TY - JOUR A1 - Gottschalk, Michael G. A1 - Richter, Jan A1 - Ziegler, Christiane A1 - Schiele, Miriam A. A1 - Mann, Julia A1 - Geiger, Maximilian J. A1 - Schartner, Christoph A1 - Homola, György A. A1 - Alpers, Georg W. A1 - Büchel, Christian A1 - Fehm, Lydia A1 - Fydrich, Thomas A1 - Gerlach, Alexander L. A1 - Gloster, Andrew T. A1 - Helbig-Lang, Sylvia A1 - Kalisch, Raffael A1 - Kircher, Tilo A1 - Lang, Thomas A1 - Lonsdorf, Tina B. A1 - Pané-Farré, Christiane A. A1 - Ströhle, Andreas A1 - Weber, Heike A1 - Zwanzger, Peter A1 - Arolt, Volker A1 - Romanos, Marcel A1 - Wittchen, Hans-Ulrich A1 - Hamm, Alfons A1 - Pauli, Paul A1 - Reif, Andreas A1 - Deckert, Jürgen A1 - Neufang, Susanne A1 - Höfler, Michael A1 - Domschke, Katharina T1 - Orexin in the anxiety spectrum: association of a HCRTR1 polymorphism with panic disorder/agoraphobia, CBT treatment response and fear-related intermediate phenotypes JF - Translational Psychiatry N2 - Preclinical studies point to a pivotal role of the orexin 1 (OX1) receptor in arousal and fear learning and therefore suggest the HCRTR1 gene as a prime candidate in panic disorder (PD) with/without agoraphobia (AG), PD/AG treatment response, and PD/AG-related intermediate phenotypes. Here, a multilevel approach was applied to test the non-synonymous HCRTR1 C/T Ile408Val gene variant (rs2271933) for association with PD/AG in two independent case-control samples (total n = 613 cases, 1839 healthy subjects), as an outcome predictor of a six-weeks exposure-based cognitive behavioral therapy (CBT) in PD/AG patients (n = 189), as well as with respect to agoraphobic cognitions (ACQ) (n = 483 patients, n = 2382 healthy subjects), fMRI alerting network activation in healthy subjects (n = 94), and a behavioral avoidance task in PD/AG pre- and post-CBT (n = 271). The HCRTR1 rs2271933 T allele was associated with PD/AG in both samples independently, and in their meta-analysis (p = 4.2 × 10−7), particularly in the female subsample (p = 9.8 × 10−9). T allele carriers displayed a significantly poorer CBT outcome (e.g., Hamilton anxiety rating scale: p = 7.5 × 10−4). The T allele count was linked to higher ACQ sores in PD/AG and healthy subjects, decreased inferior frontal gyrus and increased locus coeruleus activation in the alerting network. Finally, the T allele count was associated with increased pre-CBT exposure avoidance and autonomic arousal as well as decreased post-CBT improvement. In sum, the present results provide converging evidence for an involvement of HCRTR1 gene variation in the etiology of PD/AG and PD/AG-related traits as well as treatment response to CBT, supporting future therapeutic approaches targeting the orexin-related arousal system. KW - human behaviour KW - molecular neuroscience KW - personalized medicine KW - predictive markers KW - psychiatric disorders Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-227479 VL - 9 ER - TY - JOUR A1 - Schiele, Miriam A. A1 - Ziegler, Christiane A1 - Kollert, Leonie A1 - Katzorke, Andrea A1 - Schartner, Christoph A1 - Busch, Yasmin A1 - Gromer, Daniel A1 - Reif, Andreas A1 - Pauli, Paul A1 - Deckert, Jürgen A1 - Herrmann, Martin J. A1 - Domschke, Katharina T1 - Plasticity of Functional MAOA Gene Methylation in Acrophobia JF - International Journal of Neuropsychopharmacology N2 - Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction. KW - monoamine oxidase A KW - anxiety KW - extinction KW - epigenetics KW - DNA methylation Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-228571 VL - 21 IS - 9 ER - TY - THES A1 - Ziegler, Christiane T1 - Epigenetic Mechanisms in the Pathogenesis and Therapy of Anxiety Disorders T1 - Epigenetische Mechanismen in der Pathogenese und Therapie von Angsterkrankungen N2 - Anxiety disorders (AD) are common, disabling mental disorders, which constitute the most prevalent mental health condition conveying a high individual and socioeconomic burden. Social anxiety disorder (SAD), i.e. fear in social situations particularly when subjectively scrutinized by others, is the second most common anxiety disorder with a life time prevalence of 10%. Panic disorder (PD) has a life time prevalence of 2-5% and is characterized by recurrent and abrupt surges of intense fear and anticipatory anxiety, i.e. panic attacks, occurring suddenly and unexpected without an apparent cue. In recent years, psychiatric research increasingly focused on epigenetic mechanisms such as DNA methylation as a possible solution for the problem of the so-called “hidden heritability”, which conceptualizes the fact that the genetic risk variants identified so far only explain a small part of the estimated heritability of mental disorders. In the first part of this thesis, oxytocin receptor (OXTR) gene methylation was investigated regarding its role in the pathogenesis of social anxiety disorder. In summary, OXTR methylation patterns were implicated in different phenotypes of social anxiety disorder on a categorical, neuropsychological, neuroendocrinological as well as on a neural network level. The results point towards a multilevel role of OXTR gene hypomethylation particularly at one CpG site (CpG3, Chr3: 8 809 437) within the protein coding region of the gene in SAD. The second part of the thesis investigated monoamine oxidase A (MAOA) gene methylation regarding its role in the pathogenesis of panic disorder as well as – applying a psychotherapy-epigenetic approach – its dynamic regulation during the course of cognitive behavioural therapy (CBT) in PD patients. First, MAOA hypomethylation was shown to be associated with panic disorder as well as with panic disorder severity. Second, in patients responding to treatment MAOA hypomethylation was shown to be reversible up to the level of methylation in healthy controls after the course of CBT. This increase in MAOA methylation along with successful psychotherapeutic treatment was furthermore shown to be associated with symptom improvement regarding agoraphobic avoidance in an independent replication sample of non-medicated patients with PD. Taken together, in the future the presently identified epigenetic patterns might contribute to establishing targeted preventive interventions and personalized treatment options for social anxiety disorder or panic disorder, respectively. N2 - Angsterkrankungen sind die häufigsten psychischen Erkrankungen, welche in hohem Maße den Alltag der Betroffenen beeinträchtigen und eine große sozioökonomische Belastung darstellen. Eine der häufigsten Formen von Angsterkrankungen bildet die soziale Phobie, d.h. die Angst vor sozialen Situationen, in denen man im Mittelpunkt der Aufmerksamkeit steht, mit einer Lebenszeit-Prävalenz von circa 10%. Die Panikstörung, charakterisiert durch das wiederholte und unerwartete Auftreten von Panikattacken, ist eine weitere Form der Angsterkrankungen mit einer Lebenszeit-Prävalenz von circa 2-5%. Epigenetische Mechanismen, wie zum Beispiel die DNA Methylierung, rücken in den letzten Jahren immer weiter in den Fokus der psychiatrischen Forschung. Hier werden sie als eine mögliche Lösung für das Problem der „hidden heritability“ (versteckte Heritabilität) angesehen. Im ersten Teil dieser Arbeit wurde die DNA Methylierung des Oxytozinrezeptorgens (OXTR) hinsichtlich ihrer Rolle in der Pathogenese der sozialen Phobie untersucht. Hierbei konnte eine verringerte Methylierung des Gens, speziell an einem CpG-Dinukleotid (CpG3, Chr3: 8 809 437) innerhalb der protein-kodierenden Genregion, auf verschiedenen Ebenen mit der Erkrankung an sozialer Phobie, dimensionalen Maßen der Erkrankungsschwere sowie der Stressverarbeitung auf neuro-endokrinologischer und neuronaler Ebene in Verbindung gebracht werden. Der zweite Teil dieser Arbeit beschäftigt sich mit der Rolle von DNA Methylierungsmustern des Monoaminooxidase A (MAOA) Gens in der Pathogenese und der Therapie der Panikstörung. Zum einen konnte gezeigt werden, dass eine verringerte MAOA Methylierung mit dem Auftreten von Panikstörung sowie mit einer erhöhten Symptomschwere assoziiert ist. Zum anderen zeigten Patienten, welche auf eine kognitive Verhaltenstherapie (KVT) ansprachen, eine signifikante Erhöhung der MAOA Methylierung nach der Therapie, welche zusätzlich in einer unabhängigen Stichprobe mit einer Verringerung der Symptomschwere assoziiert war. Diese Veränderung zeigte sich jedoch nicht in Patienten, welche nicht auf die KVT ansprachen. Zusammenfassend können beide im Rahmen dieser Arbeit untersuchten epigenetischen Muster und deren Rolle in der Pathogenese der sozialen Phobie sowie der Panikstörung zur Etablierung personalisierter Therapiemöglichkeiten wie auch targetierter präventiver Interventionen beitragen. KW - Angst KW - Psychische Störung KW - DNA-Methylierung KW - Panikstörung KW - Soziale Phobie KW - Angsterkrankungen KW - Epigenetische Mechanismen KW - Epigenetik KW - Methylierung KW - DNS KW - Angsterkrankungen Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-146815 ER -