The Dynamic Interplay between Puberty and Structural Brain Development as a Predictor of Mental Health Difficulties in Adolescence: a systematic review.

Puberty is a time of intense reorganization of brain structure and a high-risk period for the onset of mental health problems, with variations in pubertal timing and tempo intensifying this risk. We conducted two systematic reviews of papers published up to 1st February 2024 focusing on (1) the role of brain structure in the relationship between puberty and mental health, and (2) precision psychiatry research evaluating the utility of puberty in making individualized predictions of mental health in young people. The first review provides inconsistent evidence on whether and how pubertal and psychopathological processes could interact in relation to brain development. While most studies found an association between early puberty and mental health difficulties in adolescents, evidence on whether brain structure mediates this relationship is mixed. The pituitary gland was found to be associated with mental health status during this time, possibly through its central role in regulating puberty and its function in the hypothalamic- pituitary-gonadal (HPG) and hypothalamic-pituitary-adrenal (HPA) axes. In the second review, the design of studies that have explored puberty in predictive models did not allow for a quantification of its predictive power. However, when puberty was evaluated through physically observable characteristics rather than hormonal measures, it was more commonly identified as a predictor of depression, anxiety, and suicidality in adolescence. Social processes might be more relevant than biological ones in the link between puberty and mental health problems, and represent an important target for educational strategies.

Electronic health records (EHRs) in clinical research and platform trials: Application of the innovative EHR-based methods developed by EU-PEARL.

OBJECTIVE: Electronic Health Record (EHR) systems are digital platforms in clinical practice used to collect patients' clinical information related to their health status and represents a useful storage of real-world data. EHRs have a potential role in research studies, in particular, in platform trials. Platform trials are innovative trial designs including multiple trial arms (conducted simultaneously and/or sequentially) on different treatments under a single master protocol. However, the use of EHRs in research comes with important challenges such as incompleteness of records and the need to translate trial eligibility criteria into interoperable queries. In this paper, we aim to review and to describe our proposed innovative methods to tackle some of the most important challenges identified. This work is part of the Innovative Medicines Initiative (IMI) EU Patient-cEntric clinicAl tRial pLatforms (EU-PEARL) project's work package 3 (WP3), whose objective is to deliver tools and guidance for EHR-based protocol feasibility assessment, clinical site selection, and patient pre-screening in platform trials, investing in the building of a data-driven clinical network framework that can execute these complex innovative designs for which feasibility assessments are critically important. METHODS: ISO standards and relevant references informed a readiness survey, producing 354 criteria with corresponding questions selected and harmonised through a 7-round scoring process (0-1) in stakeholder meetings, with 85% of consensus being the threshold of acceptance for a criterium/question. ATLAS cohort definition and Cohort Diagnostics were mainly used to create the trial feasibility eligibility (I/E) criteria as executable interoperable queries. RESULTS: The WP3/EU-PEARL group developed a readiness survey (eSurvey) for an efficient selection of clinical sites with suitable EHRs, consisting of yes-or-no questions, and a set-up of interoperable proxy queries using physicians' defined trial criteria. Both actions facilitate recruiting trial participants and alignment between study costs/timelines and data-driven recruitment potential. CONCLUSION: The eSurvey will help create an archive of clinical sites with mature EHR systems suitable to participate in clinical trials/platform trials, and the interoperable proxy queries of trial eligibility criteria will help identify the number of potential participants. Ultimately, these tools will contribute to the production of EHR-based protocol design.

Understanding treatment-resistant depression using "omics" techniques: A systematic review.

BACKGROUND: Treatment-resistant depression (TRD) results in huge healthcare costs and poor patient clinical outcomes. Most studies have adopted a "candidate mechanism" approach to investigate TRD pathogenesis, however this is made more challenging due to the complex and heterogeneous nature of this condition. High-throughput "omics" technologies can provide a more holistic view and further insight into the underlying mechanisms involved in TRD development, expanding knowledge beyond already-identified mechanisms. This systematic review assessed the information from studies that examined TRD using hypothesis-free omics techniques. METHODS: PubMed, MEDLINE, Embase, APA PsycInfo, Scopus and Web of Science databases were searched on July 2022. 37 human studies met the eligibility criteria, totalling 17,518 TRD patients, 571,402 healthy controls and 62,279 non-TRD depressed patients (including antidepressant responders and untreated MDD patients). RESULTS: Significant findings were reported that implicate the role in TRD of various molecules, including polymorphisms, genes, mRNAs and microRNAs. The pathways most commonly reported by the identified studies were involved in immune system and inflammation, neuroplasticity, calcium signalling and neurotransmitters. LIMITATIONS: Small sample sizes, variability in defining TRD, and heterogeneity in study design and methodology. CONCLUSIONS: These findings provide insight into TRD pathophysiology, proposing future research directions for novel drug targets and potential biomarkers for clinical staging and response to antidepressants (citalopram/escitalopram in particular) and electroconvulsive therapy (ECT). Further validation is warranted in large prospective studies using standardised TRD criteria. A multi-omics and systems biology strategy with a collaborative effort will likely deliver robust findings for translation into the clinic.

Cause or consequence? Understanding the role of cortisol in the increased inflammation observed in depression.

Glucocorticoids such as cortisol are a class of steroid hormones that play an important role in co-ordinating the body's response to stress. Elevated cortisol levels and increased inflammation have frequently been reported in patients with depression. The currently accepted "glucocorticoid resistance" model posits this increased inflammation as a consequence of reduced sensitivity to cortisol's putative anti-inflammatory action. However, opposing evidence has accumulated that supports a more recent model, which instead proposes that cortisol possesses immune potentiating properties and may thus directly cause the increased inflammation seen in depression. Despite all of this, a clear explanation of the neuroendocrine mechanism that contributes to the development of depression is still lacking and thus requires further investigation in improved future studies.