This study investigated the hypothesis that severity of depressive symptoms following acute ischemic stroke is associated with degree of tissue infarction and severity of white matter changes (WMCs). It employed a novel quantitative region-based approach considering both infarction and WMCs. Of 54 ischemic stroke patients recruited, 50 (72.3 ± 12.8 years, 52.0% male) had useable CT scans. The typical patient was recruited within 3 weeks of their stroke (19.7 ± 31.0 days), exhibited minor cognitive impairment (MMSE score 25.8 ± 4.6), and had mild to moderate stroke severity (NIHSS score 6.5 ± 5.4). 28.0% of patients screened positive for clinical depression with a CES-D score ≥16. While neither degree of infarction nor severity of WMCs (ARWMC score) in the 12 brain regions correlated with depressive symptoms (CES-D score), stroke severity was a significant predictor of depressive symptoms. This stressor, related to physical disability, was a predominant predictor over lesion characteristics.

Emerging evidence supports the use of methylphenidate (MPH) for the treatment of apathy in Alzheimer’s disease (AD). This study aimed to investigate the additional effects of MPH on attention in an AD sample and the relationship between apathy and attention. AD patients enrolled in a randomized, double-blind placebo-controlled study to examine the safety and efficacy of MPH (10mg PO twice daily) for the treatment of apathetic symptoms were tested on attention and apathy every 2 weeks for 6 weeks. A mixed effects linear regression revealed attention change scores (endpoint - baseline) over time favouring MPH (δ=1.01, p=0.03), though there were no significant associations between apathy and attention change scores (r=-0.08, p=0.54). These results suggest that while MPH can improve both apathy and attention, the effects appear independent in this patient population. This study provides insight into the different effects MPH can produce in a heterogeneous disease such as AD.

This study investigated the hypothesis that severity of depressive symptoms following acute ischemic stroke is associated with degree of tissue infarction and severity of white matter changes (WMCs). It employed a novel quantitative region-based approach considering both infarction and WMCs. Of 54 ischemic stroke patients recruited, 50 (72.3 ± 12.8 years, 52.0% male) had useable CT scans. The typical patient was recruited within 3 weeks of their stroke (19.7 ± 31.0 days), exhibited minor cognitive impairment (MMSE score 25.8 ± 4.6), and had mild to moderate stroke severity (NIHSS score 6.5 ± 5.4). 28.0% of patients screened positive for clinical depression with a CES-D score ≥16. While neither degree of infarction nor severity of WMCs (ARWMC score) in the 12 brain regions correlated with depressive symptoms (CES-D score), stroke severity was a significant predictor of depressive symptoms. This stressor, related to physical disability, was a predominant predictor over lesion characteristics.

Emerging evidence supports the use of methylphenidate (MPH) for the treatment of apathy in Alzheimer’s disease (AD). This study aimed to investigate the additional effects of MPH on attention in an AD sample and the relationship between apathy and attention. AD patients enrolled in a randomized, double-blind placebo-controlled study to examine the safety and efficacy of MPH (10mg PO twice daily) for the treatment of apathetic symptoms were tested on attention and apathy every 2 weeks for 6 weeks. A mixed effects linear regression revealed attention change scores (endpoint - baseline) over time favouring MPH (δ=1.01, p=0.03), though there were no significant associations between apathy and attention change scores (r=-0.08, p=0.54). These results suggest that while MPH can improve both apathy and attention, the effects appear independent in this patient population. This study provides insight into the different effects MPH can produce in a heterogeneous disease such as AD.

Environmental stimuli associated with drug use are related to drug craving and relapse. The mechanism of cue-induced craving is thought to involve the release of dopamine (DA) in brain regions associated with reward and habit formation. The aim of the study was to investigate the role of DA in cue-induced craving in tobacco-dependent smokers using Positron Emission Tomography (PET) and a picture cue paradigm. Tobacco-associated cues were capable of eliciting significantly greater subjective reports of craving relative to neutral cues in tobacco smokers (n=6) in a neuroimaging environment. Using this cue paradigm and [11C]-(+)-PHNO PET (n=6), a non-significant trend towards a greater decrease in binding potential, indicative of dopamine release, was shown in selected brain regions of interest. These findings are similar to findings in cocaine-dependent individuals and suggest the involvement of dopamine in the response to smoking-associated cues in tobacco-dependent individuals.

Background: A dysfunctional mesocorticolimbic dopamine system has been reported in alcohol dependence and major depressive disorder. Probing mesocorticolimbic dopamine function in severe depression using dextroamphetamine revealed an altered behavioural response and a disrupted mesocorticolimbic circuitry in behavioural and functional magnetic resonance imaging (fMRI) studies. The purpose of this study was to use a similar approach in alcohol dependence. Behavioural Study: to assess dextroamphetamine subjective effects in alcohol-dependent and depressed alcohol-dependent participants. FMRI Study: to assess how the mesocorticolimbic circuitry would respond to a dextroamphetamine challenge in alcohol-dependent participants exposed to alcohol cues. Methods: In both studies, a single oral 30 mg dose of dextroamphetamine was the pharmacological intervention. Behavioural Study: randomized, double-blind, placebo-controlled, between-subject study. Eighteen alcohol-dependent and 22 depressed alcohol-dependent participants were compared using validated self-report drug effect tools (e.g. Addiction Research Center Inventory). FMRI Study: single-blind, between-subject study. FMRI blood oxygen level–dependent (BOLD) activation was measured in 14 alcohol-dependent and 9 healthy control participants during an alcohol-cue exposure task pre- and post-drug. Results: Behavioural Study: DRUG (F1,40=18.6; p<0.001) and GROUP (F1,40=16.6; p<0.001) main effects but no GROUPxDRUG interaction effects (F1,40=0.02; p=0.88) were detected, even when only severely depressed alcohol-dependent individuals were included (F1,30=0.04; p=0.84). FMRI Study: Alcohol-dependent participants exhibited greater ventral striatal activation compared to controls pre-drug and post-drug effect (F1,40=20.1; z=3.8; p<0.001; k>10; (x=10;y=-2;z=-14)). A GROUPxDRUG interaction effect was detected in the medial orbitofrontal cortex (mOFC) (F1,40=21.5; z=4.0; p<0.001; k>10; (x=-12;y=28;z=-20). The alcohol-dependent group exhibited a negligible mOFC response across both pre- and post-drug scanning sessions. In contrast, controls exhibited attenuation of mOFC response post-drug. Conclusion: The lack of significant GROUPxDRUG interaction effects in the Behavioural Study may suggest different neurobiological mechanisms underlying alcohol dependence and depression mesocorticolimbic dysfunction. Alcohol dependence appeared to mitigate the impact of depression severity on participants’ behavioural responses to dextroamphetamine. The FMRI Study data suggest there may be ventral striatal and mOFC disruption in alcohol-dependent participants. We suggest the mOFC may be involved in the reported loss of prefrontal modulation of dopamine cell activity in alcohol dependence. This supports a key role for the mOFC in mesocorticolimbic dysfunction in alcohol dependence.

It is highly recommended for women to take multivitamin/mineral supplements during the periconceptional and prenatal periods. Studies have confirmed that taking prenatal multivitamins prevents maternal iron deficiency anemia, and reduces the risk for neural tube defects (NTDs). To date, research aimed at optimizing the use of multivitamins before and during pregnancy has been minimal. My thesis focused on two challenges of periconceptional and prenatal multivitamin supplementation. The first challenge was gastrointestinal (GI) adverse events such as nausea and constipation which may be attributed to iron content and tablet size. Pregnant women are highly susceptible to GI adverse events since 80% experience nausea and vomiting of pregnancy. A prospective, randomized, controlled, open-label study was conducted to investigate whether a low-iron, small-tablet prenatal multivitamin can reduce GI adverse events, and improve supplement tolerability and adherence, relative to a high-iron, small-tablet prenatal multivitamin. We determined that low iron dose did not produce a significant difference, while small tablet size could be considered an important factor. Moreover, our results confirmed that adherence was poor in pregnant women. We were prompted to identify determinants which could predict adherence to prenatal multivitamins. Our retrospective study determined that predictors of adherence are rooted in women’s prior experiences with multivitamin use. The second challenge we addressed was achieving adequate blood folate concentrations for prevention of NTDs. If adherence is poor, standard dosing of 0.4-1 mg folic acid may not produce the blood folate concentrations needed in women prior to conception. We investigated the pharmacokinetics of 5 mg folic acid. Our prospective, parallel, open-labeled study, comparing a single dose of 5 mg to 1.1 mg folic acid, confirmed that folic acid follows linear (proportional) pharmacokinetics. However, our prospective, randomized, controlled, open-labeled, multiple-dose study determined that repeated use of folic acid at these 2 doses followed non-linear pharmacokinetics. Nevertheless, our data confirmed that 5 mg folic acid can produce higher blood folate concentrations, with a faster rate, which can counter the effect of poor adherence. In conclusion, optimal use of prenatal multivitamins requires improvements in supplement tolerability, adherence, and pharmacokinetics which depend on supplement formulations, and individualized assessment and counseling.

M2 muscarinic receptor extracted from Sf9 cells in cholate-NaCl differs from that extracted from porcine sarcolemmal membranes. Whereas the latter has been shown to exhibit non-competitive effects in the binding of N-methylscopolamine (NMS) and quinuclidinylbenzilate (QNB), which can be explained in terms of cooperativity within a receptor that is at least tetravalent, binding to the former is essentially competitive. Levels of cholesterol in Sf9 membranes were only 5% of those in sarcolemmal membranes and were increased to about 100% by means of cholesterol-methyl-β-cyclodextrin. M2 receptors extracted from CHL-treated Sf9 membranes resembled those from heart; that is, cholesterol induced a pronounced heterogeneity detected in the binding of both radioligands, including a shortfall in the apparent capacity for [3H]NMS, and there were marked discrepancies in the apparent affinity of NMS as estimated directly and via the inhibition of [3H]QNB. The data can be described quantitatively in terms of cooperative effects among six or more interacting sites, apparently within an oligomer. Cholesterol also was found to increase the affinity of the receptor for NMS and QNB, and the effect was examined for its possible relationship to the known interconversion of cardiac muscarinic receptors between an agonist-specific (R*) and an antagonist-specific (R) state. Cholesterol and N-ethylmaleimide (NEM) were compared for their effect on the affinity of NMS, QNB and four muscarinic agonists, and the data were assessed in terms of an explicit mechanistic model for a receptor that interconverts spontaneously between two states. The data can be described equally well by an effect of cholesterol on either the distribution of receptors between R and R* or the affinity of all ligands for both states, with an accompanying effect of NEM on either the affinity or the distribution between states, respectively. Since NEM is known from other data to favor R* over R, cholesterol appears to increase affinity per se. Cholesterol therefore is a determinant of affinity and cooperativity in the binding of orthosteric ligands to the M2 receptor. Both effects are observed in solution and therefore appear to arise from a direct interaction between the lipid and the receptor.

Nausea and vomiting of pregnancy (NVP) is the most common medical condition in pregnancy, and, unfortunately, variability exists among pregnant women in the therapeutic effect of anti-emetics as well as in factors that can exacerbate NVP. Identifying and managing these sources of variability will result in significant improvements in the quality of life of pregnant woman. This dissertation addressed clinical pharmacology strategies in managing NVP by focusing on three predominant areas of variability. The first challenge addressed in this dissertation was women with pre-existing gastrointestinal (GI) conditions and adherence and tolerability to prenatal multivitamin supplementation. To identify the role of iron in reducing adherence and increasing NVP and GI symptoms, two separate studies were conducted. In the first study, women randomized to a prenatal multivitamin supplementation with higher iron content experienced more adverse GI effects and increased severity of NVP symptoms. In the second study, after discontinuing iron-containing prenatal multivitamins, two-thirds of women in a prospective cohort reported improvement in their NVP symptoms which was corroborated with validated scales to quantify NVP severity. The second challenge addressed in this dissertation was the effect of heartburn and acid reflux on the severity of NVP. In a controlled, prospective study, women experiencing heartburn and acid reflux experienced greater severity of NVP compared to women with no GI symptoms. Furthermore, treatment of heartburn and acid reflux with acid-reducing pharmacotherapy with associated with a reduction in GI symptoms and NVP severity. Therefore, histamine 2 blockers or proton pump inhibitors, which do not appear to be associated with increased fetal risks, should be administered when required. The third clinical pharmacology challenge addressed in this dissertation was to determine the pharmacokinetic variability of the active ingredients of Diclectin®, first-line pharmacotherapy for the treatment of NVP. Large variability was observed in the area under the curve for both active metabolites: a 6.5-fold difference for pyridoxal-5’-phosphate and a 2.1-fold difference for doxylamine. Whether these pharmacokinetic differences contribute to suboptimal efficacy remains to be determined. In conclusion, based on the results presented in this dissertation, several improvements in clinical pharmacology strategies can be made to enhance management of NVP.

Fetal alcohol spectrum disorder (FASD) is the leading non-genetic cause of brain damage. In an effort to reduce alcohol-exposed pregnancies, steps are needed to identify at risk women as early as possible so that appropriate intervention can occur. The objective of this dissertation was to examine screening methods validated in identifying pregnant women at risk for consuming alcohol and illicit drugs during pregnancy. A systematic review identified three main approaches including maternal self-report, use of standardized questionnaires and detection via biological markers. Since most screening tools were developed in alcoholic women, it was important to examine performance in problem drinkers. Alcohol screening tools (ASQ), currently the best method of predicting prenatal problem drinking, were not effective in a cohort representative of problem drinkers. ASQ performance improved minimally, using higher thresholds, but not enough to be used alone. Provider’s knowledge of complexities inherent in women under their care is an important component in screening. As illicit drug use is an important predictor of problem drinking, identifying maternal risk factors associated with substance use was necessary. Increased rates of STD’s, untreated psychiatric disorders, binge drinking and heavy smoking were all identified as predictors of prenatal methamphetamine (MA) use. These factors, combined with high rates of unplanned pregnancies have serious adverse implications for the fetus. The most widely used method to screen for illicit substance use is based on a practice-based approach that relies heavily on maternal self-report. Most providers do not ask about alcohol and substance use in the absence of a high index of suspicion due to the assumption that patient will deny use. But evidence suggests that maternal account can be accurate in a supportive environment. The last study examines the agreement between self-reported data, in comparison to illicit drug use based on positive hair test results. A reasonable agreement between the two approaches of identification demonstrates that maternal self-report can be reliable in women who are motivated enough to seek prenatal care. No single approach is sufficient to effectively identify at risk women. However, combining two or more methods will improve screening and help reduce the number of alcohol-exposed pregnancies.