<p> Although historically treated as separate systems, there is considerable interaction between the immune system and brain. It has become increasingly clear that immunebrain communication is important to both health and disease. An immunogenic challenge given during the first postnatal week in rodents impacts the developing central nervous system (CNS) leading to long-term behavioural and molecular alterations reflective of enhanced stress-reactivity. Anxiety and depression are stress-related pathologies with a proposed neurodevelopmental origin suggesting that perturbation to neonatal immunebrain signalling may contribute to psychopathology. The current body of work examined the long-term impact of an early immune challenge on behavioural and molecular phenotypes associated with anxiety and depression. Mice were administered lipopolysaccharide (LPS) on postnatal days three and five. The emergence of anxietyrelated behaviour was characterized along the developmental trajectory of LPS-mice concurrent with changes to serotonergic neurocircuitry. Adult depressive-related behaviour was assessed in the forced swim test (FST) along with hippocampal neurogenesis as revealed by immunoreactivity for bromodeoxyuridine (BrdU) and doublecortin (DCX). The results demonstrated a sex-specific alteration in both the temporal emergence and phenotypic variant of anxiety-related behaviours displayed by LPS-mice. This was accompanied by changes to CNS serotonergic-related gene expression that coincided with a critical developmental time window essential to the establishment of emotionality. Adult LPS-mice exhibited hyperactivity during the FST that was accompanied by increased doublecortin immunoreactivity in the dorsal and ventral hippocampus, reflecting enhanced immature neuronal differentiation. The current results demonstrate that an early immune challenge impacts the developing CNS leading to enhanced emotional-reactivity. Altered serotonergic neurocircuitry and adult hippocampal neurogenesis may underlie behavioural abnormalities. The current body of work demonstrates a preeminent role for early-life immune disturbance in psychopathology and advances understanding of how immune-brain signalling impacts the developing CNS and confers risk for later disease. </p> / Thesis / Doctor of Philosophy (PhD)

Abstract Student-athletes are viewed as the epitome of health due to their physical appearance and talent set; however, it is their psychological health that needs significant attention (Etzel, 2006). Psychosocial stressors such as the pressures and demands of being a student and athlete as well as the demands and expectations of the coach have significant impact on the student-athlete’s mental health and well-being (Beauchemin, 2014; Cleary et al., 2011; Lafrenière et al., 2011; Mageau & Vallerand, 2003; Watson, 2005). The purpose of this research is to investigate any correlation between student-athletes’ perceptions of coaching leadership behaviors and the symptoms associated with disorders such as anxiety, depression, suicidality, and substance abuse. The Leadership Scale for Sport (Chelladurai & Saleh, 1980) and the Symptom Assessment Measure instruments are used in this study. An exploratory analysis determined the reliability and construct validity of the instruments. Thirty-three student-athletes from a non-football Division I university engaged in the study, with twenty-eight completing some or all portions of study. All participants are between the ages of eighteen and twenty-four. A linear regression analysis demonstrated no relation between the independent variable, student-athlete perception of coaching leadership behaviors and the dependent variable, symptoms associated with anxiety, depression, suicidal behavior, and substance abuse mental health disorders, (F=.52, p=.49, R2=.061, and Beta coefficient was -0.248). Gender differences is not determined due to the skewed sample consisting of eighty five percent female and fifteen percent male. Though the linear regression analysis indicates no relation between the dependent and independent variable, supplemental contextualization was given to additional questions asked on the Symptoms Assessment Measure. These findings provide evidence that student-athletes perceive that their coach’s leadership behaviors do have influence on their mental health. This reinforces reports that coaches do wield power over their athletes and their influence is related to student-athletes’ psychological well-being (Horn, 2008; Locke et al., 2012; Stebbings et al., 2012).

Made available in DSpace on 2014-12-17T15:37:21Z (GMT). No. of bitstreams: 1 IsabellaMOP_DISSERT.pdf: 1986488 bytes, checksum: 1f1b995fa77d662628cf94f2e167faf0 (MD5) Previous issue date: 2014-05-09 / Conselho Nacional de Desenvolvimento Cient?fico e Tecnol?gico / Lithium (Li) is the first choice to treat bipolar disorder, a psychiatric illness characterized by mood oscillations between mania and depression. However, studies have demonstrated that this drug might influence mnemonic process due to its neuroprotector, antiapoptotic and neurogenic effects. The use of Li in the treatment of cognitive deficits caused by brain injury or neurodegenerative disorders have been widely studied, and this drug shows to be effective in preventing or even alleviating the memory impairment. The effects of Li on anxiety and depression are controversial and the relationship of the effects of lithium on memory, anxiety and depression remain unknown. In this context, this study aims to: evaluate the effects of acute and chronic administration of lithium carbonate in aversive memory and anxiety, simultaneously, using the plus maze discriminative avoidance task (PMDAT); test the antidepressant effect of the drug through the forced swimming test (FS) and analyze brainderived neurotrophic factor (BDNF) expression in structures related to memory and emotion. To evaluation of the acute effects, male Wistar rats were submitted to i.p. administration of lithium carbonate (50, 100 or 200 mg/kg) one hour before the training session (PMDAT) or lithium carbonate (50 or 100 mg/kg) one hour before the test session (FS). To evaluation of the chronic effects, the doses administered were 50 or 100 mg/kg or vehicle once a day for 21 days before the beginning of behavioral tasks (PMDAT and FS). Afterwards, the animals were euthanized and their brains removed and submitted to immunohistochemistry procedure to quantify BDNF. The animals that received acute treatment with 100 and 200 mg/kg of Li did not discriminated between the enclosed arms (aversive and non-aversive) in the training session of PMDAT, showing that these animal did not learned the task. This lack of discrimination was also observed in the test session, showing that the animals did not recall the aversive task. We also observed an increased exploration of the open arms of these same groups, indicating an anxiolytic effect. The same groups showed a reduction of locomotor activity, however, this effect does not seem to be related with the anxiolytic effect of the drug. Chronic treatment with Li did not promote alterations on learning or memory processes. Nevertheless, we observed a reduction of open arms exploration by animals treated with 50 mg/kg when compared to the other groups, showing an anxiogenic effect caused by this dose. This effect it is not related to locomotor alterations since there were no alterations in these parameters. Both acute and chronic treatment were ineffective in the FS. Chronic treatment with lithium was not able to modify BDNF expression in hippocampus, amygdala and pre-frontal cortex. These results suggest that acute administration of lithium promote impairments on learning in an aversive task, blocking the occurrence of memory consolidation and retrieval. The reduction of anxiety following acute treatment may have prevented the learning of the aversive task, as it has been found that optimum levels of anxiety are necessary for the occurrence of learning with emotional context. With continued, treatment the animals recover the ability to learn and recall the task. Indeed, they do not show differences in relation to control group, and the lack of alterations on BDNF expression corroborates this result. Possibly, the regimen of treatment used was not able to promote cognitive improvement. Li showed acute anxiolytic effect, however chronic administration 4 promoted the opposite effect. More studies are necessary to clarify the potential beneficial effect of Li on aversive memory / L?tio (Li) ? o f?rmaco de escolha para o tratamento do transtorno bipolar, doen?a psiqui?trica caracterizada por oscila??es de humor entre mania e depress?o. Entretanto, estudos mostram que essa droga pode ter influ?ncia sobre os processos mnem?nicos devido a seu car?ter neuroprotetor, antiapopt?tico e neurog?nico. O emprego no l?tio para o tratamento de d?ficits cognitivos provocados por les?es cerebrais ou doen?as neurodegenerativas vem sendo amplamente estudado, visto que esse f?rmaco mostra-se capaz de prevenir ou at? mesmo aliviar preju?zos na mem?ria. Os efeitos do Li na ansiedade e depress?o s?o controversos e a rela??o entre os efeitos do Li na mem?ria, ansiedade e depress?o s?o ainda desconhecidos. Neste contexto, os objetivos deste estudo foram: avaliar os efeitos da administra??o aguda e cr?nica de carbonato de l?tio na mem?ria aversiva e ansiedade, simultaneamente, utilizando a esquiva discriminativa no labirinto em cruz elevado (ED); testar o efeito antidepressivo do f?rmaco atrav?s do teste do nado for?ado (NF); avaliar a express?o de fator neurotr?fico derivado do enc?falo (BDNF) em estruturas relacionadas com mem?ria e emo??o. Para a avalia??o do efeito agudo, ratos Wistar machos foram submetidos ? administra??o intraperitoneal de carbonato de l?tio 50, 100 ou 200 mg/kg uma hora antes do treino (ED) ou carbonato de l?tio 50 ou 100 mg/kg uma hora antes do teste (NF). Para a avalia??o cr?nica, foram administradas as doses de 50 ou 100 mg/kg ou ve?culo por 21 dias antes do in?cio das tarefas comportamentais (ED e NF). Ap?s o t?rmino dessas tarefas, os animais foram eutanasiados e seus enc?falos removidos para realiza??o de imunohistoqu?mica para quantificar BDNF. Os animais que receberam tratamento agudo com Li nas doses de 100 e 200 mg/kg n?o demonstraram discrimina??o entre os bra?os fechados (aversivo e n?o-aversivo) na sess?o treino da ED, mostrando que esses animais n?o aprenderam a tarefa. Essa aus?ncia na discrimina??o foi observada tamb?m na sess?o teste, mostrando que n?o houve evoca??o da mem?ria aversiva. Foi ainda observado um aumento da explora??o dos bra?os abertos para essas mesmas doses, apontando um efeito ansiol?tico do f?rmaco. Os mesmos grupos apresentaram ainda uma redu??o na atividade locomotora, no entanto, esse efeito parece n?o estar relacionado com o efeito ansiol?tico do f?rmaco. O tratamento cr?nico com l?tio n?o promoveu altera??es nos processos de aprendizado e mem?ria. No entanto, foi observado uma redu??o da explora??o dos bra?os abertos pelos animais tratados com a dose de 50 mg/kg em rela??o aos outros grupos, mostrando um efeito ansiog?nico causado pelo tratamento cr?nico. Esse efeito n?o est? relacionado a altera??es locomotoras, visto que n?o foi detectado altera??es nesses par?metros. Ambos os tratamentos (agudo e cr?nico) foram ineficazes em demonstrar o efeito antidepressivo do l?tio na tarefa do NF. O tratamento cr?nico com l?tio tamb?m n?o foi capaz de alterar a express?o de BDNF no hipocampo, am?gdala e c?rtex pr?-frontal. Esses resultados sugerem que a administra??o aguda de l?tio promove preju?zos no aprendizado em uma tarefa aversiva, impedindo a ocorr?ncia de consolida??o e evoca??o da mem?ria. A redu??o da ansiedade no tratamento agudo pode ter impedido o aprendizado da tarefa aversiva, visto que j? foi verificado que n?veis adequados de ansiedade s?o necess?rios para que ocorra aprendizado com contexto 2 emocional. Com a continuidade do tratamento os animais recuperam a capacidade de aprender e evocar a tarefa, mas n?o apresentam altera??es em rela??o ao grupo controle e a aus?ncia de altera??o na express?o de BDNF corrobora esse resultado. Possivelmente, o regime de tratamento utilizado n?o foi capaz de promover melhora cognitiva nos animais. O l?tio demonstrou efeito ansiol?tico agudo, todavia a administra??o cr?nica promoveu efeito oposto. Mais estudos s?o necess?rios para esclarecer o potencial efeito ben?fico do l?tio sobre a mem?ria

Hintergrund: Schwindel ist ein häufig vorgetragenes Symptom beim Hausarzt. Seine erhöhte Vergesellschaftung mit Ängstlichkeit und Depressivität ist aber bisher zu wenig untersucht worden, ebenso wenig ist dieser Zusammenhang Gegenstand der hausärztlichen Behandlung von Schwindelpatienten. Zielstellung: Kommen unbekannte psychische Hintergründe in Kombination mit Schwindel im hausärztlichen Patientengut häufiger vor als ohne Schwindel? Ergeben sich daraus als Konsequenz unterschiedliche Versorgungsformen durch den Hausarzt? Wie verhält es sich mit deren subjektiven Gesundheitszustand, dem Erfolg der hausärztlichen Behandlung, dem ihnen entgegengebrachten Verständnis und der Häufigkeit der Arztbesuche der Betroffenen? Studiendesign: Prospektive Multicenterstudie in der Allgemeinpraxis Untersuchungsregion: Zehn Hausarztpraxen in Halle a.d. Saale und Nordsachsen/ Leipzig im städtischen und ländlichen Einzugsbereich, welche von Fachärzten für Allgemeinmedizin geführt wurden. Methodik: Die Studie untersuchte insgesamt 590 zufällig am Untersuchungstag eintreffende Patienten in jeweils einer von insgesamt zehn Hausarztpraxen. Die Ausprägung von Schwindelbeschwerden und eventuell vorhandene Merkmale von Ängstlichkeit und Depressivität beim jeweiligen Patienten wurden mit Elementen des Gießener Beschwerdebogens 24 und der Hospital Anxiety and Depression Scale (deutsche Version) untersucht. Ergebnisse: Die Patienten wurden in eine Gruppe mit relevanten (29,7%, n=175) und in eine Gruppe ohne relevante Schwindelbeschwerden (70,3%, n=408) eingeteilt (Cut off >=8 nach GBB 24). Die Gruppe mit relevantem Schwindel wies häufiger Merkmale für Ängstlichkeit (p<0,001) und Depressivität (p<0,001) in allen Altersgruppen auf, zeigte sich unzufriedener mit ihrem Behandlungserfolg (p=0,004), schätzte ihren aktuellen Gesundheitszustand schlechter ein (p<0,001) und konsultierte ihren Hausarzt in den letzten zwölf Monaten häufiger (p=0,020). Sie stellten sich nach ICPC-2 häufiger wegen neurologischer (p<0,001), psychologischer (p=0,026) und unspezifischer Beschwerden (p<0,001) vor. Sie erhielten mehr Diagnosen aus den ICD-10-Kapitel V (Psychische und Verhaltensstörungen) (p=0,030). Diese Patienten waren nach HADS-D auch häufiger psychisch auffällig (p<0,001). Relevanter Schwindel kam bei Frauen aller Altersgruppen häufiger vor als bei Männern (p<0,001). Dennoch ergaben sich keine Behandlungsunterschiede durch die Hausärzte zwischen beiden Gruppen (p=0,101 bis 0,930 je nach ärztlicher Maßnahme). Schlussfolgerung: Schwindelpatienten weisen häufger Ängstlichkeit und Depressivität auf, welche den Schwindel unterhalten. Dieser Zusammenhang sollte in der Sprechstunde bedacht werden. Die psychischen Hintergründe sollten vom Hausarzt aufgedeckt und behandelt werden. Dadurch könnte der Schwindel und damit der subjektive Gesundheitszustand der betroffenen Patienten verbessert und die Inanspruchnahme des Gesundheitswesens verringert werden.

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Background. Previous research suggests that individuals experiencing DSM-IV panic attacks (PA) are at increased risk for various forms of psychopathology, including anxiety, depressive and substance use disorders. However, little is known regarding whether the sole occurrence of fearful spells (FS-only; distressing spells of anxiety with less than four panic symptoms and/or lacking crescendo in symptom onset) similarly elevates the risk for subsequent psychopathology and could therefore be promising to identify high-risk groups for targeted preventive interventions. Thus, the current dissertation thesis aims to examine (a) whether FS-only predict incident mental disorders in addition to full-blown PA and whether their associations with subsequent psychopathology differ from those obtained for PA, (b) whether FS-only, PA, and panic disorder (PD) share similar etiologies, (c) which characteristics of initial FS/PA and other risk factors predict a progression to more severe panic pathology and other mental disorders, and (d) whether help-seeking/potential treatment in individuals with panic alters the risk for subsequent psychopathology. Methods. A representative community sample of adolescents and young adults (N=3021, aged 14-24 at baseline) was prospectively followed up in up to three assessment waves over a time period of up to 10 years. FS-only, PA, PD, and other mental disorders were assessed at each assessment wave using the DSM-IV-M-CIDI. Additional modules/questionnaires were used to assess characteristics of initial FS/PA (T1/T2), potential risk factors, and help-seeking/potential treatment. Logistic regressions were applied to test associations (Odds Ratios, OR) of FS-only and PA at baseline with incident mental disorders at follow-up as well as respective interactive effects with help-seeking at baseline. Associations (Hazard Ratios, HR) of putative risk factors with the onset of panic pathology (FS-only, PA, and PD) or the onset of subsequent anxiety/depressive vs. substance use disorders in those with panic pathology (aggregated data across assessment waves) were estimated with Cox regressions. Multinomial logistic regressions were used to test associations of initial FS/PA characteristics (aggregated from T1 and T2) with PA and PD (lifetime incidences aggregated across assessment waves). Results. FS-only at baseline predicted incident anxiety and depressive disorders at follow-up (OR 1.59-4.36), while PA at baseline predicted incident anxiety, depressive, and substance use disorders at follow-up (OR 2.08-8.75; reference group: No FS/PA). Merely any anxiety disorder (OR=3.26) and alcohol abuse/dependence (OR=2.26) were significantly more strongly associated with PA than with FS-only. Female sex, parental anxiety disorders, parental depressive disorders, behavioral inhibition, harm avoidance, lower coping efficacy, and parental rejection predicted FS-only, PA, and PD (HR 1.2-3.0), whereas the associations with other risk factors partially differed for FS-only, PA, and PD and tended to be more pronounced for PA and PD than for FS-only. Alcohol consumption, use of drugs/medication, and physical illness as perceived reasons for the initial FS/PA were associated with the occurrence of full-blown PA (without PD, OR 2.46-5.44), while feelings of anxiety/depression and having always been anxious/nervous as perceived reasons for the initial FS/PA, appraising the initial FS/PA as terrible and long-term irritating/burdensome, subsequent feelings of depression, avoidance of situations/places, and consumption of medication, alcohol, or drugs were associated with the development of PD (OR 2.64-4.15). A longer duration until “feeling okay again” was associated with both PA and PD (OR 1.29-1.63 per category). Moreover, partially different risk constellations in subjects with panic pathology (FS/PA/PD) predicted the onset of subsequent anxiety/depressive vs. substance use disorders. Panic pathology (FS/PA) and help-seeking/potential treatment at baseline interacted on predicting incident PD (OR=0.09) and depression (OR=0.22) at follow-up in a way that panic pathology only predicted these disorders in individuals not seeking help at baseline. Conclusions. Findings suggest that individuals with FS-only are at similar risk of developing subsequent psychopathology compared to individuals with full-blown PA. Specific initial FS/PA characteristics and additional risk factors may be used to identify sub-groups of individuals with panic pathology, which are at particular risk of progressing to more severe panic pathology or other mental disorders and might therefore profit from supplemental outcome-related preventive interventions in addition to panic-specific treatment. Future research may replicate the current findings and test the efficacy of targeted preventive interventions in panickers at elevated risk for PD and other forms of psychopathology.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96 / Theoretischer Hintergrund. Auf Grundlage früherer Forschungsbefunde ist anzunehmen, dass Personen mit DSM-IV-Panikattacken (PA) ein erhöhtes Risiko für zahlreiche psychische Störungen, einschließlich Angst-, depressiver und Substanzstörungen, aufweisen. Unklar ist jedoch, ob das alleinige Auftreten von Fearful Spells (FS-only, Angstanfälle mit weniger als vier Paniksymptomen und/oder fehlendem Crescendo in der Symptomentwicklung) das Risiko für Psychopathologie in ähnlicher Weise erhöht und hilfreich sein könnte, um Hochrisikogruppen für Präventivinterventionen zu identifizieren. Innerhalb der vorliegenden Dissertation wird daher untersucht, (a) ob FS-only zusätzlich zu PA inzidente psychische Störungen vorhersagen und ob sich Unterschiede in den Assoziationen von FS-only vs. PA mit nachfolgender Psychopathologie ergeben, (b) ob FS-only, PA und Panikstörung (PS) ähnliche Ätiologien teilen, (c) welche Merkmale initialer FS/PA und welche anderen Risikofaktoren die Entwicklung schwerer Panikpathologie und weiterer psychischer Störungen vorhersagen und (d) ob Hilfesuchverhalten/potenzielle Behandlung bei Personen mit Panik das Risiko für nachfolgende Psychopathologie verändert. Methodik. Eine repräsentative Bevölkerungsstichprobe Jugendlicher und junger Erwachsener (N=3021, 14-24 Jahre zur Baseline-Erhebung) wurde in bis zu drei Erhebungswellen über einen Zeitraum von bis zu 10 Jahren untersucht. FS-only, PA, PS und andere psychische Störungen wurden zu jeder Erhebungswelle mithilfe des DSM-IV-M-CIDI erfasst. Merkmale initialer FS/PA (T1/T2), mögliche Risikofaktoren sowie Hilfesuchverhalten/potenzielle Behandlung wurden mit weiteren Modulen und Fragebögen erhoben. Mithilfe logistischer Regressionen wurden Assoziationen (Odds Ratios, OR) von FS-only und PA zu Baseline mit inzidenten psychischen Störungen zum Follow-Up sowie diesbezügliche Interaktionen mit Hilfesuchverhalten zu Baseline getestet. Zusammenhänge zwischen möglichen Risikofaktoren und dem Auftreten von Panikpathologie (FS-only, PA und PS) bzw. nachfolgender Angst-/depressiver und Substanzstörungen bei Personen mit Panikpathologie (Verwendung von über die Erhebungswellen hinweg aggregierter Daten) wurden mithilfe von Cox-Regressionen geschätzt. Multinomiale logistische Regressionen wurden genutzt, um Assoziationen von Merkmalen initialer FS/PA (aggregiert über T1 und T2) mit PA und PS (über die Erhebungswellen hinweg aggregierte Lebenszeitinzidenzen) zu erfassen. Ergebnisse. FS-only zu Baseline sagten inzidente Angst- und depressive Störungen zum Follow-Up vorher (OR 1.59-4.36), wohingegen PA zu Baseline inzidente Angst-, depressive und Substanzstörungen zum Follow-Up vorhersagten (OR 2.08-8.75; Referenzkategorie: Keine FS/PA). Lediglich irgendeine Angststörung (OR=3.26) und Alkoholmissbrauch/-abhängigkeit (OR=2.26) waren signifikant stärker mit PA als mit FS-only assoziiert. Weibliches Geschlecht, elterliche Angst- und depressive Störungen, Verhaltenshemmung, Schadensvermeidung, geringere Coping-Erwartung und elterliche Zurückweisung sagten FS-only, PA und PS vorher (HR 1.2-3.0), während sich teils unterschiedliche Assoziationen anderer Risikofaktoren mit FS-only, PA und PS ergaben, die tendenziell stärker für PA und PS als für FS-only waren. Alkoholkonsum, Drogen-/Medikamentengebrauch und körperliche Erkrankungen als wahrgenommene Gründe für die initiale FS/PA waren mit dem Auftreten vollständiger PA assoziiert (ohne PS; OR 2.46-5.44), während Gefühle von Angst/Depression und die Einschätzung schon immer ängstlich/nervös gewesen zu sein als wahrgenommene Gründe für die initiale FS/PA, die Bewertung der initialen FS/PA als schrecklich und langfristig verunsichernd/belastend, nachfolgende Gefühle von Niedergeschlagenheit, Vermeidung von Situationen/Orten und Konsum von Medikamenten, Alkohol oder Drogen mit der Entwicklung von PS assoziiert waren (OR 2.64-4.15). Eine längere Dauer bis sich die betroffene Person wieder vollständig in Ordnung fühlte war sowohl mit PA als auch mit PS assoziiert (OR 1.29-1.63 pro Kategorie). Weiterhin sagten teils unterschiedliche Risikokonstellationen bei Personen mit Panikpathologie (FS/PA/PS) die nachfolgende Entstehung von Angst-/depressiven und Substanzstörungen vorher. Panikpathologie (FS/PA) und Hilfesuchverhalten/potenzielle Behandlung zu Baseline interagierten bei der Vorhersage von inzidenter PS (OR=0.09) und Depression (OR=0.22) zum Follow-Up; d.h. das Vorhandensein von Panikpathologie sagte diese Störungen nur bei Personen ohne, nicht aber bei Personen mit Hilfesuchverhalten zu Baseline vorher. Schlussfolgerungen. Die vorliegenden Ergebnisse implizieren, dass Personen mit FS-only im Vergleich zu Personen mit vollständigen PA ein ähnliches Risiko für die Entwicklung nachfolgender Psychopathologie aufweisen. Spezifische Merkmale initialer FS/PA und zusätzliche Risikofaktoren könnten zur Identifikation von Sub-Gruppen von Personen mit Panik genutzt werden, die sich durch ein besonderes Risiko für schwergradige Panikpathologie und andere psychische Störungen auszeichnen und demzufolge von Outcome-bezogenen Präventionen (ergänzend zu Panik-spezifischer Intervention) profitieren könnten. Zukünftige Studien sollten die vorliegenden Befunde replizieren und die Effektivität gezielter Präventivinterventionen bei Personen mit erhöhtem Risiko für PS und andere psychische Störungen testen.:CONTENT 0 Synopsis 10 1 Introduction 13 1.1 Current challenges in clinical psychology 13 1.2 Psychological models of mental disorders 13 1.3 Diagnostic approaches to psychopathology 15 1.4 Methodological issues 16 1.5 Preventive and early treatment interventions 17 2 Panic pathology 18 2.1 Definitions 18 2.2 Epidemiology 19 2.3 Etiology 20 2.4 Physiological, neurobiological, and genetic findings 21 2.5 Unresolved issues 22 3 Aims 24 4 Methods 26 5 Study I: Associations of fearful spells and panic attacks with incident anxiety, depressive, and substance use disorders: A 10-year prospective-longitudinal community study of adolescents and young adults 27 5.1 Abstract 27 5.2 Introduction 27 5.3 Materials and methods 28 5.4 Results 30 5.5 Discussion 35 6 Study II: Characteristics of initial fearful spells and their associations with DSM-IV panic attacks and panic disorder in adolescents and young adults from the community 37 6.1 Abstract 37 6.2 Introduction 37 6.3 Materials and methods 38 6.4 Results 41 6.5 Discussion 43 7 Study III: Risk factors for fearful spells and panic: A 10-year prospective-longitudinal study among adolescents and young adults 47 7.1 Abstract 47 7.2 Introduction 47 7.3 Materials and methods 49 7.4 Results 52 7.5 Discussion 60 8 Study IV: Does help-seeking alter the risk for incident psychopathology in adolescents and young adults with and without fearful spells or panic attacks? Findings from a 10-year prospective-longitudinal community study 63 8.1 Abstract 63 8.2 Introduction 63 8.3 Materials and methods 64 8.4 Results 66 8.5 Discussion 70 9 General discussion 73 9.1 Summary and discussion of main findings 73 9.2 Preventive interventions among individuals with panic pathology 75 9.3 Research implications 77 10 Conclusions 78 11 References 79 12 Appendix 94 12.1 Acknowledgements 94 12.2 Erklärung zu den Eigenanteilen an einzelnen Publikationen 95 12.3 Eigenständigkeitserklärung 96

Indiana University-Purdue University Indianapolis (IUPUI) / It has traditionally been posited that women show a "telescoped" development of alcohol use disorders (Kuhn, 2011). In particular, a number of clinical studies support striking sex differences in the progression from initial use of alcohol to dependence on the compound; with women showing a faster progression through landmark events associated with the development of alcohol addiction (Randall et al., 1999). However, recent studies have challenged this tenet (Keyes et al., 2010). The work presented herein was designed to determine whether females are indeed more vulnerable to the development of behavioral maladaptations following binge drinking and whether sex differences in GABA(A) receptor regulation might underlie this vulnerability. Using a mouse model of binge drinking this dissertation established that, compared to males, females escalate their binge drinking at a faster rate and maintain altered responsivity to the locomotor effects of alcohol after extended abstinence from binge drinking. Female mice also displayed significant increases in ethanol preference and intake in a continuous, two-bottle choice protocol following a shorter history of binge drinking than males. The final goal was to determine if binge drinking results in unique patterns of anxiety- or depressive-like symptoms in males and females and whether these behaviors would be associated with the dimorphic regulation of GABAA receptor subunits across the prefrontal cortex and hippocampus. Male binge drinkers displayed anxiety-like behavior during early withdrawal that dissipated after 2 weeks of abstinence. There were no significant changes in the expression of delta or gamma2 GABAA receptor subunit mRNA at this time point in the regions analyzed. Females also showed temporary anxiety-like behavior during early withdrawal from binge drinking. Additionally, females displayed significant depressive-like behavior after 2 weeks of abstinence from binge drinking. In particular, diestrus-phase females displayed significantly greater immobility in the forced-swim test after ethanol exposure and no longer maintained the reduced swim-time behavior associated with this phase of the cycle at baseline (when compared to the estrus-phase). qPCR analysis of hippocampal tissues from diestrus females supported a significant reduction in expression of gamma2 GABA(A) subunit mRNA after binge drinking. This effect was not noted for RNA isolated from hippocampal tissues taken during the estrus phase of bingers. These final data suggest possible interaction of estrous-cycle and binge drinking history that may result in the unique expression of deficits following binge drinking for females. Taken together, this work supports sex and estrous dependent effects of binge drinking on behavior and gene regulation.