Paul Mackin, MD, PhD, MRCPsych


 Original release date 5/04.  Approved for CME credit through 4/30/05. 

After reading this article, you will be familiar with:

The function of the hypothalamic-pituitary-adrenal axis and the significance of cortisol in the etiology of depression. 

The cognitive deficits associated with mood disorders, even during euthymia. 

Evolving strategies to target the dysfunctional HPA axis and treat mood and cognitive symptoms. 

Who will benefit from reading this article?

 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.

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.

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).

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-HT

-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.

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.

. 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.

. 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.

. 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.

. 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.

. 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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Articles

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.

Author | Paul Mackin, MD, PhD, MRCPsych

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