La stimulation cérébrale profonde (DBS) du gyrus cingulaire subgénual est actuellement en coursd’évaluation comme nouvelle cible thérapeutique chez les patients souffrant de dépression majeure.Afin de caractériser les mécanismes sous-jacents l’action de la DBS, et plus particulièrement, lapossible implication du système glial, les effets de la stimulation du cortex préfrontal infralimbique surplusieurs marqueurs précliniques de la réponse antidépressive ont été évalués chez le rat. Ce travailde thèse, en utilisant des approches électrophysiologiques, immunohistochimiques etcomportementales, montre que la DBS aigue (130 Hz, 150 μA) induit des comportements pseudoantidépresseurs(évalués dans le test de nage forcée) qui sont associés à une augmentation del’activité des neurones 5-HT du raphé dorsal et de la neurogenèse du gyrus denté. De plus, la DBSaigue est capable de renverser les effets du stress sur la métaplasticité synaptique hippocampique.Par ailleurs, la DBS à plus faible intensité (20 μA, 130 Hz) induit des effets pro-cognitifs, i.e. unefacilitation de la plasticité synaptique au sein de l’hippocampe dorsal et une amélioration desperformances mnésiques des rats dans le test de reconnaissance d’objet. De façon importante, ceseffets neurobiologiques sont prévenus par une lésion pharmacologique gliale avec la gliotoxine Lalpha-aminoadipic acid. Ensemble, nos données in vitro et in vivo soulignent pour la première fois lerôle crucial des astrocytes dans les mécanismes d’action de la DBS. Cette étude propose donc quel’intégrité du système glial au niveau le site de stimulation est un pré-requis majeur afin d’optimiserl’efficacité de la DBS / Deep brain stimulation (DBS) of the cingulated gyrus 25 is currently evaluated as a new therapy inpatients with treatment-resistant major depressive disorder. The effects of infralimbic prefrontal cortexDBS on several pre-clinical markers of the antidepressant-like response were assessed in rats toinvestigate the mechanisms underlying DBS action, and particularly, the putative involvement of glialsystem. The present study, using electrophysiological, immunohistochemical and behavioralapproaches, shows that acute DBS (130 Hz, 150 μA) induced an antidepressant-like behavior(evaluated in the forced-swim test) that was associated with an increase of dorsal raphe 5-HTneuronal activity and of dentate gyrus neurogenesis. Moreover, acute DBS was able to reverse theeffects of stress on hippocampal synaptic metaplasticity. Besides, DBS at lower intensity (20 μA, 130Hz) induced pro-cognitive effects, i.e. facilitated the hippocampal synaptic metaplasticity and improvedlearning performance in the novel object recognition task. Importantly, these neurobiological effects ofDBS were prevented by local pharmacological glial lesions with the L-alpha-aminoadipic acid gliotoxin.Taken together, our in and ex vivo findings highlights for the first time the crucial role of glial cells inthe mechanism of action of DBS. The present study, therefore, proposes that an unaltered glial systemwithin stimulation areas may constitute a major prerequisite to optimize DBS efficacy

The objective was to examine duloxetine 60–120mg/day treatment for relapse prevention in adults with generalized anxiety disorder (GAD). Adult patients (N=887; mean age=43.3 years; 61.0% female) with DSM-IV-TR-defined GAD diagnosis were treated with duloxetine for 26 weeks. Patients who completed open-label phase and were treatment responders (≥50% reduction in Hamilton Anxiety Rating Scale total score to ≤11 and “much”/“very much improved” ratings for the last 2 visits of open-label phase) were randomly assigned to receive duloxetine or placebo for a 26-week double-blind continuation phase. Relapse was defined as ≥2-point increase in illness severity ratings or by discontinuation due to lack of efficacy. During the double-blind phase, placebo-treated patients (N=201) relapsed more frequently (41.8%) than duloxetine-treated patients (13.7%, N=204, P≤0.001) and worsened on each outcome measure (P≤0.001, all comparisons). Duloxetine 60–120 mg/day treatment was efficacious and reduced risk of relapse in patients with GAD.

Psychotropic medication use is widely implicated as a risk factor for injuries, and it is believed that the adverse effect profiles of these medications are exacerbated by the consumption of alcohol. The objectives of this study are (a) to examine the associations between the use of specific classes of psychotropic medications and injuries among elderly participants of the National Population Health Survey (NPHS), and (b) to determine whether and how associations between psychotropic medications and injuries are modified by the consumption of alcohol. Data from Cycles 1 (1994/95), 2 (1996/97), and 3 (1998/99) of the NPHS household longitudinal file were used in this study, selecting community-dwelling participants aged 65 years of age and older in 1994/95. Among antidepressant medications, the magnitude of the risk of injuries was higher for users of tricyclic derivatives (OR=1.4; 95%CI: 0.7 – 2.9) than SSRIs (OR=0.3; 95%CI: 0.1 – 1.0). Benzodiazepine use for any indication increased the risk of injuries, but that effect was not consistent across indications. The use of benzodiazepine antianxiety medications resulted in an increased risk of injuries (OR=2.0; 95%CI: 1.3 – 3.1), but there were no significant effects on the injury risk among benzodiazepine hypnotic and sedative users (OR=0.8; 95%CI: 0.4 – 1.7). Results pertaining to the second objective of this study raised as many questions as they resolved. Alcohol consumption decreased the odds of injury among hypnotic and sedative users, but otherwise, no consistent results were observed. Findings from this study underscore the importance of identifying appropriate alcohol measures for research among elderly populations. They also stress the need to separately consider the impact of different classes of psychotropic medications on injuries (tricyclic antidepressants separate from SSRI antidepressants and antianxiety benzodiazepines separate from hypnotic and sedative benzodiazepines).

Psychotropic medication use is widely implicated as a risk factor for injuries, and it is believed that the adverse effect profiles of these medications are exacerbated by the consumption of alcohol. The objectives of this study are (a) to examine the associations between the use of specific classes of psychotropic medications and injuries among elderly participants of the National Population Health Survey (NPHS), and (b) to determine whether and how associations between psychotropic medications and injuries are modified by the consumption of alcohol. Data from Cycles 1 (1994/95), 2 (1996/97), and 3 (1998/99) of the NPHS household longitudinal file were used in this study, selecting community-dwelling participants aged 65 years of age and older in 1994/95. Among antidepressant medications, the magnitude of the risk of injuries was higher for users of tricyclic derivatives (OR=1.4; 95%CI: 0.7 – 2.9) than SSRIs (OR=0.3; 95%CI: 0.1 – 1.0). Benzodiazepine use for any indication increased the risk of injuries, but that effect was not consistent across indications. The use of benzodiazepine antianxiety medications resulted in an increased risk of injuries (OR=2.0; 95%CI: 1.3 – 3.1), but there were no significant effects on the injury risk among benzodiazepine hypnotic and sedative users (OR=0.8; 95%CI: 0.4 – 1.7). Results pertaining to the second objective of this study raised as many questions as they resolved. Alcohol consumption decreased the odds of injury among hypnotic and sedative users, but otherwise, no consistent results were observed. Findings from this study underscore the importance of identifying appropriate alcohol measures for research among elderly populations. They also stress the need to separately consider the impact of different classes of psychotropic medications on injuries (tricyclic antidepressants separate from SSRI antidepressants and antianxiety benzodiazepines separate from hypnotic and sedative benzodiazepines).

La non-observance représente souvent, dans la pratique clinique des professionnels de la santé, un défi à surmonter puisqu’elle est liée à une non-conformité du comportement du patient aux recommandations émises par les intervenants. Dans la région éloignée du Nunavik, divisée en 14 communautés inuit, les intervenants de la santé et des services sociaux, en raison de leur rôle élargi en première ligne, rencontrent une diversité de clientèles. La formation, l’expérience professionnelle, la perception de son rôle, le contexte de travail et le contexte socioculturel influencent l’interprétation des multiples défis au sein de la population. De hauts taux de suicide, d’alcoolisme et de violence sont présents dans les communautés inuit. La prescription des antidépresseurs est un moyen utilisé pour soulager les patients qui présentent des problèmes dépressifs. De quelle façon doit-on aborder ce phénomène complexe, et ce, dans ce contexte particulier de région autochtone éloignée? Cette recherche exploratoire descriptive vise à décrire et à interpréter le phénomène de non-observance des antidépresseurs, plus spécifiquement par l’étude des perceptions des intervenants de la santé et des services sociaux participant à l’intervention directe auprès des Inuit ayant reçu un diagnostic de dépression. L’analyse des 12 entrevues semi-dirigées répond à la question suivante : Quelles sont les perceptions des différents intervenants de la santé et des services sociaux sur le phénomène de la non-observance de la prise d’antidépresseurs chez les Inuit du Nunavik? Les résultats permettent de prendre un recul sur un phénomène courant de la pratique clinique dans cette région spécifique. Ils mettent en lumière la complexité de la relation patient-intervenant, la fragilité de l’alliance thérapeutique et l’importance des interventions d’une équipe interdisciplinaire et interculturelle dans ce contexte de pratique. / In the context of health professionals’ clinical practice, non-compliance represents overcoming an important challenge as it is pertaining to the patient’s failure to comply with the recommendations made by care providers. Social service and health care providers, given their expanded professional role as front-line workers, deal with a diversified clientele in Nunavik, which is a remote area divided into 14 inuit communities. Training, professional experience, role perception, working environment as well as sociocultural context all constitute factors having an impact on the interpretation of the various issues within the population. Inuit communities are faced with high rates of suicide, alcoholism and violence. Indeed, the prescription of antidepressants may serves as a means to relieve patient presenting depressive symptoms from their distress. How should we address this complex phenomenon happening within the particular context of an Aboriginal remote area? This exploratory descriptive research is aimed at describing and interpreting the issue of non-compliance with antidepressants, in particular by the study of the perceptions of social service and health care providers involved in the outreach intervention towards inuit patients identified as depressive. The content of the twelve semi-structured interviews was subject to an analysis which answers the following question: What are the different social service and health care providers’ perceptions towards the issue of inuit patients’ non-compliance with the use of antidepressants in Nunavik? Results help take a step back at a common phenomenon arising in the clinical practice. They highlight the complexity of patient-provider relationship, the fragility of therapeutic alliance and the importance of effective interventions made by the interdisciplinary and cross-cultural team in this clinical practice framework.

Le trouble du déficit de l’attention avec ou sans hyperactivité (TDAH) est de plus en plus reconnu chez l'adulte. Les psychostimulants représentent la première ligne de traitement, mais ceux-ci ne sont parfois pas tolérés, peuvent être contrindiqués ou ne pas être efficaces. Les médicaments non stimulants constituent une alternative mais ont été insuffisamment explorés. Cette thèse présente un essai clinique randomisé contrôlé de 30 sujets souffrant de TDAH qui ont reçu soit la duloxétine 60 mg par jour ou le placebo pendant une période de 6 semaines. Le Conners’ Adult ADHD Rating Scale (CAARS) et le Clinical Global Impression scale (CGI) ont été utilisés pour mesurer la sévérité des symptômes et l'amélioration clinique. Le Hamilton Anxiety Rating Scale (HARS) et le Hamilton Depression Rating Scale (HDRS) ont été choisis pour vérifier l'impact sur la symptomatologie anxio-dépressive. Les résultats démontrent que les sujets ayant reçu la duloxétine avait un score au CGI-Severity (CGI-S) inférieur au groupe contrôle à 6 semaines de traitement et une amélioration plus importante au CGI-Improvement (CGI-I). Ce groupe démontre également des diminutions supérieures des scores à plusieurs sous-échelles du CAARS. Aucun effet n'a été observé sur le HARS et le HDRS. Le taux de retrait du bras duloxetine remet par contre en question la dose initiale choisie dans ce protocole. La duloxétine semble donc une option prometteuse dans le traitement du TDAH chez l'adulte et la réplication des données cliniques serait la prochaine étape pour confirmer ces résultats. / Attention-deficit/hyperactivity disorder (ADHD) is increasingly recognized in adults. Stimulants are first-line treatment options but can be ineffective, poorly tolerated or contraindicated in some patients. For these patients, non-stimulants can be an interesting option; however, this heterogeneous class has been insufficiently studied. This thesis presents the results of a pilot study. In this randomized controlled clinical trial, thirty adults with ADHD received either placebo or duloxetine 60 mg daily for 6 weeks. The Conners’ Adult ADHD Rating Scale (CAARS) and the Clinical Global Impression scale (CGI) were chosen to assess symptom severity and clinical improvement. The Hamilton Anxiety Rating Scale (HARS) and the Hamilton Depression Rating Scale (HDRS) were used to measure the effect on anxiety and depressive symptoms. In summary, the duloxetine group showed a lower score on CGI-Severity at week 6, greater improvement on CGI-Improvement and greater decreases on multiple subscales of the CAARS. There was no treatment group effect on HDRS or HARS scores. Tolerability was an issue with participants in the duloxetine group and the dose titration schedule chosen in this study should be revised. This is the first clinical trial of duloxetine in adults with ADHD. This medication seams to improve symptoms in this condition but further studies are required to replicate these findings in larger samples of ADHD adults.

Major depression is a devastating disease that affects up to 20% of world population and is classified today as a leading cause of disability-adjusted life years. Since late 50s with the serendipitous discovery of the first antidepressant agents, pathophysiology and therapeutics of depression are governed by the monoaminergic hypothesis. Monoaminergic-based treatment, although still in use today, was proven inefficient to treat a significant proportion of cases and presents a delayed onset of action. Recent research has unveiled an array of new mechanisms through which antidepressant medication helps restore neuronal plasticity and neurotransmission that is disrupted in mood disorders and in animal models of depression. Glutamatergic transmission, in particular AMPA receptor, and signal transduction cascades have been implicated both in antidepressant action and the pathophysiology of depression, as here and now regulators that mediate persistent changes. In this study, AMPA receptors positive modulators demonstrated antidepressant-like effects in a chronic model of depression and preliminary data suggest a faster onset of action than conventional antidepressants. The ERK/MAPK signaling pathway was also studied as a major integrator of synaptic plasticity modifications that links extracellular signals to gene expression regulation via its downstream molecular partners. We used a new class of inhibitors of the ERK pathway, whose design was based on the particular property of ERK to bind to its downstream targets via specific docking domains. A considerable amount of data provided evidence for an antidepressant action of selective inhibition of the ERK/Elk1 signaling complex in multiple animal models of depression. Overall, the findings of this work reveal novel, promising targets for the treatment of depression.

Patients with MDD demonstrate impairments in various components of affective processing, which are believed to persist in the remitted phase of the illness and are believed to underlie the vulnerability for future relapse. Despite advances in neuropsychiatry, the neuroanatomical site of action of various treatment modalities remains unclear, leaving clinicians without an algorithm to guide optimal treatment selection for individual patients. This thesis sought to characterize differences in brain activation during affective processing between MDD treatment responders (RS) and non-responders (NR) by combining clinical and neuroimaging variables in a repeat-measure functional magnetic resonance imaging (fMRI) investigation. We induced increases in positive and negative affect using visual stimuli under fMRI conditions in 21 MDD subjects and 18 healthy controls (HC). Based on previous neuroimaging investigations and preclinical animal data, we hypothesized that increased activation of the amygdala and the pregenual cingulate during negative affect induction (NAI), and decreased activity of the ventral striatum during positive affect induction (PAI), would differentiate ultimate NR from RS. Following the first scan, treatment with fluoxetine and olanzapine was initiated in the MDD group, with follow-up scans at one- and six-weeks thereafter. We hypothesized that decreases in depressive symptoms would be associated with decreased activation of the ventromedial prefrontal cortex (PFC) and amygdala during NAI and increased activation of the hippocampus during PAI. Eleven MDD subjects met criteria for clinical remission at study endpoint. Based on trait differences between MDD and HC, we hypothesized that differences observed during NAI would be limited to brain regions involved in regulation of the affective state, including the dorsolateral PFC and the anterior midcingulate cortex. The results of the analyses confirmed the a-prior hypotheses and additionally demonstrated differential activation of the insular, medial temporal, and premotor cortex during repeat PAI and NAI between HC, RS, and NR. These findings provide: i) a neuroanatomical target of successful antidepressant therapy during PAI/NAI; ii) a differential effect of depressive symptoms and dispositional affect on brain activation during PAI/NAI; and iii) an a-prior method to differentiate RS from NR, and iv) demonstrate the need for additional treatment to prevent relapse in the remitted state.

No description available.

Depression is common in haemodialysis (HD) patients and is often unrecognised and undertreated, though associated with excess morbidity and mortality. Diagnosis is challenging due to symptom overlap with kidney failure, with fatigue being the most common overlapping symptom. Research on the effectiveness of antidepressant medication in this setting is sparse. A recent systematic review advocated well-designed Randomised Controlled Trials (RCTs) in this setting. The studies reported in this thesis had a number of aims. The main aim was to undertake a multicentre feasibility randomised, double blind, placebo-controlled trial of sertraline in patients on HD with Major Depressive Disorder (MDD). To identify suitable patients for this, a screening phase was required, which also allowed determination of the prevalence of depression in this setting and of the relative effectiveness of screening tools Patient Health Questionnaire-2 (PHQ-2), Patient Health Questionnaire-9 (PHQ-9), and Beck Depression Inventory-II (BDI-II). It also allowed examination of the relationships of fatigue in this setting (assessed mainly by the Multidimensional Fatigue Inventory (MFI), including those with a diagnosis, and management of depression. The finding, during screening, that a large proportion of the HD cohort was already on antidepressant treatment, presented the opportunity to study 'real-life' practice patterns in the management of antidepressant treatment in this setting. Recruitment into the RCT was difficult. 1,355 patients in five HD centres were considered for screening, but 243 of these were excluded, mainly because of their inability to read and understand English. Of the remaining 1,110 patients, 709 consented to screening. 231 of these screened positive for high depression symptoms but 130 were not considered for the trial phase, mainly because of concurrent treatment for depression (68 patients), and other contraindicated conditions and medication. In addition, 38 patients declined to take part in the psychiatric interview necessary for diagnosis of MDD. Of the 63 who underwent the diagnostic interview, 37 (58.7%) were diagnosed with MDD and 30 consented to enter the RCT and were randomised into sertraline or placebo groups. This was half of the anticipated recruitment into the RCT. Twenty-one patients (70%) completed the six-month study, eight of 15 in the sertraline group and 13 of 15 in the placebo group (p < 0.05). Drop out was mainly due to adverse or serious adverse events. Depression scores (BDI-II and Montgomery-Åsberg Depression Rating Scale (MADRS)) improved significantly in both the sertraline and placebo groups over six months but there were no significant differences between the treatment groups. There was a slight suggestion of more rapid improvement over the first two months on sertraline, but this was not significant. Fatigue scores were high in all sub-domains - with only a weak relationship with age and comorbidity. Mental fatigue was the strongest independent predictor of high depressive symptoms (BDI-II ≥16, PHQ-9 ≥8), while physical fatigue had the strongest relationship with dialysis recovery time, and survival. Distinguishing between these components of fatigue may have a role in refining the diagnosis and management of MDD. Forty-one of the 76 patients on antidepressant medication at screening were followed up for a mean of 14±5 months. Ten different antidepressant agents were being taken - the most common being Citalopram (39%). Most had been prescribed by GPs. Two-thirds of patients either deteriorated or failed to improve in terms of BDI-II scores during follow-up, many of whom had had no adjustment of medication during this time. Diagnostic evaluation at follow-up showed 37% to be suffering from current or recurrent major depressive episodes (MDE), 48% to have evidence of past MDE, and 15% to have no evidence of ever having been depressed. These empirical studies confirm that depression is very common in HD patients. Its diagnosis is complicated due to symptom overlap with the uraemic syndrome. Fatigue seems to be a key area of overlap with symptoms of depression with a complex relationship. There was no obvious benefit from antidepressants in this feasibility RCT and there was a high drop-out rate due to adverse events, particularly in the sertraline group. These findings raise concerns about the benefits and risks of antidepressants in patients on HD. Current practice patterns may be subjecting patients to substantial risk for little or no benefit. Identifying whether antidepressant medication is effective in this context is a major clinical need, hence the requirement for a definitive study. There is no doubt that to undertake a definitive study would pose considerable recruitment challenges. The findings presented here emphasise the importance of finding ways to overcome these challenges that might include efforts to incorporate patients already taking antidepressants.