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Hyperactivity in the hypothalamic-pituitary-adrenal axis in demented patients with delirium

Robertsson, B.; Blennow, K.; Bråne, G.; Edman, Å.; Karlsson, I.; Wallin, A.; Gottfries, C. G.

International Clinical Psychopharmacology: January 2001 - Volume 16 - Issue 1 - p 39-47
Research Papers
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Occurrence of delirium is known to be related to, among other things, organic brain disorder, somatic disease and old age. It has been hypothesized that delirium is also associated with stress. Disturbances of the hypothalamic-pituitary-adrenal (HPA) system have been found in delirious patients in various studies. The aim of the present study was to determine the activity in the HPA axis in demented patients to ascertain whether the stress regulating system was more disturbed in patients with delirium than in those without delirium. Demented inpatients with no acute medical illness were included in the study. Basal cortisol levels in serum were measured and dexamethasone suppression test (DST) was performed. The most important finding of the study was a strong relationship between delirium and DST pathology irrespective of age and severity of dementia. It is suggested that certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.

Department of Psychiatry and Neurochemistry, Institute of Clinical Neuroscience, Sahlgrenska Universitetssjukhuset/Mölndal, Mölndal, Sweden

Correspondence to Barbro Robertsson, Department of Psychiatry and Neurochemistry, Institute of Clinical Neuroscience, Sahlgrenska Universitetssjukhuset/Mölndal, S-431 80 Mölndal, Sweden Tel: +46 31 343 23 87; fax: +46 31 776 90 55; e-mail: barbro.robertsson@neurovet.gu.se

Received 26 November 1999; accepted 24 July 2000

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INTRODUCTION

Delirium or confusion (WHO, 1992; APA, 1994) with symptoms of attentional disorder and fluctuating cognitive impairment is one of the most common mental disorders among the elderly, with old age and organic brain disorder such as dementia being major risk factors (Hodkinson, 1973; Erkinjuntti et al., 1986; Rockwood et al., 1989; Francis et al., 1990; Schor et al., 1992). It is well known that trauma or conditions causing increased stress such as loss of a close relative, moving to an unfamiliar place or hospitalization may be followed by delirium in the elderly. Elderly persons seem to have a lower threshold for stress and some individuals react to severe stress with delirium.

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis which leads to increased release of cortisol. An inhibiting feedback system controls activity in the HPA axis (Keller-Wood and Dallman, 1984). It has been hypothesized that delirium is a reaction to stress and to the impact of hypercortisolism on the brain especially in individuals with an 'age-linked weakness of the stress resisting mechanism' (Kral, 1975).

Overactivity in the HPA axis as measured by the dexamethasone suppression test (DST) is often seen in depression (Carroll et al., 1976). In dementia, as well as in advanced age, the regulation of the stress system has also been found to be impaired. DST non-suppression has been reported in 7-73% of patients with dementia compared to 0-9% of controls (Raskind et al., 1982; Balldin et al., 1983; Georgotas et al., 1986; Martignoni et al., 1990; O'Brien et al., 1993; Gottfries et al., 1994). The discrepancy between the different studies is probably due to methodological differences such as inclusion or exclusion of depressed patients in the sample and different serum cortisol limits used in the identification of non-suppression. Most studies report that 40-70% of patients with vascular dementia or Alzheimer's disease are non-suppressors.

A relationship between DST pathology and severity of dementia was found in Alzheimer's disease by Jenike et al. (1984). Another study found such a relationship in male but not in female Alzheimer's disease patients (Molchan et al., 1990). Greenwald et al. (1986) found no significant relationship between dementia severity and DST pathology in Alzheimer's disease while another study found such a relationship in late onset Alzheimer's disease (LAD) and vascular dementia (Balldin et al., 1994). One study, which using the Global Deterioration Scale investigated the occurrence of non-suppression in different stages of dementia, showed that in mild and severe dementia (stages 4 and 7) 25% and 39%, respectively, of the patients were non-suppressors while in moderate dementia (stages 5 and 6) 71% and 100%, respectively, were non-suppressors (Serby et al., 1988).

Pathological DST has been found to be significantly related to advanced age in some studies (Georgotas et al., 1986; Parnetti et al., 1990; Keitner et al., 1992) while other studies have found no such relation.

Disturbances of the HPA system have also been found in several studies on delirium. Thus, patients with acute confusional state after stroke showed significantly increased activation of the HPA system compared to those without acute confusion (Olsson et al., 1992; Gustafson et al., 1993; Fassbender et al., 1994). One study found that patients developing delirium after elective surgery had an impaired stress regulating system with significantly elevated mean plasma cortisol levels compared to the preoperative baseline. In non-delirious patients, these levels were not significantly elevated (McIntosh et al., 1985). In patients developing delirium in connection with lower respiratory tract infection, 78% were found to be non-suppressors on the DST compared to 14% of the patients without delirium (O'Keeffe and Devlin, 1994).

In a previous study of a large number of demented patients with no acute medical illness, 37% were found to have delirious episodes during 2-3 weeks of hospitalization for planned neuropsychiatric evaluation (Robertsson et al., 1998). The aim of the present study was to determine activity in the HPA axis in these demented patients by measuring their basal serum cortisol levels and performing DST and to ascertain whether the stress regulating system was more disturbed in the patients with delirium than in those without delirium.

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MATERIAL AND METHODS

Patients

The present study was based on 213 under the age of 80 years who had been referred to the hospital's neuropsychiatric diagnostic unit for evaluation of suspected dementia during the period 1987-91. They had been referred by physicians in a wide range of disciplines (e.g. general practice, internal medicine, geriatrics, neurology, psychiatry). The diagnostic work-up comprised 2-3 weeks of planned hospitalization. All the patients participated in a longitudinal dementia study in which the diagnostic exclusion criteria were a history of severe psychiatric disease (e.g. schizophrenia, manic-depressive disorder), chronic alcoholism, distinct non-degenerative neurological disease (e.g. normotensive hydrocephalus, cerebral tumour, multiple sclerosis), a history of serious head injury (unconsciousness for more than 10 min), serious infections in the central nervous system, systemic disease (e.g. malignant tumours, liver disease, endocrine disorder) and exposure to toxic agents. The patients underwent a thorough clinical examination, including medical history, physical, neurological and psychiatric examinations, screening laboratory tests, lumbar puncture, electroencephalogram, electrocardiography, X-ray of the chest, computerized tomography of the brain, neuropsychological testing and rating of the behaviour.

Dementia was diagnosed according to the criteria in the third, revised edition of the Diagnostic and Statistical Manual for Mental Disorders (DSM-III-R; APA, 1987) but with the additional criterion of at least 6 months duration of dementia. The severity of dementia was evaluated according to DSM-III-R as mild, moderate or severe. Age at onset was estimated on the basis of the medical history and defined as the age at which cognitive decline was first noted by a close relative.

Alzheimer's disease was diagnosed in conformity with the criteria for 'probable Alzheimer's disease' outlined by the NINCDS-ADRDA Work Group (McKhann et al., 1984). The Alzheimer's disease patients were divided into two subgroups, early onset Alzheimer's disease (EAD) with onset before the age of 65 years and late onset Alzheimer's disease (LAD) with onset at the age of 65 years or later.

Vascular dementia (VAD) was defined as follows: dementia with (1) a clinical history of transient ischemic attacks (TIA) or stroke episodes, or (2) computed tomography scan findings of infarcts or lacunas without a clinical history of TIA or stroke episodes, or (3) the occurrence of several pronounced peripheral vascular diseases (e.g. arterial hypertension or diabetes mellitus). All the VAD patients fulfilled modified (Wallin and Blennow, 1996) NINCDS-AIREN criteria for VAD (Roman et al., 1993).

Patients with frontal lobe symptoms as the major symptomatology early in the disease and without signs of VAD or other neurological disorders were diagnosed with frontotemporal dementia (FTD) (Brun et al., 1994).

Ten percent of the patients had various secondary dementias or mixed degenerative and vascular dementia and were assigned to a diagnostic group called unspecified dementia (UNS).

Nineteen of the patients did not fulfil the DSM-III-R criteria for dementia and were diagnosed as amnestic. They were excluded from this study. Another 22 patients were excluded as either their basal cortisol or their post DST cortisol values were missing. Thus the final sample comprised 172 patients.

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METHODS

Delirium was diagnosed when the patient during the 2-3 weeks of hospitalization episodically showed clouding of consciousness or reduced clarity of awareness with attentional deficits and disorganized thinking, often accompanied by perceptual disturbances, sleep disturbances and hyperactivity. These are the symptoms required for the diagnosis of delirium according to DSM-III-R. However, in our study, it was not specified which, or how many, of the accessory symptoms had to be present. No acute medical condition was found to have triggered the delirium episodes. The pre-existing brain damage was assumed to be an organic factor aetiologically related to the delirium disturbance. Patients with acute severe confusion triggered by a known factor and with no evidence of dementia were excluded.

The behaviour of the patient was rated using the Gottfries-Bråne-Steen (GBS) scale (Gottfries et al., 1982; Bråne, 1989). In the present study, only ratings of the six symptoms of the fourth part of the scale are presented (confusion, irritability, anxiety, fear-panic, depressed mood and restlessness).

HPA function was evaluated by measuring basal cortisol levels in serum and by performing DST. The patients received 1 mg dexamethasone at 22.00 h. Venous blood samples for determination of cortisol concentrations were drawn at 08.00 h on the day of dexamethasone administration (basal cortisol level) and at 08.00 h and 15.00 h on the following day. Because of the strong relationship reported between post-DST cortisol levels measured at 08.00 h and those measured at 15.00 h (r = 0.72) (Balldin et al., 1994), only the values at 15.00 h are presented. The cut-off limit for abnormal cortisol response in the DST was the same as is generally used to establish melancholia (above 110 μmol/l) (Karlsson et al., 1988). The performing of DST was not related to the time of the occurrence of delirium.

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Statistical analysis

Data were analysed using the STATISTICA package (StatSoft, Inc., Tulsa, OK, USA). For calculation of correlations between basal serum cortisol levels and post DST cortisol levels and between age and serum cortisol levels, the Pearson's correlation coefficient was used. Correlations between serum cortisol levels and GBS scores were calculated using Spearman's correlation coefficient. Differences between groups were analysed using chi-squared for categorical variables and the t-test or the ANOVA for continuous variables.

For post-hoc comparisons of pairs of means, the least significant difference (LSD) was performed. The Kolmogorov-Smirnov test for normality was used to test the compatibility of the serum cortisol data with a normal distribution. The post-DST cortisol data were not normally distributed, but so were the log-transformed data, and these were therefore used in the ANOVA and the t-test.

Logistic regression models were used to explore the influence of putative prognostic factors on serum cortisol levels.

The study was approved by the Ethics Committee of Göteborg University.

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RESULTS

The mean age of the 172 demented patients in the sample was 69.8 ± 6.9 (SD) years. The mean basal cortisol level was 512.0 μmol/l and the mean post DST cortisol level was 141.7 μmol/l. Other characteristics of the sample are presented in Table 1.

Table 1

Table 1

The correlation between the mean basal cortisol level and the mean post-DST cortisol level was r = 0.26 (P = 0.001). Patients with pathological post-DST response had significantly higher basal cortisol levels than patients with normal post-DST response (543 μmol/l and 489 mol/l, respectively, P = 0.02).

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Cortisol levels in the various diagnostic groups

No significant differences between patients with different dementia diagnoses (EAD, LAD, FTD, VAD and UNS) were found with respect to cortisol levels (498 ± 155, 517 ± 170, 525 ± 146, 514 ± 136 and 507 ± 111 μmol/l), post-DST cortisol levels (151 ± 146, 158 ± 150, 96 ± 126, 125 ± 118 and 158 ± 97 μmol/l) or degree of non-suppression (38, 47, 28, 40 and 61%).

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Cortisol levels and severity of dementia

Significant differences in mean basal cortisol levels were found between groups of patients with different severities of dementia, with the highest levels in the moderately demented group (P = 0.02). Patients with mild dementia had significantly lower basal cortisol levels (491 ± 124 μmol/l) than patients with moderate dementia (550 ± 171 μmol/l, P = 0.04) while patients with moderate dementia had significantly higher basal cortisol levels than patients with severe dementia (455 ± 115 μmol/l, P = 0.01).

The mean post-DST cortisol levels increased with increasing severity of the dementia disorder (118 ± 122 μmol/l, 151 ± 143 μmol/l and 181 ± 134 μmol/l, respectively) (P = 0.07). The group of patients with mild dementia had a significantly lower mean post-DST cortisol level than patients with severe dementia (P = 0.03).

A significant increase in the occurrence of non-suppressors was seen with increasing severity of dementia (P = 0.04). In mild dementia (n = 71) 35%, in moderate dementia (n = 76) 42% and in severe dementia (n = 25) 64% were non-suppressors.

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Cortisol levels and age

No significant correlation was found between age and either of the basal cortisol level (r = 0.05, P = 0.48) and the post-DST cortisol level (r = 0.10, P = 0.17) in the entire group. Nor was such a correlation found in the groups of delirious or non-delirious patients.

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Cortisol levels and delirium

Significant differences were found in basal cortisol levels between groups of patients with different severity of delirium (none, mild, moderate/severe), with the highest values in the mild delirium group (483 ± 122 μmol/l, 582 ± 181 μmol/l and 499 ± 153 μmol/l, respectively) (P = 0.002). Patients without delirium (n = 105) had significantly lower basal cortisol levels than patients with mild delirium (n = 47) and these had significantly higher basal cortisol levels than patients with moderate/severe delirium (n = 20). No difference in basal cortisol levels between patients with no delirium and those with moderate/severe delirium was found.

Significant differences in post-DST cortisol levels between patients with different degrees of delirium were also found, with the highest values in the moderate/severe delirium group (113 ± 116 μmol/l, 178 ± 152 μmol/l and 206 ± 142 μmol/l) (P = 0.003). The differences between post-DST cortisol levels in patients without delirium on the one hand and in patients with mild delirium and moderate/severe delirium on the other were significant (P = 0.006 and P = 0.009, respectively).

In the total group, 42% of all patients were non-suppressors. A significant difference in the occurrence of non-suppressors was found between patients with different severity of delirium (P = 0.004). An increase in the frequency of non-suppressors with increased severity of delirium was seen: no delirium (n = 105) 33%, mild delirium (n = 47) 51% and moderate/severe delirium (n = 20) 70%, respectively (Fig. 1).

Figure 1

Figure 1

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Relation between prognostic factors and post-DST cortisol levels

The influence on the post-DST cortisol level by age, delirium, and severity of dementia was studied in a multiple forward stepwise regression model. This showed that delirium (P = 0.001) and severity of dementia (P = 0.24) explained the post-DST cortisol level (Table 2). Delirium thus significantly explained the variation in the post-DST cortisol level. Delirium and severity of dementia together explained 7% of the variation in post-DST cortisol levels.

Table 2

Table 2

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Cortisol levels and psychiatric symptoms

Significant correlations between the basal cortisol level and symptoms of confusion, irritability, anxiety and restlessness as measured by the GBS scale were found in the group as a whole (Table 3).

Table 3

Table 3

Significant correlations were found between the post-DST cortisol level and symptoms of confusion, irritability and restlessness (Table 3). However, within the different diagnostic groups the correlations do not reach significance except for those between the basal cortisol level and irritability in the LAD group and the basal cortisol level and confusion in the FTD group. Significant correlations between the post-DST cortisol level and depressed mood was found only in the FTD group (r = 0.65, P = 0.004). If the FTD group is removed from the analysis, symptoms of confusion, irritability and restlessness correlate significantly with the mean post-DST cortisol level of the rest of the patients.

Multiple regression (stepwise forward) analysis of the influence of psychiatric symptoms on post DST cortisol levels showed that symptoms of confusion, fear-panic and restlessness exerted an influence (Table 4). Taken together, they explain 10% of the variance in the post-DST cortisol level. The influence of confusion is significant. (P = 0.02) while the influence of the other symptoms is not (P = 0.14 and P = 0.17, respectively).

Table 4

Table 4

Logistic regression analysis was performed to investigate the possible influence of the post-DST cortisol level, age and severity of dementia on the rate of delirium. The analysis showed that age, the post-DST cortisol level and severity of dementia all significantly and independently predicted delirium. Taken together, they explained 21% of the occurrence of delirium.

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DISCUSSION

In a sample of 172 consecutive demented patients, 67 of whom had episodes of delirium, activity of the HPA axis was determined by measuring basal cortisol serum levels and performing DST.

The most important finding of the study was the strong relationship between delirium and DST pathology independently of age and severity of dementia.

The relationship between basal cortisol levels and severity of dementia showed an inverted 'U' pattern. The highest mean basal cortisol levels were found in moderate dementia while patients with mild dementia and severe dementia had significantly lower levels. This finding might reflect a decreased ability to experience and respond to stress in advanced dementia. Similar findings have been presented in another study in which severely demented patients but not moderately demented patients responded to DST within the normal range (Serby et al., 1988). Basal cortisol levels, however, were not reported in that study.

The relationship between severity of delirium and basal cortisol levels showed a similar pattern to that between severity of dementia and basal cortisol levels. The highest basal cortisol levels were found in the mildly delirious group and there were lower levels in the non-delirious and the moderately/severely delirious groups.

Differences in mean post-DST cortisol levels between the diagnostic groups were not significant. This might reflect lack of statistical power. However, the result is in agreement with findings in an earlier study comparing LAD, EAD and VAD (Balldin et al., 1994) but at variance with results of some other studies (McKeith, 1984; Magni et al., 1987).

In the present study, the possible diagnosis of dementia with Lewy bodies (DLB) (McKeith et al., 1996) was not considered, since no clinical diagnostic criteria for DLB were proposed at that time.

Previously published literature is also divided regarding the relationship between post-DST cortisol levels and dementia severity (Molchan et al., 1990). In the present study, a positive association was found between post-DST cortisol levels and severity of the dementia disorder. This finding supports findings in some earlier studies (Jenike and Albert, 1984; Balldin et al., 1994). In another study, 100% of the moderate/severe Alzheimer's disease patients were found to be non-suppressors (Serby et al., 1988). On the other hand Hatzinger et al. found no correlations between any HPA endocrine parameters and the degree of severity of dementia (Hatzinger et al., 1995) and, in a longitudinal study of Alzheimer's disease patients, HPA axis dysfunction did not increase with follow-up (Swanwick et al., 1998).

Thus severity of dementia but neither the specific dementia diagnosis nor age was associated with high post-DST cortisol levels in this study. On the other hand, a strong relationship between delirium and DST pathology was seen in these demented patients. Seventy percent of the moderately/severely delirious patients were non-suppressors on the DST compared to 33% of the non-delirious patients. In the mildly delirious group, 51% were non-suppressors. The mean post-DST cortisol level was 206 μmol/l in the moderate/severe delirium group and 113 μmol/l in the no delirium group. The influence by delirium on the post-DST level was independent of age and severity of dementia. In most cases, no acute medical condition was found to have triggered the delirium episodes and thus no specific medical causes were suspected to have influenced the HPA axis results.

Delirium is regarded as an exclusion criteria for the diagnosis of dementia although dementia and delirium often coexist (APA, 1987). In the present study, the presence of dementia was established in periods without delirium to reduce the risk of diagnostic blurring. The independent effect of delirium on HPA abnormalities was ensured in the statistical analysis.

The division of the severity of dementia according to DSM-III-R into mild, moderate and severe is an approximate method of classification. However, in estimating the necessity for supervision, it has the merit of taking the entire handicap into account, not just the cognitive impairment.

It has been discussed whether the high frequency of non-suppressors in dementia is due to depression which is often present in dementia (McKeith, 1984; Magni et al., 1987; Molchan et al., 1990; O'Brien et al., 1993). However, in the present study, no association was found between high cortisol levels and depressed mood in the different diagnostic groups, as rated within the scope of the GBS, except in the FTD group.

In the entire patient group, associations were found between post-DST cortisol levels and symptoms of confusion, irritability and restlessness. These symptoms might well be symptoms associated with delirium. This is in accordance with the results of a study on DST in Alzheimer patients (Lawlor et al., 1992). In that study, agitation scores but not memory impairment or degree of depressed mood was highly correlated with post-DST cortisol levels.

If DST pathology reflects hyperactivity of the HPA system, it can thus be concluded that hyperactivity of the HPA system and incapability to turn off increased cortisol release occur more often in demented patients with episodes of delirium than in non-delirious demented patients independently of age and severity of the dementia disorder. The contribution of severity of dementia to the disturbance of the HPA axis, however, did not reach significance in this model. The explained variation in post-DST cortisol by these factors was remarkably low (7%).

Whether hyperactivity of the HPA system is a consequence of delirium or a risk factor for delirium has not been investigated. If the delirious state causes hyperactivity of the HPA system, basal cortisol levels would be expected to increase with the severity of delirium, which did not happen in this study. Increased post-DST cortisol levels may reflect a more permanent underlying incapacity for self regulation of the stress system than increased basal cortisol levels. Thus delirious patients seem to have a more fundamental disturbance of the HPA system. Accordingly, an analysis of the influence of post-DST cortisol, severity of dementia and age on the occurrence of delirium was performed. This analysis showed that all three factors independently and significantly predicted delirium.

The hypothesis that the disturbance of the HPA system is an invariable feature of the delirious state is further supported by an earlier study of delirium in patients with lower respiratory tract infection. The impairment of the HPA system seen in delirious patients still remained 8 weeks after resolution of the delirium and chest infection and thus seemed to be more chronic (O'Keeffe and Devlin, 1994).

Thus it seems as if certain demented individuals have an impaired HPA system and a low delirium threshold and respond to stress with delirium.

The negative feed-back mechanism of the HPA axis is partly controlled by neurotransmitters, especially serotonin (Olsson, 1999). It has been hypothesized that the dysfunction of the HPA axis seen in dementia is due to neurotransmitter deficits, at least in dementia of the Alzheimer type (Balldin et al., 1994). Treatment with a selective serotonergic reuptake inhibitor has also been found to reduce the postdexamethasone cortisol level (Balldin et al., 1988).

Prolonged stress with hypercortisolism is toxic to neurones, especially in the hippocampus (Sapolsky and Pulsinelli, 1985). Hypercortisolism probably causes cognitive impairment with memory disturbances (Ling et al., 1981; Wolkowitz et al., 1990; McEwen and Sapolsky, 1995) and attentional deficits (Carpenter and Gruen, 1982). In addition, prolonged hypercortisolism causes resistance to cortisol feedback inhibition mediated by receptor loss in the hippocampus (McEwen and Brinton, 1988; Sapolsky and Plotsky, 1990).

Many patients with HPA axis abnormalities are not identified by the DST (Meller et al., 1988). At present, more sophisticated methods than DST for measuring the activity of the HPA axis are available. The superiority of the combined dexamethasone/CRH test for changes of the HPA regulation has been reported (Heuser et al., 1994; Deuschle et al., 1998). If this more sensitive test had been applied in the present study, the association between age, gender and severity of depressed mood on one hand and HPA system disturbances on the other would have been studied more carefully.

Delirium has a multifactorial genesis. Known risk factors include ageing and organic brain disorders. The delirious episode is triggered by somatic disorders, anticholinergic drugs, stress, etc. (Lindesay et al., 1990). In this study, it was shown that demented patients with disturbance of the HPA axis may be susceptible to delirium. This hypothesis, however, needs to be further tested in a prospective study. If this hypothesis is true, pharmacological treatment with neurotransmitter drugs to improve the feedback mechanism of the HPA axis and thereby raise the delirium threshold in demented patients might be of value. Anticortisol drugs might also be of interest.

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Acknowledgements

This work was supported by grants from Stiftelsen för Gamla Tjänarinnor and from the Medical Research Council (00946 and 12103).

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Keywords:

hypothalamic-pituitary-adrenal axis; delirium; dementia; cortisol; dexamethasone suppression test

© 2001 Lippincott Williams & Wilkins, Inc.