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Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 Antiglucocorticoids in psychiatry†
Sean A. McIsaac, Åsa Westrin & Allan H. Young
Sean McIsaac studied for his
endocrine tissue: the hypothalamus, pituitary and adrenal cortices are its major components. The Significant evidence has accrued suggesting that HPA axis is regulated by external inputs from a the hypothalamic–pituitary–adrenal (HPA) axis plays number of brain regions, including the amygdala, a role in some psychiatric disorders. This article hippocampus and nuclei within the midbrain. In reviews the physiology of the HPA axis, evidence of addition, the HPA axis also contains a number of dysfunction in this axis in psychiatric illnesses and autoregulatory mechanisms. The paraventricular the role that this dysfunction might play in pharma- cological treatment resistance. Future therapeutic nucleus of the hypothalamus secretes the peptides strategies that may potential y arise from these corticotropin­releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal in psychiatric disorders. Åsa
Westrin is a research psychiatrist
circulatory system of the pituitary stalk. These DECLARATIon of InTEREST
peptides have a synergistic effect on the release A.Y. holds related grants from the Stanley Medical of adrenocorticotropic hormone (ACTH) from the Research Institute and the Medical Research Coun- cil (UK) and has filed a provisional patent concerning anterior lobe of the pituitary. Cortisol, a gluco ­ involves stress-system alterations in depression and suicidal behaviour. the use of antiglucocorticoids as an adjunctive to corticoid released from the adrenal cortex in Allan Young currently holds the
response to ACTH, has a plethora of central and peripheral effects which are mediated primarily via glucocorticoid receptors of types I and II. Under Many of the current drug treatments in psy chiatry normal homeostatic conditions, type I recep tors were discovered without any knowledge of the are mostly saturated, owing to their high affinity under lying ‘disease processes’ concerned. Theories for cortisol and other gluco corticoids, and type II of the mechanism of drug action were all devel oped glucocorticoid receptors are the more sensitive to post hoc and are predominantly concerned with stressor­dependant changes within the axis. It is by mono amine neurotransmitter modulation. How­ the glucocorticoid receptor that cortisol primarily Correspondence Professor Allan
ever, not all patients are treated successfully by these exerts its negative feedback on the hippocampus, means and rates of full remission are frequently hypothalamus and pituitary. Under normal quite low. Current diagnostic categorisation of conditions, diurnal variation in cortisol levels is psychiatric disorders, such as unipolar depression, seen. In humans, this begins with markedly elevated bipolar disorder and schizophrenia, is provisional serum concentrations shortly after awakening, and subject to ongoing revision. Ideally, drug trailing off to the lowest levels in the evening, development should be predicated on knowledge presenting as a characteristic curve when con cen­ of ‘drug targets’ derived from understanding of tra tions are graphed over a 24 h period. Changes the pathophysiological processes involved that are in glucocorticoid receptor number or function may important for the illness in question. Although be important in altering the homeostatic function the central pathophysiological components of of the HPA axis observed in healthy individuals. most psychiatric disorders remain unknown, a These regulatory mechanisms are important in large body of evidence indicates that endocrine determining basal levels and circadian fluctuations dysfunction, particularly of the hypothalamic– pituitary–adrenal (HPA) axis, may be important for certain psychiatric illnesses, as indeed is the HPA abnormalities in psychiatric illnesses
case for some physical illnesses. Factors related to The first observations of abnormal cortisol levels the HPA axis may partially account for treatment­ in people with depression were made in England resistance (although, of course, a variety of factors by Board and colleagues (Board 1957). Sub sequent contribute) and these may also suggest targets studies have shown that HPA hyperactivity, as for development of new drugs with novel modes variously manifested by hypersecretion of CRH and AVP, increased cortisol levels in plasma, urine, cerebrospinal fluid and saliva, exaggerated cortisol The hypothalamic–pituitary–adrenal axis
responses to ACTH, and enlarged hypothalamus, The HPA axis is an endocrine system compris­ pituitary and adrenal glands, occurs in individuals ing both central nervous system and peripheral Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 In addition to unipolar depression, hyper­ 2004). This implicates the regulatory mechanisms cortisolaemia has since been found in other psy­ that involve glucocorticoid receptors and AVP and chiatric illnesses, including psychotic depression, CRH release in the HPA axis. Response to the dex/ bipolar disorder, schizophrenia and Alzheimer’s CRH test has been found to resolve with successful disease (Nelson 1997; Walder 2000; Watson 2004; treatment in acute unipolar depression (Kunugi DeBattista 2005), although these abnormalities in 2006), but in bipolar disorder preliminary results cortisol levels have not always been found in milder show that the abnormality appears stable over depression (using ICD–10 criteria) (Cowen 2002). time and is independent of mood state, persisting In severe depression, high doses of glucocorticoids have been shown to cause brief elevations in mood, suggesting that cortisol may actually Cortisol abnormalities in post-traumatic
be a resilience factor that the body releases to stress disorder
restore normal serotonergic function (Young AH Evidence is conflicting regarding the role of 1994a). Hypersecretion of CRH and AVP, causing the HPA axis in post­traumatic stress disorder hypercortisolaemia, may be a result of impaired (PTSD). Some studies indicate dysfunction of the feedback mechanisms resulting from glucocorticoid axis, showing hypocortisolaemia, rather than receptor abnormalities, such as decreased receptor hypercortisolaemia, although elevated CRH is number or altered function (Dinan 2005). This still reported (Yehuda 2001). The same group has view is supported by the demonstration of down­ found evidence indicating that ACTH is also el­ regulated glucocorticoid receptor mRNA in evated in PTSD; it is therefore likely that the dys­ post­mortem frontal and temporal cortices and function in the HPA axis lies in the output of the hippocampi of individuals with unipolar or bipolar adrenal glands (Yehuda 2006). This would suggest disorder or schizophrenia (Webster 2002). that antiglucocorticoid treatments may not be able The cortisol­suppressing activity of the synthetic to be used in the same manner for PTSD (because glucocorticoid dexamethasone is useful as a meas­ of already low cortisol levels) as for disorders ure of the functional integrity of the glucocorticoid­ with hypercortisolaemia. Other research groups receptor­mediated negative feedback mechanism. have found that salivary cortisol levels are actu­ Reports of cortisol non­suppression in response ally normal in individuals with PTSD, and that to dexamethasone in unipolar, bipolar and hypercortisolaemia is found only in individuals schizophrenic disorders suggest a primary gluco­ with PTSD and comorbid major depressive disor­ corticoid receptor abnormality in these disorders (Zhou 1987). Post­dexamethasone AVP levels have proven to be a sensitive measure of HPA dysfunction 5-HT and HPA axis interaction
when compared with healthy controls, and levels Whether hypercortisolaemia is a contributing risk are elevated in unipolar and bipolar disorder, in factor or a resulting effect of the disorders listed both currently symptomatic and remitted patients above has yet to be determined. However, when considering these putative pathophysiological processes it is important to note that there appears Supplementing the dexamethasone suppression to be complex regulatory interaction between the test with subsequent administration of exogenous HPA axis and brain serotonergic systems (for a CRH is known as the dex/CRH test, and recent work utilising this technique has verified that HPA axis Studies show that with successful treatment function is abnormal in bipolar disorder (Watson of depression using serotonergic antidepressants (i.e. selective serotonin reuptake inhibitors and KEY PoInTS 1
serotonin and noradrenaline reuptake inhibi­tors – SSRIs and SNRIs), non­suppression of • Robust evidence demonstrates abnormalities the dexamethasone suppression test and other of the HPA axis in a number of psychiatric disorders HPA dysfunctions resolve, although this is not fully established for all other antidepressants • Interaction between brain serotonergic (Harmer 2003). Precursors of serotonin (5­HT), systems and the HPA axis may be relevant to the pathogenesis of depressive symptoms and including L­tryptophan and 5­hydroxytryptophan (5­HTP), have been shown to increase ACTH, CRH and cortisol levels. Some evidence suggests • These depressive symptoms and cognitive deficits may be due to the neurocytotoxic that 5­HT may even act directly on the adrenal glands to release cortisol (for reviews see Dinan 1996; Porter 2004).
Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 In vivo work on rats has shown that after a bi­ receptor binding is reduced after administration lateral adrenalectomy, 5­HT synthesis is reduced of corticosterone (Mendelson 1992). However, in the hypothalamus, hippocampus and raphe human studies attempting to replicate this possible nuclei (Dinan 1996). Further animal work on the regulatory mechanism have thus far shown mixed somatodendritic 5­HT autoreceptor indicates that glucocorticoids modulate expression of these receptors in various regions of the brain (Man Consequences of hypercortisolaemia
2002). This has been replicated in normal human It is widely recognised that a variety of medicinal volunteers by using hydrocortisone to attenuate the steroids can cause neuropsychiatric adverse effects of the partial serotonin agonist buspirone reactions. A number of case reports from the 1980s on the hypothermia and reduced duration of rapid revealed that, though rare, even intranasal cortico­ steroid sprays can trigger relapse into episodes of The HPA overactivity observed in people with both mania and psychosis after a period of sustained depression appears to alter the diurnal rhythms administration (Lewis 1983; Meyboom 1988; of the axis, eliminating the normal decrease Goldstein 1989; Phelan 1989). Cushing’s disease is in cortisol seen in the later part of the day and an endocrine disorder in which hypercortisolaemia producing a more sustained release over time. One occurs, most commonly caused by a tumour in con sequence of this flattened glucocorticoid rhythm the pituitary but also occasionally by peripheral may be a reduced clinical efficacy of antidepressant adrenal lesions. It is now established that cognitive treatments such as chronic SSRIs. Gartside and impairments similar to those caused by medicinal collaborators modelled this flattened glucocorti­ steroids are seen across various conditions in coid rhythm in experimental animals and then which endogenous or exogenous corticosteroids examined the effects of this manipulation on the are raised, including both Cushing’s disease and neuro pharmacological effects of an SSRI (Gartside 2003). They used an implanted corticosterone­ Studies in experimental animals have shown releasing pellet (compared with sham pellets) to deficits in learning and memory following chronic reproduce the flattened glucocorticoid rhythm and administration of glucocorticoids (Lupien 1997), then administered either fluoxetine or vehicle to as well as marked atrophy of neurons in the rodents. In vivo microdialysis was then conducted hippocampal formation. It has been postulated to quantify effects on extracellular 5­HT levels. that a similar effect of cortisol may underlie some With fluoxetine treatment, 5­HT levels were sig­ of the cognitive deficits observed in humans with nificantly higher in the sham­pellet group than in the group whose glucocorticoid rhythm had been Clinical data suggest that cortisol treatment flattened by corticosterone­releasing pellets. This induces cognitive deficits in healthy humans, and evidence suggests that elevated glucocorticoids these deficits appear to be attributed partly to the (as found in mood disorders) reduce the ability of frontal lobe, suggesting that this brain area may SSRIs to elevate extracellular brain 5­HT levels in also be sensitive to these effects of cortisol (Young the forebrain and thus impair the clinical efficacy AH 1999). The deficits in healthy volunteers are reversible, but this may not be entirely the case with Similar findings were observed in a group of the cognitive deficits induced by hypercortisolaemia fluoxetine­resistant women, who demonstrated associated with mood disorders if atrophy of tissue HPA­axis overactivity, compared with a group is irreversible in long­term illness (Young AH 1999; Thompson 2005). Indeed, duration of illness successfully with fluoxetine (Young EA 2004b). is known to be negatively correlated with severity Add­on treatment of an antiglucocorticoid drug of cognitive deficits (Cavanagh 2002). Therefore, remedied this non­response and demonstrated early re­establishment of normal HPA activity in HPA axis interference with a conventional SSRI.
mood disorders may be an important therapeutic Interestingly, in people with remitted de­ goal, before irremediable deficits in cognitive pression, the risk of relapse is greatly increased when cortisol levels are chronically increased (Zobel 2001). Thus, both lack of recovery and a Consequences of hypocortisolaemia
higher risk of relapse may be related to increased cortisol levels, although this could be viewed as Just as excess cortisol has detrimental consequences, a manifestation of unresolved depression. The so does a deficiency of glucocorticoids. Although 5­HT receptor number and function have been elevated cortisol has neurotoxic effects on the shown to be reduced in people with depression, above­mentioned regions, cortisol is also known and animal studies have shown that 5­HT to have a neuroprotective role and it is critical in Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 regulating the innate immune responses of the central nervous system (Glezer 2004). In individuals The adrenal steroid dehydroepiandrosterone with Addison’s disease, primary adrenal failure (DHEA) has been used with some success in results in hypocortisolaemia as one of the major the treatment of depression (Wolkowitz 1999). presenting traits. Commonly, individuals report The physiological functions of DHEA, and its a decreased quality of life, due to chronic fatigue sulphated conjugate DHEA–S, are numerous and and a reduced sense of well­being, and although it is now known to act as both an active hormone deficits in cognition are anecdotally acknowledged, and a prohormone for sex steroids. It may have they are not yet well­defined (Hunt 2000). These antidepressant qualities and it is speculated tentatively posited consequences of low cortisol that its therapeutic effects may be accounted for levels are important to consider for putative by its potentially antiglucocorticoid properties antiglucocorticoid treatments in psychiatry, as therapy of this kind is likely to be most beneficial glucocorticoid effects of DHEA is that the Suicide risk
molecule aids in reversing nuclear localisation of the glucocorticoid receptor caused by its inter­ When looking at the influence of hyper cortisol­ action with cortisol (Cardounel 1999). Another aemia on risk of suicide, it becomes important to explanation is that DHEA is partially metabolised differentiate between suicide attempt and com­ to testosterone and oestrogen, both of which have pleted suicide. In a number of post­mortem studies, effects on mood. Other work, in mice, shows that findings have indicated increased measures of the hormone has dose­dependant neuroprotective HPA axis activity in completed suicide (Dorovini­ effects in the hippocampus and suggests that this Zis 1987; Nemeroff 1988; Arato 1989; Lopez 1992; quality is attributed to the hormone directly, Raadsheer 1995). Similarly, non­suppression of independently of its subsequent products cortisol has repeatedly been shown to be associated with subsequent completed suicide (Lester 1992). In a study of the molar ratio between cortisol From this, one might hypothesise that treatment and DHEA in drug­free patients with depression, with antiglucocorticoids might have a specific we (A.Y. and colleagues) found reduced DHEA levels and a correspondingly elevated cortisol: This association between HPA axis hyper­ DHEA ratio. This proved to be a more sensitive activity and subsequent completed suicide seems measure in depression than basal cortisol alone to be most frequent among severely ill patients (Young AH 2002). It is well established now that (Coryell 2006); it has been found in particular in in­ age­related declines in DHEA levels possibly patients with manifested suicide risk. Furthermore, reduce the effectiveness of the body’s ‘natural’ anti­ among in­patients with a recent suicide attempt, an association has been demonstrated between non­suppression of cortisol and increased scores on the Suicide Assessment Scale (Westrin 2003). High cortisol levels can be lowered by inhibiting However, attempted suicide seems to be associated steroid synthesis from cholesterol. Ketoconazole, not with HPA axis hyperactivity (Lester 1992) but metyrapone and aminoglutethimide are three rather with hypoactivity of the HPA axis (Pfennig commonly employed compounds, each of which 2005). Consequently, when evaluating the effects acts to inhibit multiple enzymes involved in of antiglucocorticoids in clinical practice and in the creation of cortisol from cholesterol. Early future research, a thorough assessment of suicide studies of their use as antidepressant therapies risk, as well as suicidal behaviour, should be taken reported promis ing results, showing successful reduction of ACTH and cortisol levels, correlated Therapeutic targets
with improvements in mood (Murphy 1997). Ketoconazole, when administered daily, reduced There is increasing evidence to suggest that the both cortisol levels and depressive symptoms consequences of HPA dysfunction described above within 72 h in an indivi dual with treatment­ are central to the pathogenesis of severe affective resistant depression (Ravaris 1988). Another study disorders and cognitive deficits (McQuade 2000). examined whether the addition of metyrapone to Modulation of the effects of hypercortisolaemia may standard serotonergic antidepressants induced a provide potential treatments for mood disorders, more rapid, efficacious and sustained treatment and such strategies are the focus of considerable response in patients with major depression (Jahn 2004). Of 63 individuals with major depression Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 and taking nefazodone or fluvoxamine, 33 were has putative antidepressant effects (Arana 1995). chosen at random also to receive metyrapone for 3 At this dose, dexamethasone does not enter the weeks of a 5­week trial. Metyrapone was reported central nervous system and consequently central to be an effective adjunct, accelerating the onset of glucocorticoid receptors are not activated (Karssen anti depressant action. Serum antidepressant levels 2005). However, glucocorticoid receptors at the did not differ between the groups, thus suggesting level of the pituitary are activated, leading to a that this acceleration was not due to a peripheral lowering of endogenous circulating cortisol. The pharmacokinetic effect. Both a better treatment brief course of dexamethasone administration in outcome and a greater antidepressive effect, these studies avoids the side­effects associated with sustained for the period of observation, were noted in the group receiving metyrapone augmentation.
Glucocorticoid receptor antagonists Glucocorticoid receptor antagonists have also been Cholesterol is the basic building block of steroid advocated as agents with potential therapeutic hormones, and although they do not act directly properties for mood disorders. This is based on hormones, cholesterol synthesis inhibitors on the ability of the glucocorticoid receptor (‘statins’) have been studied as potential means of antagonist to block any detrimental effect of reducing available adrenal steroids. It is of note hypercortisolaemia and on the theoretical ability that statins have been reported to be associated of an antagonist to up­regulate its receptor. with an increased incidence of behavioural and Admini stration of a glucocorticoid receptor ant­ personality disorders that may be hormonally agonist results in an acute antiglucocorticoid effect, while presumably causing a compensatory The use of atorvastatin and lovastatin has been up­regulation of glucocorticoid receptor numbers, linked to an increase in dopamine and homo­ leading to enhanced negative feedback on the HPA vanillic acid (HVA) levels (Ormiston 2004), but axis after the antagonist has been discontinued. no significant effect has yet been shown on steroid Initial clinical studies using the antagonist RU­486 hormones or serotonin. Moreover, lowering of (mifepristone) have shown some positive results, cholesterol may actually be attributed to an but some clinical efficacy may have been masked by increase in depressive symptoms. In a study of 20 the prolonged administration of the drug (Murphy patients with hypercholesterolaemia treated with a 1993). Animal studies suggest that glucocorticoid variety of drugs, cholesterol was effectively reduced receptor numbers are increased rapidly (within whereas the number of depressive symptoms hours) after the administration of RU­486, which significantly increased, although remaining at may restore normal feedback, thus ‘resetting’ the subclinical levels in all participants (Delva 1996).
HPA axis. Such data suggest that a brief period of treatment with the antagonist may be adequate for Corticotropin-releasing hormone antagonists RU­486 has been evaluated both as augmentation Oversecretion of CRH, resulting in hypercor­ and as monotherapy in the treatment of psychotic tisolaemia, may be normalised by acute blockade major depression. In a group of in­patients with of CRH receptors in the pituitary by means of the disorder, an open­design, open­label study compounds such as antalarmin and astressin, the invol ving acute augmentation (7 days) of current withdrawal of which causes an increased signal in medications with 600 or 1200 mg RU­486 daily the normal HPA feedback loop. These drugs are produced significant reductions in scores on the still in preclinical stages but preliminary results Brief Psychiatric Rating Scale and in measures suggest that these CRH antagonists indeed have of depressive symptoms compared with baseline, clinical potential (Broadbear 2004; French 2007). although patients who received only 50 mg RU­486 Other drug development programmes are targeting daily showed little or no benefit (Belanoff 2002). central CRH receptors that are further from the Similar findings were replicated in a study in which HPA axis. We await the results of ongoing clinical a group of patients taking neither conventional antidepressant nor antipsychotic medications received 7 days of RU­486 treatment for psychotic Activation of the glucocorticoid­receptor­mediated One of us (A.Y.) has been involved in a double­ negative­feedback mechanism that regulates cortisol blind cross­over pilot study of RU­486 for treatment­ levels is another strategy for reducing circulating resistant bipolar disorder (Young AH 2004). After cortisol levels. The synthetic glucocorticoid baseline data were collected, the 20 participants dexamethasone given at doses of 3–4 mg for 4 days received either placebo or 600 mg/day RU­486 for Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 7 days, followed by 14 days of wash­out, at which References
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Source: http://www.neuroscience.ubc.ca/CourseMat/McIsaace_Westrin_Young.pdf