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Thesis (Ph. D.)--Carleton University, 2003. / Includes bibliographical references (p. 187-221). Also available in electronic format on the Internet.

Thesis (M.H.P.A.)--Washington State University, May 2009. / Title from PDF title page (viewed on Apr. 13, 2010). "Department of Health Policy and Administration." Includes bibliographical references (p. 37-46).

Thesis (Ph. D.)--University of Texas at Austin, 2004. / Supervisor: M. Lynn Crismon. Vita. Includes bibliographical references. Also available from UMI.

Thesis (M.H.P.A.)--Washington State University, May 2010. / Title from PDF title page (viewed on July 20, 2010). "Department of Health Policy and Administration." Includes bibliographical references (p. 30-35).

Class of 2016 Abstract / Objectives: To determine if prescribers took into consideration patients’ metabolic risk factors when prescribing a low, medium or high risk second generation antipsychotic and if non-metabolic risk factors influenced prescribing. Methods: Adults 18 years or older who were admitted to an acute inpatient psychiatry unit and ordered at least one SGA were included in the study. Each patient’s metabolic syndrome risk score was determined using retrospective chart review and they were subsequently divided into low or high-risk groups. Clozapine and olanzapine were categorized as high risk for causing weight gain and diabetes, risperidone and quetiapine were moderate risk, and all others were considered low risk. A chi square test compared the two groups in regard to type of SGA selected, gender, and race, while an independent t-test analyzed the differences in age. Results: 300 patients were analyzed and divided into high (n=57) and low (n=253) risk groups. For the low risk group, 10.7%, 55.1%, and 34.2% were prescribed a low, moderate, or high risk SGA, respectively. For the high-risk group 17.5%, 56.1%, and 26.3% were prescribed a low, moderate, or high risk SGA, respectively. The type of SGA selected was not significantly different between the groups (p=0.262). Equivalence was shown between the two groups in terms of gender and race (p=0.68, p=0.65 respectively). Age was significantly different (p< 0.01). Conclusions: Prescribers may not consider metabolic risk factors when prescribing high risk SGAs such as clozapine and olanzapine.

It is well established that chronic treatment with neuroleptic agents which selectively block dopamine (DA) receptors in the brain leads to the development of DA receptor supersensitivity. However comparing the degree and duration of the changes in receptor sensitivity obtained by different investigators has been extremely difficult, because of the numerous differences that exist in individual methods of producing and examining DA receptor supersensitivity. By examining the DA receptor supersensitivity that ensues following chronic treatment with different doses and durations of pimozide, at various intervals after withdrawal from treatment, the overall parametric changes can be more directly compared. To measure the changes in DA receptor sensitivity following chronic pimozide treatment, both behavioral (d.-amphetamine-induced locomotor activity; apomorphine-induced stereotypy) and biochemical (DA receptor binding assay) techniques were utilized. With increasing doses of chronic pimozide treatment, the degree and duration of the resulting DA receptor supersensitivity increased as measured both behaviorally and biochemically. Similarily, the longer durations of chronic pimozide treatment had a greater effect on the degree and duration of the increased DA receptor sensitivity than did the shorter durations of treatment. Correlations were found between the biochemical and behavioral results both between groups of animals treated chronically with different doses and durations of pimozide and within individual groups of animals. In addition, the changes in receptor sensitivity following chronic pimozide treatment was due to an increase in the number of DA receptors with no change in the affinity of these receptors to DA. These results following chronic treatment with neuroleptics demonstrate that the behavioral supersensitivity observed in animals in response to either the direct DA agonist apomorphine or the indirect DA agonist d-amphetamine, may be a result of an increased number of DA receptors. Finally, the supersensitive DA receptors that develop as a result of chronic treatment with neuroleptics are discussed with regard to their possible relevance as an animal model of the iatrogenic disease, tardive dyskinesia, observed clinically in schizophrenic patients withdrawn from neuroleptic therapy. / Medicine, Faculty of / Graduate

Magister Curationis - MCur / There is a growing burden of disease associated with mental disorders especially in low and middle-income countries. This growing burden is accompanied by an increase in psychotic disorders and has increased the demand for antipsychotic medication. The increase in the use of antipsychotic medication has resulted in the increase in side-effects that have a detrimental effect on the health of the mental health care user. Antipsychotic medication side-effects have been classified as the primary indicator for medication non-adherence. There is a relationship between psychiatric nurses’ knowledge and attitudes towards the use and the non-adherence of antipsychotic medication.

Nanogels are soft, deformable networks of cross-linked polymer swollen in water. Nanogels have the unique ability to swell in response to external physiological conditions. Their stimuli-responsive nature affects degradability, drug uptake and release, which can be exploited to create tunable drug delivery systems. The ability to alter the composition and structure of nanogels imparts advantageous characteristics for targeted drug delivery applications. Antipsychotic drugs (APDs) used to treat schizophrenia, a chronic neuropsychiatric disorder, are typically hydrophobic. Prolonged dosing causes neurological and metabolic side effects due to the systemic administration of drug. Patient adherence to APD administration is low, causing complications that contribute to the substantial burden of disease. APDs would benefit from nanogel encapsulation through improved solubility and controlled release kinetics to reduce the adverse side effects associated with typical administration protocols. This thesis presents the development of hydrophobized, biodegradable poly(oligoethylene glycol methacrylate) (POEGMA)-based nanogels to deliver APDs to the brain. Both an adaptation of conventional precipitation polymerization as well as a spontaneous self-assembly technique are utilized to synthesize nanogels containing different hydrophobic domains. Incorporation of cross-linkers with different modalities of biodegradability enable stimuli-responsive degradation and drug release. The effects on nanogel swelling, biodegradability, and APD uptake and release kinetics are explored in vitro. The preclinical application of these APD-loaded nanogels is evaluated using the minimally invasive intranasal (IN) route for delivery. We show that these nanogel delivery systems have therapeutic effects in terms of significantly altering a range of rodent behaviours, including locomotion inhibition, the onset of catalepsy, and improvement in pre-pulse inhibition, over extended periods of time in relation to current administration strategies. These drug-loaded nanogel delivery systems show potential to minimize the effective therapeutic dose by enhancing APD bioavailability via IN administration, thus reducing adverse outcomes and improving potential patient adherence to APD-based therapies in clinical use. / Thesis / Doctor of Philosophy (PhD) / Nanogels are soft, deformable polymer networks swollen in water with potential for drug delivery given their easy-to-tune physicochemical properties. However, the poor water solubility of many therapeutics, including antipsychotic drugs (APDs) used to treat schizophrenia, limits drug encapsulation within nanogels. In addition, conventional synthetic techniques produce materials that degrade into poorly-defined byproducts, causing toxicity concerns. This thesis presents novel strategies to incorporate hydrophobic domains and biodegradable bonds within poly(oligo ethylene glycol methacrylate) (POEGMA) nanogels. We demonstrate how these moieties affect nanogel swelling, degradability, cytocompatability as well as the uptake and release of clinically prescribed APDs. Intranasal (IN) administration of drug-loaded nanogels is studied as a non-invasive delivery alternative to improve drug bioavailability. The proposed nanogel-based drug delivery systems can decrease drug dose, minimize adverse side effects, and improve patient adherence to therapeutic regimens relying on APDs, demonstrating their potential for clinical application.

The pathophysiology, etiology, and treatment of schizophrenia remain elusive, but research is closing the gap. Schizophrenia globally affects less than 1% of the population and presents with positive, negative, and cognitive symptoms. As treatment for schizophrenia is not completely and meaningfully effective at treating all of the symptoms, without eliciting side effects, the current thesis aimed to evaluate a new drug candidate. PAOPA is a novel allosteric modulator that increases dopamine binding to the dopamine D2 receptor. It has previously shown positive findings in preventing and reversing behaviours proposed to model phenotypes of schizophrenia. However, it has not yet been tested to improve cognitive deficits in animal models, nor has its effects on other animals models been investigated. Lastly, its mechanism of action has not yet been comprehensively answered. In three separate studies, PAOPA was tested on ameliorating attentional deficits using the 5-choice serial reaction time task in an amphetamine model, deficits in novel objection recognition memory, sensorimotor gating, social interaction, and locomotor activity using a PCP model, and its effects on proteins regulating G protein-coupled receptors (GRK2 and arrestin-3), downstream signalling (ERK1 and ERK2), and synaptic vesicular control (synapsin II) were investigated. Although the sample sizes were too small to draw valid interpretations, the results suggested that PAOPA partially attenuated deficits in attention, novel object recognition memory, social interaction, sensorimotor gating, but not locomotor. Furthermore PAOPA increased the protein expression of GRK2, arrestin-3, ERK1 and 2, and synapsin IIa in the medial prefrontal cortex, striatum, and the nucleus accumbens. The results suggest that PAOPA influences the dopaminergic system in the striatum to change behaviour via receptor internalization and possibly downstream signalling. The present studies illuminate new insights, and point to future explorations for the potential development of PAOPA as a therapeutic for schizophrenia. / Thesis / Master of Science (MSc)