Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted.

Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared.

GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes.

Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology.

Comorbid depression substantially affects the management of glycemia and diabetes-related complications among patients with type 2 diabetes mellitus. In this study, we sought to determine the association between weight change over 4 years and depression risk among patients with type 2 diabetes mellitus.

This population-based retrospective cohort study from the National Health Insurance Services of Korea included 1 111 345 patients with type 2 diabetes who were divided into groups according to body weight change over 4 years. Body weight changes were compared with the preceding 4-year period (2005–2008). Depression was defined according to the International Classification of Diseases 10th revision code for depression (F32 and F33) on one or more inpatient or outpatient claims.

During a median follow-up of 7.4 years, 244 081 cases of depression were identified. We observed a U-shaped association between body weight change and depression risk with a higher risk among both groups of weight loss (hazard ratio (HR) 1.17, 95% CI 1.15–1.19 for ⩾ −10%; HR 1.07, 95% CI 1.06–1.08 for −10 to −5%) and weight gain (HR 1.06, 95% CI 1.04–1.08 for ⩾10%; HR 1.02, 95% CI 1.01–1.04 for 5–10%) compared with the stable weight group (−5 to 5%).

A U-shaped association between body weight change and depression risk was observed in this large nationwide cohort study. Our study suggests that patients with type 2 diabetes and weight change, either gain or loss, could be considered a high-risk group for depression.

COVID-19 lockdowns increased the risk of mental health problems, especially for children with autism spectrum disorder (ASD). However, despite its importance, little is known about the protective factors for ASD children during the lockdowns.

Based on the Shanghai Autism Early Developmental Cohort, 188 ASD children with two visits before and after the strict Omicron lockdown were included; 85 children were lockdown-free, while 52 and 51 children were under the longer and the shorter durations of strict lockdown, respectively. We tested the association of the lockdown group with the clinical improvement and also the modulation effects of parent/family-related factors on this association by linear regression/mixed-effect models. Within the social brain structures, we examined the voxel-wise interaction between the grey matter volume and the identified modulation effects.

Compared with the lockdown-free group, the ASD children experienced the longer duration of strict lockdown had less clinical improvement (β = 0.49, 95% confidence interval (CI) [0.19–0.79], p = 0.001) and this difference was greatest for social cognition (2.62 [0.94–4.30], p = 0.002). We found that this association was modulated by parental agreeableness in a protective way (−0.11 [−0.17 to −0.05], p = 0.002). This protective effect was enhanced in the ASD children with larger grey matter volumes in the brain's mentalizing network, including the temporal pole, the medial superior frontal gyrus, and the superior temporal gyrus.

This longitudinal neuroimaging cohort study identified that the parental agreeableness interacting with the ASD children's social brain development reduced the negative impact on clinical symptoms during the strict lockdown.

Electroconvulsive therapy (ECT) is the most effective intervention for patients with treatment resistant depression. A clinical decision support tool could guide patient selection to improve the overall response rate and avoid ineffective treatments with adverse effects. Initial small-scale, monocenter studies indicate that both structural magnetic resonance imaging (sMRI) and functional MRI (fMRI) biomarkers may predict ECT outcome, but it is not known whether those results can generalize to data from other centers. The objective of this study was to develop and validate neuroimaging biomarkers for ECT outcome in a multicenter setting.

Multimodal data (i.e. clinical, sMRI and resting-state fMRI) were collected from seven centers of the Global ECT-MRI Research Collaboration (GEMRIC). We used data from 189 depressed patients to evaluate which data modalities or combinations thereof could provide the best predictions for treatment remission (HAM-D score ⩽7) using a support vector machine classifier.

Remission classification using a combination of gray matter volume and functional connectivity led to good performing models with average 0.82–0.83 area under the curve (AUC) when trained and tested on samples coming from the three largest centers (N = 109), and remained acceptable when validated using leave-one-site-out cross-validation (0.70–0.73 AUC).

These results show that multimodal neuroimaging data can be used to predict remission with ECT for individual patients across different treatment centers, despite significant variability in clinical characteristics across centers. Future development of a clinical decision support tool applying these biomarkers may be feasible.

There is a significant contribution of genetic factors to the etiology of bipolar disorder (BD). Unaffected first-degree relatives of patients (UR) with BD are at increased risk of developing mental disorders and may manifest cognitive impairments and alterations in brain functional and connective dynamics, akin to their affected relatives.

In this prospective longitudinal study, resting-state functional connectivity was used to explore stable and progressive markers of vulnerability i.e. abnormalities shared between UR and BD compared to healthy controls (HC) and resilience i.e. features unique to UR compared to HC and BD in full or partial remission (UR n = 72, mean age = 28.0 ± 7.2 years; HC n = 64, mean age = 30.0 ± 9.7 years; BD patients n = 91, mean age = 30.6 ± 7.7 years). Out of these, 34 UR, 48 BD, and 38 HC were investigated again following a mean time of 1.3 ± 0.4 years.

At baseline, the UR showed lower connectivity values within the default mode network (DMN), frontoparietal network, and the salience network (SN) compared to HC. This connectivity pattern in UR remained stable over the follow-up period and was not present in BD, suggesting a resilience trait. The UR further demonstrated less negative connectivity between the DMN and SN compared to HC, abnormality that remained stable over time and was also present in BD, suggesting a vulnerability marker.

Our findings indicate the coexistence of both vulnerability-related abnormalities in resting-state connectivity, as well as adaptive changes possibly promoting resilience to psychopathology in individual at familial risk.

The course of Bipolar Disorder (BD) is highly variable, with marked inter and intra-individual differences in symptoms and functioning. In this study, we identified illness trajectories across major clinical domains that could have etiological, prognostic, and therapeutic relevance.

Using the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, we performed univariate and multivariate trajectory modeling of depressive symptoms, manic symptoms, and psychosocial functioning. Multinomial regression was performed to identify baseline variables associated with poor outcome trajectories.

Depressive symptoms predominated, with most subjects being found in trajectories characterized by various degrees of depressive symptoms and 13% of subjects being classified in a poor outcome ‘persistently depressed’ trajectory. Most subjects experienced few manic symptoms, although approximately 10% of subjects followed a trajectory of persistently manic symptoms. Trajectory analysis of psychosocial functioning showed impairment in most of the sample, with little improvement during follow up. Multi-trajectory analyses highlighted significant impairment in subjects with persistently mixed and persistently depressed trajectories of illness. In general, poor outcome trajectories were marked by lower educational attainment, higher unemployment and disability, and a greater likelihood of adverse clinical features (rapid cycling and suicide attempts) and comorbid diagnoses (anxiety disorders, PTSD, and substance abuse/dependence disorders).

Subjects with BD can be classified into several trajectories of clinically relevant domains that are prognostically relevant and show differing degrees of associations with a broad range of negative clinical risk factors. The highest level of psychosocial disability was found in subjects with chronic mixed and depressive symptoms, who show limited improvement despite guideline-based treatment.

Although diagnostic instability in first-episode psychosis (FEP) is of major concern, little is known about its determinants. This very long-term follow-up study aimed to examine the diagnostic stability of FEP diagnoses, the baseline predictors of diagnostic change and the timing of diagnostic change.

This was a longitudinal and naturalistic study of 243 subjects with FEP who were assessed at baseline and reassessed after a mean follow-up of 21 years. The diagnostic stability of DSM-5 psychotic disorders was examined using prospective and retrospective consistencies, logistic regression was used to establish the predictors of diagnostic change, and survival analysis was used to compare time to diagnostic change across diagnostic categories.

The overall diagnostic stability was 47.7%. Schizophrenia and bipolar disorder were the most stable diagnoses, with other categories having low stability. Predictors of diagnostic change to schizophrenia included a family history of schizophrenia, obstetric complications, developmental delay, poor premorbid functioning in several domains, long duration of untreated continuous psychosis, spontaneous dyskinesia, lack of psychosocial stressors, longer duration of index admission, and poor early treatment response. Most of these variables also predicted diagnostic change to bipolar disorder but in the opposite direction and with lesser effect sizes. There were no significant differences between specific diagnoses regarding time to diagnostic change. At 10-year follow-up, around 80% of the diagnoses had changed.

FEP diagnoses other than schizophrenia or bipolar disorder should be considered as provisional. Considering baseline predictors of diagnostic change may help to enhance diagnostic accuracy and guide therapeutic interventions.

Non-suicidal self-injury (NSSI) is prevalent in major depressive disorder (MDD) during adolescence, but the underlying neural mechanisms are unclear. This study aimed to investigate microstructural abnormalities in the cingulum bundle associated with NSSI and its clinical characteristics.

130 individuals completed the study, including 35 healthy controls, 47 MDD patients with NSSI, and 48 MDD patients without NSSI. We used tract-based spatial statistics (TBSS) with a region of interest (ROI) analysis to compare the fractional anisotropy (FA) of the cingulum bundle across the three groups. receiver-operating characteristics (ROC) analysis was employed to evaluate the ability of the difficulties with emotion regulation (DERS) score and mean FA of the cingulum to differentiate between the groups.

MDD patients with NSSI showed reduced cingulum integrity in the left dorsal cingulum compared to MDD patients without NSSI and healthy controls. The severity of NSSI was negatively associated with cingulum integrity (r = −0.344, p = 0.005). Combining cingulum integrity and DERS scores allowed for successful differentiation between MDD patients with and without NSSI, achieving a sensitivity of 70% and specificity of 83%.

Our study highlights the role of the cingulum bundle in the development of NSSI in adolescents with MDD. The findings support a frontolimbic theory of emotion regulation and suggest that cingulum integrity and DERS scores may serve as potential early diagnostic tools for identifying MDD patients with NSSI.

Depression is characterized by abnormalities in emotional processing, but the specific drivers of such emotional abnormalities are unknown. Computational work indicates that both surprising outcomes (prediction errors; PEs) and outcomes (values) themselves drive emotional responses, but neither has been consistently linked to affective disturbances in depression. As a result, the computational mechanisms driving emotional abnormalities in depression remain unknown.

Here, in 687 individuals, one-third of whom qualify as depressed via a standard self-report measure (the PHQ-9), we use high-stakes, naturalistic events – the reveal of midterm exam grades – to test whether individuals with heightened depression display a specific reduction in emotional response to positive PEs.

Using Bayesian mixed effects models, we find that individuals with heightened depression do not affectively benefit from surprising, good outcomes – that is, they display reduced affective responses to positive PEs. These results were highly specific: effects were not observed to negative PEs, value signals (grades), and were not related to generalized anxiety. This suggests that the computational drivers of abnormalities in emotion in depression may be specifically due to positive PE-based emotional responding.

Affective abnormalities are core depression symptoms, but the computational mechanisms underlying such differences are unknown. This work suggests that blunted affective reactions to positive PEs are likely mechanistic drivers of emotional dysregulation in depression.

Parent-adolescent interactions, particularly parental criticism and praise, have previously been identified as factors relevant to self-concept development and, when negative, to adolescent depression. Yet, whether adolescents with depression show aberrant emotional and neural reactivity to parental criticism and praise is understudied.

Adolescents with depression (n = 20) and healthy controls (n = 59) received feedback supposedly provided by their mother or father in the form of negative (‘untrustworthy’), neutral (‘chaotic’), and positive (‘respectful’) personality evaluations while in an MRI-scanner. After each feedback word, adolescents reported their mood. Beforehand, adolescents had rated whether these personality evaluations matched their self-views.

In both groups, mood decreased after criticism and increased after praise. Adolescents with depression reported blunted mood responses after praise, whereas there were no mood differences after criticism. Neuroimaging analyses revealed that adolescents with depression (v. healthy controls) exhibited increased activity in response to criticism in the subgenual anterior cingulate cortex, temporal pole, hippocampus, and parahippocampal gyrus. Praise consistent with adolescents' self-views improved mood independent of depression status, while criticism matching self-views resulted in smaller mood increases in adolescents with depression (v. healthy controls). Exploratory analyses indicated that adolescents with depression recalled criticism (v. praise) more.

Adolescents with depression might be especially attentive to parental criticism, as indexed by increased sgACC and hippocampus activity, and memorize this criticism more. Together with lower positive impact of praise, these findings suggest that cognitive biases in adolescent depression may affect how parental feedback is processed, and may be fed into their self-views.

Psychotic symptoms in adolescence are associated with social adversity and genetic risk for schizophrenia. This gene–environment interplay may be mediated by personality, which also develops during adolescence. We hypothesized that (i) personality development predicts later Psychosis Proneness Signs (PPS), and (ii) personality traits mediate the association between genetic risk for schizophrenia, social adversities, and psychosis.

A total of 784 individuals were selected within the IMAGEN cohort (Discovery Sample-DS: 526; Validation Sample-VS: 258); personality was assessed at baseline (13–15 years), follow-up-1 (FU1, 16–17 years), and FU2 (18–20 years). Latent growth curve models served to compute coefficients of individual change across 14 personality variables. A support vector machine algorithm employed these coefficients to predict PPS at FU3 (21–24 years). We computed mediation analyses, including personality-based predictions and self-reported bullying victimization as serial mediators along the pathway between polygenic risk score (PRS) for schizophrenia and FU3 PPS. We replicated the main findings also on 1132 adolescents recruited within the TRAILS cohort.

Growth scores in neuroticism and openness predicted PPS with 65.6% balanced accuracy in the DS, and 69.5% in the VS Mediations revealed a significant positive direct effect of PRS on PPS (confidence interval [CI] 0.01–0.15), and an indirect effect, serially mediated by personality-based predictions and victimization (CI 0.006–0.01), replicated in the TRAILS cohort (CI 0.0004–0.004).

Adolescent personality changes may predate future experiences associated with psychosis susceptibility. PPS personality-based predictions mediate the relationship between PRS and victimization toward adult PPS, suggesting that gene–environment correlations proposed for psychosis are partly mediated by personality.

Affiliating with delinquent peers may stimulate the development of antisocial behavior, especially for adolescents who are sensitive to social rewards. The current study examines whether the association between delinquent peer affiliation (DPA) and disruptive behavior interacts with functional brain correlates of reward sensitivity in early onset male adolescents delinquents.

Childhood arrestees (n = 126, mean age = 17.7 [s.d. 1.6]) completed a DPA questionnaire, and participated in an fMRI study in which reward sensitivity was operationalized through responsiveness of the ventral striatum (VS), amygdala, and medial prefrontal cortex (mPFC) during the monetary incentive delay paradigm (reward anticipation and outcome). Symptoms of disruptive behavior disorders (DBD) were assessed through structured psychiatric interviews (Diagnostic Interview Schedule for Children) with adolescents.

DPA had a main effect on DBD symptoms. Adolescents with high VS reward responses showed a stronger significant positive association between DPA and DBD symptoms compared to low VS responders. No evidence for an interaction effect was found for the amygdala and mPFC. Post-hoc analyses revealed the positive association between DPA and DBD was only present in males, with a diminishing effect as age increased.

We found evidence for a biosocial interaction between DPA and reward sensitivity of the VS in relation to DBD symptom severity. This study provides the first evidence of an interaction effect between a brain mechanism and an environmental factor in relation to DBD symptoms, implying that susceptibility to influences of delinquent peers may intertwine with individual biological differences.

The right inferior frontal gyrus (RIFG) is a potential beneficial brain stimulation target for autism. This randomized, double-blind, two-arm, parallel-group, sham-controlled clinical trial assessed the efficacy of intermittent theta burst stimulation (iTBS) over the RIFG in reducing autistic symptoms (NCT04987749).

Conducted at a single medical center, the trial enrolled 60 intellectually able autistic individuals (aged 8–30 years; 30 active iTBS). The intervention comprised 16 sessions (two stimulations per week for eight weeks) of neuro-navigated iTBS or sham over the RIFG. Fifty-seven participants (28 active) completed the intervention and assessments at Week 8 (the primary endpoint) and follow-up at Week 12.

Autistic symptoms (primary outcome) based on the Social Responsiveness Scale decreased in both groups (significant time effect), but there was no significant difference between groups (null time-by-treatment interaction). Likewise, there was no significant between-group difference in changes in repetitive behaviors and exploratory outcomes of adaptive function and emotion dysregulation. Changes in social cognition (secondary outcome) differed between groups in feeling scores on the Frith-Happe Animations (Week 8, p = 0.026; Week 12, p = 0.025). Post-hoc analysis showed that the active group improved better on this social cognition than the sham group. Dropout rates did not vary between groups; the most common adverse event in both groups was local pain. Notably, our findings would not survive stringent multiple comparison corrections.

Our findings suggest that iTBS over the RIFG is not different from sham in reducing autistic symptoms and emotion dysregulation. Nonetheless, RIFG iTBS may improve social cognition of mentalizing others' feelings in autistic individuals.

Obsessive–compulsive disorder (OCD) is a classic disorder on the compulsivity spectrum, with diverse comorbidities. In the current study, we sought to understand OCD from a dimensional perspective by identifying multimodal neuroimaging patterns correlated with multiple phenotypic characteristics within the striatum-based circuits known to be affected by OCD.

Neuroimaging measurements of local functional and structural features and clinical information were collected from 110 subjects, including 51 patients with OCD and 59 healthy control subjects. Linked independent component analysis (LICA) and correlation analysis were applied to identify associations between local neuroimaging patterns across modalities (including gray matter volume, white matter integrity, and spontaneous functional activity) and clinical factors.

LICA identified eight multimodal neuroimaging patterns related to phenotypic variations, including three related to symptoms and diagnosis. One imaging pattern (IC9) that included both the amplitude of low-frequency fluctuation measure of spontaneous functional activity and white matter integrity measures correlated negatively with OCD diagnosis and diagnostic scales. Two imaging patterns (IC10 and IC27) correlated with compulsion symptoms: IC10 included primarily anatomical measures and IC27 included primarily functional measures. In addition, we identified imaging patterns associated with age, gender, and emotional expression across subjects.

We established that data fusion techniques can identify local multimodal neuroimaging patterns associated with OCD phenotypes. The results inform our understanding of the neurobiological underpinnings of compulsive behaviors and OCD diagnosis.

Little information is available on the association between gender nonconformity during adolescence and subsequent mental health. While the distress related to gender nonconformity may be socially produced rather than attributed to individual-level factors, further research is needed to better understand the role of psychosocial factors in this context.

We analyzed data from the Tokyo Teen Cohort, obtained through random sampling of adolescents born between 2002 and 2004. We used inverse probability weighting to examine the association of gender nonconformity at ages 12 and 14 as a time-varying variable with subsequent mental health at age 16, while accounting for time-fixed and time-varying confounders. Furthermore, we used a weighting approach to investigate the mediating role of modifiable psychosocial factors in this association, addressing exposure-mediator and mediator–mediator interactions.

A total of 3171 participants were analyzed. Persistent gender nonconforming behavior at ages 12 and 14 was associated with subsequent depression (β = 2.02, 95% confidence interval [CI] 0.85 to 3.19) and psychotic experiences (β = 0.33, 95% CI 0.14 to 0.52) at age 16. The results remained robust in sensitivity analyses. Approximately 30% of the association between gender nonconformity and depression was consistently mediated by a set of psychosocial factors, namely loneliness, bullying victimization, and relationships with mother, father, and friends.

Persistent gender nonconformity during adolescence is associated with subsequent mental health. Psychosocial factors play a vital mediating role in this association, highlighting the essential need for social intervention and change to reduce stigmatization and ameliorate mental health challenges.

Major depressive disorder (MDD) is highly prevalent and burdensome for individuals and society. While there are psychological interventions able to prevent and treat MDD, uptake remains low. To overcome structural and attitudinal barriers, an indirect approach of using online insomnia interventions seems promising because insomnia is less stigmatized, predicts MDD onset, is often comorbid and can outlast MDD treatment. This individual-participant-data meta-analysis evaluated the potential of the online insomnia intervention GET.ON Recovery as an indirect treatment to reduce depressive symptom severity (DSS) and potential MDD onset across a range of participant characteristics.

Efficacy on depressive symptom outcomes was evaluated using multilevel regression models controlling for baseline severity. To identify potential effect moderators, clinical, sociodemographic, and work-related variables were investigated using univariable moderation and random-forest methodology before developing a multivariable decision tree.

IPD were obtained from four of seven eligible studies (N = 561); concentrating on workers with high work-stress. DSS was significantly lower in the intervention group both at post-assessment (d = −0.71 [95% CI−0.92 to −0.51]) and at follow-up (d = −0.84 [95% CI −1.11 to −0.57]). In the subsample (n = 121) without potential MDD at baseline, there were no significant group differences in onset of potential MDD. Moderation analyses revealed that effects on DSS differed significantly across baseline severity groups with effect sizes between d = −0.48 and −0.87 (post) and d = − 0.66 to −0.99 (follow-up), while no other sociodemographic, clinical, or work-related characteristics were significant moderators.

An online insomnia intervention is a promising approach to effectively reduce DSS in a preventive and treatment setting.

Childhood adversity is associated with abnormalities in brain structure, but this association has not been tested for childhood unpredictability, one form of adversity. We studied whether abnormalities in gray matter volume (GMV) could be a mechanism linking childhood unpredictability and psychopathology, over and above the effect of childhood trauma.

Participants were 158 right-handed healthy young adults (aged 17–28 years, M = 22.07, s.d. = 2.08; 66.46% female) who underwent structural magnetic resonance imaging measurements and provided retrospective reports of childhood unpredictability. The anxiety and depression subscales of the self-report Brief Symptom Inventory-53 were used to index psychopathology.

Whole-brain voxel-based morphometric analyses showed that after controlling for the effect of childhood trauma, childhood unpredictability was correlated with greater GMV in bilateral frontal pole, bilateral precuneus, bilateral postcentral gyrus, right hemisphere of fusiform, and lingual gyrus, and left hemisphere of ventrolateral prefrontal cortex as well as occipital gyrus. Greater GMV in bilateral frontal pole, bilateral precuneus, and bilateral postcentral gyrus mediated associations between unpredictability and symptoms of depression and anxiety.

The findings suggest that childhood unpredictability could exact unique effects on neural development, over and above the effect of childhood trauma. These findings are relevant for understanding the occurrence of psychopathology following childhood unpredictability and have implications for intervention.

Affective responses to the menstrual cycle vary widely. Some individuals experience severe symptoms like those with premenstrual dysphoric disorder, while others have minimal changes. The reasons for these differences are unclear, but prior studies suggest stressor exposure may play a role. However, research in at-risk psychiatric samples is lacking.

In a large clinical sample, we conducted a prospective study of how lifetime stressors relate to degree of affective change across the cycle. 114 outpatients with past-month suicidal ideation (SI) provided daily ratings (n = 6187) of negative affect and SI across 1–3 menstrual cycles. Participants completed the Stress and Adversity Inventory (STRAIN), which measures different stressor exposures (i.e. interpersonal loss, physical danger) throughout the life course, including before and after menarche. Multilevel polynomial growth models tested the relationship between menstrual cycle time and symptoms, moderated by stressor exposure.

Greater lifetime stressor exposure predicted a more pronounced perimenstrual increase in active SI, along with marginally significant similar patterns for negative affect and passive SI. Additionally, pre-menarche stressors significantly increased the cyclicity of active SI compared to post-menarche stressors. Exposure to more interpersonal loss stressors predicted greater perimenstrual symptom change of negative affect, passive SI and active SI. Exploratory item-level analyses showed that lifetime stressors moderated a more severe perimenstrual symptom trajectory for mood swings, anger/irritability, rejection sensitivity, and interpersonal conflict.

These findings suggest that greater lifetime stressor exposure may lead to heightened emotional reactivity to ovarian hormone fluctuations, elevating the risk of psychopathology.

Rising midlife mortality in the United States is largely attributable to ‘deaths of despair’ (deaths from suicide, drug poisonings, and alcohol-related diseases) and deaths from cardiometabolic conditions. Although despair- and cardiometabolic-related mortality are increasing concurrently, it is unclear whether they share common developmental origins. We tested adolescent psychopathology as a potential common origin of midlife diseases of despair and cardiometabolic risk.

Participants (N = 4578) were from the National Longitudinal Study of Adolescent to Adult Health, a nationally representative cohort followed from adolescence to early midlife. Adolescent psychopathology included depression, anxiety, eating disorders, PTSD, conduct disorder, and ADHD at ages 11–18. Diseases of despair (suicidality, substance misuse, pain, and sleep problems) and cardiometabolic risk (hypertension, hyperlipidemia, high-risk waist circumference, diabetes, and cardiovascular conditions) were multi-modally measured at ages 33–43.

At midlife, adolescents who experienced psychopathology exhibited more indicators of despair-related diseases and cardiometabolic risk (IRRs = 1.67 [1.46–1.87] and 1.13 [1.04–1.21], respectively), even after accounting for demographics, adolescent SES, and adolescent cognitive ability. Associations were evident for internalizing and externalizing conditions, and in a dose–response fashion. In mediation analyses, low education explained little of these associations, but early-adult substance use explained 21.5% of psychopathology's association with despair-related diseases. Midlife despair-related diseases and cardiometabolic risk co-occurred within individuals (IRR = 1.12 [1.08–1.16]). Adolescent psychopathology accounted for 8.3% of this co-occurrence, and 16.7% together with adolescent SES and cognitive ability.

Adolescent psychopathology precedes both diseases of despair and cardiometabolic risk. Prevention and treatment of psychopathology may mitigate multiple causes of poor midlife health, reducing premature mortality.

Growing evidence points to the pivotal role of vitamin D in the pathophysiology and treatment of major depressive disorder (MDD). However, there is a paucity of longitudinal research investigating the effects of vitamin D supplementation on the brain of MDD patients.

We conducted a double-blind randomized controlled trial in 46 MDD patients, who were randomly allocated into either VD (antidepressant medication + vitamin D supplementation) or NVD (antidepressant medication + placebos) groups. Data from diffusion tensor imaging, resting-state functional MRI, serum vitamin D concentration, and clinical symptoms were obtained at baseline and after an average of 7 months of intervention.

Both VD and NVD groups showed significant improvement in depression and anxiety symptoms but with no significant differences between the two groups. However, a greater increase in serum vitamin D concentration was found to be associated with greater improvement in depression and anxiety symptoms in VD group. More importantly, neuroimaging data demonstrated disrupted white matter integrity of right inferior fronto-occipital fasciculus along with decreased functional connectivity between right frontoparietal and medial visual networks after intervention in NVD group, but no changes in VD group.

These findings suggest that vitamin D supplementation as adjunctive therapy to antidepressants may not only contribute to improvement in clinical symptoms but also help preserve brain structural and functional connectivity in MDD patients.