Glucocorticoid antagonists and depression

John S. Andrews*

NeurAxon Inc., Suite 318, 16-1375 Southdown Road, Mississauga, ON, Canada L5J 2Z1

Abstract: Substantial evidence exists to indicate a prominent role for chronically elevated levels of Cortisol and a dysfunctional feedback system within the hypothalamic-pituitary-adrenal (HPA) axis in major depressive disorder. Chronically elevated Cortisol levels are strongly correlated with depression and normalization of Cortisol levels accompanies recovery; failure to normalize predicts relapse or poor recovery. This dysfunction seems to especially link hyperactivity in the system to the role of glucocorticoid receptors. Studies using glucocorticoid synthesis inhibitors or glucocorticoid antagonists in both animals and man have indicated positive effects on the physiological, psychological and pharmacological changes evident in depression. The development of further specific modulators of the glucocorticoid receptors is to be welcomed, however other targets are evident within the HPA axis such as corticotropin-releasing factor (CRF) and vasopressin and may afford equally attractive targets for therapy.


The hypothalamic-pituitary-adrenal (HPA) axis plays a fundamental role in adaptive responses to stress and operates to modulate both behavioural and physiological changes. The system is complex and interacts at a number of levels including supra-hypothalamic control from cortex and hippocampus. The ultimate expression of activation is the release of glucocorticoids Cortisol in man and corticosterone in many animals. Figure 1 illustrates the overall flow and connectivity of the system and shows the complexity and points for feedback. The diagram demonstrates that corticosteroids are not isolated and form part of a complex system of regulation in conjunction with other receptors, hormones and even other neurosteroids (for reviews see Jessop, 1999, Wolkowitz and Reus, 1999).

In mammals the release of glucocorticoids (Cortisol, corticosterone) from the adrenal cortex is dependent on the action of adrenocorticotropin hormone (ACTH) following release from the pituitary. ACTH release is in turn under the control of corticotropin-releasing factor (CRF), an effect which

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may be amplified by co-release of vasopressin. CRF is in turn secreted from the paraventricular nucleus which is connected to and influenced by several brain areas including hippocampus and amygdala, areas of the brain known to be important in cognition and affect. Glucocorticoid levels are regulated by a feedback mechanism via corticosteroid receptors at the level of the hippocampus which in turn regulates the stimulatory input to the pituitary.

There are two corticosteroid receptor subtypes regulating the system, mineralocorticoid receptors (type I, sensitive to Cortisol and aldosterone) and the lower affinity glucocorticoid receptor (type II sensitive to Cortisol and dexamethasone). The glucocorticoid receptor is more widely distributed in the central nervous system (CNS) and appears to be the dominant component of the stress response, the mineralocorticoid receptor has a more limited distribution being concentrated in the hippocampal region (Reul and de Kloet, 1985).

HPA dysfunction and depression

Following the introduction of the monoamine oxidase inhibitors and tricyclic antidepressants

Fig. 1. The HPA axis, interactions and routes for feedback from Mitchell and O'Keane 1998, with permission from BMJ Publishing Group.

Hpa Dysfunction

Fig. 1. The HPA axis, interactions and routes for feedback from Mitchell and O'Keane 1998, with permission from BMJ Publishing Group.

Glucocorticoids research concentrated on the biogenic amines in general and later focused on serotonin with the emergence of the selective serotonin uptake inhibitors (SSRIs) and an understanding of serotonin pharmacology in affective disorders (e.g. Delgado et al, 1990). However, almost in parallel, interest in the neuroendocrine system in depression began to develop and has led to a greater understanding of the interactions of the HPA axis with monoamines and other hormones and thereby the myriad of potential mechanisms for influencing mood. This brief review will concentrate directly only on the glucocorticoid function of the HPA axis in depression.

The importance of the HPA axis in pyschiatric illness has grown over the last few decades to the point where it now commands a central point in any discussion or research programme, particularly in affective disorders. Disruption of the HPA axis in depression has grown from a series of observations (Michael and Gibbons, 1963; Gibbons, 1964; Sachar, 1971) to an event of accepted pathophysiological significance (Steckler et al, 1999; Varghese and Brown, 2001). It has been a gradual accumulation of evidence rather than one sudden leap which has led to an appreciation that the HPA axis may play a pivotal role in affective disorders. Thus, the evidence cited below indicates that at least some forms of major depression are characterized by an overproduction of glucocorticoids accompanied by a decreased sensitivity to feedback in the CNS.

The first observations noted the significant elevation of basal plasma Cortisol in depressed as opposed to normal controls; moreover, it appeared that Cortisol levels decreased during remission (Michael and Gibbons, 1963; Gibbons, 1964). Subsequent studies confirmed and extended these initial observations, and it appears that pulsatile and diurnal pattern of Cortisol secretion is blunted leading to lower differences in overall levels throughout the day (Deuschle et al, 1987). Cortisol abnormalities have been demonstrated in plasma, urine, CSF and saliva, offering a wide range of possibilities for monitoring.

Changes in the levels of glucocorticoids are handled in the HPA system by series of feedback loops which correct over and underproduction as appropriate (Fig. 1). In patients with major depression this feedback mechanism appears to be dysfunctional. Administration of the glucocorticoid agonist dexamethasone would normally result in a suppression of plasma corticosteroids via the usual inhibitory feedback mechanisms (Fig. 1). This feedback mechanism is dysfunctional in depressed patients with a resulting increase in ACTH and Cortisol levels discussed above. Suppression of Cortisol in response to dexamethasone is blunted or absent (Carroll, 1981). The severity of depression noted in patients appears to correlate with the degree of non-suppression, patients classified as psychotic depression showing the greatest rate of Cortisol non-suppression after dexamethasone (for a metaanalyses see Ribeiro et al, 1993, Nelson and Davis, 1997). Moreover, dexamethasone non-suppression resolves with recovery from depression (Carroll, 1981; Greden et al, 1983). The length of illness and number of episodes of depression may lead to more persistent non-suppression (Lenox et al, 1985) and failure to normalize may predict early relapse (Greden et al, 1983; Targum, 1984). Accordingly, it has been suggested that the changes in the response of the HPA system can be used as one marker of depression and response to treatment. However, some caution is required: elevated glucocorticoids and dexamethasone non-supression can occur in disorders other than depression, for example in schizophrenia (Munro et al, 1984), dementia (Spar and Gerner, 1982) and bulimia (O'Brien et al,

The discovery of (CRF, Vale et al, 1981) and its role in controlling the release of ACTH and betaendorphins from the pituitary, shed further light on the regulation of the HPA axis. CRF administration to drug-free depressed patients results in a blunted ACTH response but a normal Cortisol response (Amsterdam et al, 1987, Kathol et al,

1989). A combined dexamethasone/CRF test has been developed to measure the efficiency of the GR-mediated negative feedback loop (Holsboer et al, 1987). Depressed patients show enhanced levels of ACTH and Cortisol following the administration of CRF after dexamethasone (Holsboer et al, 1987; Modell et al, 1997; Zobel et al, 1999). It has been argued that the combined CRF/dexamethasone test is a more sensitive and reliable measure of the state of HPA functionality in depression. Moreover, changes correlate with intensity and duration of disease, and persistency of the abnormal response predicts inadequate clinical resolution or even relapse (Zobel et al, 1999; Zobel et al, 2001; Hatzinger et al, 2002, see also review by Modell and Holsboer in this volume).

Stress, HPA function and depression

Elevated corticosteroids are a feature of chronic stress. Many studies attest to the deleterious effects of chronic stress and the effects of elevated corticosteroids on brain structure and function (see reviews by Sapolsky, 1996, 2000). The development of animal models involving chronic stress, or maternal deprivation which induces a sensitivity to stressful stimuli, has resulted in a greater understanding of the consequences of chronic stress on the HPA axis and its relationship to symptoms in depression including physiological, pharmacological and behavioural disturbances (Meaney et al, 1996; Sutanto et al, 1996; Lopez et al, 1998; Kalinichev et al, 2002; Kioukia-Fougia et al, 2002; Mizoguchi et al, 2003; Ladd et al, 2004). Interestingly, such changes, including stress-induced anxiety in these models, are reversible with chronic antidepressant treatment (Lopez et al, 1998; Huot et al, 2001). In addition, changes in hippocampus and hippocampal function including cognition are prominent in stressed animals (Brown et al, 1999; McEwen, 2001). These are all thought to be direct consequences of chronically elevated steroids and mirror many of the cognitive and structural changes seen in severely depressed patients (see below).

More recently, transgenic models of hypercortiso-laemia have been produced and again a number of features similar to those observed in depression, including dexamethasone non-suppression and cognitive deficits have been established (Stec et al, 1994; Barden et al, 1997; Steckler, 2001).

Structural changes in HPA associated depression

Structural changes to components of the HPA are evident in depressed patients. Changes in size and volume have been observed for both the pituitary (Krishnan et al, 1991; Axelson et al, 1992) and the adrenal glands (Rubin et al, 1995). The enlargement of the pituitary and adrenals are associated with enhanced levels of ACTH and the changes typically reverse following antidepressant treatment (Rubin et al, 1995). In addition to changes in the adrenal and pituitary glands, a reduction in the volume of the hippocampus has been reported repeatedly (Sheline et al, 1996; MacQueen et al, 2003; Sheline et al, 2003) but not always in patients with major depressive illness (e.g. Axelson et al, 1993) and it remains unclear as to the exact mechanism for this change. Nevertheless, there is a clear and strong association between hippocampal atrophy, hyperco-tisolaemia and cognitive deficits. In Cushing's syndrome (see below) these effects seem to reverse in parallel with recovery. Moreover, antidepressant treatment may protect against further deterioration of the hippocampus (see Sheline et al, 2003) and spare cognitive function. However, the changes in hippocampal volume appear to accumulate in depressed patients and remain even in remission (Sheline et al, 1996; McQueen et al, 2003; Sheline et al, 2003). Accordingly, antidepressants may not be able to reverse previous damage and thus emphasizes the importance of early intervention.


Cushing's syndrome and Cushing's disease are both characterized by high Cortisol levels and a preponderance of depressive symptoms: insomnia, decreased memory, decreased energy and fatigue, depressed and labile mood. Approximately two-thirds of these patients qualify as depressed and the depression seems to be causally related to circulating Cortisol: depressive symptoms resolve when the hypercortisolaemia is treated either surgically (Welbourn et al, 1971) or via a variety of anti-glucocorticoid treatments (glucocorticoid synthesis inhibitors: Sonino et al, 1986; Sonino et al, 1991; or glucocorticoid antagonists: Nieman et al, 1985; Sator and Cutler, 1996; Chu et al, 2001).

The symptoms and the relief from symptoms appear related to levels of Cortisol and not ACTH: both the syndrome and disease show hypercortisolaemia, however only in Cushing's disease is the level of Cortisol normally ACTH dependent; moreover, following treatment, improvements in mood occur even when ACTH levels remain high (Starkman et al, 1986). In addition, patients suffering from Nelson's syndrome following adrenalectomy show high levels of ACTH, low levels of Cortisol and low frequency of depressed symptoms.

Cushing's patients also show cognitive deficits and hippocampal atrophy; as with recent reports in depression these effects may be reversed when glucocorticoid levels are brought under control (Starkman, 1993; see review by Sapolsky, 2000). Patients with Cushing's are also noted for physical changes, particularly associated with increased body fat. Depressed patients typically do not present with Cushing-like physical features despite chronic high levels of corticosteroids. This may reflect differences in the absolute levels of glucocorticoids found in Cushing's versus depressed patients, and differences in the sensitivity of the tissue response to glucocorticoids. However, at least one study has reported that despite normal body mass, depressed patients with high Cortisol levels show a doubling of intraabdominal fat with respect to controls (Thakore et al, 1997). Conversely, psychiatric symptoms may precede physical symptoms in Cushing's (Gifford and Gunderson, 1970).

Treatment of depression

Antidepressants and HP A function

Corticosteroids can directly and indirectly modulate monoaminergic receptor synthesis (de Kloet et al, 1998; Bush et al, 2003). Thus, changes in monoaminergic function by corticosteroids may be one mechanism leading to depression and sets a rationale for the use of monaminergic therapies. In turn, classical antidepressants reduce hypercortisolaemia in depression and restore the sensitivity of the feedback system in line with remission of symptoms (Nelson and Davis, 1997; Hatzinger et al, 2002). For a more detailed discussion on human studies see the chapter by Modell and Holsboer (this volume).

Animal studies have paralled human studies in showing that chronic administration of antidepressants will reduce HPA activity in normal animals (e.g. Shimoda et al, 1988; Reul et al, 1993) and in genetically modified animals with abnormal HPA function (Pepin et al, 1992; Montkowski et al, 1995; Barden, 1999). The mechanism of action for this change is still a matter of debate, however, changes in transcription and translocation of glucocorticoid receptors are commonly reported. In vitro studies with antidepressant treatments demonstrate that antidepressants can upregulate glucocorticoid receptors and increase expression levels (Pepin et al, 1989; Peiffer et al, 1991; Holsboer and Barden, 1996; Okugawa et al, 1999; Yau et al, 2001; Herr et al, 2003; Okuyama-Tamura et al, 2003). These effects have also been observed in vivo (Seckl and Fink, 1992; Lopez et al, 1998) and following non-drug treatments such as electroconvulsive shock (Przegalinski et al, 1993). Others have suggested that some effects may be via inhibition of membrane steroid transporters which actively remove Cortisol (and dexamethasone) from the cell (Pariante et al, 2001), or indirectly through modulation of genes regulating monoamines under glucocorticoid control (Budziszewski et al, 2000). Interestingly some selective serotonin inhibitors such as fluoxetine, appear to have the least effect in these studies (Seckl and Fink, 1992; Pariante et al, 2001). Moreover, chronic administration of corticosterone to rats reduces the ability of fluoxetine to increase serotonin levels in the brain (Gartside et al, 2003).

This reflects studies indicating that single action SSRI's may be less effective in severe depression than tricyclics (Anderson, 2000); severely depressed patients being most likely to have measurably disturbed HPA function (Rothschild, 2003).

Glucocorticoid inhibition: synthesis inhibitors ft is surprising that it took so long for antigluco-corticoid strategies to be pioneered in depression given that (a) at least some of the more severely depressed patients showed high levels of Cortisol (b) an impaired glucocorticoid feedback system as shown by dexamethasone non-suppression is evident in a high proportion of patients (c) classical antidepressants and ECT reduce Cortisol levels in depressed patients and reduce dexamethasone non-suppression (d) continuing hypercortisolaemia or abnormal CRF/ dexamethasone response in treated depressed patients is predictive of relapse (e) depressive symptoms in other disorders such as Cushing's are related to hypercortisolaemia and resolved by antiglucocorti-coid therapies (f) animal studies indicated similar effects to those observed in man and provided a testable molecular hypothesis.

In fact even as this vast array of data became evident, the number of studies evaluating glucocorticoid inhibition has remained sparse in both the animal and human literature. Of the glucocorticoid synthesis inhibitors used in the clinic several have been found to have positive effects in animal models used to identify antidepressant-like activity. Metyrapone was reported active in the olfactory bulbectomy and forced swim test models (Healy et al, 1999), as well as in repeated immobilization stress (Kennet et al, 1985) and to reduce anxiety-like behaviour after stress (Cohen et al, 2000) and the long term effects of repeated restraint stress in rats (Dal-Zoto et al, 2003).

In the clinic, few blinded or controlled studies are available and most have only a small number of subjects, sometimes a single case report. Most studies have utilized the steroid synthesis inhibitor ketoco-nazole (a current treatment of choice for Cushing's). All studies have reported some success (Murphy et al, 1991; Wolkowitz et al, 1993; Amsterdam et al, 1994; Anand et al, 1995; Thakore and Dinan, 1995;

Sovner and Fogelman, 1996; Murphy et al, 1998; Wolkowitz et al, 1999) and remarkable results for some treatment-resistant patients are evident in many studies e.g. Anand et al, 1995 but not all (see Malison et al, 1999 for poor results). Other glucocorticoid synthesis inhibitors such as metyra-pone appear to be equally effective (O'Dwyer et al, 1995; Lizuka et al, 1996; Raven et al, 1996), and one of the most active groups in this field has used ketoconazole, metyrapone and aminoglutethimide in a series of successful studies (Murphy, 1991; Murphy et al, 1991; Ghadirian et al, 1995; Murphy et al, 1998). It is apparent that antiglucocorticoid treatments work in many patients who are not only depressed but resistant to conventional therapies (e.g. Amsterdam et al, 1994; Ghadirian et al, 1995; Murphy et al, 1998). In addition, antiglucocorticoid therapies may enhance the efficacy of conventional antidepressant drugs (Amsterdam et al, 1994) in augmentation strategies akin to those involving anticonvulsants and lithium, and to treat the depressive symptoms in other psychiatric indications such as bipolar disorder (Brown et al, 2001).

Changes in Cortisol levels parallels the antidepressant response in many of these studies, interestingly, patients with non-elevated Cortisol levels did not appear to benefit significantly from the treatment (Wolkowitz et al, 1999). This may suggest subpopulations of depressed patients likely to show preferential response to antiglucocorticoid therapy and parallels results from meta-analyses of the DST studies indicating the highest correlation between DST and psychotic depressives (Nelson and Davis, 1997), the group with the highest disturbance in the HPA function.

Glucocorticoid synthesis inhibitors are unlikely ever to become drugs of choice for treating a disease as prevalent as depression. The toxic effects are well described: in summary, ketoconazole, metyrapone and aminoglutethimide each disrupt multiple pathways in steroid formation, thereby having effects on several important steroids and indirectly nonsteroidal systems (many side effects are effectively summarized in the excellent review by Wolkowitz and Reus, 1999). For example, ketoconazole decreases testosterone levels, metyrapone can induce hirsuitism, and aminoglutethimide can lower oestra-diol levels; other side effects include rashes, menstrual irregularities, GI distress, hepatotoxicity is rare but not unknown. Moreover, ketoconazole is a strong inhibitor of CYP3A4, the most important P450 enzyme in liver and responsible for metabolizing many clinically known drugs (including ketoconazole), a fact that will always limit its use. In general, the toxicity of this class of compounds is simply too high for general use in what is a chronically ill population.

Glucocorticoid antagonists

In recent years an alternative strategy has begun to develop, directly targeting glucocorticoid receptors with specifically designed antagonists. (Although ketoconazole has demonstrated in vitro activity as a glucocorticoid antagonist (Loose et al, 1983), this property is not thought to be apparent at therapeutic doses.)

Although there are many animal studies utilizing glucocorticoid antagonists, it is still surprisingly limited given the interest in this field. Chronic blockade of glucocorticoid receptors will increase circadian and stress-induced changes in the HPA axis, presumably the resulting hypercorticism to stress reflecting alterations in the feedback system (van Haarst et al, 1996). Glucocorticoid antagonists have been used to demonstrate the involvement of glucocorticoid receptors in learned helplessness and forced swim test models (de Kloet et al, 1988, Peeters et al, 1992, Papolos et al, 1993). Moreover, the same antagonist (RU 486 also known as RU 38486, mifepristone and CT 1073) can reduce both the hormonal (Briski, 1996) and behavioural consequences of stress on anxiety (Korte et al, 1996; Calvo and Valosin, 2001). The alterations in hippocampal plasticity induced by chronic stress or corticosterone applications in rats are reversed by RU 486 (Xu et al, 1998). The dampening of naturally occurring synaptic plasticity is thought to underlie the ability to respond adequately to stressful situations thereby reflecting the negative influence of chronic steroids and other adversely affected neurotransmitters on cognition and other symptoms of depression (see Duman et al, 1999; Reid and Stewart, 2001; Prickaerts and Steckler this volume). In this respect the study by Steckler et al. (2001) is especially interesting as it demonstrates that antidepressants can change hippocampal plasticity in glucocorticoid impaired transgenic mice and improve performance in maze tasks. More recent studies using a variety of novel glucocorticoid antagonists (Org 34116, Org 34850, Org 34517) differentiates their effects on the HPA axis suggesting potential differences in therapeutic application (Bachmann et al, 2003). At least one of the glucocorticoid antagonists (Org 34116) failed to improve symptoms in a primate model of depression (Van Kampen, 2002). This may reflect differences in transactivation processes and partial versus full antagonist status (Sarlis et al, 1999).

The first antagonist to become clinically available, RU 486, a glucocorticoid and progesterone antagonist initially used to abort early pregnancies, is now under clinical investigation as CT 1073 specifically for depression. Initial studies considered the effects of glucocorticoid blockade on HPA function but did not specifically analyse changes in depressive symptoms (Kling et al, 1989; Krishnan et al, 1992). Earlier studies had also indicated its usefulness in Cushing's (Neiman et al, 1985; van der Lely et al, 1991) including reversal of depressed mood. The potential to enhance mood was confirmed in an open trial with depressed patients (Murphy et al, 1993). More recent reports from Corcept have indicated significant effects in psychotically depressed patients where hypercortisolaemia is a predominant feature (Belanoff et al, 2001, 2002). Another company, Organon, also has a glucocorticoid antagonist (Org 34517) in late (Phase III) clinical trials. Meeting reports indicate Org 34517 to be comparable to paroxetine in a double-blinded, paroxetine-controlled trial with 142 patients, and may be especially effective with hypercortisolaemic patients (R Pinder personal communication). Org 34517 is now reported to be in Phase III and suggests that the future for anti-glucocorticoid therapies looks bright, and may be especially relevant to psychotic depression (Belanoff et al, 2001, 2002).

The current glucocorticoid antagonists, although clearly an improvement over the glucocorticoid synthesis inhibitors in terms of toxicity, are not without other properties of concern. Antiprogesterone activity remains significant in both compounds and may present problems over the longer term with acceptance. Chronic blockade of the glucocorticoid receptor may lead to an imbalance in mineralocorti-coid and glucocorticoid receptor activity resulting in over-activation of the mineralocorticoid receptor, an effect which has been observed following long-term administration of high doses of RU 486 to a patient with Cushing's disease (Chu et al, 2001). The initial study from Murphy's group (Murphy et al, 1993) suffered from substantial drop-outs effectively stopping the trial; this was not observed in the Corcept trials where dosing was significantly different.

Moreover, blockade of the HPA system may have consequences for the ability of the body to deal with stress and inflamed or damaged tissues, both major roles for the HPA-derived glucocorticoids. The compounds under investigation today are steroids and steroid derivatives; these structures may be difficult to optimize and show some less desirable basic physicochemical properties. It is apparent that both the CT 1073 and Org 34517 approaches are very focused; back-ups and further developments do not seem to be immediately apparent and few other companies have active programmes in this area. It may be that the recent development of novel nonsteroid ligands for steroid receptors, including glucocorticoid receptors may spur further research and development (Miner et al, 2003). The reported differences in the ability of various glucocorticoid ligands to modulate the HPA axis (Bachmann et al, 2003), will undoubtedly improve the ability to make more functionally selective drugs for therapy.

Alternatives to glucocorticoid modulation of HPA

It is apparent that in a system as complex as the HPA there are numerous points of attack apart from glucocorticoids. Indeed an equally strong case has been made for CRF as a primary force in depression and thus target in depression (see Arborelius et al, 1999 and Steckler this volume for reviews). Accordingly, several major companies have programmes to develop CRF antagonists. Progress has however been slow and to date only one clinical study of note has been published (Zobel et al, 2000). R121919, the compound used did seem to produce a positive response, unfortunately the compound was not suitable for further development.

Much research around affective disorders and corticosteroids has concentrated on glucocorticoid receptors. However, central mineralocorticoid receptors may also play a role in depression and serve as a suitable target for novel therapies. Mineralocorticoid receptors are critical for the basal regulation of the HPA axis, any dysfunction would exacerbate unwanted alterations in the overall system or after acute stress (van Haarst et al, 1997; Spencer et al, 1998). Animal studies demonstrate the importance of mineralocorticoid receptors in facilitating glucocorticoid regulation of the HPA axis at the circadian peak or acute stress (Spencer et al, 1998). Psychological stress via a CRF dependent mechanism can alter mineralocorticoid corticoid receptor levels in the hippocampus (Gesing et al, 2001). In addition, mineralocorticoid antagonists such as spironolactone can affect the sensitivity of the system in the CRF/ dexamethasone suppression test (Heuser et al, 2000) in healthy subjects; depressed patients administered spironolactone show an increase in Cortisol with respect to controls (Young et al, 2003). This has led several groups to postulate that it is the balance between glucocorticoid and mineralocorticoid function that is crucial and that the mineralocorticoid receptor is dynamically modulated and no longer to be viewed as of lesser importance in affective disorders (de Kloet et al, 1998; Reul et al, 2000; de Kloet, 2003; Young et al, 2003).

A role for modulators of vasopressin in treating depression has been suggested by a number of studies in both man and animals. Vasopressin and CRF both regulate ACTH and release (see Fig. 1). Moreover, vasopressin appears to mediate the response to the CRF/dexamethasone test in rats with inherent high anxiety states (Keck et al, 2002). In addition both vasopressin and CRF can regulate corticosteroid receptors at the level of the pituitary and the hippocampus (Hugin-Flores et al, 2003). The potential of vasopressin as a target for antidepressant therapy via normalization of the HPA dysfunction has recently been summarized by Scott and Dinan (2002). Several companies have active vasopressin antagonist programmes as alternatives to CRF or glucocorticoid antagonists for HPA modulation: results from one of these programmes with SSR149415, a selective Vlb antagonist, are summarized in the review by Griebel and Serradeil-Le Gal (this volume).

Although corticosteroid application can induce a range of psychiatric features, disorders including psychosis, negative changes in affect and cognition, hypomanic, euphoric effects and positive effects on cognition are also reported (Boston survey, 1972; Ling et al, 1981; Carpenter and Gruen, 1982; Wolkowitz, 1994; Plilal et al, 1996), it is the chronically high endogenous levels of glucocorticoids which seem related to depression, particularly to the subgroup of psychotic depression (Nelson and Davis, 1997; Belanoff et al, 2002). Finally, although this brief review has concentrated on directly blocking glucocorticoids, there are reports of positive effects of the glucocorticoid agonist dexamethasone in depression alone or in conjunction with antidepressant therapy (Arana et al, 1995; Dinan et al, 1997; Bouwer et al, 2000 see also earlier work with Cortisol Goodwin et al, 1992) including cognition (Bremner et al, 2004). This effect seems contradictory to the premise of HPA hyperactivity as a causal factor in depression. Dexamethasone doesn't penetrate the brain well (de Kloet, 1997) and the effect may be due to its ability to reduce Cortisol levels, resulting in an opportunity for recovery in the sensitivity of central glucocorticoid receptors, thereby allowing the feedback process to operate correctly. However, in some cases of depression hypocortisolaemia, not hypercor-tisolaemia may be a factor (Bouwer et al, 2000) and illustrates that depression is not a uniform disorder with only one molecular cause.

Finally, the interaction between the HPA axis and the immune system is complex and poorly understood. However, it is apparent that some current medical treatments aimed at the immune system also heavily influence the HPA axis and can induce depression (e.g. Capuron et al, 2003). This area was subject to a recent review by Leonard (2001).


The increasing interest on the HPA axis and its role in affective disorders has led to an explosion of functional research and the identification of a vast array of targets to correct imbalances in the system detrimental to brain function and mood. This short review has considered only glucocorticoids as targets for novel therapies within the system, but CRF, vasopressin are also of interest and the accumulation of data indicates the potential for successful and perhaps equally focused therapies for depression. However, depression can not be solely a product of a dysfunctional HPA and other transmitters and systems are intimately involved in the aetiology of depression. It is an important risk factor and there is much evidence to suggest a pivotal role in at least a subgroup of depressed patients with hypercortisolae-mia. It is too early yet to realistically assess the future potential of glucocorticoid antagonists for depression, either alone or as an augmentation therapy to treatment resistant patients. However, the initial results are encouraging and along with the other novel (i.e. non-monoaminergic) agents now in clinical trials (NK1 antagonists, CRF antagonists) and a host of others in the research phase, it indicates that depression is finally receiving the attention and hopefully, the breakthrough that the untreated victims of one of the world's most debilitating diseases deserve.


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