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Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Clozapine (CLZ) is considered the treatment of choice for treatment resistant schizophrenia. Although highly efficacious, the widespread use of CLZ is limited by metabolic side effects, fatal agranulocytosis and cardiovascular complications such as myocarditis via unknown mechanisms. As the autonomic nervous system (ANS) is known to regulate metabolic and cardiovascular function, we sought to assess the involvement of the ANS in the cardiometabolic effects of CLZ in rodent models. Glucose dysregulation from acute CLZ treatment was evaluated using the hyperinsulinemic euglycemic clamp (HIEC) and the intraperitoneal glucose tolerance test (IGTT). Plasma catecholamine (CAT) levels were measured using high performance liquid chromatography (HPLC) to determine autonomic activity. We also assessed the metabolic liability of the principal metabolite of CLZ, norclozapine (NOR), and compared the results to its parent compound. In a separate series of experiments, we measured cardiovascular parameters in response to CLZ in a novel rodent model of CLZ-induced tachycardia. We attempted to reverse CLZ-induced tachycardia with mecamylamine (MEC), a ganglionic blocker, and propranolol (PRO), a β-adrenoceptor blocker. Lastly, we performed a study to evaluate the use of adrenoceptor ligands in treating CLZ-induced glucose dysregulation. Our results indicate NOR does not induce metabolic dysregulation at the same severity as CLZ, despite substantial retention of NOR in plasma. NOR induced insulin resistance but not glucose intolerance at the highest dose compared to vehicle. CLZ induced tachycardia and depressor effects immediately following injection. MEC and PRO reversed the tachycardia, where MEC caused significant depressor effects. The effects were not noted with PRO. There was a significant elevation in plasma NE levels from CLZ treatment which was reversible with MEC. Our pilot study showed β-adrenoceptor blockers reversed insulin resistance associated with CLZ, whereas α-adrenoceptor antagonists had no effect. The results suggest both β1- and β2-adrenoceptor blockade contribute to insulin sensitivity. In conclusion, the present series of experiments indicate the ANS mediates CLZ’s cardiometabolic side effects and warrants further studies focusing on autonomic dysregulation as a potential target for treating these adverse effects.
Current preclinical analgesic assays suffer from major weaknesses that hamper the discovery of new drugs. This thesis describes the development of a new mouse assay, the Hypertonic Saline Analgesia Assay (HSAA). Chapter 1 provides an overview for current preclinical analgesic assays and discusses their strengths and weaknesses. It also discusses the impact of sex, strain, and circadian rhythm on nociception and antinociception. Chapter 2 describes the development of the assay. We evaluated hypertonic saline (HS) as a nociceptive agent, its optimal concentration, the responses, and the optimal time for evaluation. We also assessed sex related differences and tissue damage. Chapter 3 describes the validation of the assay. Analgesics known to be effective clinically were assayed to establish the validity of the HSAA. HSAA demonstrated that responses were attenuated by a range of clinical analgesics, produces minimal tissue damage and has lower variability compared to other assays.Chapter 4 examines the refinement of the assay. We determined the effects of repeated testing, strain, sex, and diurnal rhythm on the reproducibility of HSAA. The absence of tissue damage raised the possibility of repeated testing in a mouse to reduce the number of animals. The antinociceptive action of morphine was unchanged when HSAA was used at different times in the same hind paw of a mouse. No histological damage was observed following multiple injections of HS. Repeated testing in the same mouse reduces both the number of animals required and the variance of the results. Initial development and validation were performed with CD-1 mice. To evaluate the widespread utility of HSAA, we evaluated its ability to detect analgesics in another commonly used murine strain, C57BL/6. HSAA detected the dose-dependent attenuation of responses by morphine in C57BL/6 which was equivalent to responses found with CD-1 mice. Additionally, female mice were demonstrated to have greater response than males. The diurnal cycle had little effect. In conclusion, the HSAA rapidly detects standard analgesics and is reproducible within an animal and between strains. This assay minimizes tissue damage and the number of animals required. HSAA is a useful addition to the armamentarium of preclinical analgesic assays.
No abstract available.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.
Medical cannabis has been reported to improve the symptoms of various mental health conditions, such as anxiety, depression and chronic pain. Conversely, other studies have suggested that cannabis use contributes to mental health problems. Information gathered about medical cannabis users from previous studies have been mostly self-reported with limited diagnostic measures examining mental health. The goal of the present study was to expand on current research using standardized and clinical assessments to analyze the severity of mental health and any psychiatric conditions in a non-epidemiological population of medical cannabis users from a dispensary in Vancouver. We administered the Mini-International Neuropsychiatric Interview, based on criteria from the DSM-IV-TR and ICD-10. In order to obtain detailed information about the general well-being and mental health of individuals, seven standardized assessments evaluated perceived stress, fatigue, sleep disturbances, depression, somatic symptoms, pain, and nicotine dependence. This will provide high quality data that can be better compared to other studies in the literature. Most frequently diagnosed conditions were anxiety, depression, and substance dependence, but most self-reported conditions were anxiety, sleep and depression. Results showed that medical cannabis users with a depression diagnosis had higher perceived stress, but severity of depression was mostly minimal. Many participants reported using cannabis to treat depression, but only three had current depression. Participants with any anxiety disorder mostly preferred to use pure CBD, and many had experienced negative effects with cannabis use. A diagnosis of specific anxiety disorders, such as GAD, PTSD or social phobia, were more likely to have higher perceived stress. Those with substance dependence diagnoses showed earlier onset of regular cannabis use, higher frequency of cannabis use and dispensary visits. Alcohol or other non-cannabis dependence diagnoses were more likely to be diagnosed with panic disorder, social phobia, and higher perceived stress. Our population did not have severe disturbances with sleep, somatic symptoms or pain ratings. 74% used cannabis daily, and the average cannabis amount used per week was 4.29 grams of dried cannabis. Ultimately, cannabis may provide a therapeutic option for individuals with mental health conditions looking for alternative treatments.
Psychosis is expressed in many mental disorders and often varies in the way symptoms are presented. Two forms that have similar psychotic profiles are schizophrenia spectrum disorders (SZ) and stimulant induced psychosis (SIP). The similar profiles suggest a common mechanism involved in the development of psychosis, and the pattern of symptoms expressed in SIP and SZ. There are limited studies on the severity of psychotic symptoms in SIP and the associated drug involved. Few studies have compared brain connectivity and structural abnormalities associate with SIP and SZ.Attempting to shed light on the underlying mechanisms involved in the expression of psychosis in SIP, two studies were performed; 1) compare symptom severity of SIP between cocaine and methamphetamine dependent individuals, and 2) compare brain alterations between idiopathic psychosis and SIP individuals with and without stimulant dependence.In study 1, symptom severity was analyzed using the three and five factor models of the positive and negative syndrome scale (PANSS) between a group of 153 cocaine dependent (CD), 38 methamphetamine dependent (MD), and 32 concurrent cocaine + methamphetamine dependent (CMD) subjects defined by DSM-IV-TR criteria. The MD group was associated with more severe positive symptoms on the PANSS. The CMD group did not have an increase in psychosis severity.To investigate brain abnormalities that may be involved in the positive symptom profile of SIP, study 2, a voxel-based grey matter region of interest (ROI) approach using magnetic resonance imaging (MRI) and whole brain diffusion tensor imaging (DTI) analysis was employed. Three groups of 39 SZ subjects with stimulant dependence (SZ-dependent), 39 SIP subjects with stimulant dependence (SIP-dependent), and 18 SZ subjects without stimulant dependence (SZ-nondependent) were compared. The voxel-based analysis observed SZ-dependent group presented with significantly reduced planum temporale and parietal operculum volumes compared to the SIP-dependent group. Using tract-based spatial statistics (TBSS) to assess white matter tracts, the SIP-dependent group had reduced fractional anisotropy and increased radial diffusivity compared to the SZ-dependent group.The results characterize the effects that different stimulant drugs have on symptom severity and the specific areas of the brain that potentially promote positive psychotic symptom profile of SIP.
The treatment of psychosis typically requires the use of only one antipsychotic. Even in instances of treatment-resistant psychosis, the atypical antipsychotic clozapine has proven to be effective when used on its own. However, antipsychotic polypharmacy is commonly prescribed despite a lack of evidence for this practice. This concurrent use of two or more antipsychotics can also prolong the time before clozapine is tried. Antipsychotic polypharmacy should be reserved for instances of clozapine-resistant psychosis if it is to be used at all.In this retrospective study, data were collected from individuals who were referred to a tertiary care program for treatment-resistant psychosis. The main objectives were to compare the use of antipsychotic monotherapy to polypharmacy in treatment-resistant psychosis and to characterize within-individual changes in treatment and symptomatology secondary to hospitalization.At admission, individuals who were prescribed only one antipsychotic were comparable to those who were prescribed at least two antipsychotics with regard to demographics and symptom severity. The use of drugs other than antipsychotics was also similar between groups. However, the magnitude of antipsychotic utilization was greater in individuals who were receiving antipsychotic polypharmacy. In addition, a greater proportion of these individuals received excessive doses at admission. Similar findings were observed when monotherapy and polypharmacy were compared at discharge.Three important patterns were identified when investigating within-individual changes. First, fewer individuals were on polypharmacy at discharge. This was accompanied by a general decrease in both the number of antipsychotics prescribed and the magnitude of antipsychotic utilization. Second, the number of individuals who were prescribed clozapine had increased by discharge. Those who were already prescribed clozapine at admission typically had their doses increased. Third, improvements in symptomatology were observed across all of the subscales included in the Positive and Negative Syndrome Scale (PANSS). However, only 57.9% of individuals experienced a relative reduction in PANSS scores greater than 20%.Based on these findings, it is possible to alleviate the symptoms of psychosis in treatment-resistant psychosis while reducing antipsychotic utilization. Although this may seem counterintuitive, an increase in the use of clozapine and a decrease in antipsychotic polypharmacy may have contributed to clinical improvement.
After prolonged psychostimulant abuse, some individuals develop transient psychotic symptoms referred to as “substance induced psychosis” (SIP), which closely resemble the symptoms observed in schizophrenia spectrum disorders. The comparability in psychotic presentation between SIP and the schizophrenias suggests that similar underlying neural deficits may contribute to the emergence of psychosis across these disorders. Anatomically, only a small number of studies have attempted to characterize the structural alterations in SIP – all of which solely focus on methamphetamine associated psychosis. To further characterize the nature of psychostimulant-associated psychosis, three investigations were performed to identify 1) gray matter abnormalities, 2) white matter abnormalities, and 3) environmental risk factors of current symptom severity in psychostimulant dependent individuals with and without a DSM-IV diagnosis of substance-induced psychosis. To investigate gray matter abnormalities in study 1, a voxel-based analysis of magnetic resonance images (MRI) was performed between a group of 74 cocaine dependent nonpsychotic (CDN) individuals and a group of 29 individuals with cocaine-associated psychosis (CAP). The CAP group had significantly smaller volumes of the thalamus and left hippocampus, controlling for age, total brain volume, current methamphetamine dependence, and current marijuana dependence.To investigate white matter abnormalities in study 2, diffusion tensor imaging was employed in a group of individuals with cocaine-associated psychosis (CAP; n=24) and a cocaine dependent nonpsychotic group (CDN; n=43). Tract based spatial statistics (TBSS) was used to investigate group-differences in white matter diffusion parameters. The cocaine-associated psychosis group showed significantly lower fractional anisotropy values than the cocaine dependent nonpsychotic group (p
No abstract available.
A retrospective chart review was performed to determine the incidence and risk factors of delirium after transfemoral and transapical transcatheter aortic valve implantation (TAVI), and open-heart aortic valve replacement (AVR) (n = 45 per group). A number of secondary outcomes were also compared between the surgeries, including 24-hour, 30-day, 1-year and 2-year mortality; time spent in intensive care; total length of hospitalization; need for emergency cardiopulmonary bypass during operation (for TAVI procedures only); and frequencies of postoperative complications. Delirium occurred significantly less frequently in transfemoral TAVI (16%) than in transapical TAVI (51%) or open-heart AVR (38%) (p
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