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Myocardial infarction, a leading cause of mortality and morbidity worldwide, is often the result of coronary plaque rupture. Previous histological work has demonstrated that ruptured plaques are associated with higher stress, with in vivo intravascular studies linking higher plaque structural stress (PSS) with the presentation of acute coronary syndrome. Endothelial shear stress (ESS) on the other hand has been implicated in early plaque development and plaque growth, suggesting that both PSS and ESS can influence future plaque behaviour. The work presented in this thesis first demonstrates that PSS changes with pharmacotherapy, in particular, high-intensity statin (HIS) treatment prevented the rise in PSS in most advanced lesions (those with plaque burden [PB] > 60%). The change in PSS was both dependent on drug therapy and baseline disease severity, and the protective effect of HIS seemed to be mediated by remodelling plaque microstructure and lumen surface. Second, it shows that plaque geometric parameters, especially the longitudinal variation measured by heterogeneity index of lumen roughness, curvature, and irregularity, can identify plaques that subsequently developed adverse clinical events. Lumen roughness heterogeneity showed a weak correlation with PSS and was an independent predictor of adverse clinical events. Finally, the role of combined PSS and ESS in plaque risk prediction was assessed through a subgroup analysis of the PROSPECT (A Prospective Natural-History Study of Coronary Atherosclerosis) study, with results suggesting that incorporation of ESS, ESS gradient, and PSS heterogeneity can improve the capability of VH-IVUS to identify plaques that lead to such events.

Multimorbidity is common in older patients. Consequently, polypharmacy and potentially inappropriate prescribing (PIP) are prevalent and increase toward the end of life (EOL). One potential solution is deprescribing, a supervised discontinuation of inappropriate medicines. The overall aim of this thesis was to explore prescribing and deprescribing patterns in hospice care settings, to evaluate current deprescribing interventions, to determine deprescribing barriers and enablers from the perspectives of healthcare professionals (HCPs) and policymakers, and to evaluate the attitudes of HCPs, patients and carers in relation to deprescribing medicines for older people receiving palliative care. Qualitative and quantitative methodologies were used throughout the four studies described in this thesis. Key findings of the systematic review included the current lack of high-quality studies of deprescribing interventions in older people at the EOL. The limited number of included studies demonstrated a positive impact of deprescribing interventions on medication appropriateness but inconsistent effects on polypharmacy, and did not consider clinical and humanistic outcomes. Further key findings were the high prevalence of polypharmacy and PIP in older hospice patients in the last days of life, the largely reactive nature of current deprescribing practice, and the limited adoption of pre-emptive (proactive) deprescribing. Moreover, key barriers to deprescribing in hospice care were reported; for example, the lack of formal documentation of deprescribing outcomes, while access to information such as medication indication was identified as a key enabler. These barriers and enablers guided the prioritisation of key theoretical domains which were mapped to behavioural change techniques to be incorporated in future deprescribing interventions. Stakeholders involved in the deprescribing process (patients, carers, HCPs) showed willingness for medicines to be deprescribed. Overall, the findings highlight the complexity of prescribing in older people at the EOL and the need of further training and educational programs to optimise medicines use in this vulnerable population.

Depression is the leading cause of disability in the United States for individuals aged 15 to 44 (Anxiety and Depression Association of America, 2023). The purpose of this evidence-based practice (EBP) project was to increase early identification of depression through implementation of universal depression screening, and to implement management strategies to decrease symptoms of depression. A two-tiered approach to universal depression screening was utilized through use of the PHQ-2 and PHQ-9 screening tools. Ten young adult patients, between the ages of 18 to 25, from a university student health center clinic in Northwest Indiana participated in this project. Participants underwent an 8-week intervention consisting of management strategies that included some or all the following based on a provider and patient shared decision-making process: lifestyle modification education and associated referrals, use of digital cognitive behavioral therapy (dCBT), referral to counseling services, and/or pharmacotherapy if indicated. Participants were contacted at 2, 4, and 8 weeks from baseline to obtain PHQ-9 scores and assess adherence to interventions. A paired t test was utilized to compare the mean baseline PHQ-9 scores to mean 8-week PHQ-9 scores. A significant decrease from baseline to eight weeks was found (t(9)=8.10, p

Generalized anxiety disorder (GAD) is a debilitating psychological condition that affects 3.1% of the American population and is one of the leading causes of disability (Anxiety and Depression Association of America, 2022; Baxter, 2014). The purpose of this evidence-based practice project was to implement a multimodal intervention to decrease GAD symptoms in adults in the primary care setting. The PICOT question that guided this project was: In adults, over the age of 18, who have been diagnosed with generalized anxiety disorder (GAD), does the combination of digital cognitive behavioral therapy (CBT) through a smartphone application, lifestyle modification education, and pharmacotherapy improve patient’s GAD-7 scores over an 8-week period in the primary care setting? A comprehensive literature search of six databases and citation chasing were conducted to determine the best treatment practices for GAD in primary care. Fourteen pieces of high-level evidence graded using evidence-based appraisal tools supported the implementation of CBT, lifestyle modifications, and pharmacotherapy. A sample of 13 adult participants were recruited in a primary care clinic and screened for GAD using the GAD-7 scale. Participants underwent an eight-week intervention consisting of digital CBT, lifestyle modification including an exercise regimen, and pharmacotherapy. Participants were contacted every two weeks to obtain GAD-7 scores and assess adherence to interventions. A paired t test was used to compare the mean baseline GAD-7 scores to the mean eight-week GAD-7 scores. A significant decrease from baseline to eight weeks was found (t (13) = -3.975, p

Obstructive sleep apnoea (OSA) pathogenesis is multifactorial with contributions from anatomical and non-anatomical endotypes. Current anatomical-orientated therapies are often inadequate or poorly tolerated with no pharmacotherapies available for OSA. Recent research shows that a combination of noradrenergic and anti-muscarinic agents increases upper-airway muscle activity (key non-anatomical endotype) and reduces OSA severity. Thus, my thesis aimed to investigate alternate therapies for OSA including novel pharmacotherapies targeted towards non-anatomical OSA endotypes as well as combining with existing anatomical approaches based on OSA endotype characterisation. Study 1 investigated the effects of the noradrenergic agent atomoxetine combined with 2 different anti-muscarinics (solifenacin or biperiden) with different receptor-selectivity profiles. Previous studies combined atomoxetine with the antimuscarinic oxybutynin which has broad receptor-selectivity. The goal was to gain mechanistic insight into specific antimuscarinic receptor subtypes for OSA pharmacotherapy which may also have a better side-effect profile versus oxybutynin. The different anti-muscarinics plus atomoxetine improved upper airway function and perceived next-day sleepiness in people with OSA albeit to a lesser extent compared to oxybutynin. This suggests broad or at least M2 muscarinic receptor selectivity may be important in mediating the efficacy of this drug combination for OSA pharmacotherapy. Previous studies with noradrenergic and antimuscarinic agents have been short term (≤1 week) and have not included different doses. Accordingly, in study 2, I investigated longer term (1-month) safety, tolerability, and efficacy of different doses of atomoxetine plus oxybutynin (ato-oxy) versus placebo. 1-month of ato-oxy was generally well-tolerated with a side effect profile consistent with the known profile of each agent alone. An 80/5 mg dosage combination of ato-oxy reduced key OSA severity metrics by ~50%. In study 3 I aimed to investigate if OSA endotype characterisation can be used to inform targeted therapy to resolve OSA in the clinically relevant group of patients who have an incomplete therapeutic response to oral appliance alone (~50% of patients). In these individuals, I systematically added existing anatomical therapies and emerging non-anatomical therapies (i.e., ato-oxy) according to OSA endotype characterisation. OSA was controlled in 50% of participants with addition of other existing anatomical interventions. Almost all the remaining participants were fully treated with the addition of non-anatomical pharmacotherapies. These novel findings provide important insight for the development of novel pharmacotherapy and combination therapy approaches informed by underlying physiological mechanisms for future treatment and management of OSA.

Background: Previous studies have highlighted a robust bidirectional relationship between alcohol and cigarette use. Co-use of these substances impacts treatment outcomes, as there are no FDA approved medications for the co-use of cigarettes and alcohol. The combination of 2 FDA approved medications for smoking cessation (varenicline) and alcohol use disorder (naltrexone) have shown promise as a treatment option for heavy drinking smokers. Methods: The dissertation project examined both etiology and treatment of the unique subgroup of heavy drinking smokers. Chapter 1 (etiology) utilized a behavioral economics framework in a sample of non-treatment seeking heavy drinking smokers to examine demand for each substance using a hypothetical purchase task in which participants indicate how much of a substance they would consume at varying prices. Chapters 2 and 3 (treatment) consisted of a community sample of treatment-seeking heavy drinking smokers who completed a 12-week randomized clinical trial comparing varenicline plus placebo versus varenicline plus naltrexone for smoking cessation and drinking reduction. Chapter 2 examined the impact of sex hormones in response to pharmacotherapy for female heavy drinking smokers. Chapter 3 examined whether drinking outcomes mediated the relationship between pharmacotherapy and smoking outcomes. Results: Results from Chapter 1 (etiology) revealed cross-substance relationships, with use of one substance predicting greater demand of the opposite substance. Notably, we found a stronger effect of nicotine use on demand for alcohol than vice versa. Results from Chapter 2 (treatment) showed no interaction of sex hormones and pharmacotherapy on smoking outcomes. However, greater ratio of progesterone to estradiol was associated with greater percent days abstinent from alcohol for females assigned to the varenicline plus naltrexone condition. Results from Chapter 3 (treatment) indicated that drinking outcomes did not mediate the relationship between pharmacotherapy and smoking outcomes. However, throughout the active medication phase and follow-up phase there was a significant relationship between drinking and smoking outcomes. Conclusion: These studies use a translational framework combining pharmacology, experimental psychology, and biomarkers of sex differences to address clinical implications of the co-use of cigarettes and alcohol. These studies advance a precision medicine approach whereby the complementarity between smoking and drinking can be clinically targeted.

BACKGROUND: Identifying the relationships between physical and behavioural characteristics with the presence or absence of pharmacotherapy (on or off bone medication) for postmenopausal women with low bone mass could assist healthcare professionals to individualise bone health management plans and provide better patient-centred care. Linking patient characteristics with attitudes and motivations behind their decisions would be helpful for healthcare professionals in identifying what gaps in knowledge and types of therapy patients would most likely be open to initiating, adhering to and persisting. A cross-sectional study such as this has not previously been undertaken. METHODS: A convenience sample of 349 postmenopausal women with low bone mass were recruited from participants of the Medication and Exercise for Osteoporosis (MEDEX-OP) trial, women who were excluded from the MEDEX-OP trial and clients of The Bone Clinic in Brisbane, Australia. The baseline data from participants of the MEDEX-OP trial and the data from a routine assessment from clients of The Bone Clinic were obtained for analysis. A questionnaire requesting demographic information as well as attitudes toward medication and motivations to be on or off bone medication was emailed or sent via mail to women who had been excluded from the MEDEX-OP trial. Data was analysed via univariable and multivariable logistic regression to identify physical or behavioural characteristics related to being on or off bone medication. RESULTS: The majority of participants were aged in their early sixties, with 256 (73.4%) off bone medication and 93 (26.6%) currently taking antiresorptive bone medication. Age in years (OR 1.05, 95% CI 1.01-1.09), two or more fragility fractures (OR 5.08, 95% CI 2.60-9.94), previously took bone medication (OR 2.48, 95% CI 1.44-4.26), fracture risk calculated as a percentage using the Garvan Institute Fracture Risk Calculator (OR 1.03, 95% CI 1.01-1.06), back extensor strength measured in kilograms (OR 0.96, 95% CI 0.93-0.98), five times sit to stand measured in seconds (OR 1.16, 95% CI 1.04-1.30), and having a promedication attitude (OR 5.95, 95% CI 2.92-12.12) or ambivalent attitude toward medication in general (OR 1.51, 95% CI 0.73-3.09) were statistically significant variables that were found to be related to being on or off bone medication following the univariable logistic regression analyses. People with ambivalent attitudes were found to be just as likely as those with anti-medication attitudes to be on bone medication. At the adjusted multivariable level, having two or more fractures (OR 3.87, 95% CI 1.53-9.79), previous bone medication (OR 2.81, 95% CI 1.36-5.78), having poor back extension strength (OR 0.95, 95% CI 0.92-0.98), and having a pro-medication attitude (OR 6.41, 95% CI 2.73-15.07) were associated with being on bone medication. CONCLUSION: Fragility fracture history, previous use of bone medications, back extensor strength and attitudes toward medication in general were strongly related to being on or off bone medication among postmenopausal women with low bone mass. Healthcare professionals should consider these four characteristics when involving patients in the decision-making process of making a bone health management plan.

Abdominal aortic aneurysm (AAA) disease causes dilation of the aorta that can lead to aortic rupture and death if not treated early. It is the 14th leading cause of death in the U.S. and is cited as the 10th leading cause of death in men over age 55, affecting thousands of patients and their families. To date, AAA patients have minimal access to safe and efficient imaging modalities for diagnosis as well as pharmacotherapies. AAA is usually detected and monitored with ultrasonography or contrast-enhanced computed tomography (C.T.), which doesn’t provide biomechanical information of the AAAs that are essential for predicting rupture risks. Furthermore, unfortunately, there is no currently known pharmaceutical treatment to cure the AAAs. Key pathological processes occurring within AAAs include inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix (ECM) degradation. The deterioration of the elastic lamina in the aneurysmal wall is a consistent feature of AAAs and the fact that the adult elastic lamina does not remodel in aneurysm progression, making it an ideal target for delivering contrast agents and treatments. In this research, we have delivered gold nanoparticles (AuNPs), a commonly used C.T. contrast agent, and pentagalloyl glucose (PGG) loaded nanoparticles to the AAAs in an angiotensin II (AngII) infusion induced mouse model by conjugating the nanoparticles with antibodies that target degraded elastin. Here, owing to their degraded elastin targeting ability, we have observed a positive correlation between the quantities of the locally accumulated AuNPs in the aneurysmal tissue in C.T. scans and the elastin damage levels of the AAAs. Furthermore, the AuNPs accumulations were found negatively correlated to the mechanical properties of the AAAs, which makes AuNPs a potential non-invasive surrogate marker of AAA rupture risk. Moreover, we have shown that targeted delivery of PGG could reverse the aortic dilation, ameliorate the inflammation, restore the elastin as well as the AAA mechanical properties of the aneurysmal tissue. Therefore, PGG loaded nanoparticles can be an effective treatment option for early to middle stage aneurysms to prevent disease progression.

Maternal smoking cessation is key to improving maternal, neonatal and infant health. As pharmacotherapies for smoking cessation, which include nicotine replacement therapy (NRT), bupropion and varenicline, are the most effective cessation interventions in the general population, their use holds promise to promote quitting during and after pregnancy. This thesis aimed to identify factors that influence the prescribing and/or use of smoking cessation pharmacotherapies among women who smoke during pregnancy and after giving birth. A study based on calls to a teratology information service found that healthcare providers have more safety concerns regarding bupropion and varenicline than other medications of same pregnancy risk category. Safety concerns might limit their prescribing. A survey of Australian obstetricians and gynaecologists found that facility-level factors, including having a smoking cessation protocol and practising in remote and regional areas, were associated with familiarity with NRT patches. Among obstetricians familiar with NRT patches, those who believed that they could benefit their patients, and those who had self-efficacy to prescribe were more likely to intend to prescribe NRT patches. Although lack of knowledge of NRT patches might limit prescribing, individual beliefs might also limit the prescribing among those who were familiar with NRT. A study based on linked data comprising perinatal, hospital admission, death and dispensing records for all women who gave birth in NSW and WA, found 8.7% (95% CI 8.2-9.1) of women smoking at the time of delivery used a smoking cessation pharmacotherapy in the next 12 months. At 6.3% (95% CI 5.9-6.7), varenicline was the most used pharmacotherapy. Maternal suitability for pharmacotherapy was not an influential factor as few maternal morbidities worsened by smoking were associated with use of these pharmacotherapies. Poor birth outcomes were not capitalised on as a factor to motivate more pharmacologically assisted quit attempts. Another population-based study using linked administrative data provided evidence of varenicline’s effectiveness among postpartum maternal smokers. This evidence can be used to guide future decisions about whether to use varenicline postpartum. Robust data arerequired regarding safety of these pharmacotherapies during and after pregnancy to help support healthcare providers in seizing opportunities to assist pregnant and postpartum women in quitting smoking using these pharmacotherapies.

An emerging body of research on the functional impairments of Attention-Deficit/Hyperactivity Disorder (ADHD) in adults notes that parents with ADHD are likely to experience challenges in several facets of childrearing (e.g., Chronis-Tuscano et al., 2008a; Murray & Johnston, 2006). Despite empirical evidence suggesting parents with ADHD have particular kinds of struggles, research evaluating the effects of adult ADHD treatment on parenting challenges is quite scarce. By contrast, a breadth of research indicates that adult ADHD interventions, particularly pharmacotherapy and cognitive-behavioral therapy (CBT), are effective in ameliorating ADHD symptoms. Further, CBT has shown to be an efficacious adjunctive treatment for ADHD and is associated with improvements in global functioning among ADHD-adults (e.g., Safren et al., 2005; Weiss et al., 2012). This dissertation proposes a conceptual framework outlining the mechanisms by which combined pharmacotherapy and CBT would be an effective treatment plan to address parenting challenges in adult ADHD. A small pilot study was conducted comparing parenting ratings between ADHD-parents and non-ADHD controls. The results of the pilot study are presented in the context of providing groundwork for a proposed randomized controlled trial to compare the efficacy of pharmacotherapy and combined treatment to treat parenting difficulties in adult ADHD. The implications and limitations of the pilot study, as well as anticipated implications and limitations of the theorized research, are discussed.

Stroke is the 5th leading cause of death in the U.S. with 130,000 deaths and around 800,000 affected annually. Currently, there is a significant disconnect between basic stroke research and clinical stroke therapeutic needs. Few animal models of stroke target the large vessels that produce cortical deficits seen in the clinical setting. Also, current routes of drug administration, intraperitoneal and intravenous, do not mimic the clinical route of intra-arterial drug administration. To bridge this divide, we have retro-engineered a mouse model of stroke from the current standard of care for emergent large vessel occlusion (ELVO) stroke, endovascular thrombectomy, to include selective intra-arterial pharmacotherapy administration. Using the tandem transient common carotid and middle cerebral artery occlusion (MCAo) model to induce stroke, we threaded micro-angio tubing into the external carotid artery (ECA) towards the bifurcation of the common carotid and internal carotid arteries (CCA/ICA) allowing for the delivery of agents to the site of acute ischemia. Our model was optimized through a flow rate and injection volume study using carbon black ink injected through the intra-arterial model at different flow rates and injection volumes. The purpose of this study was to demonstrate that our injections were arriving at the site of ischemia and to improve injection volumes for future dosing while mitigating systemic side effects by preventing or minimizing systemic distribution. We determined that a flow rate of 2.5 µl/minute and injection volume of 10 µl was optimal. Next, we tested potential neuroprotective compounds nitroglycerin, verapamil, and a combination of verapamil and lubeluzole. Compounds were chosen for drug synergy and to target specific pathways in either an acute or delayed manner. Acute treatments included nitroglycerin and/or verapamil while delayed treatment included lubeluzole. The known mechanism of action for FDA approved nitroglycerin is through vessel dilation that results in increased blood flow to the treated region. A secondary mechanism of nitroglycerin is the production of nitric oxide, which has demonstrated antioxidant and anti-apoptotic effects when processed and released from cells surrounding the blood vessels. Verapamil, a calcium channel blocker, also FDA-approved for cerebral artery vasospasm: is thought to act by blocking the L-type calcium channels on the cell membrane from opening following membrane depolarization after insult. Finally, lubeluzole, also FDA-approved, is proposed to work as an NMDA modulator inhibiting the release of glutamate and nitric oxide synthase and blocking sodium and calcium channels. Through our stroke model we were able to demonstrate that each drug(s) showed a significant decrease in infarct volume and improved functional recovery while simultaneously minimizing potential systemic side effects suggesting that our stroke model may improve the preclinical validation of potential stroke therapies and help bridge the bench to bedside divide in developing new stroke therapies.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder with childhood onset that confers greater risk for many negative outcomes including future psychopathology, increased risk for substance abuse, poor self-esteem, and poor social functioning. Identification of targeted treatment approaches requires not only accurate measurement of the construct under study, but also an analytic method that can appropriately identify the effect of treatment, while accounting for the noise of measurement error. This study aimed to address the evident gap in our ability to predict an individual’s response to treatment by first identifying a best-fitting model for ADHD symptoms and then using this best fitting model to estimate treatment effect with increased precision.A sample of 1,612 children and adolescents ages 6 to 17 was used to test the best-fitting model for ADHD. Results from the confirmatory model suggest that a modified bifactor model had better fit (BIC = 47902.44, M2(1346) = 2944.68, RMSEA = .03) compared to the unidimensional and correlated factor models and best minimized mean dimension differences across gender and age. In this modified bifactor model, impulsivity items loaded only on the primary dimension, while inattention and hyperactivity items loaded on both the primary dimension and two separate specific dimensions.In the analysis of treatment effect, two randomized controlled clinical trials of pharmacotherapy for children and adolescents with ADHD were evaluated; DMPH compared to DMPH + guanfacine and atomoxetine compared to placebo. Item parameters generated in study one were used to estimate the treatment models. In the IRT analyses, atomoxetine produced significant reductions in the inattention and the general dimension, however there was more variability in children’s response to atomoxetine as measured by the general dimension. When comparing DMPH and combination treatment, combination treatment was superior in the treatment of the general dimension. Examining variability in average scores provided by the IRT analysis, it appeared that combination treatment was more effective in consistently reducing symptoms across children on the inattention dimension, while DMPH was more effective in consistently reducing symptoms across children on the general dimension. Therefore, creating conditionally independent dimensions clearly allowed for more precise modeling of treatment effect. The field of psychiatry, and more broadly treatment research, could benefit substantially from continued use of IRT models.

Obesity is a major public health problem; in the U.S. nearly one third of the population is obese. The adipose tissue is innervated by the sympathetic nervous system (SNS), which regulates fat mass by playing a key role in initiating lipolysis and regulating lipid mobilization. TLQP-21, a 21 amino acid peptide encoded by the pre-pro-peptide VGF (non acronymic) expressed in the brain and sympathetic neurons innervating the adipose organ. Complement 3a receptor 1, C3aR1, is the target receptor for TLQP-21. Based on previous finding where peripheral TLQP-21 decreases adipocyte diameter and enhance β-adrenergic receptors (β-ARs) lipolysis in adipocytes the hypothesis tested in my thesis is that C3aR1 and β-ARs are required for TLQP-21 anti-obesity effects and the pro-lipolytic effects are mediated by increased mobilization of [Ca2+]i. Departing from the first experimental structural analysis of TLQP-21 in solution and receptor-bound state, we tested our hypothesis using a combined in vitro and in vivo approach. Using 3T3L1 cells and pre-adipocytes as our in vitro model, we determined that TLQP-21 enhances lipolysis via increased intracellular Ca2+ concentration [Ca2+]i, and activation of the MAPK/ERK pathway. The physiological effects of TLQP-21 were investigated in vivo using wild type, β-less (β1, β2, β3-AR KO) and C3aR1 KO mice. Chronic TLQP-21 treatment in obese wild type mice significantly decreased body weight and fat mass promoting an overall healthier metabolic phenotype. Conversely β-less and C3aR1 KO resulted fully resistant to the anti-obesity effects. Herein we identified the mechanism of TLQP-21 pro-lipolytic and anti-obesity effect and could thus be regarded as a novel target for pharmacotherapies of obesity.

Cocaine addiction is a pervasive public health problem, but currently there are no highly effective treatments to reduce its extent or duration. Emerging research in humans and animals suggests that aerobic exercise may decrease drug use and prevent relapse. This set of experiments focused on the use of exercise as a behavioral treatment for cocaine addiction using rodent (rat) models of relapse. Concurrent access to a voluntary running wheel decreased reinstatement of cocaine-seeking behavior in response to a cocaine injection (Experiments 1-3), cocaine-paired cues (Experiment 2-3), and the pharmacological stressor yohimbine (Experiment 2). Wheel running during the withdrawal period also prevented incubation of cocaine seeking or time-dependent increases in reactivity to cocaine-paired cues, a situation that often precipitates relapse (Experiment 5). Further, using pharmacological treatments such as progesterone (Experiment 2) or atomoxetine (Experiment 3) in combination with wheel running led to an additive treatment effect, suggesting a larger role for exercise as a singular or adjunct treatment in the prevention of cocaine relapse. While these behavioral models have revealed exercise to be an efficacious method to attenuate cocaine-motivated behaviors, long-term wheel running also changed cocaine-induced activation of brain reward circuitry (Experiment 4). Using c-Fos immunohistochemistry to evaluate neuronal activation, results demonstrated that exercising and control rats showed differential activation of the nucleus accumbens, caudate putamen, and prefrontal cortex in response to an acute cocaine injection. These results suggest that exercise may alter reactivity to cocaine by inducing plasticity in the mesolimbic dopamine system. Overall, results across these experiments have demonstrated that aerobic exercise has the ability to attenuate activation of the neurobiological substrates of addiction in addition to robustly reducing relapse to cocaine-seeking behavior.

Abstract: Breast cancer is the most common malignancy among females, and the second leading cause of cancer death among Canadian women. Despite improved survival, both short and long term detrimental effects have been observed with both novel and conventional anti-cancer therapies. In particular, the effects of cancer therapy on the cardiovascular system, or ‘cardiotoxicity’, are increasingly recognized in terms of morbidity and mortality. Subtle or ‘sub-clinical’ early effects of anti-cancer therapies on cardiac structures may remain undetected, conveying potentially devastating longer-term effects. The overarching theme of this thesis is to examine the short and long-term effects of a novel anti-cancer therapy, trastuzumab, on left ventricular (LV) morphology and function in breast cancer patients. Two studies were undertaken; study #1 was a cross-sectional study of 17 female breast cancer survivors exposed to trastuzumab-based chemotherapy, examining LV remodeling and exercise capacity. We found that early breast cancer patients had significant alterations in left ventricular geometry and impairment of cardiorespiratory function four years following exposure to trastuzumab-based chemotherapy. The second study was performed to examine the effects of three months of standard heart failure therapy, consisting of angiotensin-converting enzyme inhibitor or beta-blocker vs placebo, on LV remodeling in breast cancer patients receiving trastuzumab-based therapy. The major finding was that that standard heart failure pharmacotherapy appeared to be effective in attenuating LV dysfunction associated with trastuzumab-based therapy. When compared to patients randomized to the pharmacotherapy group, significant decline in left ventricular ejection fraction occurred in the placebo group.

The relationship between therapist adherence to CT and subsequent outcome was examined in a sample of 176 depressed patients participating in cognitive therapy (CT) combined with pharmacotherapy. Following a factor analysis that identified three adherence factors, these three subscales were examined as predictors of session-to-session symptom change across the first three therapy sessions. Only one adherence scale predicted session-to-session symptom change: Behavioral Methods / Homework. The two other scales (i.e., Cognitive Methods and Negotiating / Structuring) were not significant predictors. Adherence to Behavioral Methods / Homework in early sessions predicted decreased risk of treatment dropout, while there was a non-significant trend suggesting that Negotiating / Structuring might be associated with increased risk of dropout. In examining prediction of longer-term symptom change from early adherence ratings, all three adherence measures showed a non-significant trend toward predicting more rapid symptom improvement through week 16 of treatment; Cognitive Methods and Behavioral Methods/Homework were unique predictors. However, early adherence failed to predict likelihood of meeting remission criteria over one year of treatment. The consistent predictive ability of Behavioral Methods/Homework is discussed in the context of the existing literature on adherence-outcome relations, and implications for future research.

Psychostimulant dependence is a major public health issue in many parts of the world associated with a wide range of psychological, medical and social problems. Psychosocial interventions are the mainstay of treatment for psychostimulant problems, although their effectiveness is compromised by poor uptake and compliance. Despite increasing knowledge of the neurobiological consequences of psychostimulant use, no medications to date have been any more successful than placebo in reducing psychostimulant use in dependent patients. Modafinil is a non-amphetamine type psychostimulant that may have potential as an agonist pharmacotherapy for psychostimulant dependence. The aim of this thesis was to examine the safety, efficacy and cost-effectiveness of modafinil 200 mg/day over ten weeks plus a four session brief CBT intervention for methamphetamine and cocaine dependence through two concurrent randomised placebo controlled trials. There were no statistically significant differences between modafinil and placebo in treatment retention, medication adherence, psychostimulant abstinence, psychostimulant craving or severity of psychostimulant dependence. Methamphetamine-dependent subjects tended to provide more illicit psychostimulant negative urine samples while in treatment than those who received placebo. There appeared to be a reduction in self-reported days of psychostimulant use among methamphetamine-dependent subjects who received modafinil compared to placebo, but the effect size was too small to be statistically significant in this sample. The reduction in self-reported psychostimulant use did reach statistical significance in methamphetamine-dependent subjects with no other substance dependence. Uptake of counselling was the most significant predictor of reduced psychostimulant use post treatment, and the addition of counselling improved the cost-effectiveness of modafinil relative to placebo. Modafinil appeared to be safe, well-tolerated, and non-reinforcing in this treatment population. Compared to placebo, there was a significant increase in weight in subjects who completed the 10-week course of treatment, and a significant decrease in systolic blood pressure in methamphetamine-dependent subjects who received modafinil. The results support further trials of modafinil in methamphetamine-dependent patients, although future trials in cocaine-dependent patients from this treatment population were not likely to be viable. Modafinil appeared to be modestly effective in reducing, but not stopping, methamphetamine use in selected patients. Multi-centre trials with larger sample sizes, and measures sensitive enough to detect quantitative changes in psychostimulant use would be needed to confirm the findings. Blood pressure and weight may be important indicators of clinical outcome, and warrant particular attention in future trials, particularly given the cardio-toxicity of both methamphetamine and cocaine. Strategies to enhance medication adherence including a higher dose and counselling adherence are recommended to improve outcomes. Given the predominance of behavioural and psychosocial factors in psychostimulant dependence, it is likely that the role of medications such as modafinil will be as an adjunct to psychosocial therapy.

Benign prostatic hyperplasia (BPH) is a highly prevalent disease in older men and occurs in more than 50% of men aged 60 to 70 years. BPH results in prostate enlargement with bladder outflow obstruction. Treatment with a 5α-reductase inhibitor such as finasteride induces apoptosis in epithelial cells and leads to the reduction of prostate volume. However, pharmacologic treatment is not uniformly effective in shrinking the prostate and in relieving symptoms, so the ability to predict how each patient will benefit best from varying pharmacotherapy is a question of great medical and economic importance. Finasteride is also used as a prophylaxis of BPH-associated hematuria and to reduce blood loss at surgical resection of the prostate. The important questions to be addressed include what is the optimum dose and how long should the patients be treated. An effective non-invasive tool may be helpful to solve these questions by monitoring the changes in prostatic blood flow. Twenty-four male beagles with benign prostatic hyperplasia were enrolled in a drug trial and imaged at five time points by magnetic resonance imaging (MRI). The capabilities of different MRI-based methodologies for measuring prostate volume were evaluated from anatomical MR images. The possibility of using pharmacokinetic parameters as a predictor of MRI prostate volume changes were evaluated and the use of DCE-MRI as a biologic marker of in-vivo changes in microcirculation in prostatic suburethral region was assessed. The segmented MRI prostate volume significantly correlated with post necropsy volume. The changes in prostate volume at the end of the treatment exhibited a significant linear correlation to the initial parenchymal Maximum Enhancement Ratio (MER) (p < 0.02) in the finasteride group. After completion of the therapeutic regiment, Tmax on prostatic suburethral area was significantly longer in the finasteride group compared to controls (p < 0.01), and the pharmacokinetic parameters amplitude A and exchange rate constant kep decreased 39% and 34% respectively in the finasteride group at the end of the treatment. In conclusion, MRI of prostate can supply important in-vivo biomarkers, such as organ volume and pharmacokinetic parameters, in the development of BPH pharmacotherapies such as 5α-reductase inhibitors.

This study evaluated a treatment program for anxiety disordered children, ages five to twelve years, utilizing both qualitative and quantitative methodologies. The treatment program integrated Imipramine pharmacotherapy and brief psychotherapy. The participants' nuclear and extended family histories were examined in terms of the occurrence of psychopathology and endemic transactional patterns. The examination of family patterns utilized Murray Bowen's Generational Model, as well as the T-F-A model of Hutchins and Cole, as a means of explaining the transmission of anxiety in the family. Ten children suspected of experiencing anxiety disorders were referred by pediatric physicians for treatment. Following an initial diagnostic assessment, children were placed on 25 milligrams of Imipramine per day for four to six weeks, while participating in weekly conjoint psychotherapy with their mothers for a six to eight-week period. A post-treatment evaluation was conducted by selecting ten prototypic participants. Selection was based upon age, diagnosis of overanxious disorder or separation anxiety disorder in childhood, and a time interval of no more than one year or less than one week following treatment. Semi-structured interviews were conducted with mother-child pairs separately to evaluate participants' perceptions of pre- and post-treatment symptom levels and family dynamics. DSM-III diagnostic criteria, Bowenian and T-F-A models served as the frameworks for organizing and evaluating qualitative data. All child participants experienced a dramatic and lasting resolution of both OAD and SAD symptomology. A quantitative analysis was performed utilizing the Wilcoxon sign rank to compare pre- and post-treatment symptom levels, with a significant effect by treatment occurring at the .005 level of significance. Cross-validation of treatment outcome was achieved through review of medical records, original psychotherapy notes, and videotapes of the interviews. Qualitative data regarding transgenerational medical and psychological disorders and family dynamics was generated. The data supported the Unitary model of generational family pathology. Six of seven Bowenian constructs were confirmed in this sample. The T-F-A model was used to demonstrate a cyclical pattern of reassurance, anxiety reduction, and child dependency between anxious children and their mothers. These results were discussed to provide a better understanding of the etiology and treatment of childhood anxiety disorders (OAD and SAD). The term "anxogenic family" was suggested to convey the interaction of genetics and generational learning in the families of anxiety disordered children. Implications for future research and modification of the DSM-IV regarding childhood anxiety disorders were discussed.