Dynamics of cortisol in depression and anxiety disorders

152 Pages·2010·0.83 MB·English

Dynamics of cortisol in depression
and anxiety disorders

Gerthe Veen
Gerthe Veen
Dynamics of cortisol in depression and anxiety disorders
Cover design: Maria Heesen
Print: Ponsen en Looijen, Ede, The Netherlands
© 2009 G. Veen, Amsterdam, The Netherlands
Dynamics of cortisol in depression
and anxiety disorders

Proefschrift

ter verkrijging van de graad van Doctor aan de Universiteit Leiden
op gezag van Rector Magnificus Prof. Mr. P.F. van der Heijden,
volgens besluit van College voor Promoties
ter verdediging op donderdag 29 april 2010
klokke 16.15 uur

door

Gertje Veen
geboren te Nootdorp
in 1971
Promotiecommissie:
Promotor: Prof. Dr. F.G. Zitman
Copromotoren: Dr. I.M. van Vliet
Dr. R.H. de Rijk
Overige leden: Prof. Dr. E.R. de Kloet
Prof. Dr. B.W.J.H. Penninx (Vrije Universiteit Amsterdam)
Prof. Dr. A.J.W. van der Does
Contents

Chapter 1
Introduction and thesis outline...............................................................................................7

Chapter 2
Need for alternative ways of phenotyping of mood, anxiety, and somatoform
disorders in biological resear.................................................................................................31

Chapter 3
The influence of psychiatric comorbidity on the dexamethasone/CRH test in major
depression.................................................................................................................................37

Chapter 4
Basal cortisol levels in relation to dimensions and DSM-IV categories of depression
and anxiety................................................................................................................................53

Chapter 5
Salivary cortisol, serum lipids and adiposity in patients with depressive and anxiety
disorders....................................................................................................................................73

Chapter 6
C-reactive protein polymorphisms are associated with plasma C-reactive protein
levels and the cortisol awakening response in basal conditions.......................................89

Chapter 7
Summary and discussion......................................................................................................105

Samenvatting (Dutch summary).........................................................................................133

Dankwoord (Acknowledgements)......................................................................................141

Curriculum Vitae...................................................................................................................145

List of publications................................................................................................................149

Chapter 1

Introduction and thesis outline
Introduction and thesis outline
Introduction

All organisms must maintain a complex and dynamic equilibrium, or homeostasis,
which is constantly challenged by internal and external forces termed stressors. Stress
occurs when homeostasis is threatened or perceived to be so; homeostasis is
reestablished by various physiological and behavioral adaptive responses. During
evolution the organism has developed a stress-system to deal with factors which may
disturb homeostasis, of which the Hypothalamus-Pituitary-Adrenal (HPA) axis is an
important part. Neuroendocrine hormones, such as cortisol, play a major role in the
maintenance of basal homeostasis as responses to threat, and are involved in the
pathogenesis of diseases characterized by dyshomeostasis.1;2
The stress-system needs to have a far-reaching power over the metabolism of the
body, because in times of crisis the body should be able to acutely redirect metabolism
to enable a fight, flight or freeze reaction. Especially in humans, along with the
development of the stress system, psychological stress factors became more
important, such as fear anticipation. It is generally assumed that the organism did not
develop a new stress system to cope with these psychological stressors, but used the
already working stress-system, again with the HPA axis as an important part.
If the stress-system plays an important role in psychological stress, it is to be
expected that depression and anxiety disorders are accompanied by dysfunctions of
this system.3-5 This hypothesis has been tested, mainly in research using cortisol
concentrations in blood or saliva as marker for the function of the hypothalamus-
pituitary-adrenal (HPA) axis. Thus far, the results were inconsistent: hypercortisolism,
hypocortisolism and normal cortisol levels were found.6-14
Before one can conclude that thus the HPA axis and the stress-system are not
involved in depression and anxiety disorders, several other explanations should be
considered. Cortisol may not be the right marker for the stress-system in general or
the HPA axis in particular. As cortisol has such a central place in the stress-system this
is not very probable. Besides, the problem is not that abnormal cortisol levels are
absent in patients with depressive and anxiety disorders: Abnormalities have been
found repeatedly. The problem is that the abnormalities were inconsistent. Therefore,
another possibility should be considered, i.e., that the phenotype or clinical picture is
described insufficiently. This is less improbable than it may seem: the validity of the
most used diagnostic classification system, the DSM-IV, has been questioned
frequently. To date, the DSM has focused solely on face or clinical validity, the
assertion that the diagnoses correspond to clinicians’ subjective views of a disorder.
This is a weak form of validity only requiring consensus among clinical experts. One
common form of validity is expressed by sensitivity and specificity, which are both
low for DSM-IV diagnoses due to the extensive comorbidity, the high within-category
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Chapter 1
heterogeneity, and the overlap of DSM-IV diagnoses by sharing criteria. Ideally, the
validity of a diagnosis is determined by the correlation between the diagnosis and
another criterion of the disease, for instance a biological parameter, which is
considered as ‘gold standard’. As discussed above, such a gold standard has not been
found.
In this thesis we explore whether a dimensional approach to describe the clinical
picture is a better way to disentangle the relationship between phenotype and HPA
axis functioning than the DSM-IV categories. In addition to and as a consequence of
that starting point, not the clinical picture (diagnosis or dimension) was central in our
studies, but cortisol levels. In other words, we investigated per dimension to what
extent differences in scores on that dimension correlated with cortisol levels and not
which cortisol levels were found in major depression and which in anxiety disorders.
In depression and anxiety also abnormalities in metabolic and immune parameters
have been found, but again the results were inconsistent. To date, none of the
metabolic and immune markers were sufficiently specific to contribute to the
diagnosis of major depression.15 Therefore, we also investigated the relation of the
cortisol levels with those biological markers, hoping to find a more consistent picture.
In conclusion, we moved from an approach that puts psychiatric diagnosis in the
center to an approach that puts the HPA axis in the center (see figure 1). In the
following part of this introducing chapter, background information and an outline of
this thesis are presented.

Phenotype:
HPA-axis:
▪ comorbidity
▪ cortisol
▪ dimensions
Phenotype: HPA-axis:
▪ DSM-IV ▪ cortisol
Metabolic system: Metabolic system:
Immune system: Immune system:
▪ lipid metabolism ▪ lipid metabolism
▪ C-reactive protein ▪ C-reactive protein
▪ adiposity ▪ adiposity

Figure 1. Structure of thesis
Associations between HPA axis function, phenotypic characteristics, metabolic and immune factors in
depression and anxiety disorders. Associations might be bidirectional and may also exist between ‘nodes’, but
are left out in the picture for the purpose of clarity.

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Introduction and thesis outline
Major depressive disorder and anxiety disorders
Depression and anxiety disorders are invalidating affective disorders accompanied by
diminished functioning or well-being and increased mortality. Major depressive
disorder (MDD) is characterized by a depressed mood and/or the loss of interest and
pleasure in nearly all activities. In addition to these essential features, alterations in
appetite, sleep disturbances, psychomotor changes, fatigue and decreased energy,
feelings of worthlessness, cognitive problems (e.g. inability to make decisions), and
thoughts of death are considered to be characteristics symptoms. For a diagnosis
according to DSM-IV (APA, 1994), one of the essential features together with at least
four additional symptoms have to be present most of the day, nearly every day, for at
least two weeks. MDD is a common psychiatric disorder, with a 12 month prevalence
of 5.8% in the Netherlands.16
Anxiety disorders are characterized by an excessive feeling of overwhelming
anxiety, irrational fear and avoidance behaviour. The anxiety is often accompanied by
physical symptoms such as sweating, cardiac disturbances, diarrhea or dizziness.
Anxiety disorders include panic disorder, social anxiety disorder, post-traumatic stress
disorder (PTSS), obsessive-compulsive disorder, generalized anxiety disorder, and
specific phobia. Each anxiety disorder has specific symptoms, but all the symptoms
cluster around excessive, irrational fear and threat. The 12 month prevalence of all
anxiety disorders is 12.4% in the Netherlands.16 Depressive and anxiety disorders are
considered as stress-related disorders, marked by a dysfunction of the HPA axis.5

Stress
Stress and stress vulnerability are assumed to play major etiological roles in depression
and anxiety disorders. The acute stress response is reflected in the rapid activation of
the sympathetic nervous system, which leads to the release of epinephrine and
norepinephrine. The sympathic pathways (epinephrine) elevate heart rate, blood
pressure, respiration, glucose synthesis and cognitive arousal/attention.
Simultaneously, the parasympathic pathways (e.g., norepinephrine and other
catecholamines) are activated leading to a decrease in food intake, sleep and sexual
drive. As part of the stress response, the hypothalamus releases corticotrophin-
releasing hormone (CRH) inducing the release of adrenocorticotropic hormone
(ACTH) from the pituitary gland, which stimulates the adrenal cortex to produce and
secrete corticosteroids. This leads to elevated circulating levels of corticosteroids, in
man mainly cortisol (figure 2). The acute stress response is adaptive to homeostasis. In
the long term, chronic or repeating stress may impair physiological functions, such as
growth, reproduction, metabolism, and immunocompetence, and imposes an
increased risk for depression and anxiety disorders.17-19
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