Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 6 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2010. / Härtill 5 uppsatser.

Pharmacological magnetic resonance imaging (phMRI) is the use of functional MRI techniques to elucidate the effects that psychotropic drugs have on neural activity within the brain; it is an emerging field of research that holds great potential for the investigation of drugs that act on the central nervous system by revealing the changes in neural activity that mediate observable changes in behavior, cognition, and perception. However, the realization of this potential is hampered by several unanswered questions: Are the MRI measurements reliable surrogates of changing neural activity in the presence of pharmacological agents? Is it relevant to investigate psychiatric phenomena such as reward or anxiolysis in anesthetized, rather than conscious animals? What are the methods that yield reproducible and meaningful results from phMRI experiments, and are they consistent in the investigations of different drugs? The research presented herein addresses many of these questions with the specific aims of 1) Developing pharmacological MRI methodologies that can be used in the conscious animal, 2) Validating these methodologies with the investigation of a non-stimulant, psychoactive compound, and 3) Applying these methodologies to the investigation of typical and atypical antipsychotic drugs, classes of compounds with unknown mechanisms of therapeutic action Building on recent developments in the field of functional MRI research, we developed new techniques that enable the investigator to measure localized changes in metabolism commensurate with changing neural activity. We tested the hypothesis that metabolic changes are a more reliable surrogate of changes in neural activity in response to a cocaine challenge, than changes observed in the blood-oxygen-level-dependent (BOLD) signal alone. We developed a system capable of multi-modal imaging in the conscious rat, and we tested the hypothesis that the conscious brain exhibits a markedly different response to systemic morphine challenge than the anesthetized brain. We identified and elucidated several fundamental limitations of the imaging and analysis protocols used in phMRI investigations, and developed new tools that enable the investigator to avoid common pitfalls. Finally, we applied these phMRI techniques to the investigation of neuroleptic compounds by asking the question: does treatment with typical or atypical antipsychotic drugs modulate the systems in the brain which are direct or indirect (i.e. downstream) substrates for a dopaminergic agonist? The execution of this research has generated several new tools for the neuroscience and drug discovery communities that can be used in neuropsychiatric investigations into the action of psychotropic drugs, while the results of this research provide evidence that supports several answers to the questions that currently limit the utility of phMRI investigations. Specifically, we observed that metabolic change can be measured to resolve discrepancies between anomalous BOLD signal changes and underlying changes in neural activity in the case of systemically administered cocaine. We found clear differences in the response to systemically administered morphine between conscious and anesthetized rats, and observed that only conscious animals exhibit a phMRI response that can be explained by the pharmacodynamics of morphine and corroborated by behavioral observations. We identified fundamental and drug-dependent limitations in the protocols used to perform phMRI investigations, and designed tools and alternate methods to facilitate protocol development. By applying these techniques to the investigation of neuroleptic compounds, we have gained a new perspective of the alterations in dopaminergic signaling induced by treatment with antipsychotic medications, and have found effects in many nuclei outside of the pathways that act as direct substrates for dopamine. A clearer picture of how neuroleptics alter the intercommunication of brain nuclei would be an invaluable resource for the classification of investigational antipsychotic drugs, and would provide the basis for future studies that examine the neuroplastic changes that confer therapeutic efficacy following chronic treatment with antipsychotic medications.

Made available in DSpace on 2015-07-22T20:49:11Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-02-27. Added 1 bitstream(s) on 2015-08-11T03:25:33Z : No. of bitstreams: 1 Publico-008.pdf: 1147299 bytes, checksum: c53fe718c40d4278be6155456942dfbe (MD5) / Contexto: a disfunção sexual é frequente entre pacientes com esquizofrenia, sendo relatada como um dos mais incômodos efeitos adversos dos antipsicóticos e esta diretamente relacionada com adesão ao tratamento. Objetivo: a) avaliar a frequência da disfunção sexual em uma amostra de pacientes do espectro da esquizofrenia em tratamento com antipsicóticos; b) investigar 0 efeito dos diferentes antipsicóticos na função sexual; e c) avaliar a acurácia da Escala de Experiência Sexual do Arizona (AS EX) para identificar disfunção sexual. Método: pacientes ambulatoriais com esquizofrenia ou transtorno esquizoafetivo foram entrevistados através de questionários: ASEX e Escala Dickson-Glazer (DGSFi) para avaliação do funcionamento sexual, em uma única entrevista. Resultados: 137 pacientes foram entrevistados. A sensibilidade e especificidade da ASEX em relação a DGSFi foram: 80.8% ( 95% IC= 70.0%-88.5%) e 88.1 % (95% IC=76.5%-94.7%), e a taxa de classificação incorreta foi 9.5%. A curva ROC comparando a pontuação da ASEX e DGSFi revelou valor de 0.93 (IC=0.879¬0.970) com 0 ponto de corte da ASEX encontrando sendo 14/15. A disfunção sexual foi mais alta entre as mulheres (79.2%) do que nos homens (33.3%) (X2=27.41, gl=1, p<0.001). Conclusão: pacientes em tratamento com antipsicóticos mostraram alta frequência de queixas sexuais e ASEX provou ser um instrumento eficaz para identificar disfunção sexual em amostra de pacientes ambulatoriais do espectro da esquizofrenia. Mulheres mostraram frequência mais alta de disfunção, e desejo sexual e habilidade para alcançar orgasmo foram áreas mais afetadas. 0 uso de antipsicóticos, principal mente 0 uso de combinações, foi associado com piora do funcionamento sexual.. / Background: sexual dysfunction is frequent in patients with schizophrenia, it is reported as one of the most distressing antipsychotic’s adverse effects and it is directly related to treatment compliance. Objective: a) to assess the frequency of sexual dysfunction in a sample of outpatients with schizophrenia and schizoaffective disorder under antipsychotic therapy; b) to investigate the effect of different antipsychotics on sexual function; and c) to evaluate the accuracy of the Arizona Sexual Experience Scale (ASEX) to identify sexual dysfunction. Method: Outpatients with schizophrenia or schizoaffective disorder were asked to fulfill both the ASEX and the Dickson Glazer Scale for the Assessment of Sexual Functioning Inventory (DGSFi) at a single interview. Results: 137 patients were interwied. The sensitivity and specificity of the ASEX in relation to DGSFi were: 80.8%, (95% CI= 70.0%-88.5%) and 88.1% (95% CI= 76.5%-94.7%), and the misclassification rate was 9.5%. The ROC curve comparing the ASEX and the DGSFi scores revealed a value of 0.93 (CI= 0.879-0.970), with the optimum cut-off point of ASEX being 14/15. Sexual dysfunction measured was higher in females (79.2%) than in males (33.3%) (2 = 27.41, d.f.=1, p<0.001). Discussion: Patients under antipsychotic treatment showed a high level of sexual complaints, and the ASEX proved to be an accurate instrument to identify sexual dysfunction in an outpatient sample of patients with schizophrenia spectrum. Females showed a higher frequency of sexual dysfunctions and sexual drive and ability to reach orgasm were the most affected areas. The use of antipsychotics, especially the combinations, was more likely to impair sexual functioning. / TEDE / BV UNIFESP: Teses e dissertações

Submitted by Ismael Pereira (ismael@neuro.ufrn.br) on 2017-11-03T14:45:12Z No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) / Approved for entry into archive by Ismael Pereira (ismael@neuro.ufrn.br) on 2017-11-03T14:46:05Z (GMT) No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) / Made available in DSpace on 2017-11-06T11:41:34Z (GMT). No. of bitstreams: 1 Tese_AdrianoTort_2005.pdf: 1861214 bytes, checksum: 93eb092dffbce7414f26253895b0ad28 (MD5) Previous issue date: 2005-12 / Os objetivos da presente tese de doutorado foram os de buscar novos antipsic?ticos at?picos de baixo pre?o comercial e tamb?m procurar entender o mecanismo de a??o que leva a um perfil antipsic?tico at?pico. Os resultados da tese s?o divididos em duas partes, de acordo com sua natureza, em experimentais (primeira parte) e te?ricos (segunda parte). Para o desenvolvimento da primeira parte, foi necess?ria primeiramente a programa??o de um software para medir locomo??o em roedores ap?s filmagem com webcam. A seguir, foram investigados os efeitos da guanosina, flunarizina e cinarizina em modelos animais de psicose, bem como em outros paradigmas comportamentais. A guanosina foi escolhida para estudo uma vez que tem se mostrado que ela interage com o sistema glutamat?rgico ? que sabidamente est? envolvido na fisiopatologia da esquizofrenia ? promovendo a capta??o astrocit?ria de glutamato. J? a flunarizina e a cinarizina, dois bloqueadores de canal de c?lcio empregados para tratar enxaqueca e vertigem foram escolhidas pelo fato delas produzirem sinais e sintomas extrapiramidais em pacientes idosos, o que posteriormente foi relacionado ?s suas propriedades como antagonistas moderados dos receptores dopamin?rgicos do tipo D2. A guanosina diminuiu o aumento de locomo??o induzido por um antagonista NMDA (MK-801), enquanto que n?o apresentou efeito sobre o aumento de locomo??o induzido por anfetamina, de forma que sua utilidade como potencial antipsic?tico deve ser ainda melhor estudada. Tanto a flunarizina quanto a cinarizina foram capazes de diminuir o aumento de locomo??o induzido por MK-801 e por anfetamina em doses que n?o causam efeitos catal?pticos importantes. Portanto, foi conclu?do que estes dois compostos apresentam um potencial perfil de antipsic?tico at?pico, com as vantagens de j? estarem dispon?veis para uso comercial, boa tolerabilidade e baixo custo quando comparados com os antipsic?ticos at?picos dispon?veis comercialmente nos dias de hoje. A segunda parte da tese apresenta alguns resultados te?ricos matem?ticos que podem ser derivados da teoria da lei de a??o das massas aplicada ao binding de receptores, utilizando tamb?m resultados experimentais j? conhecidos de PET. Estes resultados apresentam insights ao entendimento das diferen?as entre os perfis antipsic?ticos at?picos e t?picos em rela??o ? gera??o de sinais extrapiramidais. ? discutido que fatores culturais e comerciais relacionados ? posologia atual empregada no tratamento com antipsic?ticos t?picos podem ser os respons?veis pelas diferen?as de perfis, uma vez que alguns deles s?o prescritos em doses proporcionalmente maiores em rela??o ? sua afinidade, atingindo assim maiores n?veis de bloqueio dopamin?rgico no estriado. Uma curta meia-vida plasm?tica tamb?m ? apontada como um poss?vel par?metro importante na gera??o de um perfil at?pico. ? mostrado ainda alguns erros de concep??o relacionados ao curso temporal da ocupa??o dopamin?rgica que tem sido atualmente cometidos na literatura cient?fica, como o conceito de meia-vida de ocupa??o de receptores. Como um ?ltimo resultado te?rico, ? proposto um algoritmo para a redu??o de dose em pacientes tratados com antipsic?ticos apresentando sinais e sintomas extrapiramidais. / The aims of this work were the search for new atypical antipsychotics presenting low cost and the understanding of the mechanism of action leading to atypical antipsychotic profile. The results obtained are presented in two distinct parts based on their nature, namely, experimental (first part) or theoretical (second part). For the development of the first part, a webcam based software to measure locomotion of rodents was programmed. After that, it was investigated the effect of guanosine, flunarizine and cinnarizine on animal models of psychosis, as well as in other behavioral tasks. Guanosine was chosen because it has been shown to interact with the glutamatergic system ? which is known to be involved in the pathophysiology of schizophrenia ? by promoting astrocytic glutamate reuptake. Flunarizine and cinnarizine, two calcium channel blockers commonly used in many countries to treat vertigo and migraine, were chosen because they were shown to induce extrapyramidal signs in elder patients, which was later related to moderate antagonist properties at dopamine D2 receptors. Guanosine was able to reduce a NMDA antagonist (MK-801) induced hyperlocomotion, whereas it had no effect on the hyperlocomotion induced by amphetamine, and it is discussed that its utility as antipsychotic drug should be further evaluated. Both cinnarizine and flunarizine were able to reduce the hyperlocomotion induced by MK-801 and amphetamine at doses that presented no significant cataleptic behavior. It was therefore concluded that these compounds have a potential atypical antipsychotic profile, with the advantage of already approved for commercial use, presenting well tolerability and very low cost when compared to current commercially available atypical antipsychotics. The second part of this thesis presents some theoretical mathematical results that can be derived from the law of mass action theory applied to receptor binding linked with known PET experimental data. These results present insights to the understanding of the differences between typical and atypical profile of antipsychotics regarding the generation of extrapyramidal syndrome. It is argued that cultural and commercial aspects related to the nowadays employed posology of typical antipsychotics can be responsible for the difference seen in profile, once some typical antipsychotics are prescribed in proportionally higher doses in relation to their affinities, leading therefore to higher dopaminergic blockade. A short plasmatic half-life is also pointed as a possible important factor leading to an atipical profile. Moreover, the second part of this thesis also points to some misconception currently being used in the scientific literature regarding the time-course of dopaminergic occupation, such as the concept of receptor occupation half-life. As a last theoretical based result, it is proposed an algorithm for antipsychotic dose reduction in patients presenting extrapyramidal signs and symptoms.

A esquizofrenia à uma doenÃa heterogÃnea quanto a caracterÃsticas e gravidade dos sintomas. Diversas alteraÃÃes relacionadas ao sono, com possÃveis efeitos sobre a capacidade funcional, foram descritas. Dentre os poucos estudos que registraram ritmo circadiano na esquizofrenia, alguns sugerem que os indivÃduos com alteraÃÃes de ritmo apresentam menor rendimento em testes neuropsicolÃgicos. Os estudos neuropsicolÃgicos com pacientes esquizofrÃnicos dÃo conta de um comprometimento de diversos tipos de funÃÃes incluindo a memÃria operacional tanto verbal quanto viso-espacial. Muitos desses testes sÃo considerados longos e complicados e a utilidade de cada um deles ainda nÃo està esclarecida. Este trabalho teve por objetivo: avaliar os padrÃes do sono, o cronotipo, o perfil neurocognitivo e as suas relaÃÃes com parÃmetros clÃnicos e funcionais. Trata-se de estudo observacional, transversal, de pacientes com esquizofrenia, em uso de antipsicÃticos convencionais ou de Ãltima geraÃÃo, quanto à capacidade funcional, alteraÃÃes do sono e perfil neurocognitivo. Foram utilizadas medidas para avaliaÃÃo da capacidade de funcionamento (Escala de AvaliaÃÃo Global do Funcionamento â AGF), gravidade das comorbidades (Cumulative Illness Rating Scale â CIRS), qualidade do sono (Ãndice de Qualidade de Sono de Pittsburgh â IQSP), sonolÃncia diurna (Escala de sonolÃncia de Epworth â ESE), cronotipo (QuestionÃrio de Horne e Ãstberg) e uma bateria de testes neurocognitivos incluindo os testes de Stroop, DÃgitos Direto e Indireto, Corsi Direto e Indireto e FluÃncia Verbal (CategÃrico). Foram estudados 82 pacientes (51,2% do sexo masculino) com idade entre 17 e 59 anos (35,2Â10,4) em uso de antipsicÃticos convencionais (N=22), olanzapina (N=30) ou risperidona (N=30). Observou-se mÃ-qualidade do sono (IQSP>5) em 41 (50%) e sonolÃncia excessiva diurna (ESE&#8805;10) em 20 (24,4%) pacientes. A mà qualidade do sono associou-se com o gÃnero feminino (P=0,01). Uma tendÃncia de associaÃÃo entre a capacidade funcional e a qualidade do sono (P=0,07) foi registrada. Observou-se que a pior capacidade funcional associou-se com a idade mais avanÃada, um nÃmero reduzido de anos escolares e maior gravidade das comorbidades. Com relaÃÃo ao cronotipo e considerando o grupo total, 08 pacientes (9,8%) eram do tipo definitivamente vespertino, 39 (47,6%) eram do tipo moderadamente vespertino, 33 (40,2%) eram do tipo indiferente, dois (2,4%) eram moderadamente do tipo matutino e nenhum era definitivamente matutino. Os pacientes mais jovens e do sexo masculino apresentavam uma preferÃncia mais vespertina (F= 6,32; P= 0,01), de forma semelhante à populaÃÃo em geral. Os casos em uso de antipsicÃticos convencionais apresentaram uma tendÃncia para maior preferÃncia vespertina. As comorbidades mais frequentemente relatadas relacionaram-se a queixas osteoarticulares, sintomas psicolÃgicos e alteraÃÃes metabÃlicas. Os testes neurocognitivos apresentaram-se alterados na maioria dos casos, observando-se que a maioria dos pacientes apresentava escores inferiores a 80% dos valores historicamente normais. O teste de Stroop relacionou-se com a AGF apÃs controle para a idade e escolaridade (F= 6,43; P= 0,001). O teste de DÃgitos Indireto relacionou-se com a AGF apÃs controle para o gÃnero, a escolaridade e o tipo de antipsicÃtico (F= 4,76; P= 0,003). O teste de Corsi Direto relacionou-se com a capacidade global de funcionamento apÃs ajuste para o gÃnero (F= 3,68; P= 0,01). O teste de Corsi Indireto relacionou-se com a capacidade global de funcionamento apÃs ajuste para o gÃnero, escolaridade e tipo de tratamento (F=3,03; P= 0,02). Os testes de Stroop e DÃgitos Indireto associaram-se mais fortemente e de forma independente com a capacidade funcional seguidos pelo Teste de Corsi Direto e Indireto. Observou-se uma relaÃÃo entre o sexo feminino e a alteraÃÃo do Teste de Corsi Indireto que avalia memÃria espacial. Em conclusÃo, mà qualidade do sono à comum e associa-se ao sexo feminino. Observa-se uma tendÃncia de associaÃÃo entre a qualidade do sono e a capacidade funcional. No grupo geral, a preferÃncia vespertina foi predominante. Os testes neurocognitivos estavam alterados na maioria dos casos. Os testes de Stroop e DÃgitos Indireto, dois testes de realizaÃÃo rÃpida e fÃcil que avaliam a memÃria operacional, foram os que melhor se associaram com a capacidade funcional. / Clinical characteristics and symptom severity are heterogeneous in schizophrenia making the course and outcome less predictable. Sleep disturbances have been frequently described in association with this illness and may have deleterious effect on functional abilities. A few studies have described circadian changes in schizophrenia and some suggest a relationship between circadian alterations and poor performance after neuropsychological tests. Previously, it has been shown that patients with schizophrenia have impairment of verbal and visual-spatial working memory. However, many of these tests are laborious, complicated and time consuming. The utility of the several available neuropsychological tests in schizophrenia is not yet totally clarified. We have aimed to study sleep alterations, morning-evening preference, neurognitive function and their relationship with clinical variables. This is a cross-sectional study of patients with schizophrenia on use of conventional or atypical antipsychotic regarding functional abilities, sleep alterations and cognitive function. Assessment procedures involved the use of the Global Assessment of Functioning (GAF) Scale, Cumulative Illness Rating Scale (CIRS), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Horne e Ãstberg questionnaire, and a neuropsychological battery that included the WAIS Digit Span Forward and Backward, Corsi block-tapping task (Forward and Backward), Stroop Color Word Interference Test and the Phonemic Verbal Fluency Test. We studied 82 patients (51.2% male) aged 17 to 59 years (35.2Â10.4). Twenty-two were using conventional antipsychotic, 30 olanzapine and 30 risperidone. Poor sleep quality (PSQI>6) was observed in 41 subjects (50%) and excessive daytime sleepiness (ESE&#8805;10) in 20 (24.4%). Female gender was associated with poor sleep quality (P=0.01). A trend of association between quality of sleep and GAF was observed (P=0.07). Worse disability, as evaluated by GAF, was associated with age, reduced number of school years and greater comorbidity severity. In relation to morning-evening preference, eight patients (9.8%) were definitely evening, 39 (47.6%) were moderately evening 33 (40.2%) were indifferent, 2 (2.4%) were moderately morning and none were definitely morning type. Younger patients and of male gender showed more evening preference (F= 6.32; P= 0.01) similar to previous reports in the literature. Frequent comorbidities were related to osteoarticular complaints, psychological symptoms, and metabolic alterations. Neuropsychological tests were altered in the vast majority of patients with values below 80% of historical normal values. The Stroop test was associated with GAF after controlling for age and school years (F= 6.43; P= 0.001). The Digit Span Backward was associated with GAF after controlling for gender, school years and type of antipsychotic (F= 4.76; P= 0.003). The Corsi block-tapping task Forward was associated with GAF after controlling for gender (F= 3.68; P= 0.01). The Corsi block-tapping task Backward was associated with GAF after controlling for gender, number of school years and type of antipsychotic (F=3.03; P= 0.02). The Stroop and Digit Span Backward were best associated with functional ability followed by the Corsi block-tapping task (Forward and Backward). A correlation between female gender and visual-spatial memory as evaluated by the Corsi Block-tapping Task Backward was observed. In conclusion, poor sleep quality is common and more present in women with schizophrenia. A trend between poor sleep quality and functional disability was observed. In general, an evening preference was predominant. Neurocognitive tests were altered in the majority of cases. The Stroop and Digit Span Indirect, two quick and easy to perform tests that evaluate working memory, were those that presented the greater association with global functional ability