Psychosomatic Medicine 61:698-711 (1999)
© 1999 American Psychosomatic Society
SPECIAL ISSUE: PSYCHOPHARMACOLOGY AND PSYCHOSOMATIC RESEARCH |
Treatment of Depression With Antiglucocorticoid Drugs
Owen M. Wolkowitz, MD and
Victor I. Reus, MD
From the Department of Psychiatry (O.M.W., V.I.R.), University of California, San Francisco, School of Medicine, San Francisco, CA.
Address reprint requests to: Owen M. Wolkowitz, MD, Department of Psychiatry, University of California, San Francisco, School of Medicine, 401 Parnassus Ave., San Francisco, CA 94143-0984. Email: owenw{at}itsa.ucsf.edu
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ABSTRACT
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OBJECTIVE: The theoretical and empirical rationales for the potential therapeutic use of antiglucocorticoid agents in the treatment of depression are reviewed.
METHOD: Individual case reports, case series, open-label, and double-blind, controlled trials of the usage of cortisol-lowering treatments in Cushing’s syndrome and major depression are evaluated and critiqued.
RESULTS: In each of the 28 reports of antiglucocorticoid treatment of Cushing’s syndrome, antidepressant effects were noted in some patients; the largest two series document a response rate of 70% to 73%. Full response, however, was at times erratic and delayed. Across the 11 studies of antiglucocorticoid treatment of major depression, some degree of antidepressant response was noted in 67% to 77% of patients. Antidepressant or antiobsessional effects of antiglucocorticoid augmentation of other psychotropic medications have also been noted in small studies of patients with treatment-resistant depression, obsessive-compulsive disorder, and schizoaffective disorder or schizophrenia.
CONCLUSIONS: These promising results with antiglucocorticoid treatment must be interpreted cautiously because of the small sample sizes and heterogeneity of the studies reviewed, the bias favoring publication of positive results, and the open-label nature of most of the studies. Although definitive controlled trials remain to be conducted, there is a consistent body of evidence indicating that cortisol-lowering treatments may be of clinical benefit in select individuals with major depression and other hypercortisolemic conditions.
Key Words: antiglucocorticoid • depression • cortisol • Cushing’s syndrome • Cushing’s disease • antidepressant
Abbreviations: ACTH = adrenocorticotropic hormone; CRH =corticotropin-releasing hormone; DST = dexamethasone suppressiontest; HDRS = Hamilton Depression Rating Scale; LHPA =limbic-hypothalamic-pituitary-adrenal; PRL = prolactin; UFC =urinary free cortisol; 5HT = serotonin.
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INTRODUCTION
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Limbic-hypothalamic-pituitary-adrenal (LHPA) axis dysregulation (evidenced by basal or post–dexamethasone hypercortisolemia or hypercortisoluria) has been repeatedly demonstrated in many patients with major depression (1–4). Although this biological abnormality is one of the most well established in psychiatry, its pathophysiologic significance is unknown. Various authors have suggested that the hypercortisolism of depression is secondary to the stress accompanying depression or to the primary neurotransmitter or neuropeptide imbalances that are independently responsible for the depressive symptoms (5–7). It remains uncertain, however, whether the hypercortisolism is an epiphenomenon or whether it directly contributes to depressive symptomatology and to the biochemical alterations seen in major depression (8). This question takes on added significance when it is considered that hypercortisolemia, once established (regardless of cause), may have additional downstream effects on the brain (9–15), possibly exacerbating, perpetuating, or altering the presentation of depressive mood states. As we discuss below, to the extent that endogenous hypercortisolemia does contribute to depressive symptomatology, drug treatments that directly lower cortisol levels should have antidepressant effects.
Several investigators have speculated on the role of hypercortisolemia in psychopathology (16–28), but until recently, few suitable clinical models have existed to test this. Animal models have generally (29–33), but not invariably (34), supported a relationship between increased corticosterone secretion and increased susceptibility to "depression"-like behaviors.
In this article, we review the putative mechanisms of steroid actions in brain and how they might affect depressive symptoms, the relationship of hypercortisolemia to specific behavioral symptoms, and empirical evidence of antidepressant effects of antiglucocorticoid drugs in various conditions.
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BASIC MECHANISMS OF STEROID ACTION
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Given what we now know about corticosteroid effects on nervous tissue and on factors that mediate brain function, it should not be surprising that such hormones might influence behavior. Corticosteroids may affect brain function through two general mechanisms, interaction with the genome and interaction with cell membranes (9, 10). Corticosteroids freely cross neuronal cell membranes and, in neurons containing specific cytoplasmic steroid receptors, translocate as a steroid-receptor complex to the cell nucleus (9, 35). There, the complex binds to chromatin and regulates transcription of specific genes. Such molecular events may be particularly important for understanding the behavioral effects of corticosteroids because neurons containing corticosteroid-specific receptors are densely located in the hippocampus, septum, and amygdala (9), parts of the brain believed to be intimately involved in behavior, mood, learning, and memory (36). These molecular events include alteration of levels of enzymes, such as tyrosine hydroxylase, tryptophan hydroxylase, monoamine oxidase, dopamine ß-hydroxylase, and phenylethanolamine N-methyltransferase (9, 35), which control the activity of biogenic amines and other neurotransmitters, and alteration of levels of mRNA coding for neuropeptides, such as somatostatin, corticotropin-releasing factor, ACTH, ß-endorphin, and other proopiomelanocortin-derived substances, as well as G proteins (9, 11, 22, 24, 37–45). Corticosteroids also alter pre- and postsynaptic activity (eg, concentrations of 5HT1A and 
2- and ß2-adrenergic receptors as well as the sensitivity of norepinephrine receptor-coupled adenylate cyclase) (35). Some of these actions, mediated by elevated corticosteroid levels, may counteract antidepressant drug effects on ß-adrenergic receptor responsiveness (46). Corticosteroid effects on 5HT function may play an especially prominent role in affective and vegetative function (37–42, 47, 48). In a series of animal experiments pertinent to this issue, Kennett et al. (31) noted that chronically stressed rats developed increased corticosterone secretion, decreased hippocampal 5HT1A mRNA levels, and increased depressive behaviors, such as decreased locomotion, decreased open-field behavior, and anorexia. After 5 to 7 days of stress exposure, however, the rats showed a normalization of 5HT1A receptor activity as well as behavior. These presumably adaptive responses in 5HT1A activity and behavior were curtailed by repeated corticosterone injections but were facilitated by antiglucocorticoid drug administration. Such findings are consistent with the hypothesis of antidepressant effects of antiglucocorticoid drugs and suggest one possible mechanism of such effects (49, 50).
In addition to such genomically mediated effects, corticosteroids and their metabolites may have rapid (nongenomic) effects on brain excitability and on synaptic transmission by altering cyclic nucleotide metabolism, specific ionic conductances, and central carbohydrate, protein, and lipid metabolism (51). In addition, they may interact directly with neuronal cell membranes and membrane receptors (eg, the 
-aminobutyric acid A receptor) (52). The membrane-related effects of certain steroids may be bidirectional, with certain steroid metabolites having excitatory effects and others having inhibitory effects (52–54). Therefore, changes in levels or metabolism of these steroids may upset a fine balance of central nervous system regulation and result in behavioral disturbances (52, 53). Finally, chronic exposure of animals to high levels of corticosteroids may induce morphologic changes and even cell death in certain vulnerable neurons, eg, hippocampal CA3 neurons (55), although corticosteroids may have trophic effects in other brain regions, eg, hippocampal dentate gyrus (10). It should be noted, however, that the data supporting such effects are principally from studies with rodents and may not be applicable to primates. For example, the hippocampal atrophy observed in Cushing’s syndrome may, like ventricular enlargement, be reversible with normalization of glucocorticoid status (56), and, in a prospective study with macaques, those receiving hydrocortisone 3 to 6 mg/kg per day for 12 months could not be distinguished from those receiving placebo on the basis of the number of hippocampal cells at autopsy (57). This latter observation suggests that, at least in the absence of stress, chronically elevated cortisol concentrations do not produce hippocampal neuronal loss in nonhuman primates.
Despite these advances in our understanding of the basic actions of steroids in brain, relatively little is known about their actual role in human behavior. Although the focus of the present article is treatments that lower or block cortisol activity, it will become increasingly important to expand our focus beyond cortisol to the many other steroid hormones and steroid metabolites that are also active in brain and that might also be altered in psychiatric illness (3, 58–66). Figure 1 displays the metabolic pathway of a number of adrenally derived corticosteroids along with the sites of enzymatic blockade of steroid biosynthesis inhibitors. As is evident, enzymatic blockade with these agents affects the synthesis of multiple steroid hormones.
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Fig. 1. Steroid metabolic pathway. DHEA = dehydroepiandrosterone; DHEA-S = dehydroepiandrosterone sulfate; HSD = hydroxysteroid dehydrogenase; SCC = side-chain cleavage; SST = steroid sulfotransferase; 1 = site of blockade by ketoconazole; 2 = site of blockade by metyrapone; 3 = site of blockade by aminoglutethimide.
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EFFECTS OF EXOGENOUS CORTICOSTEROIDS
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Several clinical lines of evidence suggest that corticosteroids significantly affect human behavior. Among the earliest indications was the observation of behavioral changes, occasionally profound (eg, delirium, confusion, insomnia, emotional lability, depression, hypomania, memory and attentional impairments, sensory flooding, psychosis, and even suicidality) in some medically ill patients prescribed cortisone, dexamethasone, prednisone, and other synthetic corticosteroids (43, 67–73). Although these studies demonstrate the potential of corticosteroids to induce psychiatric symptoms, it is problematic to extrapolate from the effects of exogenous corticosteroids to those of endogenous hypercortisolemia. For example, behavioral reactions to exogenous corticosteroids tend to be hypomanic, at least initially, whereas endogenous hypercortisolemia is typically associated with depression (74). Possible reasons for such discrepancies have been reviewed elsewhere (11, 73). Also, many individuals who are prescribed corticosteroids have illnesses that may directly affect the brain, further complicating the interpretation of the results of these studies.
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CUSHING’S SYNDROME
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Two additional lines of evidence suggest that excessively high levels of endogenously produced cortisol (or dysregulation of LHPA axis negative feedback) are associated with altered mood, generally in the direction of depression, and with cognitive impairment. For example, Cushing’s syndrome is associated with a high incidence of fatigue, decreased energy, irritability, decreased memory and concentration, depressed or labile mood, decreased libido, insomnia, and crying (75–77). These symptoms are reminiscent of those commonly seen in major depression (78), although certain differences, such as a preponderance of atypical depressive features in Cushing’s syndrome, may exist (79, 80). These symptoms in patients with Cushing’s syndrome are directly correlated with circulating cortisol levels (58, 75). The incidence of depression (62–67%) is not significantly different in patients with Cushing’s syndrome (which is non-ACTH dependent) and those with Cushing’s disease (which is ACTH dependent) (3, 23, 81), suggesting a stronger relationship with circulating cortisol levels than with circulating ACTH levels. This suggestion is supported by the relatively low incidence of depression in patients with Nelson’s syndrome, a postadrenalectomy condition characterized by high ACTH but low cortisol levels (82, 83). Some studies, however, have found higher neuropsychiatric impairment in patients with elevated cortisol and ACTH levels than in patients with elevations in cortisol levels alone (75).
Depressive and cognitive symptoms in Cushing’s disease and Cushing’s syndrome typically resolve with treatment of the hypercortisolemia (25, 58, 77, 81–106) in direct relationship to the reductions in circulating cortisol levels. At least 28 separate reports have documented decreased depression, anxiety, irritability, psychosis, and cognitive impairment, even complete psychiatric remission, in patients with Cushing’s syndrome or disease who received either surgical or medical (eg, ketoconazole, metyrapone, aminoglutethimide, or RU486) treatment aimed at lowering cortisol levels. The largest two case series documented a response rate of 70% to 73% of treated patients (81, 101), although in several cases, psychiatric improvement was erratic, delayed, or incomplete. These studies are outlined in Table 1. Improvements in mood with treatment in patients with Cushing’s syndrome are not strongly related to decreases in plasma ACTH levels; indeed, continuing high ACTH levels do not prevent improvement in depressed mood (25). These observations are quite suggestive of an etiologic role of cortisol elevations in psychiatric symptomatology, although it remains difficult to factor out nonspecific illness-related contributions to the clinical presentation in patients with Cushing’s disease and Cushing’s syndrome. Another difficulty in interpreting this literature is that patients with Addison’s disease (adrenocortical insufficiency) may also present with depression (107); in such patients, glucocorticoid treatment typically relieves the depression. The relationship between cortisol and mood is undoubtedly complex and may even resemble an inverted U-shaped dose-response curve (24).
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CLINICAL CORRELATES OF HYPERCORTISOLEMIA AND DST NONSUPPRESSION IN MAJOR DEPRESSION AND OTHER PSYCHIATRIC ILLNESSES
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Hypercortisolemia (basally or in response to the DST) is evident in many patients with major depression. Cortisol hypersecretion in these patients has, in several studies, been correlated with behavioral alterations, such as sleep disturbance, decreased energy, decreased attention and cognitive performance, psychosis, suicidal thoughts, decreased libido, psychomotor disturbance, and anxiety (19, 108–110). Reus (19), using response to the DST as the independent variable, found that, regardless of psychiatric diagnosis, nonsuppressors showed evidence of increased anxiety, interpersonal sensitivity, suicidal ideation, and sleep disorder compared with suppressors.
Furthermore, Greden et al. (111) and others have reported that nonsuppression in the DST typically normalizes with recovery from depression. DST normalization typically precedes or coincides with (rather than follows) clinical recovery, and failure to normalize portends poorly for ultimate clinical outcome (112–114). Ribeiro et al. (113) performed a meta-analysis of 144 articles related to the DST. They concluded that persistent nonsuppression of cortisol on the DST after treatment is "strongly associated with early relapse and poor outcome on follow-up" and hypothesized an etiologic role of hypercortisolemia in the genesis and maintenance of depression. Such studies are informative but share the drawback common to all correlative investigations, namely the difficulty in determining the direction of causality (if any) between the related variables. Indeed, higher cortisol levels or DST nonsuppression may merely reflect a more serious depression. Other difficulties with interpreting this literature include the facts that not all depressed patients are hypercortisolemic and that not all hypercortisolemic individuals are depressed. Furthermore, and perhaps related to this, hypercortisolemia does not exist as an isolated LHPA axis abnormality (115). Major depression is also associated with altered levels of CRH, ACTH, and other neurotransmitters and neuropeptides, and a compelling model implicating excessive CRH in the pathogenesis of certain depressive symptoms has been proposed (6, 7, 79). Changes in CRH and cortisol levels occur as an integrated response to stress and have bidirectional influences. Glucocorticoids and CRH may interact to magnify such symptoms as fear, anxiety, and the anticipation of adversity (116), and it is artificial to consider either abnormality without the other in theories of causality. It is plausible, even likely, that multiple hormonal aberrations contribute to the final clinical presentation in major depression (3, 62, 117).
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EFFECT OF ANTIDEPRESSANTS ON THE LHPA AXIS
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In light of evidence that a substantial proportion of depressed patients shows evidence of defective corticosteroid negative feedback (eg, failure to suppress cortisol production in the face of dexamethasone administration), it is intriguing that antidepressant medications increase brain levels of corticosteroid receptors, rendering individuals more sensitive to corticosteroid negative feedback. A recent body of literature, reviewed by Holsboer and Barden (46), suggests that these effects are shared by most antidepressants and that the time course of these changes parallels that of clinical antidepressant responses. Pepin et al. (118) also reported that transgenic mice with defective glucocorticoid receptor expression, which display features of depression (such as LHPA axis activation, deficient glucocorticoid negative feedback, feeding disturbances, and cognitive deficits), respond to antidepressant treatment with increased glucocorticoid receptor mRNA levels and steroid-binding activity and with decreased ACTH and cortisol secretion. It has been hypothesized, on the basis of these data, that a primary and common mechanism of action of antidepressants is the stimulation of corticosteroid receptor expression, leading to enhanced negative feedback, lowered LHPA activity and lowered levels of CRH and cortisol. Secondary effects of lowered cortisol activity would be a lessening of expression of genes that are under corticosteroid regulatory control (eg, those related to biogenic amine neurotransmission). This reconceptualization of antidepressant action affords new mechanistic insights that may have important treatment implications (119, 120).
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ANTIGLUCOCORTICOID TREATMENT OF MAJOR DEPRESSION
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It is surprising that, until recently, few studies assessed the behavioral effects of direct pharmacologic lowering of cortisol levels (as described in patients with Cushing’s syndrome or disease) in patients with major depression. In each study using this approach (3, 28, 120–135), antidepressant effects were reported in at least some patients, and double-blind, controlled trials were strongly encouraged. Across the 11 studies reviewed, 77% of the treated patients showed at least a partial antidepressant response, and 67% showed a full or clinically meaningful response. These studies are presented in Table 2, and some are discussed in greater detail below.
Most of the studies in depressed patients used ketoconazole as the antiglucocorticoid agent, but similar results have been noted with all antiglucocorticoids studied. Murphy et al. (121, 122) and Ghadirian et al. (123) reported on an overlapping sample of treatment-resistant depressed subjects administered the antiglucocorticoid drugs ketoconazole, aminoglutethimide, or metyrapone in an open-label manner for 2 months. Eleven of 17 patients completing the 2-month protocol had complete remission (defined as >50% reduction in rated depressive symptoms), and an additional two had partial remission (20–50% reduction in rated symptoms). The authors noted that an early indicator of good response was improved cognitive function. They also noted that in 8 of the initial 10 patients who improved, remission was sustained for an average of more than 8 months after discontinuation of the drug. The authors cited this as evidence against a placebo effect and suggested that a "resetting" of the HPA axis may lead to lasting remissions. Biochemical data of their first 10 subjects were also reported (3). Of the responders who were nonsuppressors on DSTs before therapy was started, five of six had reverted to normal suppression when tested 1 to 2 weeks after cessation of therapy; the one patient who did not revert to normal suppression suffered an early relapse (28). Baseline 8:00 AM serum cortisol levels, however, did not predict treatment response, and treatment-associated decreases in 8:00 AM serum cortisol levels were inconsistent and not statistically significant.
Other studies, however, have noted significant correlations between antidepressant effects and changes in cortisol levels or have noted specific antiglucocorticoid efficacy in hypercortisolemic patients. Anand et al. (126), eg, in a double-blind case study using ketoconazole, noted clinically significant improvements in depression and memory in one treatment-resistant patient. There was a close correlation between treatment-associated decreases in cortisol levels and HDRS ratings. The patient remained in remission through 12 additional weeks of open-label treatment and relapsed upon discontinuation of ketoconazole. Wolkowitz et al. (124) also reported that ketoconazole, administered to medication-free depressed patients in an open-label manner for 3 to 6 weeks, significantly improved depression ratings and significantly decreased 4:00 PM serum cortisol levels. Changes in Beck Depression Inventory ratings were directly correlated with changes in serum cortisol levels. This research group subsequently reported on a sample of depressed patients treated with ketoconazole in a double-blind, placebo-controlled manner (132). Of 20 patients studied, 8 were hypercortisolemic at baseline (4:00 PM serum cortisol >10 µg/dl), and 12 were eucortisolemic. Five of the hypercortisolemic patients were randomly assigned to receive placebo, and three were assigned to receive ketoconazole. Six of the eucortisolemic patients were randomly assigned to receive placebo, and six received ketoconazole. Whereas no significant main effect of ketoconazole vs. placebo on depression ratings was observed, there was a significant interaction of drug (ketoconazole vs. placebo) and baseline cortisol status (eucortisolemic vs. hypercortisolemic). Specifically, ketoconazole was superior to placebo in alleviating depressive symptoms in hypercortisolemic, but not eucortisolemic, patients. These findings are consistent with the hypothesized specificity of antiglucocorticoid benefits in hypercortisolemic states and raise the possibility of biologically distinct subgroups of patients with major depression. Such conclusions must remain tentative, however, because of the small sample size of this study.
Two other studies have attempted to clarify the mechanisms by which antiglucocorticoids might alleviate depression. Thakore and Dinan (130) treated eight depressed patients with ketoconazole for 4 weeks and noted significant antidepressant effects (average decrease in HDRS ratings, 60%) and significant decreases in serum cortisol levels. They had postulated that elevated cortisol activity might provoke or maintain depressive symptoms via the induction of subsensitivity of the 5HT system. They based their hypothesis partially on observations that, in depressed patients, baseline cortisol levels are inversely related to the magnitude of serum PRL responses to 5HT agonists such as D-fenfluramine (a putative marker of 5HT system sensitivity). To test this hypothesis, they administered the D-fenfluramine challenge to their subjects at baseline and after 4 weeks of ketoconazole treatment. Ketoconazole normalized the PRL response to D-fenfluramine (ie, increased the response relative to baseline), and the increases in PRL responses were significantly correlated with reductions in HDRS ratings. These findings are consistent with the notion that hypercortisolemia downregulates 5HT system sensitivity and that antiglucocorticoid treatments may have antidepressant effects via a normalization (increase) of 5HT sensitivity. Lastly, O’Dwyer et al. (127) treated eight depressed patients with metyrapone (plus replacement doses of hydrocortisone) or placebo in a single-blind manner in a 2-week-per-arm crossover design and noted significant decreases in depression ratings as well as serum cortisol levels during metyrapone treatment. After discontinuation of metyrapone, depression ratings remained low despite the return of cortisol to baseline levels, supporting Murphy’s (3) report of persistent antidepressant effects. Checkley et al. (117), commenting on the same group of subjects as O’Dwyer et al. (127), noted that in addition to normalizing cortisol levels, metyrapone led to an increased urinary excretion of the neurally active steroids tetra-hydro-11-deoxycortisol and tetra-hydro-deoxycortisone. They suggested that either the decreases in cortisol levels or the increases in levels of these "neurosteroids" may have been related to the antidepressant effects.
In addition to studies of antiglucocorticoids used alone in depression, other studies have examined the utility of such drugs as augmentation agents in treatment-resistant patients with depression and other psychiatric illnesses. These studies are presented in Table 3. Ravaris et al. (98) successfully treated a patient with previously refractory bipolar II depression with ketoconazole that was added to the prior regimen of lithium and phenelzine. Improvement was correlated with decreases in UFC levels, and discontinuation of ketoconazole resulted in a depressive relapse that was preceded by increasing UFC levels. Chouinard et al. (136) reported a case of severe refractory obsessive-compulsive disorder that was successfully treated by adding aminoglutethimide to the previously ineffective fluoxetine. This patient remained significantly improved for the entire 4 years he was on this combination but relapsed when either drug was discontinued. The authors posited serotonergic potentiation as explaining this combination’s efficacy. Lastly, double-blind antiglucocorticoid augmentation of neuroleptics in schizophrenia and schizoaffective disorder was recently reported by Marco et al. (manuscript submitted). Fifteen patients were treated for 4 weeks with ketoconazole or placebo, which was added to stabilized psychotropic regimens. Ketoconazole treatment had no effect on positive or negative psychotic symptoms but was associated with a significant antidepressant effect, supporting the notion that corticosteroid activity may moderate depressive symptoms across psychiatric diagnoses (19).
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DEXAMETHASONE TREATMENT OF DEPRESSION
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In what seems a diametrically opposite approach to altering steroidal activity in depressed patients, Arana and colleagues (137–140) reported antidepressant effects of high-dose dexamethasone therapy. In this paradigm, dexamethasone was administered intravenously as a one-time bolus of 4 to 8 mg or orally at a dose of 4 mg/d for 4 days. Results of the open-label intravenous dexamethasone trial indicated 56% improvement within 10 days in 75% of depressed subjects, including five of seven treatment-refractory ones who had failed at least two prior antidepressant trials. In the blinded oral dexamethasone trial, dexamethasone was associated with only a 27.5% improvement in depression ratings, compared with a 13.6% improvement with placebo. A significantly greater number of dexamethasone-treated subjects responded to treatment (defined as a 
50% decrease in depression ratings or a final HDRS score of 
14) compared with placebo-treated subjects. The authors suggested that the beneficial effect of dexamethasone was secondary to regulation of CRH receptors, increased serotonergic activity, or other genomically mediated changes in neurotransmission.
Similar results were obtained by another group using an open-label design. Dinan et al. (141) studied 10 depressed patients who had not responded to sertraline or fluoxetine and added dexamethasone, 3 mg PO daily for 4 days, to the ongoing antidepressant regimen. By the following day (day 5), three of the six patients receiving sertraline and three of the four receiving fluoxetine demonstrated significant antidepressant responses (50% reduction in depression ratings). Remarkably, this initial improvement was maintained through day 21, the last day assessed. Cortisol changes in response to dexamethasone treatment were not reported, but baseline morning serum cortisol levels were directly correlated with antidepressant responses (viz., higher baseline cortisol was associated with better responses to dexamethasone). The dexamethasone was relatively well tolerated, but several patients reported sleep disruption, nausea, and/or anxiety during dexamethasone treatment. In one additional small-scale study, Goodwin et al. (142) noted that an acute cortisol infusion transiently improved self-rated mood in 12 depressed patients. These patients were not hypercortisolemic at baseline.
Finally, Wolkowitz et al. (143) reported negative results in a very small, double-blind replication study. Five depressed patients received one-time intravenous infusions of either 6 mg dexamethasone or placebo and were evaluated 10 days later. The three subjects who received dexamethasone fared more poorly than the two who received placebo; two of the three dexamethasone-treated subjects actually worsened after treatment. The one dexamethasone-treated subject who showed a mild antidepressant effect had the lowest baseline serum cortisol concentration of the group.
If short-term, high-dose dexamethasone treatment proves to have antidepressant effects, how might this be reconciled with antiglucocorticoids having similar effects? Antiglucocorticoids and dexamethasone administration could both have antidepressant effects via 1) their common effect of lowering cortisol levels (with resultant upregulation of brain corticosteroid receptors); 2) altering levels of other adrenal steroid hormones; or 3) increasing ACTH levels (with short-term, high-dose dexamethasone treatment, this might occur after dexamethasone’s acute inhibitory effects are terminated and the suppressed adrenal axis signals increased ACTH output). Additionally, recent evidence suggests that dexamethasone is actively excluded from brain and does not replace endogenous corticosteroids at hippocampal mineralocorticoid and glucocorticoid receptor sites (144). Its behavioral effects, therefore, may result from indirect effects of dexamethasone-induced ACTH suppression on the balance between the two corticosteroid receptor types in the hippocampus (144). Long-term dexamethasone treatment has also been shown to result in an increase in glucocorticoid receptor mRNA levels in hippocampus, an effect that parallels changes observed over the course of antidepressant treatment (33, 145).
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CHOICE OF ANTIGLUCOCORTICOID DRUG AND RISK OF SIDE EFFECTS
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Because all of the available antiglucocorticoid drugs showed some degree of efficacy in the studies reviewed above, the choice of any specific one may be guided by side effects, tolerability, and metabolic site of action (28) (Figure 1). Ketoconazole and other antiglucocorticoid drugs have the potential to induce serious side effects, such as hypoadrenalism and hepatotoxicity (146–154). These serious side effects are relatively rare and in the reviewed studies were not significant problems. Nonetheless, antiglucocorticoid treatments of depression are not yet recommended for routine clinical use because they are still experimental and their full risk/benefit ratio remains to be determined. If they are used in experimental settings or in clinical ones with appropriate informed consent, careful and frequent monitoring of liver function and cortisol and electrolyte levels should be mandatory.
1. Ketoconazole is considered by some to be the drug of choice for pharmacologic lowering of cortisol levels in Cushing’s syndrome (155, 156). Ketoconazole (at doses of >400 mg/d, resulting in plasma levels of 1–5 µg/d) inhibits cholesterol side-chain cleavage, 17,20-lyase, 11-ß-hydroxyiase, and, to a lesser extent, 17- and 18-hydroxylase. These effects result in decreased cortisol, androgen (androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone), and aldosterone synthesis and in elevated levels of pregnenolone, 17--hydroxy-pregnenolone, progesterone, 17--hydroxyprogesterone, and 11-deoxycortisol. In addition to inhibiting cortisol biosynthesis, ketoconazole acts at the receptor level as a glucocorticoid antagonist (152, 157), but this effect may be minimal in vivo at commonly achieved plasma levels. Ketoconazole may also exert its effects by directly decreasing basal and CRH-stimulated ACTH release at the level of the pituitary (149, 158), although this effect is controversial. In any event, ketoconazole (as opposed to metyrapone and aminoglutethimide) treatment of Cushing’s syndrome is not associated with a compensatory increase in ACTH release. Side effects of ketoconazole include nausea, diarrhea, menstrual irregularities, abdominal discomfort, headache, reversible increases in serum transaminase levels, and, less commonly, vomiting, sedation, decreased libido, and reversible gynecomastia and impotence. Hypoadrenalism and hepatotoxicity (potentially fatal) are rare but serious complications that mandate frequent laboratory monitoring. Hypoadrenalism responds well to parenteral hydrocortisone. Transient, clinically insignificant increases in liver transaminases occur in 5% to 10% of patients treated with ketoconazole (159). True hepatic injury, however, seems to be rare, with an estimated incidence of 0.01% to 1% (159). An additional consideration, if ketoconazole is to be administered along with other medications, is ketoconazole’s competitive inhibition of the hepatic cytochrome P450 isoenzyme, IIIA3/4, which is responsible for metabolizing various antidepressants, benzodiazepines, calcium channel blockers, and a variety of other medications.
2. Metyrapone inhibits 11-ß-hydroxylase, leading to decreased cortisol and increased 11-deoxycortisol levels. Side effects include nausea, headache, sedation, and rash. Compensatory increases in ACTH secretion are commonly observed with metyrapone; these often override the cortisol biosynthesis inhibition and necessitate combination drug therapy or increasing metyrapone doses. Furthermore, metyrapone increases androgenic and mineralocorticoid precursors, occasionally resulting in acne, hirsutism, and hypertension.
3. Aminoglutethimide inhibits cholesterol side-chain cleavage, the enzyme that converts cholesterol to pregnenolone. It also affects hydroxylation at C11 and C18, with estrogen as well as cortisol synthesis being curtailed. The resulting decrease in cortisol biosynthesis is partially overcome by increases in ACTH release. Most patients treated with aminoglutethimide develop transient generalized pruritic rashes. Other side effects include somnolence, dizziness, fever, headache, and, more rarely, goiter, hyperthyroidism, cholestasis, bone marrow suppression, and aldosterone deficiency. Significant side effects are seen in two-thirds of patients treated with aminoglutethimide.
4. RU-486 (mifepristone) does not inhibit steroid biosynthesis but blocks progesterone and, at higher doses, cortisol receptors. In fact, circulating cortisol levels may double secondary to receptor blockade. Its use for anything other than short-term administration has been inadequately assessed and has been associated with prominent rashes or exfoliative dermatitis in some subjects. Because RU-486 also blocks the effects of exogenous corticosteroids, it is more difficult to acutely treat any side effects resulting from glucocorticoid deficiency.
5. Less commonly used antiglucocorticoid drugs include mitotone and etomidate, which would not be appropriate because of their adrenolytic and sedative properties, respectively.
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SUMMARY
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The data reviewed here raise the possibility that antiglucocorticoid treatments ameliorate depressive symptoms in some patients with major depression or other psychiatric disorders. Such an effect would be consistent with that observed in Cushing’s syndrome patients treated with the same drugs. The majority of the reviewed trials, however, were not blinded or were small scale. Therefore, any conclusions at this point must be considered tentative.
Nevertheless, the studies reviewed cumulatively suggest the dual importance of further studying antiglucocorticoid agents in major depression. On a practical clinical level, it may lead to a novel pharmacotherapeutic approach to certain psychiatric patients. In many of the reviewed studies, good responses to antiglucocorticoid agents were seen in patients refractory to traditional antidepressants. Improvements often occurred rapidly (as early as 1 to 3 weeks), and remission occasionally persisted for long periods of time (in some cases even after antiglucocorticoid treatment was stopped). This latter observation has led several investigators to comment on a possible "resetting" of the LHPA axis (or the reinstitution of appropriate corticosteroid receptor sensitivity to feedback inhibition), with ensuing long-term benefits. Because a substantial proportion of depressed patients is resistant to or intolerant of traditional antidepressants, the availability of a new class of antidepressant medications would be significant.
On a theoretical level, it may lead to a better understanding of the role of hyperactivity of the LHPA axis in major depression and other psychiatric disorders. This issue has been discussed and considered for more than 40 years (16), but until the availability and use of relatively safe antiglucocorticoid drugs, no suitable paradigm has existed to test it. Such studies may identify whether neurotransmitter and neuropeptide dysregulation and insensitivity to corticosteroid negative feedback are primary or secondary pathologic events in the development of depression. The well-replicated finding that persistent DST nonsuppression after antidepressant treatment portends poorly for long-term outcome (113) suggests that reestablishment of LHPA axis negative feedback may itself be an important therapeutic goal.
Additional studies will be needed to determine the appropriate clinical role of antiglucocorticoids in psychiatric treatment. Confirmation of antidepressant effects of the currently available drugs would undoubtedly spur the development of safer compounds and would refine our notions of appropriate targets of antidepressant pharmacotherapy.
Received for publication September 29, 1998.
Revision received May 4, 1999.
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REFERENCES
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