General Information

Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF

1. Algemene gegevens / General Information Projecttitel / Project title HPA axis dysfunction and common mental disorders: To whom does it concern? Aanvrager / Applicant Drs. B Verhoeff T: 0642308172 F: E: [email protected] GGZ Buitenamstel Postbus 75902 1070 AX AMSTERDAM Projectleden / Project members Dr. RH de Rijk (Begeleider) T: 0715269111 F: E: Leiden/Amsterdam Center for Drug Research

Department of Pharmacology Postbus 9503 2300 RA LEIDEN Nederland Prof. dr. ATF Beekman (Begeleider) T: 0205736666 F: E: GGZ Buitenamstel

Psychiatrie Valeriusplein 9 1075 BG AMSTERDAM Nederland Prof. dr. WJG Hoogendijk (Promotor) T: 0205736666 F: E: GGZ Buitenamstel/VUMC

Aangemaakt door ProjectNet / Generated by ProjectNet: 29-08-2005 16:56

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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF

Psychiatrie Valeriusplein 9 1075 BG AMSTERDAM Nederland Prof. dr. FG Zitman (Promotor) T: 0715269111 F: E: Leids Universitair Medisch Centrum

Divisie 3 Psychiatrie Postbus 9600 2300 RC LEIDEN Nederland Prof. dr. R van Dyck (Bestuurlijk verantwoordelijke) T: 0205736666 F: E: GGZ Buitenamstel

Psychiatrie Valeriusplein 9 1075 BG AMSTERDAM Nederland Dr. BWJH Penninx (Projectleider en penvoerder) T: 0205736437 F: 0205736664 E: GGZ Buitenamstel

Psychiatrie Valeriusplein 9 1075 BG AMSTERDAM Nederland

Samenwerking / Collaboration Universitair Medisch Centrum Groningen Psychiatrie Postbus 30001


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF 9700 RB GRONINGEN VU medisch centrum Psychiatrie Postbus 7057 1007 MB AMSTERDAM Trimbos Instituut Postbus 725 3500 AS UTRECHT Leids Universitair Medisch Centrum Divisie 3 Psychiatrie Postbus 9600 2300 RC LEIDEN Universitair Medisch Centrum St. Radboud Werkgroep Onderzoek Kwaliteit 229 KWAZO Postbus 9101 6500 HB NIJMEGEN NIVEL Postbus 1568 3500 BN UTRECHT Rivierduinen Postbus 750 2300 AT LEIDEN

2. Projectgegevens / Project information Programma / Programme Opleiding Onderzoekers GGZ (OOG)

Subsidieronde / Subsidy round uitgewerkte aanvraag GGZ (OOG), derde ronde


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Datum indienen (via ProjectNet) / Date of application 29-08-2005 16:55 Aandachtsgebieden / Focus Doelgroep: Mensen bij de aandoening chronisch verloopt; Inhoudelijk thema: Stemmingstoornissen; Angsstoornissen; Projecttype / Project type Onderzoeksproject Samenvatting / Summary Depression and anxiety are common and often chronic disorders that also affect somatic health. Consequently, depression and anxiety are promising candidates for efforts to improve public health. To gain insight into which patients benefit from what types of interventions it is essential to understand more about the pathophysiological basis of depression and anxiety. There is a general belief that hyperactivity of the hypothalamus-pituitary-adrenal axis (HPA-axis) is associated with depression and anxiety disorders, but not all depressed and anxious patients do present hyperactivity of the HPA-axis. Although there is evidence that specific clinical aspects, genetic factors, and exposure to trauma in the past, may be important determinants of HPA-axis function, there is a lack of systematic research that explores the relative contribution of these factors to dysregulation of the HPA-axis. This study examines in a large cohort with ranging psychopathology what the relative contribution of clinical aspects, trauma exposure and genetic factors is to HPA-axis hyperactivity. In addition, the study examines the predictive validity of HPA-axis for the 2-year onset and course of anxiety and depression disorders. It is our ultimate goal that this project results in a clear indication whether and for whom endocrine measures indicating HPA-axis hyperactivity (possibly in combination with clinical characteristics, trauma exposure and genetic aspects) identify patients with an increased risk of (continuation to) depression and anxiety disorders. The specific research questions that will be addressed are: A1. What is the specific contribution of 1) past trauma exposure, 2) clinical aspects (severity, duration and type of symptoms), and 3) polymorphisms in HPA-axis regulating genes, to HPA-axis hyperactivity? A2. Do these three variable groups interact in their contribution to HPA-axis hyperactivity? B1. What is the predictive value of HPA-axis hyperactivity for the 2-year incidence of depression and anxiety disorders among persons without an initial diagnosis? B2. Is this predictive value uniform, or are there certain groups of persons (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? C1. What is the predictive value of altered HPA-axis activity of the 2-year course of depression and anxiety disorders among patients? C2. Is this predictive value uniform, or are there certain groups of patients (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? The proposed study will be conducted using already collected data from the Netherlands Study of Depression and Anxiety (NESDA), a longitudinal cohort study of 2,850 persons with a range of psychopathology (no diagnosis, subthreshold symptoms, major depression, dysthymia, generalized anxiety disorder, social phobia or panic disorder). The presence of depression and anxiety is assessed


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF using the CIDI interview, and symptomatology, severity and psychiatric history by validated questionnaires at baseline and after 1 and 2 years. The HPA-axis function is determined by cortisol concentration in seven saliva samples collected per respondent which includes a dexamethason suppression test. Questions regarding the incidence of depression and anxiety disorders will be addressed among 1100 participants at increased risk, but without a current psychiatric disorder, whereas questions regarding the course of depression and anxiety disorders will be addressed among the 1750 participants with an depression or anxiety disorder at baseline. The present project will provide data that may influence the ongoing scientific and clinical debate on whether and for which patients, hyperactivity of the HPA-axis may be of concern. In addition, through the results we hope to be able to more accurately predict, on the basis of endocrine measures of HPA-axis and possibly in combination with clinical aspects, trauma exposure and genetic characteristics, which patients have an increased risk of onset or relapse to depression or anxiety disorders. This provides us clearer evidence-based indicators for patient groups that may need specific preventative actions. It also may provide a rationale for the further development and the specific allocation of drugs that are presently being tested by various pharmaceutical companies (e.g. glucocorticoid receptor modulators or CRH receptor-antagonists). Through participation in the NESDA study, the applicant will be given an excellent and both cost- and time-efficient opportunity to build substantial research experience. The research trajectory will be guided by a group of experienced researchers in the field as well as by clinical professionals, which will enable optimal translation of research findings into practical implications.

3. Inhoud / Content Probleemstelling / Problem definition A central question is why some individuals develop psychopathology while others stay healthy following an encounter with a stressor. Central in the response of the organism to the stressor is the activation of corticotrophic releasing hormone (CRH)-systems, which induces changes in behavior including arousal and anxiety. Next, in synergy with vasopressine (AVP), CRH activates the hypothalamus-pituitary-adrenal (HPA)-axis leading to increases in plasma cortisol.(1;2) Cortisol feeds back on the brain not only to inhibit HPA-axis activity and to contain stressor-induced activations, but also to optimize behavioral responses to the stressor. The effects of cortisol are mediated by two central corticosteroid receptors, the high affinity mineralocorticoid receptor (MR) and the low affinity glucocorticoid receptor (GR). These receptors are located at high levels in limbic regions involved in behavior. Cortisol, by binding at the GR and MR, regulates not only CRH and AVP expression, but also strongly modifies the effects of serotonergic and noradrenergic neurotransmission.(3) How dysregulation of the HPA-axis is involved in the aetiology and course of psychopathology is a central theme of this project. An altered regulation of the HPA-axis has been described in various studies among patients suffering from panic attacks, affective or anxiety-related disorders.(4-7) These studies have found either elevated basal cortisol levels in the evening, an excess of cortisol after awakening in the morning or an associated finding of non-suppression to a dexamethasone suppression test. In addition, application of the combined Dex-CRH test revealed that 80 to 90% of depressed patients show a hyper-reactivity of the HPA-axis.(8) Hyperactivity of the HPA-axis can be caused by either a CRH overdrive, an increased sensitivity of the adrenal glands to adrenocorticotrophic hormone (ACTH), or a blunted feedback control at the level of the hippocampus, hypothalamus or pituitary gland.(9) Moreover, recent genetic research indicates that modification of GR-function is associated with depression and treatment-efficacy.(10) Finally, targeting the GR directly by usage of a GR-antagonist, seems to be very effective in the treatment of psychotic depression,(11) while trials are being conducted to test the efficacy of CRH and


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF AVP antagonists. Nevertheless, the association between HPA-axis activity and psychopathology is not always consistent, and clearly not all patients do demonstrate HPA-axis hyperactivity. The roles of type of psychopathology (major depression, dysthymia, GAD, panic disorder, social phobia), severity and duration (first versus recurrent episode, long versus short duration) in respect to HPA axis dysfunction are still unclear since they have not been explored in detail. Moreover, experience of early life events is one of the probable causes of hyperactivity of the HPA axis (12) and therefore the personal history may be a unique important determinant of HPA-axis dysfunction among persons with common mental disorders. Furthermore, very recently genetic polymorphisms in corticosteroid receptors have been described which affect HPA-axis regulation (13-15) which suggests that genetic factors may have an important impact on the presence of HPA-axis alterations. In sum, clinical aspects, trauma exposure in the past and genetic factors all may be important determinants of HPA axis alterations, but their relative importance for depressed and anxious patients is still undecided. Our proposed study will contribute important results that will provide us more insight into the contribution of clinical factors, trauma exposure and genetic factors to hyperactivity of the HPA-axis among persons with (or at risk for) depression and anxiety disorders. Another important flaw in the current research is the lack of longitudinal data. Only a few studies have indicated that abnormalities in HPA-axis function in depressed or anxious patients may indicate a high risk of relapse (16-19), and study findings are not always consistent. Moreover, dysfunction of the HPA-axis is probably not only involved in the onset but also in the continuation of affective disorders. This proposed study will fill several gaps in our knowledge by examining the importance of HPA-axis hyperactivity for the onset and (chronic) continuation of anxiety and depression disorders. For this purpose we will use 2-year longitudinal data from a large study that examined 2850 participants with ranging psychopathology. Relevantie / Relevance The human benefits and societial relevance of the present project are that its outcome will be important in understanding and treating depression and anxiety disorders. According to the World Health Organisation (WHO) idiopathic depression will be one of the most important medical disorders of the 21st century in terms of morbidity, mortality and healthcare costs. (18) The comorbidity between depression and anxiety disorders is large (approx. 50%). Both conditions are common and have mental as well as somatic health consequences. Therefore, they are promising candidates for efforts to improve public health. In addition, their high recurrence rates and chronic course emphasize the relevance of prevention. The primary aim of treatment is to change the natural history of a disorder. Sound knowledge on factors predicting the outcome are necessary to be able to tailor treatment, for the implementation of stepped-care type treatment strategies and to reach sustained cooperation of the patient with treatment. For this work, depression and anxiety need to be studied in concert, over longer periods. To gain the necessary insight into which patients benefit from which interventions, it is essential to understand more about the pathophysiological basis of depression and anxiety. There is still controversy about the importance of the HPA axis and for whom it is important. The present study can provide important data in this area from a large sample of 2850 persons with a range of psychopathology. This can really influence the ongoing scientific debate about the relative importance of the HPA-axis in anxiety are important and for which types of patient in particular this plays a role. The present project may provide data to more accurately predict, on the basis of endocrine measures (that indicate HPA-axis activity) in combination with clinical aspects, psychosocial (events) assessments and the presence of specific genetic markers, which patients have an increased risk of onset or relapse to depression or anxiety disorders. This provides us clear indicators for patient groups that may need specific preventative actions. It also may also provide a rationale for the further development of specific


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF drugs that are presently being tested by various pharmaceutical companies (e.g. glucocorticoid receptor modulators or CRH receptor-antagonists). For example, if cortisol level in saliva or certain polymorphisms in genes important for HPA-axis function turn out to be relevant predictors for the course and prognoses of affective disorders, these biological and genetic markers can be useful diagnostic tools for general practitioners or psychiatrists. In the further future, it may then be possible to make therapy more specific and it will make the choice between different interventions like medication, psychotherapy or psychosocial support more rational and evidence based. Kennisoverdracht, implementatie, bestendiging / Knowledge transfer, implementation, consolidation In order to ensure optimal transfer of knowledge from scientific research into mental health care, close collaboration of different partners (academic and non-academic researchers, mental health care professionals) is required. Therefore, the NESDA-consortium has been established, which is a collaboration between universities, research centres (Trimbos, Nivel, WOK) and mental health care institutions. The proposed study and the applicant will be embedded in the NESDA study and its consortium. This embedding guarantees that the applicant has adequate access to the various resources and expertise needed for communicating, implementing the results of this specific project. Communication of the aims and results of the programme will include publications in scientific and professional journals, publications in journals and other media reaching the public, translation of the results in training programs of relevant professionals (e.g. psychiatrists, general practitioners), and in direct communication with patient organisations (the 'depressie stichting', 'angst- dwang en fobieclub' and 'clientenbond' officially participate in the NESDA consortium). Other forms of communication include presentations at (scientific) meetings (such as the Annual meetings of the Society of Dutch Psychiatrists, American Psychiatrists or Biological Psychiatrists), or through websites (such as those of NESDA, the 'Expert Center Depression and Anxiety', patient organizations, etc) for the dissemination of the major research results and fact-sheets. The infrastructure and close collaboration in the consortium will shift the attention of participating academic institutes more toward research relevant for implementation and provide a basis to train a generation of researchers in issues relevant for care research and implementation. The WOK, Nivel and Trimbos Institutes, all members of the NESDA consortium, will help coordinate the implementation of scientific evidence. The translation of scientific work into applicable tools for professionals like professional guidelines and instruments for the improvement of the quality of care will receive systematic attention throughout. Several NESDA researchers have been actively involved in creating professional guidelines for depression and anxiety, and these people will be key persons to help support the implementation of the results from the present study, should they directly impact professional guidelines. With other collaborators, the NESDA-consortium has recently co-erected the National Expert Centre Anxiety and Depression. As for other NESDA projects, also for this proposed project the Expert Center Anxiety and Depression can be used to help disseminate the results. Key activities of this Expert Center are: dissemination of important findings in different media, dissemination of important findings to professionals, patients and researchers, contact with target groups and organising expert meetings. In sum, the applicant will be able to communicate and implement his research findings to professionals, researchers as well as patients through several channels. Doelstelling / Objective A more general goal of the present project is primary and secondary prevention of affective disorders by identifying patients at increased risk for the (re)occurrence of these disorders. More specifically, this project will provide further insight into the importance of dysfunction of the hypothalamus-pituitary-adrenal-axis (HPA-axis) in depression and anxiety disorders. We will explore the


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF relative contribution of clinical aspects, trauma exposure and genetic factors to HPA-axis hyperactivity, and we will examine the predictive validity of HPA-axis for the 2-year onset and course of anxiety and depression disorders. It is our ultimate goal that this project results in a clear indication whether and for whom endocrine measures indicating HPA-axis hyperactivity (possibly in combination with clinical characteristics, trauma exposure and genetic aspects) identify patients with an increased risk of (relapse to) depression and anxiety disorders. This may also provide a rationale for the further development of specific drugs that are presently being tested by various pharmaceutical companies (e.g. glucocorticoid receptor modulators or CRH receptor-antagonists). Specific research questions that will be addressed: A1. What is the specific contribution of 1) past trauma exposure, 2) clinical aspects (severity, duration and type of symptoms), and 3) polymorphisms in HPA-axis regulating genes, to HPA-axis hyperactivity? A2. Do these three variable groups interact in their contribution to HPA-axis hyperactivity? B1. What is the predictive value of HPA-axis hyperactivity for the 2-year incidence of depression and anxiety disorders among persons without an initial diagnosis? B2. Is this predictive value uniform, or are there certain groups of persons (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? C1. What is the predictive value of altered HPA-axis activity of the 2-year course of depression and anxiety disorders among patients? C2. Is this predictive value uniform, or are there certain groups of patients (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? In addition to addressing these research questions, the personal goals of the applicant are to build substantial theoretical and practical research experience through involvement in a large national research network on depression and anxiety. Plan van aanpak / Strategy The proposed study will use cross-sectional and longitudinal data from an ongoing observational cohort study, the Netherlands Study of Depression and Anxiety (NESDA). Data collection (but not investigator capacity) for NESDA is already funded through the ZonMW Geestkracht (consortia) program. The main NESDA goal is to examine the long-term course of depression and anxiety, its determinants and the quality and need of care of patients. Study sample: The NESDA study follows a large cohort of 2,850 adults aged 18 through 65 years with a range of psychopathology (no, subthreshold, minor or major depression and/or anxiety disorder) from different settings. In primary care, 825 participants with anxiety and/or depression will be recruited through a three-stage screening procedure. In secondary care, 825 respondents with anxiety and/or depression will be recruited when starting treatment at a mental health care institution. The inclusion criterion for these 1,650 participants is a current (1-month) DSM-IV diagnosis of depression (minor or major depression, dysthymia) or anxiety disorder (generalized anxiety disorder, panic disorder, social phobia) as assessed by the CIDI psychiatric interview. Excluded are patients with primary diagnoses of psychosis, bipolar disorder, obsessive compulsive disorder, or severe addiction disorder. In addition, 600 respondents without a current diagnosis of depression or anxiety will be included, who serve as healthy controls and are randomly selected (matched for age and gender) from the screen-negatives of the primary care screening procedure. Finally, 300 community-dwelling respondents with a depressive or anxiety disorder in the past (former respondents of the NEMESIS study) and 300 community-dwelling respondents with a parent with anxiety or depression (former respondents of the Ariadne study) will be included. The total of 2,850 NESDA respondents are being recruited in different regions in the


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Netherlands (Amsterdam, Leiden and Groningen). As of August 2005, we have recruited the first 700 participants. With the current speed of recruitment, we expect that recruitment of the final cohort will be completed by the end of 2006. All 2,850 respondents will undergo the same baseline and follow-up assessments after 1, 2, 4 and 8 years. For the present study, baseline data and data collected after 1 and 2 years will be available for statistical analyses. It is to be expected that a large subgroup of the final cohort (expected n=1750 of the 2850) will have a current depression and/or anxiety diagnosis, which will allow us to examine the 2-year course of psychopathology in this group. However, another quite large group (expected n=1100 of the 2850) will not have a current depression and/or anxiety diagnosis. About 70% of this latter group will have subthreshold symptoms, a psychiatric history or a high familial exposure and therefore be at a higher risk for developing affective disorders. This subgroup allows us to examine at the 2-year onset of depression and anxiety disorders. Central determinants of HPA-axis function: Clinical aspects: Type, severity and duration of depression and anxiety disorder The NESDA study has included various indicators of presence, symptomatology, severity, and psychiatric history of depressive and anxiety disorders. The lifetime as well as current (1-month recency) diagnoses of depression (minor and major depression, dysthymia) and anxiety (generalized anxiety disorder, social phobia, panic disorder) are assessed by the CIDI psychiatric interview which classifies diagnoses according to the DSM-IV criteria of the American Psychiatric Association. Severity and type of depressive and anxiety symptomatology is assessed by validated self-report questionnaires: inventory of depressive symptoms (IDS, (21)), fear questionnaire (22) and beck anxiety inventory (23). History of psychopathology is assessed using the LIFE-CHART assessment (24) and life-time questions from the CIDI psychiatric interview. Trauma exposure in the past: Exposure to physical, sexual and verbal abuse during childhood is assessed through the NEMESIS childhood trauma questionnaire. Exposure and recency of major life events (e.g. death or serious illness of intimates, violence exposure, financial or job problems) are assessed through the adapted Brugha questionnaire.(25) Genetic polymorphisms: DNA samples will be taken from blood and stored and frozen for later assessment. This is all conducted at the Center for Neurogenmics and Cognition Research (CNCR) at the VU in Asterdam (Profs P. Heutink and M. Verhage), which provides excellent population and molecular genetics facilities. Initial genotyping will be performed for the polymorphisms in the top-ten candidate genes. For sure, important HPA-axis related genetic polymorphisms will be assessed, namely the glucocorticoid receptor gene (BclI, ER22/23EK, N363S), its chaperone protein (FKBP5 (26)), and the mineralcorticoid receptor gene (I180V (15)). From prior research by our group, we know that the prevalences of these mentioned genetic polymorphisms will be high enough to allow exploration in our cohort study. For example, in our study among 89 depressed persons and in line with other literature, the prevalence of the three GR genotypes was 11% (ER22/23EK), 46% (Bc1I) and 9% (N363S). For MR genotype, the heterozygous prevalences were 50% for rs2070951 and 21% for rs5522,(15) which was 50% for the FKBP5 genotype.(27) Since new linkage, association, and expression profiling findings are published regularly for this important disease trait, we will keep a keen eye on the literature in this fast moving field. When superior candidate genes in functional (HPA-axis) pathways are suggested by linkage or expression profiling, we will update our list of candidates accordingly and these candidate genes will be included in the NESDA study. Course of psychopathology:


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Self-report questionnaires on severity of depression and anxiety symptoms will be repeated after 1 year, and all assessments are repeated in a complete assessment after 2 years, so that detailed information on the course of symptomatology, severity and presence of depression and anxiety is available. Since at baseline there is a large group of persons with depression/anxiety diagnoses (expected n= 1750) as well as a large group of persons without depression/anxiety diagnoses (expected n=1100), it is possible to examine the 2-year course among depressed/anxious patients as well as to examine the 2-year onset of depression/anxiety among those initially free of a disorder. We expect to have enough change in the outcome for psychopathology. Prior research has shown that generally the course of major depressive disorder is 40% favorable, 30% chronic intermittent and 30% chronic, (28) and rather similar patterns have been observed for anxiety disorders.(29;30) For the onset of affective disorders, the Dutch NEMESIS study showed an incidence of 8-10% over 2 years.(31) Since our cohort of about 1100 respondents without a current depression or anxiety disorder is at a higher risk for psychiatric disorders since a relatively large group (70%) has subthreshold symptoms or a personal or family history of depression and anxiety, it can be expected that the 2-year onset rate in this cohort will be around 15-20%. These numbers illustrate that we can expect enough events for both the 2-year course and the 2-year onset analyses in the subcohorts of patients and persons without a current affective disorder, respectively. Assessment of HPA-axis function: Activity of the HPA-axis will be determined by free cortisol assessment using 7 saliva samples per respondent, providing different HPA-axis indicators. Saliva cortisol assessments have shown to be associated to psychopathology.(32-34). Respondents are instructed to collect saliva samples on a regular work day, and omit teeth brushing and eating within 15 minutes of the saliva collection. First, as a measure of a natural ?stress? response of the HPA-axis, we will use the morning cortisol awakening response (CAR), by taking samples at awakening time, 30, 45 and 60 min later. Second, to obtain basal levels of the stress response, saliva will be collected at 22.00 and 23.00 h. Third, the circadian rhythm of cortisol will be determined by comparing morning (awakening) versus evening levels. Fourth, the total cortisol excretion during the day will be calculated by the area under the curve of the 6 saliva samples. Fifth, the negative feedback of the HPA-axis system will be assessed by ingesting dexamethasone, a specific antagonist of the glucocorticoid receptor which inhibits ACTH release at the pituitary gland. After ingesting 0.5 mg dexamethason at 11 pm, suppression of the morning cortisol increase is determined by a seventh saliva sample at awakening the next morning. Respondents collect saliva samples using a cotton swap (Salivettes, Sarstedt, Germany) which are mailed to the LUMC clinical lab. Here, saliva will be spun down and stored at -85ºC. Cortisol will be assayed on an Elecsys using a standard cortisol kit (Roche). Hyperactivity of the HPA-axis is indicated by a high morning cortisol awakening response, high basal levels of saliva cortisol, a high difference in morning and evening cortisol level, high total cortisol excretion, and a high cortisol level (non-suppression) after ingesting dexamethason. The availability of five HPA-axis indicators is unique and allows comparison in their association with affective disorders. Covariates: Several variables may be related to psychopathology and HPA-axis function and consequently could confound the examined associations. These variables will be considered in statistical analyses. Important sociodemographic data include age, sex, and educational level. Smoking history (never, past, current smoker), cigarette pack years, alcohol use (number of average alcoholic beverages/week), and body mass index is assessed. Physical activity level is assessed using the International Physical Activity Questionnaire.(35) Baseline prevalent chronic conditions including angina, myocardial infarction, CHF, stroke, diabetes, cancer, lung disease and osteoarthritis are assessed by standardized algorithms based on self-report, medication use, symptoms, and GP records. Somatic symptoms are assessed by the 4DSQ.(36) All received treatments (psychotherapy, drug treatment) will be monitored throughout the study, so that potential treatment effects can be explored and controlled for. Potentially confounding or


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF mediating drug use, e.g. antidepressants, benzodiazepines or contraceptives, is assessed by medication observation and registered by IDIS code.(37) Finally, we will take time of season and time of menstrual cycle (for women) into account in the analyses, since these may influence cortisol concentrations.(38) Sample size calculations: Original power analyses for the NESDA study have calculated that we need a minimum of 160 persons in a subgroup in order to detect a small difference (RR=1.5) in a continuous measure, given a two-sided test, a power of 80% and a alpha of 0.05. For cross-sectional analyses (research questions A1 and A2), our expected smallest subgroup will be at least 300 (for subtypes of anxiety disorders and the least common genetic polymorphisms, illustrating that we will have enough statistical power to examine differences between subcategories of patients. Also for the planned longitudinal analyses examining the course among initially depressed/anxious patients (research questions B1 and B2) and the onset among initially non-depressed/anxious patients (research questions C1 and C2), we also have much larger numbers than minimally required (1750 and 1100, respectively). Several of the proposed research variables, however, are continuous measures (e.g. HPA-axis indicators, change in affective symptoms) for which we have more than 7 to 17 times the minimally needed sample size. So, in all, these power calculations do indicate that even if we would have 25% non-response during follow-up and 25% missing cortisol data, we would still have adequate power to address our research questions. Statistical analyses: Research Questions A1 and A2: What is the specific contribution of 1) past trauma exposure, 2) clinical aspects (severity, duration and type of symptoms), and 3) polymorphisms in HPA-axis regulating genes, to HPA-axis hyperactivity? Do these three variable groups interact in their contribution to HPA-axis hyperactivity? Associations between continuous indicators of HPA-axis and (type, severity and duration of) depression and anxiety disorders, trauma exposure and presence of genetic polymorphisms will first be explored graphically. Regression models will be used to investigate associations after adjusting for covariates (as described above). If necessary, appropriate transformations will be used to ensure that assumptions are met (e.g. transforming skewed variables). Estimated slopes or odds ratios and their 95% confidence intervals will be calculated to indicate the variability around estimates. In addition to exploring the multivariate independent effects of type, severity, duration of disorders, trauma exposure and genetic polymorphisms with HPA-axis functioning, we will explore potential interaction effects. For instance, we will explore whether HPA-axis hyperactivity is especially present in combination of a presence of GR genetic polymorphisms with trauma exposure or type of affective disorder (which would indicate a gene-environment interaction). In order to test interaction, we will compute interaction terms (e.g. GR polymorphism*trauma exposure) and explore its significance in multivariate regression models. Research Questions B1 and B2: What is the predictive value of HPA-axis hyperactivity for the 2-year incidence of depression and anxiety disorders among persons without an initial diagnosis? Is this predictive value uniform, or are there certain groups of patients (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? Among the 1100 initially non-depressed/anxious persons, dichotomous indicators for the onset of depression and anxiety disorders will be created, as well as continuous variables that assess the change in symptomatology by subtracting baseline from follow-up continuous scores. Multivariate logistic and linear regression analyses (for dichotomous and continuous outcome variables, respectively) will be used to examine associations between HPA-axis variables and the onset of affective disorders (symptoms). In order to explore whether the predictive value of HPA-axis hyperactivity is higher among certain groups of persons, we will explore interaction terms between HPA-axis hyperactivity and clinical, genetic and trauma variables. If an interaction is observed, we will describe the predictive value of HPA-axis clearly in specific subgroups. For instance, if we find an interaction term for trauma*HPA-axis


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF hyperactivity, than we will show the predictive value of HPA-axis hyperactivity separately for those with and without trauma exposure in the past. Research Questions C1 and C2: What is the predictive value of HPA-axis hyperactivity for the 2-year course of depression and anxiety disorders among patients? Is this predictive value uniform, or are there certain groups of patients (e.g. based on trauma, clinical or genetic characteristics) for whom this predictive value is especially high? Among the 1750 depressed and anxious patients, change in severity of depressive and anxiety symptoms will be calculated by subtracting baseline from follow-up continuous scores. In addition, dichotomous indicators will be created for continuation of (symptoms of) affective disorders to identify those with chronic disorders. Multivariate logistic and linear regression analyses (for dichotomous and continuous outcome variables, respectively) will be used to examine association between HPA-axis variables and the course of affective disorders (symptoms). We will explore the presence of interactions between hyperactivity of the HPA-axis with clinical, genetic and trauma variables in order to test whether the predictive value of HPA-axis hyperactivity for the course is uniform or not (see also RQ B1 and B2). Because of the large sample size, we will not only be able to adjust analyses for receiving treatment (either drug medication or psychotherapy treatment) but we will have enough power to also examine the association between psychopathology and HPA-axis function specifically among those (expected 1/2 of the sample with depression/anxiety disorders at baseline) without currently receiving treatment, as well as to explore the specific associations between treatment and HPA-axis dysfunction. Feasibility of proposed data collection: Since the success and timeline of the proposed OOG-application is partly dependent on the feasibility of the NESDA study, it is good to add some first statistics on the NESDA ongoing data collection. As of August 18, 2005, we have included 700 NESDA respondents. With the 18 currently appointed research nurses, it is expected that the recruitment target, 2850 respondents, will be reached by the end of 2006 (as planned). The choice for the specific HPA-axis assessments included was partly based on the proven feasibility in an earlier study, conducted by the research group (we collected saliva cortisol samples in 75% of the older respondents, participating in the LASA study). Data from the first 700 NESDA respondents, do confirm that the data collection is going well and that the accuracy of data regarding the variables needed for the proposed study is high: psychopathology data is 100% complete, data on trauma history is 100% complete, data on HPA-axis is at least for 75% complete (saliva samples are still being sent back, so far only 2% refused dexamethason suppression test) and blood samples (to assay genetic polymorphisms) are for 97% of respondents complete. Overall, these preliminary results illustrate feasibility of the NESDA study and therefore do indicate that the applicant has adequate access to a promising, interesting and good quality data base. Feasibility of proposed research trajectory of applicant: When the research applicant will start this proposed study, he is more than halfway through his psychiatry-training. He will finish the final year of his clinical psychiatry-training in 2008. In the other years of this project, he will spend about half of his time doing research. NESDA provides an ideal research environment. For a good and practical insight into conducting research it is necessary that the applicant will also be involved in research assessments and interviews. Therefore, in the first years, he will be trained and he will conduct some baseline and follow-up assessments for the NESDA study. However, through the extensive already existing infrastructure, the data collection is not dependent on the applicant, which gives him the opportunity to really combine his clinical and research duty without many restrictions and without pressure. At GGZ Buitenamstel there is a lot of experience with psychiatrists-in-training who combine a clinical and research education, and the overall success rate is very high. The psychiatry-training program does provide flexibility, has opportunities for a research year, and has a supervisor, Prof. dr. ATF Beekman, who is very supportive to persons who integrate a clinical and research training. Considering all these


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF facts, the applicant is very confident that he will be able to conduct and finish this project in a timely fashion. Timeline with specific research activities by the applicant: 2006: assisting in data collection, following courses, cross-sectional analyses for RQ A1+A2 2007: following courses, cross-sectional analyses for RQ A1+A2, paper writing, dissemination 2008: clinical psychiatry-training 2009: longitudinal analyses for RQ B1+B2, paper writing, dissemination 2010: longitudinal analyses for RQ C1+C2, paper writing, dissemination 2011: finishing papers and thesis, thesis defense. Expertise, voorgaande activiteiten en producten / Expertise, prior activities and products Embedding The applicant will conduct this study embedded within the NESDA consortium. He is appointed as 'psychiatrist-in-training' at GGZ Buitenamstel, one of the five GGZ-institutions involved in the NESDA consortium. Through this embeddedness, the applicant will work among researchers and care-providers from departments of psychiatry, general practice and clinical psychology of the Leiden University Medical Center, University Medical Center Groningen, and VU University Medical Center. In addition, the Center for Quality of Care of UMC St. Radboud, the Netherlands Institute for Health Services Research (NIVEL) and the National Institute for Mental Health and Addiction (Trimbos) actively participate in the NESDA consortium. In addition to the national embedding in the NESDA consortium, the applicant will be embedded within the research line 'common-mental-disorders' of the VUMC Institute of Extramural Medicine (EMGO) and at the VUMC Institute for clinical and experimental neuroscience (ICEN) and the LUMC research line Mood, Anxiety and Somatoform disorders and the HPA-axis (MASH). International collaboration does exist as well. When determining the specific method for assessing cortisol among the NESDA participants, our group has interacted extensively with international experts in the area of HPA-axis assessment, such as Dr. Wust and Kirschbaum of Trier University and Dr. Holsboer of Max Planck Institute, Germany. Research experience of the supervision team of the applicant: The direct supervisors of the applicant, guarantee expertise in biological psychiatry (Profs Hoogendijk and Zitman), psychiatric epidemiology (Prof.Beekman, Dr. Penninx), and HPA-axis function (Dr. de Rijk). Prof. Dr. Hoogendijk, professor biological psychiatry at VU University Medical Center (VUMC), is experienced in performing effect studies with pharmacological and non-pharmacological interventions in combination with measurements of the hypothalamo-pituitary-adrenal axis and genetical association studies. This has resulted in more than 60 scientific papers and several successfully finished promovendi-trajectories. Recently he together with the department of Endocrinology and Psychiatry of the AMC and the Erasmus MC, found that in depressed patients the response to paroxetine was associated with measures of HPA axis hyperactivity and that these measures, and partly also treatment response, were associated with the presence of polymorphisms in the glucocorticoid receptor (GR) DNA sequence (Brouwer et al, submitted). Moreover, relapse rates appeared to be higher in patients with measures of post-treatment HPA axis hyperactivity. Prof. Dr. Zitman is professor of psychiatry and head of the department of psychiatry at Leiden University Medical Center (LUMC). Dr. Zitman has chaired two large-scale studies on chronic benzodiazepine use and participated in longitudinal studies on depression and optimism. He was involved in several biochemical and cognitive challenge tests in depression and anxiety disorders. He published over 100 scientific papers and is currently supervising 17 promovendi. His main current focus is the role of the HPA-axis in affective, anxiety and somatoform disorders.


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Dr. Penninx, a trained epidemiologist appointed as Associate Professor at VUMC, LUMC and UMCG (Groningen), is the principal investigator of the NESDA study. She has developed extensive national and international expertise in the conduct, data management and analyses of large population based studies and randomized controlled trials, including the EPESE, WHAS, LASA, Health ABC, ADAPT and FAST studies, which has resulted in more than 100 publications. Her research has mainly focused on the adverse health consequences of depression, and has particularly developed a strong interest in the interaction of mental and somatic and the role biological factors (such as HPA-axis activity, inflammation and metabolic abnormalities) may play in this interaction. Prof. Dr. Beekman, professor of psychiatric epidemiology at VUMC, is also 'A-opleider' and therefore the applicant's supervisor in his specialist training. Dr. Beekman has been involved in many large-scale epidemiological studies such as LASA and NEMESIS. He has published more than 120 scientific papers and is currently supervising 15 promovendi in their promotion-projects. His main research focus has been on describing and predicting the course of affective disorders, and testing effective interventions to improve prognosis or prevent the development of affective disorders. Dr de Rijk, Assistant Professor at the department of Medical Pharmacolgy (chaired by Prof.dr. E.R. de Kloet) and research associate at the department of psychiatry (chaired by Prof.dr. F.G. Zitman) of the LUMC has been involved in national and international research on HPA-axis activity since his PhD appointment. Currently, he studies the role of GR and MR genetic polymorphisms in stress-reactivity and their relations with different pathologies.

Publicaties / Publications Beekman AT, Geerlings SW, Deeg DJH, Schoevers RS, de Beurs E, Braam AW, Penninx BWJH, van Tilburg W. The natural history of late-life depression: a 6-year, 14-wave prospective study in the community. Arch Gen Psychiatry 2002;59:605-11. Beekman AT, Penninx BWJH, Deeg DJH, de Beurs E, Geerling SW, van Tilburg W. The impact of depression on the well-being, disability and use of services in older adults: a longitudinal perspective. Acta Psychiatr Scand 2002;105:20-27. Beekman AT, Deeg DJ, Smit JH, Comijs HC, Braam AW, de Beurs E, van Tilburg W. Dysthymia in later life: a study in the community. J Affect Disord 2004;81:191-9. Beekman AT, Deeg DJ, Geerlings SW, Schoevers RA, Smit JH, van Tilburg W. Emergence and persistence of late life depression: a 3-year follow-up of the Longitudinal Aging Study Amsterdam. J Affect Disord 2001;65:131-8. Beekman AT, de Beurs E, van Balkom AJ, Deeg DJ, van Dyck R, van Tilburg W. Anxiety and depression in later life: Co-occurrence and communality of risk factors. Am J Psych 2000;157:89-95. Brouwer JP, Appelhof BC, Hoogendijk WJG, Huyser J, Endert E, Zuketto C, Schene AH, Tijssen JG, Van Dyck R, Wiersinga WM, Fliers E. Thyroid and adrenal axis in major depression: a controlled study in outpatients. Eur J Endocrinol 2005;152:185-91. De Kloet ER, DeRijk R. Signaling pathways in brain involved in predisposition and pathogenesis of stress-related disease: genetic and kinetic factors affecting the MR/GR balance. Ann N Y Acad Sci. 2004;1032:14-34. DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol. 2002;81:103-22. DeRijk RH, Schaaf M, Stam FJ, de Jong IE, Swaab DF, Ravid R, Vreugdenhil E, Cidlowski JA, de Kloet ER, Lucassen PJ. Very low levels of the glucocorticoid receptor beta isoform in the human hippocampus as shown by Taqman RT-PCR and immunocytochemistry. Brain Res Mol Brain Res. 2003;116:17-26. DeRijk RH, Schaaf MJ, Turner G, Datson NA, Vreugdenhil E, Cidlowski J, de Kloet ER, Emery P, Sternberg EM, Detera-Wadleigh SD. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Rheumatol. 2001;28:2383-8. DeRijk RH, Zitman FG, de Kloet ER. Neuroendocrinologie van depressie, Nederlands handboek voor Psychiatrie. Ed: Hovens,H.; Timmermans,L.; Loonen,A.J. De Tijdstroom, Utrecht, 2004. Giltay EJ, Geleijnse JM, Zitman FG, Hoekstra T, Schouten EG. Dispositional optimism and all-cause and cardiovascular mortality in a prospective cohort of elderly dutch men and women. Arch Gen Psychiatry 2004;61:1126-35. Hoogendijk WJG, Sommer IEC, Pool ChW, Kamphorst W, Hofman MA, Eikelenboom P and Swaab DF. Lack of association between depression and loss of neurons in the locus coeruleus in AD. Arch Gen Psychiatry, 1999; 56: 45-51. Hoogendijk WJG, Purba JS, Hofman MA, de Vos RAI, Jansen-Steur ENH and Swaab DF. Depression does not affect the number of corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus in Parkinson patients. Biol Psychiatry 1998;43:913-17. Hoogendijk WJ, Feenstra MG, Botterblom MH, Gilhuis J, Sommer IE, Kamphorst W, Eikelenboom P, Swaab DF. Increased activity of surviving locus ceruleus neurons in Alzheimer's disease. Ann Neurol 1999;45:82-91. Penninx BW, Beekman ATF, Honig A, Deeg DJH, Schoevers RA, van Eijk JThM, van Tilburg W. Effect of depression on cardiac mortality. Results from a community-based longitudinal study. Arch Gen Psychiatr 2001;58:221-227. Penninx BW, Beekman AT, Hoogendijk W, Guralnik JM, Ferrucci L. Late-life depression is associated with both hyper- and hypoactivity of the HPA-axis. Submitted 2005. Penninx BW, Guralnik JM, Stabler S, Ferrucci L, Fried LP. Vitamin B12 deficiency and depression: Epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry 2000;157:715-721 Penninx BW, Geerlings SW, Deeg DJH, van Eijk JThM, van Tilburg W, Beekman AT. Minor and major depression and the risk of death in older persons. Arch Gen Psychiatry 1999;56:889-896. Penninx BW, Guralnik JM, Ferrucci L, Simonsick EM, Deeg DJH, Wallace RB. Depressive symptoms and physical decline in community-dwelling older persons. JAMA 1998;279:1720-1726. Purba JS, Hoogendijk WJ, Hofman MA, Swaab DF. Increased number of vasopressin- and oxytocin-expressing neurons in the paraventricular nucleus of the hypothalamus in depression. Arch Gen Psychiatry. 1996;53:137-43. Rinne T, de Kloet ER, Wouters L, Goekoop JG, de Rijk RH, van den Brink W. Fluvoxamine reduces responsiveness of HPA axis in adult female BPD patients with a history of sustained childhood abuse. Neuropsychopharmacology. 2003;28:126-32 Voshaar RC, Gorgels WJ, Mol AJ, van Balkom AJ, van de Lisdonk EH, Breteler MH, van den Hoogen HJ, Zitman FG. Tapering off long-term benzodiazepine use with or without group cognitive-behavioural therapy: three-condition, randomised controlled trial. Br J Psychiatry 2003;182:498-504. Voshaar RC, Verkes RJ, van Luijtelaar GL, Edelbroek PM, Zitman FG (2005) Effects of Additional Oxazepam in Long-Term Users of Oxazepam. J Clin Psychopharmacol. 25: 42-50 Weel-Baumgarten EM, van den Bosch WJ, van den Hoogen HJ, Zitman FG (2000) The long-term perspective: a study of psychopathology and health status of patients with a history of depression more than 15 years after the first episode. Gen Hosp.Psychiatry 22: 399-404 Zitman FG, Couvee JE. Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group. Br J Psychiatry. 2001 Apr;178:317-24. Zitman FG, Pennings TM, Raes DC, Hekster YA. Neuroleptic drug use in nonpsychiatric departments of a Dutch university hospital. Gen Hosp Psychiatry 1994;16:32-7. Referenties / References (1) de Kloet ER, Vreugdenhil E, Oitzl MS, Joels M. Brain corticosteroid receptor balance in health and disease. Endocr Rev 1998; 19(3):269-301.


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF (2) de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6(6):463-475. (3) de Kloet ER, Joels M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci 2005; 6(6):463-475. (4) Arana GW, Baldessarini RJ, Ornsteen M. The dexamethasone suppression test for diagnosis and prognosis in psychiatry. Commentary and review. Arch Gen Psychiatry 1985; 42(12):1193-1204. (5) Young EA, Haskett RF, Grunhaus L, Pande A, Weinberg VM, Watson SJ et al. Increased evening activation of the hypothalamic-pituitary-adrenal axis in depressed patients. Arch Gen Psychiatry 1994; 51(9):701-707. (6) Abelson JL, Curtis GC. Hypothalamic-pituitary-adrenal axis activity in panic disorder. 24-hour secretion of corticotropin and cortisol. Arch Gen Psychiatry 1996; 53(4):323-331. (7) Carson SW, Halbreich U, Yeh CM, Goldstein S. Altered plasma dexamethasone and cortisol suppressibility in patients with panic disorders. Biol Psychiatry 1988; 24(1):56-62. (8) Heuser IJ, Schweiger U, Gotthardt U, Schmider J, Lammers CH, Dettling M et al. Pituitary-adrenal-system regulation and psychopathology during amitriptyline treatment in elderly depressed patients and normal comparison subjects. Am J Psychiatry 1996; 153(1):93-99. (9) Pasquali R, Vicennati V. Activity of the hypothalamic-pituitary-adrenal axis in different obesity phenotypes. Int J Obes Relat Metab Disord 2000; 24 Suppl 2:S47-S49. (10) Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12):1319-1325. (11) Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C, Baulieu EE, Schold C et al. An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol Psychiatry 2002; 52(5):386-392. (12) Rinne T, de Kloet ER, Wouters L, Goekoop JG, DeRijk RH, Van den BW. Hyperresponsiveness of hypothalamic-pituitary-adrenal axis to combined dexamethasone/corticotropin-releasing hormone challenge in female borderline personality disorder subjects with a history of sustained childhood abuse. Biol Psychiatry 2002; 52(11):1102-1112. (13) Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12):1319-1325. (14) Wust S, Federenko IS, van Rossum EF, Koper JW, Kumsta R, Entringer S et al. A psychobiological perspective on genetic determinants of hypothalamus-pituitary-adrenal axis activity. Ann N Y Acad Sci 2004; 1032:52-62. (15) de Rijk RH, Wust S, Meijer OC, Zennaro C, Vreugdenhil E, Federenko I et al. A common polymorphism in the mineralcorticoid receptor determines stress responsivity to a psychosocial challenge in humans. Abstract book, 4th Dutch Endo-neuro-psycho meeting, Doorwerth , 50. 2005. (16) Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23(5):477-501. (17) Targum SD. Persistent neuroendocrine dysregulation in major depressive disorder: a marker for early relapse. Biol Psychiatry 1984; 19(3):305-318. (18) Nemeroff CB. Neurobiological consequences of childhood trauma. J Clin Psychiatry 2004; 65 Suppl 1:18-28. (19) Coryell W, Noyes R, Jr., Reich J. The prognostic significance of HPA-axis disturbance in panic disorder: a three-year follow-up. Biol Psychiatry 1991; 29(2):96-102. (20) Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet 1997; 349(9064):1498-1504. (21) Rush AJ, Gullion CM, Basco MR, Jarrett RB, Trivedi MH. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996; 26(3):477-486. (22) Marks IM, Mathews AM. Brief standard self-rating for phobic patients. Behav Res Ther 1979; 17(3):263-267.


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF (23) Beck AT, Epstein N, Brown G, Steer RA. An inventory for measuring clinical anxiety: psychometric properties. J Consult Clin Psychol 1988; 56(6):893-897. (24) Lyketsos CG, Nestadt G, Cwi J, Heithoff K, Eaton WW. The life chart interview: a standardized method to describe the course of psychopathology. Int J Meth Psychiatr Res 1994; 4:143-155. (25) Brugha TS, Cragg D. The List of Threatening Experiences: the reliability and validity of a brief life events questionnaire. Acta Psychiatr Scand 1990; 82(1):77-81. (26) Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12):1319-1325. (27) Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M, Putz B et al. Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment. Nat Genet 2004; 36(12):1319-1325. (28) Beekman AT, Geerlings SW, Deeg DJ, Smit JH, Schoevers RS, de Beurs E et al. The natural history of late-life depression: a 6-year prospective study in the community. Arch Gen Psychiatry 2002; 59(7):605-611. (29) Beekman AT, de Beurs E, van Balkom AJ, Deeg DJ, Van Dyck R, van Tilburg W. Anxiety and depression in later life: Co-occurrence and communality of risk factors. Am J Psychiatry 2000; 157(1):89-95. (30) de Beurs E, Beekman AT, Deeg DJ, Van Dyck R, van Tilburg W. Predictors of change in anxiety symptoms of older persons: results from the Longitudinal Aging Study Amsterdam. Psychol Med 2000; 30(3):515-527. (31) Bijl RV, de Graaf R, RAvelli A, Smit F, Vollebergh WA. Gender and age-specific first incidence of DSM-III-R psychiatric disorders in the general population. Results from the Netherlands Mental Health Survey and Incidence Study (NEMESIS). Soc Psychiatry Psychiatr Epidemiol 2002; 37(8):372-379. (32) Harris TO, Borsanyi S, Messari S, Stanford K, Cleary SE, Shiers HM et al. Morning cortisol as a risk factor for subsequent major depressive disorder in adult women. Br J Psychiatry 2000; 177:505-10. (33) Bhagwagar Z, Hafizi S, Cowen PJ. Increased salivary cortisol after waking in depression. Psychopharmacology (Berl) 2005; :1-4. (34) Peeters F, Nicolson NA, Berkhof J. Levels and variability of daily life cortisol secretion in major depression. Psychiatry Res 2004; 126(1):1-13. (35) Craig CL, Marshall AL, Sjostrom M, Bauman AE, Booth ML, Ainsworth BE et al. International physical activity questionnaire: 12-country reliability and validity. Med Sci Sports Exerc 2003; 35(8):1381-1395. (36) Terluin B, van Rhenen W, Schaufeli.W.B., de Haan M. The Four-Dimensional Symptom Questionnaire (4DSQ): measuring distress and other mental health problems in working population. Work and Stress 2004; 18(3):187-207. (37) Pahor M, Chrischilles EA, Guralnik JM, Brown SL, Wallace RB, Carbonin P. Drug data coding and analysis in epidemiologic studies. Eur J Epidemiol 1994; 10(4):405-411. (38) Bao AM, Ji YF, Van Someren EJ, Hofman MA, Liu RY, Zhou JN. Diurnal rhythms of free estradiol and cortisol during the normal menstrual cycle in women with major depression. Horm Behav 2004; 45(2):93-102.

4. Financiële gegevens / Financial data Geplande duur in maanden / Planned duration in months


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF 60 maanden / months ZonMw budget Jaar / Year Kostenpost / Cost item

1

Personeel

6.100

30.300

0

18.200

24.300

12.100

0

0

91.000

0

0

0

0

0

0

0

0

0

Implementatie

1.000

1.000

0

1.000

1.000

1.000

0

0

5.000

Apparatuur

1.600

1.200

0

800

400

0

0

0

4.000

0

0

0

0

0

0

0

0

0

8.700

32.500

0

20.000

25.700

13.100

0

0

100.000

Materieel

Overig Totaal / Total

2

3

4

5

6

7

8

Totaal / Total

Co-financiering / Cofinancing Naam co-financier / Name of cofinancier

Bedrag / Amount Status

GGZ Buitenamstel AMSTERDAM

53.358 Toegekend

Rivierduinen LEIDEN

50.000 Toegekend

5. Bijzondere gegevens / Additional information Vergunningen / Permits Vergunning nodig / Permit required? Ja / Yes METC/DEC

Vergunning verkregen / Permit obtained? Nee / No

X

Ja / Yes

Nee / No

X

WBO

X

X

Biohazards

X

X

Andere vergunningen / Other permits

Historie subsidieaanvraag / History grant application


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Subsidieaanvraagformulier / Grant Application Form Aanvraagnummer / Application number: 3952 DEFINITIEF Ondertekening / Signatures Naam Penvoerder-projectleider:

Naam bestuurlijk verantwoordelijke:

BWJH Penninx

R van Dyck

Plaats en datum:

Plaats en datum:

Handtekening:

Handtekening:

-----------------------------------------

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Curriculum Vitae Personalia Naam: Adres: Postcode: Woonplaats: Telefoon: E-mail: Geboortedatum: Geboorteplaats: Burgerlijke staat:

Berend Verhoeff Bilderdijkstraat 9hs 1052 NA Amsterdam 0642308172 [email protected]

29 augustus 1977 Amsterdam Ongehuwd

Opleidingen 10/2004 1996- 01/2004 2001- 2003 09/2001 09/1995-08/1996 08/1989-06/1995

Start opleiding tot psychiater bij GGZ Buitenamstel Geneeskunde, Universiteit Maastricht Co-schappen, afstuderen: 26 januari 2004 Doctoraal geneeskunde, Universiteit Maastricht D.E.L.E ( Diploma Espanjol para Lengua Extranjera) Universidad de Barcelona, Spanje Atheneum, Hervormd Lyceum Zuid, Amsterdam Pakket: Ned, Eng, WisB, Nat, Sck, Bio, Gesch.

Keuze-onderwijs, aanvullende cursussen 03/2003-05/2003 08/2002-10/2002 02/1999-05/1999 08/1998-12/1998 05/1998

Co-schap kindergeneeskunde, Somerset hospital, Cape Town, ZuidAfrika. Keuze-onderwijs klinische neurologie, Universidad de Barcelona, Spanje. Snijcursus, Universiteit Maastricht. Tropengeneeskunde cursus, IFMSA-Universiteit Maastricht (International Federation of Medical Student Associations). Keuzeonderwijs jaar 3, Neurologie, theorie en praktijk, Universiteit Maastricht.

Onderzoekservaring 08/2003-12/2003

Wetenschapsstage, Laboratori de Neurologia Experimental, Fundacion Clinic, Hospital Clinic, Barcelona, Spanje. 'Effect of the subthalamic lesion on the abnormal involuntary movements induced by levodopa in an experimental modal of Parkinson's disease' (Dr. de Baets, Dr. Marin).

Publicatie: Marin C, Bonastre M, Aguilera E, Verhoeff B, Effect of locus coeruleus noradrenaline depletion on levodopa-induced motor fluctuations in hemiparkinsonian rats. Movements disorders 2004; 19 (Suppl 9): S148. Poster: op het 8th International Congress of Parkinson’s disease and Movement Disorders 2004 te Rome, Italië.

Werkervaring na mijn studie 15-12 2003- heden

Arts-assistent psychiatrie, afdeling Verhulst van de Valeriuskliniek te Amsterdam. Functie: behandelend arts van ± 12 patiënten op een vervolgafdeling, deels open deels gesloten (supervisoren: drs. B. Marttin en drs. K. Konijn). Woensdagochtend waarneming op afdeling Lairesse 1, opname afdeling van de Valeriuskliniek. Werkgroep begeleiding 3dejaars geneeskunde studenten aan de Vrije Universiteit van Amsterdam. Arts-assistent bij de stedelijke crisisdienst vanuit de crisisdienst van GGZ Buitenamstel. Functie: 2 maal per maand nacht of weekenddienst, acute sociale psychiatrie, IBS beoordelingen en diagnostiek. Sinds 1 oktober 2004 in opleiding tot psychiater bij GGZ Buitenamstel.

Extra-curriculaire activiteiten 07/2000-06/2001

09/1999-06/2000 09/1999-06/2000 03/1999-05/2000 09/1998-05/1999 1996-1999

1996-1998 1994

Klimexpeditie in de Andes, verscheidene bergen beklommen in Peru, Bolivia, Chili en Argentinie, gesubsidieerd door de Nederlandse Klim en Bergsport Vereniging. Telefonisch achterwacht huisartsenpost Academisch Ziekenhuis Maastricht. Wedstrijdroeier lichte acht Maastrichtse Studenten Roeivereniging 'Saurus'. Commissielid Maassac (Maastrichtse Studenten Alpen Club), organisatie Nederlands Studenten Kampioenschap Sportklimmen. Docent EHBO aan een middelbare school, Jeanne d'Arc College, Maastricht. Organisatie en leiding van het Hooggebergte Kamp van de Nederlandse Klim en Bergsport Vereniging, een klimkamp in de Zwitserse Alpen voor kinderen van 15 tot 18 jaar. Hockeyer in Heren 1 bij de Maastrichtse Hockeyclub, trainer en coach jongens B1 en meisjes A1 (Hockey-instructeur B). Hockeyer in het Nederlands Jeugd Team tot 18 jaar.

Bijlage: klinische werkzaamheden, klinische opleiding en setting 1. Welke klinische werkzaamheden verricht u momenteel? (Omschrijf type behandeling of begeleiding, afdeling, problematiek, aantal uren per week, max 5 regels) Momenteel ben ik werkzaam als psychiater in opleiding bij GGZ Buitenamstel in het psychiatrisch ziekenhuis de Walborg. Hier werk ik fulltime als behandelaar op een open en gesloten afdeling met chronisch psychiatrische patiënten met complexe psychiatrische (vnl. psychotische- en stemmingsstoornissen) problematiek. De patiëntenzorg bestaat onder andere uit het juist instellen van medicatie, het geven van psycho-educatie, het begeleiden van resocialisatie trajecten en het creëren van een adequaat zorgkader.

2. Welke klinische werkzaamheden zult u tijdens het OOG-traject gaan verrichten? (Omschrijf type behandeling of begeleiding, afdeling, problematiek, aantal uren per week, max. 5 regels) Tijdens het OOG-traject zal ik mijn opleiding tot psychiater voltooien en hierbij klinische werkzaamheden afwisselen met wetenschappelijk onderzoek. Ik zal op verschillende stageplekken binnen GGZ Buitenamstel werkzaam zijn waaronder de algemene polikliniek, de crisisdienst, de acute opname afdeling en de consultatieve dienst. Als behandelaar zal ik verantwoordelijk zijn voor de medisch psychiatrische behandeling en in aanraking komen met verschillende patiëntenpopulaties en uiteenlopende aspecten van de klinische praktijk. Ook als psychiater binnen de GGZ Buitenamstel zal ik mijn werk graag blijven combineren met wetenschappelijk onderzoek ten einde het wetenschappelijk klimaat te bevorderen.

3. Heeft u een registratie in het kader van de wet BIG? Zo ja, a. In welk register?

x Ja 0 Nee

Het basisartsen register

b. registratienummer 59061503801

4. Volgt u momenteel een opleiding die leidt tot een BIG-registratie? x Ja 0 Nee Zo ja, a. welke opleiding volgt u? Opleiding tot psychiater

b. Wanneer is uw opleiding voltooid? April 2009

5. Heeft u een gegarandeerde opleidingsplaats? Zo ja, a. Welke opleiding? Tot psychiater

b. Waar? GGZ Buitenamstel, Amsterdam

c. Per wanneer? 01-10-04

d. Welke opleider? Prof. Dr. ATF Beekman

e. Wie geeft deze garantie? Prof. Dr. ATF Beekman

x Ja 0 Nee

6. Hoe is de klinische behandelsetting aangesloten op de onderzoeksstructuur van de universiteit? (denk aan: onderzoekslijnen, gemeenschappelijke dataverzameling, gezamenlijke refereerbijeenkomsten, toegang tot onderzoeksfaciliteiten, dubbele aanstellingen) (max. 10 regels) Het voorgestelde onderzoek is ingebed in het NESDA (Netherlands Study of Depression and Anxiety) consortium. Dit is een samenwerking tussen universiteiten, onderzoekscentra en GGZ instellingen en biedt de mogelijkheid om informatie uit te wisselen en te werken met onderzoekers, professionals in de geestelijke gezondheidszorg, huisartsen en klinisch psychologen van Leiden University Medical Center, University Medical Center Groningen, en VU University Medical Center. Door de inbedding van het onderzoek in NESDA kan ik gebruik maken van de infrastructuur, de gemeenschappelijke dataverzameling, en de aanwezige onderzoeksfaciliteiten. De voorganger van GGZ Buitenamstel, de Valeriuskliniek, was de eerste academische vakgroep psychiatrie van Nederland en de instelling heeft sindsdien ruime ervaring opgedaan in het opleiden van onderzoekers. Zij streeft naar academiesering van haar zorgprogramma’s in het bijzonder angst en depressie. De instelling zal met dit project hier een belangrijke bijdrage aan leveren.

OOG3 Bijlage Uitgebreide begroting Bij uw aanvraag dient u een uitgebreide begroting op te geven. Hieronder vindt uw diverse posten die een nadere uitwerking vragen. De onderstaande specificatie geldt alleen voor het ZonMw deel van de begroting en niet voor de andere financiering. Personeel Jaar Functie /Omschrijving Hoofdonderzoeker Projectleiding* Secretariaat*

1

2

3

4

5

6

Totaal

6100 -

30300 -

0 -

18200 -

24300 -

12100 -

91000 -

Totaal :

91000

Materiele kosten Jaar Omschrijving

1

2

3

4

5

6

Totaal

Cortisol bepalingen*

-

-

-

-

-

-

-

Totaal : Implementatiekosten Jaar Functie /Omschrijving Implementatie, verspreiding, drukkosten, bijdrage proefschrift e.d.

0

1

2

1000 1000

3

4

5

6

Totaal

-

1000

1000

1000

5000

Totaal :

D:\Documents\oog subsidie\uitgebreide begroting OOG.doc

5000

Apparatuurkosten Jaar Functie /Omschrijving Computer, software, printer

1

3 4

2

5

1600 1200 0 800

6

400 0

Totaal :

Totaal 4000

4000

Overige kosten Jaar Functie /Omschrijving

1

2

3

4

5

Totaal :

6

Totaal

0

*NB: Projectleiding, secretariaat en cortisol bepalingen worden vanuit het NESDA consortium gefinancierd en hoeven dus niet apart voor deze studie begroot te worden. Deze studie is ingebed in het NESDA consortium en kan zodoende gebruik maken van de beschikbare infrastructuur, de gemeenschappelijke dataverzameling en de aanwezige onderzoeksfaciliteiten.

1.1.1 Begroting opleidingskosten Zonmw onderscheidt als opleidingsactiviteiten: cursussen, congresbezoek en promotiekosten. Geeft per activiteit weer welke kosten u denkt te maken. Het totaal aan opgevoerde kosten mag niet hoger zijn dan 115.000 Euro. Type activiteit Cursussen (uit algemeen en specifiek deel opleidingsplan) 1

Congresbezoek (uit algemeen en 1

activiteit Introductie cursus neurowetenschappen voor PhD studenten (Gratuate School of Neuroscience Amsterdam and Rudolf Magnus Gratuate School of Neuroscience Utrecht, ONWA). Writing English for publication (ONWA). Basic course on biostatistics and clinical epidemiology, VUMC (ONWA). Inleiding SPSS, Organisatie: Postinitieel masteronderwijs Epidemiologie - Amsterdam EMGO Instituut en afd. KEB, VU medisch centrum, Amsterdam.

Kosten 570

Principes van epidemiologische data-analyse, Organisatie: Postinitieel masteronderwijs Epidemiologie - Amsterdam EMGO Instituut en afd. KEB, VU medisch centrum, Amsterdam APA, VS, (2007) state of the art psychiatry/neurology

200

521 600 100

2500

Neem de kosten over uit de bijlage ‘Aanvullende informatie kandidaat, werken opleidingsplan’


specifiek deel opleidingsplan)

promotiekosten

Voorjaarscongres NvVP (2006, ontwikkeling en levensloop, 2008) 250 per keer World Congress of Biological Psychiatry (2009, 2010), state of the art psychiatry, 2500 per keer Literatuur Proefschrift (drukken)

Totaal

500 5000 1000 4000 14991

Dit document dient u om te zetten naar PDF en via ProjectNet mee te sturen.


C

B

A salaris mnd € 578 € 3.079 € € 1.977 € 2.729 € 1.411 € € € € € €

sub tot jr 6.937 36.944 23.722 32.753 16.928

Vak. 8% 555 2.956 1.898 2.620 1.354 € € € € € €

sub tot 7.492 39.899 25.620 35.373 18.283 € € € € € €

soc.last 2.772 14.763 9.479 13.088 6.765

overhead 12%, berekend over 2006

€ € € € € € €

€ € € € € € 20.824

173.534

Totaal mnd 10.264 12 54.662 12 0 35.099 12 48.461 12 25.047 12

van - tot juli t/m dec jan t/m sept okt t/m dec jan t/m sept okt t/m dec jan t/m sept

50.000 53.358

103.358

Benodigde bijdrage co-financiering

Bijdrage GGZ Buitenamstel

115.000

Totale bijdrage OOG ZonMW

Bijdrage Rivierduinen

91.000 9000 15.000

Subsidie OOG Zon MW bijdrage ZonMW salaris bijdrage ZonMW extra kosten bijdrage ZonMW Opleiding

218.358

15.000

totaal kosten C

totaal benodigd voor onderzoek A+B+C

15.000

totaal kosten opleiding

9000

totaal kosten B

194.358

0 4000 0 0 5000 0 0 0

€

extra kosten Materieel Computer Desk. Bevord. Reiskosten promotiekosten/implementatie dataverwerking researchnurse metingen

totaal kosten A

20.824

4.164

11.700

6.100 2600 3000

36.688

3000

14.362

10.000

35.500

30.300 2200 3000

59.862

3000

2200

1000

1000

2600

1200

54.662

1600

31.088

0

0

0

0 0 0

0

0

0

0

0

0

Sociale lasten is gezet op 37% i.v.p. 30% ten behoeve van indexering & CAO aanpassingen & ziekteverzuim & eindejaarsuitkering welke over de jaren heen nog niet zijn te voorzien Eindtotaal jaar 2006 2007 2008

Berend Verhoeff Start 2006 Periodiekmmaand juli Samengestelde inschaling en 38 uur werkweek salaris onderzoeker AGIO sal AIO per 2006 fte 59/60 64 100% 21,11 2485,00 2992,00 5477,00 2738,50 105,56 2597,00 3236,00 5833,00 2916,50 0,00 2711,00 3358,00 6069,00 3034,50 63,34 2766,00 3476,00 6242,00 3121,00 84,45 2883,00 3581,00 6464,00 3232,00 42,23 2992,00 3689,00 6681,00 3340,50

2009

16.899

0

23.000

18.200 1800 3000

39.899

3000

1800

1000

800

35.099

2010

1273

22.888

28.700

24.300 1400 3000

52.861

3000

1400

1000

400

48.461

2011

0

12.947

16.100

12.100 1000 3000

29.047

3000

1000

1000

0

25.047

Commentaar op aandachtspunten van de commissie na de vooraanmelding. De subcommissie Opleiding tot Onderzoeker in de GGZ heeft de kandidaat de volgende aandachtspunten meegegeven: 1) Het feit dat de kandidaat nog maar net begonnen is met de opleiding tot psychiater vormt in de ogen van de commissie een zeker risico. De combinatie van promotieonderzoek, klinisch werk en klinische opleiding kan op de lange duur een zware belasting vormen en een vergroot afbreukrisico betekenen. Kunt u aangeven hoe u de risico’s denkt te minimaliseren? 2) In de begroting zijn de cortisol bepalingen niet terug te vinden. Hieronder volgt het commentaar op de aandachtspunten: 1) Ik denk dat het afbreukrisico minimaal zal zijn vanwege de volgende argumenten: a. Als ik met het onderzoek start, heb ik al 2 jaar basisopleiding erop zitten (en hoef dan dus nog maar 1 jaar basisopleiding). Het jaar onderzoek dat dan volgt kan ik in het kader van mijn keuze-jaar van de opleiding doen. Tijdens dit jaar heb ik geen onderwijs of andere verplichtingen vanuit mijn opleiding tot psychiater en ik kan hierdoor de volledige tijd aan mijn onderzoek werken. b. Na dit jaar onderzoek ben ik van plan mijn opleiding af te ronden. In deze periode hoef ik slechts minimale aandacht aan mijn onderzoek te besteden. In dit project is dat goed mogelijk omdat het is ingebed in het NESDA consortium, waardoor de tot standkoming van de data set niet van mij afhankelijk is. c. Na het afronden van mijn opleiding tot psychiater zal ik als psychiater onderzoek met deeltijd klinisch werk combineren en het onderzoek afronden in 2011. Ik heb dan dus geen belasting meer door mijn klinische opleiding en geoormerkte tijd voor het onderzoek. d. Mijn opleider, Prof.dr. ATF Beekman, is tevens begeleider in het onderzoek, en hij heeft toegezegd er op toe te zien dat het afbreukrisico minimaal zal zijn. e. Binnen GGZ Buitenamstel is er ruime ervaring met het opleiden van artsen die tevens onderzoek doen. Momenteel zijn er minimaal zeven artsen die in een dergelijke constructie hun opleiding volgen en promotieonderzoek doen. In de praktijk blijkt dat deze combinatie geen problemen oplevert voor de opleiding of het onderzoek en dat de belasting ook op de lange termijn niet te zwaar wordt. Dit komt deels door de goede infrastructuur voor het doen van onderzoek en deels door de structuur van de opleiding, die het doen van onderzoek goed mogelijk maakt.

2) Cortisol bepalingen worden vanuit het NESDA consortium gefinancierd en hoeven dus niet voor dit onderzoek apart begroot te worden.

BIJLAGE AANVULLENDE INFORMATIE OVER WERK- EN OPLEIDINGSPLAN, SETTING EN KANDIDAAT

Titel subsidieaanvraag

HPA-axis dysfunction and common mental disorders: To whom does it concern? 3952 GGZ Buitenamstel B. Penninx B. Verhoeff

Nummer ZonMw Aanvrager Penvoerder/projectleider Kandidaat/onderzoeker

WERKPLAN 1. Geef hieronder per onderzoeksjaar het gemiddeld aantal uren per week dat gegarandeerd is voor onderstaande activiteiten. (Ga uit van 43 weken per jaar; bij afwijkend aantal weken omrekenen).

Vanaf medio 2006 (21.5 wk p.j.)

2007

2008

2009

2010

Onderzoek

8

34

0

20

28

Tot medio TOTAAL AANTAL 2011 (21.5 wk p.j.) UREN (43 wk p.j.) 14 104

Klinisch werk

10

0

36

14

8

4

72

Klinische opleiding* Begeleiding promotie team Overige begeleiding Naam: Aanvullende wetenschappelijke opleiding (opleidingsplan)

5

0

10

2

0

0

17

1

3

0

2

2

2

10

-

-

-

-

-

-

-

Verplichte cursus ZonMw

3

2

2

2

0

9.5

40

48

40

40

20

212.5

GEMIDDELDE WERKWEEK (totaal)

0,5** 24.5

* Met inbegrip van supervisie. Klinisch werk dat in het kader van de klinische opleiding wordt verricht opnemen als ‘klinisch werk’. ** verplichte driedaagse cursus ZonMw (24 uur /43 wk)

2. In welk jaar vindt de promotie naar verwachting plaats? 2011

OPLEIDINGSPLAN Gedurende het promotietraject volgt de onderzoeker aanvullende wetenschappelijke scholing. Het opleidingsplan bestaat uit drie delen: 1. een algemeen gedeelte gericht op het verwerven van wetenschappelijke vaardigheden (bijvoorbeeld een cursus methoden van onderzoek) 2. een specifiek gedeelte gericht op het promotieonderwerp (bijvoorbeeld bijwonen van een internationaal congres over stoornis X) 3. een cursus gericht op de ontwikkeling van vaardigheden van klinisch werkende wetenschappelijk onderzoekers. Deze cursus is verplicht. De cursus beslaat drie dagen in 2006 en wordt verzorgd door ZonMw. (De cursus is reeds ingeroosterd in het werkplan). Onderzoeker, promotor en aanvrager stellen zelf een opleidingsplan samen voor het algemene en specifieke gedeelte. Het algemeen gedeelte kan naar behoefte worden uitgebreid met cursussen die gericht zijn op onderzoek in de klinische praktijk.Geef hieronder aan welke opleidingsactiviteiten u denkt te gaan volgen. (Als u reeds een voorlopig opleidingsplan heeft ingediend kunt u het in onderstaand schema onderbrengen en eventueel verder uitwerken).

Opleidingsplan algemeen deel Activiteit

Georganiseerd door

wanneer

tijdsbeslag

kosten 1

1. Cursus Writing English for publication.

Gratuate School of Neuroscience Amsterdam and Rudolf Magnus Gratuate School of Neuroscience Utrecht, ONWA (Onderzoeksschool NeuroWetenschapp en Amsterdam).

Start januari 2007.

25 uur

521 euro.

2. Basic course on biostatistics and clinical epidemiology.

ONWA

Februari 2007.

60 uur

600 euro.

3. Cursus Inleiding SPSS

Postinitieel masteronderwijs Epidemiologie Amsterdam EMGO Instituut en afd. KEB, VU medisch centrum, Amsterdam.

September 2007.

12 uur

100 euro.

4. Cursus Principes van epidemiologische data-analyse

Postinitieel masteronderwijs Epidemiologie Amsterdam EMGO Instituut en afd. KEB, VU medisch centrum, Amsterdam.

Januari 2008

24 uur

200 euro.

5. Cursus “ethische aspecten van het mensgebonden onderzoek”.

ONWA

Februari 2007

3 dagen

100 euro

6. Cursus “geschiedenis, wetenschapsleer en logica”.

ONWA

Oktober 2006

3 dagen

100 euro

7. Wetenschapslunches Psychiatrie.

VUMC/GGZ buitenamstel

maandelijks

1 uur/maand

gratis

1

Neem de bedragen over in de bijlage ‘begroting’.

Opleidingsplan specifiek deel 1. Introductie cursus neurowetenschappen voor PhD studenten.

ONWA

November 2006 50 uur

570 euro.

2. Congres: APA, VS, (2007) state of the art psychiatry/neurology, meest recente informatie op het gebied van behandeling en pathofysiologie.

American Psychiatric Association.

21-26 mei 2007 1 week

2500 euro

3. World Congress of Biological Psychiatry (2009, 2010). Meest recente informatie op het gebied van biologische psychiatrie.

The World Federation of Societies of Biological Psychiatry.

Voorjaar 2009 2x 1 week en 2010, exacte data niet bekend.

5000 euro

NvVP

05-07 april 2006. Voorjaar 2008, datum niet bekend.

2x 3 dagen

500 euro

Juni 2007

80 uur

? niet bekend

Jaarlijks

1 dag/jaar

gratis

4.Voorjaarscongres NvVP (2006, ontwikkeling en levensloop, 2008) 250 per keer.

5. Course on Molecular ONWA Neurobiology, oa genetica, proteomics en genome projects in de psychiatrie. 6. NESDA dag NESDA

SETTING (in te vullen door GGZ- instelling) 1. De setting waar de klinische werkzaamheden worden verricht is een: 0 niet- academische GGZ instelling (ga verder met vraag 2) x academisch behandelcentrum (ga door naar vraag 3) 0 anders…………………….. 2. Is er een geformaliseerd samenwerkingsverband tussen uw GGZ instelling en een universiteit of academisch behandelcentrum? 0 Ja 0 Nee 3. Hoe krijgt de samenwerking tussen GGZ instelling en academisch behandelcentrum/universiteit op het gebied van onderzoek in de praktijk gestalte? De GGZ Buitenamstel werkt intensief samen met het VU medisch centrum op het gebied van patiëntenzorg, onderzoek en onderwijs en is de werkplaats van de afdeling Psychiatrie van het VUmc. Binnen GGZBA zijn er gespecialiseerde academische poliklinieken voor angst, depressie en trauma, die een bovenregionale functie hebben voor de patiëntenzorg. Tevens streeft GGZ Buitenamstel naar academisering van haar reguliere zorgprogramma’s voor angst, depressie en trauma. De academische poliklinieken bieden de infrastructuur voor tal van onderzoeksactiviteiten van waaruit zorgprogramma’s worden ontwikkeld. Deze poliklinieken bieden de infrastructuur voor tal van onderzoeksactiviteiten, zoals NESDA. Het wetenschappelijk onderzoek vindt plaats in het kader van het samenwerkingsverband met de VU en het VUmc. Deze samenwerkingsovereenkomst biedt VU-medewerkers gelegenheid bij GGZ Buitenamstel onderwijs en onderzoek uit te voeren en de academische cliëntenzorg verder te ontwikkelen. Dit gebeurt zodanig dat academische en reguliere patiëntenzorg elkaar positief kunnen beïnvloeden. Ook het brede scala aan opleidingen in de geestelijke gezondheidszorg bij GGZ Buitenamstel vindt plaats in samenwerking met het VUmc.

4.

Waarom vindt u uw setting een goede omgeving voor een klinisch onderzoeker in opleiding? De voorganger van GGZ Buitenamstel, de Valeriuskliniek, was de eerste academische vakgroep Psychiatrie van Nederland en de instelling heeft sindsdien ruime ervaring opgedaan in het opleiden van onderzoekers. Bovendien was de Valeriuskliniek de 1ste die een assistent geneeskunde in opleiding tot onderzoeker (AGIKO) in de psychiatrie afleverde. Inmiddels is een groot aantal artsen binnen GGZ Buitenamstel werkzaam die onderzoek succesvol combineren met de opleiding tot psychiater of hun proefschrift al hebben afgerond. Hierdoor is binnen GGZ Buitenamstel de nodige routine met deze combinatie ontstaan. Bovendien bevinden zowel de academische poliklinieken als de NESDA onderzoeksgroep zich op de locatie Valeriuskliniek, waardoor er directe communicatie bestaat tussen de onderzoekswereld en de klinische praktijk. Dit maakt GGZ Buitenamstel een zeer goede omgeving voor een klinisch onderzoeker.

5. Biedt uw setting de mogelijkheid dat de kandidaat zich via (informele) contacten regelmatig op de hoogte kan stellen van ander lopend onderzoek? Licht uw antwoord toe. Ja, binnen de afdeling Psychiatrie en GGZ Buitenamstel lopen op dit moment meer dan 20 verschillende onderzoeksprojecten, variërend van interventiestudies tot grote cohortonderzoeken. Er zijn diverse bijeenkomsten waarin de verschillende expertise en resultaten worden uitgewisseld (zie hieronder, vraag 6). Daarnaast is het mogelijk om informeel onderzoekservaringen en resultaten uit te wisselen, aangezien de onderzoekers, supervisoren, zorgverleners, en arts-assistenten in opleiding allen op één locatie gehuisvest zijn en elkaar dus regelmatig tegen het lijf lopen. Door de informele sfeer binnen GGZ Buitenamstel loopt men gemakkelijk bij elkaar binnen.

6. Zijn er binnen en/of buiten uw setting regelmatig wetenschappelijke bijeenkomsten waaraan kandidaat kan participeren? Zo ja, geef een omschrijving van aard en frequentie. Wetenschapslunch psychiatrie (VUmc): 10x per jaar, presentatie van recente onderzoeksresultaten uit diverse lopende onderzoeken op psychiatriegebied op VUMC. ~40 onderzoekers/zorgverleners van vakgroep psychiatrie, GGZ Buitenamstel en andere geïnteresseerden. NESDA onderzoekers bijeenkomst Amsterdam: 6x per jaar, voortgang bespreking, presentatie van tussentijdse resultaten van analyses, discussies over in te dienen onderzoeksvoorstellen, ~20 onderzoekers van diverse vakgroepen binnen VUMC (psychiatrie, psychologie, huisartsgeneeskunde). NESDA dag (landelijk): 1x per jaar, voortgang bespreking NESDA studie, discussiegroepen over analyseplannen/onderzoeksvoorstellen, diverse sprekers over NESDA gerelateerde onderzoeksonderwerpen, ~90 onderzoekers van diverse instituten/instellingen (VUMC, RUG, LUMC, NIVEL, TRIMBOS, WOK, patiëntenverenigingen, GGZ instellingen). NESDA biologie werkgroep: 3x per jaar, bespreking van biologisch materiaal, opstellen van toetsbare vraagstellingen, discussie over meetinstrumenten en procedures, bespreken van resultaten met biologisch NESDA materiaal, ~15 onderzoekers van diverse instituten/instellingen (VUMC, RUG, LUMC). ICEN bijeenkomsten (instituut voor neurowetenschappen, VUMC): 10x per jaar, onderzoekspresentaties over neurowetenschappelijk onderwerp, soms met buitenlandse sprekers, ~70 onderzoekers van diverse faculteiten (aard- en levenswetenschappen, geneeskunde, psychologie). CNCR seminars (neurogenetica centrum VUmc): 10x per jaar, gerenommeerde (internationale) sprekers over neurogenetische onderwerpen. Gemiddeld 50 tot 100 onderzoekers van diverse faculteiten (aard- en levenswetenschappen, geneeskunde, psychologie, wis- en natuurkunde). Promovendi worden geregeld in de gelegenheid gesteld om zelf ook een bijdrage te leveren aan de wetenschappelijke bijeenkomsten en ze worden getraind in het presenteren. De bijeenkomsten zijn interactief, zodat er communicatie over en weer is met andere onderzoekers.

Vanuit de opleiding zijn er ook nog twee refereercircuits waarin veel aandacht voor onderzoek is: - Wekelijkse refereerbijeenkomst met alle psychiaters in opleiding bij GGZ Buitenamstel. - Maandelijkse refereeravond van het consortium Noord-Holland (Mentrum, Geestgronden, Sint Lucas Andreas Ziekenhuis, AMC de Meren en GGZ Buitenamstel) met de eindreferaten van de psychiaters in opleiding van de genoemde instellingen. Tot slot, voor de uitvoering van dit specifieke project zullen maandelijks projectgroepbesprekingen plaatsvinden, afwisselend in Leiden en in Amsterdam.

KANDIDAAT (in te vullen door kandidaat) 1. Wanneer en waardoor is bij U de ambitie ontstaan om klinisch onderzoeker te worden? De ambitie om klinisch onderzoeker te worden is al ontstaan tijdens mijn co-schappen en toegenomen tijdens mijn eerste baan als behandelend arts in de psychiatrie. Mijn ambitie is voortgekomen uit een confrontatie met klinische problematiek. In de eerste plaats een confrontatie met de nog gebrekkige en weinig selectieve mogelijkheden bij de behandeling van patiënten met onder andere depressie en angst. Dit maakt dat ik middels het doen van onderzoek wil bijdragen aan het verbeteren van behandel- en preventiemogelijkheden. In de tweede plaats een confrontatie met mijn eigen wetenschappelijke houding in besluitvorming en probleemanalyse in mijn klinische werk. In het bijzonder het leren toepassen en implementeren van resultaten uit wetenschappelijk onderzoek in de dagelijkse praktijk maakt, dat ik zeer graag een wetenschappelijke opleiding wil volgen. Verder zie ik het als een uitdaging de opgedane psychiatrische en neurobiologische kennis te integreren en toepasbaar te maken voor de dagelijkse praktijk van hulpverleners in de GGZ.

2. Hoe formuleert u nu uw motieven om klinisch onderzoeker te willen worden? Mijn motieven om klinisch onderzoeker te willen worden zijn: - Het leren integreren en implementeren van psychiatrische en neurobiologische resultaten uit wetenschappelijk onderzoek in de dagelijkse praktijk. - Mijn overtuiging dat wetenschappelijk onderzoek en klinische praktijk alleen in combinatie kan leiden tot verbetering van kennis die relevant is voor de praktijk. - De wens wetenschappelijke kennis toepasbaar te maken voor zorgprogramma’s en over te brengen aan de clinicus. - De combinatie van uitgesproken klinische interesse in de chronisch depressieve en angstige patiëntengroep met een fundamenteel wetenschappelijke interesse in de pathofysiologie van psychiatrische stoornissen. - Het leveren van een bijdrage aan het verbeteren van behandel- en preventiemogelijkheden voor depressie en angststoornissen. In dit project hopen wij bijvoorbeeld te komen tot een set van psychologische, biologische en genetische variabelen die een betere voorspelling kunnen geven van welke patiënt verhoogd risico loopt op het optreden of terugkeren van een depressie of angststoornis. Deze mensen zou dat intensievere zorg geboden kunnen worden, terwijl bij ander, zonder deze risicofactoren, onderhoudsmedicatie bijvoorbeeld achterwegen kan blijven.

3. Wat onderscheidt volgens u een wetenschappelijk onderzoeker van een klinisch onderzoeker? Een klinisch onderzoeker onderscheidt zich van een wetenschappelijk onderzoeker omdat hij in hoge mate voeling moet houden met de klinische praktijk. Hij moet onderzoeksresultaten uit de wetenschap kunnen overdragen en implementeren naar de praktijk. Ook heeft hij de taak de verkregen kennis te verspreiden onder clinici zodat er meer “evidence based” behandelkeuzes gemaakt kunnen worden. De klinisch onderzoeker is bij uitstek degene die de

kloof tussen wetenschap en patiëntenzorg moet overbruggen. De klinisch onderzoeker vertaalt als het ware de vragen uit de kliniek in wetenschappelijk toetsbare experimenten. Andersom dienen wetenschappelijke bevindingen vertaald te worden naar de klinische toepassing. Door het directe contact met de kliniek kan de klinisch onderzoeker beter inzicht krijgen in wat voor de klinische praktijk het meest relevant is.

4. Hoe ziet u uw carrière op langere termijn wat betreft uw onderzoeks- en/of klinische ambities? Mijn ambitie is om ook na dit onderzoek klinisch werk met wetenschappelijk onderzoek te combineren. Mijn wens is daarin ook een vertalers- en bruggenbouwfunctie te bekleden. Ik denk hierbij aan het vertalen van gegevens uit de neurowetenschappen naar de klinische praktijk door bijvoorbeeld het ontwikkelen van nieuwe behandelrichtlijnen, zorgprogramma’s en psycho-educatie materiaal voor patiënten en clinici. Binnen GGZ Buitenamstel en NESDA is het heel goed mogelijk om later, als psychiater, klinisch werk en onderzoek te blijven combineren. Ook na mijn onderzoek loopt het NESDA onderzoek nog door tot in elk geval 2015. Er zullen voor mij dan ook alle mogelijkheden zijn om door te gaan met onderzoek op dit terrein, hetgeen mij een unieke niche zou geven binnen het GGZ onderzoek.

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