Courtney Worrell

Background: There is increasing recognition of the challenge of representativeness in data, including economic, social, and ethnic diversity, in biological mental health research. This is a particular challenge in adolescence, where brain and body development are impacted by environment. The first step in addressing this is understanding the scale of the challenge. As such, this scoping review aims to explore existing literature to identify and understand the needs, barriers, and facilitators in collecting biological data in adolescent mental health research. Methods: A systematic search identified papers recruiting participants aged 11-18, collecting biological data, and focusing on mental health/related psychopathology. Screening was performed in duplicate, and data charting was iterative. Results: The initial search identified 11,896 papers. After removal of duplicates and screening exclusions, 814 papers were included; 754 were explored for recruitment, retention, and engagement. Sample sizes <99 were most common (53%), and health settings (36%) were the most frequent recruitment source. As labels for ‘barriers’, ‘facilitators’, and ‘needs’ were rarely used, information on recruitment, retention, and engagement (e.g., strategies for stakeholder engagement) were explored as a proxy. Only 9% of papers reported engagement strategies; fewer evaluated their efficacy. Less than half (48%) reported retention data, with reasons for lost data mostly relating to the nature of the data collection. Conclusions: Papers do not adequately report the methods used to ensure sufficient collection of representative data. Limited reporting challenges whether or not facilitators are being implemented. Advancing the field requires detailed guidelines. We present recommendations that serve as a first step towards this development.

Transcriptomic profiles are important indicators for molecular mechanisms and pathways involved in major depressive disorder (MDD) and its different phenotypes, such as immunometabolic depression. We performed whole-transcriptome and pathway analyses on 139 individuals from the observational, case-control, BIOmarkers in DEPression (BIODEP) study, 105 with MDD and 34 controls. We divided MDD participants based on levels of inflammation, as measured by serum high-sensitivity C-reactive protein (CRP), in n = 39 ‘not inflamed’ (CRP < 1 mg/L), n = 31 with ‘elevated CRP’ (1–3 mg/L), and n = 35 with ‘low-grade inflammation’ (>3 mg/L). We performed whole-blood RNA sequencing using Illumina NextSeq 550 and statistical analyses with the Deseq2 package for R statistics (RUV-corrected) and subsequent pathway analyses with Ingenuity Pathway Analysis. Immunometabolic pathways were activated in individuals with CRP > 1 mg/L, although surprisingly the CRP 1–3 group showed stronger immune activation than the CRP > 3 group. The main pathways identified in the comparison between CRP < 1 group and controls were cell-cycle-related, which may be protective against immunometabolic abnormalities in this ‘non-inflamed’ depressed group. We further divided MDD participants based on exposure and response to antidepressants (n = 47 non-responders, n = 37 responders, and n = 22 unmedicated), and identified specific immunomodulatory and neuroprotective pathways in responders (especially vs. non-responders), which could be relevant to treatment response. In further subgroup analyses, we found that the specific transcriptional profile of responders is independent of CRP levels, and that the inhibition of cell-cycle-related pathways in MDD with CRP < 1 mg/L is present only in those who are currently depressed, and not in the responders. The present study demonstrates immunometabolic and cell-cycle-related transcriptomic pathways associated with MDD and different (CRP-based and treatment-based) MDD phenotypes, while shedding light on potential molecular mechanisms that could prevent or facilitate an individual’s trajectory toward immunometabolic depression and/or treatment-non-responsive depression. The recognition and integration of these mechanisms will facilitate a precision-medicine approach in MDD.

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.

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 11-18, 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., (2010) [1], supplemented by subsequent recommendations from the Joanna Briggs Institute Scoping Review Methodology [2]. 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 (PPI), specifically including young people involved in our study ‘CELEBRATE’ (‘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.

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 <1 and/or controls), reflecting the gradient of CRP values. Secondary analyses on MDD individuals and controls with CRP values <1 mg/L (usually interpreted as 'no inflammation') confirmed MDD cases still had significantly different mRNA expression of immune-related genes compared with controls. These findings corroborate an immune-related molecular activation in MDD, which appears to be independent of serum CRP levels. Additional biological mechanisms may then be required to translate this mRNA signature into inflammation at protein and cellular levels. Understanding these mechanisms will help to uncover the true immune abnormalities in depression, opening new paths for diagnosis and treatment.