Genetically determined differences in drug metabolism and disposition and drug targets play a pivotal role in the interindividual variability in the clinical outcome of antipsychotic treatment. The aim of this thesis was to study the impact of polymorphisms in genes involved in the pharmacokinetics and pharmacodynamics of antipsychotics, with special focus on their extrapyramidal and metabolic adverse effects. Polymorphisms in serotonin 2A and 2C receptor coding genes (HTR2A and HTR2C) were found to be associated with the risk to develop extrapyramidal side effects (EPS) in patients on short term perphenazine treatment. A further study in a larger group of patients on long term treatment with various classical antipsychotics confirmed the association between occurrence of EPS and HTR2C polymorphisms. In another study, dose corrected steady state serum clozapine and N-desmethylclozapine concentrations (C/D) and insulin elevation during clozapine therapy were found to correlate with CYP1A2 but not with CYP2D6 polymorphisms. Furthermore, HTR2C and HTR2A polymorphisms were found to have significant influences on BMI and C-peptide levels in patients treated with olanzapine and clozapine. Evaluation of the impact of polymorphisms in genes encoding CYP3A4, CYP3A5 and P-glycoprotein (ABCB1) in addition to CYP2D6 on the steady state plasma levels of risperidone, 9-hydroxyrisperidone and their active moiety revealed a significant influence of ABCB1 genotype on 9-hydroxyrisperidone and active moiety C/Ds, while CYP2D6 genotype associated with risperidone C/Ds but not with 9-hydroxyrisperidone or active moiety C/D. We have shown that polymorphisms in genes involved in the pharmacokinetics and the pharmacodynamics of antipsychotic drugs play a role in the occurrence of adverse effects, both EPS and metabolic disturbances, induced by antipsychotic treatment. Genotyping for HTR2A, HTR2C, CYP1A2, CYP2D6 and ABCB1 polymorphisms may therefore potentially provide useful information to identify patients at higher risk to develop EPS or metabolic adverse during schizophrenia treatment with antipsychotic drugs.

Antipsychotic use is an important issue in long-term care (LTC) homes due to their widespread use, the potential for serious adverse events and limited evidence about their efficacy in treating behavioural and psychological symptoms of dementia. Rates of antipsychotic use vary across LTC homes, but little is known about the contribution of physicians to this variation. This study documented the characteristics of physicians who regularly treated residents in Ontario LTC homes and examined variation in antipsychotic prescribing across physicians. In a population-based retrospective cohort of LTC residents, 637 (52.8%) of 1,207 LTC physicians cared for 46,365 (90.4%) of all residents. Overall, 27.3% of residents received antipsychotic therapy, but extremely high prescribers prescribed antipsychotics to 42.8% of their patients. Variation in physician antipsychotic prescribing persisted after controlling for clinical and behavioural resident characteristics. This variation was reduced by 47.1% when LTC homes were accounted for in multilevel cross-classification logistic regression models.

Antipsychotic use is an important issue in long-term care (LTC) homes due to their widespread use, the potential for serious adverse events and limited evidence about their efficacy in treating behavioural and psychological symptoms of dementia. Rates of antipsychotic use vary across LTC homes, but little is known about the contribution of physicians to this variation. This study documented the characteristics of physicians who regularly treated residents in Ontario LTC homes and examined variation in antipsychotic prescribing across physicians. In a population-based retrospective cohort of LTC residents, 637 (52.8%) of 1,207 LTC physicians cared for 46,365 (90.4%) of all residents. Overall, 27.3% of residents received antipsychotic therapy, but extremely high prescribers prescribed antipsychotics to 42.8% of their patients. Variation in physician antipsychotic prescribing persisted after controlling for clinical and behavioural resident characteristics. This variation was reduced by 47.1% when LTC homes were accounted for in multilevel cross-classification logistic regression models.

Schizophrenia is a chronic and degenerative mental disease. Patients suffer from this disease for a whole life. It`s not clear the causes of schizophrenia. Correct diagnosis and treatment are essential for disease recovery, helping patients return home or community as early as possible. Up to now medicine has been the most effective treatment for schizophrenia. Antipsychotic drug has experienced the first generation and the second generation stages. The second generation antipsychotics are significantly more effective and with less side effects compared with the first generation drugs. This study focused on schizophrenia marketing strategies in Taiwan. A detailed case study of Risperdal® was undertaken to analyze the marketing strategies and marketing mix (product, price, place, and promotion). The study illustrated a successful implementation of marketing plans regarding antipsychotic drugs, shed light on how to launch new products and accelerate new product introductions.

Schizophrenia is a complex and pervasive brain disorder that effects millions of people in the United States. There are three tiers of symptoms associated with the disorder, they include: positive symptoms, negative symptoms and thought disorders. The most common method of treatment for this disorder involves the use of antipsychotic medications, and while these medications have been shown to be effective in treating certain positive symptoms of the disorder, they have a tendency to be less effective in treating the negative cluster of symptoms and the thought disorders that can be highly debilitating for patients. The aim of this review was to determine the level of effectiveness of psychosocial treatments for the disorder, and in particular to look in to Cognitive- Behavioral Therapy (CBT) as an adjunctive method of treatment to be used in conjunction with medication. By performing searches using the PsycInfo, ERIC, EBSCO and Medline databases, the researcher was able to draw the conclusion that while there are some complications and areas of improvement in study construction, CBT can indeed be a helpful method of treatment for many patients. Importantly, CBT tends to be a very flexible treatment that can accommodate many different combinations of symptoms at varying levels or severity and stages of the illness. A discussion of a possible model of treatment that uses CBT was also undertaken to provide readers with a practical example of how this form of treatment can be used. / text

Antipsychotic drugs (typical and atypical) are used in the treatment of mental disorders such as schizophrenia. Typical antipsychotic drugs (such as haloperidol) specifically target dopamine D2 receptors and produce extrapyramidal side effects. Atypical antipsychotic drugs (such as risperidone and olanzapine) primarily target dopamine D2 and serotonin 5HT2A receptors and produce fewer extrapyramidal symptoms (EPS) than do the typical antipsychotic drugs at clinically effective doses (Meltzer and Nash, 1991). It has been proposed that the prefrontal cortex (a brain region implicated in the pathophysiology of schizophrenia) is the locus of antipsychotic drug action to improve cognitive dysfunction and negative symptoms of schizophrenia (Weinberger and Lipska, 1995; Jakab and Goldman-Rakic, 1998). Moreover, it is possible that the effects in the prefrontal cortex may contribute to the differences between typical and atypical antipsychotic drugs as well as differences among atypical antipsychotic drugs (Horacek et al., 2006). The core pathology associated with the dorsolateral prefrontal cortex includes reduced cerebral volume, increased ventricle size and deficits in neuronal morphology, including increased cell packing density, reduction in dendrites and its associated dendritic spines (Selemon and Goldman-Rakic, 1999). However, since most neuropathology data emerge from in vivo imaging and post-mortem studies of patients with schizophrenia, it is difficult to interpret and distinguish between findings that have an etiological or iatrogenic basis. Thus, the objective of the current study was to examine the effects of antipsychotic drugs, at therapeutically relevant concentrations, in a rat brain region that is homologous to that of the human dorsolateral prefrontal cortex. The hypothesis upon which this study was based is that haloperidol, risperidone and olanzapine (at 65 to 80% striatal dopamine D2 receptor occupancy) induce changes to pyramidal cell architecture in the rat anterior cingulate cortex (Vogt and Gabriel, 1993; Hoover and Vertes, 2007). This hypothesis was investigated by (a) determining doses that are within the therapeutic range (65 to 80% striatal dopamine D2 receptor occupancy) by measuring the occupancy of haloperidol, risperidone and olanzapine in the presence of 3H-raclopride ( a dopamine D2 receptor antagonist) at dopamine D2 receptors in the rat striatum; and (b) examining whether therapeutic doses of antipsychotic drugs in rats cause neuropathology comparable to that observed in human post-mortem brains of patients with schizophrenia. Antipsyhcotic drug doses were selected using an appropriate in vivo dopamine D2 receptor occupancy method. The findings from this study revealed that 0.25 mg/kg/day haloperidol, 5 mg/kg/day risperidone and 10 mg/kg/day olanzapine achieved therapeutically relevant rat striatal dopamine D2 receptor occupancy in the range of 65 to 80%. To determine whether antipsychotic drugs at therapeutic doses established above induce changes in neuronal cell density and morphology; immunohistochemistry, single cell injection of lucifer yellow dye and Golgi-Cox impregnation of layer II/III pyramidal cells was performed. The results from these experiments revealed that the density of cells expressing NeuN, parvalbumin, calretinin or calbindin is highly unlikely to be affected by chronic exposure to haloperidol, risperidone and olanzapine. The current study evaluated the effects of chronic antipsychotic drug exposure on spontaneous locomotor activity of a rat in a novel environment. The purpose of this study was to differentiate between a direct and an indirect drug effect. It was found that at the doses established above, risperidone and olanzapine did not overtly reduce spontaneous locomotor activity of a rat in a novel environment relative to controls. In contrast, haloperidol reduced spontaneous locomotor activity of rat in an open field, although this was not statistically significant. Nevertheless, the data reported here allowed us to conclude that the level of activity across groups is unlikely to affect the data obtained in subsequent studies investigating the effects of chronic antipsychotic drug treatment on pyramidal cell structure. Intracellular injection of lucifer yellow dye into pyramidal cells revealed that chronic haloperidol treatment (28 days) was associated with a relative increase in basal dendritic arborisation, but neither of these drug treatments induced changes in arborisation that were different from controls. No statistically significant change in the basal dendritic arbor was detected with animals treated with risperidone relative to controls. Similarly using the Golgi-impregnation method, changes in soma size, dendritic branching, total number of branches and the density of dendritic spines in antipsychotic drug treated groups were not significantly different to controls. Taken together, this finding indicates that only relatively subtle neuritic changes may be attributed to chronic treatment with typical or atypical antipsychotic drugs administered at doses that avhieved striatal dopamine D2 receptor occupancy in the range of 65 to 80%. In summary, this study confirms that antipsychotic drugs are unlikely to induce changes to neuronal cell density or morphology in the rat anterior cingulate cortex at therapeutically relevant doses. Hence, it can be concluded that the observed neuropathology, found in the brains of patients with schizophrenia that have undergone antipsychotic drug therapy, is more likely to be caused by the disease and not the effects of the concomitant drug therapy.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Thesis (DMed)--University of Stellenbosch, 2007. / Bibliography. Also available via the Internet.