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Abstract Several multivariate prognostic models have been published to predict outcomes in patients with first episode psychosis (FEP), but it remains unclear whether those predictions generalize to independent populations. Using a subset of demographic and clinical baseline predictors, we aimed to develop and externally validate different models predicting functional outcome after a FEP in the context of a schizophrenia-spectrum disorder (FES), based on a previously published cross-validation and machine learning pipeline. A crossover validation approach was adopted in two large, international cohorts (EUFEST, n = 338, and the PSYSCAN FES cohort, n = 226). Scores on the Global Assessment of Functioning scale (GAF) at 12 month follow-up were dichotomized to differentiate between poor (GAF current

Abstract Bipolar disorder (BD) involves autonomic nervous system dysfunction, detectable through heart rate variability (HRV). HRV is a promising biomarker, but its dynamics during acute mania or depression episodes are poorly understood. Using a Bayesian approach, we developed a probabilistic model of HRV changes in BD, measured by the natural logarithm of the Root Mean Square of Successive RR interval Differences (lnRMSSD). Patients were assessed three to four times from episode onset to euthymia. Unlike previous studies, which used only two assessments, our model allowed for more accurate tracking of changes. Results showed strong evidence for a positive lnRMSSD change during symptom resolution (95.175% probability of positive direction), though the sample size limited the precision of this effect (95% Highest Density Interval [−0.0366, 0.4706], with a Region of Practical Equivalence: [-0.05; 0.05]). Episode polarity did not significantly influence lnRMSSD changes.

Despite the functional impact of cognitive deficit in people with psychosis, objective cognitive assessment is not typically part of routine clinical care. This is partly due to the length of traditional assessments and the need for a highly trained administrator. Brief, automated computerised assessments could help to address this issue. We present data from an evaluation of PsyCog, a computerised, non-verbal, mini battery of cognitive tests. Healthy Control (HC) (N = 135), Clinical High Risk (CHR) (N = 233), and First Episode Psychosis (FEP) (N = 301) participants from a multi-centre prospective study were assessed at baseline, 6 months, and 12 months. PsyCog was used to assess cognitive performance at baseline and at up to two follow-up timepoints. Mean total testing time was 35.95 min (SD = 2.87). Relative to HCs, effect sizes of performance impairments were medium to large in FEP patients (composite score G = 1.21, subtest range = 0.52–0.88) and small to medium in CHR patients (composite score G = 0.59, subtest range = 0.18–0.49). Site effects were minimal, and test-retest reliability of the PsyCog composite was good (ICC = 0.82–0.89), though some practice effects and differences in data completion between groups were found. The present implementation of PsyCog shows it to be a useful tool for assessing cognitive function in people with psychosis. Computerised cognitive assessments have the potential to facilitate the evaluation of cognition in psychosis in both research and in clinical care, though caution should still be taken in terms of implementation and study design.

Abstract Mood disorders (MDs) are among the leading causes of disease burden worldwide. Limited specialized care availability remains a major bottleneck thus hindering pre-emptive interventions. MDs manifest with changes in mood, sleep, and motor activity, observable in ecological physiological recordings thanks to recent advances in wearable technology. Therefore, near-continuous and passive collection of physiological data from wearables in daily life, analyzable with machine learning (ML), could mitigate this problem, bringing MDs monitoring outside the clinician’s office. Previous works predict a single label, either the disease state or a psychometric scale total score. However, clinical practice suggests that the same label may underlie different symptom profiles, requiring specific treatments. Here we bridge this gap by proposing a new task: inferring all items in HDRS and YMRS, the two most widely used standardized scales for assessing MDs symptoms, using physiological data from wearables. To that end, we develop a deep learning pipeline to score the symptoms of a large cohort of MD patients and show that agreement between predictions and assessments by an expert clinician is clinically significant (quadratic Cohen’s κ and macro-average F1 score both of 0.609). While doing so, we investigate several solutions to the ML challenges associated with this task, including multi-task learning, class imbalance, ordinal target variables, and subject-invariant representations. Lastly, we illustrate the importance of testing on out-of-distribution samples.

People with psychosis in Malawi have very limited access to timely assessment and evidence-based care, leading to a long duration of untreated psychosis and persistent disability. Most people with psychosis in the country consult traditional or religious healers. Stigmatising attitudes are common and services have limited capacity, particularly in rural areas. This paper, focusing on pathways to care for psychosis in Malawi, is based on the Wellcome Trust Psychosis Flagship Report on the Landscape of Mental Health Services for Psychosis in Malawi. Its purpose is to inform Psychosis Recovery Orientation in Malawi by Improving Services and Engagement (PROMISE), a longitudinal study that aims to build on existing services to develop sustainable psychosis detection systems and management pathways to promote recovery.

Abstract Attempts to delineate an immune subtype of schizophrenia have not yet led to the clear identification of potential treatment targets. An unbiased informatic approach at the level of individual immune cytokines and symptoms may reveal organisational structures underlying heterogeneity in schizophrenia, and potential for future therapies. The aim was to determine the network and relative influence of pro- and anti-inflammatory cytokines on depressive, positive, and negative symptoms. We further aimed to determine the effect of exposure to minocycline or placebo for 6 months on cytokine-symptom network connectivity and structure. Network analysis was applied to baseline and 6-month data from the large multi-center BeneMin trial of minocycline (N = 207) in schizophrenia. Pro-inflammatory cytokines IL-6, TNF-α, and IFN-γ had the greatest influence in the inflammatory network and were associated with depressive symptoms and suspiciousness at baseline. At 6 months, the placebo group network connectivity was 57% stronger than the minocycline group, due to significantly greater influence of TNF-α, early wakening, and pathological guilt. IL-6 and its downstream impact on TNF-α, and IFN-γ, could offer novel targets for treatment if offered at the relevant phenotypic profile including those with depression. Future targeted experimental studies of immune-based therapies are now needed.

Irritability is a core symptom of adolescent depression, characterized by an increased proneness to anger or frustration. Irritability in youth is associated with future mental health problems and impaired social functioning, suggesting that it may be an early indicator of emotion regulation difficulties. Adolescence is a period during which behavior is significantly impacted by one’s environment. However, existing research on the neural basis of irritability typically use experimental paradigms that overlook the social context in which irritability occurs. Here, we bring together current findings on irritability in adolescent depression and the associated neurobiology and highlight directions for future research. Specifically, we emphasize the importance of co-produced research with young people as a means to improve the construct and ecological validity of research within the field. Ensuring that our research design and methodology accurately reflect to lives of young people today lays a strong foundation upon which to better understand adolescent depression and identify tractable targets for intervention.

Abstract Individuals at Clinical High Risk for Psychosis (CHR-P) demonstrate heterogeneity in clinical profiles and outcome features. However, the extent of neuroanatomical heterogeneity in the CHR-P state is largely undetermined. We aimed to quantify the neuroanatomical heterogeneity in structural magnetic resonance imaging measures of cortical surface area (SA), cortical thickness (CT), subcortical volume (SV), and intracranial volume (ICV) in CHR-P individuals compared with healthy controls (HC), and in relation to subsequent transition to a first episode of psychosis. The ENIGMA CHR-P consortium applied a harmonised analysis to neuroimaging data across 29 international sites, including 1579 CHR-P individuals and 1243 HC, offering the largest pooled CHR-P neuroimaging dataset to date. Regional heterogeneity was indexed with the Variability Ratio (VR) and Coefficient of Variation (CV) ratio applied at the group level. Personalised estimates of heterogeneity of SA, CT and SV brain profiles were indexed with the novel Person-Based Similarity Index (PBSI), with two complementary applications. First, to assess the extent of within-diagnosis similarity or divergence of neuroanatomical profiles between individuals. Second, using a normative modelling approach, to assess the ‘normativeness’ of neuroanatomical profiles in individuals at CHR-P. CHR-P individuals demonstrated no greater regional heterogeneity after applying FDR corrections. However, PBSI scores indicated significantly greater neuroanatomical divergence in global SA, CT and SV profiles in CHR-P individuals compared with HC. Normative PBSI analysis identified 11 CHR-P individuals (0.70%) with marked deviation (>1.5 SD) in SA, 118 (7.47%) in CT and 161 (10.20%) in SV. Psychosis transition was not significantly associated with any measure of heterogeneity. Overall, our examination of neuroanatomical heterogeneity within the CHR-P state indicated greater divergence in neuroanatomical profiles at an individual level, irrespective of psychosis conversion. Further large-scale investigations are required of those who demonstrate marked deviation.

Background: Earlier pubertal timing is associated with higher rates of depressive disorders in adolescence. Neuroimaging studies report brain structural associations with both pubertal timing and depression. However, whether brain structure mediates the relationship between pubertal timing and depression remains unclear. Methods: The current registered report examined associations between pubertal timing (indexed via perceived pubertal development), brain structure (cortical and subcortical metrics, and white matter microstructure) and depressive symptoms in a large sample (N = ∼5000) of adolescents (aged 9–13 years) from the Adolescent Brain Cognitive Development (ABCD) Study. We used three waves of follow-up data when the youth were aged 10–11 years, 11–12 years, and 12–13 years, respectively. We used generalised linear-mixed models (H1) and structural equation modelling (H2 & H3) to test our hypotheses. Hypotheses: We hypothesised that earlier pubertal timing at Year 1 would be associated with increased depressive symptoms at Year 3 (H1), and that this relationship would be mediated by global (H2a-b) and regional (H3a-g) brain structural measures at Year 2. Global measures included reduced cortical volume, thickness, surface area and sulcal depth. Regional measures included reduced cortical thickness and volume in temporal and fronto-parietal areas, increased cortical volume in the ventral diencephalon, increased sulcal depth in the pars orbitalis, and reduced fractional anisotropy in the cortico-striatal tract and corpus callosum. These regions of interest were informed by our pilot analyses using baseline ABCD data when the youth were aged 9–10 years. Results: Earlier pubertal timing was associated with increased depressive symptoms two years later. The magnitude of effect was stronger in female youth and the association remained significant when controlling for parental depression, family income, and BMI in females but not in male youth. Our hypothesised brain structural measures did not however mediate the association between earlier pubertal timing and later depressive symptoms. Conclusion: The present results demonstrate that youth, particularly females, who begin puberty ahead of their peers are at an increased risk for adolescent-onset depression. Future work should explore additional biological and socio-environmental factors that may affect this association so that we can identify targets for intervention to help these at-risk youth.

Background Tackling Scotland's drug-related deaths and improving outcomes from substance misuse treatments, including residential rehabilitation, is a national priority. Aims To analyse and report outcomes up to 4 years after attendance at a substance misuse residential rehabilitation programme (Lothians and Edinburgh Abstinence Programme). Method In total, 145 participants were recruited to this longitudinal quantitative cohort study of an abstinence-based residential rehabilitation programme based on the therapeutic community model; 87 of these participants were followed up at 4 years. Outcomes are reported for seven subsections of the Addiction Severity Index-X (ASI-X), together with frequency of alcohol use, heroin use, injecting drug use and rates of abstinence from substances of misuse. Results Significant improvement in most outcomes at 4 years compared with admission scores were found. Completing the programme was associated with greater rates of abstinence, reduced alcohol use and improvements in alcohol status score (Mann–Whitney U = 626, P = 0.013), work satisfaction score (U = 596, P = 0.016) and psychiatric status score (U = 562, P = 0.007) on the ASI-X, in comparison with non-completion. Abstinence rates improved from 12% at baseline to 48% at 4 years, with the rate for those completing the programme increasing from 14.5% to 60.7% (χ2(2, 87) = 9.738, P = 0.002). Remaining abstinent from substances at follow-up was associated with better outcomes in the medical (U = 540, P < 0.001), psychiatric (U = 273.5, P < 0.001) and alcohol (U = 322.5, P < 0.001) subsections of the ASI-X. Conclusions Attending this abstinence-based rehabilitation programme was associated with positive changes in psychological and social well-being and harm reduction from substance use at 4-year follow-up, with stability of change from years 1 to 4.

Abstract Depression is assessed in various ways in research, with large population studies often relying on minimal phenotyping. Genetic results suggest clinical diagnoses and self-report measures of depression show some core similarities, but also important differences. It is not yet clear how neuroimaging associations depend on levels of phenotyping. We studied 39,300 UK Biobank imaging participants (20,701 female; aged 44.6 to 82.3 years, M = 64.1, SD = 7.5) with structural neuroimaging and lifetime depression data. Past depression phenotypes included a single-item self-report measure, an intermediate measure of ‘probable’ lifetime depression, derived from multiple questionnaire items relevant to a history of depression, and a retrospective clinical diagnosis according to DSM-IV criteria. We tested (i) associations between brain structural measures and each depression phenotype, and (ii) effects of phenotype on these associations. Depression-brain structure associations were small (β

Abstract Introduction Childhood trauma and adversity are common across societies and have strong associations with physical and psychiatric morbidity throughout the life-course. One possible mechanism through which childhood trauma may predispose individuals to poor psychiatric outcomes is via associations with brain structure. This study aimed to elucidate the associations between childhood trauma and brain structure across two large, independent community cohorts. Methods The two samples comprised (i) a subsample of Generation Scotland (n=1,024); and (ii) individuals from UK Biobank (n=27,202). This comprised n=28,226 for mega-analysis. MRI scans were processed using Free Surfer, providing cortical, subcortical, and global brain metrics. Regression models were used to determine associations between childhood trauma measures and brain metrics and psychiatric phenotypes. Results Childhood trauma associated with lifetime depression across cohorts (OR 1.06 GS, 1.23 UKB), and related to early onset and recurrent course within both samples. There was evidence for associations between childhood trauma and structural brain metrics. This included reduced global brain volume, and reduced cortical surface area with highest effects in the frontal (β=−0.0385, SE=0.0048, p(FDR)=5.43x10−15) and parietal lobes (β=−0.0387, SE=0.005, p(FDR)=1.56x10−14). At a regional level the ventral diencephalon (VDc) displayed significant associations with childhood trauma measures across both cohorts and at mega-analysis (β=−0.0232, SE=0.0039, p(FDR)=2.91x10−8). There were also associations with reduced hippocampus, thalamus, and nucleus accumbens volumes. Discussion Associations between childhood trauma and reduced global and regional brain volumes were found, across two independent UK cohorts, and at mega-analysis. This provides robust evidence for a lasting effect of childhood adversity on brain structure.

Inflammation is implicated in depression and psychosis, including association of childhood inflammatory markers on the subsequent risk of developing symptoms. However, it is unknown whether early-life inflammatory markers are associated with the number of depressive and psychotic symptoms from childhood to adulthood. Using the prospective Avon Longitudinal Study of Children and Parents birth cohort (N = up-to 6401), we have examined longitudinal associations of early-life inflammation [exposures: interleukin-6 (IL-6), C-reactive protein (CRP) levels at age 9y; IL-6 and CRP DNA-methylation (DNAm) scores at birth and age 7y; and IL-6 and CRP polygenic risk scores (PRSs)] with the number of depressive episodes and psychotic experiences (PEs) between ages 10–28 years. Psychiatric outcomes were assessed using the Short Mood and Feelings Questionnaire and Psychotic Like Symptoms Questionnaires, respectively. Exposure-outcome associations were tested using negative binomial models, which were adjusted for metabolic and sociodemographic factors. Serum IL-6 levels at age 9y were associated with the total number of depressive episodes between 10 and 28y in the base model (n = 4835; β = 0.066; 95%CI:0.020–0.113; pFDR = 0.041) which was weaker when adjusting for metabolic and sociodemographic factors. Weak associations were observed between inflammatory markers (serum IL-6 and CRP DNAm scores) and total number of PEs. Other inflammatory markers were not associated with depression or PEs. Early-life inflammatory markers are associated with the burden of depressive episodes and of PEs subsequently from childhood to adulthood. These findings support a potential role of early-life inflammation in the aetiology of depression and psychosis and highlight inflammation as a potential target for treatment and prevention.

Abstract Hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been commonly reported in major depressive disorder (MDD), but with considerable heterogeneity of results; potentially due to the predominant use of acute measures of an inherently variable/phasic system. Chronic longer-term measures of HPA-axis activity have yet to be systematically examined in MDD, particularly in relation to brain phenotypes, and in the context of early-life/contemporaneous stress. Here, we utilise a temporally stable measure of cumulative HPA-axis function (hair glucocorticoids) to investigate associations between cortisol, cortisone and total glucocorticoids with concurrent measures of (i) lifetime-MDD case/control status and current symptom severity, (ii) early/current-life stress and (iii) structural neuroimaging phenotypes, in N = 993 individuals from Generation Scotland (mean age = 59.1 yrs). Increased levels of hair cortisol were significantly associated with reduced global and lobar brain volumes with reductions in the frontal, temporal and cingulate regions (β range = −0.057 to −0.104, all P FDR

Introduction - Despite extensive debate surrounding mental health services in the UK, there is little empirical evidence regarding the views of those who use them. We therefore used data collected as part of a wider survey to examine satisfaction amongst those seeking treatment from mental and physical health services. Methods – An online survey designed with input from people with experience of mental illness was used to measure satisfaction with NHS mental and physical health services at first contact and in the previous 12 months. Results – A total of 2187 people responded. During the 12 months prior to the survey, 526 respondents had sought mental health care and 1379 had sought physical health care. Participants were significantly more satisfied with their most recent contact with mental health services (48.1% very/satisfied) than with their first contact (38.2% very/satisfied). More than 1 in 10 respondents who sought mental health care (11.4%) stated that they received no treatment/support from the NHS, compared to approximately 1 in 20 respondents who sought physical health care (4.6%). Of those who received the mental health treatment they requested (n = 424), most were satisfied or very satisfied with their care (54.7%), although this was lower than the corresponding figure (77.9%) for satisfaction with physical health care received (n = 1190). Conclusion –There was evidence that mental health services are satisfactory for a slim majority of users, but people were generally more satisfied with NHS physical health care. This survey was conducted in the year prior to the coronavirus disease 2019 pandemic. Future research could examine what influences satisfaction with care and whether this picture has changed following the emergence of the pandemic and consequent impact on health service delivery and daily life.

Abstract Introduction Duration of risk symptoms (DUR) in people at clinical high risk for psychosis (CHR-P) has been related to poorer clinical outcomes, such as reduced functioning, but it is currently unclear how different symptoms emerge as well as their link with cognitive deficits. To address these questions, we examined the duration of basic symptoms (BS) and attenuated psychotic symptoms (APS) in a sample of CHR-P participants to test the hypothesis that BS precede the manifestation of APS. As a secondary objective, we investigated the relationship between DUR, functioning and neuropsychological deficits. Methods Data from 134 CHR-P participants were assessed with the Comprehensive Assessment of At-Risk Mental State and the Schizophrenia Proneness Interview, Adult Version. Global, role and social functioning and neurocognition were assessed and compared to a sample of healthy controls (n = 57). Results In CHR-P participants who reported both APS and BS, onset of BS and APS was not significantly related. When divided into short and long BS duration ( 8 years), CHR-P participants with a longer duration of BS showed evidence for an onset of BS preceding APS (n = 8, p = 0.003). However, in the short BS duration group, APS showed evidence of preceding BS (n = 56, p = 0.020). Finally, there were no significant effects of DUR on cognition or functioning measures. Conclusion The present findings do not support the view that APS constitute a secondary phenomenon to BS. Moreover, our data could also not confirm that DUR has a significant effect on functioning and cognitive deficits. These findings are discussed in the context of current theories regarding emerging psychosis and the importance of DUR.

Abstract There has been a substantial amount of research reporting the neuroanatomical associations of psychotic symptoms in people with schizophrenia. Comparatively little attention has been paid to the neuroimaging correlates of subclinical psychotic symptoms, so-called “psychotic-like experiences” (PLEs), within large healthy populations. PLEs are relatively common in the general population (7–13%), can be distressing and negatively affect health. This study therefore examined gray and white matter associations of four different PLEs (auditory or visual PLEs, and delusional ideas about conspiracies or communications) in subjects of the UK Biobank study with neuroimaging data (N = 21,390, mean age = 63 years). We tested for associations between any PLE (N = 768) and individual PLEs with gray and white matter brain structures, controlling for sex, age, intracranial volume, scanning site, and position in the scanner. Individuals that reported having experienced auditory hallucinations (N = 272) were found to have smaller volumes of the caudate, putamen, and accumbens (β = −0.115–0.134, p corrected = 0.048–0.036), and reduced temporal lobe volume (β = −0.017, p corrected = 0.047) compared to those that did not. People who indicated that they had ever believed in unreal conspiracies (N = 111) had a larger volume of the left amygdala (β = 0.023, p corrected = 0.038). Individuals that reported a history of visual PLEs (N = 435) were found to have reduced white matter microstructure of the forceps major (β = −0.029, p corrected = 0.009), an effect that was more marked in participants who reported PLEs as distressing. These associations were not accounted for by diagnoses of psychotic or depressive illness, nor the known risk factors for psychotic symptoms of childhood adversity or cannabis use. These findings suggest altered regional gray matter volumes and white matter microstructure in association with PLEs in the general population. They further suggest that these alterations may appear more frequently with the presentation of different psychotic symptoms in the absence of clinically diagnosed psychotic disorders.

Psychosis involves changes in GABAergic and glutamatergic neurotransmission in auditory cortex that could be important for understanding sensory deficits and symptoms of psychosis. However, it is currently unclear whether such deficits are present in participants at clinical high-risk for psychosis (CHR-P) and whether they are associated with clinical outcomes. Magnetic Resonance Spectroscopy (MEGAPRESS, 1H-MRS at 3 Tesla) was used to estimate GABA, glutamate, and glutamate-plus-glutamine (Glx) levels in auditory cortex in a large sample of CHR-P (n = 99), CHR-N (clinical high-risk negative, n = 32), and 45 healthy controls. Examined were group differences in metabolite concentrations as well as relationships with clinical symptoms, general cognition, and 1-year follow-up clinical and general functioning in the CHR-P group. Results showed a marginal (p = 0.039) main group effect only for Glx, but not for GABA and glutamate concentrations, and only in left, not right, auditory cortex. This effect did not survive multiple comparison correction, however. Exploratory post-hoc tests revealed that there were significantly lower Glx levels (p = 0.029, uncorrected) in the CHR-P compared to the CHR-N group, but not relative to healthy controls (p = 0.058, uncorrected). Glx levels correlated with the severity of perceptual abnormalities and disorganized speech scores. However, in the CHR-P group, Glx levels did not predict clinical or functional outcomes. Accordingly, the findings from the present study suggest that MRS-measured GABA, glutamate and Glx levels in auditory cortex of CHR-P individuals are largely intact.

Abstract Background Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based ‘Regional Vulnerability Index’ (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N = 702, age = 59 ± 10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N = 3,825, age = 10 ± 1; 2-year follow-up N = 2,081, age = 12 ± 1). Methods MDD-RVIs quantify the correlation of the individual’s corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed. Results In adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (β = 0.099–0.281, PFDR = 0.001–0.043) than MDD-PRS (β = 0.056–0.152, PFDR = 0.140–0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (β = 0.084–0.086, p = 1.38 × 10−4−4.77 × 10−4) but not with any MDD-RVIs (β 0.05). Conclusions Our results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.

Hippocampal dysfunctions are a core feature of schizophrenia, but conflicting evidence exists whether volumetric and morphological changes are present in early-stage psychosis and to what extent these deficits are related to clinical trajectories. In this study, we recruited individuals at clinical high risk for psychosis (CHR-P) (n = 108), patients with a first episode of psychosis (FEP) (n = 37), healthy controls (HC) (n = 70) as well as a psychiatric control group with substance abuse and affective disorders (CHR-N: n = 38). MRI-data at baseline were obtained and volumetric as well as vertex analyses of the hippocampus were carried out. Moreover, volumetric changes were examined in the amygdala, caudate, nucleus accumbens, pallidum, putamen and thalamus. In addition, we obtained follow-up functional and symptomatic assessments in CHR-P individuals to examine the question whether anatomical deficits at baseline predicted clinical trajectories. Our results show that the hippocampus is the only structure showing significant volumetric decrease in early-stage psychosis, with FEPs showing significantly smaller hippocampal volumes bilaterally alongside widespread shape changes in the vertex analysis. For the CHR-P group, volumetric decreases were confined to the left hippocampus. However, hippocampal alterations in the CHR-P group were not robustly associated with clinical outcomes, including the persistence of attenuated psychotic symptoms and functional trajectories. Accordingly, our findings highlight that dysfunctions in hippocampal anatomy are an important feature of early-stage psychosis which may, however, not be related to clinical outcomes in CHR-P participants.

Background: Depression is the leading cause of disability worldwide with > 50% of cases emerging before the age of 25 years. Large-scale neuroimaging studies in depression implicate robust structural brain differences in the disorder. However, most studies have been conducted in adults and therefore, the temporal origins of depression-related imaging features remain largely unknown. This has important implications for understanding aetiology and informing timings of potential intervention. Methods: Here, we examine associations between brain structure (cortical metrics and white matter microstructural integrity) and depression ratings (from caregiver and child), in a large sample (N = 8634) of early adolescents (9 to 11 years old) from the US-based, Adolescent Brain and Cognitive Development (ABCD) Study®. Data was collected from 2016 to 2018. Findings: We report significantly decreased global cortical and white matter metrics, and regionally in frontal, limbic and temporal areas in adolescent depression (Cohen's d = -0⋅018 to -0⋅041, β = -0·019 to -0⋅057). Further, we report consistently stronger imaging associations for caregiver-reported compared to child-reported depression ratings. Divergences between reports (caregiver vs child) were found to significantly relate to negative socio-environmental factors (e.g., family conflict, absolute β = 0⋅048 to 0⋅169). Interpretation: Depression ratings in early adolescence were associated with similar imaging findings to those seen in adult depression samples, suggesting neuroanatomical abnormalities may be present early in the disease course, arguing for the importance of early intervention. Associations between socio-environmental factors and reporter discrepancy warrant further consideration, both in the wider context of the assessment of adolescent psychopathology, and in relation to their role in aetiology. Funding: Wellcome Trust (References: 104036/Z/14/Z and 220857/Z/20/Z) and the Medical Research Council (MRC, Reference: MC_PC_17209).

STratifying Resilience and Depression Longitudinally (STRADL) is a population-based study built on the Generation Scotland: Scottish Family Health Study (GS:SFHS) resource. The aim of STRADL is to subtype major depressive disorder (MDD) on the basis of its aetiology, using detailed clinical, cognitive, and brain imaging assessments. The GS:SFHS provides an important opportunity to study complex gene-environment interactions, incorporating linkage to existing datasets and inclusion of early-life variables for two longitudinal birth cohorts. Specifically, data collection in STRADL included: socio-economic and lifestyle variables; physical measures; questionnaire data that assesses resilience, early-life adversity, personality, psychological health, and lifetime history of mood disorder; laboratory samples; cognitive tests; and brain magnetic resonance imaging. Some of the questionnaire and cognitive data were first assessed at the GS:SFHS baseline assessment between 2006-2011, thus providing longitudinal measures relevant to the study of depression, psychological resilience, and cognition. In addition, routinely collected historic NHS data and early-life variables are linked to STRADL data, further providing opportunities for longitudinal analysis. Recruitment has been completed and we consented and tested 1,188 participants.

Introduction: Alterations in autonomic functioning in individuals diagnosed with schizophrenia are well-documented. Yet, it is currently unclear whether these dysfunctions extend into the clinical high-risk state. Thus, we investigated resting heart rate (RHR) and heart rate variability (HRV) indices in individuals at clinical high-risk for psychosis (CHR-P).Methods: We recruited 117 CHR-P participants, 38 participants with affective disorders and substance abuse (CHR-N) as well as a group of 49 healthy controls. CHR-P status was assessed with the Comprehensive Assessment of At-Risk Mental States (CAARMS) and the Schizophrenia Proneness Instrument, Adult Version (SPI-A). We obtained 5 min, eyes-open resting-state MEG data, which was used for the extraction of cardiac field-related inter-beat-interval data and from which heart-rate and heart-rate variability measures were computed.Results: Compared to both CHR-N and healthy controls, CHR-P participants were characterized by an increased RHR, which was not explained by differences in psychopathological comorbidity and medication status. Increased RHR correlated with the presence of subthreshold psychotic symptoms and associated distress. No differences between groups were found for heart-rate variability measures, however. Furthermore, there was an association between motor-performance and psychophysiological measures.Conclusion: The current study provides evidence of alterations in autonomic functioning as disclosed by increased RHR in CHR-P participants. Future studies are needed to further evaluate this characteristic feature of CHR-P individuals and its potential predictive value for psychosis development.

Background: The UK hosts some of the world’s longest-running longitudinal cohort studies, which make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a ’Fit-bit’ (88% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.

IntroductionAccumulating evidence for the co-occurrence autism spectrum disorder (ASD) and schizotypal personality disorder (SPD) at both the diagnostic and symptom levels raises important questions about the nature of their association and the effect of their co-occurrence on the individual’s phenotype and functional outcome. Research comparing adults with ASD and SPD, as well as the impact of their co-occurrence on outcomes is extremely limited. We investigated executive functioning in terms of response inhibition and sustained attention, candidate endophenotypes of both conditions, in adults with ASD, SPD, comorbid ASD and SPD, and neurotypical adults using both categorical and dimensional approaches.MethodsA total of 88 adults (Mean Age = 37.54; SD = 10.17): ASD (n = 26; M/F = 20/6); SPD (n = 20; M/F = 14/6); comorbid ASD and SPD (n=9; M/F=6/3) and neurotypicals (n=33; M/F=23/10) completed the Sustained Attention to Response Task (SART) in both its fixed and random forms. Positive and autistic symptom severity was assessed with the positive subscale of the Positive and Negative Syndrome Scale (PANSSpos) and the PANSS Autism Severity Score (PAUSS), respectively.ResultsControlling for full scale IQ, working memory and medication dosage, group analyses revealed that the comorbid group committed fewer omission errors than the ASD group on the fixed SART, and fewer omission errors than the ASD and SPD groups on the random SART. The individual difference analyses of the entire sample revealed that the PANSSpos and PAUSS interactively reduced omission errors in both the fixed and random SARTs, as well as increased d’ scores, indicative of improved overall performance. We observed no significant results for commission errors or reaction time.ConclusionsConcurrent elevated levels of autistic and positive psychotic symptoms seem to be associated with improved sustained attention abilities (reduced omission errors) but not inhibition (commission errors). Our findings highlight the importance of investigating the concurrent effect of ASD and SPD at both the symptom and diagnostic levels, and raise important questions for future research regarding the clinical and behavioral phenotypes of adults with dual diagnosis and, more generally, about the nature of the relationship between ASD and SPD.

Abstract Objective Occurrences of early‐life stress (ELS) are associated with the severity of psychotic symptoms and working memory (WM) deficits in patients with psychosis (PSY). This study investigated potential mediation roles of WM behavioral performance and glutamate concentrations in prefrontal brain regions on the association between ELS and psychotic symptom severity in PSY. Method Forty‐seven patients with PSY (established schizophrenia, n = 30; bipolar disorder, n = 17) completed measures of psychotic symptom severity. In addition, data on ELS and WM performance were collected in both patients with PSY and healthy controls (HC; n = 41). Resting‐state glutamate concentrations in the bilateral dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC) were also assessed with proton magnetic resonance spectroscopy for both PSY and HC groups. t tests, analyses of variance, and regression analyses were utilized. Results Participants with PSY reported significantly more ELS occurrences and showed poorer WM performance than HC. Furthermore, individuals with PSY displayed lower glutamate concentrations in the left DLPFC than HC. Neither ELS nor WM performance were predictive of severity of psychotic symptoms in participants with PSY. However, we found a significant negative correlation between glutamate concentrations in the left DLPFC and ELS occurrence in HC only. Conclusion In individuals with PSY, the current study found no evidence that the association between ELS and psychotic symptoms is mediated by WM performance or prefrontal glutamate concentrations. In HC, the association between ELS experience and glutamate concentrations may indicate a neurometabolite effect of ELS that is independent of an illness effect in psychosis.

Background: The UK hosts some of the world’s longest-running longitudinal cohort studies, who make repeated observations of their participants and use these data to explore health outcomes. An alternative method for data collection is record linkage; the linking together of electronic health and administrative records. Applied nationally, this could provide unrivalled opportunities to follow a large number of people in perpetuity. However, public attitudes to the use of data in research are currently unclear. Here we report on an event where we collected attitudes towards recent opportunities and controversies within health data science. Methods: The event was attended by ~250 individuals (cohort members and their guests), who had been invited through the offices of their participating cohort studies. There were a series of presentations describing key research results and the audience participated in 15 multiple-choice questions using interactive voting pads. Results: Our participants showed a high level of trust in researchers (87% scoring them 4/5 or 5/5) and doctors (81%); but less trust in commercial companies (35%). They supported the idea of researchers using information from both neonatal blood spots (Guthrie spots) (97% yes) and from electronic health records (95% yes). Our respondents were willing to wear devices like a ’Fit-bit’ (78% agreed) or take a brain scan that might predict later mental illness (73%). However, they were less willing to take a new drug for research purposes (45%). They were keen to encourage others to take part in research; whether that be offering the opportunity to pregnant mothers (97% agreed) or extending invitations to their own children and grandchildren (98%). Conclusions: Our participants were broadly supportive of research access to data, albeit less supportive when commercial interests were involved. Public engagement events that facilitate two-way interactions can influence and support future research and public engagement efforts.

Abstract Objective This review looked at internet-delivered cognitive behavioural therapy (iCBT) as a possible treatment for patients with bulimic symptoms. CBT has been established as an effective treatment; however, waiting lists lead to delayed initiation of treatment. iCBT is a possible delivery method to combat this. Medline, EMBASE and PsycInfo were searched for controlled trials using iCBT as a treatment for patients with bulimia nervosa (BN), subthreshold BN or ‘eating disorders not otherwise specified’ with bulimic characteristics (EDNOS-BN). The literature search returned 482 papers. 5 met the review criteria and were compared in characteristics, methodological quality and outcomes. Outcomes were analysed by calculation of effect sizes; iCBT was evaluated on reduction in binge eating and purging post treatment and at follow-up. Results Participants were mostly female with an average age range of 23.7–31 years. 4 studies demonstrated good methodological quality. 1 did not report all of the outcome data, increasing the likelihood of bias. Only 1 study showed widespread benefit over waiting list controls. iCBT was shown to reduce behaviours but was not found to be superior to bibliotherapy or waiting list. Further large-scale studies are required to make conclusive recommendations.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

BackgroundYoung people's mental health and well-being is an important concern in the UK. Provision of education and support to schools has been highlighted as an area for improvement; however, evidence-based programmes are scarce and costly.AimsTo provide an acceptable education programme to improve pupils' confidence and knowledge of mental health and well-being. It covered the mental and emotional well-being outcomes set by the Scottish Government in their schools' curriculum.MethodLessons were designed by A.P. and delivered by volunteer doctors and medical students, and supervised by a psychiatrist. Outcomes were measured using questionnaires before and after lessons with optional comments.ResultsPsychEd was piloted in 2016 in six schools to pupils between the ages of 11 and 18. There was a statistically significant improvement in pupil confidence and knowledge after the lessons (P < 0.001). Of the pupils 84% felt that having lessons on mental health was useful. Qualitative feedback was also collected and coded into positive, constructive and negative comments. In total, 72% of pupil comments were positive.ConclusionsPsychEd showed promising results. Future areas of development include reaching a greater number of local authority schools, longer training for volunteers and provision of teaching materials to teachers for their own use.Declaration of interestNone.

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

An increasing body of genetic and imaging research shows that it is becoming possible to forecast the onset of major psychiatric disorders such as depression and schizophrenia before people become ill with ever improving accuracy. Practical issues such as the optimal combination of clinical and biological variables are being addressed, but the application of predictive algorithms to individuals or in routine clinical settings have yet to be tested. The development of predictive methods in mental health comes with substantial ethical questions, including whether people wish to know their level of risk, as well as individual and societal attitudes to the potential adverse effects of data sharing, early diagnosis and treatment, which so far have been largely ignored. Preliminary data suggests that at least some people think predictive research is valuable and would take part in such studies, and some would welcome knowing the results. Future initiatives should systematically assess opinions and attitudes in conjunction with scientific and technical advances.