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Antiglucocorticoids in Psychiatry† Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 † ARTICLE Antiglucocorticoids in psychiatry Sean A. McIsaac, Åsa Westrin & Allan H. Young Sean McIsaac studied for his endocrine tissue: the hypothalamus, pituitary and SUmmary Bachelor degree in biology at the adrenal cortices are its major components. The University of British Columbia, Significant evidence has accrued suggesting that HPA axis is regulated by external inputs from a Vancouver, Canada, where he is the hypothalamic–pituitary–adrenal (HPA) axis plays number of brain regions, including the amygdala, currently a research assistant at a role in some psychiatric disorders. This article the Institute of Mental Health. He hippocampus and nuclei within the midbrain. In reviews the physiology of the HPA axis, evidence of worked for the Wellington Lab, addition, the HPA axis also contains a number of focusing on the interplay of lipid dysfunction in this axis in psychiatric illnesses and transporters in Alzheimer’s disease. the role that this dysfunction might play in pharma- autoregulatory mechanisms. The paraventricular His present work, with Professor cological treatment resistance. Future therapeutic nucleus of the hypothalamus secretes the peptides Allan Young, follows his interest in strategies that may potentially arise from these corticotropin­releasing hormone (CRH) and the impact of endocrine dysfunction researches are briefly outlined. arginine vasopressin (AVP) into the microportal in psychiatric disorders. Åsa circulatory system of the pituitary stalk. These Westrin is a research psychiatrist DeclaratiON OF INTEREST in the Department of Clinical A.Y. holds related grants from the Stanley Medical peptides have a synergistic effect on the release Neuroscience at Lund University, Research Institute and the Medical Research Coun- of adrenocorticotropic hormone (ACTH) from the Sweden. Her main research interest anterior lobe of the pituitary. Cortisol, a gluco ­ involves stress-system alterations in cil (UK) and has filed a provisional patent concerning depression and suicidal behaviour. the use of antiglucocorticoids as an adjunctive to corticoid released from the adrenal cortex in Allan Young currently holds the antidepressant therapies. response to ACTH, has a plethora of central and LEEF Endowed Chair in Research peripheral effects which are mediated primarily via in the Department of Psychiatry at the University of British Columbia, glucocorticoid receptors of types I and II. Under Many of the current drug treatments in psy chiatry Vancouver, Canada, where he is normal homeostatic conditions, type I recep tors also the Director of the Institute were discovered without any knowledge of the are mostly saturated, owing to their high affinity of Mental Health. His research under lying ‘disease processes’ concerned. Theories for cortisol and other gluco corticoids, and type II interests focus on the causes and of the mechanism of drug action were all devel oped treatments for severe psychiatric glucocorticoid receptors are the more sensitive to illnesses, particularly mood post hoc and are predominantly concerned with stressor­dependant changes within the axis. It is by disorders. mono­­­amine 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, Young, Institute of Mental Health, means and rates of full remission are frequently University of British Columbia, 5950 hypothalamus and pituitary. Under normal University Blvd, Vancouver, BC, quite low. Current diagnostic categorisation of conditions, diurnal variation in cortisol levels is V6T 2A1, Canada. Email: alyoung@ psychiatric disorders, such as unipolar depression, seen. In humans, this begins with markedly elevated interchange.ubc.ca 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, †For a commentary on this article development should be predicated on knowledge presenting as a characteristic curve when con cen­ see pp. 250–252, this issue. 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– in cortisol levels (Dinan 2005). 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 of action. 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 with a number of severe mood disorders. 242 Advances in psychiatric treatment (2009), vol. 15, 242–249 doi: 10.1192/apt.bp.105.001834 Antiglucocorticoids in psychiatry 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 in euthymia (Watson 2004). 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 der (Young EA 2004a). (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 (Dinan 2005; Watson 2006). considering these putative pathophysiological (Key points 1.) processes it is important to note that there appears Supplementing the dexamethasone suppression to be complex regulatory interaction
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