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Die Serotoninhypothese Der Zwangsstörung

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Die Serotoninhypothese Der Zwangsstörung DIE SEROTONINHYPOTHESE DER ZWANGSSTÖRUNG Assoziation genetischer Varianten des serotonergen Systems mit der Zwangsstörung und kognitiven Endophänotypen Inaugural-Dissertation zur Erlangung der Doktorwürde der Philosophischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität zu Bonn vorgelegt von Leonhard Lennertz aus Köln Bonn 2013 Gedruckt mit der Genehmigung der Philosophischen Fakultät der Rheinischen Friedrich-Wilhelms-Universität Bonn Diese Dissertation ist auf dem Hochschulschriftenserver der ULB Bonn http://hss.ulb.uni-bonn.de/diss_online elektronisch publiziert. Zusammensetzung der Prüfungskommission: Professor Dr. Una M. Röhr-Sendlmeier (Vorsitzende der Prüfungskommission) Professor Dr. Michael Wagner (Betreuer und Gutachter) Professor Dr. Ulrich Ettinger (Gutachter) PD Dr. Rainald Mössner (weiteres prüfungsberechtigtes Mitglied) Tag der mündlichen Prüfung: 26.11.2013 Inhaltsverzeichnis Zusammenfassung...................................................................................................................... 5 I. Einleitung....................................................................................................................... 6 II. Theoretischer Teil .......................................................................................................... 7 1 Genetik der Zwangsstörung ........................................................................................... 7 1.1 Familienstudien zur Zwangsstörung .............................................................................. 7 1.2 Zwillingsstudien zur Zwangsstörung ............................................................................. 8 1.3 Erkenntnisse zur molekulargenetischen Grundlage der Zwangsstörung ....................... 9 2 Die Serotoninhypothese der Zwangsstörung................................................................ 11 2.1 Die Wirksamkeit von Serotonin-Wiederaufnahme-Hemmern (SRI) in der Behandlung der Zwangsstörung................................................................................... 12 2.2 Auffälligkeiten im serotonergen System bei Patienten mit einer Zwangsstörung....... 13 2.2.1 Peripherphysiologische und zentralnervöse Veränderungen im serotonergen System bei Patienten mit einer Zwangsstörung ........................................................................ 14 2.2.2 Psychopharmakologische Manipulation serotonerger Rezeptoren .............................. 17 2.3 Genetische Varianten des serotonergen Systems bei der Zwangsstörung ................... 19 2.3.1 Das Serotonin-Transporter-Gen SLC6A4 als Kandidaten-Gen der Zwangsstörung .... 19 2.3.2 Die Rolle des HTR1A -Gens bei der Zwangsstörung.................................................... 22 2.3.3 Assoziation des HTR1B -Gens mit der Zwangsstörung................................................ 23 2.3.4 Häufige Varianten des HTR2A -Gens bei der Zwangsstörung...................................... 25 2.3.5 Kodierende Varianten der Rezeptor-Gene HTR3A-E bei der Zwangsstörung............. 28 2.3.6 Das HTR6 -Gen als potentielles Kandidatengen der Zwangsstörung ........................... 30 2.3.7 Tryptophanhydroxylase-2 ( TPH2 ) bei Zwangserkrankten .......................................... 30 3 Klinische Subtypen der Zwangsstörung....................................................................... 32 3.1 Zwangsstörungen mit frühem und spätem Ersterkrankungsalter................................. 32 3.2 Symptomdimensionen der Zwangsstörung.................................................................. 33 4 Kognitive Endophänotypen der Zwangsstörung.......................................................... 35 4.1 Neuropsychologische Defizite bei Patienten mit einer Zwangsstörung....................... 36 4.1.1 Einfache Aufmerksamkeitsprozesse ............................................................................ 36 4.1.2 Visuell-räumliche Verarbeitung und visuelles Gedächtnis.......................................... 37 4.1.3 Verbales Gedächtnis..................................................................................................... 37 4.1.4 Beeinträchtigungen des Arbeitsgedächtnisses ............................................................. 38 1 4.1.5 Defizite in exekutiven Funktionen ............................................................................... 38 4.2 Neuropsychologische Defizite bei Angehörigen von Zwangserkrankten.................... 42 4.3 Okulomotorische Auffälligkeiten: Die Antisakkadenaufgabe ..................................... 44 III. Empirieteil.................................................................................................................... 46 5 Herleitung der wissenschaftlichen Fragestellung......................................................... 46 6 Methode........................................................................................................................ 49 6.1 Studiendesign und Stichprobenbeschreibung............................................................... 49 6.1.1 Die GENOS-Stichprobe ............................................................................................... 49 6.1.2 Patientenstichprobe Bonn............................................................................................. 50 6.1.3 Kontrollstichprobe Bonn.............................................................................................. 50 6.1.4 Zusammenstellung und Beschreibung der im Einzelnen ausgewerteten Stichproben. 51 6.2 Einteilung der klinischen Subtypen der Zwangsstörung.............................................. 54 6.2.1 Definition früh und spät erkrankter Patienten.............................................................. 55 6.2.2 Erfassung der Symptomdimensionen........................................................................... 55 6.3 Neuropsychologische Testinstrumente (GENOS) ....................................................... 58 6.3.1 Visuomotorische Verarbeitungsgeschwindigkeit......................................................... 59 6.3.2 Verbales Gedächtnis..................................................................................................... 59 6.3.3 Visuelle Verarbeitung und visuelles Gedächtnis ......................................................... 59 6.3.4 Visuell-räumliches Arbeitsgedächtnis.......................................................................... 60 6.3.5 Problemlösefähigkeiten................................................................................................ 60 6.3.6 Wortflüssigkeit............................................................................................................. 61 6.4 Erfassung der Okulomotorik (GENOS)....................................................................... 61 6.5 Genotypisierung ........................................................................................................... 62 6.6 Statistische Auswertung............................................................................................... 64 7 Ergebnisse .................................................................................................................... 66 7.1 Fragestellung 1: Lassen sich genetische Varianten des serotonergen Systems mit der Zwangsstörung assoziieren?................................................................................... 66 7.2 Fragestellung 2: Besteht eine differentielle Rolle serotonerger Varianten bei klinischen Subtypen der Zwangsstörung?.................................................................... 69 7.3 Fragestellung 3: Lassen sich kognitive Funktionen als Endophänotypen der Zwangsstörung validieren? .......................................................................................... 72 7.4 Fragestellung 4: Werden kognitive Endophänotypen der Zwangsstörung durch genetische Varianten des serotonergen Systems beeinflusst?...................................... 76 2 8 Diskussion.................................................................................................................... 80 8.1 Einfluss genetischer Varianten des Serotoninsystems auf die Zwangsstörung............ 80 8.2 Die Relevanz von Subtypen der Zwangsstörung für molekulargenetische Studien .... 89 8.3 Kognitive Endophänotypen der Zwangsstörung.......................................................... 94 8.4 Einschränkungen der vorliegenden Untersuchung und Ausblick .............................. 103 Literatur.................................................................................................................................. 107 Verwendete Abkürzungen...................................................................................................... 134 Anhang ................................................................................................................................... 135 3 Danksagung Vor allen anderen gilt mein Dank den Patientinnen und Patienten, die durch ihre Zustim- mung und Teilnahme die Studie erst möglich gemacht haben. Aus der eigenen klinisch- psychotherapeutischen Arbeit mit Betroffenen weiß ich, mit wie viel Hoffnung neue Studien zu den Ursachen der Zwangsstörung begrüßt werden. Ebenfalls danken möchte ich den an der Studie beteiligten Kolleginnen und Kollegen, Friederike Rampacher, Svenja Schulze-Rauschenbach und Andrea Vogeley. Vera Guttentha- ler möchte ich für ihre sehr hilfreiche Einführung in die technischen Feinheiten der Genotypi- sierung danken. Herrn Professor Dr. Ulrich Ettinger danke ich ausdrücklich für die bereitwil-
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