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After reading this article, you will be familiar with:The function of the hypothalamic-pituitary-adrenalaxis and the significance of cortisolin the etiology of depression.
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Psychiatrists, neuropsychiatrists, primary care physicians, nurse practitioners, psychologists, psychiatric nurses, social workers and other mental health care professionals. Continuing education credit is available for most specialties. To determine if this article meets the requirements of your specialty, please contact your state licensing board.
Dr. Mackin is Academic Specialist Registrar in the department of psychiatry at the University of Newcastle upon Tyne, U.K. He has indicated that he has nothing to disclose.
Dr. Young teaches adult psychiatry at the University of Newcastle upon Tyne, U.K. He has a special interest in mood disorders and has published widely in the field of neuropsychopharmacology. He has indicated that he has nothing to disclose.
Mood disorders are leading causes of both morbidity and mortality. Depressive disorder and bipolar disorder (BD) rank among the leading causes of disability worldwide (Murray and Lopez, 1997). Traditionally, mood disorders were considered to be relapsing and remitting conditions characterized by complete inter-episode recovery, but recent evidence has suggested that even during periods of euthymia, neurocognitive impairments known to be present during mood episodes may still persist (Ferrier and Thompson, 2002).
Both Kraepelin (1896) and Freud (1905) regarded endocrinology as potentially important in the causation and treatment of major psychiatric disorders, and the role of dysfunctional endocrine systems in the pathogenesis of mood disorders has been the focus of research for many decades. Poor understanding of the complexity of endocrine systems and their interaction with neural networks, combined with primitive methodology, frustrated early attempts to establish links between endocrine dysfunction and mood disorders (Michael and Gibbons, 1963). More recently, developments in the field of neuroendocrinology have highlighted the significance of endocrine systems in the etiology and pathogenesis of mood disorders.
Despite considerable advances in the treatment of mood disorders during previous decades, there remains an urgent need to identify compounds that will successfully treat mood episodes (including the associated neurocognitive impairments) and prevent their recurrence. This article reviews some of these recent developments, with an emphasis on the role of cortisol in relation to depression.
Glucocorticoids are the end product of the hypothalamic-pituitary-adrenal (HPA) axis and are central to the stress response. There is overwhelming evidence that during periods of acute stress, glucocorticoids promote survival by mobilizing energy reserves. In addition to these short-term adaptive changes, glucocorticoids are also involved in other longer-term, stress-related adaptive changes such as shaping and regulating a number of physiological processes, including immune responsiveness and activation of the sympathetic nervous system. Although glucocorticoid production is essential for survival, overproduction is associated with a significant disruption of cellular functioning, which, in turn, leads to widespread physiological dysfunction.
The HPA Axis
Cortisol, a glucocorticoid released from the adrenal cortex, is the end product of the HPA axis. The HPA axis comprises the tissues of the hypothalamus, pituitary and adrenal cortices; regulatory neuronal inputs; and a variety of releasing factors and hormones (Figure 1). A variety of stressors, both physical and psychological, cause the neurosecretory cells within the paraventricular nucleus of the hypothalamus to secrete corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. These secretions cause the release of adrenocorticotropic hormone (ACTH) from the anterior lobe of the pituitary. Cortisol is released from the adrenal cortex in response to ACTH. Cortisol has a panoply of central and peripheral effects that are mediated via at least two intracellular specialized glucocorticoid receptor subtypes: the high-affinity type I receptor (or MR) and the low-affinity type II receptor (or GR). In the resting state, these receptors exist in the cytosol, stabilized by a variety of proteins. Glucocorticoids readily diffuse through the cellular membrane and bind to these receptors, which promotes their translocation to the nucleus. Within the nucleus, the activated receptors interact with other transcription factors or bind to specific DNA, thus promoting the expression of various genes.
The activity of the HPA axis is highly regulated. Secretory cells within the paraventricular nucleus receive neuronal inputs from a number of brain regions including the amygdala, hippocampus and nuclei within the midbrain (Figure 2). The HPA axis also has an autoregulatory mechanism mediated by cortisol. Endogenous cortisol binds to glucocorticoid receptors in the HPA axis tissues and hippocampus and acts as a potent negative regulator of HPA activity. The relative contribution of the two receptor subtypes (GR and MR) in the regulation of HPA activity is as yet unclear. The MRs have a high affinity for endogenous glucocorticoids such as cortisol, as well as for the salt-regulating hormone aldosterone. However, the GRs have a relatively low affinity for cortisol, but bind avidly to synthetic steroids such as dexamethasone. These differences in affinity suggest that MRs play a primary role in regulating basal cortisol levels when hormone levels are low. When cortisol levels rise, as from stress or circadian fluctuations, the MRs become saturated, and GRs become the main transducers of glucocorticoid activity and therefore the primary mediators of HPA feedback. These regulatory mechanisms are important in determining basal levels and circadian fluctuations in cortisol levels. Changes in GR number or function may be important in altering the homeostatic function of the HPA axis observed in healthy individuals.
Cortisol and GR Abnormalities
The first observations of abnormalities of cortisol levels in patients with depression were made in the late 1950s by Board and colleagues (Michael and Gibbons, 1963), and these observations have been consistently replicated. Subsequent studies have shown that HPA hyperactivity--as manifested by hypersecretion of CRH; increased cortisol levels in plasma, urine and cerebrospinal fluid; exaggerated cortisol responses to ACTH; and enlarged pituitary and adrenal glands--occurs in individuals suffering from severe mood disorders. Hypersecretion of CRH causing hypercortisolemia may be a result of impaired feedback mechanisms resulting from GR abnormalities, such as decreased receptor number or altered function. This view is supported by the demonstration of GR abnormalities in postmortem studies of patients with severe mood disorders (Webster et al., 2000). The dexamethasone suppression test (DST) is a measure of the functional integrity of the GR-mediated negative feedback mechanism: 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 depressive and bipolar disorders do indeed suggest a primary GR abnormality in these disorders (Zhou et al., 1987).
Glucocorticoid Receptor Modulation
Pepin and colleagues (1989) were the first to demonstrate that treatments used in mood disorders are able to affect GR function. These early in vitro studies showed that tricyclic antidepressants had the ability to increase GR mRNA in primary neuronal cultures, and subsequent in vivo studies have revealed that this increase in GR mRNA is translated into an increase in receptor protein and binding capacity. These changes have been reported following treatment with the TCAs desipramine (Norpramin), imipramine (Tofranil) and amitriptyline (Elavil) and the mood stabilizer lithium (Eskalith, Lithobid) (Peiffer et al., 1991), and following electroconvulsive therapy (Przegalinski et al., 1993). It is interesting, however, that neither citalopram (Celexa) (Seckl and Fink, 1992) nor fluoxetine (Prozac) (Rossby et al., 1995) alters GR mRNA or GR binding capacity, which suggests that the selective serotonin reuptake inhibitor class of antidepressants may lack the ability to modulate GR expression and/or function.
This evidence suggests that if indeed GR regulation is involved in the therapeutic mechanism(s) of action of antidepressant drugs and mood stabilizers, it is not a unitary mechanism. Antidepressant drugs that have the ability to regulate GR expression and binding may, however, have greater therapeutic efficacy in patients who have hypercortisolemia.
The development of a transgenic mouse line with reduced GR number has provided further support for the hypothesis that altered GR function is central to the pathogenesis of depressive disorders. As is common in humans with depression, these mice exhibit HPA disturbances and cognitive deficits that are partially normalized after antidepressant treatment (Pepin et al., 1992). Furthermore, these transgenic mice exhibit attenuated 5-HT1A-mediated hypothermia. A similar deficit is observed in drug-free people with depression, particularly in those with depression of the melancholic type, a group strongly associated with hypercortisolemia.
Consequences of Hypercortisolemia
Corticosteroids are central to many metabolic and inflammatory processes, and in recent years, their role as modulators of neurotransmission has been established. Animal studies have highlighted the importance of corticosteroids in influencing neurotransmitter receptor expression and function, long-term potentiation, and even cell survival. Manipulation of corticosteroids is likely, therefore, to influence the behavioral indices of neurotransmitter function, such as mood and cognition.
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 (Wolkowitz et al., 1990). Studies in experimental animals have shown deficits in learning and memory following chronic administration of glucocorticoids (Lupien and McEwen, 1997), as well as marked atrophy of neurons in the hippocampal formation. It has been postulated that a similar neurodegenerative effect of cortisol may underlie some of the cognitive deficits observed in humans suffering from severe mood disorders (Sapolsky et al., 1986).
While there is substantial evidence to indicate that the hippocampus is particularly sensitive to elevation of glucocorticoids, the effects on other areas of the brain are less clear. Recent clinical data have reported that cortisol treatment induces cognitive deficits in healthy humans, and these 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). The deficits in healthy volunteer study participants are reversible, but this may not be the case with the cognitive deficits induced by hypercortisolemia associated with mood disorders (Ferrier et al., 1999; Young et al., 1999). A more recent study indicated that the frontal lobes are adversely affected by cortisol, which may illustrate a similar pattern of degeneration to that which occurs in the hippocampus (Young et al., in press). Moreover, the traditional assumption that patients with severe mood disorders make a full inter-episode recovery has recently been challenged. Although cognitive deficits do show some improvement on remission of affective symptoms (paralleling the return of normal HPA function), this improvement is not sustained. Studies have identified a specific deficit in executive control in a cohort of patients prospectively verified as euthymic (Thompson et al., 2001), replicating an earlier finding by our group (Ferrier et al., 1999). Executive function is a component of Baddeley's influential model of working memory (Figure 3). In that model, working memory is a tripartite system consisting of a central executive (the attentional controller) and two slave systems: the phonological loop and the visuo-spatial scratch pad. It has been suggested that the main role of the central executive is attentional control, which coordinates a variety of processes such as set-shifting and updating and monitoring of working memory. Executive function deficits may be manifested by impaired attentional set-shifting, planning, verbal fluency and response inhibition. Clearly such deficits may have important adverse consequences with regard to the individual's social and occupational functioning, as well as insight and compliance with prescribed medication. These cognitive deficits may represent permanent and possibly irreversible hypercortisolemia-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.
It might appear contradictory 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. However, there are three possible explanations for the deleterious effects of high cortisol levels in the face of reduced GR function. 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 MRs (or a change in the balance of activation of MRs and GRs) or via non-receptor-mediated events.
There is increasing evidence to suggest that the consequences of HPA dysfunction described above are central to the pathogenesis of mood disorders and cognitive deficits. Modulation of the effects of hypercortisolemia may provide potential treatments for mood disorders, and such strategies are the focus of considerable research interest.
Dehydroepiandrosterone. The adrenal steroid dehydroepiandrosterone (DHEA) has been used with some success in the treatment of depression (Wolkowitz et al., 1999b). The physiological function of DHEA and its sulphated metabolite (DHEA-S) is unclear, but these circulating corticosteroids have been shown to possess antiglucocorticoid properties, and high cortisol/DHEA ratios are reported to be associated with persistent depression. Apart from their antiglucocorticoid properties, which may account for the therapeutic effects of DHEA, an alternative explanation is that DHEA is partially metabolized to testosterone and estrogen, both of which have effects on mood.
Steroid synthesis inhibitors. Lowering circulating cortisol levels by inhibiting steroid synthesis is one pharmacological intervention that has been utilized in the treatment of unipolar depression. Ketoconazole (Nizoral) administered daily was shown to reduce both cortisol levels and depressive symptoms within 72 hours in a case of treatment-resistant depression (Ravaris et al., 1988). Subsequent studies have investigated the use of ketoconazole as well as metyrapone (Metopirone) and aminoglutethimide (Cytadren) as antidepressant therapies, but the results have been inconsistent (Murphy, 1997). In separate double-blind research studies, Wolkowitz et al. (1999a) reported a marked reduction in depressive symptoms following ketoconazole treatment in patients suffering from major depression, but Malison and colleagues (1999) found no such benefit in a similar patient group.
CRH antagonists. Over-secretion of CRH, resulting in hypercortisolemia, may be normalized by blockade of CRH receptors. Preclinical studies have suggested that CRH antagonists will have clinical utility in conditions related to HPA hyperactivity, particularly anxiety disorders. Clinical investigations into the use of CRH antagonists in a number of psychiatric disorders are currently underway, and we await their results.
Type II glucocorticoid receptor agonists. Activation of the GR-mediated negative feedback mechanism that regulates cortisol levels is another strategy for reducing circulating cortisol levels. The synthetic glucocorticoid dexamethasone given at doses of 4 mg/day for four days has been shown to have antidepressant effects (Arana et al., 1995). At this dose, dexamethasone does not enter the central nervous system and, consequently, central GRs are not activated. Glucocorticoid receptors at the level of the pituitary are activated, leading to a lowering of endogenous circulating cortisol. The brief course of dexamethasone administration in these studies avoided the side effects associated with longer-term treatment.
GR antagonists. Paradoxically, glucocorticoid receptor antagonists have also been advocated as agents with potential therapeutic properties for mood disorders. This is based on the ability of the GR antagonist to block any detrimental effect of hypercortisolemia and on the ability of an antagonist to upregulate its receptor. Administration of a GR antagonist results in an acute antiglucocorticoid effect, while presumably causing a compensatory upregulation of GR numbers, leading to enhanced negative feedback of the HPA axis. Initial clinical studies using the GR antagonist mifepristone (Mifeprex, RU-486) have been encouraging, but some clinical efficacy may have been masked by the prolonged administration of the drug (Murphy et al., 1993). Animal studies suggest that GR numbers are increased rapidly (within hours) after the administration of mifepristone, which may restore normal feedback, thus "resetting" the HPA axis (Lupien and McEwen, 1997). Such data suggest that a brief period of treatment with the GR antagonist may be adequate for restoring normal HPA axis function. This might reduce problems of noncompliance and side effects associated with longer-term administration.
We have recently sought to establish proof of efficacy for the use of GR antagonists in the treatment of BD in a double-blind, placebo-controlled crossover design in which mifepristone was administered as adjunctive therapy (Young et al., in press). We hypothesized that antiglucocorticoid treatments, particularly corticosteroid receptor antagonists, would improve neurocognitive functioning and attenuate depressive symptoms in this disorder.
Twenty patients, ages 18 to 65, with a diagnosis of BD (confirmed using the Structured Clinical Interview for DSM-IV [SCID]) and residual depressive symptoms were recruited. Patients' medication had been unchanged for six weeks prior to participation and remained so throughout the study period. Seventeen patients were taking at least one mood stabilizer, with 13 taking at least one antidepressant and 11 taking an antipsychotic agent. Following an initial baseline assessment of neurocognitive function and mood and basal neuroendocrine profiling, patients were randomly assigned to receive either 600 mg/day mifepristone or placebo for seven days. Administration was in a double-blind design. Mood ratings were taken after the week's treatment and then at weekly intervals. At day 21, the groups crossed over and received the alternative treatment (placebo or mifepristone) for seven days, again with ratings taken following the week's treatment and at weekly intervals. Neurocognitive function was assessed on three occasions over the study period: at baseline and 21 days after both treatments.
On the basis of previous research, it was predicted that the principal cognitive domains that would be most sensitive to changes in HPA axis function were working memory and verbal declarative memory. Test batteries were therefore administered to explore these cognitive domains.
At 14 days following treatment with mifepristone, depression rating scores had significantly improved from baseline levels, without any significant change being observed at any time point following placebo. The Brief Psychiatric Rating Scale (BPRS) scores were also significantly lower in the mifepristone group at day 14 compared with baseline, with a similar lack of change in the placebo-treated group. With regard to neurocognitive performance, the mifepristone-treated group showed a significant reduction in the error rate of the spatial working memory task (Figure 4) compared with baseline. No such changes were observed in the placebo-treated patients. Furthermore, baseline cortisol output correlated positively with the percentage improvement in spatial working memory error rate following mifepristone administration. Verbal fluency and spatial recognition memory also improved in those patients treated with mifepristone.
These data suggest that the GR-antagonist mifepristone selectively improves neurocognitive function and may be an antidepressant in BD. Interestingly, mifepristone was the only GR antagonist examined in a recent study to increase both MR and GR binding in the frontal cortex (Bachmann et al., 2003). This may underpin the selective pattern of improvement in neurocognitive function seen in our study, which was restricted to tests that have been shown to be sensitive to frontal lobe dysfunction. The results of this small, preliminary trial require confirmation in studies of larger numbers of patients.
There is robust evidence demonstrating abnormalities of the HPA axis in mood disorders. Hypercortisolemia may be central to the pathogenesis of depressive symptoms and cognitive deficits, which in turn may result from the neurocytotoxic effects of raised cortisol levels. Identification and effective treatment of mood and cognitive symptoms are important clinical goals, but currently available treatments may fall short of this ideal. Manipulation of the HPA axis has been shown to have therapeutic effects in both preclinical and clinical studies, and recent data suggest that direct antagonism of GRs may be a future therapeutic strategy in the treatment of mood disorders.
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