Objective: Previous studies have established an association between number of traumatic experiences and alexithymia. The present study examines this relationship in a large-scale representative sample of the German general population (N=2,507) and explores the potential mediating effects of posttraumatic symptomatology, particularly avoidance/numbing. Methods: Alexithymia was assessed with the German version of the Toronto Alexithymia Scale (TAS-20). Posttraumatic symptomatology was operationalized by the symptom score of the modified German version of the Posttraumatic Symptom Scale, and traumatic experiences were assessed with the trauma list of the Munich Composite International Diagnostic Interview. Two mediation analyses were conducted. Results: Of the total sample, 24.2% (n=606) reported at least one traumatic experience, 10.6% (n=258) were classified as alexithymic, and 2.4% (n=59) fulfilled the criteria of posttraumatic stress disorder (PTSD). Participants who had survived five or more traumatic experiences had significantly higher alexithymia sum scores. The PTSD symptom cluster avoidance/numbing mediated the association between the number of traumatic experiences and alexithymia. Conclusions: Our findings illustrate an association between number of traumatic experiences and alexithymia and the influence of emotional avoidance and numbing within this relationship. The significant relationship between alexithymia and number of traumatic experiences in a general population sample further supports the concept of multiple and complex traumatization as associated with alexithymia. The results suggest the importance of further investigations determining the causal impact of alexithymia both as a potential premorbid trait and as consequence of traumatization. Lastly, future investigations are needed to clarify alexithymia as a distinct trauma-relevant characteristic for better diagnostics and specialized trauma-integrative therapy.

L’état de stress post-traumatique (PTSD) est un trouble anxieux, lié au stress, souvent observé chez les soldats revenant de conflits armés, les victimes de guerre ou de catastrophes naturelles, mais qui peut également survenir après exposition à des situations plus « communes » dans les pays occidentaux en temps de paix, tels les accidents de la route ou les agressions sexuelles. Le PTSD est caractérisé par des troubles des fonctions exécutives (attention, mémoire de travail), associés à des anomalies cérébrales morphologiques et fonctionnelles. Cette thèse de doctorat a permis de caractériser les effets morphologiques et fonctionnels des différents traitements actuellement reconnus de première ligne pour les troubles anxieux et le trouble dépressif majeur, indiquant un effet « top-down » de normalisation des aires frontales par les traitements psychothérapiques, alors que les traitements pharmacologiques semblent avoir un effet « bottom-up » de normalisation des aires limbiques. De plus, dans une seconde étude, nous avons montré l’importance de l’étude de réseaux cérébraux impliqués dans la performance de tâches cognitives telles des tâches de mémoire. Ces réseaux se trouvent dérégulés dans la pathologie post-traumatique, conduisant à leur inefficacité, et provoquant une impossibilité pour les patients de pouvoir répondre correctement à la tâche proposée. Finalement, nous avons pu mettre en place un protocole de recherche clinique ambitieux de part son design longitudinal (visite à 1 mois, puis suivi à 6 mois) permettant de comprendre les étapes précoces du développement du PTSD chez des victimes d’agressions sexuelles. Cette étude allie mesures neuropsychologiques des fonctions exécutives, mesures biologiques de l’axe hypothalamo-hypophyso-surrénalien (cortisol salivaire) et des mesures de neuroimagerie structurale (IRM, DTI), fonctionnelle (IRMf, ASL), incluant des mesures de connectivité cérébrale (structurale, fonctionnelle). / Posttraumatic stress disorder (PTSD) is an anxiety, stress-related disorder, often seen in soldiers returning from armed conflict, victims of war or natural disasters, but can also occur after exposure to more « common » situations in Western countries, such as motor vehicle accidents or sexual assault. PTSD is characterized by executive functioning impairments (attention, working memory) associated with morphological and functional brain abnormalities. This thesis aimed to characterize the morphological and functional effects of different treatments currently recognized as first line for anxiety disorders and major depressive disorder, indicating a « top-down » effect of normalization of frontal areas for psychotherapeutic treatments, while pharmacological treatments seem to lead to a « bottom-up » normalization effect in limbic areas. In addition, in a second study, we demonstrated the importance of the study of brain networks involved in the performance of cognitive tasks such as memory tasks. These networks are deregulated in PTSD, leading to their inefficiency, and therefore to PTSD patient’s inability to perform the required task correctly. Finally, we have set up an ambitious longitudinal (1 month and 6 months) clinical research protocol, investigating early stages of PTSD development in victims of sexual assault. This study combines neuropsychological measures of executive functions, biological measures of the hypothalamic-pituitary-adrenal axis (salivary cortisol) and measures of structural (MRI, DTI) and functional imaging (fMRI, ASL), including measures of brain connectivity (structural, functional).

O transtorno de humor associado ao transtorno de estresse pós-traumático (TEPT) tem, em geral, desfechos clínicos mais graves. Embora essa associação esteja consolidada no transtorno depressivo, esse não é o caso no transtorno bipolar (TB). Os poucos estudos realizados acerca dessa comorbidade demonstraram piora na qualidade de vida e aumento no número de tentativas de suicídio associado aos pacientes com TEPT e TB. Nenhum estudo, entretanto, avaliou o impacto do TEPT em características centrais do TB, como o número de episódios de humor ou funcionamento psicossocial. Por outro lado, estudos pré-clínicos sugerem que existe um fenômeno de sensibilização cruzada entre o TB e o TEPT. Foi proposto que a redução do brain-derived neurotrophic fator (BDNF) e alterações de marcadores inflamatórios poderiam ser mecanismos associados a esta sensibilização. Com relação a última hipótese, as alterações em marcadores inflamatórios estão bem consolidadas no TB, porém esse não é o caso no TEPT. Com a finalidade de aprofundar o estudo dessas questões, os dois primeiros estudos que compõem essa tese abordaram aspectos clínicos e biológicos relacionados a esses transtornos. O primeiro é uma metanálise e metaregressão que demonstrou que o TEPT está associado a níveis aumentados de IL-6, IL-1β, TNF-α e interferon-γ na circulação periférica. Além disso, o tempo de doença foi positivamente associado aos níveis de IL-1β, enquanto a gravidade dos sintomas foi positivamente associada aos níveis de IL-6. Esses achados podem não só apresentar um novo mecanismo biológico para explicar o fenômeno de sensibilização cruzada entre TEPT e TB, mas também abre novos horizontes na busca de novas estratégias terapêuticas e diagnósticas para o TEPT. O segundo foi um estudo caso-controle que avaliou características clínicas centrais do TB e demonstrou pela primeira vez que indivíduos com TB e comorbidade com TEPT apresentam mais episódios maníacos e pior funcionamento psicossocial. Ademais, o início dos episódios maníacos e o uso de substâncias de abuso surgiram de maneira mais precoce nesses indivíduos. Além desses dois estudos, optamos por abordar a influência da comorbidade com os transtornos ansiosos (como o TEPT) em um desfecho clínico trágico em pacientes com transtorno de humor: o suicídio. Esse estudo foi realizado em uma população diferente da do estudo clínico anterior, incluindo pacientes com depressão maior ou com TB, e foi focado em apenas um desfecho. Nosso objetivo era criar uma ferramenta que pudesse gerar um escore de probabilidade para cada paciente com transtorno de humor que refletisse o risco de tentar suicídio. Utilizando técnicas de machine learning, demonstramos que o risco de suicídio em indivíduos com transtorno de humor pode ser estimado objetivamente a partir de variáveis clínicas facilmente obtidas e variáveis demográficas. Embora tenhamos encontrado uma boa acurácia (72%) e área (area under the curve) (77%), futuros estudos podem integrar dados de variáveis de marcadores biológicos (genética, neuroimagem, neurocognição, etc.), usando também técnicas de machine learning, para atingir uma acurácia ainda maior. O uso de um instrumento objetivo é o primeiro passo na busca de um tratamento mais personalizado para aqueles pacientes com alto risco de se suicidar. / The comorbidity between mood disorders and posttraumatic stress disorder (PTSD) is associated with poorer clinical outcomes. Although this association is well established in major depressive disorder, fewer studies included patients with bipolar disorder (BD). These studies report that patients with BD and PTSD show increased number of suicide attempts and worse quality of life. However, no clinical studies so far have reported the impact of comorbid PTSD on core features of BD, such as number of mood episodes and functional impairment. On the other hand, preclinical studies showed that there is a cross-sensitization between BD and PTSD. Accordingly, it was proposed that the brain-derived neurotrophic factor (BDNF) and changes of inflammatory markers might be the biological underpinnings of this cross-sensitization. Although the changes in inflammatory markers are well established in BD, this is not the case for PTSD. In view of the above, the first two studies of this thesis addressed clinical and biological issues related to BD and PTSD. The first is a meta-analysis and metaregression study that showed increased levels of IL-6, IL-1β, TNF-α and interferon-γ in peripheral circulation among patients with PTSD. Furthermore, illness duration was positively associated with IL-1β levels, while the severity of the symptoms was positively associated with IL-6 levels. These findings may not only provide a new biological mechanism to explain the cross-sensitization between PTSD and BD, but also opens a new avenue in the search for new therapeutic targets and diagnostic strategies for PTSD. The second was a case-control study that assessed core clinical features of BD showed increased manic episodes and functional impairment among patients with BD and comorbid PTSD. In addition, those patients were younger when they started the manic episodes and substance use. Moreover, we chose to address the influence of comorbid anxiety disorders (such as PTSD) in suicide in patients with mood disorders. This study was conducted in a different population, including patients with major depressive disorder or BD, and it was focused on only one outcome. Suicide is a tragic clinical outcome, but highly preventable. Our aim was to develop a clinical tool using machine learning techniques to estimate a probability score at individual level to stratify the risk of a patient with a mood disorder attempts suicide. Therefore, our study showed that the risk of suicide in individuals with a mood disorder can be objectively estimated from easily assessed clinical and demographic variables. Although we have found a good accuracy (72%) and area under the curve (77%), future studies may integrate data from biological markers (genetic, neuroimaging, neurocognition, etc.) also using machine learning techniques to achieve a higher accuracy. This objective instrument is the first step towards a more personalized treatment for those patients at high risk of suicide.

Abstract The diploma thesis on the theme ?Factors influencing adolescents´ opinion on issues of the domestic violence? deals in the theoretical part with all important aspects of the domestic violence and stalking. The research part has been focused on adolescents aged 17 to 19 years living in Vysočina region, the research sample has consisted of 858 respondents. The aim of the thesis was to find out, by statistical methods on a statistically significant sample of adolescents, key factors influencing the adolescents´ opinion on the issue of the domestic violence. In relation to the aim of the thesis there were determined following hypotheses, which were tested on 5% significance level with six survey questions. Hypothesis 1: ?Statistically significant factor for the domestic violence among adolescents is their personal experience? was confirmed in four areas. Respondents having the personal experience with the domestic violence differ from the respondents without such experience in the following: they are more aware of a possibility of a partner´s violence at their age, they more refuse to tolerate the domestic violence, they better recognize a definition of the domestic violence and they are often aware of a possibility of a trans-generation transmission of the violence. In connection with this hypothesis it is important the finding, that 57 respondents (7%) have their personal experience with the domestic violence; 49 girls and 8 boys. Hypothesis 2: ?Statistically significant factor for the domestic violence among adolescents is the education? was not confirmed due to a low variability of responses and insufficient data to evaluate the hypothesis. Hypothesis 3: ?Statistically significant factor for the domestic violence among adolescents is the gender (women)? was confirmed in two areas. Girls differ from boys in the following: they are more aware of a possibility of the partner´s violence at their age and they more refuse to tolerate the domestic violence. The diploma thesis can serve as a source of current information related to the issue of the domestic violence, it provides an up-to-date data on the prevalence of the domestic violence in the adolescence and it presents information and opinions of adolescents on the domestic violence or partner relationship. The thesis can be used by professionals as well as lay public interested in the domestic violence and it can be a basis or a comparison for other studies and researches.

Introduction: Recent developments in the study of trauma responses have shown how some people may experience positive and life altering changes following traumatic life events which have been described as posttraumatic growth. Research is beginning to examine the role of trauma treatments in the facilitation of posttraumatic growth. Aim: This study sets out to explore participants’ experiences of posttraumatic growth during Eye Movement Desensitization and Reprocessing therapy, and the role of the therapeutic relationship in facilitating posttraumatic growth. Method: Semi-structured interviews were carried out with participants to examine their phenomenological experiences. Methodology: Interpretative Phenomenological Analysis was employed to consider emergent meanings and themes within a hermeneutic circle of interpretation. Participants: Seven participants were interviewed who had received Eye Movement Desensitization and Reprocessing therapy within National Health Service primary care psychological therapy services for posttraumatic stress disorder. Findings: Four superordinate themes emerged from the analysis of the participant accounts including: (i) Safe and secure; (ii) Taking back control; (iii) Reconstructing the self; and (iv) Journeying beyond trauma to the future. Conclusions: Person-centred conditions and client-therapist attachment were important elements of the therapeutic relationship which provided participants with the safety, trust, and relational depth necessary for the facilitation of experiences of posttraumatic growth during Eye Movement Desensitization and Reprocessing therapy. Implications: The findings emphasise the importance of a clinical focus on the quality of the therapeutic relationship as a facilitative therapeutic environment allowing affective-cognitive processing and the emergence of posttraumatic growth.

abstract: Decades of research and empirical studies support the belief that traumatic life events lead to a multitude of negative outcomes (Tedeschi & Calhoun, 1996), however, new research suggests that some survivors of trauma experience significant psychological growth, known as posttraumatic growth (PTG) (Tedeschi, Park, & Calhoun, 1998). The current study focused on the trauma of a traumatic brain injury (TBI) and its relation to the development of PTG. A TBI is both a psychological trauma and a type of acquired brain injury that occurs when physical injury causes damage to the brain (National Institutes of Health [NIH], 2013). Empirical studies examining TBIs and PTG are minimal. The current study focused on survivors who have sustained a TBI from a motor vehicle accident to help control for contextual factors of the injury that are known to affect outcomes. The aim of this study was to elucidate the physical, sociodemographic, contextual, and psychological factors that helped predict the development of PTG among a population of TBI survivors. In addition, another aim of this study was to gain a better understanding of the relationship between PTG and posttraumatic stress disorder (PTSD) symptomatology. Cross-sectional data from self-identified TBI survivors of motor vehicle accidents (n = 155) were used to construct a model of prediction of PTG. Preliminary analyses revealed a reliability issue with the measure that assessed participants’ personality, and these variables were not used in planned analyses. Results revealed that the majority of participants were female, Caucasian, highly educated, and unemployed. Overall, the sample indicated significant injury severity, disability, and lower than average mental and physical functioning. The final model accounted for approximately 15% of the variance in PTG and significant predictors included: gender, time since injury, and the interaction between PTSD symptoms and time since injury. The findings of this research can help inform treatment programs and rehabilitation services as well as funding that can aim to improve outcomes from survivors of TBI. Study limitations included the use of cross-sectional data, a homogenous and unrepresentative sample of TBI survivors, recruitment concerns, and low reliability observed in one of the integral measures of the study. / Dissertation/Thesis / Doctoral Dissertation Counseling Psychology 2016

L’objectif de cette thèse a été de comprendre les mécanismes cérébraux associés aux symptômes du trouble de stress post-traumatique (TSPT), ainsi que les mécanismes cérébraux modulés par la disparition des symptômes, en utilisant la thérapie de désensibilisation et de retraitement de l’information par les mouvements oculaires (Thérapie EMDR). Cette thérapie associe rappel du traumatisme et stimulations bilatérales alternées (SBA). Premièrement, en utilisant l’IRM fonctionnelle (IRMf), nous avons mis en évidence une altération de l’activité fonctionnelle du système de récompense dans le TSPT, correspondant à une mobilisation déséquilibrée des processus motivationnels cognitifs et hédoniques (étude 1). Deuxièmement, par l’intermédiaire d’une étude en IRMf au repos, nous avons montré que les patients présentent des altérations de connectivité fonctionnelle entre un réseau neuronal impliqué dans les processus mnésiques et émotionnels, et un réseau neuronal impliqué dans les processus attentionnels (étude 2). Troisièmement, nous avons montré que les structures initialement altérées par la pathologie évoluent après rémission symptomatique, suggérant un rétablissement des altérations neuronales induites par le stress chronique (étude 3). Enfin, nous avons montré que les SBA employées dans la thérapie EMDR facilitent l’extinction de la peur ainsi que la récupération de cette extinction au sein d’un groupe de volontaires sains (étude 4). Ainsi, ces travaux offrent de nouvelles perspectives en termes de modélisation de la pathologie, et offre de nouvelles pistes de réflexion quant à la prise en charge thérapeutique de ce trouble. / Posttraumatic Stress Disorder (PTSD) is a debilitating psychiatric disorder that arises in the aftermath of a traumatic event. To date, the Eye Movement Desensitization and Reprocessing therapy (EMDR) therapy has shown to be the most efficient therapy for the treatment of PTSD. The aim of this thesis was therefore to understand neural mechanisms underlying PTSD and its recovery. To do so, we conducted four studies. In a first study, we showed alterations in the reward circuit activity in PTSD patients, which may underlie an imbalance mobilization of cognitive and hedonic motivational processes, possibly contributing to emotional numbing in PTSD (study 1). Following this, an altered resting state functional connectivity between a network associated with attentional processes and another associated with emotional and memory processes was also found, suggesting an atypical emotional regulation and attention processing (study 2). A third study showed changes of grey matter density in regions involved in emotional regulation after symptoms remission by EMDR therapy. Finally, we were also able to replicate, in PTSD patients, the fear extinction and fear extinction recall facilitation by bilateral alternating stimulations (BAS) a major component of EMDR therapy, previously demonstrated in animal studies. Taken together, the present findings of these studies contribute to enlarge our knowledge, opening new ways of thinking the actual model of explaining the PTSD. More importantly, we believe that our findings may contribute to improve therapeutic strategies to significantly ameliorate the life of these patients.

Posttraumatic stress disorder (PTSD) is triggered after exposure to a traumatic event (experienced or witnessed) and its main symptomatology is composed of groups of avoidant, intrusive and hyperexcitability symptoms. It is estimated that 60.7% of men and 51.2% of women will experience at least one traumatic event during life and 8% of men and 20% of women will develop the disease. PTSD is associated with personal and economic costs, poor quality of life and about 1/3 of individuals will develop chronic symptoms despite adequate treatment. In January 2013, a fire of great proportions in a nightclub in Santa Maria-RS, known as KISS Nightclub, killed 242 young people and left hundreds with physical and psychological sequels. The great impact of this event caused an increase in the prevalence of several psychiatric disorders, among them PTSD. Given this, and the lack of effectiveness of standard treatment, other treatment strategies are necessary. Noninvasive neuromodulation techniques, such as Transcranial Direct Current Stimulation (tDCS), have been shown to be promising in the treatment of neuropsychiatric disorders. tDCS consists of the passage of small intensity electric current through the brain through electrodes, in order to modulate cortical excitability. It is an open experimental study with 8 patients whose primary objective was to evaluate the tDCS effect on PTSD symptoms, with exploratory analyzes to evaluate the effects on cognition and depressive and anxious symptoms. After treatment, there was improvement in PTSD symptoms, depression and anxiety, and these effects were maintained throughout the first month after treatment. The positive effects on cognition started slowly and progressively and were significant when assessed after 30 days of treatment. / O Transtorno do Estresse pós-Traumático (TEPT) é desencadeado após a exposição a um evento traumático (vivenciado ou testemunhado) e sua principal sintomatologia é composta por grupos de sintomas evitativos, intrusivos e de hiperexcitabilidade. Estima-se que 60,7% dos homens e 51,2% das mulheres experienciarão pelo menos um evento traumático durante a vida e que 8% dos homens e 20% das mulheres desenvolverão a doença. O TEPT está associado a custos pessoais e econômicos, qualidade de vida pobre e cerca de 1/3 dos indivíduos desenvolverão sintomas crônicos apesar do tratamento adequado. Em janeiro de 2013, um incêndio de grandes proporções em uma casa noturna em Santa Maria-RS, conhecida como Boate KISS, matou 242 jovens e deixou outras centenas com sequelas físicas e psicológicas. O grande impacto desse evento ocasionou aumento da prevalência de diversas patologias psiquiátricas, entre elas o TEPT. Diante disso, e da pouca efetividade do tratamento padrão, outras estratégias de tratamento se fazem necessárias. As técnicas de neuromodulação não invasiva, entre elas a Estimulação Transcraniana por Corrente Contínua (ETCC) têm se mostrado promissoras no tratamento de transtornos neuropsiquiátricos. A ETCC consiste na passagem de corrente elétrica de pequena intensidade pelo cérebro, através de eletrodos, com a finalidade de modular a excitabilidade cortical. Trata-se de um estudo experimental aberto com 8 pacientes cujo objetivo primário foi avaliar o efeito da ETCC nos sintomas de TEPT, com análises exploratórias para avaliar os efeitos em cognição e sintomas depressivos e ansiosos. Após o tratamento, houve melhora dos sintomas de TEPT, de depressão e de ansiedade, e esses efeitos se mantiveram durante todo o 1º mês após o tratamento. Os efeitos positivos na cognição iniciaram-se lenta e progressivamente e foram significativos quando avaliados após 30 dias do tratamento.

O transtorno de humor associado ao transtorno de estresse pós-traumático (TEPT) tem, em geral, desfechos clínicos mais graves. Embora essa associação esteja consolidada no transtorno depressivo, esse não é o caso no transtorno bipolar (TB). Os poucos estudos realizados acerca dessa comorbidade demonstraram piora na qualidade de vida e aumento no número de tentativas de suicídio associado aos pacientes com TEPT e TB. Nenhum estudo, entretanto, avaliou o impacto do TEPT em características centrais do TB, como o número de episódios de humor ou funcionamento psicossocial. Por outro lado, estudos pré-clínicos sugerem que existe um fenômeno de sensibilização cruzada entre o TB e o TEPT. Foi proposto que a redução do brain-derived neurotrophic fator (BDNF) e alterações de marcadores inflamatórios poderiam ser mecanismos associados a esta sensibilização. Com relação a última hipótese, as alterações em marcadores inflamatórios estão bem consolidadas no TB, porém esse não é o caso no TEPT. Com a finalidade de aprofundar o estudo dessas questões, os dois primeiros estudos que compõem essa tese abordaram aspectos clínicos e biológicos relacionados a esses transtornos. O primeiro é uma metanálise e metaregressão que demonstrou que o TEPT está associado a níveis aumentados de IL-6, IL-1β, TNF-α e interferon-γ na circulação periférica. Além disso, o tempo de doença foi positivamente associado aos níveis de IL-1β, enquanto a gravidade dos sintomas foi positivamente associada aos níveis de IL-6. Esses achados podem não só apresentar um novo mecanismo biológico para explicar o fenômeno de sensibilização cruzada entre TEPT e TB, mas também abre novos horizontes na busca de novas estratégias terapêuticas e diagnósticas para o TEPT. O segundo foi um estudo caso-controle que avaliou características clínicas centrais do TB e demonstrou pela primeira vez que indivíduos com TB e comorbidade com TEPT apresentam mais episódios maníacos e pior funcionamento psicossocial. Ademais, o início dos episódios maníacos e o uso de substâncias de abuso surgiram de maneira mais precoce nesses indivíduos. Além desses dois estudos, optamos por abordar a influência da comorbidade com os transtornos ansiosos (como o TEPT) em um desfecho clínico trágico em pacientes com transtorno de humor: o suicídio. Esse estudo foi realizado em uma população diferente da do estudo clínico anterior, incluindo pacientes com depressão maior ou com TB, e foi focado em apenas um desfecho. Nosso objetivo era criar uma ferramenta que pudesse gerar um escore de probabilidade para cada paciente com transtorno de humor que refletisse o risco de tentar suicídio. Utilizando técnicas de machine learning, demonstramos que o risco de suicídio em indivíduos com transtorno de humor pode ser estimado objetivamente a partir de variáveis clínicas facilmente obtidas e variáveis demográficas. Embora tenhamos encontrado uma boa acurácia (72%) e área (area under the curve) (77%), futuros estudos podem integrar dados de variáveis de marcadores biológicos (genética, neuroimagem, neurocognição, etc.), usando também técnicas de machine learning, para atingir uma acurácia ainda maior. O uso de um instrumento objetivo é o primeiro passo na busca de um tratamento mais personalizado para aqueles pacientes com alto risco de se suicidar. / The comorbidity between mood disorders and posttraumatic stress disorder (PTSD) is associated with poorer clinical outcomes. Although this association is well established in major depressive disorder, fewer studies included patients with bipolar disorder (BD). These studies report that patients with BD and PTSD show increased number of suicide attempts and worse quality of life. However, no clinical studies so far have reported the impact of comorbid PTSD on core features of BD, such as number of mood episodes and functional impairment. On the other hand, preclinical studies showed that there is a cross-sensitization between BD and PTSD. Accordingly, it was proposed that the brain-derived neurotrophic factor (BDNF) and changes of inflammatory markers might be the biological underpinnings of this cross-sensitization. Although the changes in inflammatory markers are well established in BD, this is not the case for PTSD. In view of the above, the first two studies of this thesis addressed clinical and biological issues related to BD and PTSD. The first is a meta-analysis and metaregression study that showed increased levels of IL-6, IL-1β, TNF-α and interferon-γ in peripheral circulation among patients with PTSD. Furthermore, illness duration was positively associated with IL-1β levels, while the severity of the symptoms was positively associated with IL-6 levels. These findings may not only provide a new biological mechanism to explain the cross-sensitization between PTSD and BD, but also opens a new avenue in the search for new therapeutic targets and diagnostic strategies for PTSD. The second was a case-control study that assessed core clinical features of BD showed increased manic episodes and functional impairment among patients with BD and comorbid PTSD. In addition, those patients were younger when they started the manic episodes and substance use. Moreover, we chose to address the influence of comorbid anxiety disorders (such as PTSD) in suicide in patients with mood disorders. This study was conducted in a different population, including patients with major depressive disorder or BD, and it was focused on only one outcome. Suicide is a tragic clinical outcome, but highly preventable. Our aim was to develop a clinical tool using machine learning techniques to estimate a probability score at individual level to stratify the risk of a patient with a mood disorder attempts suicide. Therefore, our study showed that the risk of suicide in individuals with a mood disorder can be objectively estimated from easily assessed clinical and demographic variables. Although we have found a good accuracy (72%) and area under the curve (77%), future studies may integrate data from biological markers (genetic, neuroimaging, neurocognition, etc.) also using machine learning techniques to achieve a higher accuracy. This objective instrument is the first step towards a more personalized treatment for those patients at high risk of suicide.

O transtorno de humor associado ao transtorno de estresse pós-traumático (TEPT) tem, em geral, desfechos clínicos mais graves. Embora essa associação esteja consolidada no transtorno depressivo, esse não é o caso no transtorno bipolar (TB). Os poucos estudos realizados acerca dessa comorbidade demonstraram piora na qualidade de vida e aumento no número de tentativas de suicídio associado aos pacientes com TEPT e TB. Nenhum estudo, entretanto, avaliou o impacto do TEPT em características centrais do TB, como o número de episódios de humor ou funcionamento psicossocial. Por outro lado, estudos pré-clínicos sugerem que existe um fenômeno de sensibilização cruzada entre o TB e o TEPT. Foi proposto que a redução do brain-derived neurotrophic fator (BDNF) e alterações de marcadores inflamatórios poderiam ser mecanismos associados a esta sensibilização. Com relação a última hipótese, as alterações em marcadores inflamatórios estão bem consolidadas no TB, porém esse não é o caso no TEPT. Com a finalidade de aprofundar o estudo dessas questões, os dois primeiros estudos que compõem essa tese abordaram aspectos clínicos e biológicos relacionados a esses transtornos. O primeiro é uma metanálise e metaregressão que demonstrou que o TEPT está associado a níveis aumentados de IL-6, IL-1β, TNF-α e interferon-γ na circulação periférica. Além disso, o tempo de doença foi positivamente associado aos níveis de IL-1β, enquanto a gravidade dos sintomas foi positivamente associada aos níveis de IL-6. Esses achados podem não só apresentar um novo mecanismo biológico para explicar o fenômeno de sensibilização cruzada entre TEPT e TB, mas também abre novos horizontes na busca de novas estratégias terapêuticas e diagnósticas para o TEPT. O segundo foi um estudo caso-controle que avaliou características clínicas centrais do TB e demonstrou pela primeira vez que indivíduos com TB e comorbidade com TEPT apresentam mais episódios maníacos e pior funcionamento psicossocial. Ademais, o início dos episódios maníacos e o uso de substâncias de abuso surgiram de maneira mais precoce nesses indivíduos. Além desses dois estudos, optamos por abordar a influência da comorbidade com os transtornos ansiosos (como o TEPT) em um desfecho clínico trágico em pacientes com transtorno de humor: o suicídio. Esse estudo foi realizado em uma população diferente da do estudo clínico anterior, incluindo pacientes com depressão maior ou com TB, e foi focado em apenas um desfecho. Nosso objetivo era criar uma ferramenta que pudesse gerar um escore de probabilidade para cada paciente com transtorno de humor que refletisse o risco de tentar suicídio. Utilizando técnicas de machine learning, demonstramos que o risco de suicídio em indivíduos com transtorno de humor pode ser estimado objetivamente a partir de variáveis clínicas facilmente obtidas e variáveis demográficas. Embora tenhamos encontrado uma boa acurácia (72%) e área (area under the curve) (77%), futuros estudos podem integrar dados de variáveis de marcadores biológicos (genética, neuroimagem, neurocognição, etc.), usando também técnicas de machine learning, para atingir uma acurácia ainda maior. O uso de um instrumento objetivo é o primeiro passo na busca de um tratamento mais personalizado para aqueles pacientes com alto risco de se suicidar. / The comorbidity between mood disorders and posttraumatic stress disorder (PTSD) is associated with poorer clinical outcomes. Although this association is well established in major depressive disorder, fewer studies included patients with bipolar disorder (BD). These studies report that patients with BD and PTSD show increased number of suicide attempts and worse quality of life. However, no clinical studies so far have reported the impact of comorbid PTSD on core features of BD, such as number of mood episodes and functional impairment. On the other hand, preclinical studies showed that there is a cross-sensitization between BD and PTSD. Accordingly, it was proposed that the brain-derived neurotrophic factor (BDNF) and changes of inflammatory markers might be the biological underpinnings of this cross-sensitization. Although the changes in inflammatory markers are well established in BD, this is not the case for PTSD. In view of the above, the first two studies of this thesis addressed clinical and biological issues related to BD and PTSD. The first is a meta-analysis and metaregression study that showed increased levels of IL-6, IL-1β, TNF-α and interferon-γ in peripheral circulation among patients with PTSD. Furthermore, illness duration was positively associated with IL-1β levels, while the severity of the symptoms was positively associated with IL-6 levels. These findings may not only provide a new biological mechanism to explain the cross-sensitization between PTSD and BD, but also opens a new avenue in the search for new therapeutic targets and diagnostic strategies for PTSD. The second was a case-control study that assessed core clinical features of BD showed increased manic episodes and functional impairment among patients with BD and comorbid PTSD. In addition, those patients were younger when they started the manic episodes and substance use. Moreover, we chose to address the influence of comorbid anxiety disorders (such as PTSD) in suicide in patients with mood disorders. This study was conducted in a different population, including patients with major depressive disorder or BD, and it was focused on only one outcome. Suicide is a tragic clinical outcome, but highly preventable. Our aim was to develop a clinical tool using machine learning techniques to estimate a probability score at individual level to stratify the risk of a patient with a mood disorder attempts suicide. Therefore, our study showed that the risk of suicide in individuals with a mood disorder can be objectively estimated from easily assessed clinical and demographic variables. Although we have found a good accuracy (72%) and area under the curve (77%), future studies may integrate data from biological markers (genetic, neuroimaging, neurocognition, etc.) also using machine learning techniques to achieve a higher accuracy. This objective instrument is the first step towards a more personalized treatment for those patients at high risk of suicide.