In dieser Arbeit wurden die Auswirkungen der Herzinsuffizienz und ihrer Komorbiditäten Hypertonie und Diabetes mellitus auf Morphologie und Histologie des Hippocampus am Mausmodell untersucht. / In this paper we studied the effects of heart failure and its comorbidities hypertension and diabetes mellitus on morphology and histology of the hippocampus in the mouse model.

Einleitung. Personen mit Deletionssyndrom 22q11.2 (DS22q11) weisen eine hohe Prävalenz von Angststörungen auf. Ein Faktor, der in der Entstehung von Angststörungen diskutiert wird, ist eine veränderte Angstgeneralisierung. Es konnte gezeigt werden, dass Menschen mit bestimmten Angsterkrankungen eine stärkere Angstgeneralisierung aufweisen als gesunde Vergleichspersonen. Dies kann experimentell untersucht werden, indem die Übertragung einer konditionierten Angstreaktion auf andere Stimuli gemessen wird, welche dem konditioniertem Stimulus ähneln, aber nie zusammen mit dem unkonditioniertem Stimulus präsentiert wurden. Auf Grund der hohen Prävalenz von Angststörungen bei DS22q11 wurde in der vorliegenden Forschungsarbeit die Hypothese aufgestellt, dass Menschen mit DS22q11 eine ausgeprägtere Angstgeneralisierung aufweisen als gesunde Kontrollproband*innen. Menschen mit einer gesteigerten Trait-Angst neigen dazu Situationen eher als bedrohlich einzuschätzen. Eine erhöhte Trait-Angst geht wiederum mit einer stärkeren Angstgeneralisierung einher. Dieser Befund wurde auch bei Personen mit DS22q11 erwartet. Darauf aufbauend überprüft die hier vorgelegte Arbeit die Hypothese, dass die Trait-Angst bei Personen mit DS22q11 ebenso wie bei den Kontrollproband*innen positiv mit der Angstgeneralisierung korreliert. Methoden. Es wurden Proband*innen mit DS22q11 rekrutiert und mit gesunden Kontrollproband*innen nach Alter und Geschlecht gematcht. Für die Untersuchung der Angstgeneralisierung wurde auf ein bereits etabliertes Konditionierungs- und Generalisierungsparadigma zurückgegriffen, in dem weibliche Gesichter als Stimuli zum Einsatz kommen. Die Trait-Angst wurde mit dem State-Trait-Angstinventar erhoben. Ergebnisse. In der Gruppe der Kinder und Jugendlichen zeigten sich keine signifikanten Unterschiede hinsichtlich der Angstgeneralisierung zwischen den Proband*innen mit DS22q11 und den Kontrollproband*innen. Dies war ebenso bei den Erwachsenen der Fall, jedoch fanden sich hier Anhaltspunkte für eine mögliche stärkere Angstgeneralisierung seitens der Proband*innen mit DS22q11. In Bezug auf die Trait-Angst konnte bei den Kindern und Jugendlichen weder in der Gruppe mit DS22q11 noch in der Kontrollgruppe eine Korrelation mit der Angstgeneralisierung festgestellt werden. Bei den Erwachsenen hingegen korrelierte sowohl bei den Proband*innen mit DS22q11 als auch bei den Kontrollproband*innen die Trait-Angst positiv mit der Angstgeneralisierung. Des Weiteren erbrachte die Studie Hinweise darauf, dass die Eignung des verwendeten Paradigmas zur Konditionierung von Menschen mit DS22q11 limitiert ist. Diskussion. Die Beobachtung, dass in der vorliegenden Studie Kinder und Jugendliche mit DS22q11 keine stärkere Angstgeneralisierung als ihre gesunden Altersgenossen zeigten, lässt die Interpretation zu, dass der Angstgeneralisierung im Kindesalter keine bedeutende Rolle bei der Entstehung von Angststörungen zukommt. Jedoch wurden bei den eingeschlossenen Personen mit DS22q11 vorrangig spezifische Phobien festgestellt, welche laut Studienlage eher nicht mit einer gesteigerten Angstgeneralisierung einhergehen. Die erwachsenen Personen mit DS22q11 wiesen in dieser Studie geringere Raten von Angsterkrankungen auf als in der Literatur beschrieben, wodurch fehlende signifikante Unterschiede in der Angstgeneralisierung gegenüber den Kontrollproband*innen erklärt werden könnten. Zudem wurden im Erwachsenenalter ausschließlich generalisierte Angststörungen festgestellt, bei welchen unklar ist, ob eine gesteigerte Angstgeneralisierung vorliegt. Schließlich könnten die Ergebnisse auch dafür sprechen, dass bei DS22q11 andere Pathomechanismen als die Übergeneralisierung von Angst bei der Entwicklung von Angststörungen im Vordergrund stehen. Überdies könnten mögliche Defizite in der Gesichtsverarbeitung bei Menschen mit DS22q11 die Ergebnisse beeinflusst haben und die Eignung des Paradigmas für diese Population in Frage stellen. Dass die Trait-Angst bei den Kindern und Jugendlichen nicht mit der Angstgeneralisierung korrelierte, könnte darauf zurückzuführen sein, dass die Angstgeneralisierung in dieser Altersgruppe eventuell physiologischerweise schon so stark ist, dass eine erhöhte Trait-Angst diese nicht weiter steigern „kann“. Bei den Erwachsenen stimmt das Ergebnis, dass die Trait-Angst positiv mit der Angstgeneralisierung korrelierte, mit der überwiegenden Mehrheit der Literatur überein. Da sich die Gruppen diesbezüglich nicht signifikant voneinander unterschieden, kann davon ausgegangen werden, dass das Vorliegen von DS22q11 den Einfluss der Trait-Angst auf die Angstgeneralisierung nicht verändert. / Introduction. People with 22q11.2 deletion syndrome (DS22q11) have a high prevalence of anxiety disorders. One factor discussed in the development of anxiety disorders is an altered fear generalization. It has been shown that people with certain anxiety disorders exhibit greater fear generalization than healthy comparison subjects. This can be studied experimentally by measuring the transfer of a conditioned fear response to stimuli that are similar to the conditioned stimulus but have never been presented together with the unconditioned stimulus. Based on the high prevalence of anxiety disorders in DS22q11, it was hypothesized that individuals with DS22q11 would exhibit stronger fear generalization than healthy controls. People with high trait anxiety tend to assess situations as more threatening. Increased trait anxiety is in turn associated with stronger fear generalization. This finding was also expected in individuals with DS22q11. Based on this, the thesis presented here tests the hypothesis that trait anxiety correlates positively with fear generalization in both individuals with DS22q11 and control subjects. Methods. Individuals with DS22q11 were compared with age- and gender-matched healthy controls. For the study of fear generalization, an established conditioning and generalization paradigm with female faces as stimuli was used. Trait anxiety was assessed using the State-Trait Anxiety Inventory. Results. In the group of children and adolescents, there were no significant differences in fear generalization between the subjects with DS22q11 and control subjects. This was also the case for the adults, but there were signs for a possible stronger fear generalization in the group with DS22q11. With regard to trait anxiety, no correlation with fear generalization was found in children and adolescents in either the group with DS22q11 or the control group. In adults, however, trait anxiety correlated positively with fear generalization in both subjects with DS22q11 and control subjects. Furthermore, the study yielded evidence that the suitability of the paradigm for conditioning individuals with DS22q11 is limited. Discussion. The observation that in the present study children and adolescents with DS22q11 did not show stronger fear generalization than their healthy peers suggests that fear generalization may not play a pivotal role in the development of anxiety disorders during childhood. However, the subjects with DS22q11 were primarily found to have specific phobias, which tend not to be associated with enhanced fear generalization according to the literature. The adult subjects with DS22q11 showed lower rates of anxiety disorders in this study than described in the literature, which could explain the lack of significant differences in fear generalization compared to control subjects. In addition, only generalized anxiety disorders were found in the adult subjects, in which it is unclear whether heightened fear generalization is present. Finally, the results may also suggest that pathomechanisms other than overgeneralization of fear are decisive in the development of anxiety disorders in DS22q11. Moreover, possible deficits in face processing in individuals with DS22q11 may have influenced the results and call into question the suitability of the paradigm for this population. One reason why trait anxiety does not correlate with fear generalization in children and adolescents lies in the supposition that fear generalization in this age group may already be so strong physiologically that high trait anxiety “cannot” increase it further. In adults, the finding that trait anxiety correlates positively with fear generalization is consistent with the majority of the literature, and since the groups did not differ significantly in this regard, it can be assumed that the presence of DS22q11 does not alter the influence of trait anxiety on fear generalization.

In der vorliegenden Studie wurde eine modifizierte Version des Eriksen Flanker Task verwendet, um ereigniskorrelierte Potentiale (ERPs) aufzuzeichnen und zu beurteilen, ob diese nach Richtigantworten, Falschantworten sowie Richtigantworten mit negativem Feedback ("PC-Fehlern") auftreten. Die bisher beschriebenen Fehlerpotentiale, d.h. die error-related negativity (negativer Peak nach Falschantworten) sowie die error positivity (positiver Peak nach Falschantworten), waren grundsätzlich nach Falschantworten zu beobachten, aber traten nur teilweise nach Richtigantworten mit negativem Feedback auf. Zudem trat eine späte Positivierung ausschließlich im letzteren Fall auf, welche eine bewußte Verarbeitung der unerwarteten Ereignisse widerspiegeln könnte. Diese Ergebnisse widersprechen der Vorstellung, dass die ERN/Ne die Aktivität eines generellen Fehlererkennungssystems des menschlichen Gehirns repräsentiert. / In the present study, a modified version of the Eriksen Flanker Task has been used to study event-related potentials (ERPs) elicited by correct responses, response errors, and invalid negative response feedback following correct button presses ("PC-error trials"). Conventional error potentials (error-related negativity (ERN/Ne); error-positivity (Pe)) were generally observed after incorrect button presses but only partially after negative response feedback in PC-error trials. Furthermore, a late positive deflection occured specifically after PC-errors (late positivity (Pl)), which might reflect a conscious processing of these unexpected events. These results imply some restrictions for the notion that the ERN/Ne reflects the activity of a general and "generic" neural error-detection system in the human brain.

Background. Cross-sectional findings in community surveys of adults suggest that adolescent anxiety disorders are strong predictors of the subsequent onset of alcohol use, abuse and dependence. However, prospective data that follow a sample of adolescents into adulthood are needed to confirm these associations. Method. Baseline and 4-year follow-up data from the EDSP-Study, a prospective community survey of 3021 (2548 at follow-up) adolescents and young adults aged 14 to 24 years at baseline carried out in Munich, were used. DSM-IV anxiety disorders, alcohol use and alcohol use disorders were assessed with the Munich-Composite-International-Diagnostic-Interview (M-CIDI). Multiple logistic regression analysis, controlling for age, gender, other mental disorders, substance use disorders and antisocial behaviour was used to study the associations of baseline anxiety disorders with the subsequent onset and course of alcohol use and alcohol disorders. Results. Baseline social phobia significantly predicts the onsets of regular use and hazardous use and the persistence of dependence. Panic attacks significantly predict the onsets of hazardous use and abuse as well as the persistence of combined abuse/dependence. Panic disorder significantly predicts the persistence of combined abuse/dependence. Other anxiety disorders do not significantly predict any of the outcomes. Conclusions. Panic and social phobia are predictors of subsequent alcohol problems among adolescents and young adults. Further studies are needed to investigate the underlying mechanisms and the potential value of targeted early treatment of primary panic and social phobia to prevent secondary alcohol use disorders.

Background. The proposed revisions of the ICD and DSM diagnostic systems have led to increased interest in evaluation of diagnostic criteria. This report focuses on the DSM-IV requirement that episodes of generalized anxiety disorder (GAD) must persist for at least 6 months. Community epidemiological data are used to study the implications of changing this requirement in the range 1–12 months for estimates of prevalence, onset, course, impairment, co-morbidity, associations with parental GAD, and sociodemographic correlates. Method. Data come from the US National Comorbidity Survey Replication (NCS-R), a US household survey carried out during 2001–2003. Version 3.0 of the WHO Composite International Diagnostic Interview (WMH-CIDI) was used to assess DSM-IV anxiety disorders, mood disorders, substance disorders, and impulse-control disorders. Results. Lifetime, 12-month, and 30-day prevalence estimates of DSM-IV GAD changed from 6·1%, 2·9%, and 1·8% to 4·2–12·7%, 2·2–5·5%, and 1·6–2·6% when the duration requirement was changed from 6 months to 1–12 months. Cases with episodes of 1–5 months did not differ greatly from those with episodes of [gt-or-equal, slanted]6 months in onset, persistence, impairment, co-morbidity, parental GAD, or sociodemographic correlates. Conclusions. A large number of people suffer from a GAD-like syndrome with episodes of <6 months duration. Little basis for excluding these people from a diagnosis is found in the associations examined here.

Theoretischer Hintergrund: Die diagnostischen Kriterien der Generalisierten Angststörung (GAS) und ihr Status als eigenständige psychische Störung waren lange umstritten. Inzwischen liegen neuere epidemiologische Daten vor, die ein präziseres Bild dieser Störung und ihrer Besonderheiten ermöglichen. Methode: Es wird ein systematischer Überblick zu Prävalenz, Verlauf und Komorbidität, zur Beeinträchtigung und zum Inanspruchnahmeverhalten sowie zur Spezifität des Kernsymptoms (Sorgen) erstellt. Ergebnisse: GAS ist eine häufige Störung, die im jungen Erwachsenenalter einsetzt, jedoch auch – anders als andere Angststörungen – hohe Inzidenzraten im mittleren Lebensalter aufweist. Der Verlauf ist eher chronisch. Trotz hoher Komorbidität lässt sich die Störung valide abgrenzen. Klinisch relevante Sorgen erweisen sich als störungsspezifisch. Die Beeinträchtigungen sind auch bei GAS-Patienten ohne Komorbidität beträchtlich. Schlussfolgerung: Der Forschungsstand spricht für die Bedeutung und Eigenständigkeit der Diagnose sowie für die stärkere Beachtung offener Forschungsfragen. / Background: The diagnostic criteria for generalized anxiety disorder (GAD) and its status as an independent mental disorder have been controversial. More recent epidemiological data provide a more precise picture of this disorder and its specific features. Methods: A systematic overview is given in regard to prevalence, course and comorbidity, impairment, and help-seeking behavior as well as to specificity of the core symptom (worries). Results: GAD is a frequent disorder with high incidence rates in middle-age groups, which are not seen in other anxiety disorders. Despite the high comorbidity GAD can be validly distinguished. Clinically relevant worries have been proven as specific for the disorder. The impairments are also considerable for patients without comorbid disorders. Conclusions: Research supports the independent status of GAD and the importance of this diagnosis. Unsolved questions are to be analyzed in future research.

Background and Objectives: To characterize the impact of pregabalin on sleep in patients with generalized anxiety disorder (GAD) and to determine whether the impact is a direct or an indirect effect, mediated through the reduction of anxiety symptoms. Methods: A post-hoc analysis of data from a randomized, double-blind, placebo- and active-controlled study in patients with GAD was conducted. Patients received pregabalin 300 mg/day, venlafaxine XR 75 mg/day or placebo for a week, followed by pregabalin 300-600 mg/day, venlafaxine XR 75-225 mg/day, or placebo for 7 weeks. Treatment effect on sleep was evaluated using the Medical Outcomes Study Sleep Scale. Anxiety symptoms were assessed with the Hamilton Anxiety Rating Scale. A mediation model was used to estimate separately for both treatment arms the direct and indirect treatment effects on sleep disturbance. Results: Compared with placebo (n = 128), treatment with pregabalin (n = 121) significantly reduced scores on the sleep disturbance subscale and Sleep Problems Index II at both week 4 and week 8, and the sleep adequacy subscale at week 8. Venlafaxine XR (n = 125) had no significant effect on these measures. The mediation model indicated that 53% of the total pregabalin effect on sleep disturbance was direct (p < 0.01) and 47% indirect, mediated through anxiety symptoms (p < 0.05). Conclusions: Pregabalin decreased sleep disturbance in patients with GAD both directly, and indirectly by reducing anxiety symptoms. Given the drug specificity of the results, this study provides evidence of an additional important pathway of action for pregabalin and its efficacy in GAD.

Background: Symptoms of anxiety and depression in patients with restless legs syndrome (RLS) have been observed. However, it is unclear whether rates of threshold depression and anxiety disorders according to DSM-IV criteria in such patients are also elevated. Methods: 238 RLS patients were assessed with a standardized diagnostic interview (Munich- Composite International Diagnostic Interview for DSM-IV) validated for subjects aged 18–65 years. Rates of anxiety and depressive disorders were compared between 130 RLS patients within this age range and 2265 community respondents from a nationally representative sample with somatic morbidity of other types. Results: RLS patients revealed an increased risk of having 12-month anxiety and depressive disorders with particularly strong associations with panic disorder (OR=4.7; 95% CI=2.1–10.1), generalized anxiety disorder (OR=3.5; 95% CI= 1.7–7.1), and major depression (OR=2.6; 95% CI=1.5–4.4). In addition, lifetime rates of panic disorder and most depressive disorders as well as comorbid depression and anxiety disorders were considerably increased among RLS patients compared with controls. Conclusions: The results suggest that RLS patients are at increased risk of having specific anxiety and depressive disorders. Causal attributions of patients suggest that a considerable proportion of the excess morbidity for depression and panic disorder might be due to RLS symptomatology.

Objective: To examine in a nationally representative sample (a) the differential association of specific anxiety and depressive disorders defined according to DSM-IV with pain disorder (PD) and pain symptoms, and (b) whether pain-associated anxiety and depressive disorders and their comorbidity have different implications in terms of impairment, disability, health care utilization, and substance use. Method: A nationally representative community study was conducted in Germany. Symptoms, syndromes and diagnoses of mental disorders, and pain were assessed in N = 4,181 participants aged 18–65 years using the DSM-IV/M-CIDI. Results: Logistic regressions revealed that pain is associated with both specific anxiety and depressive disorders, with increasing significant odds ratios (OR) for medically explained pain symptoms (EPS; OR range: 1.9–2.0), to unexplained pain symptoms (UPS; OR range: 2.4–7.3), to PD (OR range: 3.3–14.8). PD and UPS persistently showed associations after adjusting for comorbid other anxiety and depressive disorders and physical illnesses. All types of pain, particularly PD/UPS, are associated with decreased quality of life, greater impairment in role functioning, disability, health care utilization, and substance use. Depressive disorders, even more so anxiety disorders and their comorbidity account for a substantial proportion of variance in these functional correlates. Conclusions: Pain is strongly associated with specific anxiety and depressive disorders. In light of the individual and societal burden due to pain, and the demonstrated role of comorbid anxiety or/and depression, our results call for further investigation of the underlying mechanisms for this association as well as targeted treatments for these comorbidities.

Background: It is commonly assumed that there are clear lines of demarcation between anxiety and depressive disorders on the one hand and psychosis on the other. Recent evidence, however, suggests that this principle may be in need of updating. Methods: Depressive and/or anxiety disorders, with no previous history of psychotic disorder, were examined for the presence of psychotic symptoms in a representative community sample of adolescents and young adults (Early Developmental Stages of Psychopathology study; n=3021). Associations and consequences of psychotic symptomatology in the course of these disorders were examined in terms of demographic distribution, illness severity, onset of service use, and risk factors. Results: Around 27% of those with disorders of anxiety and depression displayed one or more psychotic symptoms, vs 14% in those without these disorders (OR 2.23, 95% CI 1.89–2.66, P < .001). Presence as compared with nonpresence of psychotic symptomatology was associated with younger age (P < .0001), male sex (P < .0058), and poorer illness course (P < .0002). In addition, there was greater persistence of schizotypal (P < .0001) and negative symptoms (P < .0170), more observable illness behavior (P < .0001), greater likelihood of service use (P < .0069), as well as more evidence of familial liability for mental illness (P < .0100), exposure to trauma (P < .0150), recent and more distant life events (P < .0006–.0244), cannabis use (P < .0009), and any drug use (P < .0008). Conclusion: Copresence of psychotic symptomatology in disorders of anxiety and depression is common and a functionally and etiologically highly relevant feature, reinforcing the view that psychopathology is represented by a network or overlapping and reciprocally impacting dimensional liabilities.