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HPA axis function in mood disorders
Pathophysiological basis of mood disorders
HPA axis function in mood disorders
The hypothalamic–pituitary–adrenal (HPA) axis Hippocampus GR/MR
Stuart Watson
Stress
GR PVN
Paul Mackin
CRH AVP –ve
GR Pituitary
Abstract Our understanding of the neurobiology of mood disorders is advanc ing rapidly. Despite the initial enthusiasm for the monoamine theory of depression, it has been unable to explain the complex actions of antidepressant drugs or to provide a comprehensive explanation of the pathophysiology of the manifold biological, cognitive, and psychological symptoms of mood disorders. In recent years, attention has turned to models of mood disorders that focus on adaptations to stress. Con siderable experimental and clinical evidence supports a role for hypo thalamic–pituitary–adrenal (HPA) axis dysfunction in the pathogenesis of major depression and bipolar disorders.
ACTH
–ve
Adrenals –ve
GR/MR-mediated negative feedback
Cortisol GRs/MRs
GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PVN, paraventricular nucleus; AVP, arginine vasopressin; CRH, corticotrophinreleasing hormone; ACTH, adrenocorticotrophic hormone.
Keywords bipolar disorder; chronic fatigue syndrome; corticotrophin; cortisol; depression; hypothalamic–pituitary–adrenal axis; neuropsycho logical; vasopressin
Figure 1
coordination of circadian events, such as the sleep/wake cycle and food intake; facilitation of our ability to cope with, adapt to, and recover from stress; and promotion of learning and memory processes. The effects of cortisol are mediated by at least two intracellular, specialized steroid receptor family subtypes: the high-affinity, type I, mineralocorticoid receptor (MR) and the low-affinity, type II, glucocorticoid receptor (GR). Cortisol readily diffuses through the cellular membrane and binds to these receptors, promoting their translocation to the nucleus. Once 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 in the paraventricular nucleus receive neuronal inputs from many regions including the amygdala, the hippocampus, and the nuclei of the midbrain. The HPA axis also has an autoregulatory mechanism mediated by cortisol binding to GRs in the HPA axis and hippocampus. This autoregulation is crucial to the mainten ance of the intrinsic homeostasis of the HPA axis. Allostasis refers to the process of maintaining stability through change and it may be that mood disorders are associated with an allostatic change with an alteration of the homeostatic set point that is brought about by genetic vulnerability, early life adversity, and/ or chronic stress.
HPA axis anatomy and physiology The hypothalamic–pituitary–adrenal (HPA) axis is a multifaceted regulatory system that integrates neuronal and endocrine function. It comprises the tissues of the hypothalamus, pituitary, and adrenal cortex, and the associated regulatory inputs, releasing factors, and hormones (Figure 1). In brief, the neurosecretory cells of the paraventricular nucleus (PVN) of the hypothalamus secrete corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. These secretagogues induce the release of adrenocorticotrophic hormone (ACTH) from the anterior lobe of the pituitary into the systemic circulation. ACTH in turn promotes the release of the glucocorticoid cortisol from the adrenal cortex. Cortisol, in some respects the final product of the HPA axis, has a wide range of central and peripheral effects, which include:
Stuart Watson MBBS MD MRCPsych is Consultant in General Adult Psychiatry and Honorary Senior Lecturer at the University of Newcastle, UK. His research interests are in the neuro-endocrinology and treatment of severe psychiatric disorders. Conflicts of interest: none declared. Paul Mackin MBBS PhD MRCPsych is a Department of Health Clinician Scientist based at the University of Newcastle, UK. He qualified in Medicine at the University of Newcastle, after gaining his PhD in diabetology. His research interests include the neurobiology of mood disorders, and metabolic disease in severe mental illness. Conflicts of interest: none declared.
PSYCHIATRY 8:3
Circadian rhythm
HPA axis abnormalities in mood disorders The CRH hypothesis:1 the relationship between major depressive disorder and hypercortisolaemia was first described more than 50 years ago. More recent studies show that average cortisol levels are higher in depression and that a quarter of depressed 97
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
of high circulating glucocorticoid levels during chronic stress. There is increasing evidence that a similar process is seen in mood disorder.
patients can be considered to be hypercortisolaemic. Numerous parameters of HPA axis function have been investigated in order to elucidate the pathophysiology of the HPA axis in depression. CRH overdrive may have a central role: CRH-expressing neurons are increased in the hypothalamus of patients with mood disorder; administration of CRH produces anxiety- and depressionlike effects in laboratory animals; and cerebrospinal fluid (CSF) levels of CRH have been shown to be increased in depression. The blunted ACTH response to CRH in people with depression may be explained by homeostatic down-regulation as a result of chronically increased CRH secretion.
Dehydroepiandrosterone (DHEA), like cortisol, is an adrenal steroid, cleaved from pregnenolone. It is part of the synthesis pathway for oestrogen and testosterone, and exists in both a free and a sulphated (DHEA-S) form. DHEA is neuroprotective and modulates corticosteroid-induced cell death. An increased cortisol/DHEA ratio is seen in adults and adolescents with depression, and appears to be an indicator of poor prognosis. Patients with Addison’s disease (see below) fail to produce adrenal steroids, including cortisol and DHEA; adding DHEA to existing steroid replacement has been shown to improve self-esteem and to reduce fatigue.
The GR hypothesis: hypersecretion of CRH may be secondary to impaired feedback mechanisms resulting from reduced number or function of GRs, a view supported by the demonstration of GR abnormalities in post-mortem studies of patients with severe mood disorders and from the recent report that mice with an acquired forebrain-specific disruption of GR develop a number of abnormalities that mimic major depressive disorder, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis, and increased depression-like behaviour. Interestingly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant imipramine.2 Neuro-endocrine tests such as the dexamethasone (dex) suppression test (DST) and its newer variant, the dex/CRH test reliably differentiate patients from controls. These tests measure the ability of the axis to suppress in the face of a synthetic steroid, a process reliant on the functional integrity of GR (Figure 2).
Bipolar affective disorder3 The HPA axis has been less well studied in bipolar disorder than in major depressive disorder; however, both manic and depressed bipolar patients appear to have similar HPA axis dysregulation to that described in major depressive disorder. Interestingly, abnormalities are also seen in bipolar patients who are in remission, suggesting that HPA axis dysregulation is a trait abnormality in bipolar disorder. Chronic fatigue syndrome Chronic fatigue syndrome (CFS) is associated with low cortisol levels, a flattened cortisol rhythm, and adrenal hypoplasia. In CFS, AVP appears to play a relatively greater regulatory role than CRH. Cortisol levels show a return towards normality with successful treatment using cognitive behavioural therapy. Patients with post-traumatic stress disorder also have low baseline cortisol levels.
AVP: raised AVP concentrations and up-regulated AVP receptors may overcome the suppressant effect of dexamethasone and result in a non-suppressed response, even with intact GRs. In animals exposed to chronic stress, the expression of AVP in CRH-secreting neurons of the PVN increases, AVP becomes the predominant regulator of ACTH secretion, and the V1b receptor, which mediates the pituitary action of AVP, up-regulates, suggesting that vasopressinergic regulation of the HPA axis is critical for sustaining corticotroph responsiveness in the presence
Medical conditions characterized by dysfunctional HPA axis Cushing’s disease, in which ACTH and hence cortisol are increased, is associated with depression in 70% of cases.
The glucocorticoid receptor theory of mood disorders
Reduced GR expression Increased CRH synthesis Increased levels of ACTH
Reduced sensitivity in dex suppression test
Possible changes in NA and 5-HT neurotransmission
Central effects of CRH/down-regulation of CRH R
Increased levels of cortisol
Neuropsychological/cognitive effects
Desensitization of 5HT1A receptor function
Blunted HPA and prolactin responses to 5-HT stimulation
GR, glucocorticoid receptor; NA, noradrenaline; 5-HT, serotonin; CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotrophic hormone.
Figure 2
PSYCHIATRY 8:3
98
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
in depression. A number of strands of evidence converge to suggest a pathophysiological role for reduced transmission through postsynaptic 5-HT1A receptors. The HPA axis and the serotonin system are intimately linked. The finding that patients with hypercortisolaemia have a relatively reduced response to antidepressants may be explained by the report that fluoxetine fails to increase forebrain 5-HT levels in rats who have been administered exogenous glucocorticoids.
Although antidepressants offer some benefit, control of cortisol levels appears to be the most effective treatment. Addison’s disease, in which cortisol synthesis is defective, is also associated with raised rates of psychiatric disorder, which improve on successful steroid replacement. Other chronic medical diseases, such as multiple sclerosis, are also associated with both raised cortisol levels and high rates of psychopathology.
Dopamine: pre-clinical studies have shown that corticosteroids increase dopamine neurotransmission. This mechanism has been hypothesized to be of pathophysiological importance in mania, psychotic depression, and substance misuse.
Psychiatric effects of corticosteroid treatment Glucocorticoid therapy is associated with a range of psycho pathology, including: • depression • euphoria • mood lability • cognitive impairment • psychosis.
Neurogenesis Throughout adult life, new neurons continue to be made in areas of the brain including the hippocampus and olfactory bulb. Corticosteroids have an important role in mediating this neurogenesis and survival of new cells. Although difficult to study in humans, it has been hypothesized that reduced neurogenesis is a causative factor in depression6 and that the therapeutic effect of antidepressants is mediated by an enhancement of new cell production and survival, perhaps via effects on the HPA axis. Animal studies have shown that stress (resulting in activation of the HPA axis), as well as exogenous corticosteroid administration, results in down-regulation of brain-derived neurotrophic factor (BDNF), a neurotrophin that has an important role in cell survival and differentiation. Recent human studies have reported reduced serum BDNF expression in major depressive disorder, and a return to normal levels following successful treatment with antidepressant drugs. Thus, BDNF, through its interaction with the HPA axis, may have an important role in the pathophysiology of mood disorders.
Origin of HPA axis dysfunction in psychiatric patients Early life adversity: it has been argued that the increased risk of developing mood and anxiety disorders in adulthood that is consequent on childhood abuse and neglect and parental loss may be mediated by persistent alterations in HPA axis regulation. Laboratory studies have provided evidence that early-life stressors, including maternal separation in rats or adverse rearing conditions in non-human primates, produce long-lived hyper activity of CRH neuronal systems as well as greater reactivity of the HPA axis to stress in adulthood with associated deficits on tasks of learning and memory. It has been demonstrated that nondepressed women with a history of childhood physical or sexual abuse have an abnormal HPA axis that is characterized by an enhanced ACTH response to both a social stress test and to CRH challenge.4 Stimulation of the HPA axis of pregnant rats has also been shown to result in offspring with a hyperactive HPA axis.
Neuropsychological impairment Corticosteroids are essential for neuropsychological performance. Mineralocorticoid receptors appear to promote reactivity in novel situations, whereas GRs are involved in consolidation of learned information. It may therefore seem paradoxical that disorders (such as Cushing’s disease and severe mood disorders) and experimental conditions in which levels of endogenous or exogenous corticosteroids are increased either acutely or chronically are associated with a significant degree of cognitive impairment. It appears that the effects of corticosteroids on cognition can become maladaptive when the activity of the two types of receptor becomes either persistently imbalanced or out of context with the situation (Figure 3).7 Corticosteroids can also cause cognitive impairment by inducing hippocampal neuronal atrophy and cell death. 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. Thus, in bipolar disorder, although cognitive deficits do show some improvement on remission of affective symptoms (paralleling the normalization of 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.
Genetics: the heritability of severe mood disorders is high; for example, in bipolar disorder it is in the region of 80%. The complex inheritance of mood disorders and the failure of multiple genome-wide scans to detect major gene effects suggest that susceptibility loci for mood disorders probably have small to moderate effects. That the familial association of depression may be mediated via the HPA axis is suggested both by the Munich vulnerability study5 (which has demonstrated that apparently healthy people with a family history of mood disorders have a dysregulated HPA axis), and by findings that HPA axis dysregulation is present in healthy adolescents before they become depressed. However, the heritability of mood disorders has not yet been convincingly shown to be mediated by specific genes acting on the HPA axis.
Impact of HPA disturbance Monoamine systems 5-HT1A: since the 1960s, it has been believed that disorders of the serotonin system have aetiological and therapeutic importance
PSYCHIATRY 8:3
99
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
High MR:GR ratio
Optimal MR:GR ratio
Cortisol levels in depressed patients and controls
Low MR:GR ratio
21
Plasma cortisol (µg/dl)
Cognitive function
18
Controls Depressed patients
15
12
9
6
3
0
Cortisol level
10 12 14 16 18 20 22
GR, glucocorticoid receptor; MR, mineralocorticoid receptor
2
4
6
8
10 12 14 16 18
Day 2
Time (hours)
Figure 3 Figure 4
Sleep and prognosis The degree of HPA axis dysregulation in depression predicts both sleep disturbance and the persistence of the HPA axis dysregulation. These findings provide further support for the hypothesis that HPA axis dysfunction is central to the pathophysiology of major depressive disorder and that it is an important therapeutic target.
shown to augment the efficacy of antidepressant treatment in a randomized controlled trial of 63 patients with major depressive disorder.12 A trial involving almost 150 patients showed that a GR antagonist is as effective as a selective serotonin-reuptake inhibitor (SSRI) in depression, and a second GR antagonist was found to be efficacious in the treatment of psychotic depression and bipolar disorder. Preliminary data suggest that DHEA improves mood symptoms and cognitive impairment in depression, and daily administration of a low morning dose of hydrocortisone appears to improve the symptoms of CFS. A recent Cochrane Review reported that antiglucocorticoid agents appear to have efficacy in non-psychotic major depression, but there were insufficient studies to draw any conclusions about the clinical efficacy of these agents in the treatment of bipolar disorder.13 Thus, exploring the relationship between dysregulation of the HPA axis and mood disorders has improved our understanding of depression and bipolar disorder, and has suggested a number of potential novel treatment strategies. ◆
Rhythm Cortisol is secreted in a diurnal pattern as well as in response to physical and psychological stressors. Patients with mood disorders have a flattened cortisol rhythm with an increased nadir (trough) (Figure 4).8 This abnormal rhythm can be expected to alter the activation of corticosteroid receptors. Flattening the cortisol rhythm in laboratory rats has been shown to reduce 5-HT1A neurotransmission – an effect that may promote depression. The biochemical, cognitive, or mood effects of the flattened cortisol rhythm have not yet been examined in humans; however, modulation of the cortisol rhythm of depressed patients may have effects on mood and cognition, and thus may represent a novel therapeutic approach.
Treatment
References 1 Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477–501. 2 Boyle MP, Brewer JA, Funatsu M, et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc Natl Acad Sci USA 2005; 102: 473–78. 3 Daban C, Vieta E, Mackin P, Young AH. Hypothalamic–pituitary– adrenal axis and bipolar disorder. Psychiatr Clin North Am 2005; 28: 469–80. 4 Heim C, Nemeroff CB. Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 2002; 7: 147–59. 5 Lauer C, Schreiber W, Modell S, Holsboer F, Krieg J. The Munich vulnerability study on affective disorders: overview of the crosssectional observations at index investigation. J Psychiatr Res 1998; 32: 393–401.
Successful treatment of depression is associated with a normalization of the HPA axis. The notion that antidepressants exert their therapeutic effect via the HPA axis is gaining increasing credence. Preclinical data suggest that this may be by normalization of dysfunctional GRs, possibly by an action on steroid transporter proteins. The HPA axis is also a target for the development of novel approaches to the treatment of psychiatric disorders.9 An antag onist at one of the two CRH receptor subtypes (CRH-R1) has been shown to have antidepressant and anxiolytic properties in a phase III trial,10 although a trial with an alternative agent was declared futile and terminated after the interim analysis revealed efficacy of the antidepressant control, but not of the CRH antagonist.11 AVP antagonists are anxiolytic in rodent studies and 3 weeks of treatment with the cortisol synthesis inhibitor metyrapone was
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Day 1
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© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34: 171–81. 11 Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 2008; 165: 617–20. 12 Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K. Metyrapone as additive treatment in major depression: a doubleblind and placebo-controlled trial. Arch Gen Psychiatry 2004; 61: 1235–44. 13 Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev 2008; (1)CD005168.
6 Sapolsky RM. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry 2004; 56: 137–39. 7 de Kloet ER, Oitzl MS, Joels M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999; 22: 422–26. 8 Wong ML, Kling MA, Munson PJ, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropinreleasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–30. 9 Reus VI, Wolkowitz OM. Antiglucocorticoid drugs in the treatment of depression. Expert Opin Investig Drugs 2001; 10: 1789–96. 10 Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919
PSYCHIATRY 8:3
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© 2008 Elsevier Ltd. All rights reserved.
HPA axis function in mood disorders
The hypothalamic–pituitary–adrenal (HPA) axis Hippocampus GR/MR
Stuart Watson
Stress
GR PVN
Paul Mackin
CRH AVP –ve
GR Pituitary
Abstract Our understanding of the neurobiology of mood disorders is advanc ing rapidly. Despite the initial enthusiasm for the monoamine theory of depression, it has been unable to explain the complex actions of antidepressant drugs or to provide a comprehensive explanation of the pathophysiology of the manifold biological, cognitive, and psychological symptoms of mood disorders. In recent years, attention has turned to models of mood disorders that focus on adaptations to stress. Con siderable experimental and clinical evidence supports a role for hypo thalamic–pituitary–adrenal (HPA) axis dysfunction in the pathogenesis of major depression and bipolar disorders.
ACTH
–ve
Adrenals –ve
GR/MR-mediated negative feedback
Cortisol GRs/MRs
GR, glucocorticoid receptor; MR, mineralocorticoid receptor; PVN, paraventricular nucleus; AVP, arginine vasopressin; CRH, corticotrophinreleasing hormone; ACTH, adrenocorticotrophic hormone.
Keywords bipolar disorder; chronic fatigue syndrome; corticotrophin; cortisol; depression; hypothalamic–pituitary–adrenal axis; neuropsycho logical; vasopressin
Figure 1
coordination of circadian events, such as the sleep/wake cycle and food intake; facilitation of our ability to cope with, adapt to, and recover from stress; and promotion of learning and memory processes. The effects of cortisol are mediated by at least two intracellular, specialized steroid receptor family subtypes: the high-affinity, type I, mineralocorticoid receptor (MR) and the low-affinity, type II, glucocorticoid receptor (GR). Cortisol readily diffuses through the cellular membrane and binds to these receptors, promoting their translocation to the nucleus. Once 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 in the paraventricular nucleus receive neuronal inputs from many regions including the amygdala, the hippocampus, and the nuclei of the midbrain. The HPA axis also has an autoregulatory mechanism mediated by cortisol binding to GRs in the HPA axis and hippocampus. This autoregulation is crucial to the mainten ance of the intrinsic homeostasis of the HPA axis. Allostasis refers to the process of maintaining stability through change and it may be that mood disorders are associated with an allostatic change with an alteration of the homeostatic set point that is brought about by genetic vulnerability, early life adversity, and/ or chronic stress.
HPA axis anatomy and physiology The hypothalamic–pituitary–adrenal (HPA) axis is a multifaceted regulatory system that integrates neuronal and endocrine function. It comprises the tissues of the hypothalamus, pituitary, and adrenal cortex, and the associated regulatory inputs, releasing factors, and hormones (Figure 1). In brief, the neurosecretory cells of the paraventricular nucleus (PVN) of the hypothalamus secrete corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) into the microportal circulatory system of the pituitary stalk. These secretagogues induce the release of adrenocorticotrophic hormone (ACTH) from the anterior lobe of the pituitary into the systemic circulation. ACTH in turn promotes the release of the glucocorticoid cortisol from the adrenal cortex. Cortisol, in some respects the final product of the HPA axis, has a wide range of central and peripheral effects, which include:
Stuart Watson MBBS MD MRCPsych is Consultant in General Adult Psychiatry and Honorary Senior Lecturer at the University of Newcastle, UK. His research interests are in the neuro-endocrinology and treatment of severe psychiatric disorders. Conflicts of interest: none declared. Paul Mackin MBBS PhD MRCPsych is a Department of Health Clinician Scientist based at the University of Newcastle, UK. He qualified in Medicine at the University of Newcastle, after gaining his PhD in diabetology. His research interests include the neurobiology of mood disorders, and metabolic disease in severe mental illness. Conflicts of interest: none declared.
PSYCHIATRY 8:3
Circadian rhythm
HPA axis abnormalities in mood disorders The CRH hypothesis:1 the relationship between major depressive disorder and hypercortisolaemia was first described more than 50 years ago. More recent studies show that average cortisol levels are higher in depression and that a quarter of depressed 97
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
of high circulating glucocorticoid levels during chronic stress. There is increasing evidence that a similar process is seen in mood disorder.
patients can be considered to be hypercortisolaemic. Numerous parameters of HPA axis function have been investigated in order to elucidate the pathophysiology of the HPA axis in depression. CRH overdrive may have a central role: CRH-expressing neurons are increased in the hypothalamus of patients with mood disorder; administration of CRH produces anxiety- and depressionlike effects in laboratory animals; and cerebrospinal fluid (CSF) levels of CRH have been shown to be increased in depression. The blunted ACTH response to CRH in people with depression may be explained by homeostatic down-regulation as a result of chronically increased CRH secretion.
Dehydroepiandrosterone (DHEA), like cortisol, is an adrenal steroid, cleaved from pregnenolone. It is part of the synthesis pathway for oestrogen and testosterone, and exists in both a free and a sulphated (DHEA-S) form. DHEA is neuroprotective and modulates corticosteroid-induced cell death. An increased cortisol/DHEA ratio is seen in adults and adolescents with depression, and appears to be an indicator of poor prognosis. Patients with Addison’s disease (see below) fail to produce adrenal steroids, including cortisol and DHEA; adding DHEA to existing steroid replacement has been shown to improve self-esteem and to reduce fatigue.
The GR hypothesis: hypersecretion of CRH may be secondary to impaired feedback mechanisms resulting from reduced number or function of GRs, a view supported by the demonstration of GR abnormalities in post-mortem studies of patients with severe mood disorders and from the recent report that mice with an acquired forebrain-specific disruption of GR develop a number of abnormalities that mimic major depressive disorder, including hyperactivity of the HPA axis, impaired negative feedback regulation of the HPA axis, and increased depression-like behaviour. Interestingly, a number of these abnormalities are normalized by chronic treatment with the tricyclic antidepressant imipramine.2 Neuro-endocrine tests such as the dexamethasone (dex) suppression test (DST) and its newer variant, the dex/CRH test reliably differentiate patients from controls. These tests measure the ability of the axis to suppress in the face of a synthetic steroid, a process reliant on the functional integrity of GR (Figure 2).
Bipolar affective disorder3 The HPA axis has been less well studied in bipolar disorder than in major depressive disorder; however, both manic and depressed bipolar patients appear to have similar HPA axis dysregulation to that described in major depressive disorder. Interestingly, abnormalities are also seen in bipolar patients who are in remission, suggesting that HPA axis dysregulation is a trait abnormality in bipolar disorder. Chronic fatigue syndrome Chronic fatigue syndrome (CFS) is associated with low cortisol levels, a flattened cortisol rhythm, and adrenal hypoplasia. In CFS, AVP appears to play a relatively greater regulatory role than CRH. Cortisol levels show a return towards normality with successful treatment using cognitive behavioural therapy. Patients with post-traumatic stress disorder also have low baseline cortisol levels.
AVP: raised AVP concentrations and up-regulated AVP receptors may overcome the suppressant effect of dexamethasone and result in a non-suppressed response, even with intact GRs. In animals exposed to chronic stress, the expression of AVP in CRH-secreting neurons of the PVN increases, AVP becomes the predominant regulator of ACTH secretion, and the V1b receptor, which mediates the pituitary action of AVP, up-regulates, suggesting that vasopressinergic regulation of the HPA axis is critical for sustaining corticotroph responsiveness in the presence
Medical conditions characterized by dysfunctional HPA axis Cushing’s disease, in which ACTH and hence cortisol are increased, is associated with depression in 70% of cases.
The glucocorticoid receptor theory of mood disorders
Reduced GR expression Increased CRH synthesis Increased levels of ACTH
Reduced sensitivity in dex suppression test
Possible changes in NA and 5-HT neurotransmission
Central effects of CRH/down-regulation of CRH R
Increased levels of cortisol
Neuropsychological/cognitive effects
Desensitization of 5HT1A receptor function
Blunted HPA and prolactin responses to 5-HT stimulation
GR, glucocorticoid receptor; NA, noradrenaline; 5-HT, serotonin; CRH, corticotrophin-releasing hormone; ACTH, adrenocorticotrophic hormone.
Figure 2
PSYCHIATRY 8:3
98
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
in depression. A number of strands of evidence converge to suggest a pathophysiological role for reduced transmission through postsynaptic 5-HT1A receptors. The HPA axis and the serotonin system are intimately linked. The finding that patients with hypercortisolaemia have a relatively reduced response to antidepressants may be explained by the report that fluoxetine fails to increase forebrain 5-HT levels in rats who have been administered exogenous glucocorticoids.
Although antidepressants offer some benefit, control of cortisol levels appears to be the most effective treatment. Addison’s disease, in which cortisol synthesis is defective, is also associated with raised rates of psychiatric disorder, which improve on successful steroid replacement. Other chronic medical diseases, such as multiple sclerosis, are also associated with both raised cortisol levels and high rates of psychopathology.
Dopamine: pre-clinical studies have shown that corticosteroids increase dopamine neurotransmission. This mechanism has been hypothesized to be of pathophysiological importance in mania, psychotic depression, and substance misuse.
Psychiatric effects of corticosteroid treatment Glucocorticoid therapy is associated with a range of psycho pathology, including: • depression • euphoria • mood lability • cognitive impairment • psychosis.
Neurogenesis Throughout adult life, new neurons continue to be made in areas of the brain including the hippocampus and olfactory bulb. Corticosteroids have an important role in mediating this neurogenesis and survival of new cells. Although difficult to study in humans, it has been hypothesized that reduced neurogenesis is a causative factor in depression6 and that the therapeutic effect of antidepressants is mediated by an enhancement of new cell production and survival, perhaps via effects on the HPA axis. Animal studies have shown that stress (resulting in activation of the HPA axis), as well as exogenous corticosteroid administration, results in down-regulation of brain-derived neurotrophic factor (BDNF), a neurotrophin that has an important role in cell survival and differentiation. Recent human studies have reported reduced serum BDNF expression in major depressive disorder, and a return to normal levels following successful treatment with antidepressant drugs. Thus, BDNF, through its interaction with the HPA axis, may have an important role in the pathophysiology of mood disorders.
Origin of HPA axis dysfunction in psychiatric patients Early life adversity: it has been argued that the increased risk of developing mood and anxiety disorders in adulthood that is consequent on childhood abuse and neglect and parental loss may be mediated by persistent alterations in HPA axis regulation. Laboratory studies have provided evidence that early-life stressors, including maternal separation in rats or adverse rearing conditions in non-human primates, produce long-lived hyper activity of CRH neuronal systems as well as greater reactivity of the HPA axis to stress in adulthood with associated deficits on tasks of learning and memory. It has been demonstrated that nondepressed women with a history of childhood physical or sexual abuse have an abnormal HPA axis that is characterized by an enhanced ACTH response to both a social stress test and to CRH challenge.4 Stimulation of the HPA axis of pregnant rats has also been shown to result in offspring with a hyperactive HPA axis.
Neuropsychological impairment Corticosteroids are essential for neuropsychological performance. Mineralocorticoid receptors appear to promote reactivity in novel situations, whereas GRs are involved in consolidation of learned information. It may therefore seem paradoxical that disorders (such as Cushing’s disease and severe mood disorders) and experimental conditions in which levels of endogenous or exogenous corticosteroids are increased either acutely or chronically are associated with a significant degree of cognitive impairment. It appears that the effects of corticosteroids on cognition can become maladaptive when the activity of the two types of receptor becomes either persistently imbalanced or out of context with the situation (Figure 3).7 Corticosteroids can also cause cognitive impairment by inducing hippocampal neuronal atrophy and cell death. 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. Thus, in bipolar disorder, although cognitive deficits do show some improvement on remission of affective symptoms (paralleling the normalization of 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.
Genetics: the heritability of severe mood disorders is high; for example, in bipolar disorder it is in the region of 80%. The complex inheritance of mood disorders and the failure of multiple genome-wide scans to detect major gene effects suggest that susceptibility loci for mood disorders probably have small to moderate effects. That the familial association of depression may be mediated via the HPA axis is suggested both by the Munich vulnerability study5 (which has demonstrated that apparently healthy people with a family history of mood disorders have a dysregulated HPA axis), and by findings that HPA axis dysregulation is present in healthy adolescents before they become depressed. However, the heritability of mood disorders has not yet been convincingly shown to be mediated by specific genes acting on the HPA axis.
Impact of HPA disturbance Monoamine systems 5-HT1A: since the 1960s, it has been believed that disorders of the serotonin system have aetiological and therapeutic importance
PSYCHIATRY 8:3
99
© 2008 Elsevier Ltd. All rights reserved.
Pathophysiological basis of mood disorders
High MR:GR ratio
Optimal MR:GR ratio
Cortisol levels in depressed patients and controls
Low MR:GR ratio
21
Plasma cortisol (µg/dl)
Cognitive function
18
Controls Depressed patients
15
12
9
6
3
0
Cortisol level
10 12 14 16 18 20 22
GR, glucocorticoid receptor; MR, mineralocorticoid receptor
2
4
6
8
10 12 14 16 18
Day 2
Time (hours)
Figure 3 Figure 4
Sleep and prognosis The degree of HPA axis dysregulation in depression predicts both sleep disturbance and the persistence of the HPA axis dysregulation. These findings provide further support for the hypothesis that HPA axis dysfunction is central to the pathophysiology of major depressive disorder and that it is an important therapeutic target.
shown to augment the efficacy of antidepressant treatment in a randomized controlled trial of 63 patients with major depressive disorder.12 A trial involving almost 150 patients showed that a GR antagonist is as effective as a selective serotonin-reuptake inhibitor (SSRI) in depression, and a second GR antagonist was found to be efficacious in the treatment of psychotic depression and bipolar disorder. Preliminary data suggest that DHEA improves mood symptoms and cognitive impairment in depression, and daily administration of a low morning dose of hydrocortisone appears to improve the symptoms of CFS. A recent Cochrane Review reported that antiglucocorticoid agents appear to have efficacy in non-psychotic major depression, but there were insufficient studies to draw any conclusions about the clinical efficacy of these agents in the treatment of bipolar disorder.13 Thus, exploring the relationship between dysregulation of the HPA axis and mood disorders has improved our understanding of depression and bipolar disorder, and has suggested a number of potential novel treatment strategies. ◆
Rhythm Cortisol is secreted in a diurnal pattern as well as in response to physical and psychological stressors. Patients with mood disorders have a flattened cortisol rhythm with an increased nadir (trough) (Figure 4).8 This abnormal rhythm can be expected to alter the activation of corticosteroid receptors. Flattening the cortisol rhythm in laboratory rats has been shown to reduce 5-HT1A neurotransmission – an effect that may promote depression. The biochemical, cognitive, or mood effects of the flattened cortisol rhythm have not yet been examined in humans; however, modulation of the cortisol rhythm of depressed patients may have effects on mood and cognition, and thus may represent a novel therapeutic approach.
Treatment
References 1 Holsboer F. The corticosteroid receptor hypothesis of depression. Neuropsychopharmacology 2000; 23: 477–501. 2 Boyle MP, Brewer JA, Funatsu M, et al. Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior. Proc Natl Acad Sci USA 2005; 102: 473–78. 3 Daban C, Vieta E, Mackin P, Young AH. Hypothalamic–pituitary– adrenal axis and bipolar disorder. Psychiatr Clin North Am 2005; 28: 469–80. 4 Heim C, Nemeroff CB. Neurobiology of early life stress: clinical studies. Semin Clin Neuropsychiatry 2002; 7: 147–59. 5 Lauer C, Schreiber W, Modell S, Holsboer F, Krieg J. The Munich vulnerability study on affective disorders: overview of the crosssectional observations at index investigation. J Psychiatr Res 1998; 32: 393–401.
Successful treatment of depression is associated with a normalization of the HPA axis. The notion that antidepressants exert their therapeutic effect via the HPA axis is gaining increasing credence. Preclinical data suggest that this may be by normalization of dysfunctional GRs, possibly by an action on steroid transporter proteins. The HPA axis is also a target for the development of novel approaches to the treatment of psychiatric disorders.9 An antag onist at one of the two CRH receptor subtypes (CRH-R1) has been shown to have antidepressant and anxiolytic properties in a phase III trial,10 although a trial with an alternative agent was declared futile and terminated after the interim analysis revealed efficacy of the antidepressant control, but not of the CRH antagonist.11 AVP antagonists are anxiolytic in rodent studies and 3 weeks of treatment with the cortisol synthesis inhibitor metyrapone was
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in major depression: the first 20 patients treated. J Psychiatr Res 2000; 34: 171–81. 11 Binneman B, Feltner D, Kolluri S, Shi Y, Qiu R, Stiger T. A 6-week randomized, placebo-controlled trial of CP-316,311 (a selective CRH1 antagonist) in the treatment of major depression. Am J Psychiatry 2008; 165: 617–20. 12 Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A, Wiedemann K. Metyrapone as additive treatment in major depression: a doubleblind and placebo-controlled trial. Arch Gen Psychiatry 2004; 61: 1235–44. 13 Gallagher P, Malik N, Newham J, Young AH, Ferrier IN, Mackin P. Antiglucocorticoid treatments for mood disorders. Cochrane Database Syst Rev 2008; (1)CD005168.
6 Sapolsky RM. Is impaired neurogenesis relevant to the affective symptoms of depression? Biol Psychiatry 2004; 56: 137–39. 7 de Kloet ER, Oitzl MS, Joels M. Stress and cognition: are corticosteroids good or bad guys? Trends Neurosci 1999; 22: 422–26. 8 Wong ML, Kling MA, Munson PJ, et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropinreleasing hormone. Proc Natl Acad Sci USA 2000; 97: 325–30. 9 Reus VI, Wolkowitz OM. Antiglucocorticoid drugs in the treatment of depression. Expert Opin Investig Drugs 2001; 10: 1789–96. 10 Zobel AW, Nickel T, Kunzel HE, et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919
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