TY - JOUR A1 - Ziegler, C. A1 - Richter, J. A1 - Mahr, M. A1 - Gajewska, A. A1 - Schiele, M.A. A1 - Gehrmann, A. A1 - Schmidt, B. A1 - Lesch, K.-P. A1 - Lang, T. A1 - Helbig-Lang, S. A1 - Pauli, P. A1 - Kircher, T. A1 - Reif, A. A1 - Rief, W. A1 - Vossbeck-Elsebusch, A.N. A1 - Arolt, V. A1 - Wittchen, H.-U. A1 - Hamm, A.O. A1 - Deckert, J. A1 - Domschke, K. T1 - MAOA gene hypomethylation in panic disorder-reversibility of an epigenetic risk pattern by psychotherapy JF - Translational Psychiatry N2 - Epigenetic signatures such as methylation of the monoamine oxidase A (MAOA) gene have been found to be altered in panic disorder (PD). Hypothesizing temporal plasticity of epigenetic processes as a mechanism of successful fear extinction, the present psychotherapy-epigenetic study for we believe the first time investigated MAOA methylation changes during the course of exposure-based cognitive behavioral therapy (CBT) in PD. MAOA methylation was compared between N=28 female Caucasian PD patients (discovery sample) and N=28 age- and sex-matched healthy controls via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. MAOA methylation was furthermore analyzed at baseline (T0) and after a 6-week CBT (T1) in the discovery sample parallelized by a waiting time in healthy controls, as well as in an independent sample of female PD patients (N=20). Patients exhibited lower MAOA methylation than healthy controls (P<0.001), and baseline PD severity correlated negatively with MAOA methylation (P=0.01). In the discovery sample, MAOA methylation increased up to the level of healthy controls along with CBT response (number of panic attacks; T0-T1: +3.37±2.17%), while non-responders further decreased in methylation (-2.00±1.28%; P=0.001). In the replication sample, increases in MAOA methylation correlated with agoraphobic symptom reduction after CBT (P=0.02-0.03). The present results support previous evidence for MAOA hypomethylation as a PD risk marker and suggest reversibility of MAOA hypomethylation as a potential epigenetic correlate of response to CBT. The emerging notion of epigenetic signatures as a mechanism of action of psychotherapeutic interventions may promote epigenetic patterns as biomarkers of lasting extinction effects. KW - Adult KW - Case-Control Studies KW - Cognitive Therapy KW - DNA Methylation KW - Epigenesis KW - Genetic KW - Female KW - Humans KW - Monoamine Oxidase/genetics KW - Panic Disorder/genetics KW - Panic Disorder/therapy KW - Sequence Analysis KW - DNA Y1 - 2016 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-164422 IS - 6 ER - TY - JOUR A1 - Biernacka, J. M. A1 - Sangkuhl, K. A1 - Jenkins, G. A1 - Whaley, R. M. A1 - Barman, P. A1 - Batzler, A. A1 - Altman, R. B. A1 - Arolt, V. A1 - Brockmöller, J. A1 - Chen, C. H. A1 - Domschke, K. A1 - Hall-Flavin, D. K. A1 - Hong, C. J. A1 - Illi, A. A1 - Ji, Y. A1 - Kampman, O. A1 - Kinoshita, T. A1 - Leinonen, E. A1 - Liou, Y. J. A1 - Mushiroda, T. A1 - Nonen, S. A1 - Skime, M. K. A1 - Wang, L. A1 - Baune, B. T. A1 - Kato, M. A1 - Liu, Y. L. A1 - Praphanphoj, V. A1 - Stingl, J. C. A1 - Tsai, S. J. A1 - Kubo, M. A1 - Klein, T. E. A1 - Weinshilboum, R. T1 - The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response JF - Translational Psychiatry N2 - Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N = 2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P = 5.03E - 08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P = 1.20E - 06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted. KW - major depressive disorder KW - genetic variation KW - schizophrenia KW - neuregulin-1 KW - population KW - microcephalin 1 KW - susceptibility KW - metaanalysis KW - MCPH1 KW - loci Y1 - 2015 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-143223 VL - 5 IS - e553 ER - TY - JOUR A1 - Straube, B. A1 - Reif, A. A1 - Richter, J. A1 - Lueken, U. A1 - Weber, H. A1 - Arolt, V. A1 - Jansen, A. A1 - Zwanzger, P. A1 - Domschke, K. A1 - Pauli, P. A1 - Konrad, C. A1 - Gerlach, A. L. A1 - Lang, T. A1 - Fydrich, T. A1 - Alpers, G. W. A1 - Stroehle, A. A1 - Wittmann, A. A1 - Pfleiderer, B. A1 - Wittchen, H.-U. A1 - Hamm, A. A1 - Deckert, J. A1 - Kircher, T. T1 - The functional - 1019C/G HTR1A polymorphism and mechanisms of fear JF - Translational Psychiatry N2 - Serotonin receptor 1A gene (HTR1A) knockout mice show pronounced defensive behaviour and increased fear conditioning to ambiguous conditioned stimuli. Such behaviour is a hallmark of pathological human anxiety, as observed in panic disorder with agoraphobia (PD/AG). Thus, variations in HTR1A might contribute to neurophysiological differences within subgroups of PD/AG patients. Here, we tested this hypothesis by combining genetic with behavioural techniques and neuroimaging. In a clinical multicentre trial, patients with PD/AG received 12 sessions of manualized cognitive-behavioural therapy (CBT) and were genotyped for HTR1A rs6295. In four subsamples of this multicentre trial, exposure behaviour (n = 185), defensive reactivity measured using a behavioural avoidance test (BAT; before CBT: n = 245; after CBT: n = 171) and functional magnetic resonance imaging (fMRI) data during fear conditioning were acquired before and after CBT (n = 39). HTR1A risk genotype (GG) carriers more often escaped during the BAT before treatment. Exploratory fMRI results suggest increased activation of the amygdala in response to threat as well as safety cues before and after treatment in GG carriers. Furthermore, GG carriers demonstrated reduced effects of CBT on differential conditioning in regions including the bilateral insulae and the anterior cingulate cortex. Finally, risk genotype carriers demonstrated reduced self-initiated exposure behaviour to aversive situations. This study demonstrates the effect of HTR1A variation on defensive behaviour, amygdala activity, CBT-induced neural plasticity and normalization of defence behaviour in PD/AG. Our results, therefore, translate evidence from animal studies to humans and suggest a central role for HTR1A in differentiating subgroups of patients with anxiety disorders. KW - randomized-controlled trial KW - panic disorder KW - 5-HT1A receptor KW - defensive reactivity KW - major depression KW - cognitive-behavioral therapy KW - receptor gene polymorphism KW - C(-1019)G polymorphism KW - anxiety disorders KW - serotonin(1A) receptor Y1 - 2014 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-114369 SN - 2158-3188 VL - 4 ER -