Abstract Bipolar disorder is a complex illness. It is a life long episodic disorder very disruptive for the patient and family. Repeated episodes lead to progressively deteriorating level of functioning and poor response to the treatment. Suicide attempts and completed suicide has been a frequent complication. The complexity and difficulties involved in treating this mental condition are well recognised .The pharmacological options include lithium, valproate, carbamazepine, lamotrigine, topiramate, benzodiazepines. The use of neuroleptics in bipolar disorder remain controversial because of the increased susceptibility of this group of patients to side effects of neuroleptics. Objectives: The aim of this research is to investigate in a population of patients with bipolar disorder who are having treatment with combination of a mood stabilizer and antipsychotics: 1) The number of prescriptions of antipsychotics, in bipolar patients in a community clinic 2) The rationale of such combination 3) Whether correlates exist between variables such as substance abuse and noncompliance and the prescription of antipsychotics Method: This retrospective, descriptive, analytic study was conducted at Voslooros Psychiatric Clinic, which is situated in the south of Johannesburg. The clinical records of all adult patients with an initial diagnosis of bipolar disorder as at December 2004 were examined Particular note was taken of demographic data, diagnosis, age of onset of psychiatric illness, V duration of illness, treatment prescribed, reasons for prescribing this medication, response to the treatment, social circumstances of each patient, substances use and compliance. Results: 74.1% of the patients were maintained on a combination of mood stabilizer with antipsychotic. Combination treatment was used in an attempt to improve the psychotic symptoms and dangerous behaviour in 48% of the patients, noncompliance in 38% of the cases and 14% patients were in transitional phase to stop antipsychotics. 80.65% of the patients were on treatment with antipsychotics for longer than 6 months. Use of atypical antipsychotics is associated with a better outcome than the conventional agents. In this study only a small percentage (10 %) of patients received atypical antipsychotics. 19.4 % patients reported side effects of the medication. The lower figures in our study can be due to underreporting and inadequate documentation. . 38.7% of the patients reported substance misuse. Our finding were much lower compared with the literature, probably due to underreporting. Alcohol was the most common substance. This study show that the need for more medication was increased 6.6 fold in patients with polysubstance abuse compared with the patients not abusing any substance. Noncompliance in the maintenance phase of the treatment is a important issue in the management of the patients with bipolar disorder. This study found that the majority of the patients (59.7%) were noncompliant with their treatment. Those findings were in line with studies done by Keck PE who reported rates of noncompliance from 51% to 64%. Our study show that 63% of the patients had a level of VI education less than matric and this may be a contributing factor to noncompliance. Conclusions: The results of the study suggest that a large number of bipolar patients are only partially responsive to mood stabilizers alone and the maintenance treatment with antipsychotics for longer than 6 months are needed because of persistence of the symptoms. More efficient strategies are necessary to educate the people, to improve the compliance and to decreased the use of substances.

Class of 2009 Abstract / Objectives: This study utilized a prescription claims database to retrospectively assess the relationship between adherence rates with a mood stabilizer in bipolar type I patients for: gender, age, psychiatric hospitalization rates, cost of services, and concomitant psychotropic medications. Methods: Adult patients with bipolar type I disorder (N=149; F=92 and M=57) who received at least two prescriptions of a mood stabilizer (i.e., carbamazepine, lamotrigine, lithium, oxcarbazepine, and valproic acid) during a 3-month intake period were included. Adherence to the mood stabilizer was retrospectively analyzed using high: >75% (> 274 days) vs. low: < 75% (< 274 days) supply of a mood stabilizer during 12-months. Results: Only 35.6% of the patients (N=53) met the criteria for > 75% adherence and 11.4% (N=17) met the criteria for > 90% adherence. There was a trend toward women having more days supply of a mood stabilizer compared to men (p=0.08) and older patients having a higher adherence rate with a mood stabilizer (p=0.06). The high adherence group had greater prescription costs (p<0.001) and total cost per year (R2=0.34, p=0.064) and more concomitant medications (p=0.04) than the low adherence group. Overall, there were no significant differences between the high and low adherence groups for mean hospital days, inpatient costs, and total cost of care. Among those patients that were hospitalized there was a negative correlation between adherence and inpatient cost (R2=0.49, p=0.024). Conclusions: Our findings suggest that patients with bipolar type I disorder demonstrate poor medication adherence with a mood stabilizer and that adherence rates based on a prescription claims database using two adherence categories may not be a predictive factor for psychiatric hospitalizations or cost of care.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23408号 / 医博第4753号 / 新制||医||1052(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 中山 健夫, 教授 古川 壽亮, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

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Die Bedeutung des Immunsystems in der Pathophysiologie von bipolaren Erkrankungen und Epilepsie ist ein aktueller Gegenstand der neuropsychoimmunologischen Forschung. Eine erhöhte Produktion von Zytokinen aufgrund von oxidativem Stress wurde dabei wiederholt als für die Pathophysiologie von Epilepsie und Bipolarer Störung relevant angesehen. In Hinblick auf Veränderungen der Zytokine Interleukin (IL)-1ß, IL-2, IL-4, IL-6 und Tumornekrosefaktor-alpha (TNF-α) wurden z. T. überlappende Ergebnisse bei beiden Erkrankungen beschrieben. Inwiefern diese Zytokine durch Stimmungsstabilisierer und Antiepileptika beeinflusst werden, wurde bisher jedoch nicht systematisch untersucht. In dieser Studie wurden systematisch in-vitro die Konzentrationen von IL-1ß, IL-2, IL-4, IL-6, IL-17, IL-22 und TNF-α im stimulierten Blut 14 gesunder Frauen mittels Vollblutverfahren (whole blood assay) nach Zugabe von Stimmungsstabilisierern bzw. Antiepileptika gemessen. Es wurden dabei die Stimmungsstabilisierer bzw. Antiepileptika Primidon, Carbamazepin, Levetiracetam, Lamotrigin, Valproat, Oxcarbazepin, Topiramat, Phenobarbital und Lithium untersucht. Die Ergebnisse lassen darauf schließen, dass der Mechanismus von erwünschter und unerwünschter anderer Wirkung von Stimmungsstabilisierern und Antiepileptika mit der Regulation von IL-1ß, IL-2, IL-22 und TNF-α in Zusammenhang stehen könnte. Getrennt nach den im Vollblutverfahren verwendeten Stimulanzien – Toxic-Shock-Syndrome-Toxin-1 (TSST-1) vs. monoklonaler Antikörper gegen das CD3-Oberflächenantigen (OKT3) in Kombination mit dem 5C3-Antikörper gegen CD40 (OKT3/CD40) – wurden die Ergebnisse in zwei unterschiedlichen Publikationen berichtet, die dieser Promotion zugrunde liegen.

Introdução: Comparados com pacientes bipolares com episódios maníacos/hipomaníacos e depressivos, os que apresentam estados mistos tendem a curso mais grave da doença, início mais precoce, ocorrência mais frequente de sintomas psicóticos, maior risco de suicídio, altas taxas de comorbidade e tempo maior para remissão. Portanto, medidas objetivas de avaliação desses estados são necessárias. Objetivo:Avaliar a concordância entre três pares formados por uma de três escalas de mania (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) ou Clinician-Administered Rating Scale for Mania (CARS-M)) e uma de depressão (21-item Hamilton Depression) na avaliação da resposta a estabilizadores do humor em pacientes mistos. Método:Sessenta e oito (n=68) consecutivos pacientes ambulatoriais bipolares Tipo I e II com sintomatologia mista pelo DSM-IV-TR e pelos critérios de Cincinatti foram incluídos nesse estudo aberto de 8 semanas entre 2010 e 2014 foram randomizados para receberem em monoterapia, ácido valproico, carbamazepina ou carbonato de lítio. Resultados: O padrão de resposta (diminuição de, pelo menos, 50% em uma das escalas de mania e na de depressão) foi muito semelhante: 21-HAM-D + YMRS = 22,1%, 21-HAM-D + BRMS = 20,6% e 21-HAM-D + CARS-M = 23,5%; p < 0,368). Os resultados referentes à concordância de resposta revelam valores de kappa bastante altos: 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0,87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0,78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0,91 (p < 0,001). Conclusões:O presente estudo sugere que qualquer uma das três escalas de mania utilizadas (YMRS, BRMS, CARS-M) pode ser associada à 21-HAM-D na avaliação da resposta em bipolares mistos. / Background: Compared with patients with bipolar disorder who exhibit pure manic/hypomanic or depressive episodes, the presence of mixed mood states is associated with a more severe course of illness, younger age of onset, more frequent ocurrence of psychotic symptoms, major risk of suicide, higher rates of comorbidities and longer time to achieve remission. Therefore, objective avaliation of these states are necessary. Objective: To evaluate the concorccance amog three pairs of three scales (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) or Clinician-Administered Rating Scale for Mania (CARS-M)) and a depression scale (21-item Hamilton Depression) in the assessment of response to humor stabizator drugs in mix bipolar patients. Methods: Sixty eight (n=68) consecutive bipolar type I and II outpatients with mixed sitomatology accordint to DSM-IV-TR and Cincinatti Criteria were included in these 8 weeks open-trial, from 2010 through 2014, to, randomly, receive monotherapy valporic acid, carbamazepine or lithium carbonate. Results: The response answer (decrease of, at least 50 %, in one of the mania and depression scales) were very similar: 21-HAM-D + YMRS = 22.1%, 21-HAM-D + BRMS = 20.6% e 21-HAM-D + CARS-M = 23.5%; p < 0,368). The kappa values were : 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0.87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0.78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0.91 (p < 0,001). Conclusions: The present study suggests that any of the three mania scales used (YMRS, BRMS, CARS-M) may be associated to 21-HAM-D in the assessment of the response o bipolar patients.

Introdução: Comparados com pacientes bipolares com episódios maníacos/hipomaníacos e depressivos, os que apresentam estados mistos tendem a curso mais grave da doença, início mais precoce, ocorrência mais frequente de sintomas psicóticos, maior risco de suicídio, altas taxas de comorbidade e tempo maior para remissão. Portanto, medidas objetivas de avaliação desses estados são necessárias. Objetivo:Avaliar a concordância entre três pares formados por uma de três escalas de mania (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) ou Clinician-Administered Rating Scale for Mania (CARS-M)) e uma de depressão (21-item Hamilton Depression) na avaliação da resposta a estabilizadores do humor em pacientes mistos. Método:Sessenta e oito (n=68) consecutivos pacientes ambulatoriais bipolares Tipo I e II com sintomatologia mista pelo DSM-IV-TR e pelos critérios de Cincinatti foram incluídos nesse estudo aberto de 8 semanas entre 2010 e 2014 foram randomizados para receberem em monoterapia, ácido valproico, carbamazepina ou carbonato de lítio. Resultados: O padrão de resposta (diminuição de, pelo menos, 50% em uma das escalas de mania e na de depressão) foi muito semelhante: 21-HAM-D + YMRS = 22,1%, 21-HAM-D + BRMS = 20,6% e 21-HAM-D + CARS-M = 23,5%; p < 0,368). Os resultados referentes à concordância de resposta revelam valores de kappa bastante altos: 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0,87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0,78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0,91 (p < 0,001). Conclusões:O presente estudo sugere que qualquer uma das três escalas de mania utilizadas (YMRS, BRMS, CARS-M) pode ser associada à 21-HAM-D na avaliação da resposta em bipolares mistos. / Background: Compared with patients with bipolar disorder who exhibit pure manic/hypomanic or depressive episodes, the presence of mixed mood states is associated with a more severe course of illness, younger age of onset, more frequent ocurrence of psychotic symptoms, major risk of suicide, higher rates of comorbidities and longer time to achieve remission. Therefore, objective avaliation of these states are necessary. Objective: To evaluate the concorccance amog three pairs of three scales (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) or Clinician-Administered Rating Scale for Mania (CARS-M)) and a depression scale (21-item Hamilton Depression) in the assessment of response to humor stabizator drugs in mix bipolar patients. Methods: Sixty eight (n=68) consecutive bipolar type I and II outpatients with mixed sitomatology accordint to DSM-IV-TR and Cincinatti Criteria were included in these 8 weeks open-trial, from 2010 through 2014, to, randomly, receive monotherapy valporic acid, carbamazepine or lithium carbonate. Results: The response answer (decrease of, at least 50 %, in one of the mania and depression scales) were very similar: 21-HAM-D + YMRS = 22.1%, 21-HAM-D + BRMS = 20.6% e 21-HAM-D + CARS-M = 23.5%; p < 0,368). The kappa values were : 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0.87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0.78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0.91 (p < 0,001). Conclusions: The present study suggests that any of the three mania scales used (YMRS, BRMS, CARS-M) may be associated to 21-HAM-D in the assessment of the response o bipolar patients.

Introdução: Comparados com pacientes bipolares com episódios maníacos/hipomaníacos e depressivos, os que apresentam estados mistos tendem a curso mais grave da doença, início mais precoce, ocorrência mais frequente de sintomas psicóticos, maior risco de suicídio, altas taxas de comorbidade e tempo maior para remissão. Portanto, medidas objetivas de avaliação desses estados são necessárias. Objetivo:Avaliar a concordância entre três pares formados por uma de três escalas de mania (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) ou Clinician-Administered Rating Scale for Mania (CARS-M)) e uma de depressão (21-item Hamilton Depression) na avaliação da resposta a estabilizadores do humor em pacientes mistos. Método:Sessenta e oito (n=68) consecutivos pacientes ambulatoriais bipolares Tipo I e II com sintomatologia mista pelo DSM-IV-TR e pelos critérios de Cincinatti foram incluídos nesse estudo aberto de 8 semanas entre 2010 e 2014 foram randomizados para receberem em monoterapia, ácido valproico, carbamazepina ou carbonato de lítio. Resultados: O padrão de resposta (diminuição de, pelo menos, 50% em uma das escalas de mania e na de depressão) foi muito semelhante: 21-HAM-D + YMRS = 22,1%, 21-HAM-D + BRMS = 20,6% e 21-HAM-D + CARS-M = 23,5%; p < 0,368). Os resultados referentes à concordância de resposta revelam valores de kappa bastante altos: 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0,87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0,78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0,91 (p < 0,001). Conclusões:O presente estudo sugere que qualquer uma das três escalas de mania utilizadas (YMRS, BRMS, CARS-M) pode ser associada à 21-HAM-D na avaliação da resposta em bipolares mistos. / Background: Compared with patients with bipolar disorder who exhibit pure manic/hypomanic or depressive episodes, the presence of mixed mood states is associated with a more severe course of illness, younger age of onset, more frequent ocurrence of psychotic symptoms, major risk of suicide, higher rates of comorbidities and longer time to achieve remission. Therefore, objective avaliation of these states are necessary. Objective: To evaluate the concorccance amog three pairs of three scales (Young Mania Rating Scale (YMRS), Bech-Rafaelsen Mania Scale (BRMS) or Clinician-Administered Rating Scale for Mania (CARS-M)) and a depression scale (21-item Hamilton Depression) in the assessment of response to humor stabizator drugs in mix bipolar patients. Methods: Sixty eight (n=68) consecutive bipolar type I and II outpatients with mixed sitomatology accordint to DSM-IV-TR and Cincinatti Criteria were included in these 8 weeks open-trial, from 2010 through 2014, to, randomly, receive monotherapy valporic acid, carbamazepine or lithium carbonate. Results: The response answer (decrease of, at least 50 %, in one of the mania and depression scales) were very similar: 21-HAM-D + YMRS = 22.1%, 21-HAM-D + BRMS = 20.6% e 21-HAM-D + CARS-M = 23.5%; p < 0,368). The kappa values were : 21-HAM-D + YMRS X 21-HAM-D + CARS-M , Kappa = 0.87; 21-HAM-D + YMRS X 21-HAM-D + BRMS, Kappa = 0.78 e 21-HAM-D + CARS-M X 21-HAM-D + BRMS, Kappa = 0.91 (p < 0,001). Conclusions: The present study suggests that any of the three mania scales used (YMRS, BRMS, CARS-M) may be associated to 21-HAM-D in the assessment of the response o bipolar patients.

Submitted by Rosangela Silva (rosangela.silva3@unioeste.br) on 2017-08-30T14:53:20Z No. of bitstreams: 2 Ana Julia Penteado.pdf: 1485037 bytes, checksum: 723d1b3bedb90392ef459d2a4cedeca8 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) / Made available in DSpace on 2017-08-30T14:53:20Z (GMT). No. of bitstreams: 2 Ana Julia Penteado.pdf: 1485037 bytes, checksum: 723d1b3bedb90392ef459d2a4cedeca8 (MD5) license_rdf: 0 bytes, checksum: d41d8cd98f00b204e9800998ecf8427e (MD5) Previous issue date: 2017-02-07 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Lithium carbonate is the main drug used to treat bipolar disorder. This medicine has a narrow therapeutic range and is usually used in a chronic way by the patients, generating the need for therapeutic monitoring by means of plasma lithium quantification. In addition, records of toxic effects from chronic medical use reinforce the need for a tool that assists in the treatment. Thus, a reliable methodology for the quantification of lithium and a therapeutic adjuvant emerge as a means to improve the quality of life of the patient. In our work, we used the flame atomic absorption spectrometer to validate the method for quantification of lithium and the results were satisfactory, because they complied with the required criteria, assuring the reliability of the method. In order to find a therapeutic adjuvant, N-acetylcysteine (NAC) was studied for presenting important characteristics against the toxic effects caused by lithium. In our results lithium presented toxic effects mainly inducing oxidative stress, while the coadministration of NAC reversed this effect in the liver, kidney and brain organs. The use of NAC as a therapeutic adjuvant has been shown to be promising, however, further studies need to be performed to better understand this relationship. / O carbonato de lítio é o principal medicamento utilizado no tratamento do transtorno bipolar. Este medicamento possuí estreita faixa terapêutica e geralmente é utilizado de forma crônica pelos pacientes, gerando a necessidade da monitorização terapêutica por meio da quantificação plasmática de lítio. Além disso, os registros de efeitos tóxicos decorrentes do uso medicinal crônico remetem a necessidade de uma ferramenta que auxilie no tratamento. Desta forma, uma metodologia confiável para a quantificação de lítio e um adjuvante terapêutico surgem como meios de melhorar a qualidade de vida do paciente. Em nosso trabalho, utilizamos o espectrômetro de absorção atômica de chama para validar um método para quantificação de lítio e os resultados foram satisfatórios, pois cumpriram os critérios exigidos, assegurando a confiabilidade do método. Com foco em buscar um adjuvante terapêutico, a N-acetilcisteína (NAC) foi estudada por apresentar características importantes contra os efeitos tóxicos causados pelo lítio. Em nossos resultados o lítio apresentou efeitos tóxicos principalmente induzindo o estresse oxidativo, enquanto que a coadministração de NAC reverteu esse efeito nos órgãos fígado, rim e cérebro. O uso da NAC como adjuvante terapêutico mostrou ser promissor, porém, mais estudos precisam ser realizados para entender melhor essa relação.

Mood disorders are serious diseases. Nevertheless, their pathophysiology is not sufficiently clarified. Biological markers that would facilitate the diagnosis or successful prediction of pharmacotherapy are still being sought. The aim of the study was to find out whether mitochondrial functions are affected by antidepressants, mood stabilizers and depression. Our research is based on recent hypotheses of mood disorders, the advanced monoamine hypothesis, the neurotrophic hypothesis, and the mitochondrial dysfunction hypothesis. We assume that impaired function of mitochondria leads to neuronal damage and can be related to the origin of mood disorders. Effects of antidepressants and mood stabilizers on mitochondrial functions can be related to their therapeutic or side effects. In vitro effects of pharmacologically different antidepressants and mood stabilizers on the activities of mitochondrial enzymes were measured in mitochondria isolated from pig brains (in vitro model). Activity of monoamine oxidase (MAO) isoforms was determined radiochemically, activities of other mitochondrial enzymes were measured spectrophotometrically. Overall activity of the system of oxidative phosphorylation was measured electrochemically using high- resolution respirometry. Methods were modified to measure the same...