Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: The etiology of anxiety disorders remains incompletely understood. Clear evidence for a genetic component has been proposed; however, there is also an increasing focus on environmental factors and the interaction between these and the genetic components that may mediate (anxiety) disorder pathogenesis. No single gene or genetic component has been explicitly identified as being involved in the development of anxiety disorders. This is most likely due to a number of reasons, which include, for example, the heterogeneity of anxiety disorders, the contribution of environmental factors and methodological limitations (e.g. small sample size) of research studies. Until now, genetic association studies usually focused on one particular psychiatric disorder at a time. However, with the difficulty in identifying susceptibility genes and/or loci in heterogeneous disorders like obsessive-compulsive disorder and other conditions in the anxiety spectrum, it is perhaps timely to consider multivariate genetics and epidemiological studies in a number of disorders sharing a core characteristic – such as anxiety. In addition to genetic underpinnings, a number of environmental variables have also been identified as risk factors for pathological anxiety, including adverse life events like childhood physical and sexual abuse. The hypothesis for this project is that a pre-existing genetic vulnerability (or genetic risk) interacts with the impact of adverse life events to result in the development of one or more anxiety disorder(s). Considering phenotypic overlap amongst the anxiety disorders, it is likely that diverse networks of genes and/ or interacting pathways are responsible for the phenotypic manifestations observed. Sprague Dawley rats exhibiting behaviours indicative of anxiety in the context of environmental stressors (maternal separation and restraint stress) were used as model for the identification of novel susceptibility genes for anxiety disorders in humans. The striatum has previously been implicated as a candidate in the brain architecture of anxiety pathogenicity, and is also a site exhibiting a high degree of synaptic plasticity. The synaptic plasticity pathway was investigated using the dorsal striatum of the rat brain and several genes were identified to be aberrantly expressed in “anxious” rats relative to controls (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 and Arc). In humans, it was found that the severity of early adversity was significantly and positively associated with the presence of an anxiety disorder in adulthood. When the human homologues of the susceptibility candidate genes that were identified using the animal model were screened in a human cohort of patients with obsessive-compulsive disorder (OCD), panic disorder (PD) or social anxiety disorder (SAD) (relative to controls), five single nucleotide polymorphisms (SNPs) were found to be significantly associated with these conditions. Four of these SNPs were also found to significantly interact with the severity of childhood trauma. Haplotype analysis of variants within the identified susceptibility candidates revealed novel haplotype associations, four of which are located in the MMP9 gene. Notably, this the first study to link these particular mutations in the MMP9 gene with anxiety disorders and this finding is consistent with previous work suggesting that MMP9 is involved in conditions like cardiovascular disease and cancer which have been associated with increased prevalence of anxiety disorders. In conclusion, this project yielded important findings pertaining to the etiology of anxiety disorders. The use of a combined anxiety disorders cohort (OCD, PD and SAD) may suggest that the associations found here may hold true for anxiety disorders in general and not only for a particular clinically delineated condition. Childhood trauma was confirmed as an increased susceptibility risk for anxiety disorders. Also, this research contributed several novel susceptibility genes (MMP9, EGR2, EGR4, NTF4, and ARC), five significant SNP associations, four significant SNP-environment interactions and five haplotype associations (within MMP9 and BDNF) as candidates for anxiety pathogenicity. The identified polymorphisms and haplotypes were demonstrated to be associated with susceptibility to anxiety disorders in a gene-environment correlation and gene-environment interaction. / AFRIKAANSE OPSOMMING: Die oorsake van angssteurings word steeds nie volledig verstaan nie. Daar is duidelike bewyse vir 'n genetiese komponent, maar daar is ook toenemende fokus op omgewingsfaktore en die interaksie tussen hierdie omgewingsfaktore en genetiese komponente by angssteurings. Geen enkele geen of genetiese komponent is al geïdentifiseer as diè wat betrokke is by die ontwikkeling van angssteurings nie. Dit is waarskynlik weens 'n aantal redes, wat byvoorbeeld, die heterogeneïteit van angssteurings, die bydrae van omgewingsfaktore en metodologiese beperkings (bv. klein steekproef) van die navorsingstudies, insluit. Verder het genetiese assosiasiestudies tot nou toe gewoonlik net op een spesifieke psigiatriese versteuring op 'n slag gefokus. Maar, gegewe die uitdaging om vatbaarheidsgene en / of loci in heterogene steurings soos obsessief – kompulsiewe steuring (OKV) en ander toestande op die angsspektrum te identifiseer, is dit tyd om genetiese en kliniese studies in ‘n aantal steurings - met ‘n oorvleuende kern-element soos angs -, gesamentlik te oorweeg. Bykomend tot die genetiese boustene, is ‘n aantal omgewingsveranderlikes soos traumatiese lewenservarings tydens die kinderjare as risikofaktore vir patologiese angs geidentifiseer. Die hipotese vir hierdie projek is dat daar 'n interaksie tussen genetiese kwesbaarheid (of genetiese risiko) en traumatiese lewensevarings is en dat dit tot die ontwikkeling van 'n / veelvoudige angssteuring(s) kan lei. Inaggenome die fenotipiese oorvleueling tussen die angssteurings, is dit waarskynlik dat diverse netwerke van gene en / of interaktiewe geen-paaie vir die manifestasie van hierdie toestande verantwoordelik is. Sprague Dawley-rotte met gedragswyses aanduidend van angs, in die konteks van omgewingstressore (d.i. skeiding van die ma-rot en bedwang-stres [restraint stress]), is as model gebruik vir die identifisering van nuwe vatbaarheidsgene vir angssteurings in mense. Die striatum is voorheen as ‘n kandidaat in die brein-argitektuur van patologiese angs voorgehou, en is ook ‘n plek met ‘n hoë mate van sinaptiese plastisiteit. Die sinaptiese plastisiteit is ondersoek deur te fokus op die dorsale striatum van die rotbrein en daar is verskeie gene gevind wat anders is in “angstige” rotte in vergelyking met kontroles (Mmp9, Bdnf, Ntf4, Egr2, Egr4, Grm2 en Arc). In mense is daar gevind dat die ernstigheidsgraad van vroeë trauma beduidend en positief met die teenwoordigheid van ‘n angssteuring tydens volwassenheid verband hou. Toe die menslike ekwivalente van die vatbaarheidsgene wat met die dieremodel geïdentifiseer is in ‘n mens-kohort met obsessief-kompulsiewe steuring (OKS), panieksteuring (PS) en sosiale angssteuring (SAS) ondersoek is, is gevind dat daar 5 enkele nukleotied polimorfismes (ENPs) is wat met die toestande verband hou. Daar is ook gevind dat vier van hierdie ENPs beduidend verband hou met die ernstigheidsgraad van trauma tydens die kinderjare. Haplotipe analise van variante binne die geïdentifiseerde vatbaarheidsgene het op nuwe haplotipe assosiasies – waarvan 4 op die MMP9-geen geleë is – gedui. Hierdie is dus die eerste studie wat gevind het dat dié spesifieke mutasies van die MMP9-geen met angssteurings verband hou. Hierdie bevinding strook met vorige werk wat daarop dui dat die MMP9-geen by toestande soos kardiovaskulêre siekte en kanker wat ook met verhoogde voorkoms van angssteurings verband hou, betrokke is. Ter afsluiting kan ons sê dat hierdie projek belangrike bevindinge oor die oorsake van angssteurings gemaak het. Die gebruik van ‘n gekombineerde angssteurings-kohort (OKS. PS en SAS) kan moontlik suggereer dat die assosiasies wat ons hier gevind het, waar is vir alle angssteurings en nie net vir ‘n spesifieke afgebakende toestand nie. Traumatiese ervarings tydens die kinderjare is ook bevestig as ‘n risiko vir die ontwikkeling van angssteurings. Hierdie navorsing het ook verskeie nuwe vatbaarheidsgene (MMP9, EGR2, EGR4, NTF4, en ARC), 5 beduidende ENP assosiasies, 4 beduidende ENP-omgewings-interaksies en 5 haplotipe assosiasies (by MMP9 en BDNF) geïdentifiseer as moontlike kandidate wat ‘n rol speel by die ontstaan van patologiese angs. Daar is ook gevind dat die geïdentifiseerde polimorfismes en haplotipes met vatbaarheid vir angssteurings in ‘n geen-omgewing- korrelasie en geen-omgewing- interaksie verband hou. Stellenbosch University http://scholar.sun.ac.za

Thesis (MA)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Background: Both human and animal studies indicate that early trauma can influence brain development and can lead to dysregulation and dysfunction. This includes cognitive deficits. The risk of childhood trauma (CHT) and resulting cognitive deficits are well established in Posttraumatic Stress Disorder (PTSD). This is not the case for Social Anxiety Disorder (SAD). The experience of CHT does not inevitably lead to later psychopathology, suggesting that resiliency factors may be at play. Indeed, research shows that resilience is protective against the development of PTSD although this has not been well studied in SAD, particularly in the context of childhood trauma and neurocognition. Methods: This exploratory study assessed for the possible contribution of CHT on cognitive functioning in adults with SAD. We assessed 44 individuals who formed part of a larger study on neurocognitive and neuroimaging correlates in a sample drawn from the Western Cape, South Africa. Using a neuropsychological test battery, memory, attention and executive functioning (EF) (underpinned by hippocampal, cingulate cortex and pre frontal-cortex function respectively) were assessed. CHT was assessed with the Childhood Trauma Questionnaire (CTQ). We compared neurocognitive and resilience (CD-RISC) variables across four groups (SAD with trauma, SAD without trauma, PTSD and healthy controls) using analysis of variance (ANOVA) statistics. Results: None of the groups differed significantly on cognitive variables, however, on average all outcomes were in the predicted direction. Separate analyses for the traumatised groups only showed a significant effect for EF and attention, suggesting an association between EF, attention and CHT. On a measure of resilience, healthy controls had significantly higher resilience scores than the other 3 groups. Unexpectedly, SAD and PTSD groups with CHT had higher resilience scores than the SAD group without CHT, suggesting that resilience moderates CHT. Lastly individuals with SAD and PTSD with CHT reported more emotional abuse and neglect than any other type of childhood trauma. Conclusion: This exploratory study is unique in its comparative assessment of the effects of CHT and resilience on discussed. / AFRIKAANSE OPSOMMING: Agtergrond: Beide mens- en dierestudies dui daarop dat vroeë trauma brein ontwikkeling kan beïnvloed en kan lei tot disfunksie. Dit sluit kognitiewe tekortkominge in. Die risiko van vroeë kinderjare trauma (KJT) en die gevolglike kognitiewe tekortkominge is goed gevestig in Posttraumatiese stresversteuring (PTSV). Dit is egter nie die geval in Sosiale angsversteuring (SAV) nie. Die ervaring van KJT lei nie noodwendig tot latere psigopatologie nie, wat daarop dui dat veerkragtigheidsfaktore 'n rol kan speel. Trouens, navorsing toon dat veerkragtigheid beskermend is teen die ontwikkeling van PTSV, maar dit is egter nie behoorlik nagevors in SAV nie - veral nie in die konteks van vroeë kinderjare en neurokognisie nie. Metodologie: Hierdie verkennende studie het die invloed van KJT op kognitiewe funksionering in 44 individue geëvalueer. Hierdie studie het deel gevorm van 'n groter studie oor neurokognitiewe- en neurobeeldingskorrelate in 'n steekproef wat gewerf is uit die Wes-Kaap, Suid-Afrika. ‘n Neurosielkundige toetsbattery was gebruik om geheue, aandag en uitvoerende funksionering (UF) (wat onderskeidelik deur die hippokampus, cingulate korteks en prefrontale korteks ondersteun word) te assesseer. KJT is beoordeel met die "Childhood Trauma Questionnaire" (CTQ). 'n Analise van variansie (ANOVA) was gebruik om die neurokognitiewe en veerkragtigheid (CD-RISC) veranderlikes oor vier groepe (SAV met trauma, SAV sonder trauma, PTSV en gesonde kontrole) te vergelyk. Resultate: Nie een van die groepe het beduidend verskil van mekaar op grond van kognitiewe veranderlikes nie, maar oor die algemeen was alle uitkomste in die voorspelde rigting. Afsonderlike analises op die getraumatiseerde groepe het 'n beduidende effek gehad vir UF en aandag, wat dui op 'n assosiasie tussen UF, aandag en KJT. Die gesonde kontrole het beduidende hoër veerkragtigheid tellings as die ander 3 groepe gehad. SAV en PTSV groepe met KJT het teen verwagtinge hoër veerkragtigheidstellings gehad as die SAV sonder KJT, wat daarop dui dat veerkragtigheid KJT modereer. Laastens, individue met SAV en PTSV met KJT het meer emosionele mishandeling en verwaarlosing gerapporteer as enige ander tipe kinderjare trauma. Bespreking: Hierdie verkennende studie is uniek in sy vergelykende evaluering van die invloed van KJT en veerkragtigheid op die neurokognisie in deelnemers met SAV en PTSV. Beperkings en aanbevelings vir toekomstige navorsing word bespreek.

No description available.

Introduction: Obesity is one of the most important medical problems in the U.S. and is considered to be an epidemic with over 30% of the population being obese. Obesity is associated with increased risk of hypertension, diabetes, cardiovascular diseases, certain cancers and a shorter life expectancy. Recent studies have shown that higher BMI levels are also significantly associated with several lifetime mental disorders such as major depressive disorder, anxiety disorders as well as panic attacks and panic disorders. Purpose: The purpose of this study was to quantify the extent to which higher BMI increased the likelihood of Depression, Anxiety Disorder and Panic Disorder and to observe if co-morbid illnesses such as Hypertension and Diabetes affect this association. Methods: A cross-sectional secondary data analysis was conducted using the 2008 National Health Interview Survey. There were 20,593 adult respondents (over 18 years of age) who were included in the study. Logistic regression models were weighted to account for the complex weighting scheme. Main Determinant measures: Based on their BMI, the participants were classified into 5 groups: Underweight (BMI <18.50), Normal Weight (BMI 18.50 – 24.99), Overweight (BMI 25.00 – 29.99), Obese (BMI 30.00-39.99) and Morbidly Obese (BMI > 40.00). Main Outcome Measures: Presence or absence of Depression, Anxiety Disorder or Panic Disorder based on self-report. Results: People who were obese or morbidly obese had higher odds of suffering from depression, anxiety disorder and panic disorder compared to people who were normal weight. Obese individuals were 35% as likely to suffer from depression, 22% as likely to suffer from anxiety disorder and 36% as likely to suffer from panic disorder relative to normal weight persons. Morbidly obese people were 85% as likely to suffer from depression, 27% as likely to suffer from anxiety disorder and 34% as likely to suffer from panic disorder. No interactions were observed based on the presence of hypertension or diabetes. Conclusion: Obesity is associated with an increased prevalence of depression, anxiety disorder and panic disorder. With obesity rates steadily increasing, understanding the impact of obesity on the occurrence of mental disorders is important.

Made available in DSpace on 2016-03-22T17:27:35Z (GMT). No. of bitstreams: 1 FERNANDAPEDROTTI_MESTRADO.pdf: 708081 bytes, checksum: 5ee01fbf7025bcd8bfa8448519f5340e (MD5) Previous issue date: 2014-11-13 / Background: Generalized Anxiety Disorder (GAD) is a common psychiatric disorder characterized by long term worry, tension, nervousness, fidgeting and symptoms of autonomic system hyperactivity. The neurobiology of this disorder is still unclear, although it has been consistently demonstrated that the environment and the genetic profile could increase its risk. We examined whether a polymorphism in the BDNF gene, which plays a role in neuroplasticity and memory, could increase the vulnerability to this disorder. Methods: In our study, 816 subjects from a population-based study were genotyped by qPCR for the BDNF functional variant rs6265 (Val66Met) and the BDNF serum levels were measured by ELISA. Results: Our results revealed a significant association between the Met allele and risk for GAD (p=0.014), but no differences were observed in the serum levels of BDNF according to diagnosis (p=0.531) or genotype distribution (p=0.197). The interaction between Val66Met genotype and GAD in explaining serum BDNF levels approached significance (F=3.93; p=0.048). The logistic regression analysis confirmed the independent association of Met allele as a risk factor to develop GAD after adjusting for confounders (&#946;=1.92; 95% IC: 1.168-3.16; p=0.010. Conclusion: These results suggest that BDNF could be involved in the neurobiology of GAD and might represent a useful marker associated with the disease. Key words: Anxiety disorders, generalized anxiety disorder, brain-derived neurotrophic factor, BDNF serum levels, Val66Met polymorphism / O transtorno de ansiedade generalizada (TAG) é uma doença crônica, caracterizada pelo excesso de ansiedade e preocupação somada à presença de outros sintomas, como tensão muscular, e irritabilidade (Hanrahan et al, 2013; Zargar et al, 2013). De acordo com o Manual Diagnóstico e Estatístico de Transtornos Mentais (DSM-IV), esse transtorno normalmente inicia na adolescência e afeta cerca de 5,7% da população em geral com altas taxas de incidência em mulheres (Kessler et al, 2005; Tempesta et al, 2013). Além disso, o TAG tem considerável impacto na qualidade de vida, sendo responsável por prejuízos na vida social, profissional e familiar dos seus portadores (Zargar et al, 2013; Tempesta et al, 2013). O TAG, geralmente é acompanhado de comorbidades psiquiátricas como a depressão maior, outros transtornos de ansiedade, e abuso de álcool, sendo caracterizado por altas taxas de falha na terapêutica, o que dificulta a resposta ao tratamento, bem como a resposta a psicoterapia (Zargar et al, 2013; Grant et al, 2005). O TAG é uma doença complexa na qual ocorre a interação de múltiplos fatores ambientais, biológicos e genéticos, cuja neurobilogia exata permanece ainda desconhecida (Zargar et al, 2013; Chen et al, 2006). O fator neurotrófico derivado do cérebro (BDNF), membro da família das neurotrofinas, age sobre certos neurônios do SNC e periférico, desempenhando um papel importante na sobrevivência, diferenciação e crescimento neuronal durante o desenvolvimento e na idade adulta (Gratacos et al, 2007; Egan et al, 2004). No cérebro está presente em regiões específicas como hipocampo, neocortex e hipotálamo, regiões-chave na regulação do humor e comportamento, bem como na aprendizagem e memória, indicando um envolvimento direto na patofisiologia das doenças psiquiátricas (Yoshii and Constantine-Paton, 2010; Lu et al, 2008). Estudos clínicos e pré-clínicos com transtornos de ansiedade demonstram que alterações no gene e nos níves de BDNF podem estar associados a doença (Hartmann et al., 2001; Rasmusson et al., 2002; Molle et al., 2012). Porém os estudos nesta área são escassos e inconsistentes, mas indicam que indivíduos com TAG apresentam uma maior frequência do alelo Met (Suliman et al, 2013; Ball et al, 2013). Dessa forma, uma melhor compreensão de alguns fatores genéticos envolvidos nos transtornos de ansiedade poderá permitir avanços não só ao nível de tratamento, mas também de prevenção e diagnóstico, podendo algumas alterações neurobiológicas vir a integrar os critérios de diagnóstico e monitoramento da doença, hoje exclusivamente semiológicos, e contribuir, assim, para a explicação da heterogeneidade desta patologia

O Transtorno de Ansiedade Social (TAS) tem sido considerado um grave problema de saúde mental pela sua alta prevalência em pessoas jovens e pelas incapacidades decorrentes no desempenho e interações sociais. É fundamental que se disponha de instrumentos validados e abrangentes que avaliem tanto os recursos e déficits comportamentais quanto os prejuízos sociais e funcionais destas pessoas. Objetivou-se, neste trabalho, verificar as associações entre as manifestações comportamentais e clínicas do TAS por meio de dois estudos, um psicométrico e outro empírico, visando: (a) aferir as propriedades psicométricas do Inventário de Habilidades Sociais (IHS-Del-Prette), enquanto medida do repertório comportamental de habilidades sociais, em relação à avaliação das manifestações clínicas próprias do TAS, medidas pelo Inventário da Fobia Social (SPIN); e (b) comparar e caracterizar o repertório de habilidades sociais apresentado por universitários brasileiros portadores de TAS e não portadores frente a uma situação experimental estruturada, o Teste de Simulação de Falar em Público (TSFP). Do estudo psicométrico, participaram 1006 universitários, na faixa etária entre 17 e 35 anos, de ambos os gêneros, provindos de duas instituições de ensino superior. Posteriormente, 86 participantes foram randomicamente selecionados desta amostra inicial e agrupados como casos e não-casos de TAS a partir de avaliação clínica sistemática por meio da Entrevista Clínica Estruturada para o DSM-IV. Do delineamento empírico, participaram 26 universitários, sendo 13 com diagnóstico de TAS e 13 não portadores de transtornos psiquiátricos. Quanto aos resultados, o IHS apresentou boa consistência interna para o escore total, reforçando a sua validade de construto. Observou-se boa validade concorrente entre o IHS e o SPIN, com um coeficiente altamente significativo de correlação negativa entre eles, indicando que quanto mais elaborado for o repertório de habilidades sociais de um indivíduo, menor é a sua probabilidade de satisfazer os critérios de rastreamento de indicadores para o TAS. O IHS demonstrou distinguir significativamente indivíduos com e sem TAS, atestando sua validade discriminativa e preditiva para esse diagnóstico, evidenciando-se assim a sua validade clínica e a possibilidade do seu uso em estudos empíricos que testem a eficácia terapêutica de programas de intervenção. No TSFP, os grupos caso e não-caso de TAS não demonstraram diferenças significativas, em termos de freqüência, para a maioria dos marcadores comportamentais de ansiedade avaliados. Um número maior de sujeitos do grupo não-caso foi avaliado como apresentando um nível de habilidades sociais apropriadas para falar em público, que variou de moderado a alto, em comparação ao grupo caso. Ao longo do TSFP, a freqüência de emissão dos marcadores comportamentais de ansiedade pelos sujeitos de ambos os grupos manteve-se estável. Os grupos diferiram significativamente na maioria dos itens indicativos da habilidade de falar em público do IHS e quanto ao escore geral desta habilidade. A análise dos resultados do estudo empírico aponta para a necessidade de novos estudos com amostras clínicas de indivíduos com TAS dos subtipos generalizado e circunscrito, e não-clínica, com maior número de sujeitos, previamente avaliados quanto ao medo de falar em público, e também para a possibilidade de uso do TSFP em programas de Treinamento em Habilidades Sociais. / Social Anxiety Disorder (SAD) has been considered a serious mental health problem for its high prevalence in young people and for the resulting disabilities in the performance and social interactions. It stands out, thus, as being fundamental to have comprehensive and validated instruments which evaluate both the resources and the social and functional impairments of these people. In this work, we aimed at verifying the associations between the behavioral and clinical manifestations of SAD by means of two studies, a psychometric study and an empirical one, in order to: (a) check the psychometric properties of the Social Skills Inventory (HIS-Del-Prette), as a measure of the social skills behavioral repertoire in relation to the evaluation of the typical clinical manifestations of SAD, measured by the Social Phobia Inventory (SPIN); (b) compare and characterize the social skills repertoire shown by Brazilian undergraduates with and without SAD in a structured experimental situation, the Simulated Public Speaking Test (SPST). A total of 1006 undergraduates of both genders participated in the psychometric study, with ages between 17 and 35, from two universities. Subsequently, 86 participants were randomly selected from this initial sample and grouped as SAD case and non-case from the systematic clinical evaluation. In the empirical outline, 26 undergraduates participated, 13 with a SAD diagnosis and 13 without the disorder. According to the results, IHS showed good internal consistency for the total score, reinforcing its construct validity. Good concurrent validity was demonstrated between IHS and SPIN, with a highly significant negative correlation coefficient between them, indicating that the more elaborate the social skills repertoire of an individual is, the smaller the probability that he or she will meet the screening criteria for the indicators of SAD. IHS proved to significantly distinguish individuals with and without SAD, attesting thus, discriminative and predictive validity for this diagnosis, showing its clinical validity for the diagnosis of this disorder and yet the possibility of using it in empirical studies testing the therapeutical efficacy in programs of intervention. In the SPST, the case and non-case groups of SAD did not show significant differences in terms of frequency for most of the social anxiety markers, except in relation to facial movements of discomfort, and the class of non-verbal markers, in which the non-case group presented higher values. A higher number of individuals from this group were evaluated as showing a level of appropriate social skills for speaking in public which varied from moderate to high, in comparison with the other group. Throughout SPST, the frequency of emission of anxiety behavioral markers by the participants of both groups was stable. The groups differed significantly in most items of IHS indicative of abilities to speak in public, as well as in the general score of this ability. The analysis of the results of the empirical study points to the necessity of new studies with clinical samples of individuals with SAD of the generalized and circumscribed subtypes and non-clinical, with a larger number of participants, previously evaluated as to the fear of speaking in public, and also to the possibility of using SPST in Social Skills Training.

O Transtorno de Ansiedade Social (TAS) caracteriza-se pelo medo acentuado e persistente de situações sociais ou de desempenho, mostrando-se associado a prejuízos funcionais . Objetiva-se avaliar a associação do TAS a prejuízos funcionais nas atividades cotidianas, por meio da validação de duas escalas de auto e de hetero-avaliação, aplicadas a universitários brasileiros. Realizou-se dois estudos, um de comparação entre grupos TAS e Não TAS e outro de estudos de casos. Procedeu-se à tradução e adaptação da Escala de Liebowitz para auto-avaliação dos prejuízos funcionais (ELAPF) e da Escala de Liebowitz para hetero-avaliação dos prejuízos funcionais (ELHPF). Participaram do estudo de comparação entre grupos 173 universitários (TAS = 84 e Não TAS = 89), de ambos os sexos, com idade entre 17 e 35 anos. Procedeu-se a aplicação da Entrevista clínica semi-estruturada para o DSM-IV, para a confirmação diagnóstica e dos instrumentos: ELAPF, ELHPF, Questionário de Saúde Geral -12 (QSG-12), Inventário de Fobia Social (SPIN). Para os estudos de casos, selecionou-se três participantes do grupo TAS e procedeu-se a uma entrevista semi-estruturada sobre o impacto do transtorno nas atividades cotidianas, nos relacionamentos e na saúde geral. Os dados das escalas foram codificados e os grupos comparados por teste estatísticos não paramétricos (p 0,05) e para os estudos de casos foram integrados e analisados qualitativamente os dados das escalas e da entrevista,. Os grupos não apresentaram diferenças significativas quanto as variáveis demográficas. O grupo TAS apresentou no QSG-12 mais dificuldades quanto ao bem estar geral, e na ELAPF e na ELHPF apresentou, com significância estatística, mais dificuldades nas últimas semanas e no curso da vida. Observou-se para o grupo TAS: a) para a ELHPF, consistência interna de 0,68 no curso da vida e 0,67 nas duas últimas semanas, o coeficiente de correlação Kappa entre os avaliadores, variou de 0,75 a 0,93, caracterizando nível de concordância satisfatória e na análise dos componentes principais extrairam-se dois fatores para os dois parâmetros temporais; a validade concorrente realizada com o SPIN, mostrou valores que variaram entre 0,11 e 0,33 para o parâmetro no curso da vida e 0,17 a 0,39 nas duas últimas semanas, e b) para a ELAPF, a consistência interna foi de 0,85 para o parâmetro no curso da vida e 0,83 nas duas últimas semanas e na análise dos componentes principais extrairam-se três fatores, para o parâmetro temporal no curso da vida e dois fatores no parâmetro nas duas últimas semanas; a validade concorrente realizada em relação ao SPIN, mostrou valores no curso da vida de -0,14 a 0,25 e nas duas últimas semanas, a correlação variou de 0 a 0,38. Os estudos de casos evidenciaram que os prejuízos funcionais associados ao TAS têm impacto negativo para os relacionamentos, as atividades cotidianas, o bem estar e a percepção de saúde. As escalas , mostraram-se válidas para a avaliação dos prejuízos funcionais associados ao TAS, o que contribui para as práticas de saúde mental, em especial as de terapia ocupacional, que tem como foco as intervenções voltadas para a vida cotidiana. / Social Anxiety Disorder (SAD) is characterized by marked and persistent fear of social or performance situations and is associated with functional impairment. The objective of the present study was to assess the association of SAD with functional impairment in daily activities by means of the validation of two scales (auto and hetero-evaluation) applied to Brazilian university students. Two studies were conducted, one of them comparing SAD and Non SAD groups and the other consisting of cases studies. The Liebowitz Disability Self Rating Scale (LDSRS) and the Disability Profile /Clinician- Rated (DP) were translated and adapted. A total of 173 university students (SAD = 84 and Non-SAD = 89) of both genders, aged 17 to 35 years participated in the study of group comparison. A semi-structured clinical interview for DSM-IV was applied for confirmation of the diagnosis and the following instruments were applied: LDSRS, DP, General Health Questionnaire-12 (GHQ-12), and Social Phobia Inventory (SPIN). Three participants of the SAD group were selected for the case studies and submitted to a semi-structured interview about the impact of the disorder on daily activities, relationships, and general health. The scale data were coded and the groups were compared by a non-parametric test (p 0.05), and for the case studies the scale and interview data were integrated and analyzed qualitatively. The groups did not differ significantly in terms of demographic variables. For the SAD group, application of the GHQ-12 revealed more difficulties regarding general well-being, and application of the LDSRS and DP revealed significantly more lifetime difficulties and difficulties in the last weeks. The following observations were made for the SAD group: a) for the DP, the internal consistency was 0.68 during the life course and 0.67 during the last two weeks; the Kappa correlation coefficient for the two raters ranged from 0.75 to 0.93, characterizing a satisfactory level of concordance, and two factors for the two temporal parameters were extracted in the analysis of the principal components; concurrent validity performed with the SPIN showed values ranging from 0.11 to 0.33 for the lifetime parameter and from 0.17 to 0.39 for the last two weeks, and b) for the LDSRS, the internal consistency was 0.85 for the lifetime parameter and 0.83 for the last two weeks; concurrent validity performed with the SPIN showed lifetime values ranging from 0.14 to 0.25 and values ranging from 0 to 0.38 in the last two weeks. The case studies demonstrated that the functional impairment associated with SAD has a negative impact on relationships, daily activities, well-being, and health perception. The scales proved to be valid for the assessment of the functional impairment associated with SAD, a fact that contributes to mental health practices, especially those of occupational therapy, that focus on interventions in daily life.

Introdução: A neurobiologia dos transtornos de ansiedade (TA) é complexa e envolve interações ambientais e genéticas ainda não conhecidas. Esses transtornos, comumente, iniciam durante a infância e adolescência, persistindo ao longo da vida. O comprometimento da resposta biológica frente ao estímulo estressor, encontrado em muitos pacientes com TA, sugere a influência do eixo hipotálamo-hipófise-adrenal (HHA) nestes transtornos e, portanto, os polimorfismos associados ao eixo HHA poderiam ser estudados em genes candidatos. Os estudos que almejam entender a etiologia dos TA devem, também, explorar as alterações epigenéticas (incluindo a metilação do DNA) decorrentes das influências ambientais. Objetivos: Estudar, em adolescentes, polimorfismos genéticos funcionais do eixo HHA, interações Gene x Ambiente (G x A) e metiloma do DNA, considerando as diferentes trajetórias dos TA. Métodos: Foi realizada a extração de DNA das células do epitélio bucal de 228 adolescentes (131 casos e 97 controles para os TA) e foram genotipados, por PCR em tempo real, polimorfismos funcionais envolvidos com o eixo HHA (FKBP5: rs3800373, rs9296158, 3800373, rs9296158, 3800373, rs9296158, rs1360780, rs9470080 rs1360780, rs9470080 e rs4713916; NR3C1NR3C1 : rs6198;: rs6198;: rs6198; NR3C2NR3C2 : rs2070951;: rs2070951;: rs2070951; CRHR1CRHR1 CRHR1 : rs878886 : rs878886 e SERPINA6 SERPINA6 : rs746530) : rs746530) . Os participantes responderam à escala auto-aplicativa SCARED (Screen for Children Anxiety Related Emotional Disorder – Children rated) e realizaram entrevistas semiestruturadas para avaliação diagnóstica utilizando o K-SADS-PL (Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime). O questionário CTQ (Childhood Trauma Questionnaire) foi aplicado em 90 adolescentes (54 casos e 36 controles para os TA) para avaliar a interação entre o trauma emocional e o polimorfismo do gene NR3C2 nos níveis séricos de BDNF. Uma subamostra de adolescentes (n=47) foi reavaliada, cinco anos após a primeira coleta, através das mesmas entrevistas psiquiátricas e nova extração de DNA salivar. Alguns participantes, na última avaliação, responderam ao MINI (Mini International Neuropsychiatric Interview) apropriado para a idade atual. A amostra foi organizada em 4 grupos, conforme o diagnóstico dos TA e o ano da coleta de saliva (anos de 2008 e 2013): (1) Desenvolvimento típico da adolescência (Controle; n=14); (2) Incidentes para os TA (ITA; n=11); (3) Persistentes para os TA (Caso; n=14) e (4) Remitentes para os TA (RTA; n=08). O metiloma do DNA foi analisado com o Infinium HumanMethylation 450 BeadChip da Illumina. Resultados: Não foi encontrada associação entre os polimorfismos estudados e os TA. Em relação à interação G x A, sugere-se que o polimorfismo rs2070951 do gene NR3C2 modera a associação entre negligência física e os níveis séricos de BDNF. Do ponto de vista epigenético, foi observada, nos grupos ITA e RTA, vias biológicas com padrão homogêneo e relacionadas ao sistema nervoso. Já nos grupos casos e controles para os TA, foram evidenciadas vias biológicas com padrão mais heterogêneo. Um perfil de hipometilação do DNA foi predominante nas vias encontradas. Na análise transversal, nós encontramos padrões opostos de metilação do DNA, conforme o período desenvolvimental avaliado: hipometilação no início da adolescência e hipermetilação em jovens adultos. Conclusão: Esse estudo abordou, em uma amostra de adolescentes, aspectos genéticos (genes candidatos envolvidos com o eixo HHA), ambientais (trauma emocional) e epigenéticos (metiloma do DNA) dos TA. Os achados sugerem que, embora sem associações entre os TA e genes envolvidos no eixo HHA, existe uma interação entre a presença de trauma emocional, polimorfismo genético do eixo HHA e marcadores biológicos. Os achados do metiloma do DNA sugerem, também, influências epigenéticas no curso dos TA. Novos estudos devem ser delineados para corroborar as influências genéticas e ambientais neste transtorno. / Background: The neurobiology of Anxiety Disorders (AD) is complex and involves environmental and genetic interactions understood. These disorders may have their onset during childhood and adolescence, persisting throughout life. The impairment of biological response against the stressor stimulus, described in many patients with AD, suggests a possible role of genetic polymorphisms of the hypothalamic-pituitary-adrenal (HPA) axis in these individuals. Studies that aim to understand the etiology of AD should also explore the epigenetic changes (including DNA methylation) arising from environmental influences. Objective: To study, in adolescents, functional genetic polymorphisms of HPA axis, Gene x Environment (G x E) interactions and DNA methylome, considering different AD outcomes. Methods: Saliva DNA was extracted from 228 adolescents (131 cases and 97 controls to AD) and we genotyped, by real time PCR, the functional polymorphisms involved with HPA axis (FKBP5: rs3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; 3800373, rs9296158, rs1360780, rs9470080 and rs4713916; NR3C1NR3C1 : rs6198; : rs6198; : rs6198; NR3C2NR3C2 : rs2070951; : rs2070951; CRHR1CRHR1CRHR1 CRHR1: rs878886 and : rs878886 and : rs878886 and : rs878886 and SERPINA6 SERPINA6 SERPINA6SERPINA6 : rs746530) : rs746530) . Participants responded to the scale self-applied Screen for Children Anxiety Related Emotional Disorder – Children rated (SCARED) and were diagnosed according to the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime (K-SADS-PL). The Childhood Trauma Questionnaire (CTQ) was applied in 90 adolescents (54 cases e 36 controls to AD) to evaluate the interaction between emotional trauma and the NR3C2 polymorphism in the serum levels of BDNF. A sub-sample of adolescents (n = 47) was reassessed five years after the first evaluation by the same psychiatric semi-structured interviews and new extraction salivary DNA was performed. Some participants in the last evaluation responded to Mini International Neuropsychiatric Interview (MINI), which is a semi structure interview appropriate for the present age. The sample was organized in four groups according to the diagnosis of AD and the year of saliva collection (2008 and 2013): (1) Typically Developing Controls (TDC; n = 14); (2) Incident Anxiety Disorder (IAD; n = 11); (3) Persistent Anxiety Disorder (PAD; n = 14); (4) Remittent Anxiety Disorder (RAD; n = 8). DNA methylome was evaluated with Infinium HumanMethylation450 BeadChip. Results: We did not find any association between the genetic polymorphisms and AD. Considering the G x E interaction we suggest that rs2070951 polymorphism of NR3C2 gene moderates the association between physical neglect and serum BDNF levels. When we evaluated the DNA methylome, we observed more homogeneous biological pathways and mostly related with nervous system in individuals from IAD and RAD groups. On the other hand, in the TDC and PAD groups, we found biological pathways with a more heterogeneous pattern. A DNA hypomethylation profile was found predominant in the pathways. In a cross-sectional analysis, we found opposite patterns of DNA methylation, as the developmental period assessed: hypomethylation at the beginning of adolescence and hypermethylation in young adults. Conclusion: This study addressed, in an adolescent sample, genetics (candidate genes linked to HPA axis), environmental (emotional trauma) and epigenetic (DNA methylome) aspects of AD. The findings suggest that although there are no associations between AD and genes involved in HPA axis, there is an interaction between the presence of trauma, genetic polymorphism involved in this axis and biomarkers. The DNA methylome findings also suggest epigenetic influences on the course of TA. Further studies should be designed to corroborate the genetic influences in this disorder.

Background and Objectives: To describe patterns of healthcare utilization among patients with generalized anxiety disorder (GAD) in general practitioner (GP) settings in Germany. Methods: Using a large computerized database with information from GP practices across Germany, we identified all patients, aged > 18 years, with diagnoses of, or prescriptions for, GAD (ICD-10 diagnosis code F41.1) between October 1, 2003 and September 30, 2004 ("GAD patients"). We also constituted an age- and sex-matched comparison group, consisting of randomly selected patients without any GP encounters or prescriptions for anxiety or depression (a common comorbidity in GAD) during the same period. GAD patients were then compared to those in the matched comparison group over the one-year study period. Results: The study sample consisted of 3340 GAD patients and an equal number of matched comparators. Mean age was 53.2 years; 66.3% were women. Over the 12-month study period, GAD patients were more likely than matched comparators to have encounters for various comorbidities, including sleep disorders (odds ratio [OR] = 6.75 [95% CI = 5.31, 8.57]), substance abuse disorders (3.91 [2.89, 5.28]), and digestive system disorders (2.62 [2.36, 2.91]) (all p < 0.01). GAD patients averaged 5.6 more GP encounters (10.5 [SD = 8.8] vs 4.9 [5.7] for comparison group) and 1.4 more specialist referrals (2.3 [2.9] vs 0.9 [1.7]) (both p < 0.01). Only 58.3% of GAD patients received some type of psychotropic medication (i.e., benzodiazepines, antidepressants, and/or sedatives/hypnotics). Conclusions: Patients with GAD in GP practices in Germany have more clinically recognized comorbidities and higher levels of healthcare utilization than patients without anxiety or depression.

Concerns have been raised that the DSM-IV requirements of 6-month duration, excessive worry, and three associated symptoms exclude a substantial number of people with clinically significant anxiety from a diagnosis of generalized anxiety disorder (GAD). We examined the implications of relaxing these three criteria for the estimated prevalence and predictive validity of GAD using nationally representative data from the US National Comorbidity Survey Replication. Relaxing all three criteria more than doubles the estimated prevalence of GAD. Broadly defined GAD significantly predicts the subsequent first onset of a wide range of temporally secondary disorders. The odds of secondary disorders are somewhat smaller for broadly defined than DSM-IV GAD, though few of these differences are statistically significant. Results suggest that subthreshold manifestations of GAD are significantly related to elevated risk of subsequent psychopathology. Further research is needed to determine whether broadening the current diagnostic criteria results in a more valid characterization of GAD.