Psychiatric Annals


The Pathophysiologic Significance of Hyperadrenocorticism: Antiglucocorticoid Strategies

Beverley E P Murphy, MD, PhD; Owen M Wolkowitz, MD


The idea that adrenal steroids might play a more direct role in major depression is perhaps not so surprising when one considers the prominent role played by other steroids in behavior.


The idea that adrenal steroids might play a more direct role in major depression is perhaps not so surprising when one considers the prominent role played by other steroids in behavior.

Major depression is associated with a high incidence of Cortisol hypersecretion, both basally and following dexamethasone suppression.1 Although this hypercortisolism is the most well-replicated biological abnormality in major depression (for review, see Murphy2 and Rothschild,3 this issue), its pathophysiologic significance is unknown. Prior investigators have suggested that it is secondary to the stress associated with depression or to the neurotransmitter/neuropeptide abnormalities that seem to be more directly related to the cause of the depression (see Musselman and Nemeroff,4 this issue). It is possible, though, that the elevated Cortisol levels, however caused, may feed back onto the brain and exacerbate, perpetuate, or alter the presentation of depressive symptoms. This notion of hormonal causality has been suggested previously as long ago as 1955, when it was observed that the administration of ACTH and cortisone was often associated with behavioral changes and, in some cases, psychosis.5


The idea that adrenal steroids might play a more direct role in major depression is perhaps not so surprising when one considers the prominent role played by other steroids in behavior. Perhaps the earliest recognized and most dramatic example is the transformation of a rampaging bull into a mild-mannered ox by castration, which removes its source of testosterone. Recently, it has been noted in human athletes that administration of anabolic steroids (all of which are androgens) leads to increased aggressiveness.6

Progestins were recognized to be potent anesthetic agents five decades ago7 and estrogens are essential for female mating behavior. Since the premenstrual syndrome is abolished by oophorectomy, and can be induced by giving oral contraceptives, or other forms of estrogen plus progestin,8 it seems likely that it is due to abnormalities of steroid production, although the relationship is not yet clear.

In considering the role of the adrenal cortex in depression, it must be remembered that Cortisol is only one of some 150 steroids produced either by synthesis within the adrenal cortex or by metabolism of these steroids elsewhere. Some of the metabolism occurs in the brain itself so that peripheral levels may not always reflect brain levels. Those with long recognized biological activity are Cortisol, aldosterone, corticosterone, desoxycorticosterone, progesterone, and dehydroepiandrosterone (DHEA). The sulfated form of the weak androgen DHEA (DHEAS) is actually the most abundant adrenal steroid circulating, its level being usually about 10 times that of Cortisol. Each of these steroids undergoes extensive metabolism resulting in 20 or more metabolites. Although most of the metabolites have for years been considered as inactive, recent studies have shown that some of them affect behavior9 and some act on the GABA receptor.10 Thus, when we observe Cortisol hypersecretion, it is an indicator that other steroids are being produced in abnormal quantities as well.11

Does Stress Play a Role in Hyperadrenocorticism?

We are all subject to stress, but it appears to be the novelty of the stress that is important in stimulating the hypothalamic-pituitary adrenal (HPA) axis (Figure 1). Once repeated several times, the response of the HPA axis to a particular stress (for example, the psychological stress of venipuncture) may be reduced or absent. The high frequency of negative life events preceding the onset of episodes of major depression is well recognized. Recently, evidence has been proposed for a role for life events in the pathogenesis of Cushing's disease.12 The stress response has been studied mainly under acute conditions where the changes quickly subside once the stressor is removed. Chronic stress states are just beginning to be studied and Sapolsky et al13 have observed decreased limbic glucocorticoid receptor levels in rats stressed for several weeks.

Basic Mechanisms of Steroid Action

The brain has been shown to be a major target organ for steroid hormones,14 and steroids may affect brain function via two distinct mechanisms: genomic (indirect) and nongenomic (direct). Corticosteroids freely cross neuronal cell membranes and, in neurons containing specific cytoplasmic steroid receptors, translocate to the cell nucleus.14 In the nucleus, transcription of specific genes is altered. For example, steroids may alter levels of enzymes such as tyrosine hydroxylase, monoamine oxidase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase (PNMT), which control the activity of catecholamines and other neurotransmitters, and alter levels of behaviorally important neuropeptides such as somatostatin, corticotropin releasing factor, adrenocorticotropin, and other proopiomelanocortin-derived substances.14"16 Certain of these molecular events may be particularly important for understanding the behavioral effects of corticosteroids, since neurons containing corticosteroidspecific receptors are located in the hippocampus, septum, and amygdala14 - areas of the brain believed to be involved in behavior, mood, and memory.

Figure 1. Hypothalamic-pituitary-adrenal (HPA) axis. CRF = corticotropin-releasing factor; POMC = proopiomelanocortin; VP = vasopressin; β-end = β-endorphin. From Murphy BEP. Stress and the anxiodepressive syndromes. Medicographica. In press. Reprinted with pemiission.

Figure 1. Hypothalamic-pituitary-adrenal (HPA) axis. CRF = corticotropin-releasing factor; POMC = proopiomelanocortin; VP = vasopressin; β-end = β-endorphin. From Murphy BEP. Stress and the anxiodepressive syndromes. Medicographica. In press. Reprinted with pemiission.

In addition to such genomically related effects, corticosteroids and their metabolites may have direct (nongenomic) effects on brain excitability as evidenced by the rapid anesthetic action of some progesterone metabolites (seconds to minutes),9 and by their interaction (either stimulatory or inhibitory) with neuronal cell membranes and membrane receptors such as the GABAA receptor.10 Given this array of biological effects, it should not be surprising that steroid hormones are important in regulating behavior. The physiologic significance of these effects in humans and their role in depressive symptoms, however, remains uncertain.

Correlational Studies in Major Depression

Several lines of evidence from clinical studies also raise the possibility that Cortisol hypersecretion is pathophysiologic in depression. Each of these lines of evidence, however, has interpretive and methodologic difficulties. A large number of studies have examined the association between Cortisol hypersecretion (either basally or following dexamethasone) with specific symptoms and with overall severity of depression. Many, but not all, studies have found a higher incidence of sleep disturbance, decreased energy, decreased attention and cognitive performance, suicidal thoughts, psychosis, decreased libido, and anxiety in Cortisol hypersecretors (see Rothschild,3 this issue). Dexamethasone nonsuppression and high serum Cortisol levels frequently normalize with clinical recovery from depression; failure of the dexamethasone response to normalize portends poorly for sustained recovery.17,18 Such studies are informative, but it remains difficult to determine the direction of causality. Indeed, rather than causing more severe depressive symptoms, hypercortisolemia may merely be a reflection of more serious pathology.

Cushing's Syndrome

Cushing's syndrome provides a natural model of the psychologic sequelae of hypercorticoidism. As reviewed by Starkman19 in this issue, patients with Cushing's syndrome frequently (about 70%) exhibit fatigue, irritability, decreased memory and concentration, depressed or labile mood, decreased libido, insomnia and crying - symptoms characteristic of major depression. Certain differences may exist, however; such patients tend to gain rather than to lose weight, a feature of "atypical" major depression. Starkman et al20 studied 35 consecutive patients with Cushing's syndrome prior to treatment. Although there was a highly significant relationship between psychiatric disability and Cortisol levels as assessed by Cortisol secretion rate, 8:00 AM plasma Cortisol level and urinary free Cortisol, there was no clear relationship between depression and either of these measures; there was, however, a significant relationship between ACTH levels and depression.

The incidence of depression is probably not significantly different in patients with Cushing's syndrome due to primary adrenal disease versus Cushing's disease in which adrenocortical hypersecretion is secondary to pituitary (or possibly hypothalamic?) dysfunction, or to an ectopic source of ACTH,21 suggesting a closer relationship with corticoid than with ACTH levels. This is also borne out by the fact that decreasing the steroid levels either medically or surgically is associated with improvement in the psychiatric symptoms (see below) even though the ACTH levels may remain unchanged.22

These findings are clearly interesting, but it is difficult to factor out nonspecific medical contributions to the psychological profile in these patients. For example, patients with more serious medical illness (e.g., disfiguring stigmata of Cushing's syndrome) may experience increased stress and depressive symptoms. A further interpretive difficulty is that patients with Addison's disease, characterized by hypoadrenocorticism with high ACTH levels, may also present with depressive symptomatology.23

Steroid Psychosis

It was noted in the early 1950s that the pharmacologic administration of corticosteroids or ACTH to medically ill patients is associated in some patients with development of behavioral changes.5 These include symptoms such as emotional lability, anxiety, distractibility, pressured speech, sensory flooding, insomnia, depression, and cognitive impairment.24 However, it has been pointed out by Murphy2 that the effects of exogenous steroids tend more to euphoria (62%) than to depression (8%), while endogenous hypocorticoidism is much more often associated with depressive (74%) than euphoric symptoms (11%). Such differences could be due to intrinsic differences between endogenous versus exogenous synthetic steroid, to different patterns of steroids and of the neuropeptides influenced by them, to circulating levels of corticosteroids, or to chronicity of exposure.

The early studies do not clearly distinguish the difference between giving single steroids (usually cortisone) and ACTH, but Fleminger,25 who studied one patient with both in a double-blind fashion, reported euphoria with cortisone and depression with ACTH; he felt that the differences in mood matched the different effects of these treatments on 17-ketosteroid output, since ACTH stimulates adrenal androgen production while cortisone suppresses it. Cameron et al,26 however, noted lessening of dysphoria with both prednisone and ACTH. The incidence in the individual of such behavioral reaction is directly related to the dose of corticosteroid administered27; however, the threshold at which any changes occur varies markedly among different patients, as does the dose at which the physical signs of Cushings syndrome develop. Other risk factors have not been clearly identified - previous mental disorder or response to previous courses of treatment do not seem to be related (see Reus and Wolkowitz,27 this issue).

Investigations of steroid psychosis have been hampered by the fact that most of those studied were medically ill; it may be difficult to separate those behavioral changes attributable to the medication from those attributable to changes in the underlying medical condition. Exogenous synthetic corticosteroids (e.g., prednisone and dexamethasone) administered to healthy volunteers have been noted to modestly alter behavior and cognition and to modify levels of dopamine and norepinephrine metabolites as well as levels of ACTH, somatostatin, β-endorphin, and β-lipotropin.16'28-29

It remains to be determined which of these biochemical changes are behaviorally relevant, although Schatzberg et al30 have hypothesized that endogenously elevated levels of Cortisol may contribute to psychotic states via a dopamine-stimulating mechanism. Although such studies provide evidence that corticosteroids are neurochemically and behaviorally active, it is not possible to extrapolate directly from the effects of exogenously administered corticosteroids to those of endogenously occurring hypercortisolemia.


Perhaps the most direct way to assess the role of hypercortisolemia in depressive symptomatology is to block Cortisol action and to observe resultant behavioral changes. Apart from adrenalectomy, there are currently three antiglucocorticoid strategies available: blocking synthesis of glucocorticoids, blocking the action of glucocorticoids at the receptor level, and inhibition of ACTH secretion. These have been applied mainly to patients with Cushing's syndrome and rarely to patients with major depression.

One problem with these approaches is that when Cortisol action is interfered with by drugs, the feedback mechanism of the HPA axis is activated to compensate for the deficit. Thus, their action may be only transitory, until the compensatory mechanism has caused return to high levels, the aim being to maintain a block that the HPA axis cannot overcome.

Inhibition of Cortisol Biosynthesis

Three drugs are in current clinical use: metyrapone (MET), aminoglutethimide (AG), and ketoconazole (KC). The steroid metabolic pathway, which is blocked by these drugs, is diagrammed in Figure 2. Mitotane (o,p'-DDD) is a toxic adrenolytic drug that causes adrenal atrophy and is used to treat Cushing's syndrome, usually when caused by adrenocortical cancer.

MET's action is confined almost entirely to the 11 β-hydroxylase, which converts 11desoxycortisol to Cortisol. The accumulating 11-deoxycorticosteroids result in increased androgen levels so that hirsutism or even virilization may result from long-term use. Tolerance is often limited by gastrointestinal complaints.

AG has a number of effects on steroidogenesis, but particularly, it inhibits the conversion of cholesterol to pregnenolone. It also affects hydroxylation at CIl, C21, and C 18. Because it also inhibits estrogen synthesis, it has been used with Cortisol replacement to treat breast cancer. Common side effects include lightheadedness, somnolence, and rash, although the rash usually subsides spontaneously.

KC, an imidazole used for many years at lower doses as an antifungal drug, affects synthesis in much the same pattern as aminoglutethimide, but, in addition, it effectively blocks androgen synthesis. Because it lowers testosterone, it has been used to treat prostate cancer in men and hirsutism in women. In addition, it is known to bind to the glucocorticoid receptor but has no agonist action; it therefore acts as an antagonist at the receptor. Side effects include headache, nausea, fatigue, elevation of liver function tests, and, very rarely, serious hepatotoxicity.

Since all three drugs (MET, AG, and KC) may cause significant side effects, they are often used at lower doses in combination. Unfortunately, although they cause prompt decreases in adrenocortical function, their effects are often transient because the HPA axis compensates for the drop in Cortisol by stimulating ACTH. Thus, Cortisol may return to its former levels after several weeks or months.

Figure 2. Steroid hormone biosynthetic pathway. Black bars indicate sites of ketoconazole and aminoglutethimide inhibition; metyrapone blocks only the ? -hydroxylase. A= cholesterol side chain cleavage, B=l7-hydroxylase, C=3β-hydroxysteroid dehydrogenase, D=17,2Q-tyase, E= steroid sulfotransferase, F= steroid sulfatase, G =21 hydroxylase, H=11-hydroxyiase, t = 18-hydroxyIase, J= 18-hydroxydehydrogenase.

Figure 2. Steroid hormone biosynthetic pathway. Black bars indicate sites of ketoconazole and aminoglutethimide inhibition; metyrapone blocks only the ? -hydroxylase. A= cholesterol side chain cleavage, B=l7-hydroxylase, C=3β-hydroxysteroid dehydrogenase, D=17,2Q-tyase, E= steroid sulfotransferase, F= steroid sulfatase, G =21 hydroxylase, H=11-hydroxyiase, t = 18-hydroxyIase, J= 18-hydroxydehydrogenase.

Glucocorticoid Receptor Blockade

A related approach is to use a steroid receptor antagonist. RU486 (mifepristone), itself a steroid, is a powerful blocker of both the progesterone and glucocorticoid receptors. It has rarely been given to humans for more than a few days, but a dose of 100 mg per day has been noted to increase serum Cortisol and ACTH levels, and to cause amenorrhea.31 Side effects include nausea, rash, and headaches.

The antiglucocorticoid receptor action of ketoconazole is noted above.

Inhibition of ACTH

Cyproheptadine, which is antiserotonergic, has been used to inhibit ACTH secretion. It also has antihistamine, anticholinergic, and antidopaminergic actions. Its side effects include sedation, increased appetite, and weight gain. Bromocriptine and sodium valproate have also been tried with less success.


Inhibition of Cortisol Synthesis: Clinical Studies

Of eight studies22,32,38 that have used this strategy in patients with Cushing's syndrome and that specifically commented on behavioral reactions, all found lessening of depressive symptoms in at least some patients (Table). All three drugs (AG, MET, KC) as well as mitotane have been successful in this respect. In one study, antiglucocorticoid medication was effective even in antidepressant-refractory depression.36 Improvements in mood in these patients were directly related to decreases in urinary Cortisol excretion but were not related to decreases in plasma ACTH levels; indeed, continued high ACTH levels did not prevent improvement in depressed mood.22

To date, only one case report and two small-scale open-label trials have reported results of antiglucocorticoid treatment in patients with major depression. Ravaris et al37 reported that ketoconazole significantly reduced the severity of depression within 72 hours of beginning drug treatment in an incompletely hypophysectomized (for Cushing's disease) hypercortisolemic patient with psychotic major depression who was resistant to treatment with standard antidepressants. This patient was entirely eu thy mie within 14 days, and mood normalization was accompanied by ketoconazole-induced lowering of circulating Cortisol levels.

Murphy et al3941 have studied 20 antidepressant-resistant patients with severe depression using ketoconazole, aminoglutethimide, and/or metyrapone. Eleven were hypercortisolemic at 8:00 AM and nine did not suppress normally with dexamethasone. Of the 17 of 20 patients who completed the eight-week course of therapy, 11 (65%) responded completely (a drop of 50% or greater in the Hamilton Depression Scale) while two (12%) responded partially; in eight (47%), the improvement lasted for five to 30 + months without further antidepressant therapy. Weekly (or more often) blood tests done at 8:00 AM showed no changes in routine hematology or biochemistry save for slight rises in liver function tests. Serum Cortisol levels fluctuated widely and were often high after the depression had improved, although those in responders were usually normal by the time that the Hamilton Depression Scale had dropped by 50%. DHEAS levels in patients receiving aminoglutethimide and ketoconazole fell more uniformly, particularly in responders. Men receiving ketoconazole had decreased testosterone levels, which rose promptly on stopping the drug. ACTH levels were all normal initially and rose slightly on therapy. Five of six responders who were dexamethasone nonsuppressors had reverted to normal when tested one to two weeks following therapy. Mood was more markedly improved in the nonpsychotic group (n - 9) compared with the psychotic group n = 8). In the responders, improvement was significant with respect to mood, insomnia, anxiety, somatic complaints, diurnal variation, and obsessive compulsiveness (Ghadirian AM, et al, unpublished data).


TABLEAntiglucocorticoid Treatment of Hypercortisolemic States Associated with Psychiatric Symptoms


Antiglucocorticoid Treatment of Hypercortisolemic States Associated with Psychiatric Symptoms

Wolkowitz et al42 treated 10 hypercortisolemic depressed patients with ketoconazole for three to six weeks. Three patients dropped out due to medication side effects or intercurrent illness, despite showing mild improvements in depression. The remaining seven patients had significant ketoconazoleassociated decreases in 4:00 PM serum Cortisol levels and in depression ratings, although only two responded completely by the above criteria. Specific symptoms that appeared most responsive to ketoconazole administration were insomnia, guilt, low self-esteem, suicidality, and somatic anxiety.

In contrast, Amsterdam and HornigRohan43 treated 10 depressed outpatients, all of whom had been refractory to five or more previous antidepressant trials, with ketoconazole, and observed partial responses in only three.

Clinical Application of Glucocorticoid Receptor Antagonists

Three cases of Cushing's syndrome successfully treated with RU486 have been reported. Neiman et al44 treated a depressed man with ectopic ACTH syndrome for nine weeks; interestingly, the suicidal depression in this patient, which had been resistant to antidepressants, resolved and libido improved. Two other cases of Cushing's syndrome secondary to adrenal cancer were treated by Van der LeIy et al45; symptoms such as depression, clouding of consciousness, mutism, psychosis, and agitation cleared within one to three days of beginning treatment.

The only report of the treatment of major depression with RU486 is that of Murphy et al,46 who administered RU486 200 mg per day for periods up to eight weeks in four patients who were antidepressant-resistant. Treatment was stopped prematurely in three: in one because of the appearance of a rash, and in two others because of side effects, which, in retrospect, were probably unrelated to the drug. ACTH, DHAS, and Cortisol levels all rose during therapy. Depression improved in three patients. Although these results are very preliminary, they suggest that glucocorticoid antagonists may also be effective in the treatment of some cases of depression.

Further larger-scale, double-blind studies of ketoconazole and other anticortisolemic drugs in major depression are currently underway. It must be emphasized, however, that such drugs have significant side effects, including the potential for adrenal insufficiency and hepatic injury. At present they remain research tools and are not recommended for the clinical treatment of depression.

Clinical Trial of Inhibition of ACTH

Although they have been used successfully in some cases of Cushing's disease, bromocriptine, cyproheptadine, and valproate have been found to be effective in only about 1Iz of such cases.47 No data regarding their effects on the psychiatric symptoms are available.

Camara47 treated 11 antidepressantresistant cortisol-hypersecreting depressed patients with cyproheptadine for four weeks in an open-label trial. Four patients had complete remission of symptoms and three more showed at least a 50% decrease in depression ratings. Responders showed normalization of Cortisol hypersecretion.


While the reviewed data are consistent with the hypothesis that hypercortisolemia contributes to depressive symptomatology, it is clear that hypercortisolemia is neither a necessary nor a sufficient condition for major depressive illness. Specifically, not all individuals who are hypercortisolemic become depressed, and a substantial number of patients with major depression do not exhibit hypercortisolemia. Further, numerous other neurotransmitter and neuropeptide abnormalities have been postulated to underlie depressive symptomatology. In particular, recent cogent theories implicating excessive release of CRH in the pathogenesis of depressive symptomatology have been proposed (see Musselman and Nemeroff,4 this issue). It is quite possible, therefore, that the causes of major depression are multifactorial.

Relevant to this point, it has been suggested that increased circulating Cortisol levels may be particularly related to specific symptoms of depression rather than to the global syndrome of major depressive illness.48 Insomnia, and decreased energy, libido, and concentration may be particularly related to hypercortisolemia.22 Lastly, antiglucocorticoid treatments generally inhibit the synthesis of many adrenocortical steroids, and it remains unclear which effects are related to antidepressant efficacy. Future investigations will be necessary to delineate the possible involvement of other adrenocortical hormones such as DHEA, progesterone, testosterone, as well as the "neurosteroids" that are their metabolites.

One puzzling feature of the hypercortisolemia of major depression is the relationship of ACTH and Cortisol. Although in earlier studies ACTH levels were found to be high, in detailed studies using more specific methods, they have been found consistently to be normal2,49; it has been suggested that the discrepancy between methods may reflect the presence of an ACTH-like factor in depressed patients, which is not measured by current methods.2,37


The interest of modern psychiatry in hypercortisolemia evolved from certain seminal papers on the dexamethasone suppression test.1 Initial enthusiasm regarding the use of this test as a diagnostic tool or as a "window" into the biochemical functions of the brain has waned. Nonetheless, the biological abnormalities of Cortisol hypersecretion and/or dexamethasone resistance are present in a substantial number of depressed and other psychiatric patients. The data reviewed here raise the possibility that further advances in this area might result from a more systematic consideration of hormonal causation of psychiatric symptomatology.


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Antiglucocorticoid Treatment of Hypercortisolemic States Associated with Psychiatric Symptoms


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