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Background Lack of coordination between screening studies for common mental disorders in primary care and community epidemiological samples impedes progress in clinical epidemiology. Short screening scales based on the World Health Organization (WHO) Composite International Diagnostic Interview (CIDI), the diagnostic interview used in community epidemiological surveys throughout the world, were developed to address this problem. Method Expert reviews and cognitive interviews generated CIDI screening scale (CIDI-SC) item pools for 30-day DSM-IV-TR major depressive episode (MDE), generalized anxiety disorder (GAD), panic disorder (PD) and bipolar disorder (BPD). These items were administered to 3058 unselected patients in 29 US primary care offices. Blinded SCID clinical reinterviews were administered to 206 of these patients, oversampling screened positives. Results Stepwise regression selected optimal screening items to predict clinical diagnoses. Excellent concordance [area under the receiver operating characteristic curve (AUC)] was found between continuous CIDI-SC and DSM-IV/SCID diagnoses of 30-day MDE (0.93), GAD (0.88), PD (0.90) and BPD (0.97), with only 9–38 questions needed to administer all scales. CIDI-SC versus SCID prevalence differences are insignificant at the optimal CIDI-SC diagnostic thresholds (χ2 1 = 0.0–2.9, p = 0.09–0.94). Individual-level diagnostic concordance at these thresholds is substantial (AUC 0.81–0.86, sensitivity 68.0–80.2%, specificity 90.1–98.8%). Likelihood ratio positive (LR+) exceeds 10 and LR− is 0.1 or less at informative thresholds for all diagnoses. Conclusions CIDI-SC operating characteristics are equivalent (MDE, GAD) or superior (PD, BPD) to those of the best alternative screening scales. CIDI-SC results can be compared directly to general population CIDI survey results or used to target and streamline second-stage CIDIs.

Cette thèse examine le rythme veille-sommeil et son association avec l’instabilité émotionnelle, l’agressivité et l’impulsivité dans le trouble de personnalité limite (TPL) à l’adolescence. Dans un premier temps, la revue de la littérature sur les perturbations objectives du sommeil dans le TPL a mis en lumière plusieurs difficultés similaires, évaluées par polysomnographie, à celles observées dans la dépression adulte. De 1980 à 2010, aucune recherche n’a examiné le rythme veille-sommeil, aucune n’a étudié les adolescents TPL et plusieurs n’ont pas contrôlé l’état dépressif comme facteur de confusion. De ce constat, il s’avérait pertinent de mener une étude sur le rythme veille-sommeil dans le TPL à l’adolescence en l’absence de dépression co-occurrente. L’adolescence comportant plusieurs caractéristiques physiologiques, psychologiques et sociales, tenir compte des aspects développementaux était essentiel. Dans un second temps, un protocole de recherche fût mis en place à la Clinique des troubles de l’humeur et le recrutement a été réalisé auprès d’adolescents souffrant d’un TPL et sans état dépressif actuel. Ils devaient porter pendant plus de neuf jours (période comprenant deux fins de semaine) un actigraphe, appareil non invasif évaluant l’alternance veille-sommeil dans l’environnement naturel. L’abandon précoce au traitement étant prévalent chez les patients TPL, la fiabilité de l’étude a été examinée afin de déterminer les raisons favorisant et celles nuisant au recrutement et à la collecte des données. La réflexion sur les aspects méthodologiques de l’étude actigraphique a permis d’expliquer les limites de ce type de protocole. Dans un troisième temps, le rythme veille-sommeil des adolescents TPL (n=18) a été caractérisé et comparé à celui des jeunes ayant un trouble bipolaire (n=6), trouble psychiatrique partageant plusieurs manifestations communes avec le TPL, et à celui des adolescents sans trouble de santé mentale (n=20). Les résultats suggèrent que l’adolescent TPL passe plus de temps en éveil durant la période de repos que les jeunes appartenant aux deux autres groupes. De plus, les adolescents TPL présentent une plus grande variabilité inter journalière des heures de lever et du temps total de sommeil que les autres adolescents. Ils se réveillent une heure de plus, et dorment donc une heure supplémentaire, que les adolescents sans trouble mental lors des journées sans routine. Dans un quatrième temps, les analyses corrélationnelles entre les données actigraphiques et les scores aux questionnaires auto-rapportés évaluant l’instabilité émotionnelle, l’agressivité et l’impulsivité suggèrent que plus l’adolescent TPL passe du temps éveillé alors qu’il est au lit, plus il déclare présenter des comportements agressifs, surtout physiques, durant le jour. En résumé, cette thèse contribue à la littérature scientifique en explorant pour la première fois le rythme veille-sommeil et son lien avec les manifestations symptomatiques dans le TPL à l’adolescence. Les résultats suggèrent fortement l’importance d’évaluer et de traiter les problèmes du rythme veille-sommeil que présentent ces jeunes lors de la prise en charge. / This dissertation examines sleep-wake patterns and their associations with emotional instability, aggressiveness, and impulsivity in adolescents with Borderline Personality Disorder (BPD). First, a literature review showed in BPD adults similar objective sleep disturbances, as assessed with polysomnography, to those observed in adult depression. Between 1980 and 2010, no study has examined sleep-wake patterns, none has recruited BPD adolescents, and many did not control depression as a confounding factor. Considering these limitations, it became relevant to conduct a study on sleep-wake patterns in euthymic adolescents with BPD. Having a developmental perspective in mind is crucial since adolescence presents many physiological, psychological and social characteristics. Second, a research protocol was set up at the Mood Disorders Clinic. Adolescents with BPD and without current depression were recruited. They wore for nine days or more (period covering two weekends) an actigraph, a non-invasive device assessing ecologically sleep-wake patterns. Because treatment dropout is highly prevalent in BPD adolescents, study feasibility was examined to determine the reasons promoting and those interfering with recruitment and data collection. Reflections on methodological aspects of this study allowed explaining the limits of this type of research protocol. Third, sleep-wake patterns in BPD adolescents (n=18) was characterised. They were compared to youth with Bipolar Disorder (n=6), a mental disorder sharing many common manifestations with BPD, and to adolescents without mental disorder (n=20). Results suggest that BPD adolescents spend more time awake during the rest interval than teenagers from the two other groups. Furthermore, BPD adolescents present higher interdaily variability for rising time and total sleep time than the other adolescents. They wake up an hour later, therefore sleeping one more hour, than adolescents without mental disorder on schedule-free days. Fourth, correlation analyses between actigraphy data and self-report questionnaire scores assessing emotional instability, aggressiveness, and impulsivity suggest that time spent awake during time in bed is associated with more daily physical aggressiveness in BPD adolescents. To summarise, this dissertation adds to the current scientific literature by exploring for the first time sleep-wake patterns and its associations with symptomatic manifestations of BPD in adolescents. From these results, it is highly recommended to assess and treat their sleep-wake disturbances during their therapeutic care.

La prise en charge des patients souffrant d’un trouble mental justifie une meilleure compréhension des mécanismes influençant les comportements des patients et des cliniciens vis-à-vis des stratégies thérapeutiques. Le principal objectif de cette thèse est d’étudier et d’identifier le rôle des attitudes des patients et des cliniciens vis-à-vis du comportement d’usage d’une thérapeutique. Pour cela, nous avons réalisé plusieurs études permettant d’appréhender cette problématique dans différentes pathologies et envers différentes thérapeutiques.Concernant les attitudes des patients envers leur traitement, nous avons détaillé un travail visant à évaluer les croyances de patients souffrant de schizophrénie envers leur antipsychotique et une étude qualitative sur les attitudes des patients bipolaires envers leur prise en charge en phase d’euthymie. Nous avons montré l’impact des attitudes négatives sur le niveau d’observance ou d’adhésion des patients à leur prise en charge et l’intérêt de cibler des stratégies de prise en charge individualisées visant à améliorer ces attitudes. Concernant les psychiatres, nous avons présenté une étude évaluant les attitudes des cliniciens vis-à-vis des recommandations professionnelles ainsi qu’un travail concernant leurs attitudes envers les antipsychotiques d’action prolongée. Certaines attitudes des psychiatres apparaissaient associées à une plus faible utilisation des recommandations ou des formulations d’action prolongée. Nos résultats montrent ainsi que l’observance ou l’adhésion des patients à une prise en charge ou le choix thérapeutique des cliniciens sont sous-tendus par leurs attitudes. L’étude des attitudes dans le domaine de la santé mentale apparaît comme une étape indispensable dans la compréhension de certains comportements d’usage des thérapeutiques. Les données issues des travaux présentés mais aussi d’études récentes permettent d’envisager un changement de paradigme dans l’appréhension des comportements d’observance des patients et de décision médicale des cliniciens dans le choix d’une thérapeutique centré sur leurs attitudes. / The management of patients with severe mental illnesses needs a better understanding of thefactors affecting the behaviours of clinicians and patients toward therapeutic strategies.The main objective of this thesis was to assess and identify the role of the clinician’s attitudes and patients’ attitudes toward the medication use behaviour. We conducted several studies to address this point in different mental disorders and for different type of treatment. Concerning the patients ‘attitudes toward treatment, we reported data from a study assessing the beliefs toward antipsychotics of schizophrenic patients and from a qualitative study assessing the patient’s attitudes toward the management of bipolar disorder in euthymic periods. We showed that the negative attitudes had a marked impact on the level of adherence of patients and could determine individual targets of interventions to improve them. Concerning the psychiatrists, we reported two studies assessing the clinician’s attitudes toward guidelines and long-acting injectable antipsychotics. Some specific attitudes were associated with a lower use of guidelines or long-acting formulations. These findings showed that the adherence of patient to treatment and the medical decisions of clinicians were related to their attitudes. The assessment of attitudes or beliefs in the field of mental health appears to be an essential step to promote a better comprehension of some treatment use behaviours. Our results and from other recent studies support a new paradigm for the patient adherence to treatment and the medical decision of clinicians focused on their attitudes as predicting variables.

Introdução: Em crianças e adolescentes, o Transtorno de Humor Bipolar (THB) é associado a danos devastadores no desenvolvimento. O Transtorno de Déficit de Atenção/Hiperatividade (TDAH), caracterizado por sintomas de desatenção, hiperatividade e impulsividade também causa prejuízo funcional significativo. O diagnóstico diferencial entre os dois transtornos é puramente clínico e, até o momento, há poucos estudos avaliando diferenças neurobiológicas. Diversas pesquisas sugerem a participação do Fator Neurotrófico Derivado do Cérebro (BDNF), cujo papel não foi elucidado em crianças e adolescentes com THB e com TDAH. Apesar das altas taxas de comorbidade entre o THB e o TDAH, de uma pior resposta ao tratamento e de um pior funcionamento psicossocial quando da comorbidade, apenas dois estudos avaliaram a resposta ao tratamento especificamente neste grupo de pacientes. Objetivos: O objetivo principal deste trabalho é avançar no entendimento do papel do BDNF na psicopatologia do THB e do TDAH, visando sua diferenciação. O tratamento da comorbidade com estimulantes tambem foi estudado. Métodos: A transmissão do alelo Val66 do BDNF foi avaliada em famílias de crianças e adolescentes com THB e TDAH, assim como o efeito do gene no nível sérico da proteína do BDNF entre os grupos. Foi realizada a comparação dos níveis séricos entre pacientes com THB em comorbidade com TDAH e TDAH isolado. Um estudo clínico cruzado com estimulantes foi realizado em crianças e adolescentes com THB e TDAH em comorbidade que tinham apresentado remissão dos sintomas de humor com o uso de aripiprazol, mas persistência dos sintomas de TDAH. Os sintomas de mania, depressão, desatenção e hiperatividade foram acompanhados ao longo de quatro semanas de tratamento, duas com placebo ou metilfenidato e duas com o tratamento inverso. Resultados: Na investigação da transmissão do gene do BDNF em crianças e adolescentes não foi detectada diferença significativa na transmissão do alelo Val66. Tampouco foi observada diferença significativa nos níveis séricos da proteína do BDNF entre os pacientes com THB em comorbidade com TDAH, quando comparados aos pacientes com TDAH e controles. No estudo cruzado com crianças e adolescentes com THB em comorbidade com TDAH, não houve diferenças entre os grupos com placebo ou estimulantes na resposta ao tratamento nos sintomas de TDAH. Os sintomas de humor mantiveram-se estáveis a despeito do uso de metilfenidato. Conclusões: Os achados quanto ao gene do BDNF não sugerem sua participação na neurobiologia do THB ou no TDAH, ou que devido à herança poligênica característica dos transtornos mentais, sua participação seja pequena. O achado de diferença significativa entre os níveis séricos do BDNF de crianças e adolescentes com THB+TDAH e TDAH indica que esse tema deve ser mais estudado, e, caso seja também encontrado de forma consistente por outros grupos, possa vir a ser utilizado como marcador biológico na diferenciação diagnóstica entre essas condições. No estudo de tratamento da comorbidade entre THB e TDAH, a ausência de resposta ao metilfenidato nos sintomas de TDAH em pacientes que apresentam a comorbidade reforça a evidência de que há pior resposta ao tratamento neste grupo, dado o elevado tamanho de efeito do metilfenidato no tratamento do TDAH em isolado O estudo de fatores biológicos para um melhor entendimento da psicopatologia e conseqüente diferenciação dos transtornos mentais tem extrema relevância porque a identificação destes fatores pode auxiliar na elaboração de tratamentos mais precisos, urgentemente necessários devido às graves conseqüências do THB e do TDAH nas vidas dos pacientes e de suas famílias. A criação de um programa específico para Crianças e Adolescentes com Transtorno Bipolar (ProCAB) e de uma linha de pesquisa com foco na etiologia e tratamento possibilitam uma constante geração de conhecimento nesta área, onde poucos estudos estão disponíveis. / Introduction: Bipolar Disorder (BD) in children and adolescents is associated to devastating developmental deficits. Attention-Deficit/Hyperactivity Disorder (ADHD), characterized by inattention, hyperactivity, and impulsivity, also promotes significant impairment. Differential diagnosis between both conditions is purely clinical – currently, there are scarce investigations on neurobiological differences. Several studies suggest the participation of the Brain-Derived Neurotrophic Factor (BDNF) in these disorders, whose role has not been elucidated in BD and ADHD in children and adolescents. Despite high comorbidity rates between BD and ADHD, worse psychosocial functioning, and worse response to treatment, only two studies addressed treatment response specifically in this group of patients. Objectives: promote advances in understanding the role of BDNF in the psychopathology of BD and ADHD. The treatment of the comorbidity was also studied. Methods: Transmission of the Val66 allele at the BDNF was assessed in children and adolescents with BD and ADHD, as well as the effect of the gene on the serum levels of BDNF protein in both conditions. BDNF serum levels were compared between patients with BD comorbid with ADHD, and ADHD. A crossover clinical trial with stimulants and placebo was performed with children and adolescents preseting BD and comorbid ADHD. Manic, depressive, inatention and hyperactivity symptoms were assessed along a 4-week treatment, 2 weeks in each treatment arm (placebo or stimulants). Results: There was no significant transmission of the Val66 allele at the BDNF gene in children and adolescents with BD or ADHD. A significant difference in BDNF protein serum levels between BD+ADHD when compared to ADHD alone and controls. In the crossover trial with children and adolescents with BD and comorbid ADHD, we did not observe differences between the placebo and stimulant treatment groups in the response of ADHD symptoms. Mood symptoms remained stable despite the use of methylphenidate. Conclusions: our results regarding the BDNF gene do not suggest its participation in the neurobiology of BD or ADHD, or that due to the polygenic characteristic of mental disorders, that this gene confers a only a small risk, undetectable in our sample. The finding of a significant difference in BDNF serum levels between BD comorbid with ADHD, and ADHD alone warrants further investigation, and in case replication studies with larger samples from other groups are positive, BDNF serum levels might be used as a biological marker in the diagnostic difference between these conditions. In the investigation of the treatment of the comorbidity between BD and ADHD, the absence of different responses between placebo and methylphenidate in ADHD symptoms strengthens the evidence that there is a worse response to treatment in this group, given the large effect size of methylphenidate response in the treatment of ADHD alone. The quest for biological markers for a better understanding of the psychopathology and subsequent differentiation of mental disorders is extremely relevant. The identification of these factors may facilitate the creation of more accurate treatment regimens, urgently needed due to the severe developmental consequences of BD and ADHD in the patients’ and families’ lives. In this sense, the creation of a specific outpatient program for children and adolescent BD (ProCAB), a research line with focus on risk factors and treatment, will enable a Constant generation of knowledge in this área, where scarce data is available.

[pt] Prejuízo de insight costuma ser reportado no Transtono Bipolar (TB), sobretudo quando os pacientes viram para o pólo maníaco do transtorno. Essa falha na consciência verbal dos déficits, sinais e sintomas do transtorno pode vir acompanhada de uma forma de insight implícito, que é a demonstração indireta de algum nível de conhecimento sobre a doença ou uma deficiência com perda parcial ou total de reconhecimento verbal. Dois estudos foram conduzidos para verificar as relações entre as formas de insight explícito e implícito no TB. Para isso, foi utilizado um modelo teórico conhecido como The Cognitive Awareness Model (CAM), que permite investigar dissociações nos padrões de consciência implícita e explícita. No primeiro estudo, os participantes foram avaliados em relação à uma série de variáveis clínicas, incluindo uma medida de insight explícito, além de uma medida de insight implícito com estímulos ligados à depressão e à mania. No segundo estudo, os participantes foram igualmente testados em relação às variáveis clinicas, incluindo uma medida de insight explícito, além de uma medida de insight implícito com estímulos ligados à condição de saudável e doente. Os resultados de ambos os estudos apontaram para diferenças nas medidas de insight explícito entre os grupos de maníacos e eutímicos, e demonstraram diferenças no tempo médio de reação para auto-associações implícitas para condição. A partir desses resultados, pode-se sugerir que os pacientes em mania se autoavaliam explicitamente de forma similar aos pacientes em eutimia, o que pode trazer prejuízos na adesão ao tratamento, ao passo que os pacientes bipolares apresentaram uma forma de insight implícito tanto para os sintomas quanto para a condição de doente avaliadas. / [en] Lack of insight is usually reported in Bipolar Disorder (TB), especially when patients have seen the manic pole of the disorder. This lack of verbal awareness of deficits, signs and symptoms of the disorder may be accompanied by an implicit insight, which is the indirect demonstration of some level of knowledge about the disease or a disability with partial or total loss of verbal recognition. Two studies were conducted to verify the relationships between explicit and implicit forms of insight into TB. For this, a theoretical model known as The Cognitive Awareness Model (CAM) was used, which allows to investigate dissociations in the patterns of implicit and explicit consciousness. In the first study, participants were assessed for a number of clinical variables, including an explicit insight measure, as well as an implicit insight measure with depression and mania-related stimuli. In the second study, participants were also tested for clinical variables, including an explicit insight measure, as well as an implicit insight measure with stimuli linked to healthy and ill status. The results of both studies pointed to differences in measures of explicit insight between the manic and euthymic groups and demonstrated differences in mean reaction time for implied self-associations for condition. From these results, it can be suggested that patients in mania explicitly self-evaluate in a similar way to patients in euthymia, which can lead to impairment in adherence to treatment, whereas bipolar patients presented an implicit insight for symptoms and for the patient s condition evaluated.

Background Polypharmacy is often prescribed for bipolar disorder, yet medication non-adherence remains a serious problem. This study investigated the regularity in the daily dosage taken of mood stabilizers and second generation antipsychotics. Methods Daily self-reported data on medications taken and mood were available from 241 patients with a diagnosis of bipolar disorder who received treatment as usual. Patients who took the same mood stabilizer or second generation antipsychotic for ≥ 100 days were included. Approximate entropy was used to determine serial regularity in daily dosage taken. Generalized estimating equations were used to estimate if demographic or clinical variables were associated with regularity. Results There were 422 analysis periods available from the 241 patients. Patients took drugs on 84.4% of days. Considerable irregularity was found, mostly due to single-day omissions and dosage changes. Drug holidays (missing 3 or more consecutive days) were found in 35.8% of the analysis periods. Irregularity was associated with an increasing total number of psychotropic drugs taken (p = 0.009), the pill burden (p = 0.026), and the percent of days depressed (p = 0.049). Conclusion Despite low missing percent of days, daily drug dosage may be irregular primarily due to single day omissions and dosage changes. Drug holidays are common. Physicians should expect to see partial adherence in clinical practice, especially with complex drug regimens. Daily dosage irregularity may impact the continuity of drug action, contribute to individual variation in treatment response, and needs further study.

This study investigates the connection between different pathophysiological processes in mitochondria and psychopathological symptoms in patients with bipolar disorder. Changes in activity of selected components of the respiratory chain and overall respiratory rate of mitochondria were analyzed in patients with bipolar disorder when compared to healthy controls. Diagnostic scales and questionnaires, high-resolution respirometry, radiochemical and spectroscopic methods were used. 37 patients with a diagnosis of bipolar disorder (F31) and 21 healthy volunteers were involved in the study. Statistical analysis included the methods of parametric and nonparametric analysis, factor analysis, one-way analysis of variance and linear regression analysis. Obtained results revealed that cellular energetics plays a great role in the pathophysiology of bipolar disorder. There was a mild difference between different mitochondrial enzymes activity in patients within manic phases and depressive phases of the disease. Changes in mitochondrial respiration in patients with BD as compared to healthy controls were also shown. Mitochondrial respiration indexes for patients with BD in remission as compared to healthy controls were altered in accordance with the previous phase of the disease. Association between the...