Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Atypical antipsychotics (AAPs) are associated with metabolic sequelae including risk of type 2 diabetes. Evidence points to a weight-gain independent and direct drug effect on glucose homeostasis. While the exact mechanisms remain elusive, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. We aimed to clarify weight-gain independent mechanisms of AAP-induced alterations in insulin secretion. Deconstruction of the receptor binding profiles of these agents was done using representative antagonists and the hyperglycemic clamp. We assessed the acute effects of several selective receptor antagonists on glucose metabolism, namely prazosin, idazoxan, MDL100907, SB242084 and WAY100635. Prazosin and MDL100907, selective α1 and 5HT2A antagonists, respectively, caused significant decreases in both insulin and C-peptide secretion. A decreased glucose infusion rate and disposition index was also found in the prazosin group. Antagonism of the α1 and 5HT2A receptors may be involved in AAP-induced glucose dysregulation, however, the responsible mechanisms remain unknown.

Atypical antipsychotics (AAPs) are associated with metabolic sequelae including risk of type 2 diabetes. Evidence points to a weight-gain independent and direct drug effect on glucose homeostasis. While the exact mechanisms remain elusive, the heterogeneous binding profiles of AAPs likely include receptors involved in glucose metabolism. We aimed to clarify weight-gain independent mechanisms of AAP-induced alterations in insulin secretion. Deconstruction of the receptor binding profiles of these agents was done using representative antagonists and the hyperglycemic clamp. We assessed the acute effects of several selective receptor antagonists on glucose metabolism, namely prazosin, idazoxan, MDL100907, SB242084 and WAY100635. Prazosin and MDL100907, selective α1 and 5HT2A antagonists, respectively, caused significant decreases in both insulin and C-peptide secretion. A decreased glucose infusion rate and disposition index was also found in the prazosin group. Antagonism of the α1 and 5HT2A receptors may be involved in AAP-induced glucose dysregulation, however, the responsible mechanisms remain unknown.

Schizophrenia is a debilitating and costly mental illness. Many patients do not respond well to currently available treatments, and adverse side effects are common. Cannabidiol (CBD), a natural component of the Cannabis Sativa plant, has been shown to have a number of therapeutic qualities, including potential as a new antipsychotic. Although CBD has been used in several different models of schizophrenia, previous research has failed to consider possible sex differences in responsiveness to the compound. The present research therefore used both male and female rats in the widely used ketamine model of schizophrenia. PVG/C Hooded rats were randomly assigned to one of four experimental conditions: a saline only control group (saline injection followed by second saline injection; N = 6M, 6F); ketamine only group (ketamine injection followed by saline injection; N = 6M, 6F); cannabidiol low dose group (ketamine injection followed by a cannabidiol injection of 10mg/kg; N = 6M, 6F); and a cannabidiol high dose group (ketamine injection followed by a cannabidiol injection of 20mg/kg; N = 6M, 6F). Behavioural testing occurred in a Y-maze and open-field, where both normal and stereotyped behaviours were recorded, as well as locomotor activity and spatial memory. Ketamine successfully induced stereotypy but failed to induce hyperlocomotion. Findings support the potential antipsychotic effects of CBD, particularly for reducing stereotypic behaviour in females. Results found data trends that suggest sex differences in responsiveness to CBD when administered with ketamine, although further research is needed due to lack of statistical significance.

Title: From openness and presence to distance and control: to be medicated and to administrate from a patient and nurse perspective. Background: Within forensic psychiatric care the patients are admitted against their will, under heavy security with long term treatments. Self-care seems, based on scientific studies, to be dependent on what the nurses involved can provide. Emphasis should focus on a humane and respectful approach when the patient is exposed to coercive measures. Aim: From a patient and nurse perspective describe experiences of beeing medicated with and to administrate antipsychotic drugs within the psychiatric inpatient care. Method: Interviews with patients and nurses, which were analyzed using qualitative content analysis with an inductive approach. Results: Patients experience frustration over not beeing able to participate in or influence descisions made regarding their neuroleptic treatment. The neuroleptic treatment is described as a coercive measure and is characterized as an experience of losing control and independence. Nurses’ experiences of administering antipsychotics were described as having to do what is needed for the long term benefit of patients’ well-being. Medicating patients meant more than just handing out pills. It was beneficial to have knowledge of patients and their problems in order to meet patients where they are in the moment. The administration of neuroleptics led to feelings of frustration as it implied that the nurse had to assume an authoritarian role. Discussion: Nurses can promote self-care by inviting the patients to participate and by showing presence open up for cooperation. Patients experience that the feeling of powerlessness characterize their existence. When nurses see the patients as individuals and not as an assignment the feeling of powerlessness whitin the patients can be alleviated. / Titel: Från öppenhet och närvaro- till distans och kontroll: Att medicineras och att administrera ur ett patient- och sjuksköterskeperspektiv. Bakgrund: Patienter inom rättspsykiatrin vårdas mot sin vilja, under hög säkerhet med långa vårdtider. Egenvård förefaller, utifrån studerad forskning, vara i beroende av vad andra människor kan erbjuda. Vid tvångsåtgärder betonas att vikt ska läggas på ett humant förhållningssätt och respektfullt bemötande gentemot patienten. Syfte: Ur ett patient- och sjuksköterskeperspektiv beskriva erfarenheter av att medicineras med och av att administrera neuroleptikaläkemedel inom rättspsykiatrisk slutenvård. Metod: En intervjustudie med patienter och sjuksköterskor som analyserats utifrån kvalitativ innehållsanalys med induktiv ansats. Resultat: Patienter upplever frustration över att inte vara delaktiga eller påverka beslut som tas gällande deras neuroleptikabehandling. Att medicineras med neuroleptika präglas av upplevelsen att förlora kontrollen och sitt självbestämmande då neuroleptikabehandling beskrevs som en tvångsåtgärd. Sjuksköterskors erfarenheter av att administrera neuroleptika beskrevs som att behöva göra det som krävs för att på längre sikt gynna patienters välbefinnande. Att medicinera patienter innebar mer än att bara dela ut tabletter. Det var gynnsamt att ha kännedom om patienter och deras problematik för att kunna möta patienter där de är. Administrering av neuroleptika medförde känslor av frustration när det innebar att sjuksköterskor behövde inta en auktoritär roll. Diskussion: Sjuksköterskor kan främja egenvård genom att invitera patienter till delaktighet och visa tillgänglighet som öppnar upp för samarbete. Patienter upplever att känslan av maktlöshet präglar deras tillvaro, vilket kan lindras genom att sjuksköterskor ser patienten som person och inte en arbetsuppgift.

Background and Objectives: Antipsychotic medications (APMs) are used for the treatment of behavioural symptoms of dementia. The use of APMs among residents of long-term care facilities (LTCFs), who have a high probability of dementia, is correspondingly high, and has been linked to adverse patient outcomes. The study objectives were to: (a) describe facility variation in APM discontinuation rates, (b) test the association between time to APM discontinuation and patient and facility explanatory variables, and (c) conduct a sensitivity analysis about the effect of changes in the measurement of APM discontinuation on variable associations. Methods: The study used a population-based retrospective cohort design. Saskatchewan’s (SK) administrative health databases for the period from April 1, 2004 to March 31, 2011 were the data sources. The study cohort included all seniors (≥65 years of age) with a first admission to a SK LTCF and an APM dispensation on or after the admission date. Discontinuation was defined as a 70-day gap after the last APM dispensation. Patient-level explanatory variables included socio-demographics, comorbidity, prior medication exposure, behavioural and cognitive status, and health services utilization. Facility-level explanatory variables included size, location, licensing status, and type. Percentage discontinuation across facilities was descriptively analyzed. Cox proportional hazards regression models with adjustment for clustering of patients within LCTFs were used to test associations with time to discontinuation. A sensitivity analysis of APM discontinuation was conducted by shortening (35 days) and lengthening (105 days) the time from last dispensation. Results: Among all residents eligible to be cohort members 35.7% were dispensed an APM. A total of 19.5% of the 8358 cohort members discontinued APMs in the observation period. The Kaplan-Meier estimate of the median time to discontinuation was 6.5 years. Demographic, comorbidity, behavioural, and drug exposure variables were most strongly associated with APM discontinuation. Discontinuation was not associated with facility characteristics. Variable associations were insensitive to the definition of APM discontinuation, but changed over time. Conclusion: Discontinuation of APMs is low, despite high rates of utilization over long periods of time. Patient characteristics are associated with APM discontinuation, but not facility characteristics, suggesting that LCTFs are applying consistent approaches to patient management. However, low levels of discontinuation suggest that there may be a need for health care providers to regularly review the prescribing, dispensing, and administration of APMs to LTCF residents in order to ensure appropriate use of these pharmaceuticals.

Schizophrenia is a devastating psychiatric disorder that affects approximately 1% of the population. The main treatments for schizophrenia are antipsychotic drugs that target dopamine receptors, yet the underlying biological mechanisms through which they alleviate the symptoms of schizophrenia remain ill defined. In this study, we used microarray analysis to profile the expression changes of thousands of genes simultaneously, following antipsychotic drug treatment of mice. Mice were treated chronically (28 days), or for a novel intermediate time-point (7 days), with one of three antipsychotic drugs: clozapine, haloperidol or olanzapine. The use of three drugs enabled us to discern antipsychotic-specific effects co-regulated by multiple drugs, rather than the side effects of individual compounds. Transcript profiling and validation by quantitative PCR of whole brain tissue revealed antipsychotic drug regulation of genes in diverse biological pathways, including: dopamine metabolism, neuropeptide and second-messenger signalling, neurogenesis, synaptic plasticity, cell adhesion, myelination, and voltage-gated ion channels. The regulation of voltage-gated channels by antipsychotic drugs has been suggested previously by electrophysiological studies, although thorough analysis has not been undertaken in vivo. Therefore, the second aim of this study was to characterise the regional mRNA and protein expression of two genes altered by multiple APDs, the voltage-gated potassium channel ??-subunit (Kcna1) and voltage-gated potassium channel interacting protein (Kchip3). Regional characterisation and expression analyses were carried out by immunohistochemistry, in situ hybridisation, and Western blot analysis of mouse brain regions of interest to schizophrenia and its treatment. Following 7-day haloperidol treatment we observed up-regulation of Kcna1 in the striatum and dentate gyrus, with increased protein in the striatum, hippocampus and midbrain; and down-regulation of Kchip3 in the striatum, with decreased protein in the cortex, hippocampus and midbrain. These studies implicate voltage-gated potassium channels in the antipsychotic drug regulation of midbrain dopaminergic neuronal activity, adult neurogenesis and/or striatothalamic GABAergic neuronal inhibition. These findings indicate that regulation of potassium channels may underlie some of the mechanisms of action of antipsychotic drugs, and that voltage-gated ion channels may provide alternative drug targets for the treatment of schizophrenia.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.