In this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM),... Show moreIn this dissertation clinical genetic investigations on migraine, related syndromes and comorbid conditions are described. The first migraine syndrome studied is Familial Hemiplegic Migraine (FHM), a monogenic migraine variant. The clinical spectrum of FHM1-3 and the relation with closely related diseases such as Alternating hemiplegia of Chilhood, Early Seizures and Cerebral Edema after Trivial Head Trauma, epilepsy and episodic ataxia were investigated. The second monogenic migraine syndrome studied is Retinal Vasculopathy with Cerebral Leukodystrophy (later renamed CHARIOT), where common migraine is part of the clinical spectrum. The identification of TREX1 as the causal gene for RVCL is described. Investigation of the clinical spectrum showed retinal, cerebral and internal organ involvement, without an apparent genotype-phenotype correlation. Endothelial dysfunction of large arteries was shown in RVCL patients and is proposed as a possible disease mechanism. Lastly, migraine patients were identified in a Dutch genetic isolate and the relation with depression and atherosclerosis was assessed. For depression it was shown that shared genetic factors, at least partly, underlie the comorbidity with migraine, in particular migraine with aura. These studies improve our insight in genetic factors and pathofysiological mechanisms involved in migraine, which may ultimately contribute to better treatment options for migraine patients Show less
The primary aim of the NormQuest study described in this thesis was to generate evidencebased, reference values for 19 self-report and observational questionnaires. The focus was on questionnaires... Show moreThe primary aim of the NormQuest study described in this thesis was to generate evidencebased, reference values for 19 self-report and observational questionnaires. The focus was on questionnaires measuring mood, anxiety, and somatoform (MAS) disorders used in Routine Outcome Monitoring (ROM). The set of cut-off values of the ROM reference group (__healthy__) can be used in specialized mental health care by therapists to support the decision whether a patient is sufficiently recovered to be considered as a member of the healthy population, and no longer as a member of the patient population. These reference values are suitable as decision support for referral back to primary care physicians. Additionally, the set of the ROM patient group (__clinically ill__) cut-off values can be used by primary care physicians as decision support for referral to the specialized mental health care. To allow determination of cut-off points for skewed distributions, percentile scores were used. In addition, we assessed the discriminative power of the questionnaire scores by means of Receiver Operating Characteristics (ROC) analyses. Finally, we calculated reference values in separate strata of gender and age. The secondary aim of the NormQuest study concerned the need for the development of public domain questionnaires. In the NormQuest study, the generic Symptom Questionnaire-48 (SQ-48), aimed at broad applicability in patients with MAS disorders, was developed. Also, for the SQ-48 reference values were calculated Show less
Research into the relation between psychopathology and etiological factors has not yet resulted in clear findings. One of the probable causes is that most researchers use the categorical DSM-IV... Show moreResearch into the relation between psychopathology and etiological factors has not yet resulted in clear findings. One of the probable causes is that most researchers use the categorical DSM-IV Classification of mental disorders. A dimensional system has several advantages compared to categorical systems: comorbidity, lack of diagnostic agreement and arbitrary nature of used boundaries are no longer a problem. Our aim was to develop a model with dimensions that can adequately describe patients with mood- and anxiety disorders. This project used data collected through Routine Outcome Monitoring (ROM), a monitoring system for patient care. First, we validated a Dutch adaptation of an instrument based on the tripartite model. Next, we formulated an extension of this model with 5 dimensions. Consequently we presented a second model with 6 dimensions: feelings of worthlessness, fatigue, somatic arousal, anxious apprehension, phobic fear and tension. We used several analysis techniques to create a valid and reliable dimensional model. Each individual factor and the total of factors can be regarded as unidimensional measurement scales. This model can describe the clinical state of patients more specifically than the tripartite model, and can be used in subsequent research into etiological factors of psychopathology (e.g. endophenotype, genotype, trauma's, personality). Show less
When a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood... Show moreWhen a child is often scolded or threatened by his parents (emotional abuse) and /or when a child is structurally ignored or isolated by his parents (emotional neglect) we call this childhood emotional maltreatment (CEM). CEM is the most common form of child abuse, however, CEM is also the most hidden, underreported and least studied form of child abuse. An important reason for this may be because that the consequences of CEM are underestimated (e.g. __Sticks and Stones may break bones, but words will never hurt me__). However, this thesis shows that CEM is related with a persistent negative impact on cognition and the brain. We discovered that individuals that report CEM show differential structure and function of a brain area (the medial prefrontal cortex) that is crucial for role in responding to stress and thinking about yourself. Individuals with CEM also showed more activity in an area that signals threat (the amygdala) which may represent a persistent vigilance towards the detection of threat from others. These brain changes may underlie our other findings that individuals with CEM think more negatively about themselves and others. Negative thoughts can evoke negative thoughts and in new situations, which reinforces more negative memories. Due to this process, emotionally abused individuals may be more vulnerable to develop a depressive and/or anxiety disorder. Our findings warrant scientific and policital investments to increase societal awareness about the detrimental impact of CEM on cognition and the brain. Increased societal knowledge will hopefully lead to better awareness, reports, and subsequent interventions for individuals with CEM. Show less
Het boek is een biografie van Karl Abraham (1877-1925), de eerste psychoanalyticus van Duitsland, waar hij de psychoanalyse tot grote bloei heeft gebracht. Zijn klinisch-theoretische bijdragen... Show moreHet boek is een biografie van Karl Abraham (1877-1925), de eerste psychoanalyticus van Duitsland, waar hij de psychoanalyse tot grote bloei heeft gebracht. Zijn klinisch-theoretische bijdragen werden al snel klassiekers die veel invloed hebben gehad op de psychoanalytische theorievorming. Hij was de eerste die een psychoanalytische theorie over depressie ontwierp, enkele jaren voor Freuds 'Trauer und Melancholie' zou verschijnen. Abraham was de laatste jaren van zijn leven na Freud de belangrijkste analyticus van de psychoanalytische beweging, voorzitter van de IPA - International Psychoanalytic Association, voorzitter van de Berlijnse psychoanalytische vereniging en lid van het geheime comit_. Hij is betrokken geweest bij een aantal grote conflicten die zich in de beginjaren van de psychoanalyse hebben afgespeeld, waarbij postuum de schuld nogal eens naar hem is geschoven. Zo kon het gebeuren dat Abraham, tijdens zijn leven zo gewaardeerd, na zijn dood regelmatig werd verguisd. Show less
The main objective of this thesis is to describe the epidemiology of long term BZD use as well as its long term consequences. This thesis is structured into three sections: In section one, the... Show moreThe main objective of this thesis is to describe the epidemiology of long term BZD use as well as its long term consequences. This thesis is structured into three sections: In section one, the correlates of BZD use, new use, chronic use, inappropriate use, and BZD dependence severity are investigated. The possible influence of the prescribing physicians on patient BZD use is also considered. In section two, the focus is on the physiological consequences of long-term BZDs use on the HPA axis and the ANS. In section three, cognitive effects of BZDs in long-term users are addressed Show less
The aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our... Show moreThe aim of this thesis was to clarify which aspects of depression and anxiety are related to an increased metabolic risk, and which factors contribute to these associations. Taken together, our findings indicate that people with more severe symptoms of depression and anxiety are at particular risk of progressive dyslipidemia and (abdominal) obesity. The higher rates of smoking and systemic inflammation among people with depression or anxiety partially accounted for their adverse metabolic profile. Dysregulations of the autonomic nervous system partly explained why users of tricyclic antidepressants displayed an increased risk of dyslipidemia and (abdominal) obesity as well, and also of hypertension. These important findings shed light on useful avenues for future research, and on preventive and therapeutic insights and directions. Show less
There is a growing awareness that research of the etiology of depressive and anxiety disorders has been hampered by their strictly categorical definition in the Diagnostic and Statistical Manual ... Show moreThere is a growing awareness that research of the etiology of depressive and anxiety disorders has been hampered by their strictly categorical definition in the Diagnostic and Statistical Manual (DSM). The DSM uses a syndrome approach, which __ although beneficial for standardization - has inherent problems that make it suboptimal for research: high rates of (artificial) comorbidity, diagnostic heterogeneity and the unrealistic assumption of discontinuity between ill and healthy. A dimensional approach that focusses on the relative severity of continuous symptom domains could be more optimal but measurement and the added value of such dimensions has been debated. Therefore, this dissertation was aimed to investigate (1) the internal validity and possibility to measure dimensions and (2) their added value in etiological and clinical research. The results showed that measurement of dimensions can be optimized using self-report questionnaires. In addition, dimensions were shown to have added value in etiological and clinical research. Because of their specific and continuous nature, dimensions could be used to uncover symptom-specific and/or non-linear association. Together, the results suggest that dimensions of depression and anxiety have internal and external validity and have the potential to improve the psychiatric research. Show less
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
In Chapter 2, results of a study are reported in which remitted depressed patients are compared to healthy controls to investigate possible residual cognitive impairments that persist into the... Show moreIn Chapter 2, results of a study are reported in which remitted depressed patients are compared to healthy controls to investigate possible residual cognitive impairments that persist into the euthymic phase. Chapter 3 will describe the effects of an alpha-lactalbumin enriched diet on cognitive performance in unmedicated recovered depressed patients and healthy controls. In Chapter 4 the effects of alpha-lactalbumin on mood and stress-induced cortisol response in unmedicated recovered depressed patients and healthy controls are reported. Chapter 5 describes the effects of low-dose and high-dose ATD on mood and neutral as well as emotional information processing in medicated remitted depressed patients. In Chapter 6, the effects of low-dose and high-dose tryptophan depletion on individual plasma tryptophan levels and the ratio tryptophan/LNAA will be discussed. In Chapter 7 the effects of ATD on heart rate variability in medicated remitted depressed patients are reported. A literature overview of studies investigating the effects of serotonin manipulations on emotional information processing and mood is given in Chapter 8. Also, evidence for a possible sequential link between serotonin induced changes in emotional information processing and mood is evaluated. Chapter 9 contains a summary and integration of the main findings, as well as methodological strengths and limitations, directions for future research and clinical implications of the findings reported in this thesis Show less
