Hypothalamic–pituitary–adrenocortical system dysregulation and new treatment strategies in...

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Preclinical and clinical studies have gathered substantial evidence that hypothalamic–pitu-itary–adrenocortical (HPA) system dysregula-tion plays an important role in the pathophysi-ology of depressive syndromes (first-episode depression and recurrent unipolar depression, bipolar depression) [1,2]. In depressed patients, elevated cortisol and adrenocorticotrophic hor-mone (ACTH) concentrations are found in the plasma [3–6] or in the cerebrospinal fluid (CSF) [7]. Additionally, this HPA axis hyperactivity is obviously reflected by elevated urinary free-cortisol levels, which appear to be approximately twofold higher in depressed patients compared with healthy controls [8]. However, it is notewor-thy that the finding of enhanced basal cortisol and/or ACTH secretion in depression, which was derived from studies in either very severe

or long-term depressives, could not be repli-cated in all studies [9–12], in particular, not in patients suffering from first-episode depression [13]. Further investigations using neuroendocrine challenge tests confirmed the hypothesis of HPA axis dys regulation, which occurs in some, but not all, depressed patients. Several studies using the corticotropin-releasing hormone (CRH)-stimulation test reported a blunted ACTH response, whereas cortisol stimulation was indistinguishable from normal controls [14,15]. In contrast to a reduced ACTH-response to CRH, depressive patients also show an enlargement of the adrenal gland [16,17], as well as elevated cortisol stimulation patterns and enhanced adrenal sensitivity after challenge with ACTH in most [18–20], but not all [21], studies. Findings in depressed patients of increased CRH levels in

Cornelius Schüle†, Thomas C Baghai, Daniela Eser and Rainer Rupprecht†Author for correspondenceDepartment of Psychiatry, Ludwig-Maximilian-University, Nussbaumstr. 7, 80336 Munich, Germany Tel.: +49 895 160 5731 Fax: +49 895 160 5738 cornelius.schuele@ med.uni-muenchen.de

According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic–pituitary–adrenocortical (HPA) system is one of the major pathophysiological factors for the development of depression and opens a broad range of new antidepressant treatment options that are related to direct interventions in HPA system regulation in depressed patients. These new therapy strategies include inhibition of hypothalamic corticotropin-releasing hormone (CRH) release, antagonism at CRH1 receptors, antagonism at vasopressin V1b receptors, inhibition of cortisol synthesis, antiglucocorticoid treatment with dehydroepiandrosterone and treatment with glucocorticoid receptor antagonists. Although preclinical data support the view that CRH1 receptor antagonists are useful in the treatment of depression, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. The use of the antiglucocorticoid neuroactive steroid dehydroepiandrosterone, the cortisol synthesis inhibitor metyrapone and the glucocorticoid receptor antagonist mifepristone in depression has been demonstrated in some small, double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depression. Thus, it is unclear at present to what extent new, clinically effective antidepressant therapies can be developed based on the corticoid receptor hypothesis of depression.

Keywords: cortisol • depression • HPA system

Hypothalamic–pituitary–adrenocortical system dysregulation and new treatment strategies in depressionExpert Rev. Neurother. 9(7), 1005–1019 (2009)

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Review Schüle, Baghai, Eser & Rupprecht

the CSF [22] and elevated numbers of CRH [23] and arginine vaso-pressin (AVP)-expressing neurons in the paraventricular nucleus of the hypothalamus [24], as well as the observation of reduced CRH binding sites in the frontal cortex of suicide victims [25], gave support to the assumption that depression is characterized by a hypothalamic overdrive of CRH and/or AVP, which conse-quently leads to receptor downregulation in the corticotrophs of the pituitary gland. Treatment of depression with fluoxetine [26], amitriptyline [27], desipramine [28] or electroconvulsive therapy [29,30] has been demonstrated to reduce CSF CRH levels within several weeks. Chronic anti depressant treatment has also been shown to decrease CRH mRNA and CRH concentrations in the hypothalamus of rats [31–33]. Based on these findings, proponents of the corticoid receptor hypothesis of depression suggest that CRH overexpression and hypersecretion in the hypothalamus may play an essential role in the etiology of depression, and suc-cessful antidepressant treatment normalizes dysregulated CRH levels. The most important endocrinological findings supporting the view of a disturbed HPA system regulation in depression are summarized in Table 1.

However, the hypothesis that HPA axis hyperactivity is causally linked to the development of depressive symptoms is disputed in some clinical investigations showing the HPA axis to be sensitive to social stress, but not to mediate vulnerability to depression [11,12]. In the study of Strickland et al., performed in moderately depressed

out-patients, salivary cortisol levels were responsive to recent psy-chosocial stress, but this effect was more pronounced in nonde-pressed controls than in depressive patients [12]. Depression per se was not associated with increased cortisol secretion; depressed patients even tended to have lower morning salivary cortisol con-centrations compared with nondepressed controls. As stated by Cowen, “in most moderately depressed patients in primary care, we may have to accept that increased cortisol secretion is not an important pathophysiological factor” [11].

Nevertheless, proponents of the corticoid receptor hypothesis of depression emphasize that CRH plays an important role in the pathophysiology of depression and that the effects of CRH are mediated through specific receptors, of which two different subtypes (CRH

1 and CRH

2 receptors) have been identified [34].

Most studies suggest that the CRH1 receptor, rather than the

CRH2 receptor, is involved in anxiety and depression disorders.

In animal models, central administration of antisense oligonucle-otides directed against CRH

1 receptors, but not CRH

2 receptors,

decreases anxiety-like behaviors [35–38]. Furthermore, CRH1 recep-

tor-deficient mice exhibit less anxiety-like behavior [39–42], whereas CRH

2 receptor-deficient mice show no behavioral differences [43]

or increased behavioral measures indicative of anxiety [44,45] and depression [46].

Moreover, it has been suggested that an impaired signaling pathway via corticosteroid-activated mineralocorticoid recep-

tor (MRs) and glucocorticoid receptors (GRs), leading to an impaired negative feedback regulation of the HPA system, causes this hyperactivity [47]. The nonselec-tive MR possesses a tenfold higher affinity for glucocorticoids, such as corticosterone or cortisol, than the GR and is, therefore, already almost completely occupied at basal levels of corticosteroid secretion [48–50]. On the contrary, the hippocampal GRs are only occupied when corticosteroid levels increase under stress conditions or at the peak of the circadian rhythm of cortico-steroid secretion. However, the transcrip-tional potency of the GR is much higher than that of the MR [51]. Thus, the MR is a high-affinity, low-capacity receptor, whereas the GR is a low-affinity, high-capacity receptor. With regard to the GR, disturbed negative-feedback control in a part of the depressed patient is reflected by cortisol escape from dexamethasone (DEX) suppression [52], as well as increased ACTH and cortisol release in the combined DEX suppression/CRH-stimulation (DEX/CRH) test [53,54]. Whereas the CRH-induced ACTH response is blunted in some depressed patients, DEX pretreatment pro-duces the opposite effect and, paradoxically, enhances ACTH release following CRH in

Table 1. Hypothalamic–pituitary–adrenocortical system in depression: clinical findings.

Author (year) Finding Ref.

Board et al. (1957), Gibbons et al. (1963)

Hypercortisolism [5,6]

Carroll et al. (1976) Increased urinary free-cortisol excretion (24 h)

[8]

Carroll et al. (1976) Nonsuppression in the DST [52]

Amsterdam et al. (1983) Increased cortisol stimulation in the ACTH test

[18]

Gold et al. (1984), Holsboer et al. (1984)

Reduced ACTH stimulation in the CRH test [14,15]

Nemeroff et al. (1984) Increased CRH levels in the CSF [22]

Nemeroff et al. (1988) Reduced CRH binding sites in the frontal cortex of suicide victims

[25]

Von Bardeleben and Holsboer (1989), Heuser et al. (1994)

Nonsuppression in the DEX/CRH test [53,54]

Nemeroff et al. (1992), Rubin et al. (1995)

Enlargement of the adrenal cortex [16,17]

Raadsheer et al. (1994) Increased numbers of CRH-producing neurons in the nucleus paraventricularis

[23]

Purba et al. (1996) Increased numbers of AVP-producing neurons in the nucleus paraventricularis

[24]

Young et al. (1998) Increased ACTH and cortisol stimulation in the spironolactones test

[61]

ACTH: Adrenocorticotropic hormone; AVP: Arginine vasopressin; CRH: Corticotropin-releasing hormone; CSF: Cerebrospinal fluid; DEX: Dexamethasone; DST: Dexamethasone-suppression test.

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ReviewHPA system dysregulation & new treatment strategies in depression

some depressed patients [1,55]. Similarly, CRH-elicited cortisol stimulation is much higher in DEX-pretreated depressive patients than following a challenge with CRH alone [1,55]. In addition, the importance of the GR in the pathophysiology of depression is underlined by genetic investigations finding that polymorphisms of the GR gene and of genes encoding chaperones of the GR possibly contribute to the development of depressive symptoms and play a role in the variability of antidepressant response [56,57].

Several groups have shown that treatment of rats with different antidepressant drugs (e.g., monoaminoxidase inhibitors, serotonin [5-hydroxytryptamine (5-HT)]- or norephinephrine-reuptake inhibitors, serotonin-reuptake enhancers) increases the binding capacity and gene expression of MRs and GRs in the hippocam-pus and other limbic and cortical brain areas [31,58–60]. Time-course analyses revealed that hippocampal MR levels increase markedly after 1–2 weeks, whereas levels of GRs increase only moderately after at least 3–5 weeks of treatment [31,59,60]. The antidepressant-induced increases in MRs also precede the decrease in CRH mRNA expression in the hypothalamic paraventricular nucleus [31] and the decline in baseline and stress-induced HPA axis activity [59,60]. Thus, it was concluded that increased effi-ciency of MR signaling appears to be an important preliminary step in antidepressant action. Following this hypo thesis, a clini-cal trial was conducted, in which the selective MR antagonist spironolactone or placebo were administered under controlled conditions to depressed patients treated with amitriptyline. In this study, patients treated with spironolactone had a less favorable treatment outcome than those who were given placebo, confirm-ing the importance of functionally effective MRs for beneficial therapeutic response [55]. However, this hypothesis is not con-firmed by a study suggesting high functional activity of the MR system in depression [61]. In this investigation, medication-free depressed patients demonstrated significantly higher cortisol secretion levels in the spironolactone test than healthy controls.

Proponents of the corticosteroid receptor hypothesis of depression emphasize that corticosteroid receptor dysfunction leads to hypothalamic neuropeptide overexpression (i.e., CRH and AVP) and may be causally related to the development of depression and the action of antidepressants [1,2,62]. According to this hypothesis, a gradual normalization of HPA system dys-regulation, as measured by the DEX/CRH test, precedes or coincides with the response to antidepressant treatment and is a necessary prerequisite for clinical remission to manifest, whereas persisting cortisol hypersecretion during the DEX/CRH test at discharge in spite of clinical improvement may be an indicator of an enhanced risk for relapse within the fol-lowing 6 months [63,64]. In addition, in out-patients with clini-cally remitted major depression, higher cortisol levels in the DEX/CRH test are apparently associated with relapse of major depression [65,66]. It has been further postulated that antidepres-sants may exert their therapeutic effects, at least partly through their actions on the HPA system, and that all antidepressants developed so far may have a uniform dampening impact on HPA axis function irrespective of their type of action within monoaminergic systems [1,2,59,60,67]. These observations suggest

that the reported normalizing effects of antidepressant drugs on the DEX/CRH test results are actually a prerequisite to clinical improvement and not just a pharmacological side effect.

However, differential effects of antidepressants on cortisol and ACTH secretion can be demonstrated both in healthy subjects and depressed patients after single administration using the pharmaco-endocrinological challenge paradigm. Noradrenaline- or serotonin-reuptake-inhibiting antidepressants, such as reboxetine [68] or citalo-pram [69], acutely stimulate cortisol and ACTH secretion in healthy volunteers, whereas mirtazapine acutely inhibits ACTH and cortisol release [70], probably owing to its antagonism at central 5-HT

2 and/

or histamine (H)1 receptors. These differential effects of antidepres-

sants on cortisol and ACTH secretion in healthy subjects after single administration are also reflected by their different time course in the downregulation of HPA axis hyperactivity in depressed patients, as assessed by serial DEX/CRH tests. Reuptake-inhibiting antidepres-sants, such as reboxetine, gradually normalize HPA axis hyperactiv-ity in depressed patients during several weeks of treatment via upreg-ulation of MR and GR function and by step-by-step restoration of the disturbed feedback control. By contrast, mirtazapine markedly reduces HPA axis activity in depressed patients within 1 week; how-ever, there is a partial re-enhancement of HPA hormone secretion after several weeks of therapy [71]. The early downregulation of HPA axis activity within the first 1 or 2 weeks of antidepressant therapy as measured by two subsequent DEX/CRH tests appears to be a predictor of certain significance for acute treatment response [72,73].

An integrative illustration of different neurobiological theories of depression, including the monoamine hypothesis, the corticoid receptor hypothesis and the neurotrophin hypothesis, is available in several reviews [74,75].

HPA system & new treatment strategies in depressionAlthough the corticoid receptor hypothesis of depression remains a matter of great debate and, to date, is discussed controversially; supporters of this hypothesis point to a broad range of new anti-depressant treatment options that are related to direct interven-tions in HPA system regulation in depressed patients. The effi -The effi-cacy and safety of antiglucocorticoid treatment for depression have been described in a recent Cochrane review [76]. The most important and promising antiglucocorticoid treatment options according to the corticoid receptor hypothesis are: • Acute inhibition of hypothalamic CRH release

• Antagonism at CRH1 receptors

• Antagonism at vasopressin V1b receptors

• Inhibition of cortisol synthesis

• Antiglucocorticoid treatment with dehydroepiandrosterone (DHEA)

• GR antagonists

Acute inhibition of hypothalamic CRH releaseReuptake-inhibiting antidepressants acutely stimulate ACTH and cortisol secretion in both healthy controls and depressed patients, probably by acute central stimulation of hypothalamic CRH



release via both noradrenergic and serotonergic mechanisms [77]. In animal studies, downregulation of CRH gene expression and CRH mRNA synthesis in the nucleus paraventricularis occurs after several weeks of treatment with reuptake-inhibiting antide-pressants [78,79]. On the contrary, the anti depressant mirtazapine, which does not act as a reuptake-inhibiting drug but is an antago-nist at central a

2, 5-HT

2, 5-HT

3 and H

1 receptors, acutely inhib-

its cortisol and ACTH secretion both in healthy volunteers [70] and depressive patients [80]; presumably due to antagonism at central 5-HT

2 and/or H

1 receptors, which are known to stimulate

hypothalamic CRH release [81–83]. Moreover, a number of atypi-cal antipsychotics, such as quetiapine [84–86], olanzapine [85] or ziprasidone [87], which also act as central blockers of 5-HT

2 and

H1 receptors, have been demonstrated to acutely inhibit cortisol

and ACTH output in normal volunteers. Interestingly, quetiapine monotherapy has been shown to possess significant anti depressant effects in both bipolar depression [88,89] and unipolar depression [90–94]. It is not clear to what extent the acute inhibitory effects of mirtazapine and some atypical antipsychotics on cortisol and ACTH secretion – probably due to central antagonism at 5-HT

2

and H1 receptors, thereby reducing hypothalamic CRH release –

may contribute to antidepressant effects of these drugs.

CRH1 receptor antagonistsCorticotropin-releasing hormone, which was originally isolated by Rivier and coworkers [95], consists of 41 amino acids and not only mediates the regulation of the HPA axis but is also respon-sible for autonomic and behavioral responses to both acute and chronic stress [1]. Since CRH hypersecretion or exogenous CRH injection have been demonstrated to cause depressive symptoms and anxiety in animal studies, antagonism of CRH receptors has to be considered as a promising new treatment option in depression [1,55]. The effects of CRH are mediated via two spe-cific G protein-coupled receptors, the CRH

1 and the CRH

2

receptors, CRH having more affinity to the CRH1 receptor.

Whereas the CRH1 receptor is located in most brain areas and

is mainly expressed in the neocortex, hippocampus, amygdala, cerebellum and anterior pituitary lobe, the CRH

2 receptor is

mainly present in the limbic system [34]. In animal models of depression and anxiety, antidepressant and anxiolytic effects of the CRH

1 receptor antagonists R121919 [96,97], DMP696 [97],

SSR125543 [98], CP-154,526 [99,100], R278995/CRA0450 [101] and CRA1000/1001 [102,103] could be demonstrated.

The first study using a CRH1 receptor antagonist in depressed

patients was an open-label trial designed to assess the safety of the specific CRH

1 receptor blocker R121919 and was conducted

at the Max-Planck Institute of Psychiatry in Munich [104]. The depressed patients (n = 20) were split into equally sized groups who, over a 30-day period, received a dosage escalating either from 5 to 40 mg/day or from 40 to 80 mg/day. A decrease in the sum scores of the depression and anxiety ratings was observed during the 30-day treatment period, which was followed by a certain relapse of depressive symptoms after treatment with R121919 was discontinued. The patient group receiving higher dosages demonstrated better improvement in depression and

anxiety symptoms. R121919 was well tolerated in this study [104], improved sleep-EEG parameters [105], did not cause any endo-crinological changes in the basal or CRH-induced cortisol and ACTH secretion [104,106], and was not followed by changes in bodyweight or plasma leptin levels [107]. The lacking endocrino-logical impact on HPA axis activity at the dosages used in the study can possibly be explained by a counter-regulatory increased activity of CRH

2 receptors or by enhanced stimulation of ACTH

by AVP [106]. However, the open-label design of the trial and the lacking association between clinical effects and endocrino-logical changes in the HPA system limit the explanatory power of the study. In the meantime, the CRH

1 receptor antagonist

R121919 has been removed from the market because elevation of liver enzymes was observed in healthy subjects in single cases, although there was a good overall tolerability.

In the first controlled trial in depressed patients investigating the antidepressant effects of a CRH

1 receptor antagonist, the

selective CRH1 receptor blocker CP-316,311 was compared with

both an active comparator drug (sertraline) and placebo [108]. A total of 123 patients suffering from a major depressive episode were randomly assigned in a 1:1:1 ratio to receive CP-316,311 400 mg twice daily, placebo or sertraline 100 mg daily in a fixed-dose, double-blind, double-dummy, parallel-group, placebo- and sertraline-controlled trial. At the planned interim ana lysis, includ-ing 28 patients in the CP-316,311 group, 31 patients in the pla-cebo group and 30 patients in the sertraline group, the change from baseline in the sum score of the Hamilton Depression Rating Scale (HAMD) at the final visit was not significantly different between the CP-316,311 and placebo groups, while change from baseline between the sertraline and placebo groups differed sig-nificantly. Although CP-316,311 was well tolerated and safe in the study population, no antidepressant efficacy could be shown for CP-316,311 in the interim ana lysis, whereas the selective serotonin-reuptake inhibitor (SSRI) sertraline was effective. Given this clear result, futility was declared for CP-316,311 and the trial was terminated. Assuming that free brain concentra-tion is equal to free plasma concentration, and given an affinity of CP-316,311 to the human CRH

1 receptor in the nanomolar

range (IC50

: 0.4–1.7 ng/ml), a clinically efficacious serum con-centration of CP-316,311 in the range of 267–1133 ng/ml had been estimated previously. In addition, a study investigating the CP-316,311 levels in the CSF and the plasma of healthy sub-jects, which was performed before the clinical trial in depressed patients, confirmed that CSF concentrations of CP-316,311 were similar to the free fraction in human plasma. In the clinical trial in depressed patients, measurement of serum CP-316,311 levels at weeks 1 and 6 indicated that adequate serum exposures were achieved. Moreover, significantly decreasing effects of CP-316,311 on urinary cortisol levels provided supportive evidence of central CRH

1 receptor antagonism at the dosages used in the trial.

Central CRH1 antagonism has been proposed as a new treat-

ment strategy in depression by proponents of the corticoid recep-tor hypothesis both for theoretical reasons and in view of animal data. However, no controlled study has been able to demonstrate antidepressant efficacy of a CRH

1 receptor antagonist superior



to placebo in depressed patients, challenging the importance of animal data for the clinical situation in depressed patients in general. Moreover, the negative results of the controlled clini-cal trial raise the question of to what extent the animal data on CRH, which are almost exclusively based on experiments investigating anxiety-like behaviors, are of specific relevance for both animal models of depression and depressive symptoms in human beings.

Antagonism at vasopressin V1b receptorsThe main activator of the HPA axis is CRH, which, together with AVP, stimulates the release of ACTH. Under chronic stress, AVP expression in the paraventricular nucleus is enhanced and AVP becomes the primary activator of ACTH [109]. The involvement of the vasopressinergic system in depression was first hypothesized by Gold and coworkers through observations of altered behav-ior in animal models after administration of vasopressin [110]. There are three distinct G protein-coupled AVP receptors. In particular, the vasopressin V1b receptor is important in regulating the responsiveness of pituitary corticotrophs to vasopressin [111]. Upregulation of V1b receptors has been suggested in depression, which could contribute to the shift in the hypothalamic drive from CRH to AVP [112]. In mice deficient for the CRH

1 receptor,

basal ACTH secretion and HPA system activity is maintained by compensatory activation of the hypothalamic vasopressin ergic, but not the oxytocinergic, system [113]. Furthermore, recent evi-dence suggests that genetic variation in the V1b gene may be associated with vulnerability to depression [114,115].

Antagonists of AVP receptors have the potential to serve as therapeutic agents in treating depression and anxiety. An antagonist with dual affinities for the V1a and V1b receptor demonstrated anxiolytic effects in the rat [116]. More recently, a specific V1b antagonist (SSR149415) has been developed that exhibits antidepressant properties in rats that are similar to those of fluoxetine [117,118]. Moreover, this nonpeptide V1b receptor antagonist demonstrated significant effects in rodent models of anxiety and depression [119], and had long-lasting antidepressant effects in the olfactory bulb ectomy-induced hyperactivity model of depression [120]. Although these observations have helped to support the hypothesis of V1b antagonism as a novel antidepres-sant strategy, they are based on the preclinical profile of a single compound, SSR149415. More confidence in this mechanism of action awaits the development and preclinical profiling of addi-tional V1b antagonists. Moreover, results from clinical trials using V1b receptor antagonists in humans are not yet available, but are awaited with interest.

Inhibition of cortisol synthesisAnother possibility to treat the presumed hyperactivity of the HPA system in depression is the inhibition of cortisol synthesis. In this regard, three cortisol synthesis inhibitors have been investigated to date: ketoconazole, aminoglutethimide and metyrapone.

Ketoconazole is a blocker of the cytochrome P450 isoenzyme CYP3A and, thus, inhibits the synthesis of steroids in the adrenal cortex [121]. A number of case reports and open trials report, in part,

pronounced antidepressive effects of ketoconazole in depressed patients [122–130]. However, the significance of these case reports and open studies is limited, since in most investigations no more than ten patients were included. Two placebo-controlled, double-blind trials using ketoconazole revealed different results: while in a 4-week, placebo-controlled, double-blind study, a significant anti-depressant efficacy was demonstrated after treatment with ketocon-azole 800 mg/day in hypercortisolemic patients [131], no antidepres-sant effects were found in another 6-week controlled study treating therapy-resistant depressive patients with ketoconazole [132].

Aminoglutethimide is an inhibitor of steroid synthesis that blocks both 3b-steroid dehydrogenase and 11b-hydroxylase. In several open case series some evidence for antidepressive efficacy was found [124,126,133]. However, controlled trials are lacking.

Metyrapone is a specific inhibitor of 11b-hydrosysteroid de hydrogenase type I and 11b-hydroxylase, which catalyses the conversion from deoxycortisol to cortisol [134,135]. In animal models, metyrapone exhibited anxiolytic and antidepressive properties [136]. As early as the 1970s, antidepressive effects of metyrapone were described in patients suffering from Cushing’s disease with con-comitant depressive symptoms [137]. In 1991, an antidepressant action of metyrapone in a depressed patient was reported for the first time [127]. Moreover, several case reports and small open-label studies were indicative of antidepressant efficacy of metyrapone in the treatment of depression as monotherapy [124,126,138] or as an aug-mentation strategy in patients pretreated with conventional anti-depressants [139]. In a 2-week, placebo-controlled, single-blind trial with crossover design, eight depressed patients were treated with up to metyrapone 1 g/day using concurrent substitution with hydro-cortisone 30 mg in order to prevent insufficiency of the adrenal cortex [140]. This study gave some evidence for the anti depressant effects of metyrapone; however, there were methodological limi-tations owing to the small sample size and the short duration of treatment. In the largest randomized, placebo-controlled, double-blind trial performed so far, 60 depressed patients were treated for 5 weeks with the SSRIs fluvoxamine or nefazodone, receiving as concomitant treatment during the first 3 weeks either placebo or metyrapone at a dosage of 1 g/day [141]. These patients, who had been treated with additional metyrapone, demonstrated an earlier onset of antidepressant action and also higher response rates at the end of the treatment period. Metyrapone was well tolerated without relevant side effects and caused higher ACTH and deoxycortisol levels, whereas the cortisol concentrations remained unchanged.

Antiglucocorticoid treatment with DHEADehydroepiandrosterone is, at least in part, produced in the adrenal gland and is therefore under the control of the HPA system. Both DHEA and cortisol are secreted by the adrenal cortex in response to ACTH [142–146]. Whereas hypersecre-tion of cortisol is well established in depression [1], conflicting results have been reported with regard to plasma or salivary levels of DHEA or its sulfated conjugated metabolite DHEA-S in depressed patients. Elevations in DHEA or DHEA-S con-centrations were found in depressed patients compared with healthy controls [147–152]; however, normal [153–156], or even



lowered [157–162], DHEA or DHEA-S levels were also reported in depressed patients. These conflicting results may be explained in part by differences in the time points of blood sampling or in clinical features (lower DHEA/DHEA-S levels in dysthymia and higher DHEA/DHEA-S levels in major depression).

It is also an important issue that DHEA may act as an antagonist to glucocorticoids, such as cortisol, in some circum-stances [163–166]. The antiglucocorticoid action of DHEA in the brain suggests that calculation of the cortisol/DHEA ratio may be a more precise method of assessing the degree of functional hyper-cortisolemia in depression than measuring the levels of either steroid alone [167,168]. In fact, significantly higher cortisol/DHEA ratios were found in depressed patients compared with healthy controls in most [155,157,158,167,169–171], but not all [154,156], studies.

There is evidence that DHEA or DHEA-S may be involved in the mechanisms of action of antidepressant treatment strat-egies: increased baseline DHEA-S levels predict nonresponse to nonpharmacological treatment, such as electroconvulsive therapy [148] or partial sleep deprivation [172]. In the majority of clinical trials in depressed patients, successful antidepressant pharmacotherapy was associated with a decline in DHEA-S concentrations [149,150,173,174].

Treatment with DHEA itself was demonstrated to improve mood and to possess antidepressant efficacy in several open-label studies [175–179] and double-blind, placebo-controlled tri-als [180–183]. Antidepressant effects of DHEA in depressed patients were reported first in a 6-month open study [175]. In a double-blind, randomized trial with crossover design (3 weeks DHEA 90 mg, DHEA 450 mg or placebo), including patients suffering from dysthymia, DHEA was superior to placebo at both dos-ages [181]. Moreover, in a small placebo-controlled, double-blind study, using DHEA as monotherapy or as augmentation strategy to conventional antidepressants, DHEA demonstrated antidepres-sant effects after 6 weeks of treatment [180]. In a further random-ized, placebo-controlled, double-blind trial, 46 depressed patients were included and those in the DHEA group were treated with DHEA monotherapy 90 mg/day during the first 3 weeks fol-lowed by 3 subsequent weeks with DHEA 450 mg/day. Again, a significant superiority of DHEA over placebo could be shown [182].

The following mechanisms of action are discussed with respect to the presumed antidepressant effects of DHEA:

• Decrease of cortisol levels during DHEA treatment [180] and antiglucocorticoid properties of DHEA [184,185]

• Direct modulation of GABAA, NMDA and s-1 receptors by

DHEA [181,182]

• Metabolization of DHEA to other neuroactive steroids with GABAergic effects [186,187]

• Increased testosterone and androgen levels during DHEA treat-ment, particularly in women with improvement of libido and mood [188]

• Neurotrophic effects of DHEA with enhancement of synaptic plasticity [189,166,190]

GR antagonistsAntagonism of the GR as a new antidepressant principle appears to be surprising, since in depressed patients a disturbed, GR-mediated negative feedback control of the HPA system is supposed, and upregulation of the GR is regarded as an important mechanism of action of conventional antidepressant drugs [1]. Nevertheless, the following pathophysiological issues may give reason for a short-term use of GR antagonists in depression leading to antidepressant effects that may persist after cessation.

First, exogenous administration of synthetic glucocorticoids in higher dosages over a longer period of time is frequently associ-ated with psychiatric symptoms, such as depression, hypo mania, insomnia, cognitive deficits and psychosis [191]. Moreover, diseases with endogenous overproduction of cortisol (e.g., Cushing’s syn-drome) are often accompanied by psychiatric symptoms, such as affective or cognitive impairments, suicidality and psychosis [137]. Apparently, a direct correlation between the amount of psychiatric symptoms and the level of the circulating cortisol concentrations exists [192] and the symptoms improve after the cortisol levels decrease [137,193]. An exaggerated basal cortisol secretion is, there-fore, not only a consequence of central HPA system dysregulation, but also causes psychiatric symptoms itself.

Second, in patients suffering from delusional depression, hyperactivity of the HPA system is observed particularly often, which can possibly be explained by a cortisol-induced inhibition of dopamine metabolism, resulting in psychotic symptoms [194].

Thus, short-term treatment with GR antagonists appears to be useful to accelerate the onset of antidepressant efficacy in these patients, especially in hypercortisolemic depressed patients showing nonsuppression in the DEX suppression test or in the combined DEX/CRH test and also in depressed patients with psychotic features [195].

Mifepristone (RU 486), a derivative of the progestin north-indon, is an antagonist with a high affinity at both progester-one receptors and GRs [196]. Moreover, mifepristone possesses a low affinity to the androgen receptor and has almost no impact on estrogen, monoamine, histamine, acetylcholine or MRs [197]. Administration of mifepristone in humans decreases the GR-mediated negative-feedback function of the HPA system and leads to an increase in cortisol and ACTH secretion [198]. An enhanced secretion of cortisol and ACTH after adminis-tration of mifepristone can also be demonstrated in depressed patients [199–201]. In several case reports and some small open-label studies mifepristone was administered in depressed patients for not more than 4–7 days in most cases [202–204], but, in one study, it was given for 8 weeks [205]. The first evidence of the anti depressant efficacy of mifepristone, especially in depressed patients with psychotic symptoms, were reported in these studies.

More recently, a number of controlled trials using mifepristone in depression have been published. In a randomized, double-blind study with crossover design, 20 patients suffering from bipolar dis-order were treated with either mifepristone (600 mg/day) or pla-cebo [206]. Mifepristone, but not placebo, was effective in improv-ing neurocognitive function and reducing depressive symptoms. In a further controlled investigation, 30 patients with delusional



depression received either mifepristone (600 mg/day) or placebo for 8 days [199]. The HAMD and the Brief Psychiatric Rating Scale (BPRS) were administered at baseline and again after 8 days of treatment. Patients in the mifepristone group demonstrated a significantly higher decline in the BPRS positive symptom sub-scale, an index of psychotic symptoms, compared with the placebo group. However, no significant differences were found with regard to the HAMD sum score and the BPRS total score. Moreover, in a double-blind, randomized, placebo-controlled study 221 patients suffering from psychotic major depression and not receiving anti-depressants or antipsychotics were randomly assigned to either 7 days mifepristone (600 mg/day) or placebo followed by 21 days of usual treatment. Again, patients treated with mifepristone were significantly more likely to achieve a 50% reduction in the BPRS positive symptom subscale; however, no significant differences were observed on measures of depression. Apparently, initial treat-ment with mifepristone in depressed patients with psychotic fea-tures has significant favorable effects on psychotic symptoms, but not on the depressive core symptomatology. However, three recently completed Phase III trials conducted by the pharmaceuti-cal company Corcept Therapeutics failed to significantly separate mifepristone from placebo, and challenge the positive results of the aforementioned small controlled studies [301]. Moreover, one major disadvantage of mifepristone is the fact that it not only blocks the GR, but is also a progesterone antagonist that is used for medical abortion [207]. Therefore, the use of mifepristone is excluded in female patients with child bearing potential. The clini-cal usefulness of specific GR antagonists in depression is currently under investigation.

Expert commentaryAccording to the corticoid receptor hypothesis of depression, hyperactivity of the HPA system is one of the major patho-physiological factors for the development of this disease. The importance of this hypothesis for the pathophysiology of depres-sion is presently a matter of great debate. There is as much evidence against the corticoid receptor hypothesis as there are findings supporting this hypothesis.

With regard to the combined DEX/CRH test, which is con-sidered to be the best tool to detect HPA axis dysregulation in depression, no study has been performed so far confirming the originally reported high sensitivity of this test of more than 80% by using a dichotomous criterion that is applicable under clini-cal conditions [73]. Apparently, HPA system hyperactivity occurs in only 30–50% of acutely depressed patients, but a considerable proportion of acutely depressed patients may still benefit from this therapy, although they show normally regulated HPA axis activity before antidepressant treatment. Moreover, an early improvement of HPA axis hyper activity (e.g., within the first week of treatment) is not necessarily followed by a favorable response and, therefore, is not a sufficient condition for a beneficial treatment outcome [208]. In addition, it is remarkable that a considerable proportion of depressed in-patients demonstrate a pronounced enhancement of HPA axis activity shortly before discharge in spite of clinical recovery, suggesting that attenuation of HPA axis activity during

antidepressant therapy is obviously not a necessary condition for acute clinical recovery [73]. Accordingly, depressed patients have been shown to respond to lithium augmentation in spite of sig-nificantly enhanced ACTH and cortisol secretion patterns during the DEX/CRH test compared with baseline, supporting the view that the increasing effect of lithium on HPA axis activity does not depend on the psychopathological state or its change [209].

In all the studies investigating the impact of antidepressants, such as reboxetine, mirtazapine, tricyclics, SSRIs or tianeptine, on the outcome of serial DEX/CRH tests, the changes over time in endocrinological parameters did not depend on the therapeutic response and were comparable in responders and nonresponders [77]. Therefore, as stated in the publication of Nickel et al., “a reduction of the plasma cortisol and ACTH values might be an important but not sufficient condition with regard to clinical improvement of depressive symptomatology. Besides the normalization of the HPA system, other, as yet unknown neurobiological factors appear to be necessary for the clinical remission of depressive disorder” [210].

Considering the conflicting results in studies investigating the importance of HPA axis hyperactivity for the development of depression and its therapy, and given the limited evidence for clinical efficacy of drugs influencing HPA system regulation, it is not clear, at present, to what extent new antidepressant treat-ment options derived from the corticoid receptor hypothesis of depression will be established as generally accepted strategies to treat depression in routine clinical practice.

Five-year viewAlthough a huge amount of preclinical data support the view that CRH

1 receptor antagonists are useful in the treatment of depres-

sion, currently no controlled studies are available that demonstrate clinical efficacy in depressed patients. Moreover, clinical trials are awaited investigating putative antidepressant effects of vaso-pressin V1b receptor antagonists in depression. The use of the anti glucocorticoid neuroactive steroid DHEA and the GR and progesterone antagonist mifepristone in depression is very much at the proof-of-concept stage, and efficacy has been demonstrated in some small double-blind, placebo-controlled studies. However, three recently completed Phase III trials failed to significantly sepa-rate mifepristone from placebo in depressed patients; the results of the fourth study have not yet been evaluated. Moreover, larger scale clinical trials are necessary to answer several important questions, including how long the treatment effects persist and how the overall efficacy and safety of this class of treatment has to be estimated. Also required is an understanding of the predictors of response, such as the presence of hypercortisolemia and also the use of treatment alone or as augmentation to standard pharmacotherapy.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.



Key issues

• According to the corticoid receptor hypothesis of depression, hyperactivity of the hypothalamic–pituitary–adrenocortical system is one of the major pathophysiological factors.

• There are a huge amount of preclinical data suggesting anxiolytic and antidepressant effects of corticotropin-releasing hormone (CRH)1

receptor antagonists.

• The only controlled trial using the CRH1 receptor blocker CP-316,311 in depression failed to show significant differences between this

drug and placebo, whereas the active comparator drug (sertraline) was significantly more effective compared with placebo.

• There is some evidence from animal studies that the selective vasopressin V1b receptor antagonist SSR149415 may have anxiolytic and antidepressant properties; however, data in depressed patients are currently lacking.

• The cortisol synthesis inhibitor metyrapone has demonstrated significant antidepressant effects as an augmentation strategy in a 6-week, double-blind, placebo-controlled trial in depressed patients pretreated with selective serotonin-reuptake inhibitors.

• Dehydroepiandrosterone possesses antiglucocorticoid properties and demonstrated significant antidepressant efficacy in several double-blind, placebo-controlled trials at dosages up to 450 mg/day.

• Mifepristone is an antagonist at glucocorticoid and progesterone receptors and has been shown in some small controlled studies to significantly reduce productive psychotic symptoms in psychotic major depression, whereas no significant effects were seen in the depressive core symptoms. However, three recently completed Phase III trials failed to significantly separate mifepristone from placebo in depressed patients.

• Owing to its progesterone antagonism, mifepristone cannot be used in female patients with childbearing potential; therefore, the clinical establishment of specific glucocorticoid receptor antagonists in the treatment of psychotic major depression is awaited.

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Website

301 Corcept Therapeutics. Press release, March 19 (2007) www.corcept.com/pressrel_03-19-2007.htm

Affiliations• Cornelius Schüle, MD

Department of Psychiatry, Ludwig-Maximilian-University, Nussbaumstr. 7, 80336 Munich, Germany Tel.: +49 895 160 5731 Fax: +49 895 160 5738 [email protected]

• Thomas C Baghai, MD Department of Psychiatry, Ludwig-Maximilian-University, Nussbaumstr. 7, 80336 Munich, Germany Tel.: +49 895 160 5335 Fax: +49 895 160 5330 [email protected]

• Daniela Eser, MD Department of Psychiatry, Ludwig-Maximilian-University, Nussbaumstr. 7, 80336 Munich, Germany Tel.: +49 895 160 3423 Fax: +49 895 160 5319 [email protected]

• Rainer Rupprecht, MD Department of Psychiatry, Ludwig-Maximilian-University, Nussbaumstr. 7, 80336 Munich, Germany Tel.: +49 895 160 2770 Fax: +49 895 160 5524 [email protected]

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