P : Major depression (MD) is one of the most costly diseases in the world (Wasserman, 2006). Untreated affective disorders tend to be chronic and also life-threatening, since depression commonly preceeds suicide. In the clinic, these patients must be assesed for their risk of suicide, as it is estimated to be the cause of death in 10-15% of individuals with MD (Wasserman, 2006). To expand the possibilities of intervention and therapy of suicidality, particularly in connection to the treatment of MD, its neurobiological causality is being explored (Mann, 2003; Wasserman, 2001). In a stress-vulnerability model, genetic set-up, as well as environmental exposure to psychological stress, contributes to a person's predisposition for suicidality, as well as to MD (Hasler et al., 2004; Mann, 2003; Wasserman, 2001). The main neurochemical findings on suicidality have suggested alterations in neurosystems which are usually implicated in MD; a lowered serotonergic (5HT) activity, depletion of the noradrenergic (NA) system and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. Whereas the genes of e.g. the 5HT system and of the key NA-biosynthesis enzyme, tyrosine hydroxylase, have been studied extensively in this context (Bondy et al., 2006; Rujescu et al., 2007), the genes in the HPA axis have only begun to be investigated recently. An over-active HPA axis is also the most consistent neurobiological indicator of MD (Bale, 2005; Hasler et al., 2004; Nemeroff & Vale, 2005; Roy et al., 1987; Swaab et al., 2005). This is true also true for some suicidal individuals, as an overactive HPA axis, particularly in connection to depression, is often preceeding suicide (Coryell & Schlesser, 2001; Young, 2005). The HPA-activity is primarilly attributed to the action of corticotropin releasing hormone (CRH) and by altered feedback regulation of the axis through the glucocorticoid and mineralocorticoid receptors, which is manifested as hypercortisolemia and a failure to supress cortisol. CRH alterations have also been observed in extrahypothalamic brain regions, e.g. the frontal cortex, limbic regions and cerebro spinal fluid (CSF). CRH acts as the key mediator of behavioral, cognitive, autonomic, neuroendocrine and immunologic responses to aversive stimuli (emotional and physical stress or inflammation), acting mainly through the CRH receptor 1 (CRHR1). In the HPA axis, CRH binds to CRHR1s in the anterior pituitary. This results in production of proopiomelanocortin (POMC)-derived peptides, such as adrenocorticotropic hormone (ACTH), which in turn stimulate the adrenal gland to secrete glucocorticoids (but also mineralocorticoids and androgens). The steroid act on GRs and MRs in many tissues, including the brain, particularly parts of the brain stem and limbic regions. A functional response in the feedback regulation, occuring through the balanced activation of GRs and MRs, as well as by downregulating the expression of CRHR1 in the pituitary (Aguilera et al., 2004), is crucial for returning to a normal state. A chronic state of CRH-mediated activity, e.g. due to adverse environmental stress or defective coping with low levels of stress, may result in disruption of the HPA axis feedback with consequences for e.g. the innervating limbic functions. Monoaminergic neurotransmission is affected, by e.g. suppression of the 5-HT receptor 1a in the dorsal raphe nuclei (Meijer & de Kloet, 1998) or by affecting NA in locus coeruleus (LC). Parallel effects of high levels of CRH (by action through its receptors), includes the increased release of pro-inflammatory cytokines by immune cells, activating the indoleamine 2,3-dioxygenase (IDO) pathway, with subsequent consequences of tryptophan(5HT-) depletion and neurotoxicity, as well as glutamatergic hyperfunction (Leonard, 2005; Muller & Schwarz, 2007). Thus, disturbances in HPA axis responsiveness connected to CRH, are relevant in MD, as well as in suicidality. The effects of CRH dysregulation are primarilly mediated through CRHR1. Consequently, antagonists active against CRHR1 are being developed as a novel type of antidepressants (Nielsen, 2006). From a pharmacogenomic perspective, it is of importance to have access to the level of individual variation in this gene in context to its functionality, which can be needed for evaluation of treatment efficacy as well as being used in diagnostic tools. Knowledge about dysfunctional CRHR1 variants may also bring about new, highly specific treatment possiblities with inhibitory RNAs (Sah, 2006). Surprisingly little is known about influence of genetic variations in the CRHR1 gene in the context of stress and depression, since only a few such studies have been reported up to date (Licinio et al., 2004; Liu et al., 2007; Liu et al., 2006; Papiol et al., 2007; Wasserman et al., 2007). In fact, our group has been the first to study the genetic variation in the CRHR1 gene in connection to depression and stress among suicidal individuals (Wasserman et al., 2007).
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Aug 21, 2023
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