The Stanley European Bipolar Research Centre, Psychiatry Research Laboratory, The Medical School, Newcastle upon Tyne, UK
Correspondence: Professor A. H. Young, The Stanley European Bipolar Research Centre, Psychiatry Research Laboratory, The Medical School, Framlington Place, Newcastle upon Tyne NE2 4H. Tel./fax: 0191222 8210; e-mail: a.h.young{at}ncl.ac.uk
![]() |
ABSTRACT |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Aims To review the evidence for the involvement of the glucocorticoid receptor in the pathogenesis and treatment of mood disorders.
Method Medline and hand searches were carried out, selecting literature relevant to psychiatrists and psychopharmacologists.
Results A dysfunction in glucocorticoid receptors is integral to the HPA abnormalities of mood disorders. Antidepressant and mood-stabilising drugs can up-regulate glucocorticoid receptors, restoring glucocorticoid function. Preliminary clinical studies targeting the glucocorticoid receptor are encouraging.
Conclusions Drugs designed specifically to up-regulate glucocorticoid receptors may be integral to future strategies in treating mood disorders.
![]() |
INTRODUCTION |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
![]() |
HYPOTHALAMIC-PITUITARY-ADRENAL AXIS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
HPA regulation
Cells in the PVN secrete CRH, which is the driving force of the HPA axis;
AVP only weakly stimulates ACTH by itself, but markedly potentiates the
effects of CRH. The secretory cells in the PVN receive neuronal inputs from
many brain regions, including amygdala, hippocampus and nuclei of the
midbrain. Excitatory and inhibitory afferents, including those containing
5-hydroxytryptamine (5-HT), noradrenaline, acetylcholine, and both excitatory
and inhibitory amino acids, have been demonstrated
(Jones et al, 1987).
In addition to these extrinsic regulatory inputs to the HPA axis, a crucial
intrinsic autoregulatory mechanism also exists. Thus, endogenous cortisol, by
binding to glucocorticoid receptors in the HPA axis tissues and the
hippocampus, acts as a potent negative regulator of HPA activity
(Sapolsky et al,
1986). The relative contribution of the two glucocorticoid
receptor subtypes (GR and MR) in the regulation of HPA activity is as yet
unclear. However, the high-affinity MRs putatively control low, basal levels
of circulating cortisol, while the lower-affinity GRs come into play during
circadian and stress-related peaks in cortisol
(Jacobson & Sapolsky,
1991). This autoregulatory role of endogenous cortisol is crucial
to the maintenance of the intrinsic homoeostasis of the HPA axis
(Sapolsky et al,
1986; Jacobson & Sapolsky,
1991). Furthermore, it is possible that by subtle changes in
glucocorticoid receptor number or function the homoeostatic
setpoint can be shifted and can contribute to the characteristic
diurnal rhythm in circulating cortisol levels in healthy individuals.
HPA dysfunction and psychiatric disorders
In the late 1950s Board and colleagues made the seminal observation that
basal plasma cortisol levels of patients with depression are higher than those
of healthy control subjects (Michael &
Gibbons, 1963). This finding was replicated by Gibbons
(1964), who further reported
that, in the majority of patients, cortisol concentrations are lower during
remission than they are during an acute illness episode. These initial
observations prompted much further research which has confirmed that
hyperactivity of the HPA axis is associated with mood disorders. This HPA
hyperactivity is revealed by increased levels of cortisol in plasma, urine and
cerebrospinal fluid, exaggerated cortisol responses to ACTH and enlarged
pituitary and adrenal glands in individuals suffering from severe mood
disorders (Owens & Nemeroff,
1993). Measurement of plasma cortisol over 24 hours reveals that,
compared with controls, people with depression exhibit a loss in the
characteristic temporal rhythms in circulating cortisol secretion and show
elevated nadir and flattening of circadian rhythm
(Deuschle et al,
1997). Evidence of increased concentrations of CRH in the
cerebrospinal fluid in patients with depression indicates that the
hypercortisolaemia seen in mood disorders can be linked to over-secretion of
CRH (Nemeroff et al,
1984). This CRH hypersecretion in mood disorders is further
suggested by the blunted ACTH responses to a CRH challenge in people with
depression and down-regulation of CRH receptors in post-mortem frontal
cortices of suicide victims (Owens &
Nemeroff, 1993; Holsboer &
Barden, 1996). The above evidence strongly indicates that the
hypercortisolaemia associated with mood disorders is a result of CRH
hypersecretion. Although AVP hypersecretion has also been postulated, as yet
there is little direct evidence to implicate AVP abnormalities in mood
disorders.
The hypersecretion of CRH and resultant hypercortisolaemia are though to be a consequence of impaired feedback inhibition by endogenous corticosteroids (see Fig. 1). Since GRs in HPA axis tissues are integral to this feedback inhibition, this receptor is the prime suspect with respect to the genesis of HPA hyperactivity (Sapolsky et al, 1986). The dexamethasone suppression test (DST) is a measure of the functional integrity of the GR-mediated negative feedback mechanism. Here, the cortisol-suppressing activity of the synthetic glucocorticoid, dexamethasone, is an approximate indicator of GR status. Reports of cortisol non-suppression in response to dexamethasone in both unipolar and bipolar disorders do indeed suggest a primary GR abnormality in these disease states (Zhou et al, 1987; Swann et al, 1992). The methodology of the DST has been criticised, however, in that it fails to take into account the regulatory role of CRH, and subsequent modifications have resulted in the combined dexamethasone/CRH (dex/CRH) test (Heuser et al, 1994). The DST and the dex/CRH test consistently indicate dysfunction in HPA axis auto-regulation in both unipolar and bipolar affective disorders. Furthermore, normalisation of responses in these tests on remission of affective symptoms suggests that reinstating GR-mediated HPA auto-regulation may be at least a correlate, if not the mechanism of action, of drugs used in the treatment of mood disorders (Zobel et al, 1999).
Although abnormalities downstream of the receptor could conceivably underlie the impaired GR function seen in mood disorders, evidence suggests that the dysfunction may simply be due to decreased receptor number. Thus, evidence of an abnormality of GRs in severe mood disorders has been directly shown by the recent post-mortem demonstration of reduced GR messenger RNA (mRNA) in the hippocampi of individuals suffering from unipolar and bipolar affective disorders (Webster et al, 1999). In addition, there is growing evidence that antidepressants and mood stabilisers stimulate GR mRNA expression in the brain, and in so doing, enhance the HPA autoregulation leading to lowered levels of CRH and cortisol.
![]() |
ANTIDEPRESSANTS, MOOD STABILISERS AND BRAIN GLUCOCORTICOID RECEPTORS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
GR-compromised mice
With the genetic engineering technologies now available to the medical
researcher it has been possible to develop a transgenic mouse line with
reduced GR number. In common with patients with depression, these mice exhibit
HPA disturbances and cognitive deficits which are partially normalised after
antidepressant treatments (Pepin et
al, 1992b;
Montkowski et al,
1995). Furthermore, initial reports suggest that these transgenic
mice exhibit attenuated 5-HT1A-mediated hypothermia
(Man et al, 1999), a
deficit observed in drug-free people with depression
(Cowen et al, 1994).
It is of particular note that in the study of Cowen et al the
hypothermia was more pronounced in people with depression of melancholic type,
a group strongly associated with hypercortisolaemia.
Although the evidence is less clear, there are reports that MRs (type I glucocorticoid receptors) are also susceptible to regulation by antidepressants (Seckl & Fink, 1992). These high-affinity, low-abundance receptors are extensively occupied by low, circulating levels of cortisol, and their role in the feedback inhibition has been established (Jacobson & Sapolsky, 1991). Clearly, any modulation of MR number by antidepressants would also have important consequences for HPA activity.
![]() |
PRIMARY CONSEQUENCES OF HYPERCORTISOLAEMIA |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Corticosteroids and cognition
One of the most interesting findings of relevance to mood disorders is the
association between hypercortisolaemia, cognitive deficits and hippocampal
atrophy. Thus, it is now established that in conditions in which there are
raised endogenous or exogenous corticosteroids (including Cushing's disease
and severe mood disorders) there is also a significant degree of cognitive
impairment (Weingartner & Silberman,
1982; Wolkowitz et
al, 1990). In line with these clinical data, studies in
experimental animals have indicated that both acute and chronic administration
of glucocorticoids result in deficits in learning and memory
(White-Gbadebo & Hamm,
1993; Lupien & McEwen,
1997). Chronic administration of glucocorticoids to rodents has
also been shown to cause marked atrophy of neurons in the hippocampal
formation, and it has been postulated that a similar neurodegenerative effect
of cortisol may underlie some of the cognitive deficits observed in humans
suffering from mood disorders (Sapolsky
et al, 1986; Brown
et al, 1999). Indeed, recent studies report that cortisol
treatment induces cognitive deficits in healthy humans
(Young et al, 1999).
Furthermore, the cognitive deficits appear to be mediated in part via the
frontal lobe, suggesting that this brain area may also be sensitive to the
neurodegenerative effects of cortisol
(Young et al,
1999).
In healthy volunteer subjects the cognitive deficits induced by cortisol administration are reversible, but this may not be the case with the deficits induced by hypercortisolaemia associated with mood disorders (Ferrier et al, 1999; Young et al, 1999). Thus, in unipolar and bipolar affective disorders, although cognitive deficits do show some improvement on remission of affective symptoms (paralleling the return of normal HPA function), this improvement is not complete, suggesting permanent and irreversible hypercortisolaemia-induced damage to crucial neuronal circuits. An early re-establishment of normal HPA activity in mood disorders before permanent deficits in cognitive function occur may therefore be an important therapeutic goal.
The argument that in mood disorders, decreased GR function underlies excessive cortisol secretion and that a high cortisol level, in turn, induces deleterious effects on mood and cognition via an action on glucocorticoid receptors might appear contradictory. However, three possible explanations for the deleterious effects of high cortisol levels in the face of reduced GR function present themselves. First, elevated levels of cortisol may be sufficient to overcome the reduction in GR function and so produce an overall increase in effect. Second, it is possible that, while GRs in the hippocampus and hypothalamus associated with autoregulation of the HPA axis are reduced in function, those in other brain regions are normal. Thus, increased cortisol levels combined with normosensitive GRs might result in an increase in the (deleterious) effects of cortisol in some regions. Third, the deleterious effects of high cortisol may, in part at least, be mediated via MR (or a change in the balance of activation of MRs and GRs) or via nonreceptor-mediated events.
![]() |
FUTURE THERAPEUTIC TARGETS |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Dehydroepiandrosterone
One strategy for counteracting the effects of hypercortisolaemia, used with
some success in the treatment of depression, makes use of the adrenal steroid
dehydroepiandrosterone (DHEA; Bloch et
al, 1999; Wolkowitz
et al, 1999a). Although the physiological
function of DHEA and its sulphated metabolite (DHEA-S) is unclear, these
circulating corticosteroids have been shown to possess antiglucocorticoid
properties, and high cortisol/DHEA ratios are reported to be associated with
persistent depression (Goodyer et
al, 1998). However, although DHEA does possess
antiglucocorticoid activity, it is partially metabolised to testosterone and
oestrogen, which have mood effects of their own and may contribute to DHEA's
antidepressant effect (Wolkowitz et
al, 1999a).
Steroid synthesis inhibitors
Raised levels of cortisol can be lowered pharmacologically by inhibitors of
steroid synthesis, and drugs of this class have been used with some success in
the treatment of unipolar depression. Ravaris et al
(1988) were the first to
report that daily doses of ketoconazole reduced both cortisol levels and
depressive symptoms within 72 hours in a case of treatment-resistant
depression. Since then there have been a number of systematic studies and case
reports investigating the use of not only ketoconazole but also metyrapone and
aminoglutethimide as antidepressant therapies; as yet, however, the results of
these studies are inconsistent (see
Murphy, 1997, for review).
This inconsistency is emphasised by two recent double-blind studies. Thus,
while Wolkowitz et al
(1999b) found a
marked reduction in depressive symptoms following ketoconazole treatment in
patients suffering from major depression, Malison et al
(1999) found no therapeutic
effect of the drug in a similar patient group. It is worth noting that in the
former study, ketoconazole was effective in hypercortisolaemic but not
normocortisolaemic patients with depression
(Wolkowitz et al,
1999b). Unfortunately, one of the main factors which
limits the use of steroid biosynthesis inhibitors as antidepressive therapy is
the high incidence of side-effects resulting from generalised steroid
biosynthesis inhibition.
Corticotropin-releasing hormone antagonists
On the basis of the evidence for oversecretion of CRH in mood disorders,
blockade of CRH receptors has been proposed as an approach to normalising
hypercortisolaemia. Preclinical studies do indeed indicate that CRH
antagonists will be of use in clinical conditions related to HPA
hyperactivity, particularly anxiety disorders. Clinical investigations into
the use of these compounds in many psychiatric conditions are presently
underway and we await their results (see
Holsboer, 1999, for
review).
Type II glucocorticoid receptor (GR) agonists
An alternative strategy for lowering circulating cortisol is activation of
the GR-mediated negative-feedback mechanism that regulates cortisol levels.
Sub-acute doses of dexamethasone (e.g. 3-4 mg daily for 4 days) have been
reported to show antidepressant efficacy
(Arana et al, 1995;
Bodani et al, 1999).
At this dose dexamethasone is thought not to enter the central nervous system
and consequently central GRs are spared activation by this exogenous
glucocorticoid. Activation of GRs at the level of the pituitary does occur,
leading to a lowering of endogenous cortisol. If dexamethasone treatment does
indeed act by lowering endogenous cortisol, then it would be interesting to
correlate its therapeutic efficacy with the response of patients in the DST.
Finally, it should be added that an advantage of the brief course of
administration advocated by these studies is a reduction of the side-effects
associated with longer-term dexamethasone treatment.
Type II glucocorticoid receptor (GR) antagonists
Paradoxically, as well as GR agonists, GR antagonists have also been
advocated as potentially of therapeutic benefit for mood disorders. This is
based on the ability of the GR antagonist to block any detrimental effects of
the raised levels of circulating cortisol and on the ability of an antagonist
to up-regulate its receptor. Thus, administration of a GR antagonist might be
predicted to have an acute antiglucocorticoid activity, while also causing a
compensatory up-regulation of GR number, leading to enhanced negative feedback
on the HPA axis. Preliminary clinical studies using the GR antagonist RU-486
(mifepristone) have been encouraging, even though some clinical efficacy may
have been obscured by the prolonged administration of the drug
(Murphy et al, 1993).
However, animal work suggests that GR numbers can be increased rapidly (within
hours) and it is possible that normal feedback is maintained after
administration of the antagonist has ceased. This indicates that a brief (i.e.
a few days) period of administration of antagonist may be adequate to increase
number and normalise HPA function. This might reduce problems of
non-compliance and side-effects associated with longer-term administration
(Laue et al, 1990). A
number of new, selective GR antagonists are currently being developed,
although preliminary reports suggest that some of these drugs may lack ability
to up-regulate the receptors (Bachmann
et al, 1999).
An evaluation and critique of case reports and clinical trials of some of the treatments outlined above has recently been reported (Wolkowitz & Reus, 1999). The cumulative evidence makes a strong case implicating GRs in the pathogenesis of affective disorders and suggests targeting these receptors in development of new therapies. We predict that drugs designed specifically to up-regulate GRs will be integral to future therapeutic strategies and may provide a long-awaited paradigm shift in the treatment of unipolar and bipolar mood disorders.
![]() |
Clinical Implications and Limitations |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
LIMITATIONS
![]() |
REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Bachmann, C. G., Linthorst, A. C. E. & Reul, J. M. H. M. (1999) Effect of chronic administration of the selective glucocorticoid receptor antagonists ORG 34850, ORG 34116, and ORG 34517 on the rat hypothalamicpituitaryadrenocortical axis. European Neuropsychopharmacology, 9, P.I.102.
Bloch, M., Schmidt, P. J., Danaceau, M. A., et al (1999) Dehydroepiandrosterone treatment of midlife dysthymia. Biological Psychiatry, 45, 1533-1541.[CrossRef][Medline]
Bodani, M., Sheehan, B. & Philpot, M. (1999) The use of dexamethasone in elderly patients with antidepressant-resistant depressive illness. Journal of Psychopharmacology, 13, 196-197.[Medline]
Brown, E. S., Rush, A. J. & McEwen, B. S. (1999) Hippocampal remodeling and damage by corticosteroids: implications for mood disorders. Neuropsychopharmacology, 21, 474-484.[CrossRef][Medline]
Cowen, P. J., Power, A. C., Ware, C. J., et al (1994) 5-HT1A receptor sensitivity in major depression. A neuroendocrine study with buspirone. British Journal of Psychiatry, 164, 372-379.[Abstract]
Deuschle, M., Schweiger, U., Weber, B., et al
(1997) Diurnal activity and pulsatility of the
hypothalamuspituitaryadrenal system in male depressed patients
and healthy controls. Journal of Clinical Endocrinology and
Metabolism, 82,
234-238.
Ferrier, I. N., Stanton, B. R., Kelly, T. P., et al (1999) Neuropsychological function in euthymic patients with bipolar disorder. British Journal of Psychiatry, 175, 246-251.[Abstract]
Freud, S. (1905) Three essays on the theory of sexuality. Reprinted (1953-1974) in the Standard Edition of the Complete Psychological Works of Sigmund Freud (trans. and ed. J. Strachey), vol. 3. London: Hogarth Press.
Gibbons, J. L. (1964) Cortisol secretion rate in depressive illness. Archives of General Psychiatry, 10, 572-575.
Goodyer, I. M., Herbert, J. & Altham, P. M. (1998) Adrenal steroid secretion and major depression in 8- to 16-year-olds, III. Influence of cortisol/DHEA ratio at presentation on subsequent rates of disappointing life events and persistent major depression. Psychological Medicine, 28, 265-273.[CrossRef][Medline]
Heuser, I., Yassouridis, A. & Holsboer, F. (1994) The combined dexamethasone/CRH test: a refined laboratory test for psychiatric disorders. Journal of Psychiatric Research, 28, 341-356.[CrossRef][Medline]
Holsboer, F. (1999) The rationale for corticotropin-releasing hormone receptor (CRH-R) antagonists to treat depression and anxiety. Journal of Psychiatric Research, 33, 181-214.[CrossRef][Medline]
Holsboer, F. & Barden, N. (1996) Antidepressants and hypothalamicpituitaryadrenocortical regulation. Endocrine Reviews, 17, 187-205.[Medline]
Jacobson, L. & Sapolsky, R. (1991) The role of the hippocampus in feedback regulation of the hypothalamicpituitaryadrenocortical axis. Endocrine Reviews, 12, 118-134.[Abstract]
Jones, M. T., Gillham, B., Campbell, E. A., et al (1987) Pharmacology of neural pathways affecting CRH secretion. Annals of the New York Academy of Sciences, 512, 162-175.[Medline]
Kraepelin, E. (1896) Psychiatrie (5th edn). Leipzig: Barth.
Laue, L., Lotze, M. T., Chrousos, G. P., et al (1990) Effect of chronic treatment with the glucocorticoid antagonist RU 486 in man: toxicity, immunological, and hormonal aspects. Journal of Clinical Endocrinology and Metabolism, 71, 1474-1480.[Abstract]
Lupien, S. J. & McEwen, B. S. (1997) The acute effects of corticosteroids on cognition: integration of animal and human model studies. Brain Research Reviews, 24, 1-27.[Medline]
Malison, R. T., Anand, A., Pelton, G. H., et al (1999) Limited efficacy of ketoconazole in treatment-refractory major depression. Journal of Clinical Psychopharmacology, 19, 466-470.[CrossRef][Medline]
Man, M. S., McAllister-Williams, R. H., Steckler, T., et al (1999) 5-HT1A receptor function in GR transgenic mice. Journal of Psychopharmacology, 13 (suppl. A), A32.
Michael, R. P. & Gibbons, J. L. (1963) Interrelationships between the endocrine system and neuropsychiatry. International Review of Neurobiology, 5, 243-302.
Montkowski, A., Barden, N., Wotjak, C., et al (1995) Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. Journal of Neuroendocrinology, 7, 841-845.[Medline]
Murphy, B. E. (1997) Antiglucocorticoid therapies in major depression: a review. Psychoneuroendocrinology, 22 (suppl. 1), S125-S132.[CrossRef][Medline]
Murphy, B. E., Filipini, D. & Ghadirian, A. M. (1993) Possible use of glucocorticoid receptor antagonists in the treatment of major depression: preliminary results using RU 486. Journal of Psychiatry and Neuroscience, 18, 209-213.[Medline]
Nemeroff, C. B., Widerlov, E., Bissette, G., et al (1984) Elevated concentrations of CSF corticotropin-releasing factor-like immunoreactivity in depressed patients. Science, 226, 1342-1344.[Medline]
Owens, M. J. & Nemeroff, C. B. (1993) The Role of CRF in the Pathophysiology of Affective Disorders: Laboratory and Clinical Studies (vol. 172). New York: John Wiley & Sons.
Pariante, C. M., Pearce, B. D., Pisell, T. L., et al
(1997) Steroid-independent translocation of the
glucocorticoid receptor by the antidepressant desipramine.
Molecular Pharmacology,
52,
571-581.
Peiffer, A., Veilleux, S. & Barden, N. (1991) Antidepressant and other centrally acting drugs regulate glucocorticoid receptor messenger RNA levels in rat brain. Psychoneuroendocrinology, 16, 505-515.[Medline]
Pepin, M. C., Beaulieu, S. & Barden, N. (1989) Antidepressants regulate glucocorticoid receptor messenger RNA concentrations in primary neuronal cultures. Brain Research. Molecular Brain Research, 6, 77-83.[Medline]
Pepin, M. C., Govindan, M. V. & Barden, N. (1992a) Increased glucocorticoid receptor gene promoter activity after antidepressant treatment. Molecular Pharmacology, 41, 1016-1022.[Abstract]
Pepin, M. C., Pothier, F. & Barden, N. (1992b) Antidepressant drug action in a transgenic mouse model of the endocrine changes seen in depression. Molecular Pharmacology, 42, 991-995.[Abstract]
Przegalinski, E., Budziszewska, B., Siwanowicz, J., et al (1993a) The effect of repeated combined treatment with nifedipine and antidepressant drugs or electroconvulsive shock on the hippocampal corticosteroid receptors in rats. Neuropharmacology, 32, 1397-1400.[Medline]
Przegalinski, E., & Budziszewska, B. (1993b) The effect of long-term treatment with antidepressant drugs on the hippocampal mineralocorticoid and glucocorticoid receptors in rats. Neuroscience Letters, 161, 215-218.[Medline]
Ravaris, C. L., Sateia, M. J., Beroza, K. W., et al (1988) Effect of ketoconazole on a hypophysectomized, hypercortisolemic, psychotically depressed woman. Archives of General Psychiatry, 45, 966-967.[CrossRef][Medline]
Raven, P. W., O'Dwyer, A. M., Taylor, N. F., et al (1996) The relationship between the effects of metyrapone treatment of depressed mood and urinary steroid profiles. Psychoneuroendocrinology, 21, 277-286.[CrossRef][Medline]
Reul, J. M., Stec, I., Soder, M., et al (1993) Chronic treatment of rats with the antidepressant amitriptyline attenuates the activity of the hypothalamicpituitaryadrenocortical system. Endocrinology, 133, 312-320.[Abstract]
Rossby, S. P., Nalepa, I., Huang, M., et al (1995) Norepinephrine-independent regulation of GRII mRNA in vivo by a tricyclic antidepressant. Brain Research, 687, 79-82.[CrossRef][Medline]
Sapolsky, R. M., Krey, L. C. & McEwen, B. S. (1986) The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Reviews, 7, 284-301.[Medline]
Seckl, J. R. & Fink, G. (1992) Antidepressants increase glucocorticoid and mineralocorticoid receptor mRNA expression in rat hippocampus in vivo. Neuroendocrinology, 55, 621-626.[Medline]
Swann, A. C., Stokes, P. E., Casper, R., et al (1992) Hypothalamicpituitaryadrenocortical function in mixed and pure mania. Acta Psychiatrica Scandinavica, 85, 270-274.[Medline]
Webster, M. J., O'Grady, J. O., Orthmann, C., et al (1999) Decreased glucocorticoid receptor mRNA levels in individuals with depression, bipolar disorder and schizophrenia. Schizophrenia Research, 41, 111.
Weingartner, H. & Silberman, E. (1982) Models of cognitive impairment: cognitive changes in depression. Psychopharmacology Bulletin, 18, 27-42.
White-Gbadebo, D. & Hamm, R. J. (1993) Chronic corticosterone treatment potentiates deficits following traumatic brain injury in rats: implications for aging. Journal of Neurotrauma, 10, 297-306.[Medline]
Wolkowitz, O. M., Reus, V. I., Weingartner, H., et al (1990) Cognitive effects of corticosteroids. American Journal of Psychiatry, 147, 1297-1303.[Abstract]
Wolkowitz, O. M., & Reus, V. I. (1999)
Treatment of depression with antiglucocorticoid drugs.
Psychosomatic Medicine,
61,
698-711.
Wolkowitz, O. M., Reus, V. I., Keebler, A., et al
(1999a) Double-blind treatment of major depression
with dehydroepiandrosterone. American Journal of
Psychiatry, 156,
646-649.
Wolkowitz, O. M., Reus, V. I., Chan, T., et al (1999b) Antiglucocorticoid treatment of depression: double-blind ketoconazole. Biological Psychiatry, 45, 1070-1074.[CrossRef][Medline]
Young, A. H., Sahakian, B. J., Robbins, T. W., et al (1999) The effects of chronic administration of hydrocortisone on cognitive function in normal male volunteers. Psychopharmacology (Berlin), 145, 260-266.[CrossRef][Medline]
Zhou, D. F., Shen, Y. C., Shu, L. N., et al (1987) Dexamethasone suppression test and urinary MHPG X SO4 determination in depressive disorders. Biological Psychiatry, 22, 883-891.[Medline]
Zobel, A. W., Yassouridis, A., Frieboes, R. M., et al
(1999) Prediction of medium-term outcome by cortisol response
to the combined dexamethasoneCRH test in patients with remitted
depression. American Journal of Psychiatry,
156,
949-951.
Received for publication December 6, 1999. Revision received April 20, 2000. Accepted for publication May 10, 2000.