Argyris Stringaris

Background: The decline of mental health among adolescents in the UK over the past two decades has occurred amidst many societal and technological changes making it difficult to identify drivers of these trends. We aimed to identify which aspect of life showed the most rapid deterioration in satisfaction in the UK since 2009 and which aspects have become increasingly correlated with mental health. Methods: Between 2009 and 2024, 15,829 adolescents aged 10-15 rated their satisfaction with life as well as five aspects of life (family, friends, school, schoolwork, appearance), via the UK Household Longitudinal Study. Population-weighted regressions were used to estimate annual summary statistics on these items (means, proportions) and the relative associations between satisfaction items and socioemotional difficulties, as measured by the Strengths and Difficulties Questionnaire (SDQ). Meta-regressions estimated linear changes over time, with interactions testing for heterogeneity across sexes, age-groups, and household income. Results: Mean satisfaction with life dropped over the 16 years of study (B=-0.028, 95% CI=-0.034,-0.022), as did satisfaction with all five aspects of life. Satisfaction with school declined most rapidly (B=-0.027, 95% CI=-0.034,-0.020), becoming accelerated in the most recent 5-year window (2020-24; B=-0.139, 95% CI=-0.178,-0.099). The proportion of dissatisfied individuals rose most rapidly for schoolwork, particularly for females. Satisfaction with appearance became increasingly associated with general life satisfaction (B=0.009, 95% CI=0.005, 0.013, p<.001) and socioemotional difficulties (B=-0.051, 95% CI=-0.073,-0.029, p<.001) over time. Conclusions: Our findings add to international evidence for academic pressure and school environments as plausible drivers of recent declines in life satisfaction, particularly among female adolescents. Future studies should aim to identify the specific aspects of school life that are influencing adolescent mental health and the impact of existing educational policies on student wellbeing should be evaluated.

The STRATIFY (Brain Network-Based Stratification of Reinforcement-Related Disorders) and ESTRA (Eating Disorders Stratification) studies were established as harmonised “sibling” cohorts to develop a mechanistically informed framework for stratifying psychiatric disorders. Here, we describe the study design, methodology, and cohort characteristics. Both studies investigate how network properties of brain structure and function, together with biological markers derived from blood-based genomics, epigenetics, and proteomics, relate to reinforcement-related behaviours that cut across major depressive disorder, alcohol use disorder, psychosis, and eating disorders. A further objective is to identify discriminative multimodal features that predict disease onset, symptom course, and functional outcomes, thereby supporting the development of targeted interventions. STRATIFY and ESTRA recruited 674 patients and 70 healthy controls aged 18–30 years (76% females), supplemented by 199 age- and sex-matched healthy controls from the population-based IMAGEN cohort assessed at the same sites using harmonised protocols. Multimodal assessment included structured clinical interviews, self-report measures, cognitive testing, biosamples for molecular analyses, and multimodal MRI (structural, diffusion, resting-state, and task-based fMRI). ESTRA participants additionally completed longitudinal follow-up, and all cohorts were assessed during the COVID-19 pandemic. STRATIFY and ESTRA together constitute a large-scale, open-science resource integrating multimodal brain, behavioural, and biological data across transdiagnostic patient cohorts in early adulthood. The anonymised dataset is available to the research community through managed access, supporting international collaboration and accelerating the development of mechanistically informed classification systems and predictive tools in psychiatry.

The “Cone of Gaze” (CoG), a measure of the range of gaze angles that one perceives to be looking at them, has been proposed as a biobehavioural marker of psychiatric disorders characterised by symptoms in the social domain, such as social anxiety disorder. However, the evidence remains inconsistent and its mechanisms unclear. Here, we combine meta-analysis and well-powered experimental replications to investigate: 1) individual differences in the CoG between those with and without social anxiety; 2) within-subjects differences in the CoG in response to faces with angry versus neutral expressions; and 3) the interaction between these factors. The meta-analyses revealed significantly wider CoG for socially anxious versus non-anxious individuals (representing 10 studies and 403 participants), and wider CoG for angry versus neutral expressions (9 studies, 523 participants). However, the existing evidence was sparse, highly heterogeneous and often involved small samples. Our experiments (N=514) did not replicate the effect of social anxiety or emotional expression on CoG. Our integrated approach, combining meta-analyses with experimental replications and extensions, provides a rigorous framework for assessing the robustness and clinical relevance of gaze perception effects. We highlight the need for larger, more transparent datasets to accurately estimate CoG effects and other putative markers to assess their translational potential.

Objective: Arts engagement has been proposed as a scalable adjunct to psychiatric care, but high-quality randomized evidence amongst psychiatric populations remains limited. This study evaluated the efficacy of arts on prescription (AoP) added to care as usual (CAU) on mental health outcomes amongst adults receiving community psychiatric care.Methods: We conducted two sequential 12-week parallel-group randomized controlled trials in Greece: a pilot (N=380) and a confirmatory trial (N=541). Adults receiving psychiatric care were referred by mental health professionals and randomized to AoP plus CAU or CAU alone. The intervention involved participation in structured arts activities (music, dance, cinema, storytelling, theatre, environmental and visual arts). Depression symptom score (Patient Health Questionnaire-9 [PHQ-9]) at 12 weeks was a primary outcome across both trials. Secondary outcomes included anxiety (GAD-7), wellbeing (WEMWBS), and loneliness. Analyses used intention-to-treat linear mixed-effects models.Results: Across both trials (N=921), AoP was associated with greater reductions in depression symptoms compared with CAU. In the pilot and the main trial, the between-group difference at 12 weeks were -1.91 PHQ-9 points (95% CI=-3.09 to -0.72; p= 0.001) and -0.97 (95% CI= -1.89 to -0.06; p= 0.001), respectively. Significant improvements were also observed for anxiety and wellbeing, but not loneliness. Attrition was modest (15.7% - 18.7%), and no serious adverse events attributable to the intervention were reported. Conclusions: AoP added to CAU produced consistent improvements in depression, anxiety, and wellbeing across two randomized trials. These findings support AoP as a scalable, person-centered adjunct within community mental health services.

Major depression (MD) treatments have limited efficacy and target few mechanisms, highlighting the need for innovative drug discovery. Drugs targeting genetically supported proteins are 2.6 times more likely to succeed in drug development. Here, we use genetic methods to identify and prioritise MD drug targets, leveraging genome-wide association study (GWAS) summary statistics from >525,000 MD cases. We derived exposure data from 10 datasets measuring protein quantitative trait loci (pQTLs) and gene expression levels (eQTLs) in blood, cerebrospinal fluid, and brain tissues. We performed cis -Mendelian randomisation (MR) on 3469 druggable targets (genes encoding proteins targeted by existing compounds or experimentally predicted to be druggable). To strengthen causal inference, we implemented robust MR estimators, colocalisation, external replication, and assessed directional consistency across tissues. We integrated cis -MR effect directions with drug mechanisms and clinical annotations to infer potential therapeutic effects. Validation analyses showed that 82% of drugs approved for depression/anxiety had ≥1 significant MR target, compared to 51% for compounds in clinical trials. For repurposing, we prioritised 54 targets of compounds developed for other conditions with estimated beneficial effects on MD (e.g., an inhibitor for a risk-increasing target). Ten high-priority targets of brain-penetrating compounds included ACE and NISCH (cardiovascular drugs), NDUFA2, NDUFB6, and NDUFS1 (metformin), CDK4, NTRK3, and MET (oncology inhibitors), and GLS and NOS2 (enzyme inhibitors). We found genetic evidence for established and novel MD targets across the drug development pipeline. Novel targets point to mechanisms beyond monoaminergic systems, most with approved drugs for other conditions, offering immediate repurposing opportunities.

BackgroundDepression is a leading cause of global disease burden, yet effective prevention strategies remain limited. Identifying targetable risk factors is therefore a priority. Rumination, a style of repetitive negative thinking, has been linked to depression and anxiety, but has traditionally been viewed a symptom of depressive episodes rather than a cognitive vulnerability. Moreover, previous studies have not consistently addressed key confounders such as anxiety or the possibility of reverse causality. This study aimed to examine the longitudinal and bidirectional associations between rumination and depression in adolescents.MethodsParticipants were drawn from the IMAGEN adolescent cohort. Depression was assessed using the Development and Wellbeing Assessment (DAWBA), and rumination using the Ruminative Responses Scale (RRS), at ages 18 and 22. Bidirectional longitudinal associations were examined using logistic and linear regression models. Analyses were conducted unadjusted and adjusted for a range of confounders, including baseline symptoms and anxiety.Results Complete data were available for 800 adolescents (59.66% female, 40.12% male, mean age at first time point 18.42 years, SD=0.67). Higher rumination at age 18 was associated with depression at age 22, including after adjustment for confounders (adjusted OR=1.45, 95% CI 1.14–1.86, P=0.003). In contrast, there was no evidence that depression at age 18 was associated with rumination at age 22 after adjustment (mean difference = -0.52, 95% CI -1.69–0.64, P=0.379).ConclusionOverall, these findings indicate that rumination is associated with later depression from late adolescence into early adulthood, independent of baseline symptoms and confounders, with no evidence of reverse effects. This supports rumination as a vulnerability marker and a potential target for prevention, although intervention studies are needed to test causal effects.

BackgroundIrritability is a distressing and disabling transdiagnostic symptom of emotion dysregulation. Despite some obvious links between irritability and eating behaviours this relationship is rarely studied.AimsWe examined longitudinal associations between eating behaviours and irritability in young adulthood. We measured people’s tendencies to approach food (e.g. higher sensitivity to hunger, higher responsiveness to food) and to avoid food (e.g. undereating in emotional contexts, food fussiness) and compared their associations with irritability.MethodsWe used data from a British birth cohort (the Avon Longitudinal Study of Parents and Children), and employed a structural equation modelling framework to investigate the dimensional structure of eating behaviours at age 23 and their longitudinal associations with irritability at age 25. We ran analyses with both full information maximum likelihood and multiple imputation by chained equations to handle missing data. We also ran models which controlled for baseline depression symptoms.ResultsOur sample comprised 4188 participants with data on eating behaviours at age 23 (65% female). We found that behaviours related to both approaching food (b = 0.12, 95% confidence interval [CI] = 0.08-0.17) and to avoiding food (b = 0.08, 95% CI = 0.04-0.12) were associated with irritability. In additional analyses, we found that constraining these two coefficients to be equal did not result in meaningfully worse model fit; suggesting that individuals who tend to approach food and individuals who tend to avoid food are at similar risk for elevated irritability. Controlling for baseline depression symptoms resulted in reduced associations for both food approach (b = 0.07, 95% CI = 0.03-0.12) and food avoidance behaviours (b = 0.03, 95% CI = 0.00-0.07).ConclusionEating behaviours are longitudinally associated with higher irritability and may represent an overlooked pathway to emotion dysregulation.

The prevalence inflation hypothesis suggests the rise in mental health awareness efforts is contributing to increased reports of common mental health problems. However, few experimental studies have tested this. In this paper, two experimental studies are described (N = 271, N = 611) with UK-based young adults aged 18–24 years old. Participants were either exposed to Instagram posts from UK mental health charities, which normalised and shared relevant psychoeducational information about mental health problems in general (Experiment 1) or anxiety disorders exclusively (Experiment 2), or to Instagram posts from UK cycling charities (the control group). Relative to the control, exposure to mental health or anxiety-related content predicted significantly higher state and trait anxiety and a wider concept breadth of mental disorder whilst adjusting for gender and baseline outcomes. Exploratory analyses found those with higher baseline trait anxiety were more sensitive to the effects of exposure on state anxiety but less sensitive to the effects of exposure on concept breadth of mental disorder. Noting small effect sizes, these findings indicate that brief exposure to mental health awareness efforts can affect in-the-moment anxiety and how young adults view symptoms within themselves and others. Mental health awareness efforts may therefore be one factor contributing to increased reports of mental health problems. Future research should examine who is susceptible to these effects and to what extent this is a helpful or unhelpful phenomenon.

Behavioral Activation (BA) as part of cognitive behavioral therapy is an effective treatment for some individuals with major depressive disorder (MDD) and is hypothesized to operate through engagement of reward-related processes. However, evidence linking BA to modulation of reward circuitry, particularly during adolescence, remains limited. The present non-randomized open-label trial examined whether adolescents receiving BA, compared to those not receiving psychotherapy, show differential longitudinal changes in reward-related neural activity and depressive symptoms. Sixty-four adolescents with MDD were assessed longitudinally, including 18 adolescents who received 13 weekly sessions of BA psychotherapy and 46 adolescents with MDD who did not receive psychotherapy. Depressive symptoms were assessed using clinical questionnaires, and neural responses to reward anticipation and consumption were measured using the Monetary Incentive Delay (MID) task during functional MRI. Depressive symptoms decreased by approximately 1 point per month more in the BA group than the non-BA group (0.03 points per day, 95% CI = -0.06 – -0.01, p = 0.008). Longitudinal neuroimaging analyses revealed greater increases over time in the consummatory contrast in the BA group relative to the non-BA group in clusters within the right nucleus accumbens and left putamen (p < 0.01, alpha < 0.025, cluster size > 17). These findings indicate that BA is associated with longitudinal changes in both depressive symptoms and reward-related neural activity in adolescents with depression. These findings support that BA is an effective treatment and a useful tool for exploring reward-related neural changes in Major Depressive Disorder.