Research has suggested a relationship between early life stress, and depression in particular longer episodes of depression with treatment resistant outcomes. However, the underlying mechanisms for ...this association remain poorly understood. Molecular studies indicate that, in general, the hereditary character of psychiatric disorders are polygenic, multifactorial and highly complex, with innumerable low-effect genetic variants interacting with each other. In addition, the importance of the environment and its interaction with genes has pointed to a fundamental role of epigenetic mechanisms in psychiatric disorders, such as methylation of deoxyribonucleic acid (DNA), alterations, histone actions and regulation of gene expression by non-coding ribonucleic acids (RNAs). This article provides an overview of the interplay of epigenetics, the HPA axis, early life stress and the development of depression. Advances in our knowledge of epigenetics in the context of early life stress and depression provide a new understanding of the genetic influence on psychopathology and could lead to the identification of new targets for clinical intervention.
•Early stressful life events play an important role in the pathogenesis of depression.•A better understanding of the mechanisms of Early Life Stress leading to HPA axis impairment and vulnerability to depression.•Early life trauma alters inflammation and causes HPA axis abnormalities increasing vulnerability to stress and depression.•Epigenetic approaches to early intervention will provide new pharmacological and psychoeducational strategies.•Neuroendocrine-stress effects and cognitive vulnerability-stress model studies are needed for a better understanding.
Depression is considered to have the highest disability burden of all conditions. Although treatment-resistant depression (TRD) is a key contributor to that burden, there is little understanding of ...the best treatment approaches for it and specifically the effectiveness of available augmentation approaches.AimsWe conducted a systematic review and meta-analysis to search and quantify the evidence of psychological and pharmacological augmentation interventions for TRD.
Participants with TRD (defined as insufficient response to at least two antidepressants) were randomised to at least one augmentation treatment in the trial. Pre-post analysis assessed treatment effectiveness, providing an effect size (ES) independent of comparator interventions.
Of 28 trials, 3 investigated psychological treatments and 25 examined pharmacological interventions. Pre-post analyses demonstrated N-methyl-d-aspartate-targeting drugs to have the highest ES (ES = 1.48, 95% CI 1.25-1.71). Other than aripiprazole (four studies, ES = 1.33, 95% CI 1.23-1.44) and lithium (three studies, ES = 1.00, 95% CI 0.81-1.20), treatments were each investigated in less than three studies. Overall, pharmacological (ES = 1.19, 95% CI 1.80-1.30) and psychological (ES = 1.43, 95% CI 0.50-2.36) therapies yielded higher ESs than pill placebo (ES = 0.78, 95% CI 0.66-0.91) and psychological control (ES = 0.94, 95% CI 0.36-1.52).
Despite being used widely in clinical practice, the evidence for augmentation treatments in TRD is sparse. Although pre-post meta-analyses are limited by the absence of direct comparison, this work finds promising evidence across treatment modalities.Declaration of interestIn the past 3 years, A.H.Y. received honoraria for speaking from AstraZeneca, Lundbeck, Eli Lilly and Sunovion; honoraria for consulting from Allergan, Livanova and Lundbeck, Sunovion and Janssen; and research grant support from Janssen. In the past 3 years, A.J.C. received honoraria for speaking from AstraZeneca and Lundbeck; honoraria for consulting with Allergan, Janssen, Livanova, Lundbeck and Sandoz; support for conference attendance from Janssen; and research grant support from Lundbeck. B.B. has recently been (soon to be) on the speakers/advisory board for Hexal, Lilly, Lundbeck, Mundipharma, Pfizer, and Servier. No other conflicts of interest.
•Early-life stress can induce persistent changes in the HPA axis to respond to stress.•The homeostatic state is based on glucocorticoids binding to MR and GR.•1st episodes may begin with a stressor, ...then the brain turns sensitized.•The secretion of HPA hormones binding to MR and GR impact in the vulnerability.•Stress in genetically predisposed individuals are related to MR and GR function.
Evidence indicates that early life stress (ELS) may act as a risk factor for the development and maintenance of adulthood severe mental health disorders due to persistent dysregulation within the hypothalamic–pituitary-adrenal (HPA) axis. It is now broadly accepted that psychological stress may change the internal homeostatic state of an individual. The dysregulation seems to be a byproduct of changes noted in the HPA axis hormone’s ability to bind to the glucocorticoid and mineralocorticoid receptors, crucial in maintaining homeostasis. Whenever there is an acute interruption of this balance, illness may result. The social and physical environments have an enormous impact on our physiology and behavior, and they influence the process of adaptation or ‘allostasis’. The HPA axis response to stress can be thought of as a mirror of the organism's response to stress: acute responses are generally adaptive, but excessive or prolonged responses can lead to deleterious effects. Evidence indicates that early-life stress can induce persistent changes in the ability of the HPA axis to respond to stress in adulthood This review aims to examine and summarise the existing literature exploring the relationship between ELS with regards specifically to HPA axis functioning. The maintenance of the internal homeostatic state of an individual is proposed to be based on the ability of circulating glucocorticoids to exert negative feedback on the secretion of HPA hormones through binding to mineralocorticoid (MR) and glucocorticoid (GR) receptors limiting the vulnerability to diseases related to psychological stress in genetically predisposed individuals.
Recent years have seen a rapid increase in the use of gut microbiota-targeting interventions, such as probiotics, for the treatment of psychiatric disorders. The objective of this update review was ...to evaluate all randomised controlled clinical trial evidence on the efficacy of probiotics for clinical depression. Cochrane guidelines for updated reviews were followed. By searching PubMed and Web of Science databases, we identified 546 new records since our previous review. A total of seven studies met selection criteria, capturing 404 people with depression. A random effects meta-analysis using treatment type (stand-alone vs. adjunctive) as subgroup was performed. The results demonstrated that probiotics are effective in reducing depressive symptoms when administered in addition to antidepressants (SMD = 0.83, 95%CI 0.49-1.17), however, they do not seem to offer significant benefits when used as stand-alone treatment (SMD = -0.02, 95%CI -0.34-0.30). Potential mechanisms of action may be via increases in brain-derived neurotrophic factor (BDNF) and decreases in C-reactive protein (CRP), although limited evidence is available at present. This review offers stronger evidence to support the clinical use of probiotics in depressed populations and provides an insight into the mode of administration more likely to yield antidepressant effects.
Introduction: In psychedelic therapy, mystical as well as challenging experience may influence therapeutic outcome. However, predictors of such experience have not been sufficiently established. ...Determining predictors of their intensity is, therefore, potentially beneficial in targeting psilocybin therapy for depression. Methods: In a post hoc data analysis of a Phase 1, randomised, double-blind, placebo-controlled, between-groups clinical trial, dosage, personality traits, affect, and individual data were analysed as possible clinical predictors. Eighty-nine healthy volunteers were randomised to receive a single dose of placebo, 10 mg of psilocybin, or 25 mg of psilocybin. ANOVA was used to analyse the relationship between dosage and mystical and/or challenging experience, and correlation analysis for all other variables. Results: The intensity of both mystical and challenging experience was strongly associated with higher dosage. Age was negatively correlated with intensity of challenging experience. Correlation between identified personality traits and either mystical or challenging experience was minimal, with the exception of positive correlation between neuroticism and challenging experience at higher dose. Neither positive nor negative affect indicated correlation with the intensity of either type of experience. Discussion: A limitation of this study is its post hoc, exploratory design; recommendations for further research are provided. Keywords: mystical experience, challenging experience, psilocybin, psychedelic therapy
Highlights • We studied the link between psychosocial stress and hair cortisol (HCC). • We recruited a community sample. • Physical neglect, war, separation, and crime were linked with HCC ...alterations. • A number of confounders of these relationships were identified. • These were age, ethnicity, heat-based treatments, season, and different medications
Abstract Background Treatment-resistant depression (TRD) is relatively common and accounts for a large proportion of the overall burden caused by depression. We conducted a systematic review of ...outcome studies of TRD in order to summarise findings on the longer term outcome of TRD and make recommendations. Methods Studies were identified through MEDLINE (1960 — June Week 1 2008), EMBASE (1974 — June Week 1 2008) and PsycINFO (1967 — June Week 1 2008) searches. We included studies that followed adults with highly probable TRD for a minimum of 6 months. Statistical analyses were conducted on selected outcome variables whenever possible. Methodological heterogeneity of studies prohibited formal meta-analysis. Results We identified nine outcome studies with a total of 1279 participants and follow-up duration of between 1 and 10 years. In the short term, TRD was highly recurrent with as many as 80% of those requiring multiple treatments relapsing within a year of achieving remission. For those with a more protracted illness, the probability of recovery within 10 years was about 40%. TRD was also associated with poorer quality of life and increased mortality. Limitations Included primary studies were heterogeneous. Conclusions TRD is associated with poorer clinical outcome, particularly among those who require multiple antidepressant medications. The main limitations of the review arise from the variability in recruitment procedures, definitions and outcome assessments of the original studies. We recommend further follow-up studies of carefully identified samples in order to gain a more detailed understanding of this domain of depression and plan effective interventions.
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