- Email: [email protected]
Mechanisms of depression: role of the HPA axis
Vol. 1, No. 4 2004
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA
DISEASE Psychiatry disorders MECHANISMS
Mechanisms of depression: role of the HPA axis Filip Van Den Eede1,2, Stephan J. Claes1,2,* 1 2
Department of Molecular Genetics VIB8, Psychiatric Genetics Group, University of Antwerp (UA), Universiteitsplein 1/Building T, B-2610 Antwerp, Belgium Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp (UA), Universiteitsplein 1/Building A, B-2610 Antwerp, Belgium
Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis is a core neurobiological feature of major
Section Editor: Daniel Hoyer – Novartis Pharma Ltd. Basel, Switzerland
depression. The responsible mechanisms are unclear. Hyperactivity is arguably a causal factor of depression, and not an epiphenomenon. It can be that the antidepressants used in clinical practice are efficacious through their effect on the HPA axis. Several drugs directly targeting the HPA axis are in development, but currently none of these has shown satisfactory efficacy and tolerability in large-scale trials.
Introduction Major depression is a complex disorder that affects approximately 8% of men and 15% of women throughout life. For 75% of patients, major depression is a recurrent, lifelong illness, characterized by repeated exacerbations and remissions. The syndrome not only causes great mental anguish with symptoms such as depressed mood and loss of interest in activities, but it also intrudes upon fundamental biological processes that regulate sleep, appetite, metabolic activity, autonomic function and neuroendocrine regulation [1]. A hyperfunction of the hypothalamic–pituitary–adrenal (HPA) axis, characterized by a corticotropin-releasing factor (CRF) hyperdrive, a reduced negative feedback function and hypercortisolism, is one of the best-documented neurophysiological changes in major depression. The stress system coordinates the adaptive responses of the organism to stressors of any kind, to obtain a complex *Corresponding author: (S.J. Claes) [email protected] 1740-6765/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2004.11.021
dynamic equilibrium or homeostasis. The main components of the stress system are the CRF and the locus ceruleus– norepinephrine system (LC–NE), which act by their peripheral effectors: the pituitary adrenal axis and the autonomic system [2]. These two systems exert control over each other’s activity. Of the two, the HPA system is slower and more persistent in its actions [3]. The HPA axis is illustrated in Fig. 1. Within seconds after the exposure to stress, the synthesis of CRF is increased in the neurons of the paraventricular nucleus (PVN) of the hypothalamus. CRF is transported through the portal vascular system to the pituitary, where it stimulates the synthesis of proopiomelancortin, the precursor of adenocorticotropin hormone (ACTH) from anterior pituitary cells. Arginine-vasopressin (AVP) is a potent synergistic factor with CRF in stimulating ACTH secretion. Finally, ACTH is secreted into the systemic circulation and stimulates the secretion of cortisol from the adrenal cortex. Cortisol is the final effector of the HPA axis and participates in response of the organism to stress. This hormone acts as a negative feedback regulator on the hypothalamus and the pituitary, decreasing the secretion of CRF and ACTH, respectively. Cortisol also exerts a negative feedback function on the HPA axis via the hippocampus. Negative feedback regulation occurs through a dual receptor system of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Under basal levels of cortisol, negative feedback is mediated mainly through the MR in the hippocampus, whereas under stress and high cortisol concentrations, the less sensitive GR in the www.drugdiscoverytoday.com
413
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
Vol. 1, No. 4 2004
Box 1. HPA axis-related findings in major depression Basal hormone secretion Elevated CRF in plasma and cerebrospinal fluid Increased number of ACTH-secretory episodes Elevated plasma cortisol levels Elevated 24-h urinary-free cortisol Imaging studies Reduced hippocampal volume/changes in hippocampal shape Pituitary gland enlargement Adrenal hypertrophy
Figure 1. HPA axis. Corticotropin-releasing factor (CRF) binds to the CRF receptor (mainly CRF receptor type 1) and stimulates the synthesis of adenocorticotropine hormone (ACTH) from anterior pituitary cells. Arginine-vasopressin (AVP) is a potent synergistic factor with CRF in stimulating ACTH secretion; in the pituitary it binds to receptor AVP-R1B. Finally, ACTH stimulates the secretion of cortisol from the adrenal cortex. Cortisol in turn acts as a negative feedback regulator on the hypothalamus and the pituitary by binding to the glucocorticoid receptor (GR), decreasing the secretion of CRF and ACTH, respectively. Cortisol also exerts a negative feedback function on the HPA axis via the hippocampus, where it binds on GR and mineralocorticoid receptors (MR).
hippocampus, hypothalamus and pituitary come into play. The balance in these MR- and GR-mediated effects on the stress system is of crucial importance to the set point of the HPA axis activity [3].
HPA axis dysfunction in major depression The stress response with the resultant activation of the HPA axis is meant to be acute or at least of a limited duration. The time-limited nature of this process renders the accompanying catabolic, antireproductive and immunosuppressive effects temporally beneficial rather than damaging. By contrast, a chronic activation can result in an imbalance or allostasis of the HPA axis. Yet, some individuals are more probable to develop a deficit in HPA regulation than others. These differences are linked to their genotype, as well as to environmental factors. A hyperfunction of the HPA axis, characterized by a CRF hyperdrive, reduced negative feedback and hypercortisolism, has been a consistent research finding in major depression. Classically, the abnormalities have been observed in patients with unipolar disorder (one or recurrent major depressions), but they can also be present in the depressive phase, the manic phase and the remission phase of patients with bipolar affective disorder (recurrent episodes of both major depression and mania or hypomania) [4,5]. The main HPA characteristics in major depression have been reviewed by Plotsky et al. [6], Holsboer [7] and Juruena et al. [8]. They are summarized in Box 1. The dysregulations situate themselves at different levels of the HPA axis and the experimental findings can be classified in basal hormonal changes, post414
www.drugdiscoverytoday.com
Postmortem findings (depressed patients) Elevated CRF mRNA levels and increased numbers of CRF expressing neurons in PVN in hypothalamus Pituitary CRF receptor downregulation Functional tests Reduced suppression of cortisol secretion after DEX administration Enhanced ACTH and cortisol response to the combined DEX–CRF test Blunted ACTH response to CRF administration Lymphocytes from DEX non-suppressors more resistant to inhibitory effect of DEX (in vitro) Reduced vasoconstrictor response to beclomethasone (in vivo) ACTH, adenocorticotropine; CRF, corticotropin-releasing factor; DEX, dexamethasone; GR, glucocorticoid receptor; PVN, paraventricular nucleus.
mortem findings, results from imaging studies and functional tests.
Mechanisms of HPA axis hyperactivity in major depression The exact pathophysiology of the hyperactivity of the HPA axis in major depression has not yet been revealed. The two main mechanisms that have been proposed are the GR hypothesis and the CRF hyperdrive (Fig. 2).
GR hypothesis The GR hypothesis focuses on the GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of CRF (Fig. 2a). Three different mechanisms of GR resistance have been considered: (1) downregulation secondary to persistent hypercortisolism, (2) a primary alternation in the genetic structure and (3) a decrease in GR function secondary to alternations in ligand-independent pathways. According to Pariante and Miller [9], scientific data do not provide a compelling case for GR downregulation secondary to hypercortisolism in major depression. As for a primary genetic alternation in the GR, currently no specific variant has been linked to GR resistance in patients with major depression. In respect to the third mechanism, the concept of ‘ligand-independent’ regulation of the GR derives from findings that steroid receptor function is regulated not only by steroid ligand binding, but also by signal transduction pathways driven by compounds unrelated to steroids, such as pro-inflammatory cytokines
Vol. 1, No. 4 2004
Figure 2. Mechanisms of HPA axis dysregulation. Pathway (a): the glucocorticoid receptor (GR) hypothesis focuses on the GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of corticotropin-releasing factor (CRF), adenocorticotropine (ACTH) and cortisol when patients with a depressive disorder are confronted with stressful events. Pathway (b): the CRF hyperdrive hypothesis proposes a system of multiple feedback loops: loop 1: the downregulation of GR due to an excess of cortisol fails to restrain the hyperfunction of the HPA axis loop 2: CRF might be capable of enhancing its own biosynthesis in the paraventricular nucleus (PVN) of the hypothalamus loop 3: persistent activation of the hypothalamic– pituitary–adrenal (HPA) axis up-regulates the amygdaloid CRF system, which stimulates the HPA axis in turn.
and elements of the cyclic adenosine monophosphate cascade.
CRF hyperdrive A system of multiple feedback loops activating the central hypothalamic and amygdaloid CRF system has been proposed [10] (Fig. 2b). As mentioned before, stress initially activates the hypothalamic CRF system, resulting in the hypersecretion of cortisol from the adrenal gland. In the chronic phase of stress, the downregulation of GR due to an excess of cortisol fails to restrain the hyperfunction of the HPA axis (loop 1 in Fig. 2b). Moreover, CRF can be capable of enhancing its own biosynthesis in the PVN of the hypothalamus [7,10] (loop 2 in Fig. 2b). By contrast, the psychological component of the stressor activates the HPA axis by stimulating the amygdaloid CRF system. This leads to an additional feedback loop, because the persistent activation of the HPA axis up-regulates the amygdaloid CRF system (loop 3 in Fig. 2b).
The problem of causality: a primary cause or an epiphenomenon? The problem of causality emerges when considering the role of the HPA axis in major depression in human beings. Can the HPA axis dysfunction be seen as the primary biological cause
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
of major depression, or a secondary phenomenon? In this paragraph we will discuss several indications that the HPA axis has a primary role in the predisposition and the onset of major depression. First, the HPA axis is a major component of the stress system and both acute and chronic stress can elicit major depression [11,12]. Considerable evidence from a variety of studies suggests that early-life stress, such as sexual, physical and emotional maltreatment during childhood, increases the risk for depression. Interestingly, early-life stress leads to persistent neurobiological adaptations that resemble the findings in depression. Of those adaptations, the most striking similarity involves the hyperactivity of the CRF system [13]. Second, Holsboer et al. [14] found that the HPA feedback disturbance observed among patients with depression was also present in otherwise healthy individuals who are at risk because they have a first-degree relative with an affective illness. Moreover, this disturbance was shown to be stable over a four-year period [15]. These data suggest that some individuals have a genetically determined vulnerability to develop a chronic HPA axis hyperdive and possibly major depression. Third, injections of CRF in rats produces numerous behavioral changes resembling the cardinal symptoms of depression [7]. Fourth, high levels of endogenously produced cortisol have been associated with depression. For instance, Cushing’s syndrome and Cushing’s disease are associated with depressed or labile mood, decreased energy, decreased memory and concentration, irritability, fatigue, decreased libido and insomnia [16]. Finally, the HPA feedback disturbance, as measured by the sensitive combined dexamethasone/CRF test, predicts the recurrence of depressive pathology in remitted patients previously suffering from major depression [17]. These observations are suggestive of an etiologic role of the HPA axis in major depression. However, we have to keep in mind that major depression is a complex and heterogenic disorder. Whereas some subtypes of major depression, such as psychotic major depression, are associated with high rates of HPA axis hyperactivity [18], some depressed patients have not a disturbed HPA axis at all. Moreover, atypical depression – another subtype of major depression – is associated with a hypofunction of the HPA axis, rather than a hyperfunction [1].
Genetics of HPA axis in major depression As the liability to develop major depression is partly dependent on genetic factors, one might assume that genes involved in HPA axis function are important functional candidates for major depression. We will give a brief summary www.drugdiscoverytoday.com
415
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
of the available data, which have been reviewed more extensively by Claes [19]. In the GR gene (GenBank accession number gi:4504132), sequence variants have been described that alter HPA axis function. Transgenic mice with an impaired GR function in the brain showed disturbances in HPA axis regulation and in behavioral responses to stress. Recently, Wust et al. [20] have reported an impact of GR polymorphisms on cortisol responses to stress in humans. The actions of CRF are mediated by two types of receptors: CRF-R1 and CRF-R2. CRF receptors are found in many sites in the brain outside the hypothalamus. CRF-R1 polymorphisms have not been associated with particular disorders in humans, but knocking out the CRF-R1 gene (GenBank accession number gi:19923244) in mice leads to disruption of the HPA axis and reduced anxiety. CRF-R2 knockout mice seem hypersensitive to stress [21]. However, a haplotype-based association study of this gene (GenBank accession number gi:32307159) in patients with major depression was negative [22]. Transgenic mice studies involving the CRF-binding protein gene (GenBank accession number gi:47080099) indicate a key role in anxiety-related behavior, and we found an association of a specific haplotype of this gene with an increased vulnerability for major depression in humans [23]. No transgenic studies for the arginine-vasopressin receptor 1B (AVP-R1B) are available, but recently our research group has reported that a haplotype of the AVP-R1B gene (GenBank accession number gi:4502333) has a protective effect against recurrent major depression [24].
Therapeutic targets and related therapies Antidepressants Antidepressants, known to act mainly on catecholaminergic and serotonergic neurotransmission, also have effects that are independent of their effects on biogenic amine metabolism or receptors and which can produce normalization of the initial HPA axis dysregulation. The time course of these neuroendocrine actions on HPA axis activity and more specifically, on corticosteroid receptors, follows closely that of clinical improvement, supporting the hypothesis that a causal link between the HPA axis activity and antidepressant effects exist [25]. According to Pariante [26] it is not clear whether HPA axis hyperactivity leads to an increase of cortisol in the brain, and that the depressive symptoms are a consequence of the putative effect of cortisol, or that patients have a hyperactive HPA axis as a compensatory mechanism, because their brain is resistant to the effects of circulating cortisol. This question is not trivial, especially in the quest for a more effective treatment. Recently, this research group has formulated an alternative and controversial hypothesis, in which they propose that antidepressants inhibit steroid transporters localized in the blood–brain barrier, such as the multidrug 416
www.drugdiscoverytoday.com
Vol. 1, No. 4 2004
resistance p-glycoprotein. By blocking this protein, which actively pumps cortisol out of the cerebrospinal fluid, antidepressants would lead to an increased cortisol concentration in the brain [27].
CRF/AVP antagonists Intense attention is being given to antagonists of CRF-R1 or AVP-R1B, the major CRF and AVP receptor subtypes, respectively, involved in the regulation of the HPA axis. Both CRFR1 and AVP-R1B antagonists were found to inhibit acute stress-induced adrenocorticotropin hormone (ACTH) secretion and exert clear anxiolytic- or antidepressant-like effects in rodents [28]. As mentioned before, two types of receptors mediate the actions of CRF: CRF-R1 and CRF-R2. The two types of receptors appear to exert opposing effects in the regulation of anxiety: CRF-R1 mediates anxiogenic actions that are opposed by the anxiolytic properties of CRF-R2 [29]. Studies with peptides that antagonize both of the CRF receptors and antisense probes that selectively reduce CRF receptor subtype levels indicate that CRF-R1 is the primary target at which selective non-peptide compounds designed to treat stress-related disorders should be directed. Most of the studies with CRF-R1 antagonists are unpublished for patent reasons [7]. Zobel et al. [30] explored the effects of R121919, a water-soluble pyrrolopyrimidine that bind with high affinity to human CRF-R1, in 24 patients with major depression. They observed significant reductions in depression and anxiety scores. Recently, R121919 has been associated with normalizing sleep EEG in patients with major depression [31]. No trials with the specific AVP-R1B antagonist SSR149415 in major depression have been published.
Antiglucocorticoid drugs Another strategy to restore equilibrium is to interfere with the production of cortisol or to antagonize its receptors. Ketoconazole, metyrapone and aminogluthetimide inhibit enzymes that are involved in cortisol biosynthesis. They all showed some degree of efficacy in clinical trials [16], but their use in a therapeutic setting is still problematic. No large-scale doubleblind clinical trials are available and these drugs have the potential to induce serious side effects. Mifepristone (RU-486) blocks progesterone, and at higher doses, cortisol receptors. A small-scale blinded trial and a larger-scale open trial indicated efficacy of this molecule in patients with major psychotic depression [32]. Recently, improvements in neurocognitive function and mood following adjunctive treatment with RU486 has been reported in patients with bipolar disorder [33]. However, it should be noted that this treatment with mifepristone is still experimental and that its full risk-benefit ratio needs to be determined. Other GR antagonists are in development, such as Org 34850 and Org 34517 [34].
Vol. 1, No. 4 2004
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
Table 1. Possible targets for HPA axis-related antidepressant drugs, with advantages and disadvantages Therapy against target
Advantages and/or disadvantages
Ref
Target 1
CRF-R1a
Proven efficacy in animal models of depression Open label trial available
[35] [30]
Target 2
AVP-R1Bb
Reverses stress-induced suppression of neurogenesis in mouse model of depression
[28]
Target 3
GRc
Open label trial and small RCTd available in psychotic depression Small controlled trial available in bipolar depression Side effect profile probably not compatible with use in first line?
[32] [33]
Target 4
Cortisol Synthesis
Some efficacy in clinical trials Potentially dangerous side effects
[16]
a
Corticotropin-releasing factor receptor 1. Arginine-vasopressin receptor 1B. Glucocorticoid receptor. d Randomized controlled trial. b c
Table 1 summarizes the possible targets for HPA axisrelated antidepressant drugs, with advantages and disadvantages.
Summary and conclusions The HPA axis is one of the main components of the stress system. A hyperfunction of the HPA axis, characterized by a CRF hyperdrive, reduced negative feedback and hypercortisolism, has been a consistent research finding in major depression. Several mechanisms have been proposed. The GR hypothesis focuses on GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of CRF, whereas the CRF hyperdrive hypothesis considers the GR resistance to be a secondary phenomenon. There are many indications that the HPA axis dysregulation has an etiologic role in the pathophysiology of depression. The CRF hypothesis allows to integrate many of the known causal factors into a single theory: chronic stress, childhood abuse and genetic factors all increase the vulnerability for major depression, and all have been associated with chronic CRF hyperdrive. Therefore, drugs that counteract CRF hyperactivity are logical candidates for the development of new antidepressants. Several such drugs have been developed, but the results are not yet convincing. One of the main problems is to find the best pathway to slow down the axis. It remains to be proven that blocking CRF receptor 1 directly is the most effective strategy. Blocking AVP-1RB might be a promising alternative approach, because AVP is a powerful synergistic stimulant of ACTH secretion. Drugs blocking cortisol synthesis are all associated with serious side effects, and therefore this pathway seems less promising. Large-scale trials with the glucocorticoid receptor antagonist RU-486 are being undertaken, but, if the trials are successful, the clinical use of this molecule will probably be restricted to a smaller group of patients with psychotic depression. In general, one has to conclude that clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. Possibly, long-term studies with these compounds are needed.
Remarkably, one of the most efficient ways to slow down CRF hyperdrive is by using classical antidepressants of the monoamine reuptake inhibitor type, which can normalize initial HPA axis dysregulation by mechanisms independent of their effects on biogenic amine metabolism or receptors. An interesting question for the future is whether the combination of classical antidepressants with drugs that target the HPA axis directly has an added value in the treatment of MDD.
References 1 Gold, P.W. et al. (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol. Psychiatry 7, 254–275 2 Tsigos, C. et al. (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871 3 de Kloet, E.R. et al. (1998) Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 4 Schmider, J. et al. (1995) Combined dexamethasone/corticotrophinreleasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I. Biol. Psychiatry 38, 797– 802 5 Watson, S. et al. (2004) Hypothalamic–pituitary–adrenal axis function in patients with bipolar disorder. Br. J. Psychiatry 184, 496–502 6 Plotsky, P.M. et al. (1998) Psychoneuroendocrinology of depression. Psychoneuroendocrinology 21, 293–307 7 Holsboer, F. (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R). antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 8 Juruena, M.F. et al. (2003) Molecular mechanisms of glucocorticoid receptor sensitivity and relevance to affective disorders. Acta Neuropsychiatr. 15, 354–367 9 Pariante, C.M. et al. (2001) Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391– 404 10 Makino, S. et al. (2002) Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol. Biochem. Behav. 73, 147–158 11 Mazure, C.M. et al. (2000) Adverse life events and cognitive-personality characteristics in the prediction of major depression and antidepressant response. Am. J. Psychiatry 157, 896–903 12 Kendler, K.S. et al. (2003) Life event dimensions of loss, humiliation entrapment, and danger in the prediction of onsets of major depression. Arch. Gen. Psychiatry 60, 789–796 13 Heim, C. et al. (2004) Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 29, 641–648 www.drugdiscoverytoday.com
417
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
14 Holsboer, F. et al. (1995) Altered hypothalamic–pituitary–adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 62, 340–347 15 Modell, S. et al. (1998) Hormonal response pattern in the combined DEX–CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology 18, 253–262 16 Wolkowitz, O.M. et al. (1999) Treatment of depression with antiglucocorticoid drugs. Psychosom. Med. 61, 698–711 17 Zobel, A.W. et al. (2001) Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. J. Psychiatr. Res. 35, 83–94 18 Schatzberg, A.F. et al. (2000) Neuropsychological deficits in psychotic versus non-psychotic major depression and no mental illness. Am. J. Psychiatry 157, 1095–1100 19 Claes, S.J. (2004) CRH, stress, and major depression: a psychobiological interplay. Vitam. Horm. 69, 117–150 20 Wu¨ st, S. et al. (2004) Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychological stress. J. Clin. Endocrinol. Metab. 89, 565–573 21 Bale, T.L. et al. (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat. Genet. 24, 410–414 22 Villafuerte, S. et al. (2002) Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression. Am. J. Med. Genet. 8, 222–226 23 Claes, S.J. et al. (2003) The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol. Psychiatry 54, 867–872 24 Van West, D. et al. (2003) A major SNP haplotype of the argininevasopressin 1B receptor protects against recurrent major depression. Mol. Psychiatry 9, 287–292
418
www.drugdiscoverytoday.com
Vol. 1, No. 4 2004
25 Holsboer, F. et al. (1996) Antidepressants and hypothalamic–pituitary– adrenocortical regulation. Endocr. Rev. 17, 187–205 26 Pariante, C.M. (2004) Depression, stress and the adrenal axis. J. Neuroendocrinol. 15, 811–812 27 Pariante, C.M. et al. (2004) Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29, 423–447 28 Alonso, R. et al. (2004) Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol. Psychiatry 9, 278–286 29 Grammatopoulos, D.K. et al. (2002) Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol. Metab. 13, 436–444 30 Zobel, A.W. et al. (2000) Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 31 Held, K. et al. (2004) Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J. Psychiatr. Res. 38, 129–136 32 Belanoff, J.K. et al. (2002) An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol. Psychiatry 52, 386–392 33 Young, A.H. et al. (2004) Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 29, 1538–1545 34 Ruigt, G.S.F. et al. (2004) Clinical data from phase I and limited phase II studies with the glucocorticoid antagonists Org 34517 and Org 34850. Proceedings of the 35th Annual International Society of Psychoneuroendocrinology, 18–21 July 2004, Glasgow, Scotland, UK. 35 Tezval, H. et al. (2004) Cortagine, a specific agonist of corticotropinreleasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model. Proc. Natl. Acad. Sci. USA 101, 9468–9473
Drug Discovery Today: Disease Mechanisms
DRUG DISCOVERY
TODAY
Editors-in-Chief Toren Finkel – National Heart, Lung and Blood Institute, National Institutes of Health, USA Tamas Bartfai – Harold L. Dorris Neurological Research Center and The Scripps Research Institute, USA
DISEASE Psychiatry disorders MECHANISMS
Mechanisms of depression: role of the HPA axis Filip Van Den Eede1,2, Stephan J. Claes1,2,* 1 2
Department of Molecular Genetics VIB8, Psychiatric Genetics Group, University of Antwerp (UA), Universiteitsplein 1/Building T, B-2610 Antwerp, Belgium Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp (UA), Universiteitsplein 1/Building A, B-2610 Antwerp, Belgium
Hyperactivity of the hypothalamic–pituitary–adrenal (HPA) axis is a core neurobiological feature of major
Section Editor: Daniel Hoyer – Novartis Pharma Ltd. Basel, Switzerland
depression. The responsible mechanisms are unclear. Hyperactivity is arguably a causal factor of depression, and not an epiphenomenon. It can be that the antidepressants used in clinical practice are efficacious through their effect on the HPA axis. Several drugs directly targeting the HPA axis are in development, but currently none of these has shown satisfactory efficacy and tolerability in large-scale trials.
Introduction Major depression is a complex disorder that affects approximately 8% of men and 15% of women throughout life. For 75% of patients, major depression is a recurrent, lifelong illness, characterized by repeated exacerbations and remissions. The syndrome not only causes great mental anguish with symptoms such as depressed mood and loss of interest in activities, but it also intrudes upon fundamental biological processes that regulate sleep, appetite, metabolic activity, autonomic function and neuroendocrine regulation [1]. A hyperfunction of the hypothalamic–pituitary–adrenal (HPA) axis, characterized by a corticotropin-releasing factor (CRF) hyperdrive, a reduced negative feedback function and hypercortisolism, is one of the best-documented neurophysiological changes in major depression. The stress system coordinates the adaptive responses of the organism to stressors of any kind, to obtain a complex *Corresponding author: (S.J. Claes) [email protected] 1740-6765/$ ß 2004 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddmec.2004.11.021
dynamic equilibrium or homeostasis. The main components of the stress system are the CRF and the locus ceruleus– norepinephrine system (LC–NE), which act by their peripheral effectors: the pituitary adrenal axis and the autonomic system [2]. These two systems exert control over each other’s activity. Of the two, the HPA system is slower and more persistent in its actions [3]. The HPA axis is illustrated in Fig. 1. Within seconds after the exposure to stress, the synthesis of CRF is increased in the neurons of the paraventricular nucleus (PVN) of the hypothalamus. CRF is transported through the portal vascular system to the pituitary, where it stimulates the synthesis of proopiomelancortin, the precursor of adenocorticotropin hormone (ACTH) from anterior pituitary cells. Arginine-vasopressin (AVP) is a potent synergistic factor with CRF in stimulating ACTH secretion. Finally, ACTH is secreted into the systemic circulation and stimulates the secretion of cortisol from the adrenal cortex. Cortisol is the final effector of the HPA axis and participates in response of the organism to stress. This hormone acts as a negative feedback regulator on the hypothalamus and the pituitary, decreasing the secretion of CRF and ACTH, respectively. Cortisol also exerts a negative feedback function on the HPA axis via the hippocampus. Negative feedback regulation occurs through a dual receptor system of mineralocorticoid receptors (MR) and glucocorticoid receptors (GR). Under basal levels of cortisol, negative feedback is mediated mainly through the MR in the hippocampus, whereas under stress and high cortisol concentrations, the less sensitive GR in the www.drugdiscoverytoday.com
413
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
Vol. 1, No. 4 2004
Box 1. HPA axis-related findings in major depression Basal hormone secretion Elevated CRF in plasma and cerebrospinal fluid Increased number of ACTH-secretory episodes Elevated plasma cortisol levels Elevated 24-h urinary-free cortisol Imaging studies Reduced hippocampal volume/changes in hippocampal shape Pituitary gland enlargement Adrenal hypertrophy
Figure 1. HPA axis. Corticotropin-releasing factor (CRF) binds to the CRF receptor (mainly CRF receptor type 1) and stimulates the synthesis of adenocorticotropine hormone (ACTH) from anterior pituitary cells. Arginine-vasopressin (AVP) is a potent synergistic factor with CRF in stimulating ACTH secretion; in the pituitary it binds to receptor AVP-R1B. Finally, ACTH stimulates the secretion of cortisol from the adrenal cortex. Cortisol in turn acts as a negative feedback regulator on the hypothalamus and the pituitary by binding to the glucocorticoid receptor (GR), decreasing the secretion of CRF and ACTH, respectively. Cortisol also exerts a negative feedback function on the HPA axis via the hippocampus, where it binds on GR and mineralocorticoid receptors (MR).
hippocampus, hypothalamus and pituitary come into play. The balance in these MR- and GR-mediated effects on the stress system is of crucial importance to the set point of the HPA axis activity [3].
HPA axis dysfunction in major depression The stress response with the resultant activation of the HPA axis is meant to be acute or at least of a limited duration. The time-limited nature of this process renders the accompanying catabolic, antireproductive and immunosuppressive effects temporally beneficial rather than damaging. By contrast, a chronic activation can result in an imbalance or allostasis of the HPA axis. Yet, some individuals are more probable to develop a deficit in HPA regulation than others. These differences are linked to their genotype, as well as to environmental factors. A hyperfunction of the HPA axis, characterized by a CRF hyperdrive, reduced negative feedback and hypercortisolism, has been a consistent research finding in major depression. Classically, the abnormalities have been observed in patients with unipolar disorder (one or recurrent major depressions), but they can also be present in the depressive phase, the manic phase and the remission phase of patients with bipolar affective disorder (recurrent episodes of both major depression and mania or hypomania) [4,5]. The main HPA characteristics in major depression have been reviewed by Plotsky et al. [6], Holsboer [7] and Juruena et al. [8]. They are summarized in Box 1. The dysregulations situate themselves at different levels of the HPA axis and the experimental findings can be classified in basal hormonal changes, post414
www.drugdiscoverytoday.com
Postmortem findings (depressed patients) Elevated CRF mRNA levels and increased numbers of CRF expressing neurons in PVN in hypothalamus Pituitary CRF receptor downregulation Functional tests Reduced suppression of cortisol secretion after DEX administration Enhanced ACTH and cortisol response to the combined DEX–CRF test Blunted ACTH response to CRF administration Lymphocytes from DEX non-suppressors more resistant to inhibitory effect of DEX (in vitro) Reduced vasoconstrictor response to beclomethasone (in vivo) ACTH, adenocorticotropine; CRF, corticotropin-releasing factor; DEX, dexamethasone; GR, glucocorticoid receptor; PVN, paraventricular nucleus.
mortem findings, results from imaging studies and functional tests.
Mechanisms of HPA axis hyperactivity in major depression The exact pathophysiology of the hyperactivity of the HPA axis in major depression has not yet been revealed. The two main mechanisms that have been proposed are the GR hypothesis and the CRF hyperdrive (Fig. 2).
GR hypothesis The GR hypothesis focuses on the GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of CRF (Fig. 2a). Three different mechanisms of GR resistance have been considered: (1) downregulation secondary to persistent hypercortisolism, (2) a primary alternation in the genetic structure and (3) a decrease in GR function secondary to alternations in ligand-independent pathways. According to Pariante and Miller [9], scientific data do not provide a compelling case for GR downregulation secondary to hypercortisolism in major depression. As for a primary genetic alternation in the GR, currently no specific variant has been linked to GR resistance in patients with major depression. In respect to the third mechanism, the concept of ‘ligand-independent’ regulation of the GR derives from findings that steroid receptor function is regulated not only by steroid ligand binding, but also by signal transduction pathways driven by compounds unrelated to steroids, such as pro-inflammatory cytokines
Vol. 1, No. 4 2004
Figure 2. Mechanisms of HPA axis dysregulation. Pathway (a): the glucocorticoid receptor (GR) hypothesis focuses on the GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of corticotropin-releasing factor (CRF), adenocorticotropine (ACTH) and cortisol when patients with a depressive disorder are confronted with stressful events. Pathway (b): the CRF hyperdrive hypothesis proposes a system of multiple feedback loops: loop 1: the downregulation of GR due to an excess of cortisol fails to restrain the hyperfunction of the HPA axis loop 2: CRF might be capable of enhancing its own biosynthesis in the paraventricular nucleus (PVN) of the hypothalamus loop 3: persistent activation of the hypothalamic– pituitary–adrenal (HPA) axis up-regulates the amygdaloid CRF system, which stimulates the HPA axis in turn.
and elements of the cyclic adenosine monophosphate cascade.
CRF hyperdrive A system of multiple feedback loops activating the central hypothalamic and amygdaloid CRF system has been proposed [10] (Fig. 2b). As mentioned before, stress initially activates the hypothalamic CRF system, resulting in the hypersecretion of cortisol from the adrenal gland. In the chronic phase of stress, the downregulation of GR due to an excess of cortisol fails to restrain the hyperfunction of the HPA axis (loop 1 in Fig. 2b). Moreover, CRF can be capable of enhancing its own biosynthesis in the PVN of the hypothalamus [7,10] (loop 2 in Fig. 2b). By contrast, the psychological component of the stressor activates the HPA axis by stimulating the amygdaloid CRF system. This leads to an additional feedback loop, because the persistent activation of the HPA axis up-regulates the amygdaloid CRF system (loop 3 in Fig. 2b).
The problem of causality: a primary cause or an epiphenomenon? The problem of causality emerges when considering the role of the HPA axis in major depression in human beings. Can the HPA axis dysfunction be seen as the primary biological cause
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
of major depression, or a secondary phenomenon? In this paragraph we will discuss several indications that the HPA axis has a primary role in the predisposition and the onset of major depression. First, the HPA axis is a major component of the stress system and both acute and chronic stress can elicit major depression [11,12]. Considerable evidence from a variety of studies suggests that early-life stress, such as sexual, physical and emotional maltreatment during childhood, increases the risk for depression. Interestingly, early-life stress leads to persistent neurobiological adaptations that resemble the findings in depression. Of those adaptations, the most striking similarity involves the hyperactivity of the CRF system [13]. Second, Holsboer et al. [14] found that the HPA feedback disturbance observed among patients with depression was also present in otherwise healthy individuals who are at risk because they have a first-degree relative with an affective illness. Moreover, this disturbance was shown to be stable over a four-year period [15]. These data suggest that some individuals have a genetically determined vulnerability to develop a chronic HPA axis hyperdive and possibly major depression. Third, injections of CRF in rats produces numerous behavioral changes resembling the cardinal symptoms of depression [7]. Fourth, high levels of endogenously produced cortisol have been associated with depression. For instance, Cushing’s syndrome and Cushing’s disease are associated with depressed or labile mood, decreased energy, decreased memory and concentration, irritability, fatigue, decreased libido and insomnia [16]. Finally, the HPA feedback disturbance, as measured by the sensitive combined dexamethasone/CRF test, predicts the recurrence of depressive pathology in remitted patients previously suffering from major depression [17]. These observations are suggestive of an etiologic role of the HPA axis in major depression. However, we have to keep in mind that major depression is a complex and heterogenic disorder. Whereas some subtypes of major depression, such as psychotic major depression, are associated with high rates of HPA axis hyperactivity [18], some depressed patients have not a disturbed HPA axis at all. Moreover, atypical depression – another subtype of major depression – is associated with a hypofunction of the HPA axis, rather than a hyperfunction [1].
Genetics of HPA axis in major depression As the liability to develop major depression is partly dependent on genetic factors, one might assume that genes involved in HPA axis function are important functional candidates for major depression. We will give a brief summary www.drugdiscoverytoday.com
415
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
of the available data, which have been reviewed more extensively by Claes [19]. In the GR gene (GenBank accession number gi:4504132), sequence variants have been described that alter HPA axis function. Transgenic mice with an impaired GR function in the brain showed disturbances in HPA axis regulation and in behavioral responses to stress. Recently, Wust et al. [20] have reported an impact of GR polymorphisms on cortisol responses to stress in humans. The actions of CRF are mediated by two types of receptors: CRF-R1 and CRF-R2. CRF receptors are found in many sites in the brain outside the hypothalamus. CRF-R1 polymorphisms have not been associated with particular disorders in humans, but knocking out the CRF-R1 gene (GenBank accession number gi:19923244) in mice leads to disruption of the HPA axis and reduced anxiety. CRF-R2 knockout mice seem hypersensitive to stress [21]. However, a haplotype-based association study of this gene (GenBank accession number gi:32307159) in patients with major depression was negative [22]. Transgenic mice studies involving the CRF-binding protein gene (GenBank accession number gi:47080099) indicate a key role in anxiety-related behavior, and we found an association of a specific haplotype of this gene with an increased vulnerability for major depression in humans [23]. No transgenic studies for the arginine-vasopressin receptor 1B (AVP-R1B) are available, but recently our research group has reported that a haplotype of the AVP-R1B gene (GenBank accession number gi:4502333) has a protective effect against recurrent major depression [24].
Therapeutic targets and related therapies Antidepressants Antidepressants, known to act mainly on catecholaminergic and serotonergic neurotransmission, also have effects that are independent of their effects on biogenic amine metabolism or receptors and which can produce normalization of the initial HPA axis dysregulation. The time course of these neuroendocrine actions on HPA axis activity and more specifically, on corticosteroid receptors, follows closely that of clinical improvement, supporting the hypothesis that a causal link between the HPA axis activity and antidepressant effects exist [25]. According to Pariante [26] it is not clear whether HPA axis hyperactivity leads to an increase of cortisol in the brain, and that the depressive symptoms are a consequence of the putative effect of cortisol, or that patients have a hyperactive HPA axis as a compensatory mechanism, because their brain is resistant to the effects of circulating cortisol. This question is not trivial, especially in the quest for a more effective treatment. Recently, this research group has formulated an alternative and controversial hypothesis, in which they propose that antidepressants inhibit steroid transporters localized in the blood–brain barrier, such as the multidrug 416
www.drugdiscoverytoday.com
Vol. 1, No. 4 2004
resistance p-glycoprotein. By blocking this protein, which actively pumps cortisol out of the cerebrospinal fluid, antidepressants would lead to an increased cortisol concentration in the brain [27].
CRF/AVP antagonists Intense attention is being given to antagonists of CRF-R1 or AVP-R1B, the major CRF and AVP receptor subtypes, respectively, involved in the regulation of the HPA axis. Both CRFR1 and AVP-R1B antagonists were found to inhibit acute stress-induced adrenocorticotropin hormone (ACTH) secretion and exert clear anxiolytic- or antidepressant-like effects in rodents [28]. As mentioned before, two types of receptors mediate the actions of CRF: CRF-R1 and CRF-R2. The two types of receptors appear to exert opposing effects in the regulation of anxiety: CRF-R1 mediates anxiogenic actions that are opposed by the anxiolytic properties of CRF-R2 [29]. Studies with peptides that antagonize both of the CRF receptors and antisense probes that selectively reduce CRF receptor subtype levels indicate that CRF-R1 is the primary target at which selective non-peptide compounds designed to treat stress-related disorders should be directed. Most of the studies with CRF-R1 antagonists are unpublished for patent reasons [7]. Zobel et al. [30] explored the effects of R121919, a water-soluble pyrrolopyrimidine that bind with high affinity to human CRF-R1, in 24 patients with major depression. They observed significant reductions in depression and anxiety scores. Recently, R121919 has been associated with normalizing sleep EEG in patients with major depression [31]. No trials with the specific AVP-R1B antagonist SSR149415 in major depression have been published.
Antiglucocorticoid drugs Another strategy to restore equilibrium is to interfere with the production of cortisol or to antagonize its receptors. Ketoconazole, metyrapone and aminogluthetimide inhibit enzymes that are involved in cortisol biosynthesis. They all showed some degree of efficacy in clinical trials [16], but their use in a therapeutic setting is still problematic. No large-scale doubleblind clinical trials are available and these drugs have the potential to induce serious side effects. Mifepristone (RU-486) blocks progesterone, and at higher doses, cortisol receptors. A small-scale blinded trial and a larger-scale open trial indicated efficacy of this molecule in patients with major psychotic depression [32]. Recently, improvements in neurocognitive function and mood following adjunctive treatment with RU486 has been reported in patients with bipolar disorder [33]. However, it should be noted that this treatment with mifepristone is still experimental and that its full risk-benefit ratio needs to be determined. Other GR antagonists are in development, such as Org 34850 and Org 34517 [34].
Vol. 1, No. 4 2004
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
Table 1. Possible targets for HPA axis-related antidepressant drugs, with advantages and disadvantages Therapy against target
Advantages and/or disadvantages
Ref
Target 1
CRF-R1a
Proven efficacy in animal models of depression Open label trial available
[35] [30]
Target 2
AVP-R1Bb
Reverses stress-induced suppression of neurogenesis in mouse model of depression
[28]
Target 3
GRc
Open label trial and small RCTd available in psychotic depression Small controlled trial available in bipolar depression Side effect profile probably not compatible with use in first line?
[32] [33]
Target 4
Cortisol Synthesis
Some efficacy in clinical trials Potentially dangerous side effects
[16]
a
Corticotropin-releasing factor receptor 1. Arginine-vasopressin receptor 1B. Glucocorticoid receptor. d Randomized controlled trial. b c
Table 1 summarizes the possible targets for HPA axisrelated antidepressant drugs, with advantages and disadvantages.
Summary and conclusions The HPA axis is one of the main components of the stress system. A hyperfunction of the HPA axis, characterized by a CRF hyperdrive, reduced negative feedback and hypercortisolism, has been a consistent research finding in major depression. Several mechanisms have been proposed. The GR hypothesis focuses on GR resistance and on the reduced negative feedback in major depression as a main cause of the elevation of CRF, whereas the CRF hyperdrive hypothesis considers the GR resistance to be a secondary phenomenon. There are many indications that the HPA axis dysregulation has an etiologic role in the pathophysiology of depression. The CRF hypothesis allows to integrate many of the known causal factors into a single theory: chronic stress, childhood abuse and genetic factors all increase the vulnerability for major depression, and all have been associated with chronic CRF hyperdrive. Therefore, drugs that counteract CRF hyperactivity are logical candidates for the development of new antidepressants. Several such drugs have been developed, but the results are not yet convincing. One of the main problems is to find the best pathway to slow down the axis. It remains to be proven that blocking CRF receptor 1 directly is the most effective strategy. Blocking AVP-1RB might be a promising alternative approach, because AVP is a powerful synergistic stimulant of ACTH secretion. Drugs blocking cortisol synthesis are all associated with serious side effects, and therefore this pathway seems less promising. Large-scale trials with the glucocorticoid receptor antagonist RU-486 are being undertaken, but, if the trials are successful, the clinical use of this molecule will probably be restricted to a smaller group of patients with psychotic depression. In general, one has to conclude that clinical results using drugs targeted at components of the HPA axis have not been very encouraging to date. Possibly, long-term studies with these compounds are needed.
Remarkably, one of the most efficient ways to slow down CRF hyperdrive is by using classical antidepressants of the monoamine reuptake inhibitor type, which can normalize initial HPA axis dysregulation by mechanisms independent of their effects on biogenic amine metabolism or receptors. An interesting question for the future is whether the combination of classical antidepressants with drugs that target the HPA axis directly has an added value in the treatment of MDD.
References 1 Gold, P.W. et al. (2002) Organization of the stress system and its dysregulation in melancholic and atypical depression: high vs low CRH/NE states. Mol. Psychiatry 7, 254–275 2 Tsigos, C. et al. (2002) Hypothalamic–pituitary–adrenal axis, neuroendocrine factors and stress. J. Psychosom. Res. 53, 865–871 3 de Kloet, E.R. et al. (1998) Brain corticosteroid receptor balance in health and disease. Endocr. Rev. 19, 269–301 4 Schmider, J. et al. (1995) Combined dexamethasone/corticotrophinreleasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I. Biol. Psychiatry 38, 797– 802 5 Watson, S. et al. (2004) Hypothalamic–pituitary–adrenal axis function in patients with bipolar disorder. Br. J. Psychiatry 184, 496–502 6 Plotsky, P.M. et al. (1998) Psychoneuroendocrinology of depression. Psychoneuroendocrinology 21, 293–307 7 Holsboer, F. (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R). antagonists to treat depression and anxiety. J. Psychiatr. Res. 33, 181–214 8 Juruena, M.F. et al. (2003) Molecular mechanisms of glucocorticoid receptor sensitivity and relevance to affective disorders. Acta Neuropsychiatr. 15, 354–367 9 Pariante, C.M. et al. (2001) Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Biol. Psychiatry 49, 391– 404 10 Makino, S. et al. (2002) Multiple feedback mechanisms activating corticotropin-releasing hormone system in the brain during stress. Pharmacol. Biochem. Behav. 73, 147–158 11 Mazure, C.M. et al. (2000) Adverse life events and cognitive-personality characteristics in the prediction of major depression and antidepressant response. Am. J. Psychiatry 157, 896–903 12 Kendler, K.S. et al. (2003) Life event dimensions of loss, humiliation entrapment, and danger in the prediction of onsets of major depression. Arch. Gen. Psychiatry 60, 789–796 13 Heim, C. et al. (2004) Importance of studying the contributions of early adverse experience to neurobiological findings in depression. Neuropsychopharmacology 29, 641–648 www.drugdiscoverytoday.com
417
Drug Discovery Today: Disease Mechanisms | Psychiatry disorders
14 Holsboer, F. et al. (1995) Altered hypothalamic–pituitary–adrenocortical regulation in healthy subjects at high familial risk for affective disorders. Neuroendocrinology 62, 340–347 15 Modell, S. et al. (1998) Hormonal response pattern in the combined DEX–CRH test is stable over time in subjects at high familial risk for affective disorders. Neuropsychopharmacology 18, 253–262 16 Wolkowitz, O.M. et al. (1999) Treatment of depression with antiglucocorticoid drugs. Psychosom. Med. 61, 698–711 17 Zobel, A.W. et al. (2001) Cortisol response in the combined dexamethasone/CRH test as predictor of relapse in patients with remitted depression: a prospective study. J. Psychiatr. Res. 35, 83–94 18 Schatzberg, A.F. et al. (2000) Neuropsychological deficits in psychotic versus non-psychotic major depression and no mental illness. Am. J. Psychiatry 157, 1095–1100 19 Claes, S.J. (2004) CRH, stress, and major depression: a psychobiological interplay. Vitam. Horm. 69, 117–150 20 Wu¨ st, S. et al. (2004) Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychological stress. J. Clin. Endocrinol. Metab. 89, 565–573 21 Bale, T.L. et al. (2000) Mice deficient for corticotropin-releasing hormone receptor-2 display anxiety-like behaviour and are hypersensitive to stress. Nat. Genet. 24, 410–414 22 Villafuerte, S. et al. (2002) Gene-based SNP genetic association study of the corticotropin-releasing hormone receptor-2 (CRHR2) in major depression. Am. J. Med. Genet. 8, 222–226 23 Claes, S.J. et al. (2003) The corticotropin-releasing hormone binding protein is associated with major depression in a population from Northern Sweden. Biol. Psychiatry 54, 867–872 24 Van West, D. et al. (2003) A major SNP haplotype of the argininevasopressin 1B receptor protects against recurrent major depression. Mol. Psychiatry 9, 287–292
418
www.drugdiscoverytoday.com
Vol. 1, No. 4 2004
25 Holsboer, F. et al. (1996) Antidepressants and hypothalamic–pituitary– adrenocortical regulation. Endocr. Rev. 17, 187–205 26 Pariante, C.M. (2004) Depression, stress and the adrenal axis. J. Neuroendocrinol. 15, 811–812 27 Pariante, C.M. et al. (2004) Do antidepressants regulate how cortisol affects the brain? Psychoneuroendocrinology 29, 423–447 28 Alonso, R. et al. (2004) Blockade of CRF(1) or V(1b) receptors reverses stress-induced suppression of neurogenesis in a mouse model of depression. Mol. Psychiatry 9, 278–286 29 Grammatopoulos, D.K. et al. (2002) Functional characteristics of CRH receptors and potential clinical applications of CRH-receptor antagonists. Trends Endocrinol. Metab. 13, 436–444 30 Zobel, A.W. et al. (2000) Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 31 Held, K. et al. (2004) Treatment with the CRH1-receptor-antagonist R121919 improves sleep-EEG in patients with depression. J. Psychiatr. Res. 38, 129–136 32 Belanoff, J.K. et al. (2002) An open label trial of C-1073 (mifepristone) for psychotic major depression. Biol. Psychiatry 52, 386–392 33 Young, A.H. et al. (2004) Improvements in neurocognitive function and mood following adjunctive treatment with mifepristone (RU-486) in bipolar disorder. Neuropsychopharmacology 29, 1538–1545 34 Ruigt, G.S.F. et al. (2004) Clinical data from phase I and limited phase II studies with the glucocorticoid antagonists Org 34517 and Org 34850. Proceedings of the 35th Annual International Society of Psychoneuroendocrinology, 18–21 July 2004, Glasgow, Scotland, UK. 35 Tezval, H. et al. (2004) Cortagine, a specific agonist of corticotropinreleasing factor receptor subtype 1, is anxiogenic and antidepressive in the mouse model. Proc. Natl. Acad. Sci. USA 101, 9468–9473