Employment and income are important determinants of mental health (MH), but the extent that unemployment effects are mediated by reduced income is unclear. We estimated the total effect (TE) of unemployment on MH and the controlled direct effect (CDE) not acting via income.

We included adults 25–64 years from nine waves of the UK Household Longitudinal Study (n = 45 497/obs = 202 297). Unemployment was defined as not being in paid employment; common mental disorder (CMD) was defined as General Health Questionnaire-12 score ≥4. We conducted causal mediation analysis using double-robust marginal structural modelling, estimating odds ratios (OR) and absolute differences for effects of unemployment on CMD in the same year, before (TE) and after (CDE) blocking the income pathway. We calculated percentage mediation by income, with bootstrapped standard errors.

The TE of unemployment on CMD risk was OR 1.66 (95% CI 1.57–1.76), with 7.09% (6.21–7.97) absolute difference in prevalence; equivalent CDEs were OR 1.55 (1.46–1.66) and 6.08% (5.13–7.03). Income mediated 14.22% (8.04–20.40) of the TE. Percentage mediation was higher for job losses [15.10% (6.81–23.39)] than gains [8.77% (0.36–17.19)]; it was lowest for those 25–40 years [7.99% (−2.57 to 18.51)] and in poverty [2.63% (−2.22 to 7.49)].

A high proportion of the short-term effect of unemployment on MH is not explained by income, particularly for younger people and those in poverty. Population attributable fractions suggested 16.49% of CMD burden was due to unemployment, with 13.90% directly attributable to job loss rather than resultant income changes. Similar analytical approaches could explore how this differs across contexts, by other factors, and consider longer-term effects.

Previous studies have confirmed that miR-146a-5p overexpression suppresses neurogenesis, thereby enhancing depression-like behaviors. However, it remains unclear how miR-146a-5p dysregulation produces in vivo brain structural abnormalities in patients with major depressive disorder (MDD).

In this case–control study, we combined cortical morphology analysis of magnetic resonance imaging (MRI) and miR-146a-5p quantification to investigate the neuropathological effect of miR-146a-5p on cortical thickness in MDD patients. Serum-derived exosomes that were considered to readily cross the blood-brain barrier and contain miR-146a-5p were isolated for miRNA quantification. Moreover, follow-up MRI scans were performed in the MDD patients after 6 weeks of antidepressant treatment to further validate the clinical relevance of the relationship between miR-146a-5p and brain structural abnormalities.

In total, 113 medication-free MDD patients and 107 matched healthy controls were included. Vertex-vise general linear model revealed miR-146a-5p-dependent cortical thinning in MDD patients compared with healthy individuals, i.e., overexpression of miR-146a-5p was associated with reduced cortical thickness in the left orbitofrontal cortex (OFC), anterior cingulate cortex, bilateral lateral occipital cortices (LOCs), etc. Moreover, this relationship between baseline miR-146a-5p and cortical thinning was nonsignificant for all regions in the patients who had received antidepressant treatment, and higher baseline miR-146a-5p expression was found to be related to greater longitudinal cortical thickening in the left OFC and right LOC.

The findings of this study reveal a relationship between miR-146a-5p overexpression and cortical atrophy and thus may help specify the in vivo mediating effect of miR-146a-5p dysregulation on brain structural abnormalities in patients with MDD.

Access to evidence-based psychological treatment is a challenge worldwide. We assessed the effectiveness of a fully automated aviophobia smartphone app treatment delivered in combination with a $5 virtual reality (VR) viewer.

In total, 153 participants from the Dutch general population with aviophobia symptoms and smartphone access were randomized in a single-blind randomized controlled trial to either an automated VR cognitive behavior therapy (VR-CBT) app treatment condition (n = 77) or a wait-list control condition (n = 76). The VR-CBT app was delivered over a 6-week period in the participants' natural environment. Online self-report assessments were completed at baseline, post-treatment, at 3-month and at 12-month follow-up. The primary outcome measure was the Flight Anxiety Situations Questionnaire (FAS). Analyses were based on intent-to-treat.

A significant reduction of aviophobia symptoms at post-test for the VR-CBT app compared with the control condition [p < 0.001; d = 0. 98 (95% CI 0.65–1.32)] was demonstrated. The dropout rate was 21%. Results were maintained at 3-month follow-up [within-group d = 1.14 (95% CI 0.46–1.81)] and at 12-month follow-up [within-group d = 1.12 (95% CI 0.46–1.79)]. Six participants reported adverse effects of cyber sickness symptoms.

This study is the first to show that fully automated mobile VR-CBT therapy delivered in a natural setting can maintain long-term effectiveness in reducing aviophobia symptoms. In doing so, it offers an accessible and scalable evidence-based treatment solution that can be applied globally at a fraction of the cost of current treatment alternatives.

Childhood maltreatment can result in lifelong psychological and physical sequelae, including coronary artery disease (CAD). Mechanisms leading to increased risk of illness may involve emotional dysregulation and shortened leukocyte telomere length (LTL).

To evaluate whether (1) childhood maltreatment is associated with shorter LTL among older adults with CAD or other chronic illnesses; (2) sex and/or CAD status influence these results; and (3) symptoms of anxiety, depression, and stress moderate or mediate the association between childhood maltreatment and LTL, men and women (N = 1247; aged 65 ± 7.2 years) with and without CAD completed validated questionnaires on childhood maltreatment, symptoms of depression, anxiety, and perceived stress. LTL was measured using quantitative polymerase chain reaction. Analyses included bivariate correlations, hierarchical regressions, and moderation/mediation analyses, controlling for sociodemographic and lifestyle variables.

Childhood maltreatment was associated with significantly shorter LTL (r = −0.059, p = 0.038, b = −0.016, p = 0.005). This relation was not moderated by depression, anxiety, nor perceived stress, though there was mitigated evidence for absence of a maltreatment-LTL relation in men with CAD. Stress perception (but not anxiety or depression) partially mediated the relation between childhood maltreatment and LTL [Indirect effect, b = −0.0041, s.e. = 0.002, 95% CI (−0.0085 to −0.0002)].

Childhood maltreatment was associated with accelerated biological aging independently of patient characteristics. Emotional dysregulation resulting in chronic stress may contribute to this process. Whether stress management or other interventions may help prevent or slow premature aging in those who have suffered maltreatment requires study.

Motivational impairment associated with deficits in processing the anticipation of future reward is hypothesized to be a cardinal feature of schizophrenia spectrum disorders (SZ). Evidence from short-term follow-up (6-week post-treatment) studies suggests that these deficits may improve or be reversed with treatment, although longer-term outcomes are unknown. Here we examined the one-year trajectory of functional activation in brain circuitry associated with reward anticipation in people with recent onset SZ who participated in coordinated specialty care (CSC) treatment, hypothesizing normalization of brain response mirroring previous short-term findings in first-episode individuals.

Blood oxygen level-dependent (BOLD) response in the dorsal anterior cingulate cortex, anterior insula, and ventral striatum (VS) associated with reward anticipation during the Incentivized Control Engagement Task (ICE-T) was analyzed in a baseline sample of 49 healthy controls (HCs) and 52 demographically matched people with SZ, with follow-up data available for 35 HCs and 17 people with SZ.

In agreement with our hypothesis, significant time × diagnosis interactions were observed across all regions, in which reward anticipation-associated BOLD response increased in SZ to above baseline HC levels at follow-up. Increased VS activation was associated with decreased reality distortion symptoms over the follow-up period. Baseline reward anticipation-associated BOLD response in the right anterior insula was associated with improvement in reality distortion symptoms.

These findings suggest that functional deficits in reward anticipation may be reversed after one year of CSC in recent onset participants with SZ, and that this improvement is associated with reduced positive symptoms in the illness.

The current study used data from an ethnically diverse population from South London to examine ethnic differences in physical and mental multimorbidity among working age (18–64 years) adults in the context of depression and anxiety.

The study included 44 506 patients who had previously attended Improving Access to Psychological Therapies services in the London Borough of Lambeth. Multinomial logistic regression examined cross-sectional associations between ethnicity with physical and mental multimorbidity. Patterns of multimorbidity were identified using hierarchical cluster analysis.

Within 44 056 working age adults with a history of depression or anxiety from South London there were notable ethnic differences in physical multimorbidity. Adults of Black Caribbean ethnicity were more likely to have physical multimorbidity [adjusted relative risk ratio (aRRR) = 1.25, 95% confidence interval (CI) 1.15–1.36] compared to adults of White ethnicity. Relative to adults of White ethnicity, adults of Asian ethnicity were more likely to have physical multimorbidity at higher thresholds only (e.g. 4 + conditions; aRRR = 1.53, 95% CI 1.17–2.00). Three physical (atopic, cardiometabolic, mixed) and three mental (alcohol/substance use, common/severe mental illnesses, personality disorder) multimorbidity clusters emerged. Ethnic minority groups with multimorbidity had a higher probability of belonging to the cardiometabolic cluster.

In an ethnically diverse population with a history of common mental health disorders, we found substantial between- and within-ethnicity variation in rates of physical, but not mental, multimorbidity. The findings emphasised the value of more granular definitions of ethnicity when examining the burden of physical and mental multimorbidity.

We need to better understand the frequency and predictors of opioid use disorder (OUD) after first opioid prescription (OP).

We followed 1 516 392 individuals from the Swedish population born 1980–2000, from 1 July 2007, until 31 Dec 2017. We examined putative risk predictors with univariable and multivariable Cox Models and the potential causal effects of predictors by propensity score and co-sibling analyses.

Of the individuals in our cohort, 24.8% (375 404) received a first OP, of whom 3034 (0.90%) developed a subsequent first OUD. The hazard ratio (HR) (± 95% CIs) for OUD after OP equaled 7.10 (6.75–7.46), with a mean time to onset of 3.41 (2.39) years. The strongest putative risk factors for development of OUD after OP were prior psychiatric and substance use disorders, criminal behavior, parental divorce/death, poor school performance, current community deprivation, divorce, and male sex. Few predictors differed across sexes. OP renewal was associated with a HR of 3.66 (3.41–3.93) for OUD. Co-sibling and propensity score analyses suggested that at least a moderate proportion of the risk factor-OUD association was likely causal. A risk score to predict OUD after OP had an AUC of 0.85, where nearly 60% of cases scoring in the top decile.

In a general population sample, an OP represents a substantial risk factor for subsequent OUD. Many of the risk factors for OUD after OP can be readily assessed at the time of potential OP, permitting clinicians to evaluate the risk of iatrogenic OUD.

The non-selective serotonin 2A (5-HT2A) receptor agonist lysergic acid diethylamide (LSD) holds promise as a treatment for some psychiatric disorders. Psychedelic drugs such as LSD have been suggested to have therapeutic actions through their effects on learning. The behavioural effects of LSD in humans, however, remain incompletely understood. Here we examined how LSD affects probabilistic reversal learning (PRL) in healthy humans.

Healthy volunteers received intravenous LSD (75 μg in 10 mL saline) or placebo (10 mL saline) in a within-subjects design and completed a PRL task. Participants had to learn through trial and error which of three stimuli was rewarded most of the time, and these contingencies switched in a reversal phase. Computational models of reinforcement learning (RL) were fitted to the behavioural data to assess how LSD affected the updating (‘learning rates’) and deployment of value representations (‘reinforcement sensitivity’) during choice, as well as ‘stimulus stickiness’ (choice repetition irrespective of reinforcement history).

Raw data measures assessing sensitivity to immediate feedback (‘win-stay’ and ‘lose-shift’ probabilities) were unaffected, whereas LSD increased the impact of the strength of initial learning on perseveration. Computational modelling revealed that the most pronounced effect of LSD was the enhancement of the reward learning rate. The punishment learning rate was also elevated. Stimulus stickiness was decreased by LSD, reflecting heightened exploration. Reinforcement sensitivity differed by phase.

Increased RL rates suggest LSD induced a state of heightened plasticity. These results indicate a potential mechanism through which revision of maladaptive associations could occur in the clinical application of LSD.

Adding short-term psychodynamic psychotherapy (STPP) to antidepressants increases treatment efficacy, but it is unclear which patients benefit specifically. This study examined efficacy moderators of combined treatment (STPP + antidepressants) v. antidepressants for adults with depression.

For this systematic review and meta-analysis (PROSPERO registration number: CRD42017056029), we searched PubMed, PsycINFO, Embase.com, and the Cochrane Library from inception to 1 January 2022. We included randomized clinical trials comparing combined treatment (antidepressants + individual outpatient STPP) v. antidepressants in the acute-phase treatment of depression in adults. Individual participant data were requested and analyzed combinedly using mixed-effects models (adding Cochrane risk of bias items as covariates) and an exploratory machine learning technique. The primary outcome was post-treatment depression symptom level.

Data were obtained for all seven trials identified (100%, n = 482, combined: n = 238, antidepressants: n = 244). Adding STPP to antidepressants was more efficacious for patients with high rather than low baseline depression levels [B = −0.49, 95% confidence interval (CI) −0.61 to −0.37, p < 0.0001] and for patients with a depressive episode duration of >2 years rather than <1 year (B = −0.68, 95% CI −1.31 to −0.05, p = 0.03) and than 1–2 years (B = −0.86, 95% CI −1.66 to −0.06, p = 0.04). Heterogeneity was low. Effects were replicated in analyses controlling for risk of bias.

To our knowledge, this is the first study that examines moderators across trials assessing the addition of STPP to antidepressants. These findings need validation but suggest that depression severity and episode duration are factors to consider when adding STPP to antidepressants and might contribute to personalizing treatment selection for depression.

Depression and anxiety are prevalent in youth populations and typically emerge during adolescence. Repetitive negative thinking (RNT) is a putative transdiagnostic mechanism with consistent associations with depression and anxiety. Targeting transdiagnostic processes like RNT for youth depression and anxiety may offer more targeted, personalised and effective treatment.

A meta-analysis was conducted to examine the effect of psychological treatments on RNT, depression and anxiety symptoms in young people with depression or anxiety, and a meta-regression to examine relationships between outcomes.

Twenty-eight randomised controlled trials examining 17 different psychological interventions were included. Effect sizes were small to moderate across all outcomes (Hedge's g depression = −0.47, CI −0.77 to −0.17; anxiety = −0.42, CI −0.65 to −0.20; RNT = −0.45, CI −0.67 to −0.23). RNT-focused and non-RNT focused approaches had comparable effects; however, those focusing on modifying the process of RNT had significantly larger effects on RNT than those focusing on modifying negative thought content. Meta-regression revealed a significant relationship between RNT and depression outcomes only across all intervention types and with both depression and anxiety for RNT focused interventions only.

Consistent with findings in adults, this review provides evidence that reducing RNT with psychological treatment is associated with improvements in depression and anxiety in youth. Targeting RNT specifically may not lead to better outcomes compared to general approaches; however, focusing on modifying the process of RNT may be more effective than targeting content. Further research is needed to determine causal pathways.

Suicidal behavior and substance use disorders (SUDs) are important public health concerns. Prior suicide attempts and SUDs are two of the most consistent predictors of suicide death, and clarifying the role of SUDs in the transition from suicide attempt to suicide death could inform prevention efforts.

We used national Swedish registry data to identify individuals born 1960–1985, with an index suicide attempt in 1997–2017 (N = 74 873; 46.7% female). We assessed risk of suicide death as a function of registration for a range of individual SUDs. We further examined whether the impact of SUDs varied as a function of (i) aggregate genetic liability to suicidal behavior, or (ii) age at index suicide attempt.

In univariate models, risk of suicide death was higher among individuals with any SUD registration [hazard ratios (HRs) = 2.68–3.86]. In multivariate models, effects of specific SUDs were attenuated, but remained elevated for AUD (HR = 1.86 95% confidence intervals 1.68–2.05), opiates [HR = 1.58 (1.37–1.82)], sedatives [HR = 1.93 (1.70–2.18)], and multiple substances [HR = 2.09 (1.86–2.35)]. In secondary analyses, the effects of most, but not all, SUD were exacerbated by higher levels of genetic liability to suicide death, and among individuals who were younger at their index suicide attempt.

In the presence of a strong predictor of suicide death – a prior attempt – substantial predictive power is still attributable to SUDs. Individuals with SUDs may warrant additional suicide screening and prevention efforts, particularly in the context of a family history of suicidal behavior or early onset of suicide attempt.

Youth suicide rates have increased markedly in some countries. This study aimed to estimate the population-attributable risk of psychiatric disorders associated with suicide among Taiwanese youth aged 10–24 years.

Data were obtained from the National Death Registry and National Health Insurance (NHI) claims database between 2007 and 2019. Youth who died by suicide were included, and comparisons, 1:10 matched by age and sex, were randomly selected from the Registry for NHI beneficiaries. We used multivariable logistic regression to estimate suicide odds ratios for psychiatric disorders. The population-attributable fractions (PAF) were calculated for each psychiatric disorder.

A total of 2345 youth suicide and 23 450 comparisons were included. Overall, 44.8% of suicides had a psychiatric disorder, while only 7.9% of the comparisons had a psychiatric disorder. The combined PAF for all psychiatric disorders was 55.9%. The top three psychiatric conditions of the largest PAFs were major depressive disorder, dysthymia, and sleep disorder. In the analysis stratified by sex, the combined PAF was 45.5% for males and 69.2% for females. The PAF among young adults aged 20–24 years (57.0%) was higher than among adolescents aged 10–19 years (48.0%).

Our findings of high PAF from major depressive disorder, dysthymia, and sleep disorder to youth suicides suggest that youth suicide prevention that focuses on detecting and treating mental illness may usefully target these disorders.

Depressive symptoms, functional impairment, and decreased quality of life (QOL) are three important domains of major depressive disorder (MDD). However, the possible causal relationship between these factors has yet to be elucidated. Moreover, it is not known whether certain symptoms of MDD are more impairing than others. The network approach is a promising solution to these shortfalls.

The baseline data of a multicenter prospective project conducted in 11 governances of China were analyzed. In total, 1385 patients with MDD were included. Depressive symptoms, functioning disability, and QOL were evaluated by the 17-item Hamilton Depression Rating Scale (HAMD-17), the Sheehan Disability Scale (SDS), and the Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form (Q-LES-Q-SF). The network was estimated through the graphical Least Absolute Shrinkage and Selection Operator (LASSO) technique in combination with the directed acyclic graph.

Three centrality metrics of the graphical LASSO showed that social life dysfunction, QOL, and late insomnia exhibited the highest strength centrality. The network accuracy and stability were estimated to be robust and stable. The Bayesian network indicated that some depressive symptoms were directly associated with QOL, while other depressive symptoms showed an indirect association with QOL mediated by impaired function. Depressed mood was positioned at the highest level in the model and predicted the activation of functional impairment and anxiety.

Functional disability mediated the relationship between depressive symptoms and QOL. Family functionality and suicidal symptoms were directly related to QOL. Depressed mood played the predominant role in activating both anxiety symptom and functional impairment.

Research suggests that there have been inequalities in the impact of the coronavirus disease 2019 (COVID-19) pandemic and related non-pharmaceutical interventions on population mental health. We explored generational, sex, and socioeconomic inequalities during the first year of the pandemic using nationally representative cohorts from the UK.

We analysed data from 26772 participants from five longitudinal cohorts representing generations born between 1946 and 2000, collected in May 2020, September–October 2020, and February–March 2021 across all five cohorts. We used a multilevel growth curve modelling approach to investigate generational, sex, and socioeconomic differences in levels of anxiety and depressive symptomatology, loneliness, and life satisfaction (LS) over time.

Younger generations had worse levels of mental and social wellbeing throughout the first year of the pandemic. Whereas these generational inequalities narrowed between the first and last observation periods for LS [−0.33 (95% CI −0.51 to −0.15)], they became larger for anxiety [0.22 (0.10, 0.33)]. Generational inequalities in depression and loneliness did not change between the first and last observation periods, but initial depression levels of the youngest cohort were worse than expected if the generational inequalities had not accelerated. Women and those experiencing financial difficulties had worse initial mental and social wellbeing levels than men and those financially living comfortably, respectively, and these gaps did not substantially differ between the first and last observation periods.

By March 2021, mental and social wellbeing inequalities persisted in the UK adult population. Pre-existing generational inequalities may have been exacerbated with the pandemic onset. Policies aimed at protecting vulnerable groups are needed.

The scale of the global mental health burden indicates the inadequacy not only of current treatment options, but also the pace of the standard treatment development process. The ‘leapfrog’ trial design is a newly-developed simple Bayesian adaptive trial design with potential to accelerate treatment development. A first leapfrog trial was conducted to provide a demonstration and test feasibility, applying the method to a low-intensity internet-delivered intervention targeting anhedonia.

At the start of this online, single-blind leapfrog trial, participants self-reporting depression were randomized to an initial control arm comprising four weeks of weekly questionnaires, or one of two versions of a four-week cognitive training intervention, imagery cognitive bias modification (imagery CBM). Intervention arms were compared to control on an ongoing basis via sequential Bayesian analyses, based on a primary outcome of anhedonia at post-intervention. Results were used to eliminate and replace arms, or to promote them to become the control condition based on pre-specified Bayes factor and sample size thresholds. Two further intervention arms (variants of imagery CBM) were added into the trial as it progressed.

N = 188 participants were randomized across the five trial arms. The leapfrog methodology was successfully implemented to identify a ‘winning’ version of the imagery CBM, i.e. the version most successful in reducing anhedonia, following sequential elimination of the other arms.

The study demonstrates feasibility of the leapfrog design and provides a foundation for its adoption as a method to accelerate treatment development in mental health. Registration: clinicaltrials.gov, NCT04791137.

Although aberrant brain regional responses are reported in social anxiety disorder (SAD), little is known about resting-state functional connectivity at the macroscale network level. This study aims to identify functional network abnormalities using a multivariate data-driven method in a relatively large and homogenous sample of SAD patients, and assess their potential diagnostic value.

Forty-six SAD patients and 52 demographically-matched healthy controls (HC) were recruited to undergo clinical evaluation and resting-state functional MRI scanning. We used group independent component analysis to characterize the functional architecture of brain resting-state networks (RSNs) and investigate between-group differences in intra-/inter-network functional network connectivity (FNC). Furtherly, we explored the associations of FNC abnormalities with clinical characteristics, and assessed their ability to discriminate SAD from HC using support vector machine analyses.

SAD patients showed widespread intra-network FNC abnormalities in the default mode network, the subcortical network and the perceptual system (i.e. sensorimotor, auditory and visual networks), and large-scale inter-network FNC abnormalities among those high-order and primary RSNs. Some aberrant FNC signatures were correlated to disease severity and duration, suggesting pathophysiological relevance. Furthermore, intrinsic FNC anomalies allowed individual classification of SAD v. HC with significant accuracy, indicating potential diagnostic efficacy.

SAD patients show distinct patterns of functional synchronization abnormalities both within and across large-scale RSNs, reflecting or causing a network imbalance of bottom-up response and top-down regulation in cognitive, emotional and sensory domains. Therefore, this could offer insights into the neurofunctional substrates of SAD.

Refractory depression is a devastating condition with significant morbidity, mortality, and societal cost. Approximately 15% of patients with major depressive disorder are refractory to currently available treatments. We hypothesized metabolic abnormalities contributing to treatment refractory depression are associated with distinct findings identifiable in the cerebrospinal fluid (CSF). Our hypothesis was confirmed by a previous small case-controlled study. Here we present a second, larger replication study.

We conducted a case-controlled, targeted, metabolomic evaluation of 141 adolescent and adult patients with well-characterized history of depression refractory to three maximum-dose, adequate-duration medication treatments, and 36 healthy controls. Plasma, urine, and CSF metabolic profiling were performed by coupled gas chromatography/mass spectrometry, and high-performance liquid chromatography, electrospray ionization, tandem mass spectrometry.

Abnormalities were identified in 67 of 141 treatment refractory depression participants. The CSF abnormalities included: low cerebral folate (n = 20), low tetrahydrobiopterin intermediates (n = 11), and borderline low-tetrahydrobiopterin intermediates (n = 20). Serum abnormalities included abnormal acylcarnitine profile (n = 12) and abnormal serum amino acids (n = 20). Eighteen patients presented with two or more abnormal metabolic findings. Sixteen patients with cerebral folate deficiency and seven with low tetrahydrobiopterin intermediates in CSF showed improvement in depression symptom inventories after treatment with folinic acid and sapropterin, respectively. No healthy controls had a metabolite abnormality.

Examination of metabolic disorders in treatment refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities. The etiology of these abnormalities and their potential roles in pathogenesis remain to be determined.