The role of BDNF in vulnerability to and treatment of stress-related disorders
|Zusammenfassung der Sitzung|
During adaption to stressors, the brain coordinates appropriate responses through close interaction with peripheral systems. The brain derived neurotrophic factor (BDNF) has emerged as a potential mediator of long-term stress and adversity effects that bridges central and peripheral pathways. BDNF is an essential facilitator of neuronal plasticity in the developing and adult brain. Following observations that chronic stress reduces BDNF expression and antidepressant administration increases its synthesis, the neurotrophic hypothesis of depression was formulated. Fifteen years later, epigenetic regulation and expression of BDNF are widely researched in pathways from adversity to neurodegeneration and disorder, and conversely, as biomarkers for treatment response. This symposium discusses recent advances in our understanding of the role of BDNF for the development and treatment of stress-related disorders, from basic research to clinical application. Roman Linz will provide insights into serum BDNF dynamics during acute stress, its relation to salivary cortisol and BDNF associations with hippocampal volume. Exploring mechanisms of resilience, Lara Puhlmann will discuss data showing serum BDNF increases following stress-relieving mental training in healthy adults. Subsequently, Eva Unternaehrer will discuss how psychopathological risk factors, symptoms, and psychological treatment relate to BDNF DNA methylation. Jan Engelmann and colleagues will present data on the role of plasma BDNF levels and BDNF exon IV promotor methylation as predictors for antidepressant treatment response, and for memory and executive dysfunctions, in a large cohort of depressed patients. Helge Frieling will present recent data on the clinical usefulness of BDNF exon IV methylation as marker of resistance towards monoaminergic antidepressants.
Brain-derived neurotrophic factor (BDNF) in acute stress settings: exploring associations to cortisol and hippocampal volume as neuro-endocrine markers of stress and health
1Research Group “Social Stress and Family Health”, Max-Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; 2Leibniz Institute for Resilience research, Mainz, Germany; Research Group “Social Stress and Family Health”, Max-Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; 3Institute of Psychosocial Medicine, Psychotherapy and Psychooncology, Jena University Hospital, Friedrich-Schiller University, Jena, Germany; Research Group “Social Stress and Family Health”, Max-Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany
Antagonistic long-term effects of BDNF and cortisol on neuroplasticity are well-described: While BDNF facilitates neuronal differentiation and survival, excess cortisol downregulates BDNF and can cause neuronal atrophy. We recently investigated the acute crosstalk of serum BDNF (sBDNF) and salivary cortisol during the Trier Social Stress Test (TSST) and found that sBDNF levels were stress-sensitive. While sBDNF post-stress increases were uncorrelated with cortisol reactivity, results indicated acute inverse relationships of sBDNF peak with cortisol recovery, and of post-stress sBDNF decline with cortisol reactivity. Resembling their long-term antagonism, the acute sBDNF-cortisol pattern potentially reflects integrity and functionality of stress-regulatory circuits.
Pivotal in this regard, the hippocampus facilitates timely downregulation of the stress response and is particularly sensitive to the opposing effects of BDNF and cortisol. Building on our previous findings, we hypothesized stress-reactive sBDNF increases to be associated with hippocampal volume (HCV) in the same healthy participants, reflecting adaptive stress-responding. Additionally, we hypothesized that basal. (non-reactive) BDNF levels would predict HCV. While studies in vulnerable populations suggest that peripheral BDNF levels correlate with HCV, their relationship in healthy adults is only insufficiently characterized.
To address both hypotheses, we conducted a registered report investigating the relationships of basal and stress-reactive sBDNF levels with HCV. Contrary to our preregistered hypotheses, both basal sBDNF and stress-reactive sBDNF changes were unassociated with hippocampal (subfield) volumes of healthy individuals.
These null-results suggest that sBDNF may only signal HCV differences in individuals at increased risk for neurodegeneration, thus providing initial evidence for their relation in healthy mid-aged adults.
Serum BDNF increase and the role of cortisol reduction following contemplative mental training
1Research Group “Social Stress and Family Health”, Max Planck Institute for Human Cognitive and Brain Sciences, Leipzig, Germany; 2Leibniz Institute for Resilience Research, Mainz, Germany; 3Department of Social Neuroscience, Institute of Psychosocial Medicine and Psychotherapy, Jena University Hospital, Friedrich-Schiller University, Jena, Germany; 4Department of Clinical Biochemistry, “Aghia Sophia” Children’s Hospital, Athens, Greece; 5First Department of Pediatrics, National and Kapodistrian University of Athens Medical School, “Aghia Sophia” Children’s Hospital, Athens, Greece; 6Centre for Brain Science, Department of Psychology, University of Essex, Colchester, UK; 7Social Neuroscience Lab, Max Planck Society, Berlin, Germany
Chronic stress reduces expression of the brain derived neurotrophic factor (BDNF), and the stress-hormone cortisol in particular has been implicated in BDNF downregulation. Alleviating subjective stress load and cortisol exposure may thus enhance BDNF expression. Growing evidence shows that contemplative mental training interventions, such as mindfulness-based stress reduction, can reduce self-reported and physiological stress indices. As part of the ReSource Project, we therefore investigated whether a nine month long contemplative mental training intervention increases circulating serum BDNF levels in 332 healthy adults. Participants were randomly assigned to either a control group or one of three intervention cohorts. Training consisted of three distinct 3-month long modules focusing on 1) attention and interoception, 2) socio-affective skills or 3) socio-cognitive skills, which were trained in counterbalanced order. The first three months of attention and interoception-based training increased BDNF levels. This change was associated with individual decreases in self-reported stress. At six and nine months of training, BDNF remained relatively stable in the cohort training first socio-affective, then socio-cognitive skills, and continued to increase for the reverse sequence. BDNF levels in the control cohort were comparatively unstable. In the combined training cohorts, mediation analyses revealed an indirect effect of training on BDNF via lowered cortisol levels in hair. These data suggest that mental training may enhance BDNF expression by reducing participants’ perceived stress load and long-term cortisol exposure. Non-pharmacological BDNF-boosting could be a promising approach for translational treatment or to enhance resilience against the development of stress-related mood disorders in non-clinical populations.
BDNF DNA methylation following narrative exposure therapy in former female child soldiers from the Eastern Democratic Republic of Congo
1Psychiatric University Hospitals Basel (UPK), Basel, Switzerland; 2University of Konstanz, Konstanz, Germany; 3University of Linköping, Linköping, Sweden; 4University of Basel, Basel, Switzerland
Brain-derived neurotrophic factor (BDNF) acts on the central and peripheral nervous system and plays a prominent role in long-term memory, which is often disorganized in trauma-related mental disorders. Moreover, BDNF DNA methylation and expression are sensitive to stress and are associated with trauma-related disorders. The aim of this study was to examine the association between BDNF DNA methylation and stress-related symptom improvement in response to an evidence-based trauma treatment compared with control treatments in a sample of severely traumatized women.
Former female child soldiers from the DR Congo (N=82) were randomly assigned to either receive narrative exposure therapy (NET, n=42), or treatment as usual (TAU, n=40). DNA methylation of 126 CpGs located on the BDNF gene was measured in salivary DNA samples collected at baseline and 6 months following treatment using the Illumina EPIC array. Symptoms of PTSD and depression were measured before and after treatment using the Posttraumatic Stress Symptoms Scale-Interview and the Patient Health Questionnaire-9, respectively.
Compared to TAU, NET substantially improved the mental health of the survivors. Change in BDNF DNA methylation in 7 CpGs also depended on treatment group (NET vs TAU). Moreover, change in methylation of several CpGs was correlated with changes in PTSD and depressive symptom severity (PTSD: 10 CpGs; depression: 4 CpGs), five of these CpGs were associated with stress and mental health in previous studies.
Our findings show a relation between epigenetic modification of BDNF and improvement of stress-related mental disorders, indicating that NET may initialize a sequence of physiological changes.
BDNF plasma levels and BDNF exon IV promotor methylation as predictors for antidepressant treatment response
Klinik für Psychiatrie und Psychotherapie, Universitätsmedizin Mainz, Deutschland
Although the currently available antidepressants are well established and safe, treatment outcomes are poor, highly unpredictable and there is a strong variability in treatment response of individual patients. To date, there is no no biological marker of sufficient clinical utility to inform the selection of specific antidepressant compound for an individual patient. Previous studies have linked the neurotrophin BDNF with both the pathophysiology of depression and the mode of action of antidepressants. Here, we present findings of a large cohort of MDD patients (N=561), which all participated in the Early Medication Change trial. We measured BDNF exon IV promotor and p11 gene methylation at baseline as well as repeated measurements of plasma BNDF during the course of antidepressant treatment and related them to treatment outcome. We could show, that patients with severe depression (Hamilton Depression Rating Scale [HAMD17] ≥ 25] and hypermethylation at CpG-87 of BDNF exon IV promotor had significantly higher remission rates than patients without methylation (p=0.032). We also found that the combination of clinical outcome parameters (e.g. early improvement; defined as a ≥ 20% HAMD17 reduction after two weeks) in combination with an increase of pBDNF led to a higher specifity of response prediction. In addition, we will report data of a subgroup of MDD patients, suffering from cognitive impairment (memory and executive dysfunctions), and the potential role of pBDNF in the normalization of these impairments.
BDNF IV methylation and antidepressant treatment response - from bench to bedside
Medizinische Hochschule Hannover, Deutschland
Treatment of patients with depressive disorders normally includes monoaminergic antidepressant medication like serotonine reuptake inhibitor (SSRI). Only one in three patients sufficiently responds to this therapy. We have recently shown that methylation of one single CpG dinucleotide within the promoter region of exon IV of the BDNF gene predicts non-responsiveness towards monoaminergic antidepressants. In the talk, most recent data from different clinical cohorts will be presented, as well as data on the putative molecular mechanisms behind this biomarker. Furthermore, first experiences with the clinical use of the biomarker will be presented and a biomarker based therapy algorithm for acute depression will be discussed.