Charles University in Prague Faculty of Pharmacy in Hradec Králové Department of Pharmacology & Toxicology Student: Lucie Hlinková Supervisor: Prof. MUDr. Radomír Hrdina, CSc. Title of diploma thesis: Treatment of schizophrenia Schizophrenia is a serious mental disease, mostly chronic. It affects about 1 % of population, first episode of the disease occurs mostly between the age of 15 and 35. It manifests itself with disorders of perception, behavior and thinking. The specific symptoms include hallucinations, delusions, disorganized speech and behavior, catatonia, disorders of attention and volition and social withdrawal. Etiopathogenesis of schizophrenia is likely affected by both genetic and environmental factors, the true cause of the disease has not been discovered yet. The goal of the treatment is to improve the patient's quality of life and prevent the occurrence of relapses. Drugs acting on the dopaminergic system are effective in the treatment of schizophrenia, where as antagonists bind to the dopamine receptors. These medicines are called antipsychotics, they are divided into two generations. The first generation is characterized by high affinity mainly for dopamine receptors, the second one in addition by binding to serotonin receptors. Each class of antipsychotics is characterized by the...

In einer Studie wurde der Zusammenhang pathologischer Werte von C-Reaktivem Protein (295 Fälle)- - sowie Leukozyten-Anzahlen (292 Fälle) einerseits und dosiskorrigierter Serumkonzentration der Antipsychotika Haloperidol, Risperidon, Olanzapin, Quetiapin und Aripiprazol andererseits mittels therapeutischem Drug Monitoring bestimmter Serumkonzentrationen sowie pathologische CRP (295 Fälle)- und Leukozyten (292 Fälle)-Werte ausgewertet. Zielsetzung der vorliegenden Arbeit war es, den Einfluss von Entzündung, gemessen durch CRP-Wert und Leukozyten, auf die dosiskorrigierten Antipsychotika-Serumkonzentrationen zu untersuchen. In der Quetiapin-Stichprobe konnte ein signifikanter Zusammenhang von pathologischen CRP-Werten und der dosiskorrigierten Serumkonzentration berechnet werden. In der Olanzapin-Stichprobe ergab sich ein trendmäßiger Zusammenhang von pathologischen CRP-Werten und der dosiskorrigierten Serumkonzentration. Dosiskorrigierte Serumkonzentrationen über der therapeutischen Obergrenze waren in der Quetiapin-Stichprobe mit pathologischen CRP-Werten assoziiert. In keiner Stichprobe konnte ein signifikanter Zusammenhang von Leukozyten-Anzahl und dosiskorrigierter Serumkonzentration aufgezeigt werden. Wir konnten damit erstmals einen signifikanten Zusammenhang von Entzündung und Serumkonzentration für Quetiapin (und partiell auch Olanzapin) zeigen. Klinische Konsequenz sollte - vor allem bei älteren Patienten - eine Quetiapin (und auch Olanzapin-)-Dosisanpassung unter inflammatorischen Bedingungen sein, um das Risiko verstärkter bzw. sogar toxischer Nebenwirkungen durch einen Anstieg der Serumkonzentration zu minimieren. Weitere Studien mit einer größeren Fallzahl für die anderen hier untersuchten und nicht signifikant assoziiert gefundenen Antipsychotika sind erforderlich, um das Risiko erhöhter Serumkonzentrationen unter inflammatorischen Bedingungen für diese ausschließen zu können. Darüber hinaus sind weitere Untersuchungen mit Berücksichtigung anderer auf CYP-Ebene interagierender Faktoren wie Komedikation, körperlichen Begleiterkrankungen, Raucherstatus oder Polymorphismen sinnvoll, um Risikogruppen noch genauer definieren zu können. / In this study, the relationship between pathological values of C-reactive protein (295 cases) and leukocyte counts (292 cases) on the one hand and dose-corrected serum concentrations of the antipsychotics haloperidol, risperidone, olanzapine, quetiapine and aripiprazole on the other hand were evaluated by therapeutic drug monitoring of certain serum concentrations as well as pathological CRP (295 cases) and leukocyte values (292 cases). The objective of the present study was therefore to investigate the influence of inflammation, measured by CRP value and leukocytes, on the dose-corrected antipsychotic serum concentrations. The Quetiapin sample showed a significant correlation between pathological CRP values and dose-corrected serum concentration. In the olanzapine sample, there was a trend correlation between pathological CRP values and the dose-corrected serum concentration. Dose-corrected serum concentrations above the therapeutic limit were associated with pathological CRP levels in the quetiapine sample. In no sample could a significant correlation between leukocyte count and dose-corrected serum concentration be demonstrated. For the first time we were able to show a significant correlation between inflammation and serum concentration for quetiapine (and partially also olanzapine). Clinical consequence - especially in older patients - should be a quetiapine (and also olanzapine) dose adjustment under inflammatory conditions in order to minimize the risk of increased or even toxic side effects due to an increase in serum concentration. Further studies with a larger number of cases for the other antipsychotics investigated here and not significantly associated are necessary to exclude the risk of increased serum concentrations under inflammatory conditions. In addition, further investigations with consideration of other factors interacting at the CYP level such as comedication, concomitant physical diseases, smoking status or polymorphisms are useful in order to be able to define risk groups even more precisely.

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The work deals with a mental illness called schizophrenia. The thesis consists of two parts, the theoretical part and the practical part. The theoretical part has five chapters, it has focused mainly on the interconnectedness of social work, psychiatry, psychology and ethics. First, it describes schizophrenia in general - how begins the illness, it signs and symptoms, diagnosis, course and prognosis and treatment options. I am focusing on the psychiatric aspects of schizophrenia, the social aspect of the disease and the ethics codes of various disciplines. The practical part is research, which is based on the interpretation of the results of a quantitative research. I opted a questionnaire as a research technice. The aim of this questionnaire is to find out which general knowledges has the adult population about schizophrenia and which views of schizophrenia are prevailing.

Psychotropic drugs are commonly used group of pharmaceuticals, their main effect is to alter psychic condition, including mental diseases treatment. Symptoms of mental illnesses are more and more common, theref orenumber of patients diagnosed with mental illnes, and thus using psychotropics, is growing stronger. But using psychotropics during gestation is not without risks for mother and embryo itself. However, thanks to the absence of controlled human studies, the knowledge of emrbyotoxic effects of pschotropics is limited to casuistics, reported side effects and animal experimental studies. Many of those studies suggests emrbyotoxic potential of psychotropic drugs, on the other hand, others claim their safety. The goal of this thesis is to test at least some of them, using CHEST method, that allows us to observe direct effect of unmetabolized substance on chick embryo. In this thesis we tested selected psychotropics, very common antidepressant fluoxetine (prozac) and antipsychotic drug olanzapine, for embryotoxicity, using in ovo method CHEST with chick embryos as model organism. By bypassing the maternal organism and his metabolism, this method allows to observe direct effect of unmetabolized substance on chick embryo. Results revealed embryotoxic effect of fluoxetin in dosage 10-2 and 10-3 on 3rd and...

The term splitting is defined as a process of formation of mental aggregates linked incompatible experiences producing numerous divisions in mental apparatus. Current findings indicate that psychological splitting in schizophrenia is likely specifically presented on a neural level as disrupted organization in neural communication. This disrupted neural communication likely underlies deficits in mental processing described by various neuroscientific concepts such as theories of disturbed connectivity, corollary discharges and dynamic complexity. In this context, a purpose of the theoretical part of the dissertation is to describe basic neuroscience theories that complementarily reflect interrelated processes between mind and brain underlying disturbances of mental integration that likely present a neural representation of the splitting. A purpose of the first part of the empirical research was to examine relationships between psychological process of splitting and disturbed cognitive and affective functions in schizophrenia. A sample of patients with borderline personality disorder (BPD) was used as a control group in this study. Methods: In the clinical study, we have assessed 30 patients with schizophrenia and 35 patients with BPD. The symptoms of splitting were measured using self- reported...

The term splitting is defined as a process of formation of mental aggregates linked incompatible experiences producing numerous divisions in mental apparatus. Current findings indicate that psychological splitting in schizophrenia is likely specifically presented on a neural level as disrupted organization in neural communication. This disrupted neural communication likely underlies deficits in mental processing described by various neuroscientific concepts such as theories of disturbed connectivity, corollary discharges and dynamic complexity. In this context, a purpose of the theoretical part of the dissertation is to describe basic neuroscience theories that complementarily reflect interrelated processes between mind and brain underlying disturbances of mental integration that likely present a neural representation of the splitting. A purpose of the first part of the empirical research was to examine relationships between psychological process of splitting and disturbed cognitive and affective functions in schizophrenia. A sample of patients with borderline personality disorder (BPD) was used as a control group in this study. Methods: In the clinical study, we have assessed 30 patients with schizophrenia and 35 patients with BPD. The symptoms of splitting were measured using self- reported...

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OBJECTIVES: The aim of our study was to assess clinical presentation of early-onset schizophrenia spectrum disoders (EO-SSD), the time to first improvement and efficacy associated with selected atypical (AAPs) and typical (TAPs) antipsychotics, as well as two main side effects - weight gain and treatment-emergent extrapyramidal symptoms (EPSs) during the treatment in patients with EO-SSD. METHODS: This was a systematic chart review of all patients receiving routine clinical care in our department, with selected AAPs (risperidone, olanzapine, ziprasidone, quetiapine and clozapine) and TAPs (haloperidol, perphenazine and sulpiride), for schizophrenic psychoses, between 1997 and 2007. During this period, our review identified 173 patients (85 males, 88 females; mean age 15.8±1.6 years); their treatment included 297 treatment trials. Data on premorbid adjustment, prodromal symptoms and psychopathology at admission, as well as comorbidity were evaluated based on the patients' medical records. The time to first improvement could be estimated in 258 treatment trials; of these, 195 (76%) comprised AAPs and 63 (24%) TAPs. The time to first improvement was assessed in agreement with the methodology established for retrospective studies as the number of treatment days prior to the first record of improvement...