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Depressive psychomotor disturbance, cortisol, and dexamethasone
.........
ORIGINALARTICLES
Depressive Psychomotor Disturbance, Cortisol, and Dexamethasone Philip Mitchell, Dusan Hadzi-Pavlovic, Gordon Parker, Ian Hickie, Kay Wilhelm, Henry Brodaty, and Philip Boyce
We examine the dexamethasone suppression test as a biological correlate of melancholia as defined by the CORE system, a scale for rating objective signs of psychomotor disturbance. Postdexamethasone cortisol concentrations and rates of nonsuppression were higher in CORE, Newcastle, and DSM-III-R defined melancholic groups. These differences, however, were no longer significant after partialling out the combined effects of age, dexamethasone, and basal cortisol concentrations. There was a significant correlation between the CORE (but not the Newcastle) scale and 8:00 AM postdexamethasone cortisol levels, which persisted after partialling out those same three covariates. Dexamethasone concentrations themselves were lower in CORE- and Newcastle-defined melancholics, though these were no longer significant after covarying for cortisol concentrations. Dexamethasone levels were also significantly inversely correlated with CORE and Newcastle scales. A significant correlation between CORE (but not Newcastle) scores and dexamethasone levels at 4:00 PM persisted after partialling out the effects of age and cortisol. These findings indicate an intriguing relationship between the CORE system as a dimensional construct for rating psychomotor disturbance, and both postdexamethasone cortisol and dexamethasone concentrations.
© 1996 Society of Biological Psychiatry Key Words: Melancholia, psychomotor disturbance, dexamethasone, cortisol, depression, classification BIOL PSYCHIATRY1996;40:941--950
Introduction "Further research is needed to empirically test the biological and psychological features associated with melancholic depression . . . "
Rush and Weissenburger (1994) From the School of Psychiatry, University of New South Wales, Sydney, N.S.W., (PM, DHP, GP, IH, KW, HB); Mood Disorders Unit, Prince Henry Hospital, Sydney, N.S.W., Australia (PM, DHP, GP, IH, KW, HB, PB); and Department of Psychological Medicine, University of Sydney, N.S.W., Australia (PB).
© /996 Society of Biological Psychiatry.
Psychomotor disturbance is one of the most consistent clinical features included in the various definitions of melancholia (Nelson and Charney 1981). We have recently developed an operationally defined scale for behavioral rating of psychomotor disturbance in depressed patients (the CORE system: Parker et al 1990, 1994). By
Address reprint requests to Associate Professor Philip Mitchell, Mood Disorders Unit, Prince Henry Hospital, Little Bay, Sydney, N.S.W., 2036, Australia. Received June 8, 1994; revised October 23, 1995.
0006-3223/96/$15.00 SSDI 0006-3,23(95)00635-4
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means of statistical techniques including latent class analysis (Parker et al 1990, 1994), and validation against a number of traditional concomitants of melancholia such as response to treatment (Hickie et al 1990) and course of illness (Parker et al 1992), we have demonstrated that this system is capable of discriminating between "melancholic" and "nonmelancholic" depression at least as well as extant classificatory systems such as DSM-III-R (APA 1987) and the Newcastle Diagnostic Index (Carney et al 1965). Unlike DSM-III-R and the Newcastle index, which include items relating both to current symptomatology as well as to longitudinal features such as premorbid personality, the CORE system is a cross-sectional assessment (or "snapshot") of current observable signs of depression. Furthermore, using principal components analysis, we have demonstrated (Parker et al 1993) three factors underlying the total CORE score, i.e., retardation, agitation, and noninteractiveness (the last being a nonmotor scale presumed to quantify dysfunctional cognitive processing). In this study, we examined the dexamethasone suppression test (DST) as a biological correlate of melancholia as defined by the CORE system, as previous research had suggested a strong relationship between psychomotor disturbance and hypothalamic-pituitary-adrenal (HPA) system overactivity. For example, Zimmerman et al (1986) tested with validity of the DST against the seven "symptoms" identified by Nelson and Charney (1981) as characteristics of endogenous depression. Of these, only scores for psychomotor retardation and depressed mood were greater in the nonsuppressors. This finding was consistent with most studies that have examined the relationship between the DST and psychomotor disturbance (Brown and Shuey 1980; Calloway et al 1984; Klein et al 1984), though there have been some negative reports (Kocsis et al 1984; Asnis et al 1982). It should be noted, however, that Zimmerman et al (1986) also found a number of nonsymptomatic features of melancholia, such as family history, demographics, and psychosocial factors, which also distinguished DST suppressed from nonsuppressed patients. Zimmerman et al (1986) also noted that nonsuppressors more frequently appeared depressed (as opposed to merely reportingfeeling depressed), leading the authors to state: " . . . observational symptom ratings may be more valid than interview based ratings, therefore possibly accounting for our failure to find a significant association with anhedonia and reactivity." The CORE system used in this present paper provides such an observational instrument, by objectively rating interactive behaviors (such as reactivity of mood) as well as features of both retardation and agitation. In this study, we examine the capacity of the DST to discriminate between patients with categorically defined
melancholic and nonmelancholic depression as defined by the DSM-III-R, Newcastle, and CORE systems. Additionally, we examine for any dimensional relationship between Newcastle and CORE scores and DST findings. Also, as age, dexamethasone levels, and basal cortisol concentrations have been found to be important determinants of postdexamethasone cortisol levels (Maes et al 1989, 1990, 1991a, 1991b), we examine for their influence as potential confounding variables.
Methods Consecutive inpatients with primary Major Depression of the Prince Henry Hospital Mood Disorders Unit, Sydney were included in the study. After applying standard exclusion criteria (Carroll et al 1981), 114 patients were recruited. Subjects taking antidepressant and antipsychotic medications were included (e.g., Klein et al 1984; Hunt et al 1989), whereas those on anticonvulsants were excluded. Fifty-seven patients were on long-term antidepressant medication, and 21 on an antipsychotic. Psychotropics were not ceased prior to the dexamethasone suppression test, nor were new treatments initiated before this was performed. Using a semistructured interview instrument (Brodaty et al 1987), patients were diagnosed according to DSM-III-R criteria. Concurrently, patients were rated on the Newcastle and CORE systems and the Hamilton Depression Severity scale (17 and 21 items) (Hamilton 1960). Diagnoses were made blind to DST results. Using preestablished cutoff scores, patients were diagnosed as "endogenous" with Newcastle scores -->6, and "melancholic" with scores -> 8 using the CORE system. Blood samples for basal predexamethasone cortisol concentrations were taken at 4:00 PM on day 1, with dexamethasone, 1 mg, being administered orally at 11:00 PM that night. The following day, blood was collected at 8:00 AM and 4:00 PM for cortisol and dexamethasone determinations, and at 11:00 PM for cortisol levels only. Blood was taken by simple needle stick venipuncture. The dexamethasone suppression tests were undertaken 3-7 days after admission. Plasma cortisol was assayed by radioimmunoassay using a kit supplied by Orion Diagnostica, Finland. The interassay and intraassay coefficients of variation were 4.5% and 7.1% at 162 nmol/L; 4.0% and 7.6% at 494 nmol/L; and 4.9% and 11.2% at 785 nmol/L, respectively. Plasma dexamethasone was measured by radioimmunoassay (based on a method used in the Endocrine Laboratory, Royal Prince Alfred Hospital, Sydney) using antisera purchased from Professor Vecsei, Department of Pharmacology, University of Heidelberg, Germany. The interassay and intraassay coefficients of variation were 9.2% and
Depressive Psychomotor Disturbance
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Table 1. Plasma Cortisol Concentrations (nmol/L, Untransformed Data) in DSM-III-R-, Newcastle-, and CORE-Defined Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (Student's t Test on Natural Log Transformed Data) Day 1 (predexamethasone)
Day 2 (postdexamethasone)
4:00 PM
8:00 AM
4:00 PM
1 I:00 PM
MEL
NON-MEL
MEL
NON-MEL
MEL
NON-MEL
MEL
NON-MEL
DSM-IIIR
295.5 ± 157.4
316.8 ± 134.8
135.2 + 168.2
83.2 ± 113.3
172.6 ± 165.0
99.0 ± 95.0 ~
119.4 ± 127.7
67.2 ± 61.9 ~
Newcastle
313.2 ± 160.8
285.9 ± 143.1
163.8 + 182.5
81.0 ± 115.7'
200.3 ± 150.0
109.2 ± 146.5 c
131.3 ± 104.7
82.5 ± 126.1 c
CORE
297.0 + 157.1
303.6 ± 149.3
160.1 ± 179.5
70.9 ± 102.9 c
192.2 ± 163.8
103.5 ± 125.3 b
122.9 + 102.8
84.8 ± 136.1 ~'
~p --< .05. t,p < .01. "p "< .001
16.5% at 1.3 nmol/L; and 10.4% and 15.5% at 10.9 nmol/L, respectively. Assays were performed in different runs.
Cortisol nonsuppression thresholds were determined in our own laboratory by comparing the depressed patients with 25 normal controls screened to exclude physical or psychiatric illnesses. Receiver operating characteristics (ROC) analysis was used to compute optimal thresholds for nonsuppression to distinguish controls from those subjects fulfilling criteria for DSM-III-R melancholia (n = 77). The resulting cutoffs were: 8:00 AM, --> 71 nmol/L; and 4:00 PM, ~ 70 nmol/U (It was not possible to determine 11:00 PM thresholds as postdexamethasone samples were only taken in controls at 8:00 AM and 4:00 PM,) Patients were only included in the final analyses if cortisol and dexamethasone results for each postdexamethasone time point were available. This resulted in a final sample of 100 subjects being included in this report. Results are expressed as means (_+ standard deviation). Postdexamethasone cortisol concentrations were examined both dimensionally (mean levels) and categorically (i.e, as suppression vs. nonsuppression). Groups were compared using Student's t test and X2 test respectively, while for correlational analyses, Pearson's correlations were performed. The effect of covariates on any differences in cortisol levels between groups was examined using A N C O V A (analysis of covariance), while their effect on DST nonsuppression rates was examined by logistic regression. Although raw (untransformed) data for cortisol and dexamethasone concentrations are presented in this paper, these were natural log (in) transformed prior to all statistical analyses.
Results Sample The final sample comprised 100 patients (69 women, 31 men; mean age 54.4 _ 17.5 years). The mean Hamilton scores were: 17 item = 23.2 ± 6.5, 21 item = 25.1 _+ 7.1.
The number of patients diagnosed as melancholic or endogenous according to the various systems were: DSMIII-R = 77, Newcastle = 51, and CORE = 59 (with a CORE rating missing for 1 patient). In the remainder of this article the term "melancholia" will be used to subsume both melancholic and endogenous depression diagnoses. Melancholic patients were significantly older than nonmelancholic patients as allocated by both the Newcastle (62.4 _+ 15.0 vs. 46.1 _+ 16.1 years; t = - 5 . 2 5 , p < .001) and CORE (60.5 -+ 15.2 vs. 45.2 --- 17.0 years; t = - 4 . 7 1 , p < .001) systems. There was a trend toward a significant difference in the ages of the respective DSM-III-R subgroups (56.1 _+ 16.5 vs. 48.6 4- 19.8 years; t = - 1 . 8 4 , p = .07). EFFECT OF PSYCHOTROPIC MEDICATIONS. In view of concern by some authorities (e.g., Kraus et al 1988) of an effect of antidepressant and antipsychotic medications on the DST, we examined for any such confound in this sample. There were no significant differences in cortisol concentrations (either pre- or postdexamethasone) or dexamethasone levels between those patients either on or off antidepressant or antipsychotic medications. For example, the 8:00 AM postdexamethasone cortisol levels on and off antidepressants (n = 57 and 43, respectively) and antipsychotics (n = 21 and 79, respectively) were: 135.4 _+ 173.3 vs. 107.1 _ 136.0 nmol/L (t = 0.18, df = 98, p = .86) and 147.4 + 161.8 vs. 116.8 -+ 157.7 nmol/L (t = 1.32, df = 98, p = .19).
Melancholia as a Categorical Construct--Cortisol Concentrations, Nonsuppression Rates, and Dexamethasone Concentrations CORTISOL
CONCENTRATIONS
IN
MELANCHOLIC
AND
NONMELANCHOLICPATIENTS. There were no significant differences between melancholic and nonmelancholic patients as allocated by the three diagnostic systems in the day 1 4:00 PM predexamethasone cortisol concentrations (Table 1).
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Table 2. Significance of Differences in Postdexamethasone Cortisol Concentrations between Melancholic and Nonmelancholic Groups after Covarying for Age, Dexamethasone Concentrations (Dex), and Basal Cortisol Concentrations (Cort), Both Individually and Combined (Analysis of Covariance) 8:00 AM
4:00 PM
l l : 0 0 PM
Dex
Basal
Age, Dex,
Dex
Basal
Age,
Age
(8:00 AM)
cortisol
Cort
Age
(4:00PM)
cortisol
Dex, Cort
Age
cortisol
Basal
DSM-III-R Newcastle
n.s. n.s.
" b
" d
n.s. n.s.
n.s. c
" ~
b d
~ n.s.
~ b
c d
CORE
n.s.
'
d
n.s.
a
a
d
n.s.
n.s.
"
n.s. = non significant. °p -< .10. bp <_ .05. "p <_ .ol. dp < .001.
At 8:00 AM on day 2, cortisol concentrations were significantly higher in both Newcastle- and CORE-, but not DSM-III-R-defined melancholies. At 4:00 PM and 11 PM cortisol levels were higher in the melancholies as defined by each system, particularly so in the Newcastleand CORE-defined groups. CORTISOL
CONCENTRATIONS
NONMELANCHOLIC
IN
MELANCHOLIC
DEPRESSIVES--THE
EFFECTS
Third, for CORE-defined subgroups, the differences in cortisol levels at 8:00 AM, 4:00 PM, and 11:00 PM all lost significance after covarying for age. After covarying for dexamethasone concentrations, the differences in cortisol levels only remained significant at 8:00 AM. In general, differences remained significant after covarying for basal cortisol levels. As with the Newcastle scale, however, there were no remaining significant differences between CORE-defined groups after age, dexamethasone, and basal cortisol levels were covaried out together.
AND
O F AGE~
D E X A M E T H A S O N E C O N C E N T R A T I O N S , AND BASAL C O R T I S O L
LEVELS. The effects of these factors were examined using analysis of covariance (ANCOVA) (Table 2). First, for DSM-III-R-defined melancholic and nonmelancholic groups, at 8:00 AM and 4:00 PM, there were no remaining significant differences after covarying for these variables either singly or in combination, with the exception of the 4:00 PM comparison after controlling for basal cortisol levels alone. Second, with Newcastle-defined groups, the differences in cortisol concentrations were no longer significant after covarying for age at 8:00 AM, though significant differences remained at 4:00 PM and 11:00 PM. After covarying for the relevant dexamethasone concentrations, the differences in cortisol levels continued to remain significant at both 8:00 AM and 4:00 PM. Similarly, significant differences remained at each time point after covarying for basal cortisol levels. When covarying for age, dexamethasone levels and basal cortisol levels together, however, there were no remaining significant differences.
NONSUPPRESSION RATES
IN M E L A N C H O L I C
AND
NON-
MELANCHOLIC PATIENTS. Nonsuppression rates were significantly different between melancholic and nonmelancholic patients using both the Newcastle and CORE systems at either individual time points (i.e., 8:00 AM or 4:00 PM) or when combined time points (8:00 AM and/or 4:00 PM) were considered (p < .01-p < .001). (Table 3) For DSM-III-R melancholic patients, nonsuppression rates were not higher at any single or combined time points. NONSUPPRESSION MELANCHOLIC METHASONE~
RATES
IN M E L A N C H O L I C
PATIENTS~THE AND
BASAL
EFFECTS
CORTISOL
AND
NON-
O F AGE~ D E X A -
CONCENTRATIONS.
The effects of these covariates on nonsuppression rates were examined using logistic regression (Table 4). As dexamethasone levels were only assayed at 8:00 AM and 4:00 PM, we will focus on those time points. For Newcastle-defined subgroups, the difference in
Table 3. Nonsuppression Rates (%) in Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (X2 Comparison) 8:00 A M MEL
4;00 PM NON-MEL
8:00 A M or 4:00 PM
MEL
NON-MEL
MEL
NON-MEL 43.5
DSM-III-R
44.2
26.1
57.1
43.5
61.0
Newcastle
52.9
26.5 ~
72.5
34.7 b
74.5
38.8 b
CORE
50.8
25.0 a
67.8
35.0 b
69.5
40.0"
~p --< .01. bp _< .001.
Depressive Psychomotor Disturbance
BIOL PSYCHIATRY 1996;40:40:941-950
945
Table 4. Logistic Regression of Suppression and Nonsuppression: Effects of Age, Basal Cortisol Concentrations, and Dexamethasone Concentrations on the Significance of Diagnostic Status 8 : 0 0 AM
Newcastle
4 : 0 0 PM
.008
.463
.083
.008
.904
.000
.006
.034
.000
.418
Age
--
.001
--
--
.002
--
.150
--
--
.028
Dexamethasone
--
--
.005
--
.006
--
--
.000
--
.000
Basal cortisol
--
--
--
.297
.348
--
--
--
.002
.005
concentrations CORE
.012
.402
.037
.011
.636
.002
.030
.084
.001
.484
Age
--
.001
--
--
.002
--
.061
--
--
.015
Dexamethasone
--
--
.002
--
.005
--
--
.000
--
.000
Basal cortisol
--
--
--
.177
.347
--
--
--
.001
.004
concentrations - not entered.
nonsuppression rates at the 8:00 AM time point were no longer significant after partialling out age, though the significant difference persisted at 4:00 PM. W h e n relevant dexamethasone concentrations were partialled out, the differences between groups were again significant at 4:00 eM, but not at 8:00 AM. Basal cortisol levels did not have a significant effect upon the differences. When all three covariates, however, were partialled out in combination there were no residual differences at either 8:00 AM or 4:00
though there was still a difference at 4:00 PM. When the effect of dexamethasone concentrations was partialled out, significant differences persisted at 8:00 AM but not at 4:00 PM. Basal cortisol levels had no apparent effect. As with the Newcastle system, there were no residual significant differences when all three covariates were considered in combination.
PM.
AND
For CORE-defined groups, differences were no longer significant at 8:00 AM after partialling out the effect of age, Table 5. Plasma Dexamethasone Concentrations (nmol/L, Untransformed Data) in DSM-III-R-, Newcastle-, and COREDefined Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (Student's t Test on natural log Transformed Data) 8 ; 0 0 AM
4 : 0 0 PM
MEL
NON-MEL
MEL
NON-MEL
DSM-III-R
8.5 _+ 3.5
8.8 ± 4.2
2.7 + 1.7
3 . 0 ± 1.9
Newcastle
7.5 ± 3.3
9 . 6 ± 3.8 b
2.1 ± 1.3
3.5 ± 2.0 <
CORE
8 . 0 _+ 3.5
9.4 ± 3.9"
2.3 ± 1.3
3 . 5 ± 2.1 c
DEXAMETHASONE
CONCENTRATIONS
IN
MELANCHOLIC
Examining D S M III-R allocations, there were no significant differences in dexamethasone concentrations between DSM-III-R-allocated melancholic and nonmelancholic patients (Table 5). For both Newcastle and CORE allocations, however, dexamethasone concentrations were lower in melancholic patients. At 8:00 AM, dexamethasone concentrations were significantly lower in Newcastle melancholics, while there was a trend for lower levels in CORE melancholics. The differences were more distinct at 4:00 PM, when concentrations were significantly lower in both Newcastle- and CORE-allocated melancholics. NONMELANCHOLIC
DIFFERENCES "p _< .I0.
~p -< .01.
BETWEEN
~p-< .001
TIENTS--THE
IN
PATIENTS.
DEXAMETHASONE
MELANCHOLIC
AND
EFFECTS
AGE
OF
CONCENTRATIONS
NONMELANCHOLIC AND
CORTISOL
PA-
LEVELS.
Table 6. Significance of Differences in Dexamethasone Concentrations between Melancholic and Nonmelancholic Groups after Covarying for Age and Cortisol Concentrations, Both Individually and Combined 8 : 0 0 AM
Definition of melancholia Newcastle CORE n.s. = non significant. "p --< .10.
"p <- .o5. ~p _< .0L ~p _< .001.
Age
4 : 0 0 PM
Cortisol
Age,
Cortisol
Age,
(8:00 AM)
cortisol
Age
( 4 : 0 0 PM)
cortisol
d
a
c
c
a
b
,
a
b
n.s.
n.s.
n.s.
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Table 7. Intercorrelations of Age, CORE, Hamilton Depression Rating Scale (21-Item), Newcastle, Postdexamethasone Cortisol, and Dexamethasone Concentrations (Pearson's Product Moment Correlations with Natural Log Transformations of Cortisol and Dexamethasone Concentrations) P o s t d e x a m e t h a s o n e cortisol
Predexamethasone Age
CORE
Newcastle
C O R E score
+.46 c
N e w c a s t l e score
+.54 c
+.76 C
Hamilton score
+.22 a
+.54 c
+.49 C
+ .03
+ .02
Predexamethasone
.05
Hamilton
cortisol
8:00 AM
4:00 PM
11:00 PM
Dexamethasone 8:00 AM
-.20'
cortisol Postdexamethasone cortisol 8:00 AM
+.44'
+.45 '
+ . 3 6 ~'
+.12"
4:00 PM
+.35'
+.41 ~
+.42"
+.20 a
+.14 ~ +.39 C
+.70 C
1 1 : 0 0 PM
+.32 ~
+.40':
+.38'
+.17 b
+ .34 b
+ .65 c
+ .76" -.47 ~
-.33 C
.50 ~
.39 ~
Dexamethasone 8:00 AM
--.18
--.24 b
--.23"
.05
-.11
-.49 C
4:00 PM
--.16
--.39"
--.3U
+.04
-.13
-.51"
+.81 c
"p --< .05.
~p -< .01. rp _< .001.
The effects of these covariates on the differences between dexamethasone levels were examined using analysis of covariance (Table 6). For Newcastle-defined subgroups, the differences in dexamethasone levels remained significant at both 8:00 AM and 4:00 PM after covarying for age, though there were only trends after covarying for cortisol levels. For the CORE-defined groups, the previous significant difference at 4:00 PM remained significant after covarying for age, though there was once more only a trend after accounting for 4:00 PM cortisol concentrations.
Melancholia as a Dimensional Construct-Correlations between CORE and Newcastle Scores, Cortisol, and Dexamethasone Concentrations CORRELATIONS. Intercorrelations between age, Newcastle scores, CORE scores, Hamilton Depression Scale scores, cortisol concentrations, and dexamethasone concentrations were examined (Table 7). Age correlated significantly with both Newcastle and CORE scores (p -< .001). Age also correlated significantly with 8:00 AM, 4:00 PM, and 11:00 PM cortisol concentrations (p --< .001), but not with either 8:00 AM or 4:00 PM dexamethasone concentrations. Both Newcastle and CORE scores correlated significantly with cortisol concentrations at 8:00 AM, 4:00 PM, and 11:00 PM (p --< .01 o r p --< .001). Newcastle and CORE scores also correlated significantly (in a negative direction) with dexamethasone concentrations at 8:00 AM and 4:00 PM, with the strongest correlations occurring at 4:00 PM (r = --.32, p --< .001; and r = - . 3 9 , p <-- .001, respectively).
There were only weak and inconsistent correlations between Hamilton scores and cortisol or dexamethasone concentrations.
THE EFFECTS
O F AGE~ D E X A M E T H A S O N E C O N C E N T R A -
TIONS~ A N D B A S A L C O R T I S O L L E V E L S O N C O R R E L A T I O N S BETWEEN NEWCASTLE/CORE SCORES AND CORTISOL CON-
The effects of age, dexamethasone concentrations, and basal cortisol levels singly and in combination were examined using partial correlations (Table 8). First, focusing on the correlations between Newcastle scores and cortisol concentrations, the correlation at 8:00 AM was no longer significant after partialling out the effect of age, but the correlations at 4:00 PM and 11:00 PM persisted. After partialling out the effects of either the relevant dexamethasone concentrations or basal cortisol levels, correlations remained significant at 8:00 AM, 4:00 PM, and 11:00 PM; however, the correlations between the Newcastle score and cortisol concentrations did not remain significant after partialling out the effects of age, dexamethasone, and basal cortisol levels in combination. Second, with respect to the correlations with CORE scores, these remained significant after partialling out for age at 8:00 AM, 4:00 PM, and 11:00 PM. Similarly, the correlations remained significant after partialling out either dexamethasone concentrations or basal cortisol levels. Even after partialling out the three covariates in combination, the correlation between CORE scores and 8:00 AM cortisol concentrations remained significant (r = .26, p --< .01). When the effect of CORE and Newcastle scores respectively on cortisol concentrations were partialled out, there CENTRATIONS.
Depressive Psychomotor
Disturbance
BIOL PSYCHIATRY 1996;40:40:941-950
T a b l e 8. E f f e c t s o f A g e , D e x a m e t h a s o n e C o n c e n t r a t i o n s ( D e x ) , a n d B a s a l C o r t i s o l C o n c e n t r a t i o n s Newcastle and CORE Melancholia Measures and Cortisol Concentrations
947
on the Correlations between the
Variable(s) partialled out f r o m m e l a n c h o l i a measure × cortisol correlations Melancholia measure Newcastle
CORE
Time 8:00 4:00 11:00 8:00 4:00 11:00
AM PM r'M AM PM eM
Nil
Age
Dex
.36 b .42' .38' .45" .4P .40'
.16 .30 b .26 b
.30' .32 C
.31 b
.39 c .28 b
.30 b .30 b
Basal cortisol
Age, Dex, basal cortisol
.36" .43" .38 c .4Y' .43' .41'"
.09 .19 .2C ~ .17
CORE
Newcastle
.06 .20 a .12 ----
---.27 t' .14 .19
"p --< .05.
~p _~ .OOl. was an effect of CORE over and above Newcastle at 8:00 AM (19 ~ .01), and an effect of Newcastle over and above CORE at 4:00 eM (p --< .05). CORRELATIONS
BETWEEN
DEXAMETHASONE
CONCEN-
T R A T I O N S AND N E W C A S T L E AND C O R E S C O R E S - - T H E FECTS
OF AGE
AND C O R T I S O L
CONCENTRATIONS.
EFThe
effects of age and cortisol concentrations on the correlations between the two melancholia measures and dexamethasone levels were examined using partial correlations (Table 9). First, the significant correlations between dexamethasone levels and both Newcastle and CORE scores at 4:00 eM (but not 8:00 AM) persisted after partialling out age. Second, when cortisol levels were partialled out there was only a significant residual correlation between dexamethasone concentrations and the CORE (but not the Newcastle) score at 4:00 PM. W h e n age and cortisol concentrations were partialled out together, there was still a significant correlation between the CORE score and dexamethasone levels at 4:00 PM (r = --.25; p --< .05) Finally, when the effect of CORE and Newcastle scores respectively on dexamethasone concentrations were partialled out, there was an effect of the CORE system over and above the Newcastle scale at 4:00 PM (p ----- .05), T a b l e 9. E f f e c t s o f A g e a n d C o r t i s o l C o n c e n t r a t i o n s and Dexamethasone Concentrations Melancholia measure Newcastle CORE
"p ~ .05.
bp ~ .Ol.
whereas there was no effect of Newcastle over and above CORE.
Discussion In this paper we examined for an association between the dexamethasone suppression test and DSM-III-R, Newcastle, and CORE definitions of m e l a n c h o l i a - - b o t h as categorical and as dimensional constructs. A standard DST procedure using plasma cortisol measurements was employed, though we acknowledge that some authorities have found postdexamethasone adrenocorticotropic hormone or 24-hour urinary free cortisol levels to offer a better index of HPA-axis disturbances in melancholia (e.g., Maes et al 1991a). First, some comments upon our findings examining melancholia and nonmelancholia when considered as categorically distinct. The CORE system performed as well as Newcastle (and better than DSM-III-R) in that both mean cortisol concentrations and nonsuppression rates were significantly increased in melancholic subjects defined by those systems; however, differences in both postdexamethasone cortisol levels and nonsuppression rates for each of these systems were dependent upon the variables of age, dexamethasone concentrations, and basal cortisol levels, with a loss of significance once these were
on the Correlations between the Newcastle
and CORE
Melancholia
Measures
Variable(s) partialled out f r o m melancholia measure × d e x a m e t h a s o n e correlations Time 8;00AM 4:00 PM 8:00 AM 4:00 PM
Nil .23 ~
--.32 h - - . 2 4u --.39b
Age
Cortisol
Age, cortisol
CORE
--.16
--.06
--.10
--.07
--.28 " --.18 .36 b
--.14 --.01 --.22 ~
--.17 --.04 --.25 a
--.04 ----
Newcastle --
---.11 --.24"
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partialled out in combination. Such an outcome is consistent with other reports that these three variables in combination provide a significant contribution to the variance of postdexamethasone cortisol levels (Maes et al 1989, 1990, 1991a, 1991b). These findings, however, do present a dilemma of interpretation. For example, although age is clearly related to cortisol concentrations independent of the depressed state, melancholic patients are also usually older than nonmelancholic subjects (Zimmerman 1986). If the chance of melancholia increases with age, then partialling out the effect of age may obscure a "true" association between a variable such as plasma cortisol levels and this clinical syndrome. There are, therefore, arguments for either covarying or not covarying for this variable. An intriguing finding when examining melancholia as a putative category was that dexamethasone levels were lower in melancholic subjects as defined by both the Newcastle and CORE systems. There was no difference in dexamethasone levels using the DSM-III-R system, a result akin to the negative findings of Maes et al (1989) with DSM-III, and consistent with that of Ritchie et al (1990), who reported a nonsignificant trend toward lower dexamethasone concentrations in their melancholic patients. The differences that we demonstrated were, however, no longer significant after partialling out the effect of cortisoi concentrations. Perhaps the most interesting and robust findings of this study were the significant correlations between both cortisol and dexamethasone levels and CORE scores when this classificatory system was considered dimensionally. A significant positive correlation between the Newcastle scale and cortisol levels has been previously reported by both Coppen et al (1983) and Christensen et al (1986). The significant correlation that we demonstrated between CORE and postdexamethasone cortisol levels is consistent with the reports of Klein et al (1984) and of Smith et al (1988), who both found a significant correlation between postdexamethasone cortisol levels and other psychomotor retardation scales (derived from the Inpatient Multidimensional Psychiatric Scale and Present State Examination, respectively). Staner et al (1992) also found, using stepwise multiple regression, that the Newcastle scale items for psychomotor retardation and weight loss contributed most to the variance of the 11:00 PM cortisol levels. After we allowed for the effects of age, dexamethasone concentrations, and basal cortisol concentrations in combination, the correlation between CORE scores and 8:00 AM cortisol concentrations remained significant. A possible effect of any of these three covariates on the correlation between cortisol levels and psychomotor retardation was not examined in the studies of Klein et al 1984 and of Smith et al 1988; however, our finding with respect to the
effect of dexamethasone levels is consistent with that of Smith et al (1988), who also found that the correlation between cortisol levels and psychomotor retardation persisted after controlling for that particular variable. In our study, the correlations between the Newcastle scale and cortisol concentrations were no longer significant at either 8"00 AM or 4:00 PM after accounting for these variables in combination. Our findings indicate a positive dimensional relationship between the CORE rating system for psychomotor disturbance and HPA-system overactivity (at least as assessed at 8:00 AM) Similarly, we found a robust correlation between CORE as a dimensional measure and dexamethasone concentrations at 4:00 eM after partialling out the effects of age, dexamethasone concentrations, and postdexamethasone cortisol levels in combination. There was no such residual significant correlation for the Newcastle system after partialling out these factors. We are not aware of any previous reports of correlates between dexamethasone levels and the Newcastle or psychomotor retardation scales. The dexamethasone findings suggest an impairment of either the absorption or metabolism of dexamethasone that is related to the psychopathology identified by the CORE rating system. Delayed absorption is an attractive proposition, as constipation (indicative of reduced gastrointestinal motility) has been classically associated with overt psychomotor retardation and psychotic depression (Parker et al 1991). Reduced gastrointestinal motility would be expected to be associated with impaired absorption of dexamethasone; however, the limited number of quality research studies of dexamethasone pharmacokinetics in depression (eg., Maguire et al 1990; Holsboer et al 1986a, 1986b; Guthrie 1991) suggest that impaired absorption is unlikely, though not definitely excluded, and rather that there may be some abnormality of dexamethasone metabolism. The significant negative correlation between CORE and dexamethasone levels suggests that high CORE scores may be associated with an increased metabolism of dexamethasone independent of the hepatic enzyme induction known to be related to hypercortisolism. This finding is consistent with the report of Devenand et al (1991), who found that clinical recovery with electroconvulsive therapy correlated more closely with normalization of dexamethasone (from low levels) than improvement in cortisol concentrations. To summarize, this study has demonstrated two potential novel determinants of HPA activity in depression. First, the CORE system for rating psychomotor disturbance correlated positively with postdexamethasone cortisol concentrations at 8:00 AM independent of age, dexamethasone levels, and basal cortisol concentrations. No significant difference persisted when melancholic patients
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were defined categorically using this system. This suggests a greater utility of dimensional over categorical melancholia constructs in examining HPA-axis activity in d e p r e s s i o n - - a conclusion also reached by Maes et al (1990). Second, CORE scores at 4:00 r'M correlated negatively with dexamethasone concentrations independent of age and cortisol levels. When we defined melancholia categorically by both this system and the Newcastle scale, differences in dexamethasone concentrations no longer remained significant after partialling out the effect of cortisol levels. As for results with CORE and cortisol, this suggests that CORE measured as a dimensional system has an advantage over CORE measured as a categorical
construct in identifying HPA-system dysfunction in melancholia. These two findings suggest, therefore, that the rates of cortisol production and dexamethasone metabolism may be independently related to the degree of "central biological disturbance" in melancholia as reflected by the C O R E system for rating psychomotor disturbance. Supported by the Australian National Health and Medical Research Council. The authors are grateful for the comments of Associate Professor Isaac Schweitzer on an earlier draft of this paper, and for the assistance of Mrs. Zora Vuckovic and Mrs. Kerrie Eyers in the preparation of the manuscript. Michael Frost recruited the normal controls.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, 3rd ed rev. Washington, DC: American Psychiatric Press. Asnis GM, Halbreigh V, Nathan RS, et al (1982): The dexamethasone suppression test in depressive illness: Clinical correlates. Psychoneuroendocrinology 7:295-301. Brodaty H, Boyce P, Wilhelm K, Mitchell PB, Parker G (1987): The establishment of a Mood Disorders Unit. Aust N Z J Psychiatry 21:375-382. Brown WA, Shuey I (1980): Response to dexamethasone and subtype of depression. Arch Gen Psychiatry 37:747-751. Calloway SP, Dolan RJ, Fonagy P, DeSouza VFA, Wakeling A (1984): Endocrine changes and clinical profiles in depression: I. The dexamethasone suppression test. Psychol Med 14:749758. Carney MWP, Roth M, Garside RF (1965): The diagnosis of depressive syndromes and the prediction of ECT response. Br J Psychiatry 11:659-674. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific laboratory test for the diagnosis of melancholia: Standardization, validation and clinical utility. Arch Gen Psychiatry 38:15-22. Christensen P, Gram LF, Kragh-Sorensen P, Nielsen S (1986): Afternoon cortisol levels before (spontaneous) and after suppression with dexamethasone or oxazepam in depressed patients. J Affect Disord 10:171-176. Coppen A, Abou-Saleh M, Milln P, Metcalfe M, Harwood J, Bailey J (1983): Dexamethasone suppression test in depression and other psychiatric illness. Br J Psychiatry 142:498504. Devanand DP, Sackeim HA, Lo E-S, et al (1991): Serial dexamethasone suppression tests and plasma dexamethasone levels. Arch Gen Psychiatry 48:525-533. Guthrie S (1991): The impact of dexamethasone pharmacokinetics on the DST: A review. Psychopharmacol Bull 27:565576. Hamilton M (1990): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62. Hickie I, Parsonage B, Parker G (1990): Predicting ECT re-
sponse: Preliminary validation of a sign-based typology of depression. Br J Psychiatry 157:65-71. Holsboer F, Wiedemann K, Gerken A, Boll E (1986a): The plasma dexamethasone variable in depression: Test-retest studies and early biophase kinetics. Psychiatry Res 17:97103. Holsboer F, Widemann K, Boll E (1986b): Shortened dexamethasone half-life in depressed dexamethasone nonsuppressors [Letter]. Arch Gen Psychiatry 43:813- 814. Hunt GE, Johnson GFS, Caterson ID (1989): The effect of age on cortisol and plasma dexamethasone concentrations in depressed patients and controls. J Affect Disord 17:21-32. Klein HE, Bender W, Mayr H, Niederschweiberer A, Schmauss M (1984): The DST and its relationship to psychiatric diagnosis, symptoms and treatment outcome. Br J Psychiatry 145:591-599. Kocsis JH, Brockner N, Butler J, Fanelli C, Stokes PE (1984): Dexamethasone suppression in major depression. Biol Psychiatry 19:1255-1259. Kraus RP, Grof P, Brown GM (1988): Drugs and the DST: Need for a reappraisal. Am J Psychiatry 145:666-673. Maes M, Minner B, Suy E (1989): The influence of dexamethasone levels on the predictive value of the DST for unipolar major depression and the relationships between postdexamethasone cortisol and ACTH levels. J Affect Disord 17:3946. Maes M, Jacobs MP, Suy E, Minner B, Raus J (1990): Prediction of the DST results in depressives by means of urinary free cortisol excretion, dexamethasone levels, and age. Biol Psychiat©' 28:349-357. Maes M, Vandervorst C, Suy E, Minner B, Raus J (1991a): A mutivariate study of simultaneous escape from suppression by dexamethasone of urinary free cortisol, plasma cortisol, adrenocorticotropic hormone and beta-endorphin in melancholic patients. Acta Psychiatr Scand 83:480-491. Maes M, Minner B, Suy E, D'Hondt P, Jacoba MP, Raus J (1991 b): Cortisol escape from suppression by dexamethasone during depression is strongly predicted by basal cortisol hypersecretion and increasing age combined. Ps3,choneuroendocrinology 16:295-310.
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Maguire KP, Tuckwell VM, Schweitzer I, Tiller JWG, Davies BM (1990): Dexamethasone kinetics in depressed patients before and after clinical response. Psychoneuroendocrinology 15:113-123. Nelson JC, Charney DS (1981): The symptoms of major depressive illness. Am J Psychiatry 138:1-13. Parker G, Hadzi-Pavlovic D, Boyce P, et al (1990): Classifying depression by mental state signs. Br J Psychiatry 157:55-64. Parker G, Hadzi-Pavlovic D, Hickie I, et al (1991): Distinguishing psychotic and non-psychotic melancholia. J Affect Disord 22:135-148. Parker G, Hadzi-Pavlovic D, Brodaty H, et al (1992): Predicting the course of melancholic and non-melancholic depression: A naturalistic comparison study. J Nerv Ment Dis 180:693702. Parker G, Hadzi-Pavlovic D, Brodaty H, et al (1993): Psychomotor disturbance in depression: Defining the constructs. JAffect Disord 27:255-265.
P. Mitchell et al
Parker G, Hadzi-Pavlovic D, Wilhelm K, et al (1994): Melancholia: Replication and refinement of a sign-based measure. Br J Psychiatry 164:316-326. Ritchie JC, Belkin BM, Krishnan KR, Nemeroff CB, Carroll BJ (1990): Plasma dexamethasone concentrations and the dexamethasone suppression test. Biol Psychiatry 27:159-173. Rush AJ, Weissenburger JE (1994): Melancholic symptom features and DSM-IV. Am J Psychiatry 151:489-498. Smith J, Carr V, Morris H, Gilliard J (1988): The dexamethasone suppression test in relation to symptomatology: Preliminary findings controlling for serum dexamethasone concentrations. Psychiatry Res 25:123-133. Staner L, Maes M, Bouillon E, Linkowski P (1992): Biological correlates of the Newcastle Scale in depressive illness: A multivariate approach. Acta Psychiatr Scand 85:345-350. Zimmerman M, Boryell W, Pfohl B (1986): The validity of the dexamethasone suppression test as a marker for endogenous depression. Arch Gen Psychiatry 43:347-355.
ORIGINALARTICLES
Depressive Psychomotor Disturbance, Cortisol, and Dexamethasone Philip Mitchell, Dusan Hadzi-Pavlovic, Gordon Parker, Ian Hickie, Kay Wilhelm, Henry Brodaty, and Philip Boyce
We examine the dexamethasone suppression test as a biological correlate of melancholia as defined by the CORE system, a scale for rating objective signs of psychomotor disturbance. Postdexamethasone cortisol concentrations and rates of nonsuppression were higher in CORE, Newcastle, and DSM-III-R defined melancholic groups. These differences, however, were no longer significant after partialling out the combined effects of age, dexamethasone, and basal cortisol concentrations. There was a significant correlation between the CORE (but not the Newcastle) scale and 8:00 AM postdexamethasone cortisol levels, which persisted after partialling out those same three covariates. Dexamethasone concentrations themselves were lower in CORE- and Newcastle-defined melancholics, though these were no longer significant after covarying for cortisol concentrations. Dexamethasone levels were also significantly inversely correlated with CORE and Newcastle scales. A significant correlation between CORE (but not Newcastle) scores and dexamethasone levels at 4:00 PM persisted after partialling out the effects of age and cortisol. These findings indicate an intriguing relationship between the CORE system as a dimensional construct for rating psychomotor disturbance, and both postdexamethasone cortisol and dexamethasone concentrations.
© 1996 Society of Biological Psychiatry Key Words: Melancholia, psychomotor disturbance, dexamethasone, cortisol, depression, classification BIOL PSYCHIATRY1996;40:941--950
Introduction "Further research is needed to empirically test the biological and psychological features associated with melancholic depression . . . "
Rush and Weissenburger (1994) From the School of Psychiatry, University of New South Wales, Sydney, N.S.W., (PM, DHP, GP, IH, KW, HB); Mood Disorders Unit, Prince Henry Hospital, Sydney, N.S.W., Australia (PM, DHP, GP, IH, KW, HB, PB); and Department of Psychological Medicine, University of Sydney, N.S.W., Australia (PB).
© /996 Society of Biological Psychiatry.
Psychomotor disturbance is one of the most consistent clinical features included in the various definitions of melancholia (Nelson and Charney 1981). We have recently developed an operationally defined scale for behavioral rating of psychomotor disturbance in depressed patients (the CORE system: Parker et al 1990, 1994). By
Address reprint requests to Associate Professor Philip Mitchell, Mood Disorders Unit, Prince Henry Hospital, Little Bay, Sydney, N.S.W., 2036, Australia. Received June 8, 1994; revised October 23, 1995.
0006-3223/96/$15.00 SSDI 0006-3,23(95)00635-4
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means of statistical techniques including latent class analysis (Parker et al 1990, 1994), and validation against a number of traditional concomitants of melancholia such as response to treatment (Hickie et al 1990) and course of illness (Parker et al 1992), we have demonstrated that this system is capable of discriminating between "melancholic" and "nonmelancholic" depression at least as well as extant classificatory systems such as DSM-III-R (APA 1987) and the Newcastle Diagnostic Index (Carney et al 1965). Unlike DSM-III-R and the Newcastle index, which include items relating both to current symptomatology as well as to longitudinal features such as premorbid personality, the CORE system is a cross-sectional assessment (or "snapshot") of current observable signs of depression. Furthermore, using principal components analysis, we have demonstrated (Parker et al 1993) three factors underlying the total CORE score, i.e., retardation, agitation, and noninteractiveness (the last being a nonmotor scale presumed to quantify dysfunctional cognitive processing). In this study, we examined the dexamethasone suppression test (DST) as a biological correlate of melancholia as defined by the CORE system, as previous research had suggested a strong relationship between psychomotor disturbance and hypothalamic-pituitary-adrenal (HPA) system overactivity. For example, Zimmerman et al (1986) tested with validity of the DST against the seven "symptoms" identified by Nelson and Charney (1981) as characteristics of endogenous depression. Of these, only scores for psychomotor retardation and depressed mood were greater in the nonsuppressors. This finding was consistent with most studies that have examined the relationship between the DST and psychomotor disturbance (Brown and Shuey 1980; Calloway et al 1984; Klein et al 1984), though there have been some negative reports (Kocsis et al 1984; Asnis et al 1982). It should be noted, however, that Zimmerman et al (1986) also found a number of nonsymptomatic features of melancholia, such as family history, demographics, and psychosocial factors, which also distinguished DST suppressed from nonsuppressed patients. Zimmerman et al (1986) also noted that nonsuppressors more frequently appeared depressed (as opposed to merely reportingfeeling depressed), leading the authors to state: " . . . observational symptom ratings may be more valid than interview based ratings, therefore possibly accounting for our failure to find a significant association with anhedonia and reactivity." The CORE system used in this present paper provides such an observational instrument, by objectively rating interactive behaviors (such as reactivity of mood) as well as features of both retardation and agitation. In this study, we examine the capacity of the DST to discriminate between patients with categorically defined
melancholic and nonmelancholic depression as defined by the DSM-III-R, Newcastle, and CORE systems. Additionally, we examine for any dimensional relationship between Newcastle and CORE scores and DST findings. Also, as age, dexamethasone levels, and basal cortisol concentrations have been found to be important determinants of postdexamethasone cortisol levels (Maes et al 1989, 1990, 1991a, 1991b), we examine for their influence as potential confounding variables.
Methods Consecutive inpatients with primary Major Depression of the Prince Henry Hospital Mood Disorders Unit, Sydney were included in the study. After applying standard exclusion criteria (Carroll et al 1981), 114 patients were recruited. Subjects taking antidepressant and antipsychotic medications were included (e.g., Klein et al 1984; Hunt et al 1989), whereas those on anticonvulsants were excluded. Fifty-seven patients were on long-term antidepressant medication, and 21 on an antipsychotic. Psychotropics were not ceased prior to the dexamethasone suppression test, nor were new treatments initiated before this was performed. Using a semistructured interview instrument (Brodaty et al 1987), patients were diagnosed according to DSM-III-R criteria. Concurrently, patients were rated on the Newcastle and CORE systems and the Hamilton Depression Severity scale (17 and 21 items) (Hamilton 1960). Diagnoses were made blind to DST results. Using preestablished cutoff scores, patients were diagnosed as "endogenous" with Newcastle scores -->6, and "melancholic" with scores -> 8 using the CORE system. Blood samples for basal predexamethasone cortisol concentrations were taken at 4:00 PM on day 1, with dexamethasone, 1 mg, being administered orally at 11:00 PM that night. The following day, blood was collected at 8:00 AM and 4:00 PM for cortisol and dexamethasone determinations, and at 11:00 PM for cortisol levels only. Blood was taken by simple needle stick venipuncture. The dexamethasone suppression tests were undertaken 3-7 days after admission. Plasma cortisol was assayed by radioimmunoassay using a kit supplied by Orion Diagnostica, Finland. The interassay and intraassay coefficients of variation were 4.5% and 7.1% at 162 nmol/L; 4.0% and 7.6% at 494 nmol/L; and 4.9% and 11.2% at 785 nmol/L, respectively. Plasma dexamethasone was measured by radioimmunoassay (based on a method used in the Endocrine Laboratory, Royal Prince Alfred Hospital, Sydney) using antisera purchased from Professor Vecsei, Department of Pharmacology, University of Heidelberg, Germany. The interassay and intraassay coefficients of variation were 9.2% and
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Table 1. Plasma Cortisol Concentrations (nmol/L, Untransformed Data) in DSM-III-R-, Newcastle-, and CORE-Defined Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (Student's t Test on Natural Log Transformed Data) Day 1 (predexamethasone)
Day 2 (postdexamethasone)
4:00 PM
8:00 AM
4:00 PM
1 I:00 PM
MEL
NON-MEL
MEL
NON-MEL
MEL
NON-MEL
MEL
NON-MEL
DSM-IIIR
295.5 ± 157.4
316.8 ± 134.8
135.2 + 168.2
83.2 ± 113.3
172.6 ± 165.0
99.0 ± 95.0 ~
119.4 ± 127.7
67.2 ± 61.9 ~
Newcastle
313.2 ± 160.8
285.9 ± 143.1
163.8 + 182.5
81.0 ± 115.7'
200.3 ± 150.0
109.2 ± 146.5 c
131.3 ± 104.7
82.5 ± 126.1 c
CORE
297.0 + 157.1
303.6 ± 149.3
160.1 ± 179.5
70.9 ± 102.9 c
192.2 ± 163.8
103.5 ± 125.3 b
122.9 + 102.8
84.8 ± 136.1 ~'
~p --< .05. t,p < .01. "p "< .001
16.5% at 1.3 nmol/L; and 10.4% and 15.5% at 10.9 nmol/L, respectively. Assays were performed in different runs.
Cortisol nonsuppression thresholds were determined in our own laboratory by comparing the depressed patients with 25 normal controls screened to exclude physical or psychiatric illnesses. Receiver operating characteristics (ROC) analysis was used to compute optimal thresholds for nonsuppression to distinguish controls from those subjects fulfilling criteria for DSM-III-R melancholia (n = 77). The resulting cutoffs were: 8:00 AM, --> 71 nmol/L; and 4:00 PM, ~ 70 nmol/U (It was not possible to determine 11:00 PM thresholds as postdexamethasone samples were only taken in controls at 8:00 AM and 4:00 PM,) Patients were only included in the final analyses if cortisol and dexamethasone results for each postdexamethasone time point were available. This resulted in a final sample of 100 subjects being included in this report. Results are expressed as means (_+ standard deviation). Postdexamethasone cortisol concentrations were examined both dimensionally (mean levels) and categorically (i.e, as suppression vs. nonsuppression). Groups were compared using Student's t test and X2 test respectively, while for correlational analyses, Pearson's correlations were performed. The effect of covariates on any differences in cortisol levels between groups was examined using A N C O V A (analysis of covariance), while their effect on DST nonsuppression rates was examined by logistic regression. Although raw (untransformed) data for cortisol and dexamethasone concentrations are presented in this paper, these were natural log (in) transformed prior to all statistical analyses.
Results Sample The final sample comprised 100 patients (69 women, 31 men; mean age 54.4 _ 17.5 years). The mean Hamilton scores were: 17 item = 23.2 ± 6.5, 21 item = 25.1 _+ 7.1.
The number of patients diagnosed as melancholic or endogenous according to the various systems were: DSMIII-R = 77, Newcastle = 51, and CORE = 59 (with a CORE rating missing for 1 patient). In the remainder of this article the term "melancholia" will be used to subsume both melancholic and endogenous depression diagnoses. Melancholic patients were significantly older than nonmelancholic patients as allocated by both the Newcastle (62.4 _+ 15.0 vs. 46.1 _+ 16.1 years; t = - 5 . 2 5 , p < .001) and CORE (60.5 -+ 15.2 vs. 45.2 --- 17.0 years; t = - 4 . 7 1 , p < .001) systems. There was a trend toward a significant difference in the ages of the respective DSM-III-R subgroups (56.1 _+ 16.5 vs. 48.6 4- 19.8 years; t = - 1 . 8 4 , p = .07). EFFECT OF PSYCHOTROPIC MEDICATIONS. In view of concern by some authorities (e.g., Kraus et al 1988) of an effect of antidepressant and antipsychotic medications on the DST, we examined for any such confound in this sample. There were no significant differences in cortisol concentrations (either pre- or postdexamethasone) or dexamethasone levels between those patients either on or off antidepressant or antipsychotic medications. For example, the 8:00 AM postdexamethasone cortisol levels on and off antidepressants (n = 57 and 43, respectively) and antipsychotics (n = 21 and 79, respectively) were: 135.4 _+ 173.3 vs. 107.1 _ 136.0 nmol/L (t = 0.18, df = 98, p = .86) and 147.4 + 161.8 vs. 116.8 -+ 157.7 nmol/L (t = 1.32, df = 98, p = .19).
Melancholia as a Categorical Construct--Cortisol Concentrations, Nonsuppression Rates, and Dexamethasone Concentrations CORTISOL
CONCENTRATIONS
IN
MELANCHOLIC
AND
NONMELANCHOLICPATIENTS. There were no significant differences between melancholic and nonmelancholic patients as allocated by the three diagnostic systems in the day 1 4:00 PM predexamethasone cortisol concentrations (Table 1).
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Table 2. Significance of Differences in Postdexamethasone Cortisol Concentrations between Melancholic and Nonmelancholic Groups after Covarying for Age, Dexamethasone Concentrations (Dex), and Basal Cortisol Concentrations (Cort), Both Individually and Combined (Analysis of Covariance) 8:00 AM
4:00 PM
l l : 0 0 PM
Dex
Basal
Age, Dex,
Dex
Basal
Age,
Age
(8:00 AM)
cortisol
Cort
Age
(4:00PM)
cortisol
Dex, Cort
Age
cortisol
Basal
DSM-III-R Newcastle
n.s. n.s.
" b
" d
n.s. n.s.
n.s. c
" ~
b d
~ n.s.
~ b
c d
CORE
n.s.
'
d
n.s.
a
a
d
n.s.
n.s.
"
n.s. = non significant. °p -< .10. bp <_ .05. "p <_ .ol. dp < .001.
At 8:00 AM on day 2, cortisol concentrations were significantly higher in both Newcastle- and CORE-, but not DSM-III-R-defined melancholies. At 4:00 PM and 11 PM cortisol levels were higher in the melancholies as defined by each system, particularly so in the Newcastleand CORE-defined groups. CORTISOL
CONCENTRATIONS
NONMELANCHOLIC
IN
MELANCHOLIC
DEPRESSIVES--THE
EFFECTS
Third, for CORE-defined subgroups, the differences in cortisol levels at 8:00 AM, 4:00 PM, and 11:00 PM all lost significance after covarying for age. After covarying for dexamethasone concentrations, the differences in cortisol levels only remained significant at 8:00 AM. In general, differences remained significant after covarying for basal cortisol levels. As with the Newcastle scale, however, there were no remaining significant differences between CORE-defined groups after age, dexamethasone, and basal cortisol levels were covaried out together.
AND
O F AGE~
D E X A M E T H A S O N E C O N C E N T R A T I O N S , AND BASAL C O R T I S O L
LEVELS. The effects of these factors were examined using analysis of covariance (ANCOVA) (Table 2). First, for DSM-III-R-defined melancholic and nonmelancholic groups, at 8:00 AM and 4:00 PM, there were no remaining significant differences after covarying for these variables either singly or in combination, with the exception of the 4:00 PM comparison after controlling for basal cortisol levels alone. Second, with Newcastle-defined groups, the differences in cortisol concentrations were no longer significant after covarying for age at 8:00 AM, though significant differences remained at 4:00 PM and 11:00 PM. After covarying for the relevant dexamethasone concentrations, the differences in cortisol levels continued to remain significant at both 8:00 AM and 4:00 PM. Similarly, significant differences remained at each time point after covarying for basal cortisol levels. When covarying for age, dexamethasone levels and basal cortisol levels together, however, there were no remaining significant differences.
NONSUPPRESSION RATES
IN M E L A N C H O L I C
AND
NON-
MELANCHOLIC PATIENTS. Nonsuppression rates were significantly different between melancholic and nonmelancholic patients using both the Newcastle and CORE systems at either individual time points (i.e., 8:00 AM or 4:00 PM) or when combined time points (8:00 AM and/or 4:00 PM) were considered (p < .01-p < .001). (Table 3) For DSM-III-R melancholic patients, nonsuppression rates were not higher at any single or combined time points. NONSUPPRESSION MELANCHOLIC METHASONE~
RATES
IN M E L A N C H O L I C
PATIENTS~THE AND
BASAL
EFFECTS
CORTISOL
AND
NON-
O F AGE~ D E X A -
CONCENTRATIONS.
The effects of these covariates on nonsuppression rates were examined using logistic regression (Table 4). As dexamethasone levels were only assayed at 8:00 AM and 4:00 PM, we will focus on those time points. For Newcastle-defined subgroups, the difference in
Table 3. Nonsuppression Rates (%) in Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (X2 Comparison) 8:00 A M MEL
4;00 PM NON-MEL
8:00 A M or 4:00 PM
MEL
NON-MEL
MEL
NON-MEL 43.5
DSM-III-R
44.2
26.1
57.1
43.5
61.0
Newcastle
52.9
26.5 ~
72.5
34.7 b
74.5
38.8 b
CORE
50.8
25.0 a
67.8
35.0 b
69.5
40.0"
~p --< .01. bp _< .001.
Depressive Psychomotor Disturbance
BIOL PSYCHIATRY 1996;40:40:941-950
945
Table 4. Logistic Regression of Suppression and Nonsuppression: Effects of Age, Basal Cortisol Concentrations, and Dexamethasone Concentrations on the Significance of Diagnostic Status 8 : 0 0 AM
Newcastle
4 : 0 0 PM
.008
.463
.083
.008
.904
.000
.006
.034
.000
.418
Age
--
.001
--
--
.002
--
.150
--
--
.028
Dexamethasone
--
--
.005
--
.006
--
--
.000
--
.000
Basal cortisol
--
--
--
.297
.348
--
--
--
.002
.005
concentrations CORE
.012
.402
.037
.011
.636
.002
.030
.084
.001
.484
Age
--
.001
--
--
.002
--
.061
--
--
.015
Dexamethasone
--
--
.002
--
.005
--
--
.000
--
.000
Basal cortisol
--
--
--
.177
.347
--
--
--
.001
.004
concentrations - not entered.
nonsuppression rates at the 8:00 AM time point were no longer significant after partialling out age, though the significant difference persisted at 4:00 PM. W h e n relevant dexamethasone concentrations were partialled out, the differences between groups were again significant at 4:00 eM, but not at 8:00 AM. Basal cortisol levels did not have a significant effect upon the differences. When all three covariates, however, were partialled out in combination there were no residual differences at either 8:00 AM or 4:00
though there was still a difference at 4:00 PM. When the effect of dexamethasone concentrations was partialled out, significant differences persisted at 8:00 AM but not at 4:00 PM. Basal cortisol levels had no apparent effect. As with the Newcastle system, there were no residual significant differences when all three covariates were considered in combination.
PM.
AND
For CORE-defined groups, differences were no longer significant at 8:00 AM after partialling out the effect of age, Table 5. Plasma Dexamethasone Concentrations (nmol/L, Untransformed Data) in DSM-III-R-, Newcastle-, and COREDefined Melancholic (MEL) and Nonmelancholic (NON-MEL) Depression (Student's t Test on natural log Transformed Data) 8 ; 0 0 AM
4 : 0 0 PM
MEL
NON-MEL
MEL
NON-MEL
DSM-III-R
8.5 _+ 3.5
8.8 ± 4.2
2.7 + 1.7
3 . 0 ± 1.9
Newcastle
7.5 ± 3.3
9 . 6 ± 3.8 b
2.1 ± 1.3
3.5 ± 2.0 <
CORE
8 . 0 _+ 3.5
9.4 ± 3.9"
2.3 ± 1.3
3 . 5 ± 2.1 c
DEXAMETHASONE
CONCENTRATIONS
IN
MELANCHOLIC
Examining D S M III-R allocations, there were no significant differences in dexamethasone concentrations between DSM-III-R-allocated melancholic and nonmelancholic patients (Table 5). For both Newcastle and CORE allocations, however, dexamethasone concentrations were lower in melancholic patients. At 8:00 AM, dexamethasone concentrations were significantly lower in Newcastle melancholics, while there was a trend for lower levels in CORE melancholics. The differences were more distinct at 4:00 PM, when concentrations were significantly lower in both Newcastle- and CORE-allocated melancholics. NONMELANCHOLIC
DIFFERENCES "p _< .I0.
~p -< .01.
BETWEEN
~p-< .001
TIENTS--THE
IN
PATIENTS.
DEXAMETHASONE
MELANCHOLIC
AND
EFFECTS
AGE
OF
CONCENTRATIONS
NONMELANCHOLIC AND
CORTISOL
PA-
LEVELS.
Table 6. Significance of Differences in Dexamethasone Concentrations between Melancholic and Nonmelancholic Groups after Covarying for Age and Cortisol Concentrations, Both Individually and Combined 8 : 0 0 AM
Definition of melancholia Newcastle CORE n.s. = non significant. "p --< .10.
"p <- .o5. ~p _< .0L ~p _< .001.
Age
4 : 0 0 PM
Cortisol
Age,
Cortisol
Age,
(8:00 AM)
cortisol
Age
( 4 : 0 0 PM)
cortisol
d
a
c
c
a
b
,
a
b
n.s.
n.s.
n.s.
946
BIOLPSYCHIATRY
P. Mitchell et al
1996;40:40:941-950
Table 7. Intercorrelations of Age, CORE, Hamilton Depression Rating Scale (21-Item), Newcastle, Postdexamethasone Cortisol, and Dexamethasone Concentrations (Pearson's Product Moment Correlations with Natural Log Transformations of Cortisol and Dexamethasone Concentrations) P o s t d e x a m e t h a s o n e cortisol
Predexamethasone Age
CORE
Newcastle
C O R E score
+.46 c
N e w c a s t l e score
+.54 c
+.76 C
Hamilton score
+.22 a
+.54 c
+.49 C
+ .03
+ .02
Predexamethasone
.05
Hamilton
cortisol
8:00 AM
4:00 PM
11:00 PM
Dexamethasone 8:00 AM
-.20'
cortisol Postdexamethasone cortisol 8:00 AM
+.44'
+.45 '
+ . 3 6 ~'
+.12"
4:00 PM
+.35'
+.41 ~
+.42"
+.20 a
+.14 ~ +.39 C
+.70 C
1 1 : 0 0 PM
+.32 ~
+.40':
+.38'
+.17 b
+ .34 b
+ .65 c
+ .76" -.47 ~
-.33 C
.50 ~
.39 ~
Dexamethasone 8:00 AM
--.18
--.24 b
--.23"
.05
-.11
-.49 C
4:00 PM
--.16
--.39"
--.3U
+.04
-.13
-.51"
+.81 c
"p --< .05.
~p -< .01. rp _< .001.
The effects of these covariates on the differences between dexamethasone levels were examined using analysis of covariance (Table 6). For Newcastle-defined subgroups, the differences in dexamethasone levels remained significant at both 8:00 AM and 4:00 PM after covarying for age, though there were only trends after covarying for cortisol levels. For the CORE-defined groups, the previous significant difference at 4:00 PM remained significant after covarying for age, though there was once more only a trend after accounting for 4:00 PM cortisol concentrations.
Melancholia as a Dimensional Construct-Correlations between CORE and Newcastle Scores, Cortisol, and Dexamethasone Concentrations CORRELATIONS. Intercorrelations between age, Newcastle scores, CORE scores, Hamilton Depression Scale scores, cortisol concentrations, and dexamethasone concentrations were examined (Table 7). Age correlated significantly with both Newcastle and CORE scores (p -< .001). Age also correlated significantly with 8:00 AM, 4:00 PM, and 11:00 PM cortisol concentrations (p --< .001), but not with either 8:00 AM or 4:00 PM dexamethasone concentrations. Both Newcastle and CORE scores correlated significantly with cortisol concentrations at 8:00 AM, 4:00 PM, and 11:00 PM (p --< .01 o r p --< .001). Newcastle and CORE scores also correlated significantly (in a negative direction) with dexamethasone concentrations at 8:00 AM and 4:00 PM, with the strongest correlations occurring at 4:00 PM (r = --.32, p --< .001; and r = - . 3 9 , p <-- .001, respectively).
There were only weak and inconsistent correlations between Hamilton scores and cortisol or dexamethasone concentrations.
THE EFFECTS
O F AGE~ D E X A M E T H A S O N E C O N C E N T R A -
TIONS~ A N D B A S A L C O R T I S O L L E V E L S O N C O R R E L A T I O N S BETWEEN NEWCASTLE/CORE SCORES AND CORTISOL CON-
The effects of age, dexamethasone concentrations, and basal cortisol levels singly and in combination were examined using partial correlations (Table 8). First, focusing on the correlations between Newcastle scores and cortisol concentrations, the correlation at 8:00 AM was no longer significant after partialling out the effect of age, but the correlations at 4:00 PM and 11:00 PM persisted. After partialling out the effects of either the relevant dexamethasone concentrations or basal cortisol levels, correlations remained significant at 8:00 AM, 4:00 PM, and 11:00 PM; however, the correlations between the Newcastle score and cortisol concentrations did not remain significant after partialling out the effects of age, dexamethasone, and basal cortisol levels in combination. Second, with respect to the correlations with CORE scores, these remained significant after partialling out for age at 8:00 AM, 4:00 PM, and 11:00 PM. Similarly, the correlations remained significant after partialling out either dexamethasone concentrations or basal cortisol levels. Even after partialling out the three covariates in combination, the correlation between CORE scores and 8:00 AM cortisol concentrations remained significant (r = .26, p --< .01). When the effect of CORE and Newcastle scores respectively on cortisol concentrations were partialled out, there CENTRATIONS.
Depressive Psychomotor
Disturbance
BIOL PSYCHIATRY 1996;40:40:941-950
T a b l e 8. E f f e c t s o f A g e , D e x a m e t h a s o n e C o n c e n t r a t i o n s ( D e x ) , a n d B a s a l C o r t i s o l C o n c e n t r a t i o n s Newcastle and CORE Melancholia Measures and Cortisol Concentrations
947
on the Correlations between the
Variable(s) partialled out f r o m m e l a n c h o l i a measure × cortisol correlations Melancholia measure Newcastle
CORE
Time 8:00 4:00 11:00 8:00 4:00 11:00
AM PM r'M AM PM eM
Nil
Age
Dex
.36 b .42' .38' .45" .4P .40'
.16 .30 b .26 b
.30' .32 C
.31 b
.39 c .28 b
.30 b .30 b
Basal cortisol
Age, Dex, basal cortisol
.36" .43" .38 c .4Y' .43' .41'"
.09 .19 .2C ~ .17
CORE
Newcastle
.06 .20 a .12 ----
---.27 t' .14 .19
"p --< .05.
~p _~ .OOl. was an effect of CORE over and above Newcastle at 8:00 AM (19 ~ .01), and an effect of Newcastle over and above CORE at 4:00 eM (p --< .05). CORRELATIONS
BETWEEN
DEXAMETHASONE
CONCEN-
T R A T I O N S AND N E W C A S T L E AND C O R E S C O R E S - - T H E FECTS
OF AGE
AND C O R T I S O L
CONCENTRATIONS.
EFThe
effects of age and cortisol concentrations on the correlations between the two melancholia measures and dexamethasone levels were examined using partial correlations (Table 9). First, the significant correlations between dexamethasone levels and both Newcastle and CORE scores at 4:00 eM (but not 8:00 AM) persisted after partialling out age. Second, when cortisol levels were partialled out there was only a significant residual correlation between dexamethasone concentrations and the CORE (but not the Newcastle) score at 4:00 PM. W h e n age and cortisol concentrations were partialled out together, there was still a significant correlation between the CORE score and dexamethasone levels at 4:00 PM (r = --.25; p --< .05) Finally, when the effect of CORE and Newcastle scores respectively on dexamethasone concentrations were partialled out, there was an effect of the CORE system over and above the Newcastle scale at 4:00 PM (p ----- .05), T a b l e 9. E f f e c t s o f A g e a n d C o r t i s o l C o n c e n t r a t i o n s and Dexamethasone Concentrations Melancholia measure Newcastle CORE
"p ~ .05.
bp ~ .Ol.
whereas there was no effect of Newcastle over and above CORE.
Discussion In this paper we examined for an association between the dexamethasone suppression test and DSM-III-R, Newcastle, and CORE definitions of m e l a n c h o l i a - - b o t h as categorical and as dimensional constructs. A standard DST procedure using plasma cortisol measurements was employed, though we acknowledge that some authorities have found postdexamethasone adrenocorticotropic hormone or 24-hour urinary free cortisol levels to offer a better index of HPA-axis disturbances in melancholia (e.g., Maes et al 1991a). First, some comments upon our findings examining melancholia and nonmelancholia when considered as categorically distinct. The CORE system performed as well as Newcastle (and better than DSM-III-R) in that both mean cortisol concentrations and nonsuppression rates were significantly increased in melancholic subjects defined by those systems; however, differences in both postdexamethasone cortisol levels and nonsuppression rates for each of these systems were dependent upon the variables of age, dexamethasone concentrations, and basal cortisol levels, with a loss of significance once these were
on the Correlations between the Newcastle
and CORE
Melancholia
Measures
Variable(s) partialled out f r o m melancholia measure × d e x a m e t h a s o n e correlations Time 8;00AM 4:00 PM 8:00 AM 4:00 PM
Nil .23 ~
--.32 h - - . 2 4u --.39b
Age
Cortisol
Age, cortisol
CORE
--.16
--.06
--.10
--.07
--.28 " --.18 .36 b
--.14 --.01 --.22 ~
--.17 --.04 --.25 a
--.04 ----
Newcastle --
---.11 --.24"
948
BIOLPSYCHIATRY
P. Mitchell et al
1996:40:40:941-950
partialled out in combination. Such an outcome is consistent with other reports that these three variables in combination provide a significant contribution to the variance of postdexamethasone cortisol levels (Maes et al 1989, 1990, 1991a, 1991b). These findings, however, do present a dilemma of interpretation. For example, although age is clearly related to cortisol concentrations independent of the depressed state, melancholic patients are also usually older than nonmelancholic subjects (Zimmerman 1986). If the chance of melancholia increases with age, then partialling out the effect of age may obscure a "true" association between a variable such as plasma cortisol levels and this clinical syndrome. There are, therefore, arguments for either covarying or not covarying for this variable. An intriguing finding when examining melancholia as a putative category was that dexamethasone levels were lower in melancholic subjects as defined by both the Newcastle and CORE systems. There was no difference in dexamethasone levels using the DSM-III-R system, a result akin to the negative findings of Maes et al (1989) with DSM-III, and consistent with that of Ritchie et al (1990), who reported a nonsignificant trend toward lower dexamethasone concentrations in their melancholic patients. The differences that we demonstrated were, however, no longer significant after partialling out the effect of cortisoi concentrations. Perhaps the most interesting and robust findings of this study were the significant correlations between both cortisol and dexamethasone levels and CORE scores when this classificatory system was considered dimensionally. A significant positive correlation between the Newcastle scale and cortisol levels has been previously reported by both Coppen et al (1983) and Christensen et al (1986). The significant correlation that we demonstrated between CORE and postdexamethasone cortisol levels is consistent with the reports of Klein et al (1984) and of Smith et al (1988), who both found a significant correlation between postdexamethasone cortisol levels and other psychomotor retardation scales (derived from the Inpatient Multidimensional Psychiatric Scale and Present State Examination, respectively). Staner et al (1992) also found, using stepwise multiple regression, that the Newcastle scale items for psychomotor retardation and weight loss contributed most to the variance of the 11:00 PM cortisol levels. After we allowed for the effects of age, dexamethasone concentrations, and basal cortisol concentrations in combination, the correlation between CORE scores and 8:00 AM cortisol concentrations remained significant. A possible effect of any of these three covariates on the correlation between cortisol levels and psychomotor retardation was not examined in the studies of Klein et al 1984 and of Smith et al 1988; however, our finding with respect to the
effect of dexamethasone levels is consistent with that of Smith et al (1988), who also found that the correlation between cortisol levels and psychomotor retardation persisted after controlling for that particular variable. In our study, the correlations between the Newcastle scale and cortisol concentrations were no longer significant at either 8"00 AM or 4:00 PM after accounting for these variables in combination. Our findings indicate a positive dimensional relationship between the CORE rating system for psychomotor disturbance and HPA-system overactivity (at least as assessed at 8:00 AM) Similarly, we found a robust correlation between CORE as a dimensional measure and dexamethasone concentrations at 4:00 eM after partialling out the effects of age, dexamethasone concentrations, and postdexamethasone cortisol levels in combination. There was no such residual significant correlation for the Newcastle system after partialling out these factors. We are not aware of any previous reports of correlates between dexamethasone levels and the Newcastle or psychomotor retardation scales. The dexamethasone findings suggest an impairment of either the absorption or metabolism of dexamethasone that is related to the psychopathology identified by the CORE rating system. Delayed absorption is an attractive proposition, as constipation (indicative of reduced gastrointestinal motility) has been classically associated with overt psychomotor retardation and psychotic depression (Parker et al 1991). Reduced gastrointestinal motility would be expected to be associated with impaired absorption of dexamethasone; however, the limited number of quality research studies of dexamethasone pharmacokinetics in depression (eg., Maguire et al 1990; Holsboer et al 1986a, 1986b; Guthrie 1991) suggest that impaired absorption is unlikely, though not definitely excluded, and rather that there may be some abnormality of dexamethasone metabolism. The significant negative correlation between CORE and dexamethasone levels suggests that high CORE scores may be associated with an increased metabolism of dexamethasone independent of the hepatic enzyme induction known to be related to hypercortisolism. This finding is consistent with the report of Devenand et al (1991), who found that clinical recovery with electroconvulsive therapy correlated more closely with normalization of dexamethasone (from low levels) than improvement in cortisol concentrations. To summarize, this study has demonstrated two potential novel determinants of HPA activity in depression. First, the CORE system for rating psychomotor disturbance correlated positively with postdexamethasone cortisol concentrations at 8:00 AM independent of age, dexamethasone levels, and basal cortisol concentrations. No significant difference persisted when melancholic patients
Depressive Psychomotor Disturbance
BIOL PSYCHIATRY
949
1996;40:40:941-950
were defined categorically using this system. This suggests a greater utility of dimensional over categorical melancholia constructs in examining HPA-axis activity in d e p r e s s i o n - - a conclusion also reached by Maes et al (1990). Second, CORE scores at 4:00 r'M correlated negatively with dexamethasone concentrations independent of age and cortisol levels. When we defined melancholia categorically by both this system and the Newcastle scale, differences in dexamethasone concentrations no longer remained significant after partialling out the effect of cortisol levels. As for results with CORE and cortisol, this suggests that CORE measured as a dimensional system has an advantage over CORE measured as a categorical
construct in identifying HPA-system dysfunction in melancholia. These two findings suggest, therefore, that the rates of cortisol production and dexamethasone metabolism may be independently related to the degree of "central biological disturbance" in melancholia as reflected by the C O R E system for rating psychomotor disturbance. Supported by the Australian National Health and Medical Research Council. The authors are grateful for the comments of Associate Professor Isaac Schweitzer on an earlier draft of this paper, and for the assistance of Mrs. Zora Vuckovic and Mrs. Kerrie Eyers in the preparation of the manuscript. Michael Frost recruited the normal controls.
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