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Psychological Medicine, 2001, 31, 1331–1345.
DOI : 10.1017\S0033291701004664 Printed in the United Kingdom The neuroendocrinology of chronic fatigue syndrome and A. J. R. P A R K E R , S. W E S S E L Y  A. J. CLEARE" From the Department of Psychological Medicine, Guys, Kings and St ThomasSchool of Medicine and the Institute of Psychiatry, London ABSTRACT
Background.
Disturbance of the HPA axis may be important in the pathophysiology of chronic fatigue syndrome (CFS) and fibromyalgia. Symptoms may be due to : (1) low circulating cortisol ;(2) disturbance of central neurotransmitters ; or (3) disturbance of the relationship between cortisoland central neurotransmitter function. Accumulating evidence of the complex relationship betweencortisol and 5-HT function, make some form of hypothesis (3) most likely. We review themethodology and results of studies of the HPA and other neuroendocrine axes in CFS.
Medline, Embase and Psychlit were searched using the Cochrane Collaboration strategy.
A search was also performed on the King’s College CFS database, which includes over 3000relevant references, and a citation analysis was run on the key paper (Demitrack et al. 1991).
Results.
One-third of the studies reporting baseline cortisol found it to be significantly low, usually in one-third of patients. Methodological differences may account for some of the varying results.
More consistent is the finding of reduced HPA function, and enhanced 5-HT function onneuroendocrine challenge tests. The opioid system, and arginine vasopressin (AVP) may also beabnormal, though the growth hormone (GH) axis appears to be intact, in CFS.
Conclusions.
The significance of these changes, remains unclear. We have little understanding of how neuroendocrine changes relate to the experience of symptoms, and it is unclear whether thesechanges are primary, or secondary to behavioural changes in sleep or exercise. Longitudinal studiesof populations at risk for CFS will help to resolve these issues.
heated debate between sufferers, doctors and the INTRODUCTION
media (Wessely et al. 1998). While psychiatrists Chronic fatigue syndrome (CFS) is defined as have been keen to emphasize its close relation to medically unexplained, disabling fatigue of 6 psychiatric disorders – depression is present in months or more duration, often accompanied about 50 % (David, 199l) – sufferers often main- by several of a long list of physical complaints tain that their fatigue has a solely physical cause, (Fukuda et al. 1994 ; Sharpe et al. 1991). It is perhaps viral. Epstein–Barr virus has been relatively common, with a prevalence of around shown to be a risk factor for CFS (White et al.
0n5% in primary care (Wessely et al. 1998) and 1998), though epidemiological studies suggest poor spontaneous recovery at 18 months follow- that viruses can not account for the majority of up (Vercoulen et al. 1996). Discussion of its cases (Horwitz et al. 1985 ; Holmes et al. 1987 ; nature and causes has initiated occasionally Buchwald et al. 1987). Findings from immuno-logical studies have also been non-specific and " Address for correspondence: Dr A. J. Cleare, Section of inconsistent (Wessely et al. 1998).
Neurobiology of Mood Disorders, Academic Department of Psychological Medicine, GKT School of Medicine and Institute ofPsychiatry, 103, Denmark Hill, London SE5 8AF.
nature of CFS is the hypothalamic–pituitary– adrenal axis (HPA). Interest led from observa- tions that conditions of low circulating cortisol are characterized by debilitating fatigue, forexample in Addison’s disease, and following bilateral adrenalectomy (Riordain et al. 1994).
These conditions also share other symptoms with CFS, such as arthralgias, myalgias andsleep and mood disorder (Baxter & Tyrell, 1981). It has therefore been suggested that thefatigue of CFS is mediated by low circulating levels of cortisol. This hypothesis has gainedcredence in the last decade or so, though a glance at history shows that it is not in fact new.
From 1902 to 1925 the term hypoadrenia or ‘ a bit of Addison’s disease ’ held sway as thediagnosis of the time for such symptoms, thoughwithout firm scientific grounding (Tattersall,1999).
Recent interest in cortisol and the HPA axis in CFS has applied greater scrutiny to the hy-potheses. Poteliakhoff was the first to dem- onstrate significantly lower baseline cortisol in F. 1. The hypothalamic–pituitary–adrenal axis. (GR, Glucocorti- patients with chronic fatigue, compared to coid ; MR, mineralcorticoid ; CRH, corticotrophin releasing hor- controls (Poteliakhoff, 1981). However, since mone ; AVP, arginine vasopressin ; ACTH, adrenocorticotrophic then, attempts to replicate and extend Poteli- akhoff’s findings have been far from straight-forward. This review examines the current interactions are complex and not yet fully evidence for neuroendocrine disturbance in CFS, understood, though hippocampal 5-HT" re- highlighting the methodological problems that ceptors are thought to be of central importance have hampered consistency, but also led to and are involved in controlling CRH release greater appreciation of the complexity of the from the hypothalamus (Lesch et al. 1990). 5- neuroendocrine\behavioural interplay.
HT system modulation of the HPA probablyextends beyond the hippocampus, as 5-HT isalso thought to stimulate ACTH release at OVERVIEW OF THE HPA
hypothalamic and pituitary levels. In turn, The HPA axis is the primary endocrine stress circulating cortisol, regulates central 5-HT sys- axis in man. Secretion of cortisol from the tem activity, as well as directly inhibiting the adrenal cortex is regulated by a complex system release of CRH and ACTH (Dinan, 1996). In of long and short feedback loops. Corticotrophin depression, both 5-HT system down-regulation releasing hormone (CRH) and arginine vaso- pressin (AVP), released by the hypothalamus act prominent neuroendocrine hypotheses over the synergistically to regulate the output of adreno- last decade. Advances in the understanding of corticotrophic hormone (ACTH) from the an- the relationship between these two systems allow terior pituitary. In the systemic circulation a preliminary synthesis with implications for the ACTH acts at the adrenal cortex stimulating the treatment of depression (McAllister-Williams & release of cortisol, which has a negative feedback effect at hypothalamic and pituitary levels,decreasing the output of CRH, AVP and ACTH.
centrally via the hippocampus, partly through Medline, Embase and Psychlit were searched reciprocal interactions with the 5-HT (serotonin) using the Cochrane Collaboration search strat- system (Chaouloff, 1993). The HPA – 5-HT egy for CFS (available from authors), linked to a key word search for relevant neuroendocrine ACTH, cortisol responses were significantly lower than controls, suggesting an overall CRH, synacthen, neuroendocrine, neuroendo- reduced maximal secretory capacity of the crinology, hypothalamus, pituitary, adrenal, adrenal cortex. On stimulation with ovine CRH, growth hormone, IGF), for the years 1966–1999.
subjects with CFS had significantly attenuated A second search was performed on the King’s ACTH responses, but cortisol responses were College CFS database, which has been main- similar to controls, demonstrating proportion- tained (by S. W.) since 1991 with over 3000 ately higher cortisol secretion per unit of relevant references. Finally, a citation analysis ACTH – further evidence for hypersensitivity of was run on the key relevant paper (Demitrack et the adrenal cortex to ACTH. These findings led the NIH group to suggest that the hyper-responsiveness of the adrenal cortex in subjectswith CFS was secondary to increased sensitivity SETTING THE SCENE : THE NIH
of ACTH receptors due to chronically inad- RESEARCH
equate levels of ACTH. Further, they hypothe- The most comprehensive study of the HPA axis sized that the decreased maximal cortisol re- in CFS remains that of Demitrack and colleagues at the National Institute of Health, USA – the atrophy of the adrenal cortex itself, again NIH study (Demitrack et al. 1991). They studied consequent upon chronically inadequate levels 30 CFS patients and 72 normal controls, in a complex design that included baseline measures hypocortisolism reflects a defect at or above the of cortisol, ACTH and cortisol-binding globulin level of the hypothalamus resulting in a defi- (CBG). They also evaluated the response of the ciency in CRH and\or other secretagogues that HPA axis to challenge tests, using ovine CRH serve to activate the pituitary–adrenal axis. Their evidence was inconsistent with either a primary to controls, patients with CFS showed re- adrenal insufficiency or impairment of the ductions of approximately 40 % in evening basal plasma cortisol and 24 h urinary free cortisol One finding which is not consistent with the NIH group’s interpretation, though, is the raised creased, it was concluded that basal cortisol evening ACTH – in contrast to the chronically levels were low throughout the day, and not low levels that they hypothesize. However, only in the evening as reflected in the low basal although three plasma samples were taken for plasma sample. In addition, significantly higher levels of CBG were found in CFS subjects. This evening. This is undoubtedly inadequate for a may relate to a decreased cortisol effect con- hormone with a known diurnal variation, and a sidering the evidence in rodents (Fleshner et al.
pulsatile nature of release (Pincus et al. 1999).
1995 ; Spencer et al. 1996) and in humans The radio-immune assay employed is also likely (Schlecte & Hamilton 1987 ; Gala & Westphal, to be less reliable than more recently developed l966), for a negative feedback of circulating assays for ACTH (Kertesz et al. 1998).
glucocorticoids on CBG levels. Also significantly raised in CFS subjects were basal levels of major hypotheses in need of further study. First, ACTH, suggesting that the cortisol deficiency that in CFS, the experience of fatigue is mediated was not secondary to under-functioning pitu- by inadequate levels of circulating cortisol, and a reduced ability to mount an adequate cortisol On challenge with ACTH, cortisol responses response to stress. This remains an appealing were proportional to the dose of ACTH in all hypothesis considering the clinical correlation subjects. However, at low doses of ACTH, only with medical conditions of low circulating CFS subjects showed cortisol rises above pla- cortisol. How the lack of cortisol exerts this cebo, suggesting a hypersensitivity of the adrenal effect warrants further study – is it centrally, cortex to ACTH compared with controls. This peripherally, or a combination of both? The would be incompatible with a primary adrenal second hypothesis is that the fatigue is centrally insufficiency. In contrast, at higher doses of mediated, not by low cortisol itself, but by reduced CRH or other mediators controlling the Salivary cortisol is arguably a better way to HPA axis. Although central neurohormones\ measure baseline cortisol, since as well as being neurotransmitters cannot be measured directly non-invasive, it is thought to provide a more in humans, indirect evidence suggests that these accurate and valid measure of biologically active central mediators have an important part to free cortisol than plasma or serum (Kirschbaum & Hellhammer, 1994). If low levels of cortisolwere to mediate the symptoms of CFS it wouldbe the free, unbound fraction that is important.
STUDIES OF BASAL HPA AXIS
However, while Strickland et al. (1998) found FUNCTION
significantly reduced cortisol from two morning The strength of the first hypothesis has been saliva samples, Wood et al. (1998), who took tested by several studies that measured basal 16 samples throughout the day, found signifi- cortisol in patients with CFS. These are sum- cantly raised baseline cortisol, and Young et al.
marized in Table 1. Despite the early finding of (1998) found no significant difference. Aside low basal cortisol by Poteliakhoff (1981) and the from the differences in the number and timing NIH group (Demitrack et al. 1991), the majority of saliva samples, characteristics of the study of further studies have failed to replicate this.
samples may help to explain the inconsistent Differences in methodology, and sample charac- teristics may explain the variety of results.
Methodology
Sample confounds
Three basic methods of measuring baseline One important confound is co-morbid depress- cortisol have been employed : plasma, urine – ive illness, present in approximately 50 % of 24 h urinary free cortisol (UFC) excretion – and CFS patients. High circulating cortisol is a well saliva. The majority of studies finding no replicated finding in major depression (Dinan, significant difference in baseline cortisol in 1994) and so presence of depression makes the patients with CFS used plasma samples (Bearn cortisol findings more difficul to interpret.
et al. 1995 ; Yatham et al. 1995 ; Dinan et al.
Indeed, the subjects studied by Wood et al.
1997 ; Scott et al. 1998 a, b, c). Plasma samples (1998) included five out of 10 subjects with high entail intravenous cannulation in a hospital Beck Depression Inventory scores (15–19). This setting, both of which may induce a stress may explain their unique finding of significantly response, and a subsequent rise in circulating raised baseline cortisol in their sample of CFS cortisol. In addition, plasma samples measure patients. Other studies have been inconsistent in more than just the biologically active free cortisol their exclusion of co-morbid psychiatric illness, (Kirschbaum & Hellhammer, 1994). Three and several do not even report data (see Table 1). Length of illness is another potential con- measured UFC – a non-invasive method. The founding factor, not always reported on (Table Bart’s group (Scott & Dinan, 1998) and the 1). The original study by the NIH group used King’s group (Cleare et al. 2001 a) replicated the subjects with a particularly long illness (mean finding of low basal cortisol, but Young et al.
7n2 years). Some groups who failed to replicate (1998) found no significant difference. However, their finding used subjects with considerably despite the wide usage of UFC in depression shorter illness duration (Wood et al. 1998 ; research (Murphy, 1968 ; Stokes et al. 1984), a Young et al. 1998). Few studies report on controlled study of different cortisol measures severity of the fatigue or disability, and there is found it to be an unreliable indicator of HPA reason to suggest that some behavioural conse- activity (Thompson et al. 1992). Also, since quences of fatigue may themselves cause the free cortisol only represents 2–3 % of the cir- shift in adrenocortical functioning observed by culating cortisol metabolites (Raven & Taylor, the NIH group (Demitrack et al. 1991). For 1996), a shift in the balance of cortisol metabolic example Leese et al. (1996) found that short- pathways could potentially affect the measured UFC even in the presence of no change in total changes observed in patients with CFS. They conclude that the changes observed in CFS may Summary of baseline studies of cortisol CDC, Centers for Disease Control definition (Fukuda et al. 1994) ; NS l not significant ; Oxford, Oxford definition (Sharpe et al. 1991) ; be secondary to disrupted sleep and social thermore, several authors have noted (Sharpe et routine, and thus an epiphenomenon in terms of al. 1996) that basal values may not be the most appropriate measure to determine HPA axis Thus, the significance of basal cortisol levels dysfunction, which leads us to consider the in mediating fatigue is still not clarified. Fur- by the Munich group (Heuser et al. 1994). This CHALLENGE STUDIES
test is well validated and has been demonstrated CRH challenge
to be of superior sensitivity compared to the Measuring the response of the HPA axis to challenge – pharmacological, physiological or 80 % v. 44 % ) for detecting HPA changes in psychological, is arguably a better way to depression (Deuschle et al. 1998).
investigate HPA dysfunction, since the HPA’srole is a dynamic one, in response to stress. The ACTH challenge
first pharmacological challenge test in CFS was by the NIH group, reported earlier. The Bart’s suggested that there is up-regulation of ACTH group (Scott et al. 1998 a) has recently repeated receptors in the adrenal cortex of patients with the CRH stimulation part of the NIH study, this CFS (Demitrack et al. 1991). Further evidence time in a sample of CFS patients without co- for this comes from the Bart’s group (Scott et al.
morbid psychiatric disorder. They too found 1998 b) who measured cortisol responses to a attenuated ACTH responses to exogenous ovine low dose ACTH challenge test (1 µg). They demonstrated an inverse relationship between basal levels of ACTH, and on that evidence the baseline cortisol and the incremental cortisol ruled out underfunctioning pituitary cortico- rise in response to ACTH, again suggesting trophs being responsible for the poor ACTH hypersensitivity of the adrenal cortex to ACTH in CFS subjects with impaired HPA activity.
normal in the Bart’s sample, and they suggest They also found significantly attenuated cortisol desensitization of CRH receptors on the pitu- responses overall, which they interpret as re- itary corticotrophs as a possible explanation.
flecting a diminished adrenocortical reserve Such an explanation would not be consistent with the theory of decreased hypothalamic CRH, ACTH, in line with the NIH group’s interpret- since then up-regulation of CRH receptors ation of their data. The results from both groups would predict adrenal cortical atrophy, and a responses to exogenous CRH. To reconcile these recent study from the Bart’s group has found contrasting theories, the Bart’s group suggest preliminary evidence for this in a group of eight that CFS is a stress-related disorder. They CFS subjects, using computerized tomography hypothesize first, that initial stress may cause an (Scott et al. 1999 a). However, since subjects elevation in CRH with consequent down-regu- were chosen specifically to have a blunted cortisol response to ACTH, the authors admit corticotrophs. Secondly, they hypothesize that that this may not generalize to all CFS subjects ; this down-regulation may fail to normalize indeed, it is possible that normals selected for following reduction in CRH levels. This would low cortisol responses would also show smaller be an example of abnormal plasticity in the CRH receptor which could be investigated by Recent work from the King’s group attempted studying pituitary–adrenal activation by CRH, to replicate the results of low dose ACTH during and following recovery from CFS. This challenge in 20 non-depressed, medication-free would also provide evidence on whether the CFS subjects. The authors found no difference HPA axis abnormalities are a state- or trait- in cortisol response in comparison to a matched dependent phenomenon (Scott et al. 1998 a).
control group, though in males there was a trend What might give rise to such abnormal func- towards a blunted response (Hudson & Cleare, tioning of the CRH receptor is far from clear.
The differing basal levels of ACTH between thetwo groups may also be due to the inherent 5-HT agonist challenge (see Table 2)
difficulties of measuring this pulsatile hormone, In the pathophysiology of depression, the re- lationship between the hypercortisolaemia and A further challenge test, which may help to 5-HT may be important (Cleare et al. 1996 ; clarify the state of the HPA in CFS, is the Dinan, 1996 ; McAllister-Williams & Young, combined dexamethasone\CRH test pioneered 1998). Glucocorticoids have been demonstrated Summary of studies of 5-HT agonist challenge changes in dopamine function, ratherthan 5-HT CFS, may explain fatigue or besecondary to behavioural changes CDC, Centers for Disease Control definition (Fukuda et al. 1994) ; PVFS, Post-viral fatigue syndrome ; Oxford, Oxford definition (Sharpe et al. 1991).
to exert an inhibitory effect on central 5-HT for increased 5-HT function in CFS, it also neurotransmitter function (De Kloet et al. 1986 ; suggests that HPA and 5-HT function may be McAllister-Williams et al. 1998), while on the pathologically altered in opposite directions in other hand, stress-induced CRH secretion is the two conditions. The King’s group also note modulated by 5-HT (Delbende et al. 1992 ; that in depression, the neurochemical changes Dinan, 1996). Accumulating evidence, from the are associated with insomnia, anorexia and use of 5-HT agonists, now suggests that 5-HT agitation, whereas the opposite chemical changes neurotransmission may be altered in CFS. 5-HT in CFS are associated with the reverse of these pathways from the dorsal raphe nuclei to the paraventricular nucleus of the hypothalamus are While some have replicated the finding of thought to bring about the secretion of hypotha- enhanced prolactin response to -fenfluramine lamic–pituitary releasing peptides involved in (Sharpe et al. 1997), others have not (Bearn et al.
the release of prolactin and ACTH from the 1995 ; Yatham et al. 1995). Methodological anterior pituitary (Checkley, 1980). Therefore, measuring serial prolactin and cortisol responses inconsistencies. Bearn et al.’s sample had poor to 5-HT agonist drugs are thought to reflect age and gender matching, and Yatham et al.’s hypothalamic-5-HT neurotransmitter function.
subjects had a heterogeneous psychiatric history.
Several different 5-HT agonists have been Also, Yatham et al. used ,-fenfluramine used. Bakheit et al. (1992) measured the prolactin instead of -fenfluramine. The former includes response to the 5-HT" receptor agonist bus- both stereoisomers and has less specific neuro- pirone, and found it to be significantly raised in chemical effects, including additional catechol- CFS subjects compared with controls, suggesting up-regulation of post-synaptic 5-HT" receptors Further evidence for disturbed functioning of in the hypothalamus. However, buspirone also the 5-HT and HPA axis relationship comes from binds to dopamine D2 receptors, and so its a study by the Bart’s group (Dinan et al. 1997), ability to increase prolactin may be mediated in who used ipsapirone – a partial agonist of 5- part by D2 receptor blockade (Meltzer et al.
HT" receptors, like buspirone, but without 1991 ; Maskall et al. 1995). Sharpe et al. (1996) action at dopamine receptors. They were testing tested this by measuring growth hormone re- the hypothesis that in CFS, abnormalities of sponses in addition to prolactin, since it is HPA function arise from disturbance in sero- known that GH release is much more likely to tonergic (5-HT) inputs. In healthy controls be mediated via 5-HT" receptors (Cowen, 1993). ACTH and cortisol rise in a dose-dependent While prolactin was significantly increased in fashion on stimulation with ipsapirone, though CFS subjects, GH was not, suggesting that the in CFS patients they found significantly attenu- enhanced prolactin response may be due to abnormalities in dopamine neurotransmission, responses. This finding could be interpreted as evidence of decreased responsivity of 5-HT"A receptors at the hypothalamic level. However, selective 5-HT-releasing agent -fenfluramine.
other interpretations such as either decreased The King’s group (Cleare et al. 1995) measured responsivity of CRH receptors on the pituitary prolactin and cortisol responses to -fenflura- corticotrophs, or underactivity of the pituitary corticotrophs are possible which do not necess- healthy controls, and patients with major de- arily invoke abnormalities of the 5-HT system.
pression. Relative to controls, prolactin respon- As noted earlier, the Bart’s group (Scott et al.
ses were significantly higher in CFS patients, 1998 a) have already suggested decreased re- and significantly lower in those with major de- sponsivity of CRH receptors on the pituitary pression. In addition, prolactin responses were corticotroph to explain the attenuated ACTH found to be inversely proportional to the baseline response to exogenous CRH stimulation, found cortisol. Thus, CFS patients had low baseline cortisol and enhanced prolactin response to - although the Bart’s group found significantly fenfluramine, and depressed subjects the con- attenuated 5-HT" mediated ACTH responses verse. Not only does this study provide evidence to ipsapirone, the site of abnormality (5-HT"A receptor, CRH receptor or pituitary cortico- Indeed, Conti et al. (1998) have found decreased β-endorphin levels in patients with CFS. Further investigation of the opioid system is now probes used in CFS are perfect. As well as the indicated, including measures of the other problems of selectivity for the 5-HT system and endogenous opioids, and investigation of the its many receptor subtypes, most studies do not endogenous opioid receptor ligands. Future measure plasma levels of the probes or take into studies should include objective measures of account active metabolites. These problems physical activity, since activity levels may affect could potentially account for the inconsistencies opioid tone (Inder et al. 1995).
in the 5-HT challenge tests reported in CFS.
Argenine vasopressin
Naloxone challenge
Another hormone exerting control over the Several other neurotransmitters are also being HPA is argenine vasopressin (AVP), which acts implicated in CFS, such as the opioidergic system, which unlike the stimulatory 5-HT release (Lamberts et al. 1984 ; Antoni, 1993).
system, exerts a predominantly inhibitory influ- Therefore a deficit in endogenous AVP could ence upon the HPA axis in man (Taylor et al.
contribute towards the attenuated ACTH re- 1983). The Bart’s group (Scott et al. 1998 c) put sponse seen with exogenous CRH stimulation.
forward the hypothesis that the documented Indeed, Bakheit et al. (1993) found basal levels down regulation of the HPA axis in CFS may be of AVP to be significantly reduced in response to secondary to increased opioidergic tone. They water deprivation challenge in CFS patients.
stimulated CFS patients and controls with the The Bart’s group (Scott et al. 1999 b) found that opiate receptor antagonist, naloxone. In healthy desmopressin, a vasopressin analogue, was able subjects naloxone will decrease central opio- to normalize the blunted ACTH response to idergic tone, thereby releasing the HPA axis from inhibitory control, and causing a rise in hypothesized that this was due to upregulated ACTH and cortisol. They found that in CFS AVP receptors on the pituitary, again consistent patients compared to controls there was an attenuated ACTH response to naloxone. Theyconclude that this effectively rules out increased CIRCADIAN RHYTHMS
opioidergic tone as a cogent explanation for theabnormal HPA function in CFS – the opposite In contrast to the many studies observing finding to that which they predicted. However, neuroendocrine function at one time point, there their conclusion may be inaccurate due to the have been relatively few studies of diurnal difficulty of interpreting challenge tests using a variation, or circadian rhythm. MacHale et al.
receptor antagonist as the probe. The outcome (1998) demonstrated a significantly attenuated will depend upon receptor affinities of the probe diurnal variation of serum cortisol in CFS, compared with endogenous opioids, and relative though the absolute concentrations at each time changes in receptor occupancies. The balance of point were not significantly different compared these factors may theoretically determine quite to controls. However, the relevance of diurnal different outcomes from the naloxone challenge.
variation is highlighted by their additional This issue warrants further detailed study.
observation of a significant relationship between If however, the Bart’s group is correct in their the degree of diurnal variation in cortisol and interpretation of decreased opioidergic tone in measures of functional improvement over the CFS, then it is interesting considering that pain past year and current social functioning. Loss of prone individuals have been found to have lower diurnal variation in cortisol has previously been than normal concentrations of opiates in the demonstrated in fibromyalgia, pain syndromes CSF (Terenius & Wahlstrom, 1978). Thus, the and depressive illness (Lascelles et al. 1974 ; Bart’s group suggest that a reduction in en- Carroll et al. 1976 ; McCain & Tilbe, 1989), all dogenous opioid tone may explain the common of which have significant symptom overlap with pain symptoms which CFS patients experience, CFS. Supporting McHale et al. (1998), a such as myalgia, arthralgia and headaches.
significant decrease in the early morning surge dopoulos et al. 1997), although other studies directions. The HPA-stress axis and the growth have found no significant difference in the hormone (GH) axis do interact with one another, circadian rhythm of cortisol (Raciatti et al.
as demonstrated, for example, by blunted growth 1998 ; Wood et al. 1998 ; Young et al. 1998).
following prolonged stress in childhood. How-ever, a different observation led to the first GHstudy in fibromyalgia. In 1975 Moldofsky et al.
FIBROMYALGIA
demonstrated a distinct disturbance of stage-4, Fibromyalgia is a condition characterized by non-REM sleep in patients with fibromyalgia, widespread muscle pain, fatigue and sleep characterized by alpha-wave intrusion into the disturbances. Most authors agree that the delta rhythm. They also induced a transient symptomatology of fibromyalgia overlaps with syndrome similar to fibromyalgia by depriving CFS, and some now believe that it is essentially healthy subjects of this stage of sleep. Stage-4 the same condition (Wessely et al. 1999). Of sleep is closely related to the pulsatile secretion particular interest are the findings from neuro- of GH, and approximately 80 % of the total endocrine studies, which on some, but not all, daily production of GH is secreted during this parameters show remarkable similarities to those stage. GH regulates the hepatic production and in CFS. At least two groups have demonstrated release of somatomedin C (IGF-1) which is an reduced 24 h urinary free-cortisol in patients important mediator of muscle homeostasis and with fibromyalgia (McCain & Tilbe, 1989 ; repair, a deficiency of which would predispose to Crofford et al. 1994). Furthermore, in response muscle microtrauma and pain. This led Bennett to exhaustive physical exercise, Van Denderen et et al. (1992) to hypothesize that disruption of al. (1992) reported reduced adrenocortical ac- stage-4 sleep in fibromyalgia would lead to low tivation, and in response to exogenous CRH, levels of IGF-1, and indeed their study confirmed Griep et al. (1993) demonstrated a blunted cortisol response. In contrast to CFS, both Crofford et al. (1994) and Griep et al. (1993, have been demonstrated in CFS by two groups 1998) found exaggerated ACTH responses to (Allain et al. 1997 ; Berwaerts et al. 1998), CRH stimulation. The reason for this divergence although not by another (Bennett et al. 1997).
is not clear, though Demitrack (1997) suggests The study by Allain et al. (1997) also demon- that a clue may come from AVP levels. Whereas strated a reduced GH response to insulin- induced hypoglycaemia, though Berwaerts et al.
(Bakheit et al. 1993), in fibromyalgia they were (1998) failed to repeat this. In an attempt to found to be high compared to controls, in clear away the confusion from inconsistent response to postural challenge. Since AVP acts results, the King’s group (Cleare et al. 2000) carried out the largest and most comprehensive difference in AVP levels would be consistent study of the GH axis to date in patients with with the differences demonstrated in ACTH CFS closely matched to healthy controls. They failed to find any significant differences in either Thus, comparison of CFS with fibromyalgia baseline or challenge tests of GH function, and highlights both similarities and differences in concluded that there is no evidence for GH neuroendocrinology. It may be that the dif- deficiency in CFS patients free from co-morbid ferences reflect distinct pathophysiologies for the two syndromes. However, the similarities,both in reduced HPA activation, symptoma-tology and abrupt stress-related onset suggest TREATMENT STUDIES
Several treatment studies have attempted toreverse the symptoms of CFS and fibromyalgia GROWTH HORMONE, CFS AND
by artificially replacing hormones thought to be FIBROMYALGIA
deficient in these conditions. Such studies serve The rationale for studying growth hormone in the dual purposes of : (1) testing new logical therapeutic strategies ; and (2) further testing the in dietary salt intake. The aim had been to hypothesis that symptoms are due to disordered suppress the supposed reflex underlying neurally mediated hypotension by increasing blood vol- In fibromyalgia, Bennett and colleagues fol- lowed up their earlier finding of low somato- However, two further trials, this time using medin C (IGF-1) levels in 30 % of patients, by hydrocortisone, were able to show significant conducting a randomized, double-blind, con- improvements in patients with CFS. McKenzie trolled trial of growth hormone replacement et al. (1998) used a dosing regime chosen to (Bennett et al. 1998). They included only those approximate the normal diurnal variation in patients who had low levels of the growth cortisol (20–30 mg at 8 a.m., and 5 mg at 2 p.m., medin C). Daily subcutaneous GH injections significant benefit on a global health scale, resulted in a prompt and sustained increase in though not on other scales. The cost of this mild IGF-1 levels, and at 9 months, a significant improvement was significant adrenal suppres- overall improvement in symptomatology and sion in 12 out of 33 patients, which led the number of tender points. The authors conclude authors to advise against the use of hydro- that although the high cost-benefit ratio pre- cortisone in clinical practice. The King’s group cludes its therapeutic use in fibromyalgia (Cleare et al. 1999) also reported a randomized, patients, the study provides further support for controlled trial of hydrocortisone in CFS.
the theory that a secondary growth hormone deficiency is responsible for some of their 5–10 mg, which are consistent with replacement of the reduction in cortisol output of between Moorkens et al. (1998) carried out a similar, 30–40 % in CFS, reported in some studies though smaller, randomized controlled trial of (Demitrack et al. 1991 ; Scott & Dinan, 1998). In contrast to McKenzie et al. study, no significant selected patients with a demonstrated deficiency adrenal suppression was seen, and there were no of GH, though their results were less marked.
other serious adverse effects. There was a There was no improvement in quality of life, clinically significant fall in fatigue scores in 34 % after 12 months, although 4 out of 17 patients on active treatment, compared with 13 % on were able to return to work after prolonged sick placebo, and this benefit declined rapidly on leave. The lack of any clear benefit in patients crossover to placebo treatment. In those whose with CFS is perhaps not surprising following the fatigue improved, physical role limitations were extensive study of the GH axis by the King’s also significantly improved, as were mean dis- group (Cleare et al. 2000), noted above.
ability scores. Although pre-treatment endocrine Of interest to the hypothesis of low circulating disturbance did not predict response to hy- glucocorticoids as the mediator of symptoms in drocortisone, those that did respond showed CFS, are three recent randomized controlled normalization of the cortisol response to CRH trials of steroid replacement therapy. The first challenge, whereas non-responders did not was by Peterson et al. (1998), who used low- (Cleare, 2001 b). Overall, this lends support to doses (0n1–0n2 mg) of the mineralocorticoid the suggestion that HPA axis disturbance may fludrocortisone. They found no improvement on be one reversible factor contributing to fatigue any symptom or test of function, over 6 weeks, in CFS. Despite this, the authors warn against between active drug and placebo groups. Their simple acceptance that normalization of the rationale for treating with fludrocortisone was HPA axis is a direct effect of hydrocortisone, as unconnected with the neuroendocrine hypoth- clinical improvement leads to a complex of eses presented here. Their study followed the changes in sleep, exercise, mood and circadian demonstration by Bou-Holaigh et al. (1995) that rhythms (above, and Cleare, 2001 b). Clearly, CFS is associated with neurally mediated hy- further evaluation is needed of hydrocortisone potension. Bou-Holaigh et al. also noted in an as a possible treatment in some patients with uncontrolled study, that some CFS patients CFS, and further study of the HPA axis in those responding to non-pharmacological treatments treatment with fludrocortisone and an increase such as graded exercise or cognitive–behavioural therapy, both of which are effective in CFS SUMMARY AND CONCLUSIONS
Anti-depressants have also been tried in the treatment of CFS – the rationale being the 1991 suggested three related theories for the overlap in symptoms between depressed, and mediation of symptoms in CFS (Demitrack et chronic fatigue patients, and the suggestion that al. 1991). First, that the fatigue is due directly to CFS may be a variant form of depression.
low circulating cortisol ; secondly that it is due to However, the neuroendocrine studies of the abnormalities of central neurotransmitters in- HPA axis reviewed above, demonstrate marked volved in HPA axis function (e.g. CRH) ; and differences between the two conditions, suggest- thirdly that symptoms are a result of a more ing different pathophysiologies (Cleare et al.
complex disturbance of the relationship between 1995 ; Scott & Dinan, 1998 ; Strickland et al.
the two. Support for all three hypotheses has 1998). In further support of distinct pathologies, been found, though it has been problematical is the randomized controlled trial of fluoxetine providing consistent evidence, and attempts to in CFS reported by Vercoulen et al. (1996). On make causal attributions require caution on the a range of measures, including subjective fatigue, available evidence. On balance, there does depression, well-being, functional impairment appear to be down-regulation of the HPA axis and activity, they found no beneficial effect for in at least some patients with CFS, and that this fluoxetine. Even those CFS patients with co- is most apparent on challenge tests, rather than morbid depression showed no improvement in measures of baseline function. This would mood, suggesting that dysphoria in CFS may concur with patients’ reports of symptoms have a different basis to that in primary major worsening following physical or emotional stress depression. Three further trials using mono- amine oxidase inhibitors (MAOIs) to treat CFS In keeping with the first hypothesis, reduced have been carried out. Natelson et al. (1996) circulating cortisol may also explain the modest, used a low-dose of the non-specific MAOI, non-specific activation of immune responses phenelzine, in a double-blind, randomized con- reported in CFS (Wessely et al. 1998), since trolled trial. They found a very small, though glucocorticoids usually dampen immune acti- statistically significant improvement, which was vation. Several studies have supported the role independent of any anti-depressant effect. They followed this up with a single-blind, placebo (Bakheit et al. 1992 ; Demitrack et al. 1992 ; phase-in trial of the specific MAO B receptor Cleare et al. 1995 ; Sharpe et al. 1996, 1997). In inhibitor selegiline (Natelson et al. 1998), again particular, a deficiency of hypothalamically finding a small, but significant benefit, in the derived CRH is an attractive hypothesis con- absence of any anti-depressant effect. The most sidering that central administration of this recent study found the strongest effect seen to neurohormone to animals produces marked be- date, comparing 450–600 mg of moclobemide havioural and locomotor activation (Britton et to placebo over 6 weeks (Hickie et al. 2000).
al. 1982 ; Sutton et al. 1982 ; Swerdlow et al.
Significant subjective global improvement was 1986). The possibility of the third, complex, but reported in 24\47 patients on active treatment vaguer hypothesis serves to illustrate our current (51 %) compared to 14\43 on placebo (33 %).
ignorance of how any such chemical changes There was a significant and progressive improve- may translate into subjective symptoms.
ment in ratings of ‘ vigour ’, though the re- duction in disability over the short treatment dysregulated in CFS, it is far from clear how the period was not significantly greater than that two relate causally. Leese et al. (1996) provided seen with placebo. Interestingly, improvement evidence that the HPA changes may be sec- was seen equally in those with and without co- ondary to behavioural change, whilst the King’s morbid depression, while the largest response group (Cleare et al. 2001 b) have demonstrated sizes were seen in a subgroup with immuno- that symptomatic improvement is associated logical changes. Once again, these studies suggest with a reversal of the endocrine changes. Down- a rather different pattern of antidepressant regulation of the HPA axis is still weak as an response to that seen in classical depression.
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History of Psychiatric Education in Singapore—EH Kua 137C History of Psychiatric Education in Singapore Abstract Psychiatry was largely a forgotten discipline in the first 75 years of the medical school. In the last 2 decades, there has been steady progress in the extension of teaching time and clinical postings. The focus of psychiatric education has shifted from the mental institut

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Deirdre Gallagher has been a practicing trial attorney for seventeen years, representing companies in complex litigation in both Missouri and Illinois. She has tried over 30 cases to verdict in various state and federal courts. Although Ms. Gallagher’s practice encompasses the defense of class actions, mass torts, and toxic exposure

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