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The aims of this study were to explore professionals’ and clients’ experiences of diagnosis and treatment of auditory verbal hallucinations with a view to identifying important clinical issues for counselling psychologists. Six professionals, three psychologists and three psychiatrists, who had worked with people who hear voices, alongside four clients who hear voices, volunteered and participated in a semi-structured interview. These interviews were transcribed and analysed using Interpretative Phenomenological Analysis (IPA) as described by Smith, Flowers and Larkin (2009). A table of super-ordinate and sub-ordinate themes was created as a result of this analysis. A number of themes arose from both groups of participants’ experiences. The main themes that arose for the professionals was: professional ambivalence; varying theories on causes of voices; perspectives on diagnosis and formulation; perspectives on medication; thoughts on working therapeutically; and, thinking on recovery. The themes that arose from the clients’ experiences were feelings about diagnosis and experiences of treatment. This research concludes that there is professional ambivalence in working with people who hear voices that is caused by a lack of certainty about the causes of the phenomenon alongside a lack of training in working with clients who have symptoms of psychosis. This impacts clients in several ways. The clients in this study were not offered the option to have any involvement in their own care and none of them were offered therapy as a treatment option. The study also concludes that psychiatric diagnosis does not consider all pertinent information related to clients’ issues which can lead to inconsistency in the diagnosis of clients who hear voices.

Les antipsychotiques atypiques sont des options de traitement de première ligne pour la schizophrénie. Cependant, la prise d’antipsychotiques atypiques, comme l’olanzapine, est associée à des effets secondaires métaboliques : l’augmentation du poids, la dyslipidémie et l’intolérance au glucose. Les mécanismes en lien avec ces effets secondaires sont à ce jour peu connus. Ce mémoire étudie l’évolution de différents paramètres, tant au niveau biométrique (poids, IMC, circonférence abdominale), qu’au niveau sérique (bilan lipidique, glycémie à jeun, insuline, leptine, ghreline) et clinique (mesures des symptômes positifs, négatifs et généraux de la schizophrénie, de même que des comportements alimentaires) chez des sujets schizophrènes, traités pendant 16 semaines avec l’olanzapine. Des examens de résonance magnétique, structurale et fonctionnelle, ont été effectués au début et à la fin du traitement d’olanzapine chez les sujets schizophrènes et chez un groupe de sujets contrôles afin d’identifier les régions cérébrales dont les volumes ou les activations pourraient être associés aux mécanismes d’effets secondaires métaboliques. Nos résultats confirment l’émergence de multiples effets secondaires métaboliques, associés à des modifications des comportements alimentaires, en lien avec la prise d’olanzapine auprès de notre échantillon. Des associations ont été retrouvées entre les changements métaboliques et les volumes de plusieurs régions cérébrales, notamment les hippocampes, les précunei et le gyrus orbitofrontal droit. De plus, des différences en terme d’activations cérébrales entre les sujets contrôles et les patients schizophrènes, qui ont été accentuées par le traitement d’olanzapine, ont aussi été décrites notamment au niveau amygdalien, cérébelleux et des insulas, suggérant l’implication de mécanismes neuronaux dans l’apparition des troubles métaboliques associés aux antipsychotiques atypiques. / Atypical antipsychotics are first line treatment options for schizophrenia. Nevertheless atypical antipsychotics, such as olanzapine, are associated with metabolic adverse effects: weight gain, dyslipidemia and glucose intolerance. Mechanisms underlying these side effects are still poorly understood. This thesis represents a study of the evolution of biometric (body weight, BMI, abdominal circumference), biological (lipid profile, fasting glucose, insulin, leptin, ghrelin) and clinical parameters (positive, negative and general symptoms of schizophrenia as well as eating behavior measures) in schizophrenia patients treated with olanzapine during 16 weeks. Healthy subjects and schizophrenia patients passed structural and functional magnetic resonance examinations (one examination for healthy controls and two examinations for schizophrenia patients, one at the beginning and one after 16 weeks of olanzapine treatment) in order to identify cerebral regions where grey matter volumes or activations could be associated with metabolic side effects mechanisms. Our results confirm that various metabolic adverse effects emerged in our sample of patients during the 16 weeks olanzapine treatment. Eating behavior changes have also been associated with specific metabolic changes. Many associations have been found between cerebral volumes (e.g. bilateral hippocampi and précunei and right orbitofrontal cortex) and metabolic changes. Moreover, cerebral activations differences between healthy controls and schizophrenia patients, that were increased following olanzapine treatment, were also described in the amygdala, cerebellum and insulas, suggesting that neuronal mechanisms were involved in the development of metabolic disorders associated with atypical antipsychotics.

Les antipsychotiques (APs) sont fréquemment prescrits pour les troubles comportementaux associés à la démence. Or, ces produits ont fait l'objet de trois mises en garde (2002, 2004, 2005) en raison d'une augmentation du risque d'événement cérébrovasculaire et de décès. L’objectif de ce mémoire est d’évaluer l'utilisation d’APs dans la population de personnes âgées démentes vivant à domicile, et de déterminer l’effet des mises en garde sur les profils observés. Une cohorte rétrospective de 10,969 personnes âgées démentes ayant débuté un traitement par AP entre le 1er janvier 2000 et le 31 décembre 2009 fut identifiée à partir des banques de données de la Régie de l'assurance maladie du Québec (RAMQ). Des séries chronologiques segmentées ont permis de quantifier l’effet des mises en garde sur l'utilisation d’APs. L'effet de la mise en garde de 2005 sur les caractéristiques des patients traités ainsi que sur les profils d'utilisation (dose et durée) a été évalué, respectivement par des modèles de régression logistique et de régression linéaire multivariés. Le taux délivrance d'APs atypiques a augmenté au cours du temps jusqu'à la mise en garde de 2005 pour ensuite diminuer de 8.96% (IC 95% : -11.91% – -6.02%). L'analyse par produit a révélé la même tendance pour la rispéridone, le seul AP approuvé au Canada pour les personnes âgées démentes. En revanche, le taux de délivrance de quétiapine, qui est hors-indication, a continué d'augmenter. Le taux d'initiation de traitement par APs a cependant diminué au cours du temps pour tous les produits. Les mises en garde ne semblent pas être associées avec un changement dans les caractéristiques des patients traités, ni avec les doses et durées d’utilisation. Le manque d'efficacité des mises en garde est probablement en partie lié à l'absence d'alternatives thérapeutiques pour le traitement des troubles psychologiques et comportementaux chez les patients atteints de démence. / Antipsychotics (APs) are frequently prescribed for the management of behavioural and psychological symptoms of dementia (BPSD). However, three safety warnings have been issued (2002, 2004 and 2005) due to an increased risk of cerebrovascular event and mortality. The aim of this thesis was to evaluate AP usage in the population of community-dwelling elderly with dementia, and to determine the effect of safety warnings on usage patterns. A retrospective cohort of 10,969 elderly with dementia who initiated an AP treatment between January 1st, 2000 and December 31st, 2009 was identified through in the databases of Régie de l’assurance maladie du Québec (RAMQ). Segmented time series analysis was used to quantify the effect of safety warnings on AP dispensing rate. The effect of the 2005 warning on the characteristics of treated patients and on usage patterns (dose and duration) was evaluated, respectively through multivariate logistic and multiple linear regression models. Atypical AP dispensing rates increased until the 2005 safety warning and decreased by 8.96% (95% CI: -11.91% – -6.02%) thereafter. Analysis by individual products yielded similar trends for risperidone, the only AP approved in Canada for elderly with dementia. However, usage of quetiapine, which is off-label, kept increasing. For all products, rate of treatment initiation decreased over time. Safety warnings did not seem to be associated with either changes in prescribed treatment dosage or duration, nor with prescription channeling toward lower risk patients. Apparent lack of efficacy of safety warnings is likely due, in part, to absence of effective treatment alternatives for BPSD.

Cette thèse vise à mieux comprendre le rôle du facteur de transcription Nur77 au sein des fonctions physiologiques et pathologiques des voies de neurotransmission dopaminergiques des gaglions de la base. Nous basant sur une implication motrice de Nur77 au sein des dyskinésies induites à la L-DOPA (LIDs), nous avons voulu tester in vivo son implication éventuelle dans les phénomènes moteurs et de sensibilisation associés à l’amphétamine ainsi qu’une implication possible du récepteur nucléaire aux rétinoïdes RXR dont nous avons déjà démontré une implication dans les effets moteurs des antipsychotiques. Un deuxième volet de la recherche à consisté en l’étude de l’implication des extracellular signal-regulated kinase (ERK) et de la protéine kinase C (PKC) dans l’induction de l’ARNm des membres de la famille des Nurs suite à l’activation des cascades de signalisation des récepteurs dopamiergiques D1 et D2 in vivo pour une meilleure compréhension des mécanismes physiopatholoiques liés aux désordres dopaminergiques. Pour ce faire, nous avons, premièrement, soumis des souris sauvages et Nur77-/- à un paradigme de sensibilisation à l’amphétamine ainsi qu’a différents agonistes antagonistes RAR/RXR afin de tester l’implication de Nur77 et d’un éventuel complexe Nur77/RXR dans les effets de l’amphétamine. Deuxièmement, soumis des souris sauvages à une combinaison d’agonistes D1/D2 ou une injection d’antagoniste D2 avec ou sans inhibiteur (ERK1/2 ou PKC) afin de tester l’implication de ces kinases sur l’induction de l’ARNm des membres de la famille des Nurs par hybridation in situ. Nous avons ainsi pu démontrer 1- un rôle moteur de Nur77 dans les effets liés à l’amphétamine notamment avec une absence de stéréotypies et un allongement de la durée de la phase de locomotion chez les souris Nur77-/-; ainsi qu’un rôle éventuel du complexe potentiel Nur77/RXR dans les D1 à mieux définir. 2- un rôle des kinases ERKs et PKCs dans les cascades de signalisation des récepteurs dopaminergiques D1 et D2 menant à l’induction des ARNms de Nur77, Nor-1 et Nurr-1. En perspective, ces résultats nous ouvrent la voie vers une implication éventuelle de Nur77 dans les mécanismes d’apprentissage que sont le Long Terme Potentiation (LTP) et la Long Terme Depotentialisation (LTD) liés aux LIDs et à l’amphétamine. / This thesis aims to better understand the role of the transcription factor Nur77 in the physiological and pathological functions of dopaminergic neurotransmission pathways of the basal gaglia. Based on a motor involvement of Nur77 in L-DOPA induced dyskinesias (LIDs), we wanted to test its possible involvement in the motor mechanisms associated with amphetamine, a drug of abuse that targets the direct neuronal population of the basal ganglia such as L-DOPA. Involvement of extracellular signal-regulated kinase (ERK) and protein kinase C (PKC) has been widely demonstrated in the LIDs and the effects of amphetamine, we wanted to know whether Nur77 mRNA was controlled by these kinases in both the striatonigral and striataux palidal neurons in response to specific activation of the D1 and D2 receptors in vivo. Finally, a possible involvement of RXR has been demonstrated in the motor effects of antipsychotic drugs, so we wanted to test its potential involvement in the effects of amphetamine. To do this, we subjected wild-type mice and Nur77-/- mice to a paradigm of sensitization to amphetamine with or without RXR agonist (DHA) and antagonsite (HX531) to test: 1 - the involvement of Nur77 in the motor effects and the phenomenon of sensitization to amphetamine and 2 - the involvement of any complex Nur77/RXR in these effects. Second, wild-type mice were subjected to a combination of D1/D2 agonists or antagonists D2 with or without ERK inhibitor or PKC inhibitor to test in vivo the induction of the mRNA of the Nurs members family by in situ hybridization. We were able to demonstrate a role of Nur77 in the motor effects associated with amphetamine namely in the absence of stereotypy and a lengthening of the duration of the phase of locomotion in Nur77-/ - mice; and a possible role of the potential complex Nur77/RXR in D1 neurones needed to be better defined. In addition, it is clearly demonstrated that the induction of Nurs members mRNA responds to the activation of signaling cascades of dopaminergic D1 or D2 receptors within the involvement of PKC and ERK kinases is undubtable which opens us the way to a possible involvement of Nur77 in learning mechanisms associated with LIDs and amphetamine that are the Long Terme Potentiation (LTP) and the Long Terme Depotentialisation (LTD).

Este trabalho apresenta a continuidade da avaliação farmacológica das substâncias LASSBio-579, LASSBio-580 e LASSBio-581, através de ensaios in vitro e in vivo, em busca de um novo protótipo para o desenvolvimento de novos fármacos antipsicóticos de segunda geração. LASSBio-581 se liga a receptores D2-like (Ki=0,95 μM), 5-HT1A (Ki=1,2 μM) e 5-HT2A (Ki=11 μM) com afinidades moderadas. Esta substância é capaz de reduzir a temperatura corporal de roedores, um efeito provavelmente mediado pela ativação de receptores 5-HT1A, e inibir o desenvolvimento de head-twiches e ear-scratches induzidos pela administração de um antagonista de receptores 5-HT2A. Estes efeitos demonstram a capacidade de LASSBio-581 em modular o sistema serotonérgico in vivo e in vitro. Porém, quanto avaliado em modelos animais preditivos de ação antipsicótica, LASSBio-581 foi inativo. LASSBio-580 também é capaz de se ligar a receptores D2-like (Ki=0,73 μM), 5-HT1A (Ki=0,48 μM) e 5-HT2A (Ki=5,7 μM) com afinidades moderadas. Esta substância não foi capaz de inibir o desenvolvimento do comportamento de escalada nem a redução da temperatura corporal de roedores induzidos por apomorfina, não apresentando potencial atividade antipsicótica nos ensaios realizados. Já LASSBio-579 é capaz de modular três diferentes sistemas neurotransmissores envolvidos na patofisiologia da esquizofrenia: a neurotransmissão dopaminérgica, serotonérgica e glutamatérgica. Esta substância se liga a receptores D2-like (Ki=0,11 μM), 5-HT1A (Ki=0,09 μM) e 5-HT2A (Ki=2,2 μM) com afinidades adequadas para uma molécula protótipo que se liga a múltiplos alvos. Apresenta ação antidopaminérgica in vivo, demonstrada em três modelos animais preditivos de atividade antipsicótica (sintomas positivos): inibição da estereotipia anfetamínica (NEVES et al., 2003), bloqueio do comportamento de escalada induzido por apomorfina e hipotermia apomorfínica. A ação agonista 5-HT1A de LASSBio-579 in vivo foi claramente demonstrada através de ensaios de aferição da temperatura corporal, onde o efeito hipotérmico induzido por esta substância é completamente bloqueado pela pré-administração de WAY 100635. Porém, a habilidade de LASSBio-579 em modular a atividade de receptores 5-HT2A in vivo permanece incerta. Ensaios eletrofisiológicos preliminares demonstraram um aumento da liberação de glutamato induzido por LASSBio-579 que parece ser mediado pela ativação de receptores 5-HT2A, porém comportamentos ou efeitos relacionados a ativação deste sub-tipo de receptor serotonérgico não foram identificados em roedores tratados com LASSBio-579. Além disso, a administração de LASSBio-579 não induziu efeitos catatônicos em camundongos em doses até 12 vezes superiores àquela ativa no modelo do bloqueio do comportamento de escalada induzido por apomorfina. Estes resultados demonstram que a estratégia de planejamento de fármacos baseado na estrutura do ligante empregada neste trabalho se mostrou bem sucedida. LASSBio-579 pode ser considerado um novo protótipo de fármaco antipsicótico de segunda geração, ativo em modelos animais de sintomas positivos da esquizofrenia e com baixo potencial de indução de efeitos motores. Porém, algumas limitações em seu perfil farmacológico pode ser identificadas. A afinidade desta substância por receptores dopaminérgicos e serotonérgicos é considerada moderada e inferior a de antipsicóticos atualmente no mercado. Ainda, LASSBio-579 induziu um prejuízo na coordenação motora em roedores e apresentou um perfil farmacocinético pouco adequado a utilização clinica (CONRADO et al., 2008). Estes dados encorajam a busca de substâncias com um perfil farmacológico superior ao de LASSBio-579. Neste sentido, uma triagem farmacológica de 18 derivados N-fenilpiperazínicos análogos a LASSBio-579 foi realizada. Os resultados obtidos nos ensaios de radioligação a receptores D2-like, 5-HT1A e 5-HT2A foram utilizados na proposição de relações qualitativas entre estrutura química das substâncias e a afinidade apresentada pelos diferentes receptores. A partir dos resultados obtidos in vitro, cinco outras substâncias foram selecionadas para avaliação da potencial atividade frente a sintomas positivos da esquizofrenia no modelo de bloqueio do comportamento de escalada induzido por apomorfina. Neste ensaio, apenas LASSBio-664 apresentou atividade, sem induzir catatonia nos animais. Porém, esta substância também induz um importante prejuízo motor nos animais. Ensaios adicionais são necessários a fim de diferenciar o perfil farmacológico de LASSBio-664 e LASSBio-579. Outro objetivo deste trabalho foi iniciar o desenvolvimento de um modelo animal de sintomas da esquizofrenia. Os resultados obtidos até o momento apontam para a possibilidade do desenvolvimento de um modelo relacionado a sintomas negativos/cognitivos da esquizofrenia baseados na esposição à natação forçada repetida. Foi demonstrado que apenas clozapina e não imipramina é capaz de reverter o aumento de imobilidade ao longo dos dias acarretado pela exposição repetida à natação forçada em roedores. Este dado demonstra uma potencial validade preditiva, o primeiro grau de validação necessário para um novo modelo animal. O efeito de LASSBio-579 também foi avaliado neste procolo experimental. / This study strengthened the pharmacological evaluation of the heterocyclic Nphenylpiperazine derivatives LASSBio-579, LASSBio-580 and LASSBio-581 by means of in vitro and in vivo pharmacological assays searching a new second generations antipsychotic lead compound. LASSBio-581 presented moderate affinitties for D2-like (Ki=0.95 μM), 5-HT1A (Ki=1.2 μM) e 5-HT2A (Ki=11 μM). This compound induced an hypothermic effect in rodents probably mediated by 5-HT1A receptor activation. LASSBio-581 administration inhibited the induction of head-twiches and ear-scratches by a 5-HT2A agonist. These results shown that LASSBio-581 modulates serotonergic neurotransmission in vivo and in vitro. However, it was inactive on animal models predictive of antipsychotic activity. LASSBio-580 presented moderate affinitties for D2-like (Ki=0.73 μM), 5-HT1A (Ki=0.48 μM) e 5-HT2A (Ki=5.7 μM). This compound did not inhibited apomophine-induced climbing nor apomorphine-induced hypothermia. Thus, among the three compounds initially evaluated, LASSBio-579 was the only one that exhibited promising results. This derivative was able to modulate three neurotransmitter systems involved in schizophrenia’s pathophysiology: dopaminergic, serotonergic and glutamateric ones. As a multi-target lead compound, LASSBio-579 presented adequated affinities for D2-like, 5-HT1A and 5-HT2A receptors (Ki D2-like = 0.11 μM, 5-HT1A = 0.093 μM and 5-HT2A = 2.2 μM). Its antidopaminergic in vivo effect was demonstrated in three animal models of positive symptons of schizophrenia: amphetamineinduced stereotypy (NEVES et al., 2003), apomorphine-induced climbing behavior and apomorphine-induced hypothermia. Regarding the serotonergic system, LASSBio-579 was considered a 5-HT1A receptor agonist, since the hypothermia induced by this compound was blocked by WAY 100,635 pre-administration. The ability of LASSBio-579 to modulate 5-HT2A receptors was not fully characterized. Electrophysiological assays demonstrated an increase on synaptic glutamate release induced by LASSBio-579 that may be related to 5-HT2A receptor activation, however this compound did not induce any behavior related to 5-HT2A activation in rodents. In addition, LASSBio-579 did not induce catalepsy in mice at doses 12 folds higher than those active at apomorphine-induced climbing test. Thus, LASSBio-579 represents a new antipsychotic lead compound active in animal models of positive symptoms of schizophrenia and with a mild propensity to induce motor side effects. However, some limitations on LASSBio-579’s pharmacological profile could be identified. The affinity of LASSBio-579 for dopamine and serotonin receptors is moderate and lower than those presented by second generation antipsychotics. Furthermore, this compound induced a mild decrease on locomotion and exploratory behavior, a meaningful motor coordination impairment and presents a limited oral bioavailability and a low brain penetration (CONRADO et al., 2008). Considering this, a pharmacologycal screening of 18 N-phenylpiperazine derivatives were done in order to achieve an optimized analogue of LASSBio-579. Structural features of this molecular scaffold were discussed regarding binding affinity and selectivity for D2-like, 5-HT1A and 5-HT2A receptors. Among the compounds prepared, LASSBio-664 exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. However, the motor coordination impairment remained. Additional pharmacological characterization of LASSBio-664 is still needed to find differences from LASSBio-579’s profile. Another aim of this study was to start the development of an animal model of schizophrenia symptons. It was shown that clozapine but not imipramine presented an anti-immobility effect in animals repeated exposed to forced swimming. This result points to the usefullness of repeated forced swimming protocol for developing new animal models predictive of antipsychotic action. The effect of LASSBio-579 in this protocol was also evaluated.

A não adesão ao tratamento farmacológico é um fator determinante ao agravamento das doenças crônicas e está intimamente ligada à recaída de quadros psicóticos. Mesmo sendo uma opção de incentivo à adesão e prevenção de recaída, o Decanoato de Haloperidol por si só não garante o sucesso do tratamento. O objetivo deste trabalho foi descrever as características sócio-demográficas e clínicas de pacientes com prescrição de Decanoato de Haloperidol assistidos em um serviço ambulatorial de saúde mental. Utilizamos um questionário estruturado para a coleta dos dados via prontuário dos pacientes e listagens mensais de retirada da medicação na farmácia do serviço. Foram analisados 167 prontuários de pacientes. A maioria dos pacientes apresentou um maior risco para ocorrência de recaídas frente à retiradas irregulares da medicação no serviço de saúde. De modo geral, o uso irregular da medicação esteve associado a maiores intervalos de dias prescritos para administração de Decanoato de Haloperidol, maior tempo de tratamento/prescrição e diagnóstico de esquizofrenia. Os profissionais de saúde mental precisam estar mais atentos à complexidade do fenômeno da adesão. Ao conhecer melhor sua clientela, estes profissionais podem refletir acerca da assistência psicossocial que um serviço de saúde mental comunitário deve a sua clientela e de ações que minimizem o risco de recaídas nessa população. / No adherence to pharmacological treatment is a determinant factor in the severity of chronic illnesses and is closely related to relapses. Indicated as option of better control the adhesion and fallen again prevention, Haloperidol Decanoate by itself does not guarantee the success of the treatment. The objective was to describe demographic and clinical characteristics of patients with lapsing of Haloperidol Decanoate attended in outside service of mental health. We used structure questionary to tax data in handbooks and withdrawals medication lists of pharmacy service. We analyse 167 handbooks of patients. The analysis of the data showed that the majority of patients presented a bigger risk to occurrence of fallen again front the irregular withdrawals of the medication in health service. In general way, the irregular use of the medication was associates the biggest intervals of days prescribed for administration of Haloperidol Decanoate, greater treatment/indicate time and diagnosis of schizophrenia. Professionals of mental health need to be more intent the complexity adhesion phenomenon. When knowing better its clientele, these professionals can reflect concerning the psicossocial assistance that a communitarian service of mental health must its clientele and of actions that minimize the risk of fallen again into this population.

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