Thesis (M. Pharm.)--North-West University, Potchefstroom Campus, 2008.

Thesis (M. Pharm.)--North-West University, Potchefstroom Campus, 2008.

Background and aims: This interdisciplinary thesis was designed to deepen understanding of the co-morbidity of anxiety and depression with chronic diseases of the digestive tract, and inflammatory bowel disease (IBD) in particular. The first part of the thesis aimed to explore the prevalence of psychological problems in IBD compared to irritable bowel syndrome (IBS) and chronic hepatitis C (HCV) groups. It also explored the relationship between the number of co-morbid functional gastrointestinal disorders and the severity of psychological problems in IBD and IBS. It also aimed to determine whether there is a relationship between psychological problems and the response to standard medical treatment/physical outcomes in patients with IBD, IBS and HCV. Furthermore, it aimed to explore whether disclosure of the psychological status of depressed and/or anxious IBD patients to their gastroenterologists influences doctors’ behaviour and affects patients’ responses to treatment/physical outcomes. The second part of the thesis aimed to investigate the potential role of antidepressants in IBD and to determine the feasibility of future randomised controlled trials on the role of antidepressants in IBD. Methods: Overall, a cohort of 139 outpatients (64 IBD, 41 HCV, and 34 IBS) and 18 gastroenterologists participated in the six studies comprising this thesis. A mixed methods design was applied. Two cross-sectional studies, an observational cohort prospective management study, a randomised controlled trial, a systematic review and an exploratory interview study were conducted. Differences between the groups for continuous variables were assesed with one way analysis of variance (ANOVA) and independent samples ttests. Differences in categorical variables were assessed with contingency tables with the Chi-Square test and the Fisher’s Exact Test. Propsective analyses were conducted with repeated measures ANOVA, logistic regression and Poisson regression. Qualitative data were analysed using content analysis. Results: Overall, 42% of participants were anxious and 19% were depressed. Participants with HCV had higher levels of psychological impairment compared with the IBS, the IBD group and the general population (p<0.05). Those IBD participants with fewer co-morbid functional disorders had better physical quality of life than participants with a greater number of these disorders (p=0.025). Moreover, depression/anxiety at baseline did not explain medical outcomes after 12 months in this cohort of patients with chronic diseases of the digestive tract. Doctors’ knowledge of patients’ psychological status was found to have no impact on IBD patients’ outcomes after 12 months. However, interestingly, the level of anxiety in IBD participants significantly dropped between the baseline and nine months indicating a possible benefit from participating in the study. In the literature review, insufficient evidence was found to conclude that antidepressants are efficacious for treatment of psychological co-morbidities or somatic complaints in IBD. However, the qualitative interview study indicated a potential positive impact of treatment with antidepressants on coping with disease symptoms and general wellbeing in patients with IBD. Conclusion: The thesis confirms that there is a significant burden of psychological co-morbidity in patients with chronic gastroenterological diseases. Interdisciplinary approaches to the management of these diseases are therefore warranted in Australian gastroenterology clinics. Anxiety targeted interventions and research in this setting are urgently needed, especially with respect to patients with HCV. Larger studies exploring the gastroenterologists’ role in treatment of co-morbid psychological problems in their patients are recommended. Longer prospective studies on homogenous samples of patients are also needed to clarify the nature of the relationship between psychological problems and relapse of somatic symptoms. Finally, randomised controlled trials exploring the efficacy of antidepressants in IBD are warranted. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1321006 / Thesis (Ph.D.) -- University of Adelaide, School of Population Health and Clinical Practice, 2008

Un tiers des patients déprimés inclus dans les essais cliniques ne répondent pas à un traitement antidépresseur. La dérégulation de l’axe HPA et la réduction de la neurogènese hippocampique sont les principaux facteurs de la résistance aux antidépresseurs. L’objectif de ce travail est de développer un modèle de résistance à l’antidépresseur lié à l’axe HPA et d’utiliser ce modèle pour comprendre les mécanismes sous-jacents. Nos résultats suggèrent qu'une mauvaise régulation de rétrocontrôle négatif de l'axe HPA au début du protocole peut être un facteur prédictif de l'échec du traitement antidépresseur dans la dépression. Notre protocole montre que l’échec de la fluoxétine à induire des effets antidépresseurs a été associé à une mauvaise aptitude des composés à stimuler la prolifération des cellules dans le gyrus denté de l'hippocampe. D'autres études sont nécessaires pour étudier la relation de causalité entre ces phénomènes. / One-third of depressed patients included in clinical trials do not respond to antidepressant treatment. Dysregulation of the HPA axis and reduced hippocampal neurogenesis are the main factors of resistance to antidepressants. The objective of this work is to develop a model of resistance to antidepressant related to the HPA axis and to use this model to understand the underlying mechanisms. Our results suggest that dysregulation of negative feedback of the HPA axis at the beginning of the protocol can be a predictor of antidepressant treatment failure in depression. Our protocol shows that the failure of fluoxetine to induce antidepressant effects was associated with poor ability of compounds to stimulate cell proliferation in the dentate gyrus of the hippocampus. Further studies are needed to investigate the causal relationship between these phenomena.

A depressão, tida como a doença do final do século XX, acarreta diversos distúrbios físicos, mentais e emocionais. Amitriptilina,. imipramina, nortriptilina e desipramina são antidepressivos tricíclicos (ADT) largamente usados no tratamento de desordens depressivas. Os ADT são fármacos que apresentam alta variabilidade interindividual na farmacocinética e resposta clínica não facilmente ou não imediatamente mensurável. Assim faz-se necessário o desenvolvimento e validação de métodos analíticos capazes de determinar com a devida confiabilidade suas concentrações em amostras de plasma. Os métodos desenvolvidos possuem uma etapa de extração para posterior separação e quantificação. Os métodos de extração avaliados foram a extração líquido-líquido (LLE) e a microextração em fase sólida (SPME). As técnicas usadas para separação e quantificação foram cromatografia líquida (LC) e eletroforese capilar (CE). Dois métodos foram desenvolvidos e validados: LLE/LC e LLE/CE. Usando uma fibra com recobrimento PDMS 100 mm, um método SPME/LC (modo de dessorção off-line) foi desenvolvido e os parâmetros relativos a SPME foram otimizados fazendo uso de planejamento fatorial (23) e simplex. Usando as mesmas condições otimizadas para a fibra PDMS testou-se uma fibra PDMS/DVB 65 mm. Avaliou-se a CE para a determinação dos ADT em formulações farmacêuticas e o comportamento eletroforético destes compostos em diferentes meio (água, metanol e acetonitrila) foi avaliado. De acordo com os parâmetros avaliados (linearidade, precisão (intra e inter ensaios), recuperação, limites de quantificação (LOQ) e detecção) ambos os métodos (LLE/LC e LLE/CE) mostraram-se aplicáveis para a determinação dos ADT em níveis plasmáticos. O método SPME/LC (off-line) que fez uso da fibra com recobrimento PDMS/DVB apresentou LOQ suficientemente baixos para determinar os ADT em concentrações plasmáticas, apesar de consumir um tempo maior para execução, quando comparado aos métodos LLE/LE e LLE/CE. A validação e aplicação de um método fazendo uso de CE para a análise dos ADT em formulações farmacêuticas mostra a aplicabilidade desta técnica para análises de rotina. Determinou-se por CE o pKa* dos ADT em água, metanol e ACN. A ordem dos valores obtidos em meio aquoso e metanólico é inversa em relação a ordem obtida em ACN. Assim, pôde-se correlacionar a carga das espécies em cada condição de análise com a ordem de migração dos ADT em cada meio. / Depressive disorders imply in a variety of physical, mental and emotional disturbances. Amitriptyline, imipramine, nortriptyline e desipramine are tricyclic antidepressants (TAD) largely used in depression treatment. The TADs are drugs that show high inter individual variability in pharmacokinetics, low clinical response or even they are not straightforwardly measured. Therefore, it is necessary the development and validation of analytical methods for TAD determination in plasma samples. The developed methods have an extraction step for subsequently separation and quantification. The extraction methods appraised were liquid-liquid extraction (LLE) and solid phase microextraction (SPME). The analytical techniques used for separation and further quantification were liquid chromatography (LC) and capillary electrophoresis (CE). Two methods were developed and validated: LLE/LC and LLE/CE. Using a PDMS coating (100 mm), a SPME/LC method (with off-line dessorption) was developed and the experimental conditions relative to SPME were optimized using a factorial planning (23) and a simplex methodology. The same optimized conditions (for PDMS) were used for a PDMS/DVB (65 mm) coating. According to the appraised parameters such as linearity, precision (intra and inter assays), recovery and limits of quantification and detection, the methods LLE/LC and LLE/CE showed suitable for TAD determination in plasma samples regarding the therapeutic plasmatic concentration. The SPME/LC method (off-line desorption) with PDMS/DVB coating has also shown LOQ lower than the minimum therapeutic plasmatic concentration, implying that may be subject to validation. This method may be used for TAD analysis even though the total analysis time was greater those from LLE/LC and LLE/CE methods. CE was also applied for TAD determination in pharmaceutical formulations and the electrophoretic behavior such compounds in different separation media, especially non-aqueous solvents, was studied. The validation and application of a method using CE for TAD determination in pharmaceutical formulations has shown the applicability of this technique for routine analysis. The migration order in aqueous and methanolic media is opposite to obtained in acetonitrile, and the pKa* of the TAD were determined in different media (aqueous, methanol and acetonitrile) by CE. With the calculated values, it was possible to correlate the species total charge to the migration order in each medium.

Made available in DSpace on 2014-10-09T12:42:31Z (GMT). No. of bitstreams: 0 / Made available in DSpace on 2014-10-09T14:02:09Z (GMT). No. of bitstreams: 0 / A ampla utilização de medicamentos, a falta de gerenciamento na produção e no descarte desses produtos, bem como a dificuldade na remoção de resíduos de fármacos das águas residuais durante as fases do tratamento de efluentes tem causado a liberação destes micropoluentes nos recursos hídricos. O cloridrato de fluoxetina, conhecido comercialmente como Prozac®, tem sido muito utilizado em diversos países. Estudos demonstram sua presença no meio ambiente e o potencial de danos que este fármaco pode causar à biota. Desta forma, este trabalho estudou uma tecnologia de tratamento (POA - Processo Oxidativo Avançado) utilizando-se radiação ionizante, proveniente de um acelerador de elétrons, para a degradação do fármaco cloridrato de fluoxetina em solução aquosa e na mistura com esgoto doméstico. Após a irradiação foram feitas análises químicas na solução aquosa do fármaco com Espectrofotometria UV/VIS, Cromatografia Líquida Ultra Rápida (detectores UV/VIS e fluorescência) e quantificação do Carbono Orgânico Total (COT). Também foram empregados ensaios de toxicidade aguda (Daphnia similis e Vibrio fischeri) e crônica (Ceriodaphnia dubia). A eficiência na degradação do fármaco foi superior a 98,00% na menor dose de radiação (0,5 kGy), porém houve baixa taxa de mineralização para as doses aplicadas neste estudo. Para a Daphnia similis na dose de 0,5 kGy houve eficiência de 83,75% na redução da toxicidade do cloridrato de fluoxetina e 87,24% para 5,0 kGy, houve eficiência de 100,00% na redução da toxicidade para o esgoto doméstico e para a mistura (CF + esgoto) 79,32% na dose de 5,0 kGy. A eficiência para a Vibrio fischeri foi de 17,26% (melhor eficiência na dose de 5,0 kGy) e após a correção do pH das amostras a melhor eficiência foi para 20,0 kGy (26,78%), para o esgoto e para a mistura as eficiências ficaram em torno dos 20,00% para todas as doses de radiação aplicadas. Em relação a toxicidade crônica para Ceriodaphnia dubia a eficiência foi de 97,50% para 5,0 kGy. Verificou-se que a Ceriodaphnia dubia possui maior sensibilidade ao fármaco, seguido da bactéria Vibrio fischeri e por fim a Daphnia similis. / Dissertação (Mestrado) / IPEN/D / Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP

INTRODUÇÃO: Os transtornos psiquiátricos são altamente prevalentes e têm sido associados ao maior uso de serviços e de medicamentos. Entretanto resultados do World Health Organization (WHO) World Mental Health (WHM) Surveys, conduzidos em diversos países, têm apresentado baixas prevalências de uso de psicofármacos entre sujeitos com diagnóstico de transtornos psiquiátricos no ano anterior à entrevista. OBJETIVOS: Estimar a prevalência, o padrão, e os fatores associados ao uso de psicofármacos em amostra da população geral e entre sujeitos com diferentes diagnósticos para doenças psiquiátricas, de acordo com DSM-IV. MÉTODOS: Os dados são provenientes do São Paulo Megacity Mental Health Survey (SPMHS), segmento brasileiro do estudo World Mental Health Survey (WMH survey). O WMH survey é uma iniciativa da Organização Mundial da Saúde (OMS), da Universidade de Harvard e Universidade de Michigan, que vem sendo realizada em mais de 28 centros de pesquisa no mundo. O São Paulo Megacity Mental Health Survey é um estudo de corte transversal, de base populacional, desenhado para avaliar a morbidade psiquiátrica em uma amostra representativa da população geral, com 18 anos ou mais, residentes na Região Metropolitana de São Paulo. Uma amostra de 5.037 indivíduos (taxa de resposta: 81,3%) foi entrevistada por leigos treinados, utilizando a versão do Composite International Diagnostic Interview para o World Mental Health Survey, elaborado para gerar diagnósticos de acordo com o DSM-IV. O foco do presente estudo foi uma subamostra de 2.935 entrevistados, os quais foram avaliados com a versão longa da entrevista e que foram questionados sobre psicofármacos prescritos no ano anterior à entrevista para \"problemas com emoções, nervos, saúde mental, uso de substâncias, energia, concentração, sono ou a capacidade de lidar com o estresse\". Os dados foram ponderados para ajustar a subamostragem dos não casos dessa subamostra e para ajustar as discrepâncias residuais entre as distribuições amostrais e populacionais de uma série de variáveis sociodemográficas, garantindo, assim, a representatividade dessa subamostra. RESULTADOS: Apenas 6,13% dos respondentes relataram o uso de psicofármacos no ano anterior à entrevista. Os hipnóticos e sedativos (incluindo os benzodiazepínicos) (3,63%) e os antidepressivos (3,46%) foram os mais comumente relatados, enquanto os estabilizadores de humor (0,64%) e os antipsicóticos (0,61%) foram pouco frequentes. Ser do sexo feminino (OR= 2,55; 95% IC=1,58-4,11), avançar da idade, escolaridade abaixo do nível superior e ter maior renda foram fatores associados ao maior uso de psicofármacos, assim como ter comorbidades e transtornos graves. A prevalência de transtornos psiquiátricos de acordo com os critérios do DSM-IV/WMH-CIDI no ano anterior à entrevista foi 29,49%. Entretanto, somente 13,75% dos sujeitos com diagnóstico de transtorno psiquiátrico no ano anterior à entrevista, 24,93% com transtorno de humor, 14,43% com transtorno de ansiedade e, aproximadamente, 10% com transtorno por uso de substância e com transtorno de controle do impulso relataram uso de psicofármacos no mesmo período. Respondentes sem diagnóstico também reportaram uso de psicofármacos (2,94%). O uso de antidepressivos (9,10%) e de hipnóticos e sedativos (7,81%) foi pouco frequente naqueles com diagnóstico, apresentando a seguinte distribuição, respectivamente: sujeitos com transtorno de humor (17,94% e 14,70%), ansiedade (9,04% e 8,08%), controle de impulso (6,76% e 5,80%) e por uso de substâncias (5,08% e 7,86%). O uso de psicofármacos foi maior entre sujeitos que apresentaram três transtornos ou mais (26,91%) quando comparado aos que apresentaram dois (15,21%) ou um transtorno (8,96%). Entre os sujeitos com transtornos considerados leve, de moderada gravidade e grave, a prevalência de uso de psicofármacos foi 6,60%, 10,68% e 23,77%, respectivamente. Entretanto aproximadamente 75% casos graves e com três ou mais transtornos, permaneceram sem tratamento farmacológico. CONCLUSÃO: Os resultados sugerem que a maioria dos sujeitos com transtornos psiquiátricos ativos não estão recebendo tratamento farmacológico para seus transtornos psiquiátricos na Região Metropolitana de São Paulo. Políticas públicas poderiam aumentar o acesso aos cuidados de saúde adequado, particularmente entre sujeitos com transtornos graves e comorbidades / INTRODUCTION: Mental Disorders are highly prevalent and have been associated with high use of health services and medications. However results of the World Health Organization (WHO) World Mental Health (WHM) Surveys carried out in several countries have found low prevalence rates of psychotropic medication among those with 12-month disorders. OBJECTIVES: To estimate the prevalence, pattern, and associated factors with the use of psychotropic medication in a sample in the general population and, within this sample, among those with different diagnoses for psychiatric disorders, according to DSM-IV. METHODS: Data were from the São Paulo Megacity Mental Health Survey (SPMHS), the Brazilian segment of the World Mental Health (WMH) Survey Initiative, coordinated by the World Health Organization and Harvard University, which has been held in more than 28 research centers in the world. The São Paulo Megacity Mental Health Survey is a cross-sectional population-based study, designed to evaluate psychiatric morbidity in a representative sample in the general population, aged 18 years or more, living in the São Paulo Metropolitan Area. A sample of 5,037 individuals (response rate: 81.3%) was assessed by trained lay interviewers using the World Mental Health version of the Composite International Diagnostic Interview, designed to generate DSM-IV diagnoses. The focus of the current report was a subsample of 2,935 subjects to whom the long version of the interview was applied and were asked about prescription medicines that used in the previous12 months for \"problems with emotions, nerves, mental health, substance use, energy, concentration, sleep or ability to cope with stress\". Data were weighted to adjust the undersampling of long interview respondents non-cases and to adjust residual discrepancies between the sample and population distributions of a range of sociodemographic variables. RESULTS: Only 6.13% of the respondents reported psychotropic medication use in the previous year the interview. Hypnotics and sedatives (including benzodiazepines) (3.63%) and antidepressants (3.46%) were the most commonly reported, while mood stabilizers (0.64%) and antipsychotics (0.61%) were used less frequently. In the general population of the SPMHS, be female gender (OR= 2.55; 95% IC=1.58-4.11), older, education low level high and higher income were associated the higher psychotropic medication use, well as have comorbidity and serious disorders. The 12-month prevalence of DSM-IV/WMH-CIDI disorder was 29.49%. However, only 13.75% of those with 12-month disorders, 24.93% among those with mood disorder, 14.43% in those with anxiety disorder and, approximately 10% impulse-control disorder and substance use disorder reported psychotropic medication use in the same period. Respondents without diagnosis also reported psychotropic medication use (2.94%). Antidepressants (9.10%) and hypnotics and sedatives (7.81%) were commonly reported, with the following distribution, respectively: subjects with mood disorder (17.94% and 14.70%), anxiety (9.04 % and 8.08%), impulse control (6.76% and 5.80%), and substance use (5.08% and 7.86%). Psychotropic medication use was higher among the respondents with three or more disorders (26.91%), when compared with those with two (15.21%) or with one disorder (8.96%). Among the respondents with mild, moderate, or severe disorders, the prevalence of Psychotropic medication use was 6.60%, 10.68%, and 23.77%, respectively. However approximately 75% severe cases and comorbidities, remained without pharmacologic treatment. CONCLUSION: These findings suggest that the majority of individuals diagnosed with an active mental disorder are not being treated with psychotropic medication in the São Paulo Metropolitan Area. Public policies should increase access to appropriate care, particularly among subjects with serious disorders and comorbidities

The development of new solid forms of active pharmaceutical ingredients (API) is relevant both from fundamental as well as industrial perspectives. To this end, Crystal Engineering plays an ever-increasing important role in pharmaceutical sciences. Among the crystal engineering strategy, salt formation is the most important and implemented approach. The salt forms of API could be used to modulate and tuned the solubility and stability of API to provide optimal practical uses. Herein, we report pharmaceutical salts of two Selective Serotonin Reuptake Inhibitor antidepressants used in the treatment of depression and anxiety disorders, Paroxetine (PRX) and Fluoxetine (FLX). For this purpose, salt formers, supramolecular synthesis and crystallization protocols have been driven by the systematization of structural and supramolecular data of molecules and analogues from the Cambridge Structural Database. Paroxetine bromide hemihydrate ((PRXBr)0.5H2O), Paroxetine Nitrate hydrate (PRXNO3H2O) and two polymorphs of Fluoxetine Nitrate (FLXNO3) have obtained. All were characterized by a combination of techniques including Single Crystal X-ray Diffraction, Differential Scanning Calorimetry (DSC), Thermogravimetry analysis (TGA), Hot Stage Microscopy, Fourier transform infrared spectroscopy (IR) and solubility measurements. Since the hydration/dehydration process in APIs induces phase transitions that compromise its efficiency, the structural characterization of (PRXBr)0.5H2O help to understand its reversible dehydration process. Also, this study has implication in the understating of dehydration of isostructural PRX hydrochloride salt. Additionally, the (PRXNO3)H2O have shown the conformational flexibility and supramolecular diversity of PRX. On the other hand, the chirality of FLX is related to two nitrate salt polymorphs. A racemate and a non-centrosymmetric structure with independent enantiomers in the asymmetric unit were obtained for FLXNO3. Their packing have shown the existence of different racemic motifs, resulting in different enantiomer orientations The rare occurrence of racemic systems in non-centrosymmetric space groups becomes this event a noteworthy case. By their physicochemical properties, the polymorphs were monotropically related. The scientific contributions of this thesis show the diversity of the solid forms and define candidates to new antidepressants APIs solid formulations. / O desenvolvimento de novas formas sólidas de ingredientes farmacêuticos ativos (API) é relevante tanto numa perspectiva fundamental como industrial. Para tal, a Engenharia de cristais tem desempenhado um papel importante nas ciências farmacêuticas. Dentre as estratégias, a formação de sais é a abordagem mais importante e implementada. Os sais de APIs são capazes de modular e ajustar a solubilidade e a estabilidade, a fim de proporcionar uso prático. Nesta tese, são reportados sais de dois fármacos Inibidores Seletivos de Recaptação de Serotonina, consolidados no tratamento da depressão e distúrbios de ansiedade, a Paroxetina (PRX) e a Fluoxetina (FLX). Brometo de Paroxetina hemiidratado ((PRXBr)0.5H2O), Nitrato de Paroxetina hidratado (PRXNO3H2O) e polimorfos de Nitrato de Fluoxetina (FLXNO3), síntese e protocolos de cristalização foram cuidadosamente delineados, com base na sistematização de dados estruturais e supramoleculares das moléculas e seus análogos, depositados no Cambridge Structural Database. Todos os sais foram caracterizados por Difração de Raios-X por Monocristal, Calorimetria Explanatória Diferencial (DSC), Análise termogravimétrica (TGA), Termomicroscopia, Espectroscopia vibracional na região do infravermelho (IR) e solubilidade. Considerando que a hidratação/desidratação induz mudanças de fases que comprometem a eficiência do API, a caracterização do (PRXBr)0.5H2O auxiliou no entendimento do processo de desidratação reversível que ocorre para esse fármaco. Estas mudanças de fase resultam também em implicações sobre a compreensão do processo de desidratação do sal isoestrutural de cloreto de PRX hemiidratado. Além disso, por meio da elucidação estrutural do (PRXNO3)H2O, foi possível analisar a diversidade conformacional e supramolecular da PRX. Quanto à FLX, verificou-se que sua quiralidade está relacionada com seu polimorfismo. Um racemato e uma estrutura não centrossimétrica com dois enatiômeros independentes na unidade assimétrica foram obtidos para o FLXNO3. A comparação destas estruturas permitiu mostrar a existência de arranjos supramoleculares racêmicos, constituídos por diferentes orientações de enatiômeros. A rara ocorrência de sistemas racêmicos em grupos espaciais não-centrossimétricos tornou este evento um caso notável. A partir das propriedades físico-químicas, os polimorfos puderam ser monotropicamente relacionados. Os resultados desta tese trazem importantes contribuições científicas para diversidade de formas sólidas e também define novas formulações sólidas para utilização como antidepressivos.

A estimulacao transcraniana por corrente continua (ETCC) e uma tecnica nao-invasiva de estimulacao cerebral que consiste na aplicacao de uma corrente eletrica de baixa intensidade atraves de eletrodos colocados sobre a cabeca, levando a efeitos neuromodulatorios e de neuroplasticidade. Avaliamos o papel da ETCC no transtorno depressivo maior (TDM), uma condicao prevalente e cronica, atraves de um ensaio clinico duplo-cego, 2 x 2 (fatorial), com uma intervencao farmacologica (sertralina 50mg/dia) e uma nao-farmacologica (ETCC), comparando, portanto a eficacia e seguranca da ETCC ativa vs. simulada, vs. sertralina e da combinacao ETCC/sertralina vs. demais. Dos 850 voluntarios iniciais, incluimos aqueles com depressao moderada/grave, baixa ideacao suicida, ausencia de outras co-morbidades psiquiatricas e clinicas e que nao usavam (ou aceitaram retirar) medicacoes antidepressivas. Nao incluimos aqueles usando sertralina. Randomizamos os 120 participantes em 4 grupos: ETCC simulada/placebo (placebo), ETCC simulada/sertralina (sertralina), ETCC ativa/placebo (ETCC), ETCC ativa/sertralina (tratamento combinado). A ETCC foi aplicada em 2mA/25cm2, sendo o anodo e o catodo posicionados sobre as areas correspondentes ao cortex dorsolateral pre-frontal esquerdo e direito, respectivamente, por 30 minutos diarios, por dez dias consecutivos, excluindo finais de semana. Apos este periodo, duas outras estimulacoes, em semanas alternadas, foram realizadas ate o fim do estudo (6a semana). A ETCC simulada foi realizada da mesma maneira que a ETCC ativa, mas o aparelho era desligado apos 30 segundos iniciais. 103 participantes terminaram o estudo, sendo a analise estatistica por intencao de tratamento. A escala de depressao de Montgomery-Asberg (MADRS) foi o desfecho primario. No inicio, os quatro grupos eram semelhantes. Na 6a semana, o grupo tratamento combinado foi estatisticamente superior (p0,01 para todas as comparacoes) aos grupos placebo (diferenca de 11,5 pontos, Intervalo de Confianca [IC] 95%= 6-17), sertralina (8,5 pontos, IC 95%= 2,9-14) e ETCC (5,9 pontos, IC 95%= 0,36-11,43). ETCC e sertralina nao foram diferentes entre si (2,6 pontos, IC 95%=-2,9 a 8,1, p=0,35). Os resultados medidos por outras escalas foram semelhantes. Apenas vermelhidao na pele na regiao da estimulacao foi um efeito adverso mais observado na ETCC ativa. Os grupos tiveram desempenho semelhante nos testes cognitivos realizados, porem, de sete episodios de hipomania/mania, cinco foram no tratamento combinado. Nos estudos auxiliares, a ETCC nao levou a alteracoes na variabilidade da frequencia cardiaca (medida no inicio e ao fim do tratamento), tambem sugerindo seguranca da tecnica. Alem disso, observamos uma interacao entre o gene transportador da serotonina e a resposta a ETCC, sendo que o alelo curto (s) associou-se a uma pior resposta. Nao observamos interacoes com o polimorfismo Val66Met do BDNF. Finalmente, no estudo de seguimento, dos 42 pacientes que receberam ETCC quinzenal, por 3 meses, seguida de mensal, por 3 meses, a recaida foi de 47%. Em conjunto, os resultados demonstram que, na depressao aguda, a ETCC ativa e superior a simulada, comparavel a sertralina, e o tratamento combinado, superior aos demais. Clinicamente, a ETCC poderia substituir antidepressivos nos pacientes que nao toleram, nao podem ou nao desejam toma-los, ou combinada a estes, por exemplo, no tratamento de episodios graves / Transcranial direct current stimulation (tDCS) is a non-invasive technique of brain stimulation that applies a weak, direct electric current over ones scalp through electrodes, leading to neuromodulatory and neuroplastic effects. We evaluated the role of tDCS as a treatment for major depressive disorder (MDD), a chronic, prevalent condition, through a double-blind, 2x2 (factorial) trial, with one pharmacological (sertraline 50mg/day) and one non-pharmacological (tDCS) intervention; therefore comparing the efficacy and safety of active vs. sham tDCS, vs. sertraline and the combination active tDCS/sertraline vs. other interventions. Of 850 volunteers, we included only those with moderate-tosevere depression, low suicidal ideation, absence of other psychiatric and medical comorbidities and also those either not currently on antidepressants or using and agreeing to discontinue their use. We did not enrol patients on sertraline. The 120 patients were randomized into 4 groups: tDCS sham/placebo (placebo), tDCS sham/sertraline (sertraline), active tDCS/placebo (tDCS) and active tDCS/sertraline (combined treatment). TDCS was applied at 2mA/25cm2, with the anode and the cathode over the left and right dorsolateral prefrontal cortex, respectively, per 30 minutes daily, per 10 weekdays. Thereafter, tDCS was applied every other week, until the endpoint at 6 weeks (i.e., two extra sessions). For sham tDCS, the device was turned off after 30 seconds of stimulation. We performed an intention-to-treat analysis in the 103 patients who finished the study. The Montgomery- Asberg depression rating scale (MADRS) was the primary outcome. The four groups were similar at baseline. At week 6, the combined treatment group was significantly more effective (p0.01 for all comparisons) than placebo (mean difference of 11.5 points, 95% Confidence Interval [CI] =6-17), sertraline (8.5 points, 95% CI=2.9-14) and tDCS (5.9 points, 95% CI=0.36-11.43). TDCS and sertraline presented similar efficacy (2.6 points, 95% CI=-2.9 to 8.1, p=0.35). Other depression scales yielded similar results. The only adverse effect significantly more observed in the active tDCS was skin redness on the stimulated scalp region. The groups had similar performance in the cognitive assessments; although 5 of 7 (hypo)manic episodes were in the combined treatment group. The ancillary studies showed that tDCS treatment did not change heart rate variability (measured at baseline and endpoint), further suggesting that the intervention is safe. Moreover, there was an interaction between the short allele (s) of the serotonin transporter gene (5-HTTLPR) and lower tDCS antidepressant response; no association was observed with the Val66Met BDNF genotypes and tDCS response. Finally, we followed 42 patients for up to 24 weeks, performing tDCS sessions every other week for 3 months and then each month per 3 months, with a relapse rate of 47%. Taken together, these results showed that, for the acute depressive episode, active tDCS is more effective than sham, as effective than sertraline, and less effective than the combined treatment, which is the most effective. In clinical settings, tDCS could be either a substitutive treatment for antidepressants in patients that cannot or would not use them, or as an augmentative treatment that, combined with antidepressants, could boost clinical response in severe cases

Abstract The aim of this thesis was to explore the associations between the use of nervous system medications and suicidal ideation and behaviour in various different diagnostic groups in a large population-based cohort. Information on prescribed antipsychotic, antidepressant, benzodiazepine and antiepileptic medications within the Northern Finland Birth Cohort 1966 was collected from the register of the Social Insurance Institution of Finland and from a postal questionnaire sent to all cohort members in 1997. The presence of suicidal ideation and depression and anxiety symptoms was assessed via the Hopkins Symptom Checklist-25 questionnaire in 1997. Data on suicides were collected from the cause-of-death statistics and on suicide attempts from the Finnish Care Register for Health Care in a 15-year follow up. The use of antipsychotic, antidepressant, or benzodiazepine medication was associated with increased suicidal ideation, suicide attempts, and suicides. Antiepileptic medication was not associated with increased suicidality. The polypharmacy of nervous system medications was associated with increased suicidality. All nervous system medications were associated with increased severity of depression and anxiety symptoms. When depression and anxiety symptoms were taken into account, most of the associations between medication and suicidal ideation were statistically non-significant. Regarding specific groups, among those who did not have psychosis, high doses of antipsychotic medication correlated particularly with increased suicidal ideation even when other symptoms of depression and anxiety were taken into account. Among those with insomnia, the use of antidepressant medication associated with increased suicidal ideation also when other symptoms were taken into account. Although nervous system medication is associated with increased suicidal ideation, the association with other symptoms is also strong, and therefore it could not be stated that medication associates specifically with suicidal ideation. However, certain groups, i.e., non-psychotic subjects with high doses of antipsychotic medication, or subjects with insomnia and using antidepressant medication, should be closely monitored as they could be more vulnerable to suicidal ideation. / Tiivistelmä Tämän väitöstutkimuksen tarkoituksena oli tutkia hermostoon vaikuttavien lääkkeiden, lähinnä psykoosilääkkeiden, masennuslääkkeiden, bentsodiatsepiinien sekä epilepsialääkkeiden, yhteyttä itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Aihetta tutkittiin eri diagnoosiluokissa suuressa väestöaineistossa, Pohjois-Suomen vuoden 1966 syntymäkohortissa. Tieto tutkimushenkilöiden lääkkeenkäytöstä vuodelta 1997 kerättiin Kelan lääkeostorekisteristä sekä postikyselyn avulla. Itsetuhoisten ajatusten ja muiden masennus- ja ahdistusoireiden vakavuutta mitattiin Hopkins Symptom Checklist-25 -kyselyn avulla vuonna 1997. Tieto itsemurhista kerättiin 15 vuoden seurannassa kuolinsyyrekisteristä ja tieto itsemurhayrityksistä hoitoilmoitusrekisteristä. Psykoosilääkkeiden, masennuslääkkeiden ja bentsodiatsepiinien käyttö oli yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, itsemurhayrityksiin ja itsemurhiin. Epilepsialääkkeet eivät liittyneet itsetuhoisuuteen. Usean hermostoon vaikuttavan lääkkeen yhtäaikainen käyttö oli yhteydessä lisääntyneeseen itsetuhoisuuteen. Kaikki hermostoon vaikuttavat lääkkeet liittyivät lisääntyneisiin masennus- ja ahdistusoireisiin. Kun lääkityksen yhteys masennus- ja ahdistusoireisiin otettiin huomioon, lääkkeet eivät olleet erityisesti yhteydessä itsetuhoisiin ajatuksiin. Diagnostisten ryhmien välillä ei ollut eroa hermostoon vaikuttavien lääkkeiden ja itsemurhayritysten tai itsemurhien välisessä yhteydessä. Henkilöillä, joilla ei ole psykoosia, suuremmat psykoosilääkeannokset olivat yhteydessä itsetuhoisten ajatusten vakavuuteen kun muiden masennus- ja ahdistusoireiden vakavuus otettiin huomioon. Unettomuudesta kärsivillä henkilöillä masennuslääkkeen käyttö oli liittyi lisääntyneisiin itsetuhoisiin ajatuksiin kun muut oireet huomioitiin. Hermostoon vaikuttavat lääkkeet ovat yhteydessä lisääntyneisiin itsetuhoisiin ajatuksiin, mutta ne ovat myös vahvasti yhteydessä muihin masennus- ja ahdistusoireisiin. Tietyt henkilöt voivat kuitenkin olla erityisen herkkiä nimenomaan itsetuhoisille ajatuksille, ja heitä tulisi seurata erityisen tiiviisti. Tällaisia ovat henkilöt, joilla ei ole psykoosia, mutta jotka käyttävät suuria psykoosilääkeannoksia, sekä vakavasta unettomuudesta kärsivät henkilöt, jotka käyttävät masennuslääkettä.