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Netherlands Study of Depression and Anxiety

Objectives

Depression and anxiety are common in all age groups. Approximately 19% of Dutch adults will experience depressive or anxiety disorders at some point in their lives. The considerable effects of these disorders on well-being and daily functioning are comparable to those of major chronic physical illnesses. In economic terms, the costs of depression – loss of productivity and use of health services – rank among the top five of all disorders. Depression is the most important risk factor for suicidal behaviour. Given the fact that several effective treatment options exist for both depression and anxiety, these disorders are promising targets for efforts to improve public health.

Given their undisputed relevance for public health, it is surprising how little is known about the long-term course and consequences of anxiety and depression. From both a clinical and a public-health perspective, accurate data on the prognosis are necessary to make it possible to plan and monitor treatment and to educate patients. In addition, although it is well known that depression and anxiety often coincide, very little is known about the pathways leading to co-morbidity. This is of clinical importance, because patients with co-morbid anxiety and depression suffer from more severe symptoms, more disability, and longer illness episodes and are less likely to respond to treatment. There is a scarcity of large-scale epidemiological studies, either national or international, that monitor cohorts of patients with depressive and anxiety disorders over a long period of time.
The main aim of NESDA is to examine the long-term (eight-year) prognosis and co-morbidity of anxiety and depression in order to improve quality of care and prevent  chronicity. Four specific research objectives are:
  1. To describe the long-term course of anxiety and depression and their consequences for public health.
  2. To identify important demographic, psychosocial, clinical, biological, and genetic determinants of the long-term course of anxiety and depression and their consequences for public health.
  3. To investigate the role of stress-regulating brain systems and gene-expression profiles in predicting the prognosis and consequences of anxiety and depression.
  4. To describe patients’  preferences in and barriers to the utilisation of healthcare, and their relationship to the long-term course of anxiety and depression, in order to promote the implementation of promising interventions in primary and specialised mental healthcare.
To address these objectives, NESDA was designed as a prospective cohort study spanning eight years of follow-up, during which the data needed to address the four study objectives will be collected.
 

Collaborations

The NESDA consortium consists of:
  • Departments of psychiatry, general practice and psychology of Leiden University Medical Center
  • Departments of psychiatry, general practice and psychology of University Medical Center Groningen
  • Research Institute NIVEL, Utrecht
  • IQ healthcare, Radboud University Medical Center, Nijmegen
  • Netherlands Institute of Mental Health and Addiction (Trimbos Institute), Utrecht
 Other national collaborations:
  • Department of biological psychology, VU University 
  • NeuroCampus Amsterdam (NCA), VU University (Medical Center)
  • Department of psychiatry, Radboud Medical Center Nijmegen
 International collaborations:
  • Genome-wide study of Major Depressive Disorder: collaboration with University of North-Carolina, USA.
  • Collaboration within the Psychiatric Genetic Consortium (PGC) to conduct meta-analyses of genome wide studies in the area of depression. For this purpose collaboration exists with various research groups from USA, England, Australia and Germany.
  • Epidemiological study using combined data from many European population studies to examine the genetics of cardiovascular risk: ENGAGE: European Network of Genetic And Genomic Epidemiology (ENGAGE) 

Results

A total of 2981 respondents, aged 18-65 years, have been recruited between September 2004 and February 2007 in different health care settings (community, primary care and specialised mental health care). Table 1 presents the stratified sampling frame and the recruited number of participants according to anxiety and/or depression disorder status. Details are described elsewhere (Penninx et al. 2008). As the sample is intended to represent patients seen in different settings, there were very few a priori exclusion criteria. However, patients were excluded if they have a primary diagnosis of a psychotic disorder, or an addiction disorder, because both the course and the care trajectories of such patients are largely determined by the primary disorder, which is not of interest in this study. 

Table 1: Overview of the number of NESDA respondents per recruitment setting

Total
N
N without any dep/anx disorder
N with current¹ dep/anx disorder
N with lifetime2 dep/anx disorder
Recruited from community
Subjects with life-time dep/anx disorder3
Subjects with parents with dep/anx disorder4

303
261

0
138

104
47

303
123
Recruited from primary care
Controls: no dep/anx symptoms or disorder
Subjects with subthreshold symptoms5
Subjects with non-current dep/anx disorder¹
Subjects with current dep/anx disorder¹

373
141
353
743

373
141
0
0

0
0
0
743

0
0
353
743
Recruited from mental health organizations
Subjects with current dep/anx disorder¹

807

0

807

807
Total
2981
652
1701
2329

Dep/anx disorder=depressive or anxiety disorder
¹ current = 6-month prevalence
   history of dep/anx disorder according to the CIDI interview. 

² lifetime disorders include current diagnoses as well as diagnoses earlier in life
³ recruited from NEMESIS study
4 recruited from the ARIADNE study
5 defined as Kessler10 score³ 20 or positive anxiety screening questions or a DSM-diagnosis of minor depression, but not having a (prior) history of dep/anx disorder according to the CIDI interview. 

The baseline assessment lasted on average 4 hours and was conducted a one of the clinic sites. It included face-to-face interviews and self-report questionnaires, which broadly cover concepts such as psychopathology, quality of life, physical functioning, healthcare utilisation and preferences, personality and social characteristics. In addition, blood and saliva samples were collected during a physical examination.
First observations were that many participants with a depressive or anxiety disorder appeared to have multiple disorders. The comorbidity between depression and anxiety disorders was extremely high: close to 70%. This comorbidity was associated with more symptom severity and poorer functioning.

Using baseline assessments, we explored the pathophysiological basis of depressive disorder by examining the hypothalamus-pituitary-adrenal (HPA) axis and the autonomic nervous system functions in the NESDA cohort. We observed that depressed persons had significantly lower heart rate variability – an indicator of lower vagal tone, a known risk factor for cardiovascular disease. This reduced heart rate variability, however, appeared to be mainly driven by the use of antidepressants (Licht et al. 2008). Regarding the HPA-axis, we observed a modest but significantly higher cortisol awakening rise among persons with depression, as compared to controls (Vreeburg et al. 2008).

NESDA also collected DNA samples of all participants, which was used for genetic studies of major depressive disorder. Through the GAIN-program of the foundation of the National Institutes of Health, we received a grant which allowed for genome-wide association analysis. Through a collaboration with the Netherlands Twin Register, we were able to compare information on more than 400,000 SNPs between cases with major depressive disorder and healthy controls. This yielded evidence for a new potentially interesting genetic area involved in depression (Sullivan et al. 2008 epub). The genome wide data were further used to examine the genetic basis of various cardiovascular traits in a large-scale European collaborative study, which has results in two high-impact papers (Aulchenko et al. 2008; Prokopenko et al. 2008).

The NESDA study is still in an early phase. Many baseline analyses are currently ongoing. We are confident that NESDA will grow into a research infrastructure of tremendous use to scientists interested in addressing questions related to anxiety and depression. Currently, we already have initiated over 20 ancillary projects that will investigate a specific, more detailed research question using NESDA data. Most of those projects are being led by a multidisciplinary team of NESDA investigators and host a PhD-student who will complete a thesis in the coming years. At this moment, the 2-year and 4-year follow-up assessments are ongoing, which will soon provide us with the first longitudinal data that will provide information on the course of depressive and anxiety disorders.

REFERENCES

Penninx BW, Beekman AT, Smit JH, Zitman FG, Nolen WA, Spinhoven P, Cuijpers P, de Jong PJ, van Marwijk HWJ, Assendelft WJJ, van der Meer K, Verhaak P, Wensing M, de Graaf R, Hoogendijk WJ, Ormel J, van Dyck R. The Netherlands Study of Depression and Anxiety (NESDA): Rationale, objectives and methods. Int J Meth Psychiatr Res 2008;17:121-140.

Boomsma DI, Willemsen G, Sullivan PF, Heutink P, Meijer P, Sondervan D, Kluft C, Smit G, Nolen WA, Zitman FG, Smit JH, Hoogendijk WJ, van Dyck R, de Geus EJ, Penninx BW. Genome-wide association for Major Depression: Description of samples for the GAIN Major Depressive Disorder Study: NTR and NESDA biobank projects. Eur J Hum Genet 2008;16:335-42.

Licht CM, de Geus EJ, Zitman FG, Hoogendijk WJ, van Dyck R, Penninx BW. Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Arch Gen Psychiatry 2008;65:1358-67.

Prokopenko I, Langenberg C, Florez JC, Saxena R, Soranzo N, Thorleifsson G, Loos RJ, Manning AK, Jackson AU, Aulchenko Y, Potter SC, Erdos MR, Sanna S, Hottenga JJ, Wheeler E, Kaakinen M, Lyssenko V, Chen WM, Ahmadi K, Beckmann JS, Bergman RN, Bochud M, Bonnycastle LL, Buchanan TA, Cao A, Cervino A, Coin L, Collins FS, Crisponi L, de Geus EJ, Dehghan A, Deloukas P, Doney AS, Elliott P, Freimer N, Gateva V, Herder C, Hofman A, Hughes TE, Hunt S, Illig T, Inouye M, Isomaa B, Johnson T, Kong A, Krestyaninova M, Kuusisto J, Laakso M, Lim N, Lindblad U, Lindgren CM, McCann OT, Mohlke KL, Morris AD, Naitza S, Orrù M, Palmer CN, Pouta A, Randall J, Rathmann W, Saramies J, Scheet P, Scott LJ, Scuteri A, Sharp S, Sijbrands E, Smit JH, Song K, Steinthorsdottir V, Stringham HM, Tuomi T, Tuomilehto J, Uitterlinden AG, Voight BF, Waterworth D, Wichmann HE, Willemsen G, Witteman JC, Yuan X, Zhao JH, Zeggini E, Schlessinger D, Sandhu M, Boomsma DI, Uda M, Spector TD, Penninx BW, Altshuler D, Vollenweider P, Jarvelin MR, Lakatta E, Waeber G, Fox CS, Peltonen L, Groop LC, Mooser V, Cupples LA, Thorsteinsdottir U, Boehnke M, Barroso I, Van Duijn C, Dupuis J, Watanabe RM, Stefansson K, McCarthy MI, Wareham NJ, Meigs JB, Abecasis GR. Variants in MTRN1B influence fasting glucose levels. Nat Gen 2008; in press.

Sullivan P, de Geus EJC, Willemsen G, James MR, Smit JH, Zandbelt T, Arolt V, Baune BT, Blackwood D, Cichon S, Coventry WL, Domschke K, Dumenil T, Farmer A, Fava M, Gordon SD, Heutink P, Holsboer F, Hoogendijk WJ, Hottenga JJ, Kohli M, Lin D, Lucae S, MacIntyre DJ, Maier W, McGhee KA, McGuffin P, Montgomery G, Muir WJ, Nolen W, Nöthen MM, Perlis R, Pirlo K, Posthuma D, Rietschel M, Schosser A, Smoller JW, AB Smit, Tzeng JY, van Dyck R, Zitman FG, Verhage M, Martin NG, Wray NR, Boomsma DI, Penninx BW. Genome-wide association for Major Depressive Disorder: a possible role for the protein PCLO. Mol Psychiatry 2009; in press.

Ferrarini L, Veer IM, Baerends E, van Tol MJ, Renken R, van der Wee NJ, Veltman D, Aleman A, Zitman F, Penninx BW, van Buchem MA, Reiber JHC, Rombouts S, Milles J. Hierarchical functional modularity in the resting-state human brain. Human Brain Mapping 2009; in press.

Aulchenko YS, Ripatti S, Lindqvist I, Boomsma D, Heid IM, Pramstaller PP, Penninx BW, Janssens AC, Wilson JF, Spector T, Martin NG, Pedersen NL, Kyvik KO, Kaprio J, Hofman A, Freimer NB, Jarvelin MR, Gyllensten U, Campbell H, Rudan I, Johansson A, Marroni F, Hayward C, Vitart V, Jonasson I, Pattaro C, Wright A, Hastie N, Pichler I, Hicks AA, Falchi M, Willemsen G, Hottenga JJ, de Geus EJ, Montgomery GW, Whitfield J, Magnusson P, Saharinen J, Perola M, Silander K, Isaacs A, Sijbrands EJ, Uitterlinden AG, Witteman JC, Oostra BA, Elliott P, Ruokonen A, Sabatti C, Gieger C, Meitinger T, Kronenberg F, Döring A, Wichmann HE, Smit JH, McCarthy MI, van Duijn CM, Peltonen L; for the ENGAGE Consortium. Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts. Nat Gen 2008; epub.

Vreeburg SA, Hoogendijk WJ, van Pelt J, de Rijk RH, van Dyck R, Smit JH, Zitman FG, Penninx BW. Major Depressive Disorder and HPA axis activity: findings from a large cohort study. Arch Gen Psychiatry 2009.

Pardo L, Bochdanovitz Z, de Geus E, Hottenga JJ, Sullivan P, Posthuma D, Penninx BWJH, Boomsma D, Heutink P. Global similarities with local differences in Linkage disequilibrium between the Dutch and the HapMap CEU populations. Eur J Hum Gen 2009; in press.

Wiersma J, Hovens J, van Oppen P, Giltay E, van Schaik A, Beekman AT, Penninx BW. Childhood trauma as a risk factor for chronicity of depression. J Clin Psychiatry 2009; in press.

Verhaak PF, Prins MA, Spreeuwenberg P, Draisma S, van Balkom A, Bensing JM, Laurant MG, van Marwijk HW, van der Meer K, Penninx BW. Being treated for common mental disorders. Gen Hosp Psychiatry 2008; in press.

Current research projects based on NESDA

  • Prognosis of depression: depressive course and trajectories of functional and work disabilities
  • The pathophysiological basis of depression and anxiety: an epidemiological examination of the roles of the autonomic nervous system and the hypothalamus-pituitary-adrenal axis
  • Depression, Anxiety and Atherosclerosis: shared pathways? Cardiovascular extension of the Netherlands Study of Depression and Anxiety
  • Mental health in the life course: the impact of work and social capital
  • HPA- and HPT- axis dysfunction and common mental disorders: to whom does it concern?

Contact information

Prof. Dr. B.W.J.H. Penninx: +31207885674; mail: b.penninx@vumc.nl