The Stanley Research Centre, University of Newcastle upon Tyne, The Royal Victoria Infirmary, Newcastle upon Tyne, UK
Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
The Stanley Research Centre, University of Newcastle upon Tyne, The Royal Victoria Infirmary, Newcastle upon Tyne, UK
Correspondence: Professor A. H. Young, Department of Psychiatry, Leazes Wing, The Royal Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, UK. Tel: +44 (0)191 2824473; fax: +44 (0)191 2825708; e-mail: a.h.young{at}ncl.ac.uk
Declaration of interest Funded by the Stanley Medical Research Institute.
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ABSTRACT |
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Aims To test the hypothesis that HPA axis dysfunction persists in patients in remission from bipolar disorder.
Method Salivary cortisol levels and the plasma cortisol response to the DST and dex/CRH test were examined in 53 patients with bipolar disorder, 27 of whom fulfilled stringent criteria for remission, and in 28 healthy controls. Serum dexamethasone levels were measured.
Results Patients with bipolar disorder demonstrated an enhanced cortisol response to the dex/CRH test compared with controls (P=0.001). This response did not differ significantly between remitted and non-remitted patients. These findings were present after the potentially confounding effects of dexamethasone levels were accounted for.
Conclusions The dex/CRH test is abnormal in both remitted and non-remitted patients with bipolar disorder. This measure of HPA axis dysfunction is a potential trait marker in bipolar disorder and thus possibly indicative of the core pathophysiological process in this illness.
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INTRODUCTION |
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METHOD |
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Patients in remission were rated prospectively over 4 weeks and defined as
remitted if they satisfied the criteria of the Newcastle Euthymia Protocol
(Thompson et al,
2000). Briefly, these criteria consist of a SCID diagnosis of
bipolar disorder in full remission, with a 21-item Hamilton Rating Scale for
Depression (HRSD; Hamilton,
1960) score of 7 and a Young Mania Rating Scale (YMRS;
Young et al, 1978)
score
7 both at baseline and when repeated 4 weeks later. Additionally,
scores on self-rating scales, including the Beck Depression Inventory (BDI;
Beck et al, 1961) and
the Altman Mania Rating Scale (AMRS; Altman
et al, 1997), completed at weekly intervals throughout
the assessment period are required to remain unchanged from baseline. The time
spent in clinically defined remission was also determined. The non-remitted
patients who satisfied the SCID diagnostic criteria for bipolar disorder
current episode depressive were classified as depressed.
Twenty-eight control participants (age range 2460 years) were
recruited. They were confirmed as healthy by medical examination and by the
SCID to be free of neurological or psychiatric disorder. No control
participant gave a history of having a first-degree relative with psychiatric
disorder. Both patients and controls were excluded if they had a neurological
or medical condition, if they were taking corticosteroids or antihypertensive
medication or had a history of substance or alcohol misuse. Gender, age and
menstrual status have been reported previously to have an impact on HPA axis
function (Viau & Meaney,
1991; Seeman et al,
2001). The groups were therefore carefully matched for age
(F[1,78]=0.2; P=0.63), gender (2 = 0.64;
d.f.=1; P=0.43) and menstrual and menopausal status
(
2=3.2; d.f.=3; P=0.36) and the impact of these
variables on the neuroendocrine output was determined. The Joint Newcastle and
North Tyneside Ethics Committee approved the study. All participants gave
written informed consent.
Neuroendocrine testing
The dex/CRH test was performed following the protocol previously used in
studies of major depressive disorder
(Heuser et al, 1994).
Participants took 1.5 mg dexamethasone orally at 23.00 h on the evening before
neuroendocrine testing. They attended the research unit on the morning of the
test day and had a light lunch at noon, following which they were canulated in
the antecubital fossa at 13.00 h. Participants then fasted, remained
semi-supine and did not sleep. Human CRH (Ufelfingen, Switzerland) 100 µg
was administered over 30 s via the canula at 15.00 h. Blood was taken serially
for measurement of cortisol levels at 15-minute intervals until 17.00 h. The
dexamethasone suppression test (DST) response was determined by the 15.00 h
(pre-CRH) cortisol level. Participants lightly chewed a citricacid-impregnated
cotton-wool salivette (Sarstedt, UK) at 08.00, 12.00, 16.00 and 20.00 h on the
day prior to neuroendocrine testing to allow assessment of both basal cortisol
secretion and diurnal variation
(Kirschbaum & Hellhammer,
1994). Participants were permitted to smoke as usual throughout
the procedure to reduce any effects of nicotine withdrawal.
Biochemical measures
Blood was collected in ethylenediamine-tetracetic acid and centrifuged at
1000 g for 10 min to prepare plasma, which was removed and
immediately frozen at -20 °C until assayed. Dexamethasone was assayed at
Emory University, Georgia, using a method described previously
(Ritchie et al,
1990). In this laboratory, the 80%, 50% and 20% binding points
averaged to 0.07, 0.33 and 1.46 ng/ml, respectively. At a level of 0.52 ng/ml,
the inter-assay coefficient of variation was 8% and the intra-assay
coefficient of variation was 4%. Cortisol was determined using corti-cote
radioimmunoassay kits (ICN Pharmaceuticals, California, USA). The sensitivity
of the plasma cortisol assay was 1.9 nmol/l. The inter-assay and intra-assay
coefficients of variation for the low (107.7 nmol/l), medium (25.1 nmol/l) and
high (51.1 nmol/l) quality controls were 5.9%, 7.8%, 9.6% and 7.7%, 6.6%,
9.4%, respectively.
Saliva collected using the salivette system was extracted from the cotton-wool swab by centrifugation and stored at -20 °C until analysis. Samples were analysed for cortisol using radioimmunoassay. The sensitivity of the saliva cortisol assay was 0.08 nmol/l at 98% binding and the inter-assay and intra-assay coefficients of variation for the low (8.6 nmol/l), medium (31.5 nmol/l) and high (87.5 nmol/l) quality controls were 17.2%, 10.3%, 9.6% and 25.8%, 16.3%, 9.1%, respectively.
Effect of treatments
Dexamethasone clearance is increased in patients receiving drugs, including
carbamazepine, which induces the main enzyme involved in dexamethasone
clearance, CYP3A4, potentially producing false-positive DST results.
Medication may also exert effects on cortisol output that are independent of
dexamethasone metabolism. We therefore also examined the effect of
carbamazepine levels and other medications on dexamethasone and cortisol
output.
Statistical analysis
For statistical analysis we used SPSS for Windows, version 9. Data were
first examined to see whether they fulfilled the assumptions for parametric
statistical analyses. If violations of these assumptions occurred, data were
logarithmically transformed (to base ten). If this failed to satisfy
assumptions, the data were analysed non-parametrically. Basal cortisol was
logarithmically transformed to normalise the distribution and compared between
groups using repeated-measures ANOVA, with the four time points as the
within-subject variable. The mean and 95% confidence interval (CI) of mean
basal cortisol levels were calculated. All other data were analysed
non-parametrically. KruskalWallis one-way ANOVA on ranks was utilised
to determine group differences when comparing more than two groups.
Non-parametric data are reported as median and 95% CI of the median. When
comparing two groups, the median difference
(Campbell & Gardner, 2000) and MannWhitney U-test were used.
Correlations were carried out using Spearmans rank coefficient
(rs). Categorical variables were analysed using
2 tests. The 15.00 h (immediately pre-CRH) plasma cortisol was
used for analysis of the DST. Delta cortisol (the difference between the peak
cortisol response to the dex/CRH test and the 15.00 h cortisol plasma
concentration) was used for analysis of the dex/CRH response. To investigate
whether the results differ between patients and controls, receiver operating
characteristic curves were plotted for basal cortisol area under the curve,
15.00 h plasma cortisol and delta cortisol. The area under the receiver
operating characteristic curve and the 95% CI were determined using the
Wilcoxon estimate. All cortisol levels are presented as nmol/l and plasma
dexamethasone levels as pmol/l. Based on the effect size seen in the most
recent study comparing patients with symptomatic and asymptomatic bipolar
disorder (Schmider et al,
1995), the principal comparisons of remitted with non-remitted
patients and remitted with depressed patients had a power of >99% at the
0.05 level of significance. Because carbamazepine had such a profound effect
on dexamethasone metabolism, post hoc analysis was performed after
exclusion of patients taking carbamazepine.
Dexamethasone levels
Earlier studies have demonstrated that there is marked variability in serum
dexamethasone levels during the DST and that the rate of dexamethasone
metabolism and hence dexamethasone levels are a significant determinant of DST
response (Morris et al,
1986; Lowy & Meltzer,
1987; Stokes et al,
2002a). There is a middle range of dexamethasone values
below which individuals tend to escape from DST suppression and above which
they tend to suppress (Ritchie et
al, 1990). It has been suggested, therefore, that the DST may
not be valid in people whose dexamethasone levels fall outside this window and
these individuals should be excluded from analysis
(Morris et al, 1986;
Lowy & Meltzer, 1987; Stokes et al,
2002a). However, it has been argued that enhanced
metabolism of dexamethasone is a component of affective illness and may be
secondary to hepatic enzyme induction in hypercortisolaemic subjects
(Holsboer et al,
1986; Stokes et al,
2002b).
Cut-off points for the dexamethasone window analysis were defined empirically according to the method of Ritchie et al, 1990) as 0.85 and 2.5 pmol/l.
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RESULTS |
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Responses for patients with bipolar disorder compared with controls
The DST
The 15.00 h plasma cortisol levels were significantly higher in patients
with bipolar disorder than in controls (P=0.017). Similarly, the area
under the receiver operating characteristic curve revealed that patients with
bipolar disorder could be discriminated from controls using the 15.00 h
cortisol level. The difference in 15.00 h cortisol concentrations between
remitted and non-remitted patients and controls was present at the trend level
(P=0.058) (see Table
2).
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Cortisol response to the dex/CRH test
Dexamethasone and human CRH were well tolerated by all subjects and, other
than transient facial flushing, no side-effects were experienced. Delta
cortisol was significantly greater in patients with bipolar disorder than in
controls (P=0.001). The area under the receiver operating
characteristic curve revealed that patients with bipolar disorder could be
discriminated from controls using delta cortisol. Examination of cortisol
response to dex/CRH challenge in remitted and non-remitted patients and
controls revealed a significant group difference. Post hoc analysis
revealed that delta cortisol was significantly greater in remitted
(P=0.004), non-remitted (P=0.003) and depressed patients
(P=0.02) than in controls. There was no significant difference in
delta cortisol levels between depressed patients and controls, between
remitted and non-remitted patients or between remitted and depressed patients
(Table 2 and
Fig. 1).
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Correlations and predictions
The cortisol response to the dex/CRH test did not differ between males and
females or between pre-menopausal and post-menopausal females. Neither age nor
cycle frequency correlated with delta cortisol in the patients with bipolar
disorder. The length of the clinically defined period of remission did not
correlate with the magnitude of the cortisol response to the dex/CRH test in
the remitted patients. Neither the duration nor the severity (as measured by
the HRSD) of depressive episodes correlated with the magnitude of the cortisol
response in the depressed patients (data not shown).
Basal salivary cortisol
Salivary cortisol levels were obtained for 39 patients and 22 controls.
Because samples were taken prior to dexamethasone administration, subjects
were not excluded from analysis on the basis of dexamethasone levels.
Comparison between patients with bipolar disorder and controls revealed a
significant effect of time (F[3,177]=3.8; P=0.05) but no
main effect of diagnosis or timexdiagnosis interaction
(P>0.3). The area under the receiver operating characteristic
curve revealed that patients with bipolar disorder could not be discriminated
reliably from controls using this measure. Basal salivary cortisol levels
between remitted and non-remitted patients and controls did not differ over
time (F[3,171]=3.5; P=0.06) and there was no main effect of
diagnosis and no timexdiagnosis interaction (P>0.3)
(Table 3).
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Results from analysis after exclusion of patients with dexamethasone levels outside the dexamethasone window (see Fig. 2)
Results are reported in Table
3. The dexamethasone window analysis included 21 controls and 27
patients with bipolar disorder, of whom 14 were remitted. The results remain
unchanged except that delta cortisol was no longer significantly greater in
depressed patients than in controls, 15.00 h cortisol levels (the DST
response) were no longer greater in patients with bipolar disorder than in
controls and the area under the receiver operating characteristic curve
revealed that patients with bipolar disorder could not be differentiated
reliably from controls using the DST response.
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Effects of medication on dexamethasone levels and cortisol response
Overall, patients taking carbamazepine had lower dexamethasone levels
(U=0.0; P<0.0005), a higher delta cortisol level
(U=56.0; P<0.0005) and were more likely to respond to the
dex/CRH test than those not taking carbamazepine (difference=63.4%,
Fishers exact test P<0.0005). Overall, there were ten
patients taking known CYP3A4-inhibiting drugs. Dexamethasone levels or delta
cortisol did not differ between those taking and not taking CYP3A4-inhibiting
drugs, lithium or selective serotonin reuptake inhibitors (data not
shown).
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DISCUSSION |
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Confounding factors
Medication may have an impact on the cortisol response. A number of studies
have shown that successful resolution of depressive symptoms normalises the
HPA axis (Heuser et al,
1996; Nickel et al,
2003) but a recent study has shown that in the absence of a
treatment response antidepressants did not alter the cortisol output on the
dex/CRH test (Kunzel et al,
2003). Bschor et al
(2002) have shown that lithium
augmentation in treatment-resistant unipolar depression increases the cortisol
response to the dex/CRH test. However, in our study patients on lithium did
not have a greater cortisol response. All patients in this study taking
carbamazepine had dexamethasone levels outside the normal window and all had
an abnormal response on the dex/CRH test. We found no other relationship
between psychotropic medication and dexamethasone levels. When dexamethasone
windows were applied, there was no difference in dexamethasone levels between
patients and controls, therefore an effect of psychotropic medication on
cortisol output via dexamethasone metabolism appears unlikely.
After applying dexamethasone windows, 33 of the 81 participants were excluded but the study was still adequately powered and the principal findings remained unchanged. Specifically, the dex/CRH test remained abnormal in patients with bipolar disorder. Furthermore, remitted patients continued to have an abnormal response to the dex/CRH test that could not be differentiated from the response of non-remitted patients (including those who satisfy the SCID criteria for a depressive episode). The reduced power after application of dexamethasone windows may explain the finding that the DST no longer separated patients from controls.
The magnitude of the cortisol response to the dex/CRH test could not be predicted by any single illness or demographic factor, including the period of remission in remitted patients or the cycle frequency. This suggests that the HPA axis dysfunction in patients with bipolar disorder does not have a temporal relationship to the period of remission.
Measures of HPA axis function
We did not demonstrate elevation in basal salivary cortisol levels in
patients with bipolar disorder, whereas previous studies employing serial
plasma sampling techniques at more frequent intervals have found clear
evidence of hypercortisolaemia in bipolar disorder
(Cervantes et al,
2001). The relatively infrequent salivary sampling employed in
this study may have failed to detect the subtleties of the pulsatile and
diurnal pattern of cortisol secretion
(Windle et al, 1998;
Wong et al, 2000) and
hence did not uncover the hypercortisolaemia that may be present in the
patient group. Nevertheless, the DST and dex/CRH tests are more sensitive than
basal measures of cortisol. There are a number of potential explanations for
this. It may be that the extra complexity of the tests (addition of
dexamethasone and CRH) reveals additional facets of the HPA axis (such as the
ability to respond to negative feedback and positive drive;
Holsboer & Barden, 1996).
Alternatively the dexamethasone and CRH challenge may exaggerate the
differences in HPA axis function between patients with bipolar disorder and
controls or reduce the variance in response, thereby allowing underlying
differences in function to be revealed.
We did not measure the adrenocorticotrophic hormone response to the dex/CRH test. Some previous studies have measured adrenocorticotrophic hormone and cortisol but the adrenocorticotrophic hormone responses tend to parallel cortisol responses and therefore add little to the overall sensitivity of the test (Heuser et al, 1994). Another potential criticism of our study is that we did not examine patients in manic or hypomanic states. Schmider et al (1995) have previously demonstrated that the dex/CRH test is abnormal in patients with mania. Moreover, in addition to the practical problems, a recent prospective study of patients with bipolar disorder reported that time spent in the depressive spectrum predominates threefold over time with manic symptoms and fivefold over time with cycling/mixed symptoms (Judd et al, 2002). The present study therefore examines patients with bipolar disorder in the predominant clinical states.
Comparison with previous research
Previous studies have shown that the HPA axis is abnormal during a bipolar
relapse and suggest some degree of normalisation but with residual abnormality
on symptom resolution (Greden et
al, 1982; Schmider et
al, 1995; Rybakowski
& Twardowska, 1999). The present study is the first to use a
rigorous prospective protocol to define remission. The sample also had a mean
clinically defined duration of remission of 2 years prior to entering the
euthymic protocol. It is noteworthy that, in accordance with previous studies,
we found an abnormal HPA axis during relapse. However, we also found that the
response to the dex/CRH test remains abnormal to a similar degree in
remission.
In the Munich Vulnerability Study (Holsboer et al, 1995) 54 apparently healthy people with a family history of affective disorder underwent a similar assessment of HPA axis function. Only a minority of the subjects had a family history of bipolar rather than unipolar affective disorder. None the less, this demonstration of an abnormal response to the dex/CRH test in a proportion of apparently healthy individuals with a family history of affective disorder taken in conjunction with our data suggests that HPA axis dysfunction may be a trait abnormality in bipolar disorder. Whether this dysfunction occurs premorbidly (a potential cause of the illness) or arises as a consequence of the disorder (a biological scar) should be addressed further by examination and longitudinal follow-up of a larger rigorously defined population at high risk of developing bipolar disorder.
Future studies
Our results suggest that HPA axis dysfunction may be involved in the
disease process underlying bipolar disorder. Further studies should examine
the temporal evolution of HPA axis function and bipolar disorder.
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Clinical Implications and Limitations |
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LIMITATIONS
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ACKNOWLEDGMENTS |
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Received for publication October 28, 2003. Revision received January 8, 2004. Accepted for publication February 6, 2004.
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