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The dramatic fluctuations in the energy demands of living organisms by the rhythmic succession of night and day on our planet has prompted a geophysical evolutionary need for a biological temporal organization necessary for maintenance of homeostasis and adaptation to environmental changes across phylogeny. The intrinsic circadian system (CS) represents a highly conserved and complex internal biological "clock", adjusted to the 24-hour rotation of the earth about itself. This system creates and maintains cellular and organismal rhythmicity and enables a nyctohemeral coordination of multi-level physiologic processes, ranging from gene expression to behaviour. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker of the circadian system of the organism, while a ubiquitous peripheral oscillating network of cellular molecular clocks participates in a complex circadian hierarchy. A critical loss of this harmoniously timed circadian order at different organizational levels is defined as "chronodisruption", a condition that may alter the fundamental properties of basic homeostatic systems at molecular, cellular and organismal levels, and lead to a breakdown of biobehavioral adaptive mechanisms, resulting in maladaptive stress regulation and increased sensitivity and vulnerability to stress. Chronodisruption has been linked to neuroendocrine, immune, cardiometabolic and autonomic dysregulation, with blunted diurnal rhythms, specific sleep pattern pathologies and cognitive deficits, as well as with altered circadian gene expression. This condition may, thus, play a central role in the development of mental and somatic disease. Nevertheless, circadian and sleep disturbances are often clinically considered as "secondary" manifestations in most disorders, neglecting the potentially important pathophysiological role of CS. Understanding the pathophysiologic mechanisms of circadian dysregulation and their role in stress-related, systemic disease could provide new insights into disease mechanisms and could help advance chronobiological treatment possibilities and preventive strategies in populations at risk.

The COVID-19 pandemic, which rapidly spread worldwide in early 2020, has affected the daily lives of parents and their children in various ways. This study assessed the overall mental health status and stress experienced by parents during the COVID-19 pandemic and the differences between parents of children with special educational needs and parents of typically developing children. Additionally, we explored potential demographic factors that may influence these experiences. In this cross-sectional study, data were collected through questionnaires completed by a sample of 205 parents (103 of children with typical development attending regular mainstream schools and 102 of children with special educational needs attending special education schools) from February to April 2021. Participants completed the Perceived Stress Scale (PSS-10), the short form of the Profile of Mood States (POMS-S), and a demographic questionnaire. Our findings confirmed that parents of children attending special education schools reported higher levels of anxiety, reduced coping abilities, and poorer overall emotional well-being during the pandemic compared to parents of children attending regular schools. The type of educational setting that children attended was identified through multivariate analyses as the only factor consistently influencing all psychometric outcomes. Factors influencing anxiety levels included gender, older age, and family status, while family status and unemployment negatively impacted coping abilities. Taken together, the pandemic appears to have had a greater impact on the mental health of parents of children with special education needs compared to parents of children attending regular schools, highlighting the need for increased psychosocial support within this population group.

Early life stressors display a high universal prevalence and constitute a major public health problem with two thirds of youth being exposed to potentially traumatic experiences by the age of 17. Traumatic stress exposure during critical periods of development may have essential and long-lasting effects on the physical and mental health of individuals and represents a developmental risk factor mediating risk for disease. Early-life stress (ELS) and childhood trauma (CT) can both have an impact on sensitive neuronal brain networks involved in stress reactions, and could exert a programming effect on glucocorticoid signaling leading to chronic hyper- or hypo-activation of the stress system. In addition, alterations in emotional and autonomic reactivity, circadian rhythm disruption, functional and structural changes in the brain, as well as immune and metabolic dysregulation have been lately identified as important risk factors for a chronically impaired homeostatic balance after ELS/CT. Furthermore, human genetic background and epigenetic modifications through stress-related gene expression could interact with these alterations and explain inter-individual variation in vulnerability or resilience to stress. This narrative review presents relevant evidence from mainly human research on the most acknowledged neurobiological allostatic pathways exerting enduring adverse effects of ELS/CT even decades later. Future studies should prospectively investigate potential confounders, their temporal sequence and combined effects at the biological level, while considering the potentially delayed time-frame for the expression of their effects. Finally, screening strategies for ELS/CT and trauma need to be improved. Information about ELS/CT history and the number of adverse experiences could help to better identify the individual risk for disease development, predict individual treatment response and design prevention strategies to reduce the negative effects of ELS/CT.

Major depressive disorder is a serious mental health disorder of high prevalence and the leading cause of disability worldwide. While there are several classes of therapeutic agents with proven antidepressant efficacy, only about 40-60% of patients respond to initial antidepressant monotherapy, and 30-40% of patients may even show resistance to treatment even under optimal antidepressant pharmacotherapy. Despite the existence of international guidelines, there are still no clear and widely accepted treatment algorithms, no established predictive biomarkers of response to treatment, while the management treatment- resistant depression is usually based on clinical experience. The present article offers a brief narrative review of studies published so far on the predictive quality of various blood-based peripheral biomarkers with respect to response to pharmacological, stimulation or behavioral treatment in patients with treatment-resistant depression. To summarize the results, there does not yet appear to be any specific biomarker that has sufficient discriminative predictive validity and can be used in the routine clinical practice of treating resistant depression. Many factors are likely to account for the above-mentioned research findings, including the wide variety of treatment protocols and the non-uniformly accepted definition of resistant depression used by the various studies, the small number of patients with treatment-resistant depression included, and the existence of different pathophysiological phenotypes of the disorder. The ineffective treatment of major depressive disorder requires an immediate improvement of our therapeutic approach by establishing clinically useful and easily accessible predictive biomarkers of response with high accuracy. The discovery of new and better clinical characterization of known biomarkers in the treatment of treatment-resistant depression could support a better staging and classification of the disorder, the development of personalized treatment algorithms for specific patient subgroups, the achievement of higher rates of stable remission, and the development of new precision drugs with minimal side effects.