Over 16 million people in the US suffer from major depressive disorder (MDD) each year. Approximately 1/3rd of MDD patients (~5 million) obtain only partial remission or no benefit after trials with multiple drugs or drug combinations. Recently, Ordway and colleagues have reportedelevated levels of DNA oxidation and upregulated gene expression of the base excision repair enzyme poly(ADP-ribose) polymerase-1 (PARP1) in postmortem brain from donors who had MDD at the time of death, as compared to age-matched psychiatrically normal control donors. This study was designed to test whether an inhibitor of PARP, 3-aminobenzamide (3-AB), may be effective to alleviate depressive-like behaviors in a rodent model of treatment-resistant depression. Male rats were ip administered lipopolysaccharide (LPS;100ug/kg) daily for 28 days, and administered a chronic unpredictable stressor on each day. All rats were also administered saline, 3-AB (40 mg/kg), or the serotonin-reuptake inhibitor (SSRI) fluoxetine (trade name: Prozac; 10 mg/kg) on each day, approximately 30 min after LPS treatment. During the 28 day period of LPS treatment, animals were behaviorally tested 5 times on sucrose preference (a test of anhedonia). At the end of the 28 day period, rats were behaviorally tested on a test of acute stress, the Porsolt swim test. Results revealed that 3-AB alleviated anhedonia and the response to acute stress in the Porsolt swim test superior to the fluoxetine group, demonstrating the utility of a PARP inhibitor to alleviate depressive-like behavior in this model. In addition, fluoxetine produced a loss of weight which recovered over days, but not to control levels, and 3-AB did not produce this effect. This study shows that PARP inhibitors may be effective in treatment-resistant depression.

Although the link between androgens and depression is well established in adults, the effects of cofactors on this association are less clearly understood, particularly in youth. Epidemiological cohort study of adolescents in Dresden, Germany. Analyses comprised data of 985 individuals assessed at baseline and of 512 individuals at 1-year follow-up. We investigated multivariable regression models for cross-sectional and longitudinal associations of hair testosterone, dehydroepiandrosterone (DHEA), and their cortisol ratios with 12-month diagnoses of major depressive disorder (MDD) and MDD without any anxiety disorder assessed with standardized diagnostic interview (DIA-X-5), and with dimensional depression scores (PHQ-9, PROMIS), separately for males and females. The potential moderating effect of social support was determined. Cross-sectional analyses yielded inverse associations of testosterone and DHEA with MDD and MDD without any anxiety disorders in males. In cross-sectional and longitudinal analyses, baseline ratio cortisol/DHEA was significantly, inversely associated to PROMIS-depression in males. Only cross-sectional associations for ratio cortisol/DHEA and PROMIS-depression remained significant after Bonferroni-Holm correction. No robust associations were observed in female participants. Social support exerted no consistent moderating effect on the investigated association. The present observational cohort study showed no consistent association of hair androgen concentrations with depressive disorders in adolescents. However, findings provide some support for the association between the cortisol/DHEA ratio and depression in males. Longitudinal research designs in large samples are needed to understand the interplay between androgens, depression, and developmental and social factors in youth.

No description available.

No description available.

Previous research has revealed heterogeneity in outcome trajectories among individuals seeking psychotherapy. However, questions remain as to the number, nature, and predictors of these trajectories. Therefore, the present study had three aims: 1) to identify heterogeneous latent groups among treatment trajectories of 212 clients with major depressive disorder (MDD) seeking psychotherapy at a community mental health training clinic; 2) to identify significant associations between clinical and demographic variables and group membership; and 3) to identify correlations between trajectory shape and positive treatment outcome. Prior to treatment, participants provided demographic information and completed symptom severity ratings. Once in treatment, participants completed a self-report of distress via the Outcome Questionnaire (OQ-45) at every session. Growth mixture modeling was utilized to identify distinct patient subgroups based on outcome trajectories among the sample. Three distinct latent classes of treatment trajectory were identified, providing evidence of heterogeneity in treatment trajectories among individuals with MDD. Baseline distress, pre-treatment work problems, and sleep difficulties were found to be predictive of an individual's membership in a specific trajectory group. Finally, specific shapes of change, namely early response and sudden gains, were associated with positive treatment outcome. Findings from this study can be used to identify patients at risk for treatment failure, allowing clinicians to intervene earlier to enhance mid-treatment feedback and prognosis.

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

The main aim of the thesis was to measure antidepressant (AD) non-compliance, to determine which factors are closely associated with AD non-compliance and the consequences of prolonged AD non-compliance in the private health sector of South Africa. The empirical study followed an observational, prospective, cohort study using longitudinal medicine claims data provided by a nationally representative Pharmaceutical Benefit Management company (PBM) from 1 January 2006 to 31 December 2011. Failure to respond to AD treatment and achieving remission has severe neurobiological and clinical consequences. The clinical consequences include increased social and functional impairment, higher risk for recurrence and relapse of a depressive episode, a weak treatment outcome, significant increase in treatment cost, over-utilization of health care systems, and ultimately an increased suicide risk. However, the neurobiological consequences are much more far reaching. One of the more serious yet under-recognized neurobiological complications of AD non-compliance is the development of antidepressant discontinuation syndrome (ADS), which is the result of non-compliance or the abrupt discontinuation of AD treatment. Altered serotonergic dysfunction appears central to ADS so that how an antidepressant targets serotonin will determine its relative risk for inducing ADS and thereby affect later treatment outcome. Low ADS risk with agomelatine versus other antidepressants can be ascribed to its unique pharmacokinetic characteristics as well as its distinctive actions on serotonin, including melatonergic, monoaminergic and glutamatergic-nitrergic systems. After the first four months only 34% (n=12 397) of patients were compliant. What’s more a statistically significant association was found between active ingredient consumed and compliance (p < 0.0001). Only 26.2% of patients who received amitriptyline-containing products were complaint compared to 38.8% and 38.7% in the cases of venlafaxine and duloxetine, respectively. The current study found that females have a significantly higher prevalence of MDD and HIV/AIDS when compared to males. The co-morbidity between HIV/AIDS and major depressive disorder (MDD) had a significant effect on AD treatment compliance as patients diagnosed with both HIV/AIDS and MDD (74.43. ± 32.03, 95%Cl: 71.51-77.34) displayed a lower compliance vs. MDD patients (80.94% ± 29.44, 95%Cl: 80.56-81.33). Noteworthy, observations were that 75% (p < 0.0217; Cramer’s V = 0.0388) of venlafaxine and 28.6% (p < 0.0197; Cramer’s V = -0.0705) of the paroxetine items were compliant in patients diagnosed with both HIV/AIDS and MDD. The overall compliance (35.19% acceptable compliance; n = 42 869) of patients taking both ADs and GDs was weak. In the group receiving both AD and GDs, an increased AD treatment period was associated with a significant increase (p < 0.0001) in AD compliance (406.60 days; 95%Cl: 403.20 – 409.90 vs. 252.70 days; 95%Cl: 250.20 – 255.20). In this cohort amitriptyline (29.57%), mirtazapine (31.36%) and fluoxetine (32.29%) were associated with the lowest levels of compliance, while duloxetine (40.67%) was found to have the highest compliance. Lastly, ADs with highest non-compliance were associated with an increase use in GDs. Alprazolam (n = 10 201) and zolpidem (n = 9 312) were the most frequently dispensed GDs in combination with AD treatment. In conclusion the current study confirms that AD non-compliance is as big an obstacle in developing countries as it is in developed countries. Antidepressant treatment non-compliance has far reaching consequences especially with the development of ADS which further complicates MDD and might be a precursor for the development of TRD. Several factors were found to be closely associated with AD treatment non-compliance which include; pharmacological class of AD, gender, chronic co-morbid illnesses and a short treatment period. / PhD (Pharmacy Practice), North-West University, Potchefstroom Campus, 2015

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.

Objectifs: Malgré que les patients souffrant de dépression majeure (DM) rapportent souvent des symptômes douloureux, la relation entre la douleur et la dépression n’est pas encore claire. Ce n’est que récemment que des études employant des paradigmes de sommation temporelle ont pu offrir une explication préliminaire de la cooccurrence de la douleur et de la dépression. Notre étude vise à évaluer la contribution des procédés spinaux et surpraspinaux dans la sensibilisation de la douleur dans la DM en utilisant un paradigme de sommation temporelle. Participants : Treize sujets sains et quatorze patients souffrant de DM ont été inclues dans l’analyse finale. Méthodes : Pour induire une sommation temporelle, nous avons utilisé des stimulations intermittentes du nerf sural de basses et hautes fréquences. La sensibilisation spinale de la douleur a été quantifiée en mesurant la variation de l’amplitude du réflex de retrait nociceptif (NFR) entre les deux conditions de stimulations, ainsi que la sensibilisation supraspinale de la douleur a été obtenue en mesurant le changement dans l’appréciation verbale de la douleur entre ces deux conditions. Résultats : Nous avons observé une sensibilisation plus élevée de la réponse NFR chez les patients dépressifs durant la condition de stimulation à haute fréquence, un effet qui n’a pas été reflété par une sensibilisation amplifiée des appréciations subjectives de la douleur durant l’expérience. Néanmoins, nous avons observé une association entre la sensibilisation spinale et les symptômes somatiques douloureux chez les patients DM. Conclusion : Ces résultats suggèrent une sensibilisation spinale amplifiée dans la DM, ce qui pourrait expliquer la prévalence élevée des symptômes somatiques douloureux chez ces patients. / Objectives: Although patients suffering from major depressive disorder (MDD) often complain from painful symptoms, the relationship between pain and depression has yet to be clearly characterized. Only recently have studies employing temporal summation paradigms offered some preliminary insight into the co-occurrence of pain and depression. This study sets out to evaluate the contribution of spinal and supraspinal processes in pain sensitization in MDD using a temporal summation paradigm. Subjects: Thirteen healthy controls and fourteen MDD patients were included in the final analysis. Methods: To induce temporal summation, we used low- and high-frequency intermittent stimulations of the sural nerve. Spinal pain sensitization was quantified by measuring the change in the amplitude of the nociceptive-specific flexion reflex (NFR) response, and supraspinal pain sensitization was obtained by measuring change in subjective pain rating, from the low- to high-frequency stimulation condition. Results: We found an increased sensitization in the NFR response in MDD patients in the high-frequency condition, which did not translate into an increased amplification of their subjective responses during testing. However, we found a positive association between spinal sensitization and painful somatic symptoms in MDD patients. Conclusion: Together, these results suggest increased spinal pain sensitization in MDD, which might explain the high prevalence of painful somatic symptoms in these patients.

Plus de 150 millions de personnes souffrent de troubles dépressifs à travers le monde. Malgré le nombre croissant d’études s’intéressant à la physiopathologie de ce trouble, aucune amélioration majeure concernant ses traitements ou la compréhension des mécanismes biologiques sous-jacents n’a été faite. Bien qu’une prédisposition génétique et des évènements stressants aient été proposés comme facteurs de risque, ni les gènes impliqués ni le fonctionnement des interactions gène x environnement ne sont encore connus. Cela peut s’expliquer par le manque de modèles animaux satisfaisants et par le fossé existant entre les connaissances / méthodes de diagnostic appliquées en recherche clinique et celles disponibles en recherche fondamentale. Des manipulations pharmacologiques, lésionnelles, génétiques ou de l’environnement sont quasi exclusivement utilisées chez le rongeur. Certains primates non-humains (PNH), plus proches de nous sur les plans comportementaux et phylogénétiques, montrent pourtant, comme l’Homme, des modifications comportementales et physiologiques atypiques et spontanées en réponse à des conditions de vie stressantes. Malgré les travaux pionniers et prometteurs d’Harlow et de ses collaborateurs dans les années 60, rares sont les équipes qui étudient la dépression chez le macaque aujourd’hui. Nous avons émis l’hypothèse que parmi des grandes populations de PNH captifs, une petite proportion d’individus exprime des comportements atypiques pouvant s’apparenter à des symptômes dépressifs. Mon projet de thèse a eu pour but de proposer une approche novatrice et non invasive d’identification de ces profils « depressive-like » chez le macaque, en combinant les compétences et connaissances de l’éthologie, de la psychiatrie et des neurosciences. L’impact des expériences de vie précoces et de l’espèce a également été abordé. Les comportements, les postures et orientations du corps, les localisations spatiales, les regards et/ou les distances inter-individuelles ont été relevés chez plus de 200 macaques rhésus et cynomolgus d’élevage, nés en captivité ou dans la nature. Des sous-groupes d’individus ont été identifiés à l’aide d’analyses multifactorielles. Dans chaque population observée, un profil « depressive-like » a été mis en évidence par comparaison avec les symptômes décrits dans le Manuel Diagnostique et Statistiques des Troubles Mentaux et avec les modèles animaux existants dans la littérature. La prévalence de ces profils étant supérieure chez les macaques rhésus et chez les animaux nés en captivité, nos résultats concordent avec le rôle suggéré du stress dans l’expression des troubles dépressifs. En plus d’exprimer ce profil comportemental atypique dans leur environnement habituel, les singes « depressive-like » présentaient une réactivité émotionnelle altérée au cours 2 tests comportementaux, associée à des taux élevés de cortisol plasmatique et noradrénaline cérébro-spinale. Pris dans leur ensemble, ces résultats prometteurs confèrent une bonne validité de représentation à notre modèle macaque de symptômes dépressifs. Une caractérisation plus complète de ce modèle est bien sûr nécessaire et pourrait ouvrir de nouvelles perspectives quant à la compréhension de l’étiologie et de la physiopathologie des troubles dépressifs. / More than 150 million people worldwide suffer from major depressive disorder (MDD). Although investigations of its pathophysiology have dramatically increased in the last decade, no substantial improvement has been made concerning the treatments and the understanding of its underlying mechanisms. A genetic predisposition and stressful experiences have been acknowledged as risk factors involved in MDD. However, no specific genes have been identified so far and little is known about the gene x environment interactions. This is likely due to the lack of bona fide animal models of depressive-like symptoms. Indeed, there is a huge gap between the knowledge / diagnostic methodology of clinical research and the animal models used in fundamental research, mainly focusing on environmental, pharmacological, lesional or genetic manipulations. Phylogenetically and behaviourally closer to Humans compared to rodents, non-human primates (NHPs) can show spontaneous behavioural and physiological modifications in response to stressful life events. Although promising results had been reported in the 1960’s by the pioneering studies of Harlow and colleagues, the investigation of depressive-like symptoms in macaques are scarce in the current literature. We hypothesize that, among large captive NHP populations, a few individuals will display atypical behaviours that could mimic depressive symptoms. Combining the skills and knowledge of ethology, psychiatry and neurosciences, my PhD project aimed at proposing an innovative non-invasive detection method of such depressive-like profiles. The impact of birth origin and species was questioned as well. Behaviours, body postures, body orientations, spatial location, gaze direction and/or inter-peer distances were collected among more than 200 rhesus and cynomolgus captive- or wild-born farm-bred macaques. Using multifactorial analyses, clusters of individuals displaying distinct behavioural profiles were identified. In each population, a common depressive-like profile was characterised by its similarities with symptoms described in the Diagnostic and Statistical Manual of Mental Disorder and with other animal models of depression. The prevalence of such profiles was increased in the rhesus populations and by captive early life experience, corroborating the role of stress in the development of MDD. In addition to expressing depressive-like features in their home cage, these animals displayed higher levels of plasmatic cortisol and cerebrospinal noradrenaline which correlated with a passive emotional reactivity in 2 behavioural paradigms. Altogether these promising results conferred good face validity to our NHP model of depressive-like symptoms. Further characterization of this model is required and might bring new insights to the understanding of MDD pathophysiology and etiology.