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Recent studies suggest mental health in youths is deteriorating. The current policy in the United Kingdom emphasizes the role of schools for mental health promotion and prevention, but little data exist on what aspects of schools influence mental health in pupils. This study explored school-level influences on the mental health of young people in a large school-based sample from the United Kingdom.Baseline data from a large cluster randomized controlled trial collected between 2016 and 2018 from mainstream secondary schools selected to be representative in relation to their quality rating, size, deprivation, mixed or single-sex pupil population, and country were analyzed. Participants were pupils in their first or second year of secondary school. The study assessed whether school-level factors were associated with pupil mental health.The study included 26,885 pupils (response rate = 90%; age range, 11‒14 years; 55% female) attending 85 schools in the United Kingdom. Schools accounted for 2.4% (95% CI: 2.0%‒2.8%; p .0001) of the variation in psychopathology, 1.6% (95% CI: 1.2%‒2.1%; p .0001) of depression, and 1.4% (95% CI: 1.0%‒1.7%; p .0001) of well-being. Schools in urban locations, with a higher percentage of free school meals and of White British, were associated with poorer pupil mental health. A more positive school climate was associated with better mental health.School-level variables, primarily related to contextual factors, characteristics of pupil population, and school climate, explain a small but significant amount of variability in mental health of young people. This information might be used to identify schools that are in need of more resources to support mental health of young people.MYRIAD: My Resilience in Adolescence, a Study Examining the Effectiveness and Cost-Effectiveness of a Mindfulness Training Programme in Schools Compared With Normal School Provision; https://www.isrctn.com/; 86619085.

Highlights • One-in-five adolescents reported suicidality or pain. • Pain was associated with an increased risk of suicidality and vice versa (OR=4.00). • Network analysis supported the pain-suicidality association (aOR=1.39). • This cross-sectional association was not moderated by depression. • Pain should be considered as a key risk correlate of suicidality in adolescents., Background Whilst growing research suggests that pain is associated with suicidality in adolescence, it remains unclear whether this relationship is moderated by co-morbid depressive symptoms. The present study aimed to investigate whether the pain-suicidality association is moderated by depressive symptoms. Methods We performed secondary analyses on cross-sectional, pre-intervention data from the ‘My Resilience in Adolescence’ [MYRIAD] trial (ISRCTN ref: 86619085; N=8072, 11-15 years). Using odds ratio tests and (moderated) network analyses, we investigated the relationship between pain and suicidality, after controlling for depression, anxiety, inhibitory control deficits and peer problems. We investigated whether depression moderates this relationship and explored gender differences. Results Overall, 20% of adolescents reported suicidality and 22% reported pain, whilst nine percent of adolescents reported both. The experience of pain was associated with a four-fold increased risk of suicidality and vice versa (OR=4.00, 95%-CI=[3.54;4.51]), with no gender differences. This cross-sectional association remained significant after accounting for depression, anxiety, inhibitory control deficits and peer problems (aOR=1.39). Depression did not moderate the pain-suicidality association. Limitations The item-based, cross-sectional assessment of pain and suicidality precludes any conclusions about the direction of the effects and which aspects of suicidality and pain may drive this association. Conclusions Our findings underscore the need to consider pain as an independent risk correlate of suicidality in adolescents. Longitudinal research should examine how this relationship develops during adolescence. Clinically, our findings emphasise the need to assess and address suicidality in adolescents with pain, even in the absence of depressive symptoms.

Early adaptive schemas (EAS) are resilience-oriented counterparts to early maladaptive schemas (EMS), which are central in schema therapy. The Young Positive Schema Questionnaire (YPSQ) was developed as a measure of EAS but has been evaluated neither in relation to a clinical population nor in a German-speaking sample. Objectives of this study were therefore the psychometric validation of a German YPSQ in a community sample and the comparison of EAS to psychiatric patients. Participants were 1,418 individuals from a community sample and 182 psychiatric patients with a main diagnosis of major depressive disorder. A factor structure of 10 EAS, instead of the original 14, demonstrated satisfactory factorial validity and internal consistency in both samples. EAS exhibited divergent validity to EMS, childhood trauma, and psychopathology. Convergent validity was evident with resilience, self-efficacy, and satisfaction with life. Support for incremental validity beyond EMS was especially shown for resilience, self-efficacy, and satisfaction with life, and was also evident for several dimensions of psychopathology. Individuals in the community sample exhibited more pronounced EAS compared to psychiatric patients with the exception of empathic consideration. Especially for concepts associated with mental health, the YPSQ has the potential to be a highly valuable addition to current research and practice.

Background About every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis. Methods This study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n = 110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n = 1058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n = 1143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples. Results Network analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria. Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods. Conclusions Genetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.

SummaryGlucocorticoids are important for proper organ maturation1. Increased exposure to these hormones during pregnancy, as a result of commonly prescribed synthetic glucocorticoids such as dexamethasone in preterm births2, has been associated with lasting effects on the offspring, including on neurodevelopment and neuropsychiatric disease risk3. While the consequences of glucocorticoid excess in term and especially adult brain have been extensively studied, mainly in rodents4, studies on their effects during early human cortical development are absent. Here we use human cerebral organoids and mice to study cell-type specific effects of glucocorticoids on neurogenic processes. We show that glucocorticoid administration during neurogenesis alters the cellular architecture of the developing cortex by increasing a specific type of gyrencephalic species-enriched basal progenitors that co-express PAX6 and EOMES. This effect is mediated via the glucocorticoid-responsive transcription factor ZBTB16 as shown with overexpression, genetic knock-down and reporter assays experiments in organoids and embryonic mouse models and leads to increased production of deep-layer neurons. A phenome-wide mendelian randomization analysis of a genetic intronic enhancer variant that moderates glucocorticoid-induced ZBTB16 levels, as shown with enhancer assays and enhancer-editing in organoids, reveals potential causal relationships with increased educational attainment as well as neuroimaging phenotypes in adults. In this study we provide a cellular and molecular pathway for the effects of glucocorticoids on human neurogenesis that potentially explains postnatal phenotypes and may be used to refine treatment guidelines.

BackgroundEducation is broader than academic teaching. It includes teaching students social–emotional skills both directly and indirectly through a positive school climate.ObjectiveTo evaluate if a universal school-based mindfulness training (SBMT) enhances teacher mental health and school climate.MethodsThe My Resilience in Adolescence parallel group, cluster randomised controlled trial (registration: ISRCTN86619085; funding: Wellcome Trust (WT104908/Z/14/Z, WT107496/Z/15/Z)) recruited 85 schools (679 teachers) delivering social and emotional teaching across the UK. Schools (clusters) were randomised 1:1 to either continue this provision (teaching as usual (TAU)) or include universal SBMT. Data on teacher mental health and school climate were collected at prerandomisation, postpersonal mindfulness and SBMT teacher training, after delivering SBMT to students, and at 1-year follow-up.FindingSchools were recruited in academic years 2016/2017 and 2017/2018. Primary analysis (SBMT: 43 schools/362 teachers; TAU: 41 schools/310 teachers) showed that after delivering SBMT to students, SBMT versus TAU enhanced teachers’ mental health (burnout) and school climate. Adjusted standardised mean differences (SBMT minus TAU) were: exhaustion (−0.22; 95% CI −0.38 to −0.05); personal accomplishment (−0.21; −0.41, −0.02); school leadership (0.24; 0.04, 0.44); and respectful climate (0.26; 0.06, 0.47). Effects on burnout were not significant at 1-year follow-up. Effects on school climate were maintained only for respectful climate. No SBMT-related serious adverse events were reported.ConclusionsSBMT supports short-term changes in teacher burnout and school climate. Further work is required to explore how best to sustain improvements.Clinical implicationsSBMT has limited effects on teachers’ mental and school climate. Innovative approaches to support and preserve teachers’ mental health and school climate are needed.

Background Advancements in the treatment of depression are pivotal due to high levels of non-response and relapse. This study evaluated the role of personality pathology in the treatment of depression by testing whether maladaptive personality traits (1) predict changes in depression over treatment or vice versa, (2) change themselves over treatment, (3) change differentially depending on treatment with schema therapy (ST) or cognitive behavioural therapy (CBT), and (4) moderate the effectiveness of these treatments. Methods We included 193 depressed inpatients (53.4% women, Mage = 42.9, SD = 13.4) participating in an assessor-blind randomized clinical trial and receiving a 7-week course of ST or CBT. The research questions were addressed using multiple indicator latent change score models as well as multigroup structural equation models implemented in EffectLiteR. Results Maladaptive traits did not predict changes in depressive symptoms at post-treatment, or vice versa. However, maladaptive trait domains decreased over treatment (standardized Δμ range: −0.38 to −0.89), irrespective of treatment with ST or CBT. Maladaptive traits at baseline did not moderate the effectiveness of these treatments. Conclusions Self-reported maladaptive personality traits can change during treatment of depression, but may have limited prognostic or prescriptive value, at least in the context of ST or CBT. These results need to be replicated using follow-up data, larger and more diverse samples, and informant-rated measures of personality pathology.

Adaptations to the gold standard randomised controlled trial (RCT) have been introduced to decrease trial costs and avoid high sample sizes. To facilitate development of precision medicine algorithms that aim to optimise treatment allocation for individual patients, we propose a new RCT adaptation termed the nested-precision RCT (npRCT). The npRCT combines a traditional RCT (intervention A versus B) with a precision RCT (stratified versus randomised allocation to A or B). This combination allows online development of a precision algorithm, thus providing an integrated platform for algorithm development and its testing. Moreover, as both the traditional and the precision RCT include participants randomised to interventions of interest, data from these participants can be jointly analysed to determine the comparative effectiveness of intervention A versus B, thus increasing statistical power. We quantify savings of the npRCT compared to two independent RCTs by highlighting sample size requirements for different target effect sizes and by introducing an open-source power calculation app. We describe important practical considerations such as blinding issues and potential biases that need to be considered when designing an npRCT. We also highlight limitations and research contexts that are less suited for an npRCT. In conclusion, we introduce the npRCT as a novel precision medicine trial design strategy which may provide one opportunity to efficiently combine traditional and precision RCTs.

Depression and psychosis have a developmental component to their origin. Epidemiologic evidence, which we synthesize in this nonsystematic review, suggests that early-life infection, inflammation, and metabolic alterations could play a role in the etiology of these psychiatric disorders. The risk of depression and psychosis is associated with prenatal maternal and childhood infections, which could be mediated by impaired neurodevelopment. Evidence suggests linear dose-response associations between elevated concentrations of circulating inflammatory markers in childhood, particularly the inflammatory cytokine interleukin 6, and the risk for depression and psychosis subsequently in early adulthood. Childhood inflammatory markers are also associated with persistence of depressive symptoms subsequently in adolescence and early adulthood. Developmental trajectories reflecting persistently high insulin levels during childhood and adolescence are associated with a higher risk of psychosis in adulthood, whereas increased adiposity during and after puberty is associated with the risk of depression. Together, these findings suggest that higher levels of infection, inflammation, and metabolic alterations commonly seen in people with depression and psychosis could be a cause for, rather than simply a consequence of, these disorders. Therefore, early-life immuno-metabolic alterations, as well as factors influencing these alterations such as adversity or maltreatment, could represent targets for prevention of these psychiatric disorders. Inflammation could also be an important treatment target for depression and psychosis. The field requires further research to examine sensitive periods when exposure to such immuno-metabolic alterations is most harmful. Interventional studies are also needed to test the potential usefulness of targeting early-life immuno-metabolic alterations for preventing adult depression and psychosis.

BackgroundSystematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health.ObjectiveThe My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU).MethodsMYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11–14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included.FindingsAnalysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI −0.05 to 0.06) for risk for depression; 0.02 (−0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (−0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed.ConclusionsFindings do not support the superiority of SBMT over TAU in promoting mental health in adolescence.Clinical implicationsThere is need to ask what works, for whom and how, as well as considering key contextual and implementation factors.Trial registrationCurrent controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

The majority of COVID-19 survivors experience long-term neuropsychiatric symptoms such as fatigue, sleeping difficulties, depression and anxiety. We propose that neuroimmune cross-talk via inflammatory cytokines such as interleukin-6 (IL-6) could underpin these long-term COVID-19 symptoms. This hypothesis is supported by several lines of research, including population-based cohort and genetic Mendelian Randomisation studies suggesting that inflammation is associated with fatigue and sleeping difficulties, and that IL-6 could represent a possible causal driver for these symptoms. Immune activation following COVID-19 can disrupt T helper 17 (TH17) and regulatory T (Treg) cell responses, affect central learning and emotional processes, and lead to a vicious cycle of inflammation and mitochondrial dysfunction that amplifies the inflammatory process and results in immuno-metabolic constraints on neuronal energy metabolism, with fatigue being the ultimate result. Increased cytokine activity drives this process and could be targeted to interrupt it. Therefore, whether persistent IL-6 dysregulation contributes to COVID-19-related long-term fatigue, sleeping difficulties, depression, and anxiety, and whether targeting IL-6 pathways could be helpful for treatment and prevention of long COVID are important questions that require investigation. This line of research could inform new approaches for treatment and prevention of long-term neuropsychiatric symptoms of COVID-19. Effective treatment and prevention of this condition could also help to stem the anticipated rise in depression and other mental illnesses ensuing this pandemic.

OBJECTIVE Anxiety symptoms are highly prevalent among individuals with bipolar disorder (BD) but there is little guidance on pharmacotherapy for these symptoms. The objective of this systematic review and meta-analysis was to evaluate the available evidence for pharmacotherapy of comorbid anxiety symptoms in BD. METHODS Completed randomized clinical trials (RCTs) of medications for BD published prior to December 2020 were identified through a systematic search of MEDLINE, Embase, PsycInfo, Web of Science, clinicaltrials.gov, and the ISRCTN. Data from RCTs measuring anxiety symptoms at baseline and endpoint and all-cause discontinuation were pooled to compare the efficacy and acceptability of medications with control conditions. RESULTS Thirty-seven RCTs met our inclusion criteria; 13 placebo-controlled RCTs with 2175 participants had sufficient data to be included in the meta-analysis assessing anxiety symptoms. Compared with placebo, the overall effect size of medications (primarily atypical antipsychotics) on anxiety symptoms was small with a standardized mean difference (SMD) = -0.22 (95% CI: -0.34 to -0.11). Study heterogeneity was low (I2 = 26%). The acceptability of these medications was comparable with placebo with odds ratio of discontinuation from all causes = 0.98 (95% CI: 0.91-1.06). CONCLUSION There is limited evidence for a small anxiolytic effect and good acceptability of pharmacotherapy (primarily atypical antipsychotics) in the treatment of comorbid anxiety symptoms in BD. These results highlight the need for further research on medications other than atypical antipsychotics.

BackgroundAbout every fourth patient with major depressive disorder (MDD) shows evidence of systemic inflammation. Previous studies have shown inflammation-depression associations of multiple serum inflammatory markers and multiple specific depressive symptoms. It remains unclear, however, if these associations extend to genetic/lifetime predisposition to higher inflammatory marker levels and what role metabolic factors such as Body Mass Index (BMI) play. It is also unclear whether inflammation-symptom associations reflect direct or indirect associations, which can be disentangled using network analysis.MethodsThis study examined associations of polygenic risk scores (PRSs) for immuno-metabolic markers (C-reactive protein [CRP], interleukin [IL]-6, IL-10, tumour necrosis factor [TNF]-α, BMI) with seven depressive symptoms in one general population sample, the UK Biobank study (n=110,010), and two patient samples, the Munich Antidepressant Response Signature (MARS, n=1,058) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D, n=1,143) studies. Network analysis was applied jointly for these samples using fused graphical least absolute shrinkage and selection operator (FGL) estimation as primary analysis and, individually, using unregularized model search estimation. Stability of results was assessed using bootstrapping and three consistency criteria were defined to appraise robustness and replicability of results across estimation methods, network bootstrapping, and samples.ResultsNetwork analysis results displayed to-be-expected PRS-PRS and symptom-symptom associations (termed edges), respectively, that were mostly positive. Using FGL estimation, results further suggested 28, 29, and six PRS-symptom edges in MARS, STAR*D, and UK Biobank samples, respectively. Unregularized model search estimation suggested three PRS-symptom edges in the UK Biobank sample. Applying our consistency criteria to these associations indicated that only the association of higher CRP PRS with greater changes in appetite fulfilled all three criteria.Four additional associations fulfilled at least two consistency criteria; specifically, higher CRP PRS was associated with greater fatigue and reduced anhedonia, higher TNF-α PRS was associated with greater fatigue, and higher BMI PRS with greater changes in appetite and anhedonia. Associations of the BMI PRS with anhedonia, however, showed an inconsistent valence across estimation methods.ConclusionsGenetic predisposition to higher systemic inflammatory markers are primarily associated with somatic/neurovegetative symptoms of depression such as changes in appetite and fatigue, consistent with previous studies based on circulating levels of inflammatory markers. We extend these findings by providing evidence that associations are direct (using network analysis) and extend to genetic predisposition to immuno-metabolic markers (using PRSs). Our findings can inform selection of patients with inflammation-related symptoms into clinical trials of immune-modulating drugs for MDD.

Funder: Partially supported by the Complex Trait Genetics programme of Amsterdam Neuroscience, Funder: Supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP), Funder: MQ: Transforming Mental Health (MQ); doi: https://doi.org/10.13039/501100008162; Grant(s): MQDS17/40, MQDS17/40, MQDS17/40, Funder: EC | EC Seventh Framework Programm | FP7 People: Marie-Curie Actions (FP7-PEOPLE - Specific Programme "People" Implementing the Seventh Framework Programme of the European Community for Research, Technological Development and Demonstration Activities (2007 to 2013)); doi: https://doi.org/10.13039/100011264; Grant(s): PCIG12-GA-2012-334065, Funder: BMA Foundation (J Moulton grant 2019), We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05-1.08), altered appetite (OR = 1.25, 95%CI = 1.23-1.28), sleep problems (OR = 1.05, 95%CI = 1.04-1.06), and fatigue (OR = 1.12, 95% CI = 1.11-1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05-1.08) and worrying control (OR = 1.03, 95% CI = 1.02-1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12-1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13-1.43) and IL-6 (OR = 1.26, 95% CI = 1.07-1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08-1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18-1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.

Background Concentrations of C-reactive protein (CRP), interleukin 6 (IL-6) and other inflammatory markers are elevated in people with depression and anxiety compared to controls, but evidence for disorder-specificity, linearity and potential causality is sparse. Methods Using population-based data from up to 144,890 UK Biobank cohort participants, we tested associations of circulating CRP concentrations with depression and anxiety symptom scores and probable diagnosis, including tests for linearity, disorder-specificity and sex difference. We examined potential causality using 1-sample and 2-sample Mendelian randomisation (MR) analyses testing associations of genetically-predicted CRP concentration and IL-6 activity with depression and anxiety. The study was conducted from June 2019 to February 2021. Findings CRP concentration was associated with depressive and anxiety symptom scores and with probable diagnoses of depression and generalised anxiety disorder (GAD) in a dose-response fashion. These associations were stronger for depression than for anxiety, and for women than for men although less consistently. MR analyses provided consistent results suggesting that genetically predicted higher IL-6 activity was associated with increased risk for depressive symptoms, while genetically-predicted higher CRP concentration was associated with decreased risks of depressive and anxiety symptoms. Interpretation Altered activity of the IL-6/IL-6R pathway could be a risk factor for depression. The field now requires experimental studies of IL-6 modulation in humans and animal models to further examine causality, mechanisms and treatment potential. Such studies are also needed to elucidate mechanisms for divergent associations of genetically-predicted higher IL-6 activity (risk increasing) and higher CRP concentrations (protective) with depression/anxiety. Funding This research was funded in whole, or in part, by the Wellcome Trust (grant code: 201486/Z/16/Z). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This work was supported by a Data Science Award from the MQ: Transforming Mental Health (grant code: MQDS17/40) to GMK and PBJ, which also supported ZY. GMK also acknowledges funding support from the Wellcome Trust (grant code: 201486/Z/16/Z), the Medical Research Council UK (grant code: MC_PC_17213 and MR/S037675/1), and the BMA Foundation (J Moulton grant 2019). NK and SM are supported by the International Max Planck Research School of Translational Psychiatry (IMPRS-TP). GDS works in the Medical Research Council Integrative Epidemiology Unit at the University of Bristol, which is supported by the Medical Research Council (MC_UU_00011/1).

BACKGROUND: Schizophrenia, bipolar disorder and depression are associated with inflammation. However, it is unclear whether associations of immunological proteins/traits with these disorders are likely to be causal, or could be explained by reverse causality/residual confounding.METHODS: We used bi-directional two-sample Mendelian randomization (MR) and multi-variable MR (MVMR) analysis to examine evidence of causality, specificity and direction of association of 20 immunological proteins/traits (pro-inflammatory cytokines: interleukin (IL)-6, tumour necrosis factor (TNF)-α, IL-12, IL-16, IL-17, IL-18; anti-inflammatory cytokines: IL-1 receptor antagonist (RA), IL-10, IL-13; chemokines: IL-8, monocyte chemo-attractant protein-1 (MCP-1); lymphoid growth-factors: soluble (s) IL-2Rα, IL-4, IL-7, IL-9; myeloid growth-factor: IL-5; acute phase protein: C-Reactive Protein (CRP); immune cells: neutrophils, lymphocytes; neurotrophic factor: brain derived neurotrophic factor (BDNF)) with schizophrenia, major depression and bipolar disorder.RESULTS: Genetically-predicted IL-6 was associated with increased risk of schizophrenia in univariable MR (OR = 1.24; 95% C.I., 1.05-1.47) and with major depression in MVMR (OR = 1.08; 95% C.I., 1.03-1.12). These results survived Bonferroni-correction. Genetically-predicted sIL-2Rα (OR = 1.07; 95% C.I., 1.01-1.12) and IL-9 (OR = 1.06; 95% C.I., 1.01-1.11) were associated with increased schizophrenia risk. Genetically-predicted BDNF (OR = 0.97; 95% C.I., 0.94-1.00) and MCP-1 (OR = 0.96; 95% C.I., 0.91-0.99) were associated with reduced schizophrenia risk. However, these findings did not survive correction for multiple testing. The CRP-schizophrenia association attenuated completely after taking into account IL-6 and sIL-2Rα in MVMR (OR = 1.02; 95% C.I., 0.81-1.28). No significant associations were observed for bipolar disorder. Evidence from bidirectional MR did not support reverse causality.CONCLUSIONS: We report evidence in support of potential causal associations of several immunological proteins/traits with schizophrenia, and of IL-6 with depression. Some of the findings did not survive correction for multiple testing and so replication in larger samples is required. Experimental studies are also required to further examine causality, mechanisms, and treatment potential for these immunological proteins/pathways for schizophrenia and depression.

The prefrontal cortex is a key player in stress response regulation. Electroencephalographic (EEG) responses, such as a decrease in frontal alpha and an increase in frontal beta power, have been proposed to reflect stress-related brain activity. However, the stress response is likely composed of different parts such as cognitive effort, time pressure, and social-evaluative threat, which have not been distinguished in previous studies. This distinction, however, is crucial if we aim to establish reliable tools for early detection of stress-related conditions and monitoring of stress responses throughout treatment. This randomized cross-over study (N = 38) aimed to disentangle EEG correlates of stress. With linear mixed models accounting for missing values in some conditions, we found a decrease in frontal alpha and increase in beta power when performing the Paced Auditory Serial Addition Test (PASAT; cognitive effort; n = 32) compared to resting state (n = 33). No change in EEG power was found when the PASAT was performed under time pressure (n = 29) or when adding social-evaluative threat (video camera; n = 29). These findings suggest that frontal EEG power can discriminate stress from resting state but not more fine-grained differences of the stress response.

Contains fulltext : 214596pub.pdf (Publisher’s version ) (Closed access) Contains fulltext : 214596pre.pdf (Author’s version preprint ) (Open Access) Background and objectives: In anxiety disorders, cognitive behavioural therapy (CBT) improves information-processing biases such as implicit fear evaluations and avoidance tendencies, which predicts treatment response. Thus, these cognitive biases might constitute important treatment targets. This study investigated (i) whether information-processing biases could be changed following single-session computerised CBT for spider fear, and (ii) whether this effect could be augmented by administration of D-cycloserine (DCS). Methods: Spider-fearful individuals were randomized to receiving either 250 mg of DCS (n = 21) or placebo (n = 17). Three hours after drug administration, they received single-session computerized CBT, characterized by psychoeducation and exposure elements. Spider fear was assessed using self-report, behavioural, and information processing (Extrinsic Affective Simon Task & Approach Avoidance Task) measures at baseline (before drug administration), post-treatment, 1-day, and 1-month follow-up. Results: Linear mixed-effects analyses indicated significant improvements on self-report and behavioural spider fear indices following CBT, but not on cognitive bias measures. There was no evidence of an augmentation effect of DCS on any outcome. Cognitive bias measures at 1-day were not predictive of 1-month follow-up spider fear in adjusted linear regression analyses. Limitations: Results might be biased by limited representativeness of the sample (high education and intelligence, largely Caucasian ethnicity, young age). The study was also only powered for detection of medium-sized DCS effects. Conclusions: These findings do not provide evidence for information-processing biases relating to treatment outcome following computerised CBT for spider fear or augmentation with DCS. 10 p.

Neuronal surface autoantibodies (NSAbs) against various antigens cause autoimmune encephalitis. Some of these antigens are also involved in the pathology of depression and anxiety. To study whether NSAbs are more common in plasma of individuals with depression and anxiety than in controls, and to investigate if NSAbs correlate with disease status, plasma samples of 819 individuals with a current diagnosis of depression and/or anxiety, 920 in remission and 492 individuals without these disorders were included in this study. Samples were tested by a combination of immunohistochemistry (IHC), staining on live rat hippocampus neurons and cell-based assay (CBA). By IHC, 50 (2.2%) samples showed immunoreactivity to rat brain tissue, with no significant differences between the aforementioned groups (22/819 vs 18/920 vs 11/492, P > 0.99). In addition, eight IHC positive samples were positive for NSAbs on live neurons (7/819 vs 0/920 vs 1/492, P = 0.006). The IHC-staining patterns of these eight samples were atypical for autoimmune encephalitis and accordingly, they tested negative for known NSAbs by CBA. No obvious difference in the clinical characteristics between individuals with or without NSAbs was observed. In conclusion, novel NSAbs were rare but predominately found in patients with current anxiety or depression indicating they might affect mental health in a small group of patients.

Background Antidepressant medication (ADM) and psychotherapy are effective treatments for major depressive disorder (MDD). It is unclear, however, if treatments differ in their effectiveness at the symptom level and whether symptom information can be utilised to inform treatment allocation. The present study synthesises comparative effectiveness information from randomised controlled trials (RCTs) of ADM versus psychotherapy for MDD at the symptom level and develops and tests the Symptom-Oriented Therapy (SOrT) metric for precision treatment allocation. Methods First, we conducted systematic review and meta-analyses of RCTs comparing ADM and psychotherapy at the individual symptom level. We searched PubMed Medline, PsycINFO, and the Cochrane Central Register of Controlled Trials databases, a database specific for psychotherapy RCTs, and looked for unpublished RCTs. Random-effects meta-analyses were applied on sum-scores and for individual symptoms for the Hamilton Rating Scale for Depression (HAM-D) and Beck Depression Inventory (BDI) measures. Second, we computed the SOrT metric, which combines meta-analytic effect sizes with patients’ symptom profiles. The SOrT metric was evaluated using data from the Munich Antidepressant Response Signature (MARS) study (n = 407) and the Emory Predictors of Remission in Depression to Individual and Combined Treatments (PReDICT) study (n = 234). Results The systematic review identified 38 RCTs for qualitative inclusion, 27 and 19 for quantitative inclusion at the sum-score level, and 9 and 4 for quantitative inclusion on individual symptom level for the HAM-D and BDI, respectively. Neither meta-analytic strategy revealed significant differences in the effectiveness of ADM and psychotherapy across the two depression measures. The SOrT metric did not show meaningful associations with other clinical variables in the MARS sample, and there was no indication of utility of the metric for better treatment allocation from PReDICT data. Conclusions This registered report showed no differences of ADM and psychotherapy for the treatment of MDD at sum-score and symptom levels. Symptom-based metrics such as the proposed SOrT metric do not inform allocation to these treatments, but predictive value of symptom information requires further testing for other treatment comparisons.

Background The antihypertensive drug losartan has been shown to improve memory in humans as well as learning and fear extinction in rodent models, highlighting its potential to have similar synergistic effects on exposure-based cognitive behavioral therapy for anxiety disorders. This study investigated the effect of losartan on neural correlates of processing threat versus safety stimuli in highly anxious individuals to identify potential pathways of how the drug might facilitate psychological treatment. Methods Thirty healthy volunteers high in trait anxiety were randomly assigned to a single dose of losartan (50 mg) versus placebo before undergoing functional magnetic resonance imaging. We measured brain response to happy and fearful faces presented for 80 seconds to assess emotional processing and habituation over time. Results The placebo group showed similarly high left amygdala activation early on during presentation of fearful and happy faces, which decreased over time. In contrast, losartan reduced amygdala response to happy faces early on. In response to fearful faces, the drug prevented habituation, caused sustained amygdala activation, and led to increased activation in other brain areas associated with threat processing, such as the insula and putamen. Conclusions Our findings suggest two distinct effects of losartan on emotional processing, including an improvement of early discrimination of stimuli as threatening versus safe, and facilitation of threat processing. Both processes are known to be relevant for successful exposure, highlighting two potential pathways by which losartan might exert facilitative effects on psychological treatment.

Based on the emerging interest in the effects of gut microbiota on cognition, this proof-of-concept study assessed how children aged 7 to 9 with low reading scores responded to the ingestion of a 3-month prebiotic supplement versus a placebo. As a secondary aim, the effects of the prebiotic on cognition, sleep, behaviour, mood, anxiety, and cortisol were assessed. In this sample, the prebiotic did not affect any of the outcome measures.

This genetic correlation and 2-sample mendelian randomization study uses large-scale genome-wide association data sources to explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms.Importance Observational studies highlight associations of C-reactive protein (CRP), a general marker of inflammation, and interleukin 6 (IL-6), a cytokine-stimulating CRP production, with individual depressive symptoms. However, it is unclear whether inflammatory activity is associated with individual depressive symptoms and to what extent metabolic dysregulation underlies the reported associations. Objective To explore the genetic overlap and associations between inflammatory activity, metabolic dysregulation, and individual depressive symptoms. GWAS Data Sources Genome-wide association study (GWAS) summary data of European individuals, including the following: CRP levels (204402 individuals); 9 individual depressive symptoms (3 of which did not differentiate between underlying diametrically opposite symptoms [eg, insomnia and hypersomnia]) as measured with the Patient Health Questionnaire 9 (up to 117;907 individuals); summary statistics for major depression, including and excluding UK Biobank participants, resulting in sample sizes of 500 199 and up to 230 214 individuals, respectively; insomnia (up to 386533 individuals); body mass index (BMI) (up to 322154 individuals); and height (up to 253280 individuals). Design In this genetic correlation and 2-sample mendelian randomization (MR) study, linkage disequilibrium score (LDSC) regression was applied to infer single-nucleotide variant-based heritability and genetic correlation estimates. Two-sample MR tested potential causal associations of genetic variants associated with CRP levels, IL-6 signaling, and BMI with depressive symptoms. The study dates were November 2019 to April 2020. Results Based on large GWAS data sources, genetic correlation analyses revealed consistent false discovery rate (FDR)-controlled associations (genetic correlation range, 0.152-0.362; FDR P = .006 to P < .001) between CRP levels and depressive symptoms that were similar in size to genetic correlations of BMI with depressive symptoms. Two-sample MR analyses suggested that genetic upregulation of IL-6 signaling was associated with suicidality (estimate [SE], 0.035 [0.010]; FDR plus Bonferroni correction P = .01), a finding that remained stable across statistical models and sensitivity analyses using alternative instrument selection strategies. Mendelian randomization analyses did not consistently show associations of higher CRP levels or IL-6 signaling with other depressive symptoms, but higher BMI was associated with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. Conclusions and Relevance This study reports coheritability between CRP levels and individual depressive symptoms, which may result from the potentially causal association of metabolic dysregulation with anhedonia, tiredness, changes in appetite, and feelings of inadequacy. The study also found that IL-6 signaling is associated with suicidality. These findings may have clinical implications, highlighting the potential of anti-inflammatory approaches, especially IL-6 blockade, as a putative strategy for suicide prevention.Question Do inflammatory pathways share a genetic background with individual depressive symptoms, and do they potentially causally contribute to them? Findings Based on large genome-wide association study data sources, this genetic correlation and 2-sample mendelian randomization study found genetic overlap between a higher C-reactive protein (CRP) level, a broad marker of inflammation, and 9 depressive symptoms; upregulated interleukin-6 signaling, a major stimulator of CRP, emerged as a potential causal risk factor for suicidality. Body mass index, but not interleukin 6 or CRP, was potentially causally associated with 4 other depressive symptoms. Meaning Interleukin 6 overactivity could be associated with suicidality; interleukin-6 blockade may be a novel treatment target that warrants future research.

Although suicidal ideation is one of the most consistent symptoms across recurrent episodes of depression, the mechanisms underpinning its maintenance are poorly understood. In order to develop effective treatments for suicidally depressed patients, understanding what maintains suicidal distress is critical. We hypothesised that Thought–Action Fusion (TAF), i.e., to assume that having a thought has real world consequences, originally described in Obsessive–Compulsive Disorder, might be a bias in recurrently suicidally depressed people. To assess this, we revised the original TAF scale, and assessed TAF in three samples: healthy controls, recurrently depressed individuals with no history of suicidality (D-NS) and individuals with a history of recurrent suicidal depression (D-S). Exploratory and confirmatory factor analyses indicated a three-factor solution of TAF: (1) TAF for uncontrollable events, (2) self-suicidal TAF for suicidal acts related to oneself, and (3) TAF for positive controllable events. Compared to healthy controls, the D-NS group reported significantly higher total TAF, TAF uncontrollable, and TAF self-suicidal subscales, whilst positive controllable TAF was lower compared to healthy controls. Both D-S and D-NS samples reported higher TAF for suicidal thought compared to healthy controls, i.e., believing that having suicidal thoughts means they will act on them, however in the context of low mood this became more pronounced for the D-S group. These findings suggest that targeting TAF both in suicidal and non-suicidal depression has merit. Electronic supplementary material The online version of this article (10.1007/s10608-018-9924-7) contains supplementary material, which is available to authorized users.

Background Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in the pathogenesis of psychosis. Methods Population-based data on ESR and IQ from 638 213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. The co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk. Results Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ = 0.961; 95% confidence interval (CI) 0.960–0.963) and ONAP (adjusted HR = 0.973; 95% CI 0.971–0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR = 1.14; 95% CI 1.01–1.28) and decreased risk for ONAP (adjusted HR = 0.85; 95% CI 0.74–0.96), although these effects were specific to one ESR band (7–10 mm/hr). Familial confounding explained ESR-IQ but not ESR-psychoses associations. IQ partly mediated the ESR-psychosis relationships. Conclusions Lower IQ is associated with low-grade systemic inflammation and with an increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis.

BACKGROUND: Importance: Associations between childhood infection, IQ and adult non-affective psychosis (NAP) are well established. However, examination of sensitive periods for exposure, effect of familial confounding, and whether IQ provides a link between childhood infection and adult NAP may elucidate pathogenesis of psychosis further. Objective: To test (1) association of childhood infection with IQ and adult NAP; (2) whether shared familial confounding explains the infection-NAP and IQ-NAP relationships; (3) whether IQ mediates and/or moderates the childhood infection-NAP relationship. METHODS: Design, Setting and Participants: Longitudinal design using linkage of Swedish national registers. The risk set included all Swedish men born 1973–1992 and conscripted into military until end of 2010 (N=771,698). We included 647,515 participants in the analysis. Measurement of exposure: Hospitalisation with any infection from age 0–13 years. Main outcomes and measures: Hospitalisation with an ICD diagnosis of NAP until end of 2011. IQ was assessed at conscription around age 18 years. RESULTS: Exposure to infections particularly in early-childhood was associated with lower IQ (adjusted mean difference for infection at 0-1y: -1.61; 95% CI, -1.74, -1.47), and with increased risk of adult NAP (adjusted hazard ratio for infection at 0-1y: 1.19; 95% CI, 1.06–1.33). There was a linear association between lower premorbid IQ and adult NAP, which persisted after excluding prodromal cases (adjusted hazard ratio per 1-point increase in IQ: 0.976; 95% CI, 0.974–0.978). The infection-NAP and IQ-NAP associations were similar in the general population and in full-sibling pairs discordant for exposure. IQ both moderated (P=0.02 and P=0.001) and mediated (P

Human memory benefits from information clustering, which can be accomplished by chunking. Chunking typically relies on expertise and strategy, and it is unknown whether perceptual clustering over time, through temporal integration, can also enhance working memory. The current study examined the attentional and working memory costs of temporal integration of successive target stimulus pairs embedded in rapid serial visual presentation. ERPs were measured as a function of behavioral reports: One target, two separate targets, or two targets reported as a single integrated target. N2pc amplitude, reflecting attentional processing, depended on the actual number of successive targets. The memory-related CDA and P3 components instead depended on the perceived number of targets irrespective of their actual succession. The report of two separate targets was associated with elevated amplitude, whereas integrated as well as actual single targets exhibited lower amplitude. Temporal integration thus provided an efficient means of processing sensory input, offloading working memory so that the features of two targets were consolidated and maintained at a cost similar to that of a single target.

Dr Khandaker is supported by an Intermediate Clinical Fellowship from the Wellcome Trust (201486/Z/16/Z) and a Clinical Lecturer Starter Grant from the Academy of Medical Sciences, UK (80354). Dr Jones reports having grant support from the Wellcome Trust (095844/Z/11/Z and 088869/Z/09/Z) and from the National Institute for Health Research: RP-PG-0616-20003, Cambridge Biomedical Research Centre and Collaboration for Leadership in Applied Health Research and Care East of England. Dr Dalman reports grant support from the Swedish Research Council. Dr Karlsson reports grant support from the Stanley Medical Research Institute.