To explore the association of cardiovascular-kidney-metabolic (CKM) health with the risk of depression and anxiety and to investigate the joint association of CKM health and social connection with depression and anxiety.

This prospective cohort study included 344 956 participants from the UK Biobank. CKM syndrome was identified as a medical condition with the presence of metabolic risk factors, cardiovascular disease, and chronic kidney disease, and was classified into five stages (stage 0–4) in this study. Loneliness and social isolation status were determined by self-reported questionnaires. Cox proportional hazards models were applied for analyses.

Compared with participants in stage 0, the HRs for depression were 1.17 (95% CI 1.10–1.25), 1.40 (95% CI 1.33–1.48), and 2.14 (95% CI 1.98–2.31) for participants in stage 1, 2–3, and 4, respectively. Similarly, participants in stage 2–3 (HR = 1.20, 95% CI 1.14–1.26) and stage 4 (HR = 1.63, 95% CI 1.51–1.75) had greater risks of incident anxiety. We found additive interactions between loneliness and CKM health on the risk of depression and anxiety. Participants simultaneously reported being lonely and in stage 4 had the greatest risk of depression (HR = 4.44, 95% CI 3.89–5.07) and anxiety (HR = 2.58, 95% CI 2.21–3.01) compared with those without loneliness and in stage 0. We also observed an additive interaction between social isolation and CKM health on the risk of depression.

Our findings suggest the importance of comprehensive interventions to improve CKM health and social connection to reduce the disease burden of depression and anxiety.

We aimed to identify the common types of outcome trajectories for patients with psychosis who take up specialist psychological therapy for persecutory delusions. Knowing the different potential responses to therapy can inform expectations. Further, determining predictors of different outcomes may help in understanding who may benefit.

We analyzed delusion conviction data from 767 therapy sessions with 64 patients with persistent persecutory delusions (held with at least 60% conviction) who received a six-month psychological intervention (Feeling Safe) during a clinical trial. Latent class trajectory analysis was conducted to identify groups with distinct outcome profiles. The trajectories were validated against independent assessments, including a longer-term follow-up six months after the end of therapy. We also tested potential predictors of the trajectories.

There were four outcome trajectories: (1) Very high delusion conviction/Little improvement (n = 14, 25%), (2) Very high delusion conviction/Large improvement (n = 9, 16%), (3) High delusion conviction/Moderate improvement (n = 17, 31%) and (4) High delusion conviction/Large improvement (n = 15, 27%). The groups did not differ in initial overall delusion severity. The trajectories were consistent with the independent assessments and sustained over time. Three factors predicted trajectories: persecutory delusion conviction, therapy expectations, and positive beliefs about other people.

There are variable responses to psychological therapy for persecutory delusions. Patients with very high delusion conviction can have excellent responses to therapy, though this may take a little longer to observe and such high conviction reduces the likelihood of positive responses. A trajectory approach requires testing in larger datasets but may prove highly informative.

Unpredictability is a core but understudied dimension of adversities and has been receiving increasing attention recently. The effects of unpredictability on psychopathology and the underlying neural mechanisms, however, remain unclear. It is also unknown how unpredictability interacts with other dimensions of adversities in predicting brain development and psychopathology of youth.

We applied cluster robust standard errors to examine how unpredictability was associated with the developmental changes in resting-state functional connectivity (rsFC) of large-scale brain networks implicated in psychopathology, as well as the moderating role of deprivation, using data from the Adolescent Brain Cognitive Development (ABCD) study, which included four measurements from baseline (mean ± s.d. age, 119.13 ± 7.51 months; 2815 females) to 3-year follow-up (N = 5885).

After controlling for threat, unpredictability was associated with a smaller increase in rsFC within default mode network (DMN) and a smaller decrease in rsFC between cingulo-opercular network (CON) and DMN. Neighborhood educational deprivation moderated the associations between unpredictability and changes in rsFC within DMN and fronto-parietal network (FPN), as well as between CON and DMN. A smaller decrease in rsFC between CON and DMN mediated the association between unpredictability and externalizing problems. Neighborhood educational deprivation moderated the indirect pathway from unpredictability to externalizing problems via a smaller decrease in CON-DMN rsFC.

Our findings shed light on the neural mechanisms underlying the associations between unpredictability and adolescents' psychopathology and the moderating role of deprivation, highlighting the significance of providing stable environment and abundant educational opportunities to facilitate optimal development.

ADHD symptoms are associated with emotional problems such as depressive and anxiety symptoms from early childhood to adulthood, with the association increasing with age. A shared aetiology and/or a causal relationship could explain their correlation. In the current study, we explore these explanations for the association between ADHD symptoms and emotional problems from childhood to adulthood.

Data were drawn from the Twins Early Development Study (TEDS), including 3675 identical and 7063 non-identical twin pairs. ADHD symptoms and emotional symptoms were reported by parents from childhood to adulthood. Self-report scales were included from early adolescence. Five direction of causation (DoC) twin models were fitted to distinguish whether associations were better explained by shared aetiology and/or causal relationships in early childhood, mid-childhood, early adolescence, late adolescence, and early adulthood. Follow-up analyses explored associations for the two subdomains of ADHD symptoms, hyperactivity-impulsivity and inattention, separately.

The association between ADHD symptoms and emotional problems increased in magnitude from early childhood to adulthood. In the best-fitting models, positive genetic overlap played an important role in this association at all stages. A negative causal effect running from ADHD symptoms to emotional problems was also detected in early childhood and mid-childhood. When distinguishing ADHD subdomains, the apparent protective effect of ADHD symptoms on emotional problems in childhood was mostly driven by hyperactivity-impulsivity.

Genetic overlap plays an important role in the association between ADHD symptoms and emotional problems. Hyperactivity-impulsivity may protect children from emotional problems in childhood, but this protective effect diminishes after adolescence.

Involuntary admissions to psychiatric hospitals are on the rise. If patients at elevated risk of involuntary admission could be identified, prevention may be possible. Our aim was to develop and validate a prediction model for involuntary admission of patients receiving care within a psychiatric service system using machine learning trained on routine clinical data from electronic health records (EHRs).

EHR data from all adult patients who had been in contact with the Psychiatric Services of the Central Denmark Region between 2013 and 2021 were retrieved. We derived 694 patient predictors (covering e.g. diagnoses, medication, and coercive measures) and 1134 predictors from free text using term frequency-inverse document frequency and sentence transformers. At every voluntary inpatient discharge (prediction time), without an involuntary admission in the 2 years prior, we predicted involuntary admission 180 days ahead. XGBoost and elastic net models were trained on 85% of the dataset. The models with the highest area under the receiver operating characteristic curve (AUROC) were tested on the remaining 15% of the data.

The model was trained on 50 634 voluntary inpatient discharges among 17 968 patients. The cohort comprised of 1672 voluntary inpatient discharges followed by an involuntary admission. The best XGBoost and elastic net model from the training phase obtained an AUROC of 0.84 and 0.83, respectively, in the test phase.

A machine learning model using routine clinical EHR data can accurately predict involuntary admission. If implemented as a clinical decision support tool, this model may guide interventions aimed at reducing the risk of involuntary admission.

Short-term exposure to antipsychotics has proven to be beneficial. However, naturalistic studies are lacking regarding the long-term use of antipsychotics. This study aimed to investigate changes in use of antipsychotics over 20 years after a first-episode schizophrenia.

This study is part of the Danish OPUS trial (1998–2000), including 496 participants with first-episode schizophrenia. Participants were reassessed four times over 20 years. The main outcomes were days on medication, redeemed prescriptions of clozapine, psychiatric hospitalizations, and employment.

At the 20-year follow-up, an attrition of 71% was detected. In total, 143 out of 496 participated, with 36% (n = 51) in remission-of-psychotic-symptoms-off-medication. The lowest number of days on medication (mean [s.d.], 339 [538] days) was observed in this group over 20 years. Register data on redeemed antipsychotics were available for all trial participants (n = 416). Individuals in treatment with antipsychotics (n = 120) at the 20-year follow-up had spent significantly more days in treatment (5405 [1857] v. 1434 [1819] mean days, p = 0.00) and more had ever redeemed a prescription of clozapine (25% v. 7.8%, p = 0.00) than individuals who had discontinued antipsychotics (n = 296). Further, discontinuers had significantly higher employment at the 20-year follow-up (28.4% v. 12.5%, p = 0.00).

In a cohort of individuals with first-episode schizophrenia, 36% were in remission-of-psychotic-symptoms-off-medication. However, high attrition was detected, potentially affecting study results by inflating results from individuals with favorable outcomes. From register data, free from attrition, approximately 30% were in treatment with antipsychotics, and 70% had discontinued antipsychotics. Individuals in treatment had the least favorable outcomes, implying greater illness severity.

Major psychiatric disorders (MPDs) are delineated by distinct clinical features. However, overlapping symptoms and transdiagnostic effectiveness of medications have challenged the traditional diagnostic categorisation. We investigate if there are shared and illness-specific disruptions in the regional functional efficiency (RFE) of the brain across these disorders.

We included 364 participants (118 schizophrenia [SCZ], 80 bipolar disorder [BD], 91 major depressive disorder [MDD], and 75 healthy controls [HCs]). Resting-state fMRI was used to caclulate the RFE based on the static amplitude of low-frequency fluctuation, regional homogeneity, and degree centrality and corresponding dynamic measures indicating variability over time. We used principal component analysis to obtain static and dynamic RFE values. We conducted functional and genetic annotation and enrichment analysis based on abnormal RFE profiles.

SCZ showed higher static RFE in the cortico-striatal regions and excessive variability in the cortico-limbic regions. SCZ and MDD shared lower static RFE with higher dynamic RFE in sensorimotor regions than BD and HCs. We observed association between static RFE abnormalities with reward and sensorimotor functions and dynamic RFE abnormalities with sensorimotor functions. Differential spatial expression of genes related to glutamatergic synapse and calcium/cAMP signaling was more likely in the regions with aberrant RFE.

SCZ shares more regions with disrupted functional integrity, especially in sensorimotor regions, with MDD rather than BD. The neural patterns of these transdiagnostic changes appear to be potentially driven by gene expression variations relating to glutamatergic synapses and calcium/cAMP signaling. The aberrant sensorimotor, cortico-striatal, and cortico-limbic integrity may collectively underlie neurobiological mechanisms of MPDs.

Machine learning (ML) has developed classifiers differentiating patient groups despite concerns regarding diagnostic reliability. An alternative strategy, used here, is to develop a functional classifier (hyperplane) (e.g. distinguishing the neural responses to received reward v. received punishment in typically developing (TD) adolescents) and then determine the functional integrity of the response (reward response distance from the hyperplane) in adolescents with externalizing and internalizing conditions and its associations with symptom clusters.

Two hundred and ninety nine adolescents (mean age = 15.07 ± 2.30 years, 117 females) were divided into three groups: a training sample of TD adolescents where the Support Vector Machine (SVM) algorithm was applied (N = 65; 32 females), and two test groups– an independent sample of TD adolescents (N = 39; 14 females) and adolescents with a psychiatric diagnosis (major depressive disorder (MDD), generalized anxiety disorder (GAD), attention deficit hyperactivity disorder (ADHD) & conduct disorder (CD); N = 195, 71 females).

SVM ML analysis identified a hyperplane with accuracy = 80.77%, sensitivity = 78.38% and specificity = 88.99% that implicated feature neural regions associated with reward v. punishment (e.g. nucleus accumbens v. anterior insula cortices). Adolescents with externalizing diagnoses were significantly less likely to show a normative and significantly more likely to show a deficient reward response than the TD samples. Deficient reward response was associated with elevated CD, MDD, and ADHD symptoms.

Distinguishing the response to reward relative to punishment in TD adolescents via ML indicated notable disruptions in this response in patients with CD and ADHD and associations between reward responsiveness and CD, MDD, and ADHD symptom severity.

Childhood bullying is a public health priority. We evaluated the effectiveness and costs of KiVa, a whole-school anti-bullying program that targets the peer context.

A two-arm pragmatic multicenter cluster randomized controlled trial with embedded economic evaluation. Schools were randomized to KiVa-intervention or usual practice (UP), stratified on school size and Free School Meals eligibility. KiVa was delivered by trained teachers across one school year. Follow-up was at 12 months post randomization. Primary outcome: student-reported bullying-victimization; secondary outcomes: self-reported bullying-perpetration, participant roles in bullying, empathy and teacher-reported Strengths and Difficulties Questionnaire. Outcomes were analyzed using multilevel linear and logistic regression models.

Between 8/11/2019–12/02/2021, 118 primary schools were recruited in four trial sites, 11 111 students in primary analysis (KiVa-intervention: n = 5944; 49.6% female; UP: n = 5167, 49.0% female). At baseline, 21.6% of students reported being bullied in the UP group and 20.3% in the KiVa-intervention group, reducing to 20.7% in the UP group and 17.7% in the KiVa-intervention group at follow-up (odds ratio 0.87; 95% confidence interval 0.78 to 0.97, p value = 0.009). Students in the KiVa group had significantly higher empathy and reduced peer problems. We found no differences in bullying perpetration, school wellbeing, emotional or behavioral problems. A priori subgroup analyses revealed no differences in effectiveness by socioeconomic gradient, or by gender. KiVa costs £20.78 more per pupil than usual practice in the first year, and £1.65 more per pupil in subsequent years.

The KiVa anti-bullying program is effective at reducing bullying victimization with small-moderate effects of public health importance.

The study was funded by the UK National Institute for Health and Care Research (NIHR) Public Health Research program (17-92-11). Intervention costs were funded by the Rayne Foundation, GwE North Wales Regional School Improvement Service, Children's Services, Devon County Council and HSBC Global Services (UK) Ltd.

There is a compelling need for innovative intervention strategies for patients with affective disorders, given their increasing global prevalence and significant associated disability and impaired functioning. This study aimed to investigate whether a comprehensive multimodule individualized intervention (AWARE), targeting known mediators of functioning, improves functioning in affective disorders.

AWARE was a randomized, controlled, rater-blind clinical trial conducted at two centers in the Capital Region of Denmark (Clinicaltrials.gov, NCT 04701827). Participants were adults with bipolar disorder or major depressive disorder and impaired functioning. Participants were randomized to the six-month AWARE intervention or treatment as usual (TAU). The AWARE intervention is based on the International Classification of Functioning, Disability and Health (ICF) Brief Core Set for Bipolar and Unipolar Disorder.

The primary outcome was observation-based functioning using the Assessment of Motor and Process Skills (AMPS). Secondary outcomes were functioning, QoL, stress, and cognition.

Between February 2021 and January 2023, 103 patients were enrolled; 50 allocated to AWARE treatment and 53 to TAU (96 included in the full analysis set). There was no statistically significant differential change over time between groups in the primary outcome (AMPS), however, both groups showed a statistically significant improvement at endpoint. The AWARE intervention had a statistically significant effect compared with TAU on secondary outcomes of patient-reported functioning, stress and cognition.

Compared with TAU, the AWARE intervention was ineffective at improving overall functioning on the primary outcome, presumably due to the short duration of the intervention. Further development of effective treatments targeting functioning is needed.

Delirium is a severe neuropsychiatric syndrome caused by physical illness, associated with high mortality. Understanding risk factors for delirium is key to targeting prevention and screening. Whether severe mental illness (SMI) predisposes people to delirium is not known. We aimed to establish whether pre-existing SMI diagnosis is associated with higher risk of delirium diagnosis and mortality following delirium diagnosis.

A retrospective cohort and nested case–control study using linked primary and secondary healthcare databases from 2000–2017. We identified people diagnosed with SMI, matched to non-SMI comparators. We compared incidence of delirium diagnoses between people with SMI diagnoses and comparators, and between SMI subtypes; schizophrenia, bipolar disorder and ‘other psychosis’. We compared 30-day mortality following a hospitalisation involving delirium between people with SMI diagnoses and comparators, and between SMI subtypes.

We identified 20 566 people with SMI diagnoses, matched to 71 374 comparators. Risk of delirium diagnosis was higher for all SMI subtypes, with a higher risk conferred by SMI in the under 65-year group, (aHR:7.65, 95% CI 5.45–10.7, ⩾65-year group: aHR:3.35, 95% CI 2.77–4.05). Compared to people without SMI, people with an SMI diagnosis overall had no difference in 30-day mortality following a hospitalisation involving delirium (OR:0.66, 95% CI 0.38–1.14).

We found an association between SMI and delirium diagnoses. People with SMI may be more vulnerable to delirium when in hospital than people without SMI. There are limitations to using electronic healthcare records and further prospective study is needed to confirm these findings.

Harsh parenting in early childhood is related to offspring's adverse behavioral outcomes. Due to the scarcity of longitudinal neuroimaging data, few studies have explored the neurobiological underpinnings of this association, focusing on within-person variability. This study examined the temporal associations among harsh parenting, later behavioral problems, and the developmental trajectories of amygdala volume and amygdala resting-state functional connectivity (RSFC) profiles, using longitudinal neuroimaging data.

The study was embedded in the Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. T1-weighted (296 children, 642 scans) and resting-state functional scans (256 children, 509 scans) were collected at ages 4.5, 6, 7.5, and 10.5 years. Amygdala volume and RSFC between the amygdala and six brain regions that have leading roles in emotional regulation were extracted. Harsh parenting at 4.5 years and child behavioral problems at 10.5 years were assessed via parent-report questionnaires. Linear regression and linear mixed models were applied.

Harsh parenting was associated with more severe externalizing problems in girls (β = 0.24, 95% CI 0.08–0.40) but not boys (pint = 0.07). In the overall sample, harsh parenting was associated with the developmental trajectories of amygdala-ACC, amygdala-OFC, and amygdala-DLPFC RSFC. In addition, the developmental trajectory of amygdala-ACC RSFC mediated the harsh parenting–externalizing problems association in girls (indirect effect = 0.06, 95% CI 0.01–0.14).

Harsh parenting in early childhood was associated with amygdala neurocircuitry development and behavioral problems. The developmental trajectory of amygdala-ACC RSFC is a potential neural mechanism linking harsh parenting and externalizing problems in girls.

In schizophrenia (SZ), impairments in cognitive functions, such as working memory, have been associated with alterations in certain types of inhibitory neurons that utilize the neurotransmitter γ-aminobutyric acid (GABA) in the dorsolateral prefrontal cortex (DLPFC). For example, GABA neurons that express parvalbumin (PV) or somatostatin (SST) have more prominent gene expression alterations than those that express vasoactive intestinal peptide (VIP). In bipolar disorder (BD) and major depression (MD), which exhibit similar, but less severe, cognitive impairments than SZ, alterations of transcript levels in GABA neurons have also been reported. However, the extent to which GABA neuron subtype-selective transcripts in the DLPFC are affected, and the relative magnitudes of the diagnosis-associated effects, have not been directly compared across SZ, BD, and MD in the same study.

We used quantitative polymerase chain reaction to examine levels of GABA neuron subtype-selective transcripts (PV, potassium voltage-gated channel modifier subfamily-S member-3, SST, VIP, and calretinin mRNAs), as well as the pan-GABA neuron marker 67 kDa glutamate decarboxylase mRNA, in DLPFC total gray matter of 160 individuals, including those with SZ, BD, or MD and unaffected comparison (UC) individuals.

Relative to UC individuals, individuals with SZ exhibited large deficits in levels of all transcripts except for calretinin mRNA, whereas individuals with BD or MD showed a marked deficit only for PV or SST mRNAs, respectively.

These findings suggest that broader and more severe alterations in DLPFC GABA neurons might contribute to the greater cognitive impairments in SZ relative to BD and MD.

Despite the growing interest in the prevalence and consequences of loneliness, the way it is measured still raises a number of questions. In particular, few studies have directly compared the psychometric properties of very short measures of loneliness to standard measures.

We conducted a large epidemiological study of midwife students (n = 1742) and performed a head-to-head comparison of the psychometric properties of the standard (20 items) and short version (3 items) of the UCLA Loneliness Scales (UCLA-LS). All participants completed the UCLA-LS-20, UCLA-LS-3, as well as other measures of mental health, including anxiety and depression.

First, as predicted, we found that the two loneliness scales were strongly associated with each other. Second, when using the dimensional scores of the scales, we showed that the internal reliability, convergent-, discriminant-, and known-groups validities were high and of similar magnitude between the UCLA-LS-20 and the UCLA-LS-3. Third, when the scales were dichotomized, the results were more mixed. The sensitivity and/or specificity of the UCLA-LS-3 against the UCLA-LS-20 were systematically below acceptable thresholds, regardless of the dichotomizing process used. In addition, the prevalence of loneliness was strikingly variable as a function of the cut-offs used.

Overall, we showed that the UCLA-LS-3 provided an adequate dimensional measure of loneliness that is very similar to the UCLA-LS-20. On the other hand, we were able to highlight more marked differences between the scales when their scores were dichotomized, which has important consequences for studies estimating, for example, the prevalence of loneliness.

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.

One in eight children experience early life stress (ELS), which increases risk for psychopathology. ELS, particularly neglect, has been associated with reduced responsivity to reward. However, little work has investigated the computational specifics of this disrupted reward response – particularly with respect to the neural response to Reward Prediction Errors (RPE) – a critical signal for successful instrumental learning – and the extent to which they are augmented to novel stimuli. The goal of the current study was to investigate the associations of abuse and neglect, and neural representation of RPE to novel and non-novel stimuli.

One hundred and seventy-eight participants (aged 10–18, M = 14.9, s.d. = 2.38) engaged in the Novelty task while undergoing functional magnetic resonance imaging. In this task, participants learn to choose novel or non-novel stimuli to win monetary rewards varying from $0 to $0.30 per trial. Levels of abuse and neglect were measured using the Childhood Trauma Questionnaire.

Adolescents exposed to high levels of neglect showed reduced RPE-modulated blood oxygenation level dependent response within medial and lateral frontal cortices particularly when exploring novel stimuli (p < 0.05, corrected for multiple comparisons) relative to adolescents exposed to lower levels of neglect.

These data expand on previous work by indicating that neglect, but not abuse, is associated with impairments in neural RPE representation within medial and lateral frontal cortices. However, there was no association between neglect and behavioral impairments on the Novelty task, suggesting that these neural differences do not necessarily translate into behavioral differences within the context of the Novelty task.