Depression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the... Show moreDepression involves multiple mental problems, including low mood, inability to experience pleasure and emotional, cognitive and behavioral problems. It has a lifetime prevalence of ~15% in the Dutch population, striking women twice as often as men. The disorder often comprises persisting disturbances in the neuroendocrine stress system, the hypothalamic- pituitary-adrenal (HPA) axis, including disregulation of its end-hormone cortisol. Cortisol normally stimulates emotional, cognitive and behavioral processes in order to cope with a stressor and promotes recovery, learning and memory. This thesis describes the identification of a specific genetic variant of the mineralocorticoid receptor (MR), one of the two receptors for cortisol, which protects against depression. MR transcript expression was found to be lower in postmortem limbic brain regions of depressed patients compared to non-depressed subjects. In addition, a specific and common MR gene variant was identified that results in higher MR expression in vitro. This same variant was found to associate with personality characteristics that predict the risk of depression later in life and with a lower risk of depression itself. All associations were found only in women and not in men. To conclude, the MR is an important determinant of resilience; increased MR expression seems to be protective against depression. Show less
Background: It is assumed that the endogenous subtype of depression is a form of depression with various biological abnormalities and a genetic predisposition. The clinical picture rarely shows... Show moreBackground: It is assumed that the endogenous subtype of depression is a form of depression with various biological abnormalities and a genetic predisposition. The clinical picture rarely shows prior stress and/or an abnormal personality. According to the DSM-IV, this subtype is reproduced as the melancholic subtype, but this subtype has insufficient external validity. This is mainly due to the specific operational method used in the categorical DSM system. Question: Reformulating the melancholic subtype by means of a multidimensional approach. This would be formulated and tested on different external validity levels, which should result in better external validity. An improvement at one level of investigation could lead to improvements in relation to other levels, and vice versa. The development of diagnostic concepts could therefore progress according to a cyclic validation process. For this reason, we also investigated whether a later-found subgroup with above-normal plasma AVP could be a more useful endophenotypic parameter as well. This subtype was also tested on different external validation levels. Results: We found a two-dimensionally based, highly anxious retarded subcategory, with better external validation criteria than the melancholic subtype. We also found a second subtype, namely above normal AVP depression, that also had better external validation criteria. Show less
To fail or not to fail __ Clinical trials in depression investigates the causes of the high failure rate of clinical trials in depression research. Apart from the difficulties in the search for new... Show moreTo fail or not to fail __ Clinical trials in depression investigates the causes of the high failure rate of clinical trials in depression research. Apart from the difficulties in the search for new antidepressants during drug discovery, faulty clinical trial designs hinder their evaluation during drug development. This thesis focuses on three important aspects of clinical trials in depression: clinical endpoints, data analysis and trial design-related factors. Show less
Arnold, Ingrid Antonette; Waal, Margaretha Wilhelmina Maria de 2006
De huisarts ziet veel patienten met onverklaarde lichamelijke klachten, vaak in combinatie met angst- en depressieve klachten. Dit proefschrift beschrijft de resultaten van een prevalentie studie... Show moreDe huisarts ziet veel patienten met onverklaarde lichamelijke klachten, vaak in combinatie met angst- en depressieve klachten. Dit proefschrift beschrijft de resultaten van een prevalentie studie met een prospectieve follow-up en een daarop volgende behandelstudie. De prevalentie van somatoforme stoornissen (DSM-IV) was 16,1%: één op de zes patienten die de huisarts bezoekt had tenminste zes maanden last van onverklaarde lichamelijk klachten met aanzienlijke beperkingen. De overlap met angst en depressie was substantieel en vergrootte de ernst van de ziektelast. Deze bevindingen onderstrepen het belang van een brede diagnostiek in de huisartspraktijk die zowel angst en depressie als somatoforme stoornissen omvat. Het aantal symptomen, zowel lichamelijk als psychisch, kan een nuttig instrument zijn bij het identificeren van de ernstigste patiënten. Het gegeven dat bijna driekwart van alle patiënten met een somatoforme stoornis langdurig klachten houdt impliceert een grote behoefte aan behandeling. In een gecontroleerde behandelstudie konden we echter niet aantonen dat een cognitief-gedragsmatige interventie volgens het gevolgenmodel door getrainde huisartsen effectiever was dan gebruikelijke zorg. Aangezien de behandelde patiënten vaak ernstige klachten hadden stellen de auteurs voor om een stapsgewijze behandelmethode te ontwikkelen zodat zowel kortdurende als chronische klachten goed aangepakt kunnen worden. Show less
