This thesis sought to explore the phenomenon of discontinuing neuroleptic medication for psychosis. It comprises three standalone papers. Papers one and two have been prepared for submission to journals and in accordance with the journal guidelines. Paper one is a systematic literature review synthesising studies investigating the association between neuroleptic discontinuation and functional outcomes. Databases were systematically searched and thirteen studies were included in the review. Evidence regarding the association between discontinuation from neuroleptic medication and functional outcomes was mixed. Findings are limited by the scarcity of evidence, diversity in the study methods and designs used, and methodological and design quality issues. Paper two is a qualitative study exploring personal accounts of making choices about neuroleptic medication, specifically considering decisions to discontinue. Twelve participants were interviewed and a constructivist grounded theory approach was used to analyse transcripts. The findings suggest that making sense of choices relates to a continuation-discontinuation spectrum and involves three interrelated tasks. The tasks are: forming a personal theory of the need for, and acceptability of, neuroleptic medication; negotiating the challenges of forming alliances with others; and weaving a safety net to safeguard wellbeing. A theoretical model explaining the processes involved in the tasks and the mediating factors is presented and discussed. The clinical implications of the findings are discussed with reference to existing literature. Paper three is not intended for publication and is a critical review of the research process, in which the strengths and weaknesses of the systematic review and empirical study are evaluated. Personal and professional reflections on the experience of conducting a systematic review and an empirical qualitative study are discussed and the implications of the research for future clinical practice and research are considered.

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No. of bitstreams: 2 Dissertação - Nícolas Gustavo Matias de Oliveira - 2018.pdf: 1671663 bytes, checksum: 77209b17924ba8b6327e4442c9878a74 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2018-03-01 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Schizophrenia (EQZ) is a chronic mental illness that affects about 1% of the world population and is characterized by behavioral domains such as positive symptoms characterized by hallucinations and delusions and negative symptoms that involve apathy, anhedonia and social blunting. The cause of EQZ remains unknown, but it is known to be a disease whose etiology involves environmental and genetic factors. Several studies seek to identify factors that clarify the etiology of the disease. The agent that causes toxoplasmosis, Toxoplasma gondii, seems to be related to the development and progression of the disease, evidenced by studies that argue that T. gondii infection may be a triggering factor for psychosis in some individuals, since the parasite has a certain tropism by the central nervous system. Furthermore, studies have reported parasite infection as a factor related to genotoxicity, including toxoplasma infection in an animal model. Based on the foregoing, the present study aimed to evaluate the seropositivity to T. gondii (IgM or IgG) and the avidity of IgG in a group of individuals diagnosed with EQZ in the city of Goiânia and to evaluate the occurrence of genotoxicity in these, of genotoxicity with exposure to xenobiotics such as tobacco, alcohol, especially drugs, and / or T. gondii infection. Seropositivity was observed above 70% among individuals diagnosed with EQZ in relation to the controls, with avidity above 50%, indicating that individuals had contact with T. gondii at some time prior to the survey. Despite the genotoxic damage found, there was no significant difference in genotoxic damage among the infected individuals evaluated. The present study did not demonstrate that T. gondii may be a contributing factor to the occurrence of DNA damage, and the use of antipsychotic drugs, tobacco and alcohol, despite being a risk factor for genotoxicity, did not demonstrate an influence significant difference in the present study. However, it is necessary to carry out other analyzes and investigate parameters such as the time of drug use and exposure to other xenobiotics. In order to know better the life habits of individuals, it may help to provide more information about this relationship between T. gondii and EQZ. / A esquizofrenia (EQZ) é uma doença mental crônica que afeta cerca de 1% da população mundial e se caracteriza por domínios comportamentais, como sintomas positivos, caracterizados por alucinações e delírios e sintomas negativos, que envolvem apatia, anedonia e embotamento social. A causa da EQZ ainda permanece desconhecida, mas sabe-se que se trata de uma doença que cuja etiologia envolve fatores ambientais e genéticos. Vários estudos buscam identificar fatores que esclareçam a etiologia da doença. O agente causador da toxoplasmose, Toxoplasma gondii, parece ter relação com o desenvolvimento e progressão da doença, evidenciado por estudos que defendem que a infecção por T. gondii pode ser um fator desencadeante de psicoses em alguns indivíduos, já que o parasito apresenta um certo tropismo pelo sistema nervoso central. Ainda, estudos tem reportado a infecção por parasitos como fator relacionado a genotoxicidade, incluindo a infecção pelo toxoplasma em um modelo animal. Com base no exposto, o presente trabalho teve por objetivo avaliar a soropositividade para T. gondii (IgM ou IgG) e a avidez da IgG em um grupo de indivíduos diagnosticados com EQZ do município de Goiânia e avaliar a ocorrência de genotoxicidade nestes, procurando relação da genotoxicidade com a exposição a xenobióticos como tabaco, álcool, especialmente medicamentos, e/ou com a infecção pelo T. gondii. Observou- se soropositividade acima de 70% entre os indivíduos diagnosticados com EQZ em relação aos controles, com avidez acima de 50%, indicando que os indivíduos tiveram contato com o T. gondii em algum momento anterior a pesquisa. Apesar do dano genotóxico encontrado, não houve diferença significativa no dano genotóxico entre os indivíduos infectados avaliados. O presente estudo não demonstrou que T. gondii pode ser um fator contribuinte para a ocorrência de danos ao DNA, e o uso de fármacos antipsicóticos, o fumo e o álcool, apesar de serem um fator de risco para a genotoxicidade, não demonstraram uma influência significativa no presente estudo. Entretanto, há a necessidade de realizar outras análises e investigar parâmetros como o tempo de uso dos fármacos, e de exposição a outros xenobióticos, enfim, o melhor conhecimento dos hábitos de vida dos indivíduos pode ajudar a trazer mais informações acerca dessa relação entre T. gondii e a EQZ.

Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico / A esquizofrenia à um transtorno mental crÃnico, grave e incapacitante que afeta cerca de 1% da populaÃÃo mundial, cujos sintomas podem ser induzidos pela Cetamina. Neste sentido, hà evidÃncias de que o estresse oxidativo tenha importante papel na patogÃnese desta doenÃa. Desta forma, o presente estudo avaliou os efeitos neurocomportamentais e neuroquÃmicos, atravÃs da determinaÃÃo de parÃmetros do estresse oxidativo, apÃs administraÃÃo aguda da Clorpromazina (Cp) ou Clozapina (Cz), no modelo de esquizofrenia induzido pela Cetamina (Ket) em camundongos. Este estudo examinou alteraÃÃes neurocomportamentais, apÃs administraÃÃo de Cp (1 ou 5mg/Kg, ip) ou Cz (5 ou 10mg/Kg, ip), sozinhos ou 30 minutos antes da Ket (10mg/kg, i.p) em camundongos, e no estresse oxidativo apÃs administraÃÃo de esquema anterior incluindo Vitamina E (Vit E) (400 mg/kg) sozinha ou 30 minutos antes da Ket. Os resultados mostraram que a Cetamina induziu a hiperlocomoÃÃo e aumentou o nÃmero de rearring e grooming no teste de campo aberto. No teste de suspensÃo de cauda, a Cetamina diminuiu o tempo de imobilidade. Sendo esses efeitos bloqueados pela Cp ou Cz nos testes neurocomportamentais. Em adiÃÃo as mudanÃas comportamentais, a cetamina induziu aumento na peroxidaÃÃo lipÃdica, atividade da catalase e concentraÃÃo de nitrito. A Cp ou Cz reverteram os efeitos da Cetamina sobre estresse oxidativo. Em conclusÃo, os resultados confirmam efeitos semelhantes à Esquizofrenia, atividade antidepressiva e pro-oxidativa pela cetamina e reversÃo destes efeitos pela Cp ou Cz. / Schizophrenia is a serious and debilitating chronic mental disease, affecting about 1% of the world population and whose symptoms can be induced by ketamine. In this sense, evidences show that oxidative stress has an important role in the pathogenesis of this condition. Thus, this study evaluated the neurobehavioral and neurochemical effects, through the dosage of oxidative stress, after acute administration of Chlorpromazine (Cp) or Clozapine (Cz), in a model of schizophrenia induced by ketamine (Ket) in mice. Neurobehavioral changes were examined after administration of Cp (1 or 5 mg/Kg, ip) or Cz (5 or 10 mg/Kg, ip), either alone or 30 minutes before Ket (10mg/kg, ip) in mice, and during oxidative stress after administration of the previous scheme including Vitamin E (Vit E) (400 mg/Kg) alone or 30 minutes before the Ket. Results showed that ketamine induced hyperlocomotion and increased the number of rearring and grooming events in the open field test and decreased the immobility time in the tail suspension test. Interestingly, these effects were blocked by Cp or Cz administration in the neurobehavioral tests. In addition to the behavioral changes, ketamine induced increase in lipid peroxidation, catalase activity and nitrite concentration. Again, either Cp or Cz reversed the effects of ketamine, this time on oxidative stress. In conclusion, these findings demonstrate effects similar to schizophrenia, antidepressant activity and pro-oxidative conditions induced by ketamine and reversal of these effects by Cp or Cz.

Schizophrenia is a prevalent neurological disorder characterized by disrupted neuronal circuitry. Antipsychotic drugs (APDs) are capable of ameliorating the symptoms of schizophrenia with varying efficacy. Clozapine, the "gold-standard" for antipsychotic drug treatment, has been shown by this lab to induce the outgrowth of mediodorsal thalamic (MDT) dendritic arbor in rodents, a brain region which has altered function and decreased regional volume in schizophrenic patients. These studies further explored the ability of APD treatment to restructure dendrite arbor and the mechanisms of clozapine's ability to elaborate MDT arbor. Additionally, glutamate hypofunction is thought to contribute to the schizophrenic disease state. Using a novel model of perinatal glutamate hypofunction, we examined the long-term effects on dendritic architecture of developmental glutamate signaling disruption. MDT dysfunction is hypothesized to contribute to cognitive symptoms of schizophrenia. Clozapine has increased efficacy in ameliorating these symptoms. To further understand clozapine’s actions to remodel MDT dendritic architecture, we examined whether clozapine-induced morphological alterations are limited to the thalamus or if they also occur in additional regions associated with cognitive schizophrenic pathology, the hippocampus and striatum. We found that clozapine can induce dendritic remodeling in the hippocampus, but the not to the amplitude of remodeling seen in the thalamus, indicating that the MDT is uniquely altered by clozapine treatment and may be an important locus of clozapine's action. The mechanisms of clozapine's remodeling of MDT arbor, we examined changes to mRNA and miRNA expression and calcium dynamics in the MDT in response to APD treatment. Clozapine-treatment altered the expression of genes involved in cytoskeletal remodeling, external membrane receptors, and calcium dynamics, as well as increased the rate of calcium influx into thalamic neurons. Disruption to glutamate signaling has been hypothesized to contribute to schizophrenic pathology. Disruption to perinatal vesicular glutamate packaging along the corticolimbic axis has long term effects for neuronal morphology and function. Interestingly, we find that disruption along the corticolimbic axis also has downstream effects on MDT dendritic architecture. These studies show that the MDT is an important locus of action for clozapine and is capable of remodeling dendritic architecture in response to afferent circuitry dysfunction. / acase@tulane.edu

Abstract not available

Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population. The main treatments for schizophrenia are antipsychotic drugs that target dopamine receptors, yet the underlying biological mechanisms through which they alleviate the symptoms of schizophrenia remain ill defined. In this study, we used microarray analysis to profile the expression changes of thousands of genes simultaneously, following antipsychotic drug treatment of mice. Mice were treated chronically (28 days), or for a novel intermediate time-point (7 days), with one of three antipsychotic drugs: clozapine, haloperidol or olanzapine. The use of three drugs enabled us to discern antipsychotic-specific effects co-regulated by multiple drugs, rather than the side effects of individual compounds. Transcript profiling and validation by quantitative PCR of whole brain tissue revealed antipsychotic drug regulation of genes in diverse biological pathways, including: dopamine metabolism, neuropeptide and second-messenger signalling, neurogenesis, synaptic plasticity, cell adhesion, myelination, and voltage-gated ion channels. The regulation of voltage-gated channels by antipsychotic drugs has been suggested previously by electrophysiological studies, although thorough analysis has not been undertaken in vivo. Therefore, the second aim of this study was to characterise the regional mRNA and protein expression of two genes altered by multiple APDs, the voltage-gated potassium channel ??-subunit (Kcna1) and voltage-gated potassium channel interacting protein (Kchip3). Regional characterisation and expression analyses were carried out by immunohistochemistry, in situ hybridisation, and Western blot analysis of mouse brain regions of interest to schizophrenia and its treatment. Following 7-day haloperidol treatment we observed up-regulation of Kcna1 in the striatum and dentate gyrus, with increased protein in the striatum, hippocampus and midbrain; and down-regulation of Kchip3 in the striatum, with decreased protein in the cortex, hippocampus and midbrain. These studies implicate voltage-gated potassium channels in the antipsychotic drug regulation of midbrain dopaminergic neuronal activity, adult neurogenesis and/or striatothalamic GABAergic neuronal inhibition. These findings indicate that regulation of potassium channels may underlie some of the mechanisms of action of antipsychotic drugs, and that voltage-gated ion channels may provide alternative drug targets for the treatment of schizophrenia.

Objective - To assess the relationship between schizophrenia and cardiovascular disease by evaluating metabolic risk associated with treatment for schizophrenia, prevalence of cardiovascular risk factors (CV-RF) and disease (CV-D), and health care utilization in people with schizophrenia compared to the non-schizophrenic population. Methods Four studies were completed to evaluate the dissertation objectives. A systematic review was completed to quantify the change in metabolic parameters associated with use of atypical antipsychotic agents. The second study utilized a period prevalence design to compare prevalence of CV-RF (diabetes, hypertension, dyslipidemia) and CV-D in people with and without schizophrenia using the administrative databases of Alberta Health and Wellness. General and cardiac specialist health care utilization was evaluated in people with schizophrenia using data from Alberta Health and Wellness. Lastly, results from the Canadian Community Health Survey were used to evaluate prevalence of CV-RF and CV-D while controlling for important lifestyle and demographic variables unavailable in the databases of Alberta Health and Wellness. Results Use of atypical agents, particularly clozapine, resulted in statistically significant weight gain and increases in total cholesterol and blood glucose compared to typical agents. Having schizophrenia was associated with a significantly higher prevalence of diabetes, obesity, smoking, and CV-D compared to people without schizophrenia. Individuals with schizophrenia visited a general practitioner and the emergency department more often, and were more likely to be hospitalized than those without schizophrenia. Despite having a higher prevalence of coronary artery disease, individuals with schizophrenia were significantly less likely to visit a cardiologist or undergo revascularization compared to people with coronary artery disease who did not have schizophrenia. Conclusion Individuals with schizophrenia have a considerable burden of cardiovascular disease compared to people without schizophrenia. This is likely a result of a number of factors, including medications used to treat schizophrenia, the increased prevalence of smoking and other unhealthy lifestyle factors, and the increased prevalence of cardiovascular risk factors in people with schizophrenia. Individuals with schizophrenia utilize the general health care system more frequently than their non-schizophrenic counterparts, therefore the opportunity exists for monitoring for and management of modifiable cardiovascular risk factors in this vulnerable population.

Syftet med studien var att beskriva vilka biverkningar individer som behandlas med antipsykotika upplever och dess konsekvenser för livskvaliteten samt hur vårdpersonalen kan ge stöd till drabbade individer i vardagen för att minska obehaget av biverkningar. Metoden som användes var en avgränsad systematisk litteraturstudie. Vetenskapliga artiklar söktes via två databaser. Totalt inkluderades tio artiklar som genomgick kvalitets- och resultatanalys. Resultatet visade att vanligt förekommande biverkningar av antipsykotika som patienterna upplevde och rapporterade var psykiska, extrapyramidala följt av endokrina och metaboliska effekter samt övriga biverkningar som autonoma, antikolinerga och allergirelaterade. Resultaten visade att en sjuksköterskeledd vårdtjänst kunde upptäcka fysiska problem som ohälsosam livsstil och fetma och därmed åstadkomma positiv livsförändig och viktnedgång. Studierna ger även förslag på copingstrategier som stöd vid biverkningar trötthet och viktuppgång. Slutsatsen: Studien har visat att patienter med psykossjukdomar upplevde olika biverkningar av antipsykotika som de måste ta för att förebygga återfall i psykos. Det finns omvårdnadsåtgärder och stöd till patienter som gör det lättare att klara vardagslivet trots biverkningar. Dock behövs mer forskning om omvårdnadsåtgärder och stöd. / The aim of this study was to describe the side effects experienced by individuals treated with antipsychotics, their consequence in life quality and how care staff can give support to these individuals to reduce discomfort of the side effects in their daily life. The method was a determinate literature review. The scientific articles where found in the database PubMed. A total of ten articles where included and were analyzed based on their quality and contents. The results showed that the most common of antipsychotic side effects that the patient experienced and reported  were psychic, extrapyramidal followed by endocrine and the metabolic issue and other side effects with autonomic, anticholinergic and allergy related. The result showed that a nurse-led service with provided care delivery could discover physical health problems such as unhealthy lifestyle and obesity, and consequently achieve positive changes of life and weight loss. The studies even gave suggestions of strategies to cope with sedation, tiredness and weight gain. Conclusion of this literature review was that the patients with psychotic illnesses perceived different side effects from the antipsychotic medication that they had to take to prevent fallback in psychos. There is even nursing care and support to patients which make daily life easier in spite of side effects. However more research is needed about nursing methods and support.

<b>Background. </b> Although antipsychotic medications are primarily intended to treat schizophrenia and psychotic symptoms in adults, they are commonly administered to nursing home residents as pharmacotherapy for "off-label" indications such as disruptive behaviour. However, clinical trials have demonstrated limited efficacy and serious side-effects of antipsychotics among the elderly. As previous studies have reported inappropriate use in several countries, their use in nursing home residents ought to be monitored to detect and reduce inappropriate administration. <br /><br /> <b>Objectives. </b> The aim of this study was a) to determine and compare prevalence rates of antipsychotic use in Ontario and Swiss nursing homes, b) to identify determinants of antipsychotics use in these two countries, by means of a cross-sectional design, and c) to investigate the impact of antipsychotic use on behaviours over time in Ontario and Swiss residents, by means of a longitudinal design. <br /><br /> <b>Methods. </b> This study involved secondary data analysis of 1932 residents from 24 nursing homes in the province of Ontario in Canada and 1536 residents from 4 nursing homes in a German-speaking canton in Switzerland. Residents were assessed with the Minimum Data Set (MDS) tool. Resident characteristics and prevalence rates were compared internationally with the chi-square test. Demographic and clinical determinants of antipsychotic use, as well as behavioural change associated with antipsychotics, were analyzed using logistic regression. <br /><br /> <b>Results. </b> Although Ontario nursing home residents had an overall heavier-care profile than Swiss residents, antipsychotics were administered to 25% of the Ontario residents compared to 29. 5% of the Swiss residents. The adjusted rate among residents without appropriate conditions was also lower in Ontario (14%) than in Switzerland (24. 5%). Apart from schizophrenia, bipolar disorder and cognitive impairment, antipsychotic use was determined by a different range of characteristics in these two countries. Antipsychotic use was not predictive of behavioural improvement. <br /><br /> <b>Conclusion. </b> The high adjusted rates of antipsychotic use in Ontario and Swiss nursing home residents, as well as the presence of "inappropriate indications" and "facility" as determinants of their use, raise concerns about the appropriateness of their administration in both countries. Their lack of effectiveness to improve behaviours also questions their use as long-term treatment for behaviour disturbances. Changes in practice patterns and implementation of policies are warranted to reduce inappropriate prescribing practices to enhance the quality of care provided to residents in nursing homes.

No description available.