<p>Individuals afflicted with childhood and adolescent mental disorders have an increased risk for poor outcome in adulthood. The progression of psychopathology from childhood to adult life may be influenced by a multitude of interacting variables, both biological and psychosocial. There is limited information on the relationships between child psychopathology and adult personality and personality disorders. The main aim of this thesis was therefore to gain better knowledge concerning adult personality outcome in patients with early onset of mental disorders. </p><p>Former child psychiatric patients as compared to controls had a significantly higher prevalence of all DSM-IV personality disorders (38.0 vs. 10.9 percent, p<0.001) and also a considerably higher personality disorder co-morbidity. They also had more psychosocial and environmental problems. This was exaggerated in those diagnosed with a personality disorder. Major depression, disruptive disorders and substance use disorders at a young age were strong predictors for adult personality disorder.</p><p>Patients with an early onset major depression had more personality disorders and more deviant personality traits than those with a late onset. </p><p>Forensic psychiatric male patients diagnosed with a previous conduct disorder as compared to those without had more cluster B personality disorders, and more repeated violent criminality and mixed abuse. They also exhibited more deviant personality traits and higher psychopathy scores.</p><p>The instrument "Child and Adolescent Psychiatric Screening Inventory-Retrospect" had acceptable sensitivity and specificity for assessment of child psychiatric disorders. Subscales demonstrated good internal reliability (Crohnbach´s alpha = 0.76-0.93).</p><p>The results suggest that adult personality disturbances are prevalent in individuals affected with mental problems at young ages. A better understanding of the transition of psychopathology from childhood to adulthood and a better identification of those at risk will be of help in attempts to prevent permanent impact on the adult personality.</p>

The familial aggregation of Major Depressive Disorder (MDD) has been repeatedly demonstrated. Several studies have investigated associations between various clinical characteristics of MDD in probands and overall rates of MDD in relatives. Few studies, however, have considered the familial aggregation of clinical characteristics of MDD. The aim of the present report is to examine mother–offspring associations of a variety of clinical characteristics of MDD in a general population sample. Data were derived from baseline and 4-year-follow-up data of 933 adolescents and their biological mothers of the Early Developmental Stages of Psychopathology (EDSP) study, a prospective-longitudinal community study. MDD and its characteristics were assessed with the Munich-Composite International Diagnostic Interview. We found that children of mothers who had a lifetime history of severe MDD and high number of symptoms, high impairment and/or melancholia, revealed elevated odds of MDD regarding the same characteristics as their mothers (ORs between 5.2 and 13.9). The observed associations did not differ by the children’s sex. DSM-IV melancholia and severity as well as impairment were found to aggregate within families. This finding can be interpreted as a validation of the DSM-IV MDD severity subtypes as well as of the melancholic specifier. Severe and melancholic MDD reveal a considerable high degree of familiar aggregation making the search for mechanisms involved in the familiar transmission of these forms of MDD particularly promising.

Conflict resolution is essential for human cognitive system which renders adaptability to the environment, providing humans to fulfill daily activities. The main aim of this thesis is to create a task where the conflict activates emotional networks exclusively, while investigating how the cognitive and emotional conflicts are monitored and then resolved in the brain. After creating the appropriate material composed of controlled words in terms of emotional dimensions and concreteness values, a new Word-face Stroop Task is designed using Turkish words. Firstly subjects participated in a classical Stroop task to measure cognitive conflict and then in the Word-face Stroop task, the conflict between emotional words and emotional faces is investigated. The same Stroop tasks are then administered to depression patients. The results of the classical Stroop replicated the previous findings: (1) Healthy population was slower in responding to incongruent cases than congruent cases (2) Depressed patients were significantly slower than healthy population. The Word-face Stroop, conducted on healthy population also replicated the earlier findings: (1) People were slower in reacting to incongruent stimuli than congruent stimuli (2) People reacted faster to positive words than negative ones. Same Stroop tasks conducted on depressed patients however revealed interesting results, novel to the literature: (1) Congruency scores were significantly different when healthy population and Depressive Disorder patients with Hamilton scores higher than 20 were compared (2) Patients with Hamilton scores higher than 20 and lower than 20 significantly differed in congruency scores (3) Patients showed a tendency to react faster to incongruent stimuli rather than congruent stimuli, contrary to normal population (4) Normal population showed greater congruency effect in positively valenced abstract words, whereas depression patients showed greater congruency effect in negatively valenced concrete words.

Individuals afflicted with childhood and adolescent mental disorders have an increased risk for poor outcome in adulthood. The progression of psychopathology from childhood to adult life may be influenced by a multitude of interacting variables, both biological and psychosocial. There is limited information on the relationships between child psychopathology and adult personality and personality disorders. The main aim of this thesis was therefore to gain better knowledge concerning adult personality outcome in patients with early onset of mental disorders. Former child psychiatric patients as compared to controls had a significantly higher prevalence of all DSM-IV personality disorders (38.0 vs. 10.9 percent, p&lt;0.001) and also a considerably higher personality disorder co-morbidity. They also had more psychosocial and environmental problems. This was exaggerated in those diagnosed with a personality disorder. Major depression, disruptive disorders and substance use disorders at a young age were strong predictors for adult personality disorder. Patients with an early onset major depression had more personality disorders and more deviant personality traits than those with a late onset. Forensic psychiatric male patients diagnosed with a previous conduct disorder as compared to those without had more cluster B personality disorders, and more repeated violent criminality and mixed abuse. They also exhibited more deviant personality traits and higher psychopathy scores. The instrument "Child and Adolescent Psychiatric Screening Inventory-Retrospect" had acceptable sensitivity and specificity for assessment of child psychiatric disorders. Subscales demonstrated good internal reliability (Crohnbach´s alpha = 0.76-0.93). The results suggest that adult personality disturbances are prevalent in individuals affected with mental problems at young ages. A better understanding of the transition of psychopathology from childhood to adulthood and a better identification of those at risk will be of help in attempts to prevent permanent impact on the adult personality.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Background: Major depressive disorder is a debilitating psychiatric condition with high rates of treatment resistance that may be associated with working memory (WM) deficits. For treatment resistant depression (TRD) patients, deep brain stimulation (DBS) is emerging as an effective therapeutic option. Objective: To determine if electroencephalography signals recorded during DBS ON and OFF states while performing WM tasks can serve as biomarkers of therapeutic efficacy for DBS in TRD patients. Results: DBS stimulation suppressed frontal gamma oscillations (30–50Hz) during the ON state relative to the OFF state, an effect that was more pronounced with higher WM load. This suppression strongly correlated with depressive symptoms reduction. Conclusion: Suppression of gamma oscillations by DBS is likely mediated by indirect activation of inhibitory circuits in the frontal cortex. It represents a potential treatment biomarker for DBS in TRD and may lead to more tailored treatment parameters that can result in enhanced efficacy.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

The stress response that is triggered in an organism when facing a stressor is crucial to maintain stability and health. However, exposure to a severe or a chronic stressor can be maladaptive and cause several impairments in the body, such as cardiovascular diseases, atrophy of the brain, and psychopathologies mainly characterized by anxiety and depression. Resilience or vulnerability to stress is mediated through different biopsychosocial factors, one of which is the use of coping strategies. Different types of coping strategies have been linked to either adaptive or maladaptive outcomes, and are an important factor to consider regarding stress resilience. Cultural differences in symptoms of stress, anxiety, depression, and coping strategies were assessed through self-report measurements in the form of two questionnaires. 75 Swedes and 67 Sri Lankans between the age of 18-50 took part in the study. The most significant findings of this study suggest that 1) Sri Lankans experience more symptoms of stress, anxiety, and depression compared to Swedes, 2) dysfunctional coping is correlated with higher levels of stress, anxiety, and depression in both Sweden and Sri Lanka, 3) higher levels of stress predicts higher levels of anxiety and depression in both Sweden and Sri Lanka, and 4) both countries tend to favor problem-focused coping over emotion-focused and dysfunctional coping. A discussion regarding the current findings, including limitations of the study is provided, as well as directions for future research.

Os Transtornos psiquiátricos acompanham a história da humanidade. Classificados em categorias distintas podemos observar que dentre todas as patologias que constituem os transtornos mentais e de comportamento, as doenças mais prevalentes são as doenças de Ansiedade e de Transtorno Depressivo Maior (TDM). Mesmo com muitos avanços nas neurociências, assim como na terapêutica (psicofarmacologia), ainda hoje a fisiopatologia e o desenvolvimento farmacológico são áreas que necessitam intenso estudo. Avanços recentes tem sugerido que drogas capazes de modular os sistemas glutamatérgico e purinérgico possuem potencial efeito neuromodulador, sendo promissores candidatos para o desenvolvimento de novas drogas com ação ansiolítica e/ou antidepressiva. Dessa maneira, o objetivo desta tese foi investigar o potencial efeito ansiolítico da guanosina (GUO) em modelos animais preditivos para o estudo da potencial atividade ansiolítica de novos compostos, assim como seu potencial efeito antidepressivo no modelo animal de depressão da Bulbectomia Olfatória Bilateral (OBX). Inicialmente, nossos resultados demonstram que a administração de GUO foi capaz de produzir um consistente efeito ansiolítico modulando os níveis de adenosina (ADO) e glutamato cerebral. Ainda, pela primeira vez, foi observado que a GUO per se promoveu uma diminuição da liberação de glutamato em preparações de sinaptosomas de hipocampo, um efeito dependente da ativação dos receptores A1 de ADO. Após a caracterização do potencial efeito ansiolítico da GUO, nosso objetivo foi avaliar o potencial efeito antidepressivo da GUO em um modelo animal com validade de face e de constructo, como o modelo da OBX. Contudo, após revisão da literatura em estudos que utilizaram o modelo da OBX, observou-se a necessidade de uma investigação a longo prazo, das principais alterações comportamentais e neuroquímicas induzidas pela OBX. Nossos resultados, mostram pela primeira vez, que camundongos submetidos a OBX apresentaram simultaneamente alterações comportamentais e neuroquímicas transitórias e de longa duração. Ademais, as evidências indicam que o hipocampo possui alta susceptibilidade aos danos induzidos pela OBX, visto que uma sinaptotoxicidade transitória, acompanhada de um duradouro desequilíbrio redox e aumento da resposta inflamatória foram observados. Por fim, o tratamento crônico com GUO foi capaz de reverter a maioria das alterações identificadas previamente como duradouras nos parâmetros comportamentais e neuroquímicos no modelo da OBX. Considerando os resultados neuroquímicos obtidos pelos diferentes protocolos de tratamento realizados neste estudo, novas hipóteses de mecanismos de ação exercidos pela GUO foram apresentadas, e mecanismos já estabelecidos foram reproduzidos. Por fim, de uma maneira geral os dados apresentados nesta tese reforçam a hipótese do envolvimento do sistema purinérgico nos transtornos psiquiátricos, e sugerem que a GUO apresenta uma potencial ação terapêutica para o tratamento destas doenças, abrindo assim novas perspectivas para elucidação dos mecanismos envolvidos na fisiopatologia da ansiedade e TDM. / Psychiatric disorder had accompanied the course of human history. Mental and behavioral disorders are classified in different categories and among all different psychiatric disorders; anxiety and major depressive disorder (MDD) are the most prevalents. Despite the substantial advances in our knowledge on the neurobiological bases of both anxiety and MDD, as well as in the therapeutic area (psychopharmacology), even today, the pathophysiology of these disorders as well as pharmacological development are still under investigation. Recent advances have suggested that drugs able to modulate glutamatergic and purinergic systems present a potential neuromodulatory effect, and are promising candidates for the development of new drugs with both anxiolytic and antidepressant effects. Thus, the aim of this work was to investigate the potential guanosine (GUO) anxiolytic-like effects in predictive animal models largely used to elucidate anxiolytic properties of new compounds, as well as investigate the potential GUO antidepressant effect in Olfactory Bulbectomy (OBX) model of depression. Initially, our results demonstrate that acute GUO administration was able to induce a consistent anxiolytic-like effect, by modulating the adenosine and glutamate cerebrospinal levels. Here, for the first time, it was observed that GUO per se was able to decrease the glutamate release in hippocampal synaptosome. After characterizing the potential anxiolytic-like effect promoted by GUO, our second goal was to evaluate the potential GUO antidepressant-like effect in an animal model with recognized face and construct validity as the OBX model of depression. However, given the lack of studies in the literature considering the time course of the behavioral and neurochemical changes after the depressive-like behavior onset induced by OBX we firstly characterize some important features regarding the OBX model. Collectively, mice submitted to the OBX model of depression and followed up to 8 weeks simultaneously presented transient and long-lasting deleterious effects in behavioral and neurochemical parameters. The evidences pointed that hippocampus was the most affected brain structure, since a transient hippocampal-related synaptotoxicity, accompanied by a long-lasting hippocampal imbalance in redox and inflammatory homeostasis were observed. Additionally, the neurochemical effects seem to strengthen our behavioral findings. Finally, chronic GUO treatment, similarly to the classical tricyclic antidepressant imipramine, was able to improve the long-term behavioral phenotype impairment induced by OBX, specifically improving behavioral performances that require cognitive functions, accompanied by reversion of hippocampal redox imbalance parameters, as well as in peripheral and central anti-inflammatory IL-10 release. Thus, in present study, the pre-clinical evaluation of GUO as a potential drug for treatment of the most prevalent psychiatric disorders (anxiety and MDD) presented promising results. Furthermore, additional GUO mechanisms of action were evidenced and new perspectives were established. Thus, the data presented in this thesis support the hypothesis of the involvement of the purinergic system in mood disorders, and suggest that GUO has a potential therapeutic activity for the treatment of psychiatric disorders.

Os Transtornos psiquiátricos acompanham a história da humanidade. Classificados em categorias distintas podemos observar que dentre todas as patologias que constituem os transtornos mentais e de comportamento, as doenças mais prevalentes são as doenças de Ansiedade e de Transtorno Depressivo Maior (TDM). Mesmo com muitos avanços nas neurociências, assim como na terapêutica (psicofarmacologia), ainda hoje a fisiopatologia e o desenvolvimento farmacológico são áreas que necessitam intenso estudo. Avanços recentes tem sugerido que drogas capazes de modular os sistemas glutamatérgico e purinérgico possuem potencial efeito neuromodulador, sendo promissores candidatos para o desenvolvimento de novas drogas com ação ansiolítica e/ou antidepressiva. Dessa maneira, o objetivo desta tese foi investigar o potencial efeito ansiolítico da guanosina (GUO) em modelos animais preditivos para o estudo da potencial atividade ansiolítica de novos compostos, assim como seu potencial efeito antidepressivo no modelo animal de depressão da Bulbectomia Olfatória Bilateral (OBX). Inicialmente, nossos resultados demonstram que a administração de GUO foi capaz de produzir um consistente efeito ansiolítico modulando os níveis de adenosina (ADO) e glutamato cerebral. Ainda, pela primeira vez, foi observado que a GUO per se promoveu uma diminuição da liberação de glutamato em preparações de sinaptosomas de hipocampo, um efeito dependente da ativação dos receptores A1 de ADO. Após a caracterização do potencial efeito ansiolítico da GUO, nosso objetivo foi avaliar o potencial efeito antidepressivo da GUO em um modelo animal com validade de face e de constructo, como o modelo da OBX. Contudo, após revisão da literatura em estudos que utilizaram o modelo da OBX, observou-se a necessidade de uma investigação a longo prazo, das principais alterações comportamentais e neuroquímicas induzidas pela OBX. Nossos resultados, mostram pela primeira vez, que camundongos submetidos a OBX apresentaram simultaneamente alterações comportamentais e neuroquímicas transitórias e de longa duração. Ademais, as evidências indicam que o hipocampo possui alta susceptibilidade aos danos induzidos pela OBX, visto que uma sinaptotoxicidade transitória, acompanhada de um duradouro desequilíbrio redox e aumento da resposta inflamatória foram observados. Por fim, o tratamento crônico com GUO foi capaz de reverter a maioria das alterações identificadas previamente como duradouras nos parâmetros comportamentais e neuroquímicos no modelo da OBX. Considerando os resultados neuroquímicos obtidos pelos diferentes protocolos de tratamento realizados neste estudo, novas hipóteses de mecanismos de ação exercidos pela GUO foram apresentadas, e mecanismos já estabelecidos foram reproduzidos. Por fim, de uma maneira geral os dados apresentados nesta tese reforçam a hipótese do envolvimento do sistema purinérgico nos transtornos psiquiátricos, e sugerem que a GUO apresenta uma potencial ação terapêutica para o tratamento destas doenças, abrindo assim novas perspectivas para elucidação dos mecanismos envolvidos na fisiopatologia da ansiedade e TDM. / Psychiatric disorder had accompanied the course of human history. Mental and behavioral disorders are classified in different categories and among all different psychiatric disorders; anxiety and major depressive disorder (MDD) are the most prevalents. Despite the substantial advances in our knowledge on the neurobiological bases of both anxiety and MDD, as well as in the therapeutic area (psychopharmacology), even today, the pathophysiology of these disorders as well as pharmacological development are still under investigation. Recent advances have suggested that drugs able to modulate glutamatergic and purinergic systems present a potential neuromodulatory effect, and are promising candidates for the development of new drugs with both anxiolytic and antidepressant effects. Thus, the aim of this work was to investigate the potential guanosine (GUO) anxiolytic-like effects in predictive animal models largely used to elucidate anxiolytic properties of new compounds, as well as investigate the potential GUO antidepressant effect in Olfactory Bulbectomy (OBX) model of depression. Initially, our results demonstrate that acute GUO administration was able to induce a consistent anxiolytic-like effect, by modulating the adenosine and glutamate cerebrospinal levels. Here, for the first time, it was observed that GUO per se was able to decrease the glutamate release in hippocampal synaptosome. After characterizing the potential anxiolytic-like effect promoted by GUO, our second goal was to evaluate the potential GUO antidepressant-like effect in an animal model with recognized face and construct validity as the OBX model of depression. However, given the lack of studies in the literature considering the time course of the behavioral and neurochemical changes after the depressive-like behavior onset induced by OBX we firstly characterize some important features regarding the OBX model. Collectively, mice submitted to the OBX model of depression and followed up to 8 weeks simultaneously presented transient and long-lasting deleterious effects in behavioral and neurochemical parameters. The evidences pointed that hippocampus was the most affected brain structure, since a transient hippocampal-related synaptotoxicity, accompanied by a long-lasting hippocampal imbalance in redox and inflammatory homeostasis were observed. Additionally, the neurochemical effects seem to strengthen our behavioral findings. Finally, chronic GUO treatment, similarly to the classical tricyclic antidepressant imipramine, was able to improve the long-term behavioral phenotype impairment induced by OBX, specifically improving behavioral performances that require cognitive functions, accompanied by reversion of hippocampal redox imbalance parameters, as well as in peripheral and central anti-inflammatory IL-10 release. Thus, in present study, the pre-clinical evaluation of GUO as a potential drug for treatment of the most prevalent psychiatric disorders (anxiety and MDD) presented promising results. Furthermore, additional GUO mechanisms of action were evidenced and new perspectives were established. Thus, the data presented in this thesis support the hypothesis of the involvement of the purinergic system in mood disorders, and suggest that GUO has a potential therapeutic activity for the treatment of psychiatric disorders.