · 2026 Jun · PMID 42349525 · Publisher ↗
BACKGROUND: Differentiating the depressive phase of bipolar disorder (BD) from major depressive disorder (MDD) remains a significant clinical challenge. As CACNA1C is a prominent susceptibility gene for BD across diverse...
BACKGROUND: Differentiating the depressive phase of bipolar disorder (BD) from major depressive disorder (MDD) remains a significant clinical challenge. As CACNA1C is a prominent susceptibility gene for BD across diverse populations, this study evaluated the utility of its polymorphisms, combined with clinical risk factors, in distinguishing BD from MDD, while investigating the potential mediating role of sleep quality. METHODS: Subjects (188 MDD, 69 BD) were compared using Mann-Whitney U or chi-square tests. Logistic regression identified independent discriminative factors. Forty-two CACNA1C SNPs were analyzed via Haploview and UNPHASED to assess genetic distributions. Mediation analysis evaluated whether sleep quality mediates the relationship between CACNA1C variants and the BD phenotype. RESULTS: Younger onset age, positive family history, and psychotic symptoms were independently associated with BD diagnosis. Genetically, SNP rs2239128 showed a significant association with BD (adjusted P = 0.04895). Moderate linkage disequilibrium (LD) was observed for rs215976/rs215992 (r = 0.543, D' = 0.801), and weak LD for rs215995/rs123263 (r = 0.157, D' = 0.433). Four haplotypes-rs215976/rs215992 CC (OR = 0.257) and rs215995/rs123263 T-G (OR = 0.112), C-T (OR = 0.029), and C-G (OR = 0.814)-were significantly associated with BD (all P < 0.05). Sleep quality showed no significant mediating effect. CONCLUSION: Integrated clinical risk factors and CACNA1C genetic variations are promising indicators for differentiating BD from MDD. Although sleep quality did not demonstrate a mediating role, these findings contribute preliminary insights into the distinct genetic and phenotypic architecture of these disorders, offering a foundation for future mechanistic exploration and personalized interventions.
Increased morning cortisol after ketamine treatment for suicidal depression: Exploratory report from a randomized trial.
Choo TH, Galfalvy HC, Keilp JG … +3 more , Burke AK, Mann JJ, Grunebaum MF
J Affect Disord · 2026 Jun · PMID 42349524 · Publisher ↗
Depression and its severe outcomes, suicidal ideation and behavior, are exacerbated by stress. A broad literature links dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) stress response system to depressio...
Depression and its severe outcomes, suicidal ideation and behavior, are exacerbated by stress. A broad literature links dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) stress response system to depression, suicidal ideation and behavior. Our midazolam-controlled clinical trial of subanesthetic, intravenous ketamine infusion for suicidal depressed patients found rapid reduction in suicidal ideation within 24 h. Here we report on an exploratory aim of the trial to investigate relationships of treatment effect and clinical response to HPA axis function via saliva cortisol analysis. Saliva cortisol awakening response was measured at baseline/pre-infusion and 24 h after with samples obtained upon morning awakening and 30 min later. A significant increase in waking cortisol 24 h after ketamine treatment was observed (t(61) = -3.15, p = 0.0025). Baseline to post-infusion increase in waking cortisol had a small to medium, nonsignificant, correlation with decrease in SI (r = -0.25, p = 0.052). These preliminary results need to be replicated but are consistent with studies suggesting increases in cortisol, if not excessive or prolonged, may enhance stress-resilience.
Mapping the association between cognitive disengagement syndrome and internalizing disorders: A systematic scoping review with meta-analysis and meta-regression.
Boccaccio FM, Rizzo R, Pirrone C … +1 more , Buitelaar JK
J Affect Disord · 2026 Jun · PMID 42341946 · Publisher ↗
Cognitive Disengagement Syndrome (CDS), previously known as Sluggish Cognitive Tempo, has increasingly been recognized as a construct distinct from ADHD inattention yet strongly associated with internalizing disorders. T...
Cognitive Disengagement Syndrome (CDS), previously known as Sluggish Cognitive Tempo, has increasingly been recognized as a construct distinct from ADHD inattention yet strongly associated with internalizing disorders. This scoping review synthesized evidence from 82 studies published between 2002 and 2025, combining narrative synthesis with three-level meta-analysis and meta-regression. Across healthy and clinical samples, individuals with elevated CDS consistently showed higher rates of depression and anxiety, with more than one-third reaching clinical thresholds. Associations remained significant after controlling for ADHD inattention and were observed in children, adolescents, and adults. Longitudinal evidence suggested that CDS may operate as a developmental risk factor for later depression, though findings for anxiety were less consistent. Despite robust evidence of comorbidity, very few studies examined the functional consequences of CDS-internalizing overlap, and none employed analytic strategies to address symptom overlap, despite substantial phenomenological similarities. Meta-analyses confirmed moderate-to-strong associations, with the strongest link for depression (r = 0.56), followed by anxiety (r = 0.46) and broader internalizing symptoms (r = 0.44). Meta-regression identified depression as a significant moderator and revealed inflated effect sizes in same-informant studies, while demographic factors such as age, sex, population type, and sample size did not significantly account for variability. These findings support the conceptualization of CDS as a structurally distinct yet transdiagnostic construct, particularly tied to depressive symptomatology. However, methodological limitations, including scarce longitudinal and multi-informant studies, lack of symptom-overlap controls, and limited evidence on functional outcomes, constrain clinical interpretation and highlight the need for more rigorous, developmentally informed research.
Impact of sex differences on the association between clinical predictors and electroconvulsive therapy outcomes: results from the Dutch ECT Consortium (DEC).
Blanken MAJT, Oudega ML, Loef D … +32 more , Tuijp PFA, Exel EV, Somers M, van Dellen E, Mocking RJT, Karaszewska D, de Wit AE, Hegeman JM, van den Berg K, Rhebergen D, Rutten BPF, Broekman BFP, Vergouwen ACM, Zoon TJC, Kok RM, Somers K, Verwijk E, Rovers JJE, Schuur G, van Waarde JA, Verdijk JPAJ, Bloemkolk D, Gerritse FL, van Welie H, Haarman BCM, van Belkum SM, Vischjager M, Birkenhager TK, Heijnen W, Tendolar I, van Eijndhoven PFP, Dols A
J Affect Disord · 2026 Jun · PMID 42341945 · Publisher ↗
OBJECTIVE: Medical research historically underrepresented women, often generalizing findings from men to women. Sex-specific analyses could enhance guideline accuracy and support personalized care. Electroconvulsive ther...
OBJECTIVE: Medical research historically underrepresented women, often generalizing findings from men to women. Sex-specific analyses could enhance guideline accuracy and support personalized care. Electroconvulsive therapy (ECT) is highly effective in major depressive disorder (MDD), however research regarding the impact of sex on ECT efficacy is scarce. This study aimed to explore sex differences in ECT outcome and clinical variables associated with ECT outcome to replicate and extend previous research. METHODS: Clinical data from sites participating in the Dutch ECT Consortium. Remission was defined as a post-ECT Hamilton Depression Rating Scale (HDRS) score of 7 points or below. Clinical variables influencing ECT outcome were selected based on prior research. RESULTS: Data included 1892 MDD patients (N = 1210 women), with a mean age of 59.5 years. Remission rate did not differ among sexes (χ(1) = 2.0, p = 0.17). We observed significant sex-related interaction effects for duration of index episode (χ(1) = 4.36, p = 0.04) and for failed psychotherapy in the current episode (χ(1) = 4.56, p = 0.03). Women's remission rates remained stable regardless of episode duration, while men's remission likelihood decreased with longer episodes. Women treated with prior evidence-based psychotherapy showed lower remission rates than men. CONCLUSION: This study highlights that ECT is equally effective for both men and women. The tentative sex-related interaction effects are of clinical interest though modest in size. Clinicians must understand sex differences in ECT outcomes and the potential for sex-specific side-effects to make a fully informed decision.
Two neuroanatomical subtypes of major depressive disorder exhibit dissociable clinical profiles and distinct molecular signatures.
Wang C, Zhang C, Li Z … +9 more , Liu C, Zhang C, Qi M, Zhao Z, Pang T, Gao Z, Zhang X, Yu Y, Wang S
J Affect Disord · 2026 Jun · PMID 42341944 · Publisher ↗
BACKGROUND: Major depressive disorder (MDD) is characterized by marked neurobiological and clinical heterogeneity; however, biologically informed neuroanatomical subtypes and their molecular correlates remain insufficien...
BACKGROUND: Major depressive disorder (MDD) is characterized by marked neurobiological and clinical heterogeneity; however, biologically informed neuroanatomical subtypes and their molecular correlates remain insufficiently defined. METHODS: We applied the Subtype and Stage Inference (SuStaIn) model to large-scale multi-center structural MRI data from the REST-meta-MDD consortium, including 1276 patients with MDD and 1104 healthy controls, and externally validated the findings in an independent SRPBS cohort (254 patients and 701 controls). Imaging transcriptomic, bioinformatic, cell-type enrichment, and clinical analyses were performed to characterize subtype-specific features. RESULTS: Two neuroanatomical subtypes were identified, characterized by distinct SuStaIn-inferred patterns of gray matter variation: one showing a cortical-to-cerebellar pattern and the other a cerebello-subcortical-to-cortical pattern. The subtypes showed differential clinical characteristics and brain-symptom associations. The cortical-to-cerebellar subtype was associated with greater guilt and hypochondriasis, with cerebellar structure related to affective and anxiety symptoms, whereas the second subtype showed an association between inferior frontal gyrus volume and insomnia-related symptoms. Cross-modal analyses identified distinct transcriptomic correlates associated with the two subtypes. The first subtype showed spatial enrichment of synaptic and mitochondrial pathways preferentially expressed in cortical projection neurons, whereas the second subtype showed spatial enrichment of pathways related to chromatin organization, epigenetic regulation, and calcium-MAPK signaling in cerebellar granule cells. CONCLUSION: These findings identify two neuroanatomical subtypes of MDD with distinct clinical and molecular profiles, providing evidence for biologically informed stratification and offering a multiscale framework for understanding disease heterogeneity.
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