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In adolescence, parental care is associated with lower depression symptoms whereas parental overprotection is associated with greater depression symptoms, effects which may be mediated by adolescent brain activity and connectivity. The present study examined associations between perceived parenting, brain activity and connectivity, and depression symptoms in adolescents from Brazil, a middle-income country (MIC). Analyses included 100 adolescents who underwent functional magnetic resonance imaging scanning while completing a face matching task. Parental care and overprotection were associated with adolescent depression symptoms in expected directions. We also found that parental care and overprotection were associated with amygdala connectivity with several brain regions; however, amygdala activity was not associated with parenting and neither activity or connectivity mediated the association between parenting and depression symptoms. Results identify how parenting influences brain function and depression symptoms in youth from a MIC.

Abstract The biological mechanisms underlying the onset of major depressive disorder (MDD) have predominantly been studied in adult populations from high-income countries, despite the onset of depression typically occurring in adolescence and the majority of the world’s adolescents living in low- and middle-income countries (LMIC). Taking advantage of a unique adolescent sample in an LMIC (Brazil), this study aimed to identify biological pathways characterizing the presence and increased risk of depression in adolescence, and sex-specific differences in such biological signatures. We collected blood samples from a risk-stratified cohort of 150 Brazilian adolescents (aged 14–16 years old) comprising 50 adolescents with MDD, 50 adolescents at high risk of developing MDD but without current MDD, and 50 adolescents at low risk of developing MDD and without MDD (25 females and 25 males in each group). We conducted RNA-Seq and pathway analysis on whole blood. Inflammatory-related biological pathways, such as role of hypercytokinemia/hyperchemokinemia in the pathogenesis of influenza (z-score = 3.464, p

IntroductionRecent evidence suggests the blood-to-brain influx rate (K1) in TSPO PET imaging as a promising biomarker of blood–brain barrier (BBB) permeability alterations commonly associated with peripheral inflammation and heightened immune activity in the brain. However, standard compartmental modeling quantification is limited by the requirement of invasive and laborious procedures for extracting an arterial blood input function. In this study, we validate a simplified blood-free methodologic framework for K1 estimation by fitting the early phase tracer dynamics using a single irreversible compartment model and an image-derived input function (1T1K-IDIF).MethodsThe method is tested on a multi-site dataset containing 177 PET studies from two TSPO tracers ([11C]PBR28 and [18F]DPA714). Firstly, 1T1K-IDIF K1 estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [11C]PBR28 scans before and after inflammatory interferon-α challenge, and on test–retest dataset of [18F]DPA714 scans.ResultsComparison with standard kinetic methodology showed good-to-excellent intra-subject correlation for regional 1T1K-IDIF-K1 (ρintra = 0.93 ± 0.08), although the bias was variable depending on IDIF ability to approximate blood input functions (0.03–0.39 mL/cm3/min). 1T1K-IDIF-K1 unveiled a significant reduction of BBB permeability after inflammatory interferon-α challenge, replicating results from standard quantification. High intra-subject correlation (ρ = 0.97 ± 0.01) was reported between K1 estimates of test and retest scans.DiscussionThis evidence supports 1T1K-IDIF as blood-free alternative to assess TSPO tracers’ unidirectional blood brain clearance. K1 investigation could complement more traditional measures in TSPO studies, and even allow further mechanistic insight in the interpretation of TSPO signal.

Introduction While research into adolescent mental health has developed a considerable understanding of environmental and psychosocial risk factors, equivalent biological evidence is lacking and is not representative of economic, social and ethnic diversity in the adolescent population. It is important to understand the possible barriers and facilitators to conduct this research. This will then allow us to improve our understanding of how biology interacts with environmental and psychosocial risk factors during adolescence. The objective of this scoping review is to identify and understand the needs, barriers and facilitators related to the collection of biological data in adolescent mental health research.Methods and analysis Reviewers will conduct a systematic search of PubMed, Medline, Scopus, Cochrane, ERIC, EMBASE, ProQuest, EBSCO Global Health electronic databases, relevant publications and reference lists to identify studies published in the English language at any time. This scoping review will identify published studies exploring mental health/psychopathology outcomes, with biological measures, in participants between the ages of 11 and 18 and examine the reported methodology used for data collection. Data will be summarised in tabular form with narrative synthesis and will use the methodology of Levac et al, supplemented by subsequent recommendations from the Joanna Briggs Institute Scoping Review Methodology.Ethics and dissemination Ethical approval is not required for this scoping review. The scoping review will be conducted with input from patient and public involvement, specifically including young people involved in our study (‘Co-producing a framework of guiding principles for Engaging representative and diverse cohorts of young peopLE in Biological ReseArch in menTal hEalth’—www.celebrateproject.co.uk) Youth Expert Working Group. Dissemination will include publication in peer-reviewed journals, academic presentations and on the project website.

Objective: The Identifying Depression Early in Adolescence Risk Score (IDEA-RS) was recently developed in Brazil using data from the Pelotas 1993 Birth Cohort to estimate the individualized probability of developing depression in adolescence. This model includes 11 sociodemographic variables and has been assessed in longitudinal studies from four other countries. We aimed to test the performance of IDEA-RS in an independent, community-based, school-attending sample within the same country: the Brazilian High-Risk Cohort. Methods: Standard external validation, refitted, and case mix-corrected models were used to predict depression among 1442 youth followed from a mean age of 13.5 years at baseline to 17.7 years at follow-up, using probabilities calculated with IDEA-RS coefficients. Results: The area under the curve was 0.65 for standard external validation, 0.70 for the case mix-corrected model, and 0.69 for the refitted model, with discrimination consistently above chance for predicting depression in the new dataset. There was some degree of miscalibration, corrected by model refitting (calibration-in-the-large reduced from 0.77 to 0). Conclusion: IDEA-RS was able to parse individuals with higher or lower probability of developing depression beyond chance in an independent Brazilian sample. Further steps should include model improvements and additional studies in populations with high levels of subclinical symptoms to improve clinical decision making.

Abstract Compelling evidence demonstrates that some individuals suffering from major depressive disorder (MDD) exhibit increased levels of inflammation. Most studies focus on inflammation-related proteins, such as serum or plasma C-reactive protein (CRP). However, the immune-related modifications associated with MDD may be not entirely captured by CRP alone. Analysing mRNA gene expression levels, we aimed to identify broader molecular immune-related phenotypes of MDD. We examined 168 individuals from the non-interventional, case–control, BIODEP study, 128 with a diagnosis of MDD and 40 healthy controls. Individuals with MDD were further divided according to serum high-sensitivity (hs)CRP levels (n = 59 with CRP 3 mg/L). We isolated RNA from whole blood and performed gene expression analyses using RT-qPCR. We measured the expression of 16 immune-related candidate genes: A2M, AQP4, CCL2, CXCL12, CRP, FKBP5, IL-1-beta, IL-6, ISG15, MIF, GR, P2RX7, SGK1, STAT1, TNF-alpha and USP18. Nine of the 16 candidate genes were differentially expressed in MDD cases vs. controls, with no differences between CRP-based groups. Only CRP mRNA was clearly associated with serum CRP. In contrast, plasma (proteins) IL-6, IL-7, IL-8, IL-10, IL-12/IL-23p40, IL-16, IL-17A, IFN-gamma and TNF-alpha, and neutrophils counts, were all differentially regulated between CRP-based groups (higher in CRP >3 vs. CRP

Given the rate of advancement in predictive psychiatry, there is a threat that it outpaces public and professional willingness for use in clinical care and public health. Prediction tools in psychiatry estimate the risk of future development of mental health conditions. Prediction tools used with young populations have the potential to reduce the worldwide burden of depression. However, little is known globally about adolescents’ and other stakeholders’ attitudes toward use of depression prediction tools. To address this, key informant interviews and focus group discussions were conducted in Brazil, Nepal, Nigeria and the United Kingdom with 23 adolescents, 45 parents, 47 teachers, 48 health-care practitioners and 78 other stakeholders (total sample = 241) to assess attitudes toward using a depression prediction risk calculator based on the Identifying Depression Early in Adolescence Risk Score. Three attributes were identified for an acceptable depression prediction tool: it should be understandable, confidential and actionable. Understandability includes depression literacy and differentiating between having a condition versus risk of a condition. Confidentiality concerns are disclosing risk and impeding educational and occupational opportunities. Prediction results must also be actionable through prevention services for high-risk adolescents. Six recommendations are provided to guide research on attitudes and preparedness for implementing prediction tools.

Background/Purpose: Orexin-A levels are reportedly increased in antipsychotic (APD)-treated patients with schizophrenia compared to healthy controls and have been associated with metabolic abnormalities. It is not clear whether the orexin-A elevation is related specifically to the drug (APDs) effect, which should be clarified by including a drug-free group for comparison, or related to drug-induced metabolic abnormalities. Methods: Blood orexin-A levels and metabolic profiles were compared between 37 drug-free, 45 aripiprazole-treated, and 156 clozapine-treated patients with schizophrenia. The association between orexin-A and metabolic outcomes were examined. We explored the effects of APDs treatment and metabolic status on orexin-A levels by linear regression. Results: Patients under APDs treatment had increased orexin-A levels compared to drug-free patients, with aripiprazole-treated group having higher orexin-A levels than clozapine-treated group. Higher orexin-A levels reduced the risks of metabolic syndrome (MS) and type 2 diabetes mellitus, indicating a relationship between orexin-A levels and metabolic problems. After adjusting the effect from metabolic problems, we found APD treatment is still associated with orexin-A regulation, with aripiprazole more significantly than clozapine. Conclusion: With the inclusion of drug-free patients rather than healthy controls for comparison, we demonstrated that orexin-A is upregulated following APD treatment even after we controlled the potential effect from MS, suggesting an independent effect of APDs on orexin-A levels. Furthermore, the effect differed between APDs with dissimilar obesogenicity, i.e. less obesogenicity likely associated with higher orexin-A levels. Future prospective studies exploring the causal relationship between APDs treatment and orexin-A elevation as well as the underlying mechanisms are warranted.

BackgroundMental health status assessment is mostly limited to clinical or research settings, but recent technological advances provide new opportunities for measurement using more ecological approaches. Leveraging apps already in use by individuals on their smartphones, such as chatbots, could be a useful approach to capture subjective reports of mood in the moment. ObjectiveThis study aimed to describe the development and implementation of the Identifying Depression Early in Adolescence Chatbot (IDEABot), a WhatsApp-based tool designed for collecting intensive longitudinal data on adolescents’ mood. MethodsThe IDEABot was developed to collect data from Brazilian adolescents via WhatsApp as part of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo) study. It supports the administration and collection of self-reported structured items or questionnaires and audio responses. The development explored WhatsApp’s default features, such as emojis and recorded audio messages, and focused on scripting relevant and acceptable conversations. The IDEABot supports 5 types of interactions: textual and audio questions, administration of a version of the Short Mood and Feelings Questionnaire, unprompted interactions, and a snooze function. Six adolescents (n=4, 67% male participants and n=2, 33% female participants) aged 16 to 18 years tested the initial version of the IDEABot and were engaged to codevelop the final version of the app. The IDEABot was subsequently used for data collection in the second- and third-year follow-ups of the IDEA-RiSCo study. ResultsThe adolescents assessed the initial version of the IDEABot as enjoyable and made suggestions for improvements that were subsequently implemented. The IDEABot’s final version follows a structured script with the choice of answer based on exact text matches throughout 15 days. The implementation of the IDEABot in 2 waves of the IDEA-RiSCo sample (140 and 132 eligible adolescents in the second- and third-year follow-ups, respectively) evidenced adequate engagement indicators, with good acceptance for using the tool (113/140, 80.7% and 122/132, 92.4% for second- and third-year follow-up use, respectively), low attrition (only 1/113, 0.9% and 1/122, 0.8%, respectively, failed to engage in the protocol after initial interaction), and high compliance in terms of the proportion of responses in relation to the total number of elicited prompts (12.8, SD 3.5; 91% out of 14 possible interactions and 10.57, SD 3.4; 76% out of 14 possible interactions, respectively). ConclusionsThe IDEABot is a frugal app that leverages an existing app already in daily use by our target population. It follows a simple rule-based approach that can be easily tested and implemented in diverse settings and possibly diminishes the burden of intensive data collection for participants by repurposing WhatsApp. In this context, the IDEABot appears as an acceptable and potentially scalable tool for gathering momentary information that can enhance our understanding of mood fluctuations and development.

Objectives: To explore differences in regional cortical morphometric structure between adolescents at risk for depression or with current depression. Methods: We analyzed cross-sectional structural neuroimaging data from a sample of 150 Brazilian adolescents classified as low-risk (LR) (n=50) or high-risk (HR) for depression (n=50) or with current depression (n=50) through a vertex-based approach with measurements of cortical volume (CV), surface area (SA), and cortical thickness (CT). Differences between groups in subcortical volume and in the organization of networks of structural covariance were also explored. Results: No significant differences in brain structure between groups were observed in whole-brain vertex-wise CV, SA, or CT. Also, no significant differences in subcortical volume were observed between risk groups. In relation to the structural covariance network, there was an indication of an increase in the hippocampus betweenness centrality index in the HR group network compared to the LR and current depression group networks. However, this result was only statistically significant when applying false discovery rate correction for nodes within the affective network. Conclusion: In an adolescent sample recruited using an empirically based composite risk score, no major differences in brain structure were detected according to the risk and presence of depression.

Background There is mounting interest in the potential efficacy of low carbohydrate and very low carbohydrate ketogenic diets in various neurological and psychiatric disorders. Aims To conduct a systematic review and narrative synthesis of low carbohydrate and ketogenic diets (LC/KD) in adults with mood and anxiety disorders. Method MEDLINE, Embase, PsycINFO and Cochrane databases were systematically searched for articles from inception to 6 September 2022. Studies that included adults with any mood or anxiety disorder treated with a low carbohydrate or ketogenic intervention, reporting effects on mood or anxiety symptoms were eligible for inclusion. PROSPERO registration CRD42019116367. Results The search yielded 1377 articles, of which 48 were assessed for full-text eligibility. Twelve heterogeneous studies (stated as ketogenic interventions, albeit with incomplete carbohydrate reporting and measurements of ketosis; diet duration: 2 weeks to 3 years; n = 389; age range 19 to 75 years) were included in the final analysis. This included nine case reports, two cohort studies and one observational study. Data quality was variable, with no high-quality evidence identified. Efficacy, adverse effects and discontinuation rates were not systematically reported. There was some evidence for efficacy of ketogenic diets in those with bipolar disorder, schizoaffective disorder and possibly unipolar depression/anxiety. Relapse after discontinuation of the diet was reported in some individuals. Conclusions Although there is no high-quality evidence of LC/KD efficacy in mood or anxiety disorders, several uncontrolled studies suggest possible beneficial effects. Robust studies are now needed to demonstrate efficacy, to identify clinical groups who may benefit and whether a ketogenic diet (beyond low carbohydrate) is required and to characterise adverse effects and the risk of relapse after diet discontinuation.

Abstract Background There is a lack of research on the adolescent experience of depression in low- and middle-income countries. Criteria derived from research conducted primarily among adult Western populations inform current diagnostic standards for depression. These clinical categories are often used without exploration of their relevance to adolescent experience. Also, reliance on these categories may overlook other symptoms of depression that manifest in non-western settings. Cross-cultural qualitative work with adults in non-Western settings has suggested some differences with experience of depression and symptoms that are most relevant to service users. Research into adolescent experiences of depression is warranted to inform the development of effective interventions. Methods Qualitative interviews were conducted in Nepal with adolescents with depressive symptoms (n = 9), healthy adolescents (n = 3), parents (n = 6), teachers (n = 10), social workers (n = 14), primary (n = 6) and mental (n = 6) healthcare providers, and policymakers (n = 6). Two focus groups were conducted with parents (n = 12) of depressed and non-depressed adolescents. Data were analyzed according to the framework approach methodology. Results Loneliness was the hallmark experience that stood out for all adolescents. This was connected with 5 other clusters of symptoms: low mood and anhedonia; disturbances in sleep and appetite, accompanied by fatigue; irritability and anger; negative self-appraisals including hopelessness and self-doubt; and suicidality. Adolescents distinguished depression from other forms of stress, locally referred to as tension, and described depression to involve having “deep tension.” Perceived causes of depression included (1) Family issues: neglectful or absent parents, relationship problems, and family discord; (2) Peer relationships: romantic problems, bullying, and friendship problems; and (3) Social media: social comparison, popularity metrics, cyberbullying, and leaking of personal information. Conclusions Consistent with other cross-cultural studies, loneliness was a core element of the adolescent experience of depression, despite its absence as a primary symptom in current psychiatric diagnostic classifications. It is important to note that among youth, symptoms were clustered together and interrelated (e.g., sleep and appetite changes were connected with fatigue). This calls for the need for more cross-cultural qualitative research on experience of depression among adolescents, and potential for modification of diagnostic criteria and prevention and treatments to focus on the experience of loneliness.

Introduction Evidence suggests a potentially causal role of interleukin 6 (IL-6), a pleiotropic cytokine that generally promotes inflammation, in the pathogenesis of psychosis. However, no interventional studies in patients with psychosis, stratified using inflammatory markers, have been conducted to assess the therapeutic potential of targeting IL-6 in psychosis and to elucidate potential mechanism of effect. Tocilizumab is a humanised monoclonal antibody targeting the IL-6 receptor to inhibit IL-6 signalling, licensed in the UK for treatment of rheumatoid arthritis. The primary objective of this study is to test whether IL-6 contributes to the pathogenesis of first episode psychosis and to examine potential mechanisms by which IL-6 affects psychotic symptoms. A secondary objective is to examine characteristics of inflammation-associated psychosis.Methods and analysis A proof-of-concept study employing a randomised, parallel-group, double-blind, placebo-controlled design testing the effect of IL-6 inhibition on anhedonia in patients with psychosis. Approximately 60 participants with a diagnosis of schizophrenia and related psychotic disorders (ICD-10 codes F20, F22, F25, F28, F29) with evidence of low-grade inflammation (IL-6≥0.7 pg/mL) will receive either one intravenous infusion of tocilizumab (4.0 mg/kg; max 800 mg) or normal saline. Psychiatric measures and blood samples will be collected at baseline, 7, 14 and 28 days post infusion. Cognitive and neuroimaging data will be collected at baseline and 14 days post infusion. In addition, approximately 30 patients with psychosis without evidence of inflammation (IL-6

Background: Inflammation is a well-known risk factor for depression. Specifically, patients who do not respond to antidepressant treatment show higher levels of inflammatory biomarkers compared with responders. Thus, several studies have investigated the efficacy of anti-inflammatory add-on treatment in this population. However, major depressive disorder is more prevalent in females than in males, with sex differences present in antidepressant treatment response and in immune system regulation. To explore sex differences in inflammatory profiles and treatment responses, we investigated a cohort of patients with treatment resistant depression (TRD), for which they received an adjunctive, anti-inflammatory treatment with minocycline – the Minocycline in Depression (MINDEP) study. Methods: The MINDEP study is a 4-week double-blind, randomised, placebo-controlled clinical trial (stratified by sex) with 39 TRD participants, which demonstrated the efficacy of minocycline, an antibiotic with anti-inflammatory properties, in TRD patients with major depressive disorder (MDD) and evidence of low-grade inflammation measured with C-reactive protein (CRP) ≥ 3 mg/L. In these secondary analyses, we investigated the differential effects of minocycline in females (N = 22, 10 randomised to minocycline and 12 randomised to placebo) and in males (N = 17, 8 randomised to minocycline and 9 randomised to placebo) on changes in depressive symptoms (Δ- Hamilton Rating Scale for Depression (HAMD)-17), taking also into consideration CRP levels (CRP ≥3 mg/L vs. CRP

There is growing policy, practice, and research interest in reducing the treatment gap for adolescent depression in low- and middle-income countries, where 90% of the world's adolescents live. Despite increased efforts for adolescent depression services in these settings, there is a risk that services will not be utilized if initiatives are not culturally compelling. Therefore, we propose three considerations for culturally compelling programs and examine how these considerations can be defined using anthropological theories and methods. Consideration 1: public health problems are locally prioritized; Consideration 2: mechanisms of change are locally identified; Consideration 3: programs can be implemented by locally identified actors and institutions. We employed the anthropological concept of ethnotheories of adolescent development to elicit information for culturally compelling interventions using qualitative methods in Lagos, Nigeria, from November 2018 to November 2019. Participants included 13 teachers, 12 social workers, 11 mental health specialists, six health workers, four policy makers, and three parents. Transcripts were analyzed by three researchers using a framework approach (inter-rater reliability ​= ​0.7). For the first consideration, locally defined adolescent mental health problems were aggression, irritability, poor academic performance, substance use, sexual behavior, and social withdrawal/isolation. For the second consideration, perceived mechanisms of change were providing protection from abuse, economic assistance, high-quality schooling, guidance from religious institutions, and emotional support. For the third consideration, key stakeholders were parents, religious leaders, teachers, and peers, with religious institutions and schools as key sites for services. Therefore, rather than be limited to an exclusive focus on interventions for clinical symptoms of depression delivered by mental health specialists in clinical settings, a culturally compelling intervention portfolio for adolescent depression would focus on these locally identified concerns and strategies. This research demonstrates how elucidation of stakeholders' perspectives of symptoms, supports, and structural factors can shape development of culturally compelling mental health initiatives.

Abstract Several studies reported abnormal cortisol and inflammatory biomarker levels in youths with attention deficit hyperactivity disorder (ADHD), but the results have not been conclusive. We conducted a systematic review followed by a meta-analysis of case-control studies assessing blood or saliva cortisol levels and blood levels of inflammatory biomarkers in youth with ADHD. The effect sizes (ES) were synthesized by using a random-effects model. In the 19 studies on cortisol levels (totaling n = 916 youth with ADHD and n = 947 typically developing (TD), healthy youth), youth with ADHD have lower basal cortisol levels at any time-points during the day (effect size: .68; p = 0.004) and lower cumulative levels of cortisol (ES: .39, p = .008) throughout the day than TD youth. Moreover, morning cortisol levels were lower in ADHD youth when compared with TD youth (14 studies, n = 1679, ES: .84, p = 0.003), while there is no difference for the afternoon cortisol levels (p = 0.48). The meta-analysis on inflammation biomarker was conducted on 4 studies (totaling n = 404 youth) showed that Tumour Necrosis Factor-alpha (TNF-α) was lower in ADHD when compared with TD (3 studies, n = 257 youth, p = 0.004), while no differences for Interleukin-1β(IL-1β) (p = 0.21), IL-6 (p = 0.09) and IL-10 (p = 0.77). The lower cortisol in the context of low TNF-α levels may indicate a specific pattern of biomarkers in ADHD, and further investigation is warranted.

Objective: To explore associations between self-reported weekly physical activity and depressive symptomatology among adolescents in a school-based sample from Brazil. Methods: We surveyed 7,405 adolescents aged 14 to 16 years in 101 public schools in Porto Alegre, Brazil. We assessed physical activity using an adapted version of the Patient-Centered Assessment and Counseling for Exercise Plus Nutrition – Adolescent Physical Activity Measure (PACE+), and depressive symptoms using the Brazilian Portuguese version of the Patient Health Questionnaire – Adolescent Version. We compared the depressive symptom scores among adolescents with varying levels of physical activity. Results: Of the overall sample, 84.4% exercised less than the recommended frequency of 60 minutes/day, at least 5 days/week, of moderate to intense physical activity (PACE+ score ≥ 5). Adolescents whose physical activity levels fell below that threshold had higher median depression scores (8 [IQR = 10] vs. 7 [IQR = 9], W = 4060461, p < 0.001). A similar pattern was observed for depression scores in those with PACE+ < 1 (median of 10 [IQR = 11]) and ≥ 1 (7 [IQR = 9], W = 7457608, p < 0.001). Conclusion: In this large sample of Brazilian adolescents, those who exercised less frequently and vigorously than their peers reported more depressive symptoms.

Background: Recent studies have shown that choroid plexuses (CP) may be involved in the neuro-immune axes, playing a role in the interaction between the central and peripheral inflammation. Here we aimed to investigate CP volume alterations in depression and their associations with inflammation. Methods: 51 depressed participants (HDRS score > 13) and 25 age- and sex-matched healthy controls (HCs) from the Wellcome Trust NIMA consortium were re-analysed for the study. All the participants underwent full peripheral cytokine profiling and simultaneous [11C]PK11195 PET/structural MRI imaging for measuring neuroinflammation and CP volume respectively. Results: We found a significantly greater CP volume in depressed subjects compared to HCs (t(76) = +2.17) that was positively correlated with [11C]PK11195 PET binding in the anterior cingulate cortex (r = 0.28, p = 0.02), prefrontal cortex (r = 0.24, p = 0.04), and insular cortex (r = 0.24, p = 0.04), but not with the peripheral inflammatory markers: CRP levels (r = 0.07, p = 0.53), IL-6 (r = -0.08, p = 0.61), and TNF-α (r = -0.06, p = 0.70). The CP volume correlated with the [11C]PK11195 PET binding in CP (r = 0.34, p = 0.005). Integration of transcriptomic data from the Allen Human Brain Atlas with the brain map depicting the correlations between CP volume and PET imaging found significant gene enrichment for several pathways involved in neuroinflammatory response. Conclusion: This result supports the hypothesis that changes in brain barriers may cause reduction in solute exchanges between blood and CSF, disturbing the brain homeostasis and ultimately contributing to inflammation in depression. Given that CP anomalies have been recently detected in other brain disorders, these results may not be specific to depression and might extend to other conditions with a peripheral inflammatory component.

Extensive research suggests a role for the innate immune system in the pathogenesis of depression, but most of the studies are conducted in adult populations, in high-income countries and mainly focus on the study of inflammatory proteins alone, which provides only a limited understanding of the immune pathways involved in the development of depression. The IDEA-FLAME study aims to identify immune phenotypes underlying increased risk of developing depression in adolescence in a middle-income country. To this end, we will perform deep-immunophenotyping of peripheral blood mononuclear cells and RNA genome-wide gene expression analyses in a longitudinal cohort of Brazilian adolescents stratified for depression risk. The project will involve the 3-year follow-up of an already recruited cohort of 150 Brazilian adolescents selected for risk/presence of depression on the basis of a composite risk score we developed using sociodemographic characteristics (50 adolescents with low-risk and 50 with high-risk of developing depression, and 50 adolescents with a current major depressive disorder). We will 1) test whether the risk group classification at baseline is associated with differences in immune cell frequency, phenotype and functional status, 2) test whether baseline immune markers (cytokines and immune cell markers) are associated with severity of depression at 3-year follow-up, and 3) identify changes in gene expression of immune pathways over the 3-year follow-up in adolescents with increased risk and presence of depression. Because of the exploratory nature of the study, the findings would need to be replicated in a separate and larger sample. Ultimately, this research will contribute to elucidating key immune therapeutic targets and inform the development of interventions to prevent onset of depression among adolescents.

Inflammatory processes in the Central Nervous System (CNS) have been proposed to mediate the association between peripheral inflammation and the development of psychiatric disorders, but we currently lack sensitive measures of CNS inflammation for human studies in vivo. Here we used quantitative MRI (qMRI) to explore the in vivo central response to a peripheral immune challenge in healthy humans, and we assessed whether changes in quantitative relaxometry MRI parameters were associated with changes in peripheral inflammation.Quantitative relaxation times (T1 & T2) and Proton Density (PD) were measured in n ​= ​6 healthy males (mean age ​= ​30.5 ​± ​6.8 years) in two MRI assessments collected before and 24 ​hours after a subcutaneous injection of the proinflammatory cytokine and immune activator, interferon-alpha (IFN-α). Serum levels of immune markers and markers of blood-brain barrier integrity (S100B) were also measured before and after the injection.Region of interest and histogram-based analyses (optimized for the small sample size) showed a statistically significant increase of both T1 (t(5) ​= ​3.78, p ​= 0.013) and PD (t(5) ​= ​2.91, p ​= ​0.033) parameters in the bilateral hippocampus after IFN-α administration. T1 peak values in bilateral hippocampus were positively correlated with serum Tumour Necrosis Factor-alpha levels at 24 ​h after the injection, when this cytokine peaked (Spearman's rho ​= ​0.67, p ​= ​0.018) and negatively correlated with S100B levels (Spearman's rho ​= ​−0.826, p ​= ​0.001).Our data suggest that peripheral administration of IFN-α produces acute changes in brain qMRI which might indicate a brain immune response. This is supported by the association of such changes with low-grade peripheral inflammation.

Abstract Background Depression is a leading contributor to disability-adjusted life-years because of early onset and chronicity throughout the lifecycle. It is crucial to identify early predictors of depression among adolescents and young people to effectively target prevention. A gap in the literature is a comprehensive systematic review of predictors of depression among adolescents around the globe, especially in low- and middle-income countries LMICs. This review aims to identify evidence for biological, psychological, and contextual risk factors for the development of depression among adolescents and young adults (10–24 years of age) in high-income countries (HICs) and LMICs, ultimately contributing to (a) identification of potential mechanisms underlying depression development, (b) selection of common risk and protective factors as targets for detection, and (c) refinement of risk models that can be evaluated through existing cohorts in HICs and LMICs. Methods This review will follow the Population, Exposure, Comparison, Outcome (PI(E)CO) model and adheres to the PRISMA-P guidelines. A search strategy was developed by a multidisciplinary research consortium. Seven databases (MEDLINE via Ovid, PsycINFO, Cochrane Database of Systematic Reviews, Web of Science, Lilacs, African Journals Online, Global Health) will be searched to identify articles. Independent raters will screen and retrieve articles for inclusion, conduct quality ratings, and extract data. The Systematic Assessment of Quality in Observational Research adapted for Cultural Psychiatry Epidemiology (SAQOR-CPE) will be used to assess quality of observational studies. We will assess for publication bias using funnel plots and statistical methods. We will use narrative synthesis to present results, addressing the study’s objectives following the Cochrane Handbook guidelines. Meta-analyses will be used to report summary statistics for association of risk factors with development of depression. Discussion This systematic review will summarize evidence-based research that examines the psychological, biological, and contextual factors contributing to the onset of depression in adolescents across the globe. Results will support the development of a model that can be evaluated in existing cohorts around the world. Systematic review registration PROSPERO registration CRD42018103973.

Neuroimmunology in the broadest sense is the study of interactions between the nervous and the immune systems. These interactions play important roles in health from supporting neural development, homeostasis and plasticity to modifying behaviour. Neuroimmunology is increasingly recognised as a field with the potential to deliver a significant positive impact on human health and treatment for neurological and psychiatric disorders. Yet, translation to the clinic is hindered by fundamental knowledge gaps on the underlying mechanisms of action or the optimal timing of an intervention, and a lack of appropriate tools to visualise and modulate both systems. Here we propose ten key disease-agnostic research questions that, if addressed, could lead to significant progress within neuroimmunology in the short to medium term. We also discuss four cross-cutting themes to be considered when addressing each question: i) bi-directionality of neuroimmune interactions; ii) the biological context in which the questions are addressed (e.g. health vs disease vs across the lifespan); iii) tools and technologies required to fully answer the questions; and iv) translation into the clinic. We acknowledge that these ten questions cannot represent the full breadth of gaps in our understanding; rather they focus on areas which, if addressed, may have the most broad and immediate impacts. By defining these neuroimmunology priorities, we hope to unite existing and future research teams, who can make meaningful progress through a collaborative and cross-disciplinary effort.

Background: The characterization of adolescents at high risk for developing depression has traditionally relied on the presence or absence of single risk factors. More recently, the use of composite risk scores combining information from multiple variables has gained attention in prognostic research in the field of mental health. We previously developed a sociodemographic composite score to estimate the individual level probability of depression occurrence in adolescence, the Identifying Depression Early in Adolescence Risk Score (IDEA-RS).Objectives: In this report, we present the rationale, methods, and baseline characteristics of the Identifying Depression Early in Adolescence Risk Stratified Cohort (IDEA-RiSCo), a study designed for in-depth examination of multiple neurobiological, psychological, and environmental measures associated with the risk of developing and with the presence of depression in adolescence, with a focus on immune/inflammatory and neuroimaging markers.Methods: Using the IDEA-RS as a tool for risk stratification, we recruited a new sample of adolescents enriched for low (LR) and high (HR) depression risk, as well as a group of adolescents with a currently untreated major depressive episode (MDD). Methods for phenotypic, peripheral biological samples, and neuroimaging assessments are described, as well as baseline clinical characteristics of the IDEA-RiSCo sample.Results: A total of 7,720 adolescents aged 14–16 years were screened in public state schools in Porto Alegre, Brazil. We were able to identify individuals at low and high risk for developing depression in adolescence: in each group, 50 participants (25 boys, 25 girls) were included and successfully completed the detailed phenotypic assessment with ascertainment of risk/MDD status, blood and saliva collections, and magnetic resonance imaging (MRI) scans. Across a variety of measures of psychopathology and exposure to negative events, there was a clear pattern in which either the MDD group or both the HR and the MDD groups exhibited worse indicators in comparison to the LR group.Conclusion: The use of an empirically-derived composite score to stratify risk for developing depression represents a promising strategy to establish a risk-enriched cohort that will contribute to the understanding of the neurobiological correlates of risk and onset of depression in adolescence.

Adolescents comprise one fourth of the world's population, with about 90% of them living in low- and middle-income countries (LMICs). The incidence of depression markedly increases during adolescence, making the disorder a leading cause of disease-related disability in this age group. However, most research on adolescent depression has been performed in high-income countries (HICs). To ascertain the extent to which this disparity operates in neuroimaging research, a systematic review of the literature was performed. A total of 148 studies were identified, with neuroimaging data available for 4,729 adolescents with depression. When stratified by income group, 122 (82%) studies originated from HICs, while 26 (18%) were conducted in LMICs, for a total of 3,705 and 1,024 adolescents with depression respectively. A positive Spearman rank correlation was observed between country per capita income and sample size (rs=0.673, p = 0.023). Our results support the previous reports showing a large disparity between the number of studies and the adolescent population per world region. Future research comparing neuroimaging findings across populations from HICs and LMICs may provide unique insights to enhance our understanding of the neurobiological processes underlying the development of depression.

Promising research investigating the association between inflammatory biomarkers and response to antipsychotic and/or adjunctive therapy, observed by improvement in psychiatric assessment, is emerging. Increased inflammation has been suggested to contribute to higher severity of symptoms/treatment resistance through the effects that this has on brain structure and function. The present systematic review aims to clarify the potential role of peripheral inflammatory markers as predictors of clinical outcomes and their association with neuroimaging markers in patients with psychosis. Systematic searches of the literature using the databases PsychInfo, OVID Medline, and Embase were conducted to collate studies investigating the association of inflammatory biomarkers with clinical outcome in patients with psychotic disorders and studies examining the relationships between inflammatory biomarkers and neuroimaging data. Seventeen studies on predictors of clinical outcome and 14 on associations between neuroimaging data and inflammatory biomarkers in psychosis were identified, and risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). The main inflammatory markers associated with clinical outcome in psychosis were interleukin (IL)-6, IL-10, and C-reactive protein (CRP). High levels of CRP and IL-6 were associated with worse clinical outcome and deterioration of symptoms over time; in contrast, increased levels of IL-10 were associated with greater symptoms improvement. Smaller hippocampal volume and reduced cortical thickness were the main neuroimaging markers associated with increased peripheral inflammation. The heterogeneity across the studies (i.e., treatments strategies, duration) suggests that potential prediction power of inflammatory biomarkers could partially depend on the methodologies, supported by the overall NOS ratings of the studies. Future studies may need to consider whether a combination of these inflammatory and neuroimaging markers could further improve our ability of predicting clinical outcome in patients with psychosis.

Purpose The goal of this study was to explore the perspectives of different stakeholders regarding the experiences of adolescent depression in Porto Alegre, Brazil. Methods We conducted 54 key-informant interviews with adolescents, parents, social workers, health workers, educators, and policy makers and two focus group discussions with 5 adolescents and 6 parents. Data were analysed using a framework approach and guided by the adolescents’ personal narratives, with adult stakeholders’ views supplementing these perspectives. Results Four main themes emerged, creating a relational model of adolescent depression that highlights isolation as a central component of the experience. In relation to the self, the experience of depression led to a feeling of detachment from others resulting from the sensation that usual interactions did not have the same meaning as before. This disruption of interactions is perceived as self-isolation and is described in relation to coping mechanisms. Conclusion These findings shed light on important aspects of the identification and management of adolescent depression in Brazil. Since social interaction was a core component of the descriptions and experiences of depression, we speculate that promising interventions are those that could enhance the promotion of a supportive environment and interpersonal relationships.

Introduction Globally, depression is a leading cause of disability among adolescents, and suicide rates are increasing among youth. Treatment alone is insufficient to address the issue. Early identification and prevention efforts are necessary to reduce morbidity and mortality. The Identifying Depression Early in Adolescence (IDEA) consortium is developing risk detection strategies that incorporate biological, psychological and social factors that can be evaluated in diverse global populations. In addition to epidemiological and neuroscience research, the IDEA consortium is conducting a qualitative study to explore three domains of inquiry: (1) cultural heterogeneity of biopsychosocial risk factors and lived experience of adolescent depression in low-income and middle-income countries (LMIC); (2) the feasibility, acceptability and ethics of a risk calculator tool for adolescent depression that can be used in LMIC and high-income countries and (3) capacity for biological research into biomarkers for depression risk among adolescents in LMIC. This is a multisite qualitative study being conducted in Brazil, Nepal, Nigeria and the UK.Methods and analysis A systematic set of qualitative methods will be used in this study. The Delphi method, Theory of Change (ToC) workshops, key-informant interviews and focus group discussions will be used to elicit perspectives on the study topics from a broad range of stakeholders (adolescents, parents, policy-makers, teachers, health service providers, social workers and experts). Delphi panellists will participate in three survey rounds to generate consensus through facilitated feedback. Stakeholders will create ToC models via facilitated workshops in the LMIC sites. The framework approach will be used to analyse data from the study.Ethics and dissemination Ethical approvals were received from the Ethics Review Board of George Washington University and from site-specific institutions in Brazil, Nepal, Nigeria and the UK. The findings generated from this study will be reported in highly accessed, peer-reviewed, scientific and health policy journals.

BackgroundIndividuals with established psychosis and those at high-risk for the disorder have been found to show abnormalities within the hypothalamic-pituitary-adrenal (HPA) axis, including elevations in basal and diurnal cortisol, but a blunted cortisol awakening response. However, the extent to which these features are associated with psychosocial stressors encountered in the natural environment (which are known to be more commonly experienced by these groups, and more distressing) is currently unclear. We therefore conducted a systematic review and meta-analysis to investigate the concordance between naturally-occurring psychosocial stressors and cortisol levels in these populations.MethodsPubMed, PsycINFO, and EMBASE were searched up to November 2019 to identify studies examining the concordance between psychosocial stressors and cortisol in healthy controls and individuals on the psychosis spectrum (patients with established psychosis and/or high-risk individuals). An overall meta-analysis (including data for all stressor-cortisol pairings) was performed to determine the degree of concordance irrespective of group status, with meta-regression employed to test whether the degree of concordance differed in established psychosis and high-risk groups compared to controls. Planned stratified analyses were then performed to examine group differences (where established psychosis and high-risk groups were combined) within individual stressor-cortisol pairings.ResultsEighteen studies (16 datasets) were eligible for inclusion. The overall model, comprising 134 effect sizes, showed that stressors and cortisol measures were only weakly correlated [r=0.05 (95% CI: -0.00 to 0.10), p=0.059] and that neither established psychosis status (r=0.01, p=0.838) nor high-risk status (r=0.02, p=0.477) had a significant effect of the strength of correlation. In stratified analyses, significant differences between healthy controls and psychosis spectrum groups were observed for only one of the six stressor-cortisol pairings examined, where life event exposure and diurnal cortisol were positively correlated in controls [r=0.25 (95% CI: 0.01 to 0.46)], but negatively correlated in the psychosis spectrum group [r=-0.28 (95% CI: -0.49 to -0.04)].ConclusionsOverall, we observed poor concordance between naturally-occurring psychosocial stressors and cortisol irrespective of stressor type, cortisol measure, or group status. We consider a range of methodological factors that may have obscured the ability to detect “true” associations and provide recommendations for future studies in this field.

With the seminal discovery of somatic cell reprogramming with defined genetic factors, it is now a routine laboratory procedure to reprogram somatic cells to generate patient-specific induced pluripotent stem cells (iPSCs) [1] Patient-specific iPSCs can be differentiated to generate mature neurons as well as three-dimensional brain organoids that show appropriate functional activity in electrophysiological studies [2,3]. However, there is a significant gap in the thoughtful incorporation of patient-derived neuronal cells in clinical studies addressing disease risk.

Background The association between childhood adversity and psychosis in adulthood is well established. However, genetic factors might confound or moderate this association. Aims Using a catchment-based case-control sample, we explored the main effects of, and interplay between, childhood adversity and family psychiatric history on the onset of psychosis. Method Childhood adversity (parental separation and death, physical and sexual abuse) was assessed retrospectively in 224 individuals with a first presentation of psychosis and 256 community controls from South London, UK. Occurrence of psychotic and affective disorders in first-degree relatives was ascertained with the Family Interview for Genetic Studies (FIGS). Results Parental history of psychosis did not confound the association between childhood adversity and psychotic disorder. There was no evidence that childhood adversity and familial liability combined synergistically to increase odds of psychosis beyond the effect of each individually. Conclusions Our results do not support the hypothesis that family psychiatric history amplifies the effect of childhood adversity on odds of psychosis.

A history of childhood adversity is associated with psychotic disorder, with an increase in risk according to number or severity of exposures. However, it is not known why only some exposed individuals go on to develop psychosis. One possibility is pre-existing genetic vulnerability. Research on gene-environment interaction in psychosis has primarily focused on candidate genes, although the genetic effects are now known to be polygenic. This pilot study investigated whether the effect of childhood adversity on psychosis is moderated by the polygenic risk score for schizophrenia (PRS). Data were utilised from the Genes and Psychosis (GAP) study set in South London, UK. The GAP sample comprises 285 first-presentation psychosis cases and 256 unaffected controls with information on childhood adversity. We studied only white subjects (80 cases and 110 controls) with PRS data, as the PRS has limited predictive ability in patients of African ancestry. The occurrence of childhood adversity was assessed with the Childhood Experience of Care and Abuse Questionnaire (CECA.Q) and the PRS was based on genome-wide meta-analysis results for schizophrenia from the Psychiatric Genomics Consortium. Higher schizophrenia PRS and childhood adversities each predicted psychosis status. Nevertheless, no evidence was found for interaction as departure from additivity, indicating that the effect of polygenic risk scores on psychosis was not increased in the presence of a history of childhood adversity. These findings are compatible with a multifactorial threshold model in which both genetic liability and exposure to environmental risk contribute independently to the etiology of psychosis.

Objective: To test the feasibility and to present preliminary results of a neuroimaging protocol to evaluate adolescent depression in a middle-income setting. Methods: We assessed psychotropic medication-free adolescents (age range 14-16 years) with a diagnosis of major depressive disorder (MDD). Participants underwent a comprehensive clinical evaluation and both structural and functional magnetic resonance imaging (fMRI). In this pilot study, a preliminary single-group analysis of resting-state fMRI (rs-fMRI) data was performed, with a focus on the default mode network (DMN), cognitive control network (CCN), and salience network (SN). Results: The sample included 29 adolescents with MDD (mean age 16.01, SD 0.78) who completed the protocol. Only two participants were excluded due to MRI quality issues (head movement), and were not included in the analyses. The scans showed significant connectivity between the medial prefrontal cortex and posterior cingulate cortex (DMN), the ACC and anterior insula (SN), and the lateral prefrontal cortex and dorsal parietal cortex (CCN). Conclusion: We demonstrated the feasibility of implementing a complex neuroimaging protocol in a middle-income country. Further, our preliminary rs-fMRI data revealed patterns of resting-state connectivity consistent with prior research performed in adolescents from high-income countries.