| The association between atopic disorders and depression: The Northern Finland 1966 Birth Cohort Study | ||
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Depression is known to be a multifactorial disease by origin. Different biological, genetical and psychosocial factors are known to be behind the psychopathology of depressive disorders (Isometsä 1999, Kaplan et al. 1994). The etiological factors presented in this chapter are considered to be the most relevant ones in the context of this thesis.
Several lines of evidence – family, twin and adoption studies – suggest that major depression is a familial disorder and that in the majority of the cases in which a tendency of familial preponderance is noticed, it is caused by genetic factors (Kendler & Aggen 2001). It has been estimated that among first degree relatives (parents, siblings or children) of persons suffering from depressive disorders the occurrence of unipolar depression varies from 6.4% up to even 29.4% (Isometsä 1999). In addition, in a large twin study, genetic factors have recently been shown to play a greater role in the etiology of major depression among females than in males (Kendler et al. 2001a). The concept of psychosocial/environmental factors behind the etiology of depression is based on the fact that the onset of depression is often preceded by stressful life events and/or crises of a person’s life-cycle (Isometsä 1999). The overall sensitivity to the depressogenic effects of stressful life events seems to be equal for both genders, even though the psychosocial stressors themselves, preceding major depression in adulthood, differ between genders (Kendler et al. 2001c).
There are many biological theories attempting to explain the pathophysiology behind depressive disorders. One of the earliest is the so called monoamine-hypothesis, which was introduced in the 1960s (Isometsä 1999). Since then, evidence has been accumulating to indicate that the dysregulation of biogenic amines is associated with depressive disorders. Serotonin and norepinephrine are the most important biogenic amines, which are known to be behind the psychopharmacology of depression (Kaplan et al. 1994). The disorganized catecholamine and serotonin metabolisms have formed also a basis for the development of drugs against depression over several decades (Horrobin & Bennet 1999).
Dopamine, epinephrine and norepinephrine are classified as catecholamines. They are all synthesized from tyrosine. In addition to the fact that the dopamine hypothesis has been the leading neurochemical hypothesis for schizophrenia, there has also been some evidence that dopamine might be associated with the pathophysiology of depressive disorders. Low levels of dopamine metabolites have been found in depressed patients in several previous studies (e.g., Kaplan et al. 1994).
When compared with epinephrine, norepinephrine is considered to be the more important neurotransmitter in psychiatry (Kaplan et al. 1994). The locus ceruleus, which is located bilaterally in the dorsal pons near the floor of the fourth ventricle, is the most important noradrenergic nucleus in the brain. The locus ceruleus has connections to many areas of the central nervous system (CNS), including the hippocampus, the amygdala, the hypothalamus, the limbic system, and the cerebral cortex (Kaplan et al. 1994, Kaye et al. 2000). In noradrenergic neurons, dopamine is converted to norepinephrine by dopamine β –hydroxylase. Thereafter it is stored in synaptic vesicles until it is released during the depolarization of the neuron. As with dopamine, also norepinephrine is deactivated either by uptake from the synaptic cleft back into the presynaptic neuron or via the metabolism by monoamine oxidase (MAO) and by catechol-O-methyltransferase. There exist many subtypes of the α –adrenergic receptors and of the β −adrenergic receptors, by which catecholamines are mediating their effects on the target cells. In reference to these receptors, the knowledge in the field of molecular biology is rapidly increasing. For example, presynaptic α2-adrenoreceptrors are known to be acting as autoreceptors and noradrenergic neurotransmission is under the control of these receptors. Stimulation of these receptors results in a decrease in the amount of released norepinephrine (Kaplan et al. 1994, Isometsä 1999). The MAO inhibitors and the tricyclic antidepressants are blocking the metabolism and the uptake of the norepinephrine, respectively, whereas, e.g., α2-adrenoreceptror antagonists are blocking the presynaptic α2-adrenoreceptros. Thus, the immediate effect of these drugs is to enhance noradrenergic neurotransmission (Kaplan et al. 1994, de Boer 1995). In spite of the intensive work in this field, the exact role of norepinephrine behind the pathophysiology of depression has still remained unclear (Kaplan et al. 1994).
Serotonin (5-HT, i.e., hydroxy tryptamine) is synthesized from tryptophan in the axonal terminals of the serotonergic neurons. Most of the serotonergic nuclei of the brain are situated in the brainstem with median and dorsal raphe nuclei being one of the most important ones (Kaplan et al. 1994). The main metabolite of 5-HT is 5-hydroxyindoleacetic acid (5-HIAA). The concentration of 5-HIAA in the cerebrospinal fluid of depressed patients has been shown to be lowered in numerous previous studies, indicating decreased serotonergic metabolism during depression (Kaplan et al. 1994, Mann & Malone 1997, Isometsä 1999). In the most simplified form, the monoamine-hypothesis meant that depression is associated with too low a level of serotonin in the CNS. Nowadays it is known that the monoamine-hypothesis has proved to be incorrect in this simplified form (Kaplan et al. 1994, Isometsä 1999). While there exist numerous different 5-HT receptor subtypes, which mediate the effects of 5-HT, there is only one 5-HT transporter (5-HTT), which takes the 5-HT up from the synaptic cleft and returns it into the presynaptic neuron. Therefore, the modulation of 5-HTT is an important mechanism to influence the serotonergic neurotransmission (Mösner et al. 2001). Likewise in the noradrenergic neurotransmission, MAO inhibitors and tricyclic antidepressants are blocking the metabolism and the uptake of serotonin, respectively (Kaplan et al. 1994). The introduction of selective serotonin re-uptake inhibitors has improved the safety and has reduced adverse effects, but not efficacy in the treatment of depression when compared with tricyclic antidepressants and MAO inhibitors (Kaplan et al. 1994, Anderson 2000).
5-HT is also an important mediator of bidirectional interactions between the nervous and the immune systems (Mössner & Lesch 1998; Mössner et al. 2001). As reviewed by Mössner and Lesch (1998), the CNS can, via the autonomic nervous system, induce the neural release of 5-HT to the immune system. 5-HT receptors and the 5-HTT are distributed widely in immune cells and 5-HT is known to have various immunological effects.
The theories of the pathophysiology of depression, which are based on disorders in catecholamine and serotonin metabolism, have been criticized, because they are inadequate to provide a full explanation for the depression (Kaplan et al. 1994, Horrobin & Bennet 1999); Many patients fail to respond to drugs developed on the basis of those theories. There has therefore been a search for other mechanisms, which could explain the biological backgrounds behind depression. Disturbances in fatty acid metabolism have been suggested to provide one mechanism, which could also serve as a plausible theory behind the pathophysiology of depression (Horrobin & Bennet 1999). Several lines of evidence have been put together and collectively suggest that diminished omega-3 fatty acid intake or concentrations are associated with unipolar depressive disorders: A reduction in omega-3 polyunsaturated fatty acids (PUFAs), including eicosapentaenoic acid and docosahexaenoic acid, has been noted in plasma, serum phospholipids, or red cell membranes of depressive patients (Adams et al. 1996, Seko 1997, Peet et al. 1998, Maes et al. 1999). Secondly, previous findings in a cross-national analysis showed a highly significant inverse relationship between prevalence of major depression and fish consumption (Hibbeln 1998). By using a postal questionnaire survey, a higher consumption of fish has recently been shown to be associated with a reduced risk of major depression in two large general population samples (Tanskanen et al. 2001a, 2001b). A significant gender difference was found in another of these surveys, infrequent female fish-consumers being more depressive than frequent (more than once a week) consumers (Tanskanen et al. 2001b). Recently, highly purified ethyl eicosapentaenoic acid was shown to be effective in improving major depression in two randomized, placebo-controlled studies (Peet & Horrobin 2002, Nemets et al. 2002).
On the other hand, as reviewed by Maes and Smith (1998), it has been suggested that changes in 5-HT receptor number and function caused by changes in PUFAs, could also provide the theoretical rationale connecting fatty acids with the current receptor and neurotransmitter theories of depression. With regard to immunological effects, dietary fatty acids are known to have important effects on immune and inflammatory processes as reviewed previously (Kelley 2001, Maes & Smith 1998).
Among other neuropeptides, corticotropin-relasing hormone (CRH) is synthesized in the paraventricular nucleus of the hypothalamus. CRH is released into the portal circulation via which it enters the anterior lobe of the pituitary gland, where it then induces the synthesis and release of corticotropin. The biosynthesis and the release of corticosteroids from the adrenal cortex are stimulated by corticotropin (Holsboer 2001). The effects of the glucocorticoids, the end products of this hypothalamic-pituitary-adrenocortical (HPA)-axis, are mediated by intracellular receptors including glucocorticoid receptors (GRs), which play also an essential role in the feedback regulation of the HPA-axis (Pariante & Miller 2001).
Hypercortisolism and dysfunction of GRs are usually present in depression (Murphy 1997, Holsboer 2001, Pariante & Miller 2001). It has remained undefined, where exactly in the HPA-axis this dysfunction arises (Jiang et al. 2000). However, there is evidence CRH is hypersecreted from hypothalamic as well as from extrahypothalamic neurons in depression (Arborelius et al. 1999), and HPA-axis alterations are suggested to be secondary to the hypersecretion of the CRH (Pariante & Miller 2001). In addition, recent evidence shows that cytokines might be causing GR resistance (Pariante & Miller 2001).
With regard to immunological effects, it has been found that glucocorticoids, the end products of the HPA-axis, selectively suppress cellular immunity and favour humoral immune responses, and that glucocorticoid receptor binding affinity has been found to be reduced in atopic diseases (Clayton et al. 1995, Elenkov et al. 1999, Leung 2000, Nimmagadda et al. 1997).
As mentioned earlier, stressful life events play an important role in the etiology of depressive disorders (Isometsä 1999, Olff 1999) and it has been suggested that depression may be conceived as a component of chronic stress (Olff 1999). It is also known that psychological stress modulates the immune system and changes are seen in many immune parameters (Olff 1999, Maddock & Pariante 2001). In addition, there are several similarities in the immune alterations in times of chronic stress and depression (Olff 1999). Even though the findings are to some extent heterogeneous, there is now quite reliable evidence that depressed patients are likely to exhibit changes in major immune cell classes with an increase in total white blood cell counts and a relative increase in the numbers of neutrophils. Further, the relative number of lymphocytes has been shown to be reduced in patients with depression. Depression has also been found to be associated with a suppression of mitogen-induced lymphocyte proliferation and with a reduction of Natural Killer (NK) cell activity (Irwin 1999).
With regard to immune parameters, depression has also been shown to be associated with an excessive secretion of proinflammatory cytokines, such as IL-1, IL-6 and TNF (Maes et al. 1998, Maddock & Pariante 2001). Proinflammatory cytokines regulate the acute phase reaction, which is an early immune reaction against invading organisms (Maddock & Pariante 2001).
During an immune response, proinflammatory cytokines such as IL-1β and IL-6, which also are involved in the local inflammatory responses in atopic disorders (Abbas et al. 2000), are also capable to induce a non-specific systemic reaction to inflammation – a so-called syndrome of “sickness behaviour” (Dantzer 2001, Schwarz et al. 2001). As reviewed by Dantzer (2001), cytokines can affect the brain via both the afferent neurons of the vagus nerves and by direct targeting to the brain regions such as the amygdala after diffusing to the brain side of the blood-brain barrier at the circumventricular organs and the choroid plexus. In addition, cytokines do not always have to reach the brain from the periphery (directly or indirectly), because most cytokines, including IL-1, IL-4 and IL-6, can be synthesized and released within the central nervous system (Kronfol & Remic 2000). The “sickness behaviour” shares many features with major depression, including anhedonia, fatigue, loss of appetite, reduced activity, altered sleep patterns, social withdrawal, decreased libido, and depressed mood (Dantzer 2001, Maddock & Pariante 2001, Musselman et al. 2001). The overlap of symptoms in sickness behaviour with depression has led to the concept that cytokines secreted during stress would serve as an important etiological factor behind the pathophysiology of depressive disorders (Maes & Smith 1998, Musselman et al. 2001).
Psycho-neuro-immunology is a paradigm, which began to develop in the 1970s. It evaluates the complex interactions which are involved in the body-mind connection including nervous, endocrine, and immune systems, and the contribution of psychosocial factors as well as behavioural processes to these interactions (Bonneau et al. 1998, Kaye et al. 2000). The CNS and the immune system are two of the main adaptive systems of the human body (Elenkov et al. 2000). During an immune response, the CNS and the immune system communicate with each other in order to maintain homeostasis in the body (Elenkov et al. 2000, Kronfol & Remick 2000). Two major pathways, the HPA-axis and the sympathetic nervous system (SNS) are involved in this bidirectional interaction (Mössner & Lesch 1998, Elenkov et al. 2000). Cytokines play also a crucial role in this interaction. Besides acting as chemical messengers between immune cells, they can serve also as mediators between immune system and the brain (Kronfol & Remick 2000, Dantzer 2001).