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Noradrenergic function and the cortisol response to dexamethasone in depression
Pswhiarrja Research,
15, 5- I5
5
Elsevier
Noradrenergic Function and the Dexamethasone in Depression A. Lawrence Rubin, Lawrence George R. Heninger
H. Price,
Cortisol
Dennis
Received June 29. 1984; revised version received November 1984.
S. Charney,
Response
to
and
26, 1984; accepted December 20,
Abstract. Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and the noradrenergic system have been reported in depression. To study possible interrelations between these two systems, plasma free 3-methoxy-4-hydroxyphenylglycol (MPHG) was compared with the cortisol response to dexamethasone in 64 depressed patients. Postdexamethasone cortisol nonsuppressors had higher baseline plasma free MHPG values than did cortisol suppressors. Increased severity of some depressive symptoms was associated with increased postdexamethasone cortisol levels. These results indicate that depressed patients with dexamethasone nonsuppression have increased noradrenergic turnover. Key Words. Norepinephrine, dexamethasone 3-methoxy-4-hydroxyphenylglycol (MHPG).
suppression cortisol.
test. depression,
It has been suggested that the hypersecretion of cortisol seen in depression might reflect an underlying noradrenergic deficiency (Schildkraut and Kety, 1967; Bunney and Davis, 1965; Checkley, 1979; Sachar et al., 1981). This hypothesis is based on research in laboratory animals indicating that norepinephrine inhibits adrenocorticotropic hormone (ACTH) secretion by inhibiting corticotropin-releasing factor (CRF) release within the hypothalamus (Weiner and Ganong, 1978). Other preclinical investigations, however, have indicated excitatory actions of the noradrenergic system on the hypothalamic-pituitary-adrenal (HPA) axis (Rees et al., 1970; Weiner and Ganong, 1978; Raymond et al., 1981; Mezey et al., 1983). Several clinical studies seem to be consistent with this excitatory effect in demonstrating positive correlations between cortisol secretion and measures of noradrenergic function (Stokes et al., 198 I; Jimerson et al., 1983; Rosenbaum et al., 1983). However, most studies have involved relatively small patient samples or have not systematically controlled several clinical factors that might affect noradrenergic and HPA function. In the present study, we examined the relationship between norepinephrine turnover and HPA function in a large sample of depressed patients who were
A. Lawrence Rubin. M.D., is Postdoctoral Fellow; Lawrence H. Price, M.D., and Dennis S. Charney. M.D.. are Assistant Professors of Psychiatry; and George R. Heninger, M.D., is Professor of Psychiatry, Yale University School of Medicine and The Connecticut Mental Health Center, Ribicoff Research Facilities. New Haven, CT. Dr. Rubin is currently at Falkirk Hospital. P.O. Box 194. Central Valley. NY 10917. (Reprint requests to Dr. L.H. Price, The Connecticut Mental Health Center, 34 Park St., Rm. 358, New Haven. CT 06508. USA.) 0165-1781
85 $03.30 % 1985 Elsevier Science Publishers
B.V.
6
participating
in controlled
clinical
studies
of noradrenergic
function
using a challenge
paradigm as previously reported (Charney et al.. 198 I, 1984). Noradrenergic turnover was assessed by measurement of plasma free Smethoxy-4-hydroxyphenylglycol (MHPG). Plasma MHPG correlates with more direct measures of brain norepinephrine 1982),
turnover
suggesting
(Karoum that
it may
et al.,
1977; Jimerson
serve
as a valid
index
et al..
1981; Elsworth
of central
et al.,
noradrenergic
metabolism (Leckman and Maas. 1984). even though a substantial proportion of plasma M HPG appears to be derived from peripheral sources (Blombery et al. 1980; Kopin et al.. 1984). HPA activity was assessed by measurement of plasma cortisol following oral administration of dexamethasone (Carroll et al., 1981). in addition. depressive symptomatology was assessed using a modified version of the Hamilton Rating Scale for Depression (Hamilton. 1960).
Methods Subjects. Sixty-four depressed patients (3 I male. 33 female; mean age. 41.X + SD 13.4 years: age range. 18-68 years) participated in this study. Forty-one patients were hospitalired on the Clinical Research Unit of the Connecticut Mental Health Center and 23 were treated as outpatients at the same facility. All patients met DSM-//I criteria (American Psychiatric Association, 1980) for major depression; 60 were unipolar and 4 were bipolar. Unipolar DSM-//I depressive subtypes were as follows: 29 nonmelancholic. 21 nonpsqchotic melancholic. and IO psychotIc melancholic. The bipolar L>SM-///depressive subtypes included 2 nonmelancholic, I nonpsychotic melancholic. and I psychotic melancholic. As there were no significant differences between unipolar and bipolar patients on postdexamethasone cortisol measures or plasma M H PC, the two groups were combined according 10 LIShf-l/l subtype. Similarly, psychotic and nonpsychotic melancholic patients were combined because of the lack of cortisol differences between these groups. All patients were free of significant medical problems as determined by a complete medical and neurological examination. including ECG and laboratory tests of renal, hepatic. pancreatic. hematopoetic. and thyroid function. A modified 32-item Hamilton Rating Scale for Depression (HRSD) was completed by trained psychiatric research nurses within 8 days of the M H PG samplings. The nurse raters were unaware of results of the plasma cortisol and M H PC; determmatlons. The mean pretreatment total HRSD score was 41.9 f SD 10.X. Procedures. A dexamethasone suppression test (DST) was administered to all patients (Carroll et al.. 1981). Dexamethasone. I mg. was given orall) at I I p.m.. and blood was drawn for cortisol determination the following day. al 4 p.m. and I I p.m. for inpatients and at 4 p.m. only for outpatients. Fifty-one patients were tested before beginning antidepressant treatment. and I3 patients were being treated with antidepressants and/or neuroleptics at the time of the DST. Since it has been reported that the DST is unaffected by antidepressant or neuroleptic use (Carroll et al., 1981). the results of these two groups were combined. Patients were judged nonsuppressors if any postdexamethasone plasma cortisol level was 2 5 pg;dl (Carroll et al.. 19X1). For determination of plasma cortisol. 5 cc of blood was collected in a hepariniled tube. Plasma was separated and stored at -20°C until assayed. Cortisol concentrations were measured by a fluorometric assay (DeMoor et al.. 1960; Mattingly. 1962). with an intra-assay coefficient of variation of 3Fc and an interassay coefficient of variation of 8C; (R.K. Donabedian. M.D.. personal communication). At the time blood samples for MHPG were obtained. 52 subjects had been free of psychotropic medication (except for benrodiarepine hypnotics) for at least 2 weeks, X subjects had been medication-free between 2 weeks and 7 days. and 4 subjects had been off medication for only 7 days. The correlation between days off medication and MHPG was not significant (r = -0.17. p > 0. IO). Beginning at X:30 a.m.. two baseline blood samples were obtained I5
7
minutes apart on each of two noradrenergic challenge days. Thus. four determinations of baseline MHPG were obtained. The mean of the four MHPG values was used to calculate “baseline M HPG.” The mean time interval between the two test days was 5.5 days (range, I to 18 days). Patients were instructed to adhere to a vanillylmandelic acid exclusion diet for 3 days before each M H PG test day. The DST was given at least I day before M H PC sampling (mean lO.2+ 8.0days) in 51 patientsandafter MHPG sampling(mean 12.5 f 20.7days)in I3 patients. All patients were in the same clinical state at the time of the DST and MHPG sampling. For determination of plasma free M H PG. blood samples were kept on ice for a maximum of 2 hours before separation of plasma in a refrigerated centrifuge. Each blood sample yielded two l-ml aliquots of plasma. Sodium metabisulfite (0.5 mg) and deuterated MHPG (200 ng) were added to each plasma aliquot. The plasma specimens then were frozen at -7O’C until assay. Preparation of the sample was carried out according to a modified version of the method of Dekirmenjian and Maas (1974). Quantitation of the plasma free MHPG was carried out by selected ion monitoring, as described elsewhere (Maas et al., 1976). using a quadrupole mass spectrometer equipped with a gas chromatographic inlet system. To reduce the variance in method, plasma specimens were assayed in duplicate. The individual values reported for each specimen were the means of these two determinations. The intra-assay and interassay coefficients of variation for this method are 6%, and II’%, respectively. Peak postdexamethasone cortisol values were used to assess dexamethasone resistance (Carroll et al.. 198 I). The cortisol values were log-transformed to obtain a normal distribution (Heath, 1967). On the basis of previous clinical studies, measures of dexamethasone resistance were examined with respect to the following variables in addition to baseline MHPG: age, days free of psychotropic medication before initial MHPG sampling, days between DSTand MH PC; sampling, sex. diagnosis of melancholia (yes; no), and benzodiazepine use within 24 hours of the DST (yes,‘no). Although inpatients were more likely than outpatients to be nonsuppressors (~2= 4.05-p < 0.05), this difference disappeared when we controlled for the difference in cortisol sampling frequency between the two groups (once, at 4 p.m. for outpatients vs. twice, at 4 p.m. and I I p.m.. for inpatients). Consequently, postdexamethasone cortisol sampling frequency was included as an independent variable in the analysis, but inpatient vs. outpatient status was not. Analysis. Pearson’s product-moment and point biserial coefficients were used for bivariate correlations involving continuous and dichotomous variables, respectively. The PI R program of the BM DP series (Dixon et al.. 1983) was used to perform multiple linear regression of cortisol on these same variables. Differences between dexamethasone suppressors and nonsuppressors were examined using nonpaired I tests and x? analysis with Yates’correction, as appropriate. All tests of significance were two-tailed. Statistical
Results There was a significant positive correlation between peak postdexamethasone cortisol and baseline plasma MHPG (r = 0.50,~ < 0.0001) (Table 1). The degree of relationship between these two measures is illustrated in Fig. 1. Cortisol levels were also positively correlated with benzodiazepine use (r = 0.33,~
8 (r = 0.52 vs.
given within 7 days or greater than 7 days before or after M HPG sampling r q 0.50). Table 1. Multiple regression plasma MHPG and clinical
analysis1 variables
of postdexamethasone
MHPG Benzodiazepine Cortisol Age Sex
frequency
ionce/twice;
I male/female)
Diagnosis
of melancholia
Days drug Days
use iyes/no,
sampling
free
between
before
[yes/no
on
Multiple regression2
Correlation with postdexamethasone cortisol
Variables
cortisol
Standardized coefficient
t
0.5023
0.352
2.85
0.006
0.3254
0.214
1.81
0.075
0.3004
0.099
0.79
NS
0.2915 0.208
0.096
0.81 -
NS -
P
0.131
MHPG
-0 120
DST and MHPG
0.087
1. Multiple regression analysis includes first 4 variables; analysts using all 8 variables did not yield substantially different results 2. Multiple r = 0.54, F = 5.97; df = 4. 58; p < 0 0004 3. p < 0.0001. 4. p < 0.01. 5. D < 0.02.
Fig. 1. Peak depressed
postdexamethasone patients (n = 64)
cortisol
levels
I6 [
$
and plasma
free
MHPG
in
0 0
14.
\
312’
*
.
0
r L-
.
M..
I
I
. --L-
30
40
PLASMA Open circles 101 are nonsuppressors,
.
20
I
IO
-
0
00
FREE MHPG
~~~~
_I~___ 50
--1-l 60
70
(ng/ml)
closed circles 1.1 are suppressors
Thirty-three of the 64 patients (52Yc) were nonsuppressors. Table 2 shows that nonsuppressors had significantly higher baseline M H PG values (I 3.52. p < 0.0008) and were significantly older (t 2.89, p < 0.005) than suppressors. Comparison with plasma MHPG values (mean. 3.4 k SD 0.7 ng: ml) in a group of 20 normal controls, as determined in this laboratory using identical procedures (Charney et al.. 1984). showed nonsuppressors to have significantly higher levels (r = 2.87, p < 0.006). q
q
9
Nonsuppressors were significantly f SD 9.1 years; t = 2.15, p < 0.036) Nonsuppressors continued to have age was controlled for by analysis difference in M H PC levels between
older than normal controls (mean age, 39.3 but did not significantly differ in sex distribution. significantly higher plasma MHPG values when of covariance (t = 2.02, p < 0.048). There was no suppressors and normals.
Table 2. Differences between dexamethasone nonsuppressors pressors on plasma MHPG and clinical variables1 Nonsuppressors (Mean f SD) MHPG Age
ing/ml/
4.142
Iyears I
Hamilton
total
Days drug
46.2 score
free before
Days between
MHPG
1.13
Diagnosis Cortisol
of melancholia
sampling
frequency
Sex
3.27-t
(n=331
37.1 f
12.7
45.0
+
9.4
65.2
2191.0
in=
k
(n = 321
7.2
(n-26)
6.7
No. use
\n=331
?
DST and MHPG
Benzodiazepine
Suppressors (Mean f SD)
291
0.82 (n = 31)
0.001 0.005
(n = 27)
2.16
0.035
(n =27)
0.87
NS
jn = 31)
0.87
NS
38.9 + 11.3
Nonsuppressors
Suppressors
~2
p
3.18
0.075
2.23
NS
4.05
0.044
2.22
NS
Yes
21
14
7
No
42
18
24
Yes
33
20
13
No
31
13
18
Once
23
8
15
Twice
41
25
16
Male
23
9
14
Female
41
24
17
1. Data on some measures unavailable for all
64
P
2.89
in = 31)
3.9 IL 20.0
t 3.52
12.6
114.2 2225.5
and sup-
patients
Relationships between the cortisol response to dexamethasone and HRSD ratings were also examined. Postdexamethasone cortisol values were positively correlated with 4 of the 32 H RSD items: observed psychomotor retardation (r = 0.47,~ < 0.0004), lack of responsiveness during the interview (r=0.38.p< O.OOS),weight loss (r = 0.30,~ < 0.03). and diminished work and activities (r = 0.27, p < 0.05). Correlations with terminal insomnia (r < 0.25, p < 0.08) and total HRSD score (r = 0.25, p < 0.08) approached significance. Comparison of nonsuppressors and suppressors by t test (Table 3) revealed that nonsuppressors had significantly higher ratings on the HRSD total score (t 2.16, p < 0.035). observed psychomotor retardation (t = 3.26, p < 0.002). terminal insomnia (t = 2.65, p < 0.01). and lack of responsiveness during the interview (t = 2. IO, p < 0.042). Closely approaching significance were higher ratings for nonsuppressors on diurnal variation (t = I .98, p < 0.053), psychic anxiety (t = I .97, p < 0.055). and decreased physical activity (t = I .97, p < 0.055). Analysis of covariance was used to examine the possibility that differences in MHPG between nonsuppressors and suppressors might account for the HRSD differences (Table 4). Controlling for M HPG eliminated loss of sex drive, helplessness, and weight loss from the list of nearly significant H RSD items, but added worthlessness. Effects on most of the other items were minimal. q
Table 3. Differences between Rating Scale for Depression
Hamilton Total
item
44.0 psychomotor
Terminal
retardation
insomnia
of
and suppressors
Nonsuppressors (n = 26) (Mean + SD)
score
Observed
Lack
nonsuppressors items1
responsiveness
during
interview
Suppressors (n = 27) (Mean&SD)
on Hamilton
t
p
I
9.4
38.9
i- 11.3
2.16
0.035
1 2
I
0.8
0.4
i
0.8
3.26
0.002
1 2
i
0.8
0.7
+
0.8
2.65
0.01
0.5
+
0.7
0.2
?
0.4
2.10
0.42
Diurnal
variation
1.2
i
0.9
0.7
i
0.8
1.98
0.053
Psychic
anxiety
2.5
i
1.0
1.9 i
1.3
1.97
0.055 0.055
Decreased
physical
Decreased
work
Loss
of
sex
activity
and
activities
drive
2 4
t
0.6
2.0
?I
0.7
1.97
2.9
t
0.7
2.5
+
0.8
1.93
0.059
1.5
-t
0.7
1.1 t
0.9
1.93
0.059
Helplessness
2.1
+
1.1
1.6
?
0.9
1.83
0.073
Weight
0.5
?
0.8
0.2
+
0.5
1.80
0.077
loss
1 Total
number
of Hamilton
items
= 32. Only
those
Items
wth
p 5 0 10 are shown
Table 4. Adjusted differences between nonsuppressors and suppressors Hamilton Rating Scale for Depression items (controlling for MHPG analysis of covariance)l
Hamilton Total
Nonsuppressors (n = 26) (Adjusted mean f SD)
item
score
Observed
44 7 -t 10.7 psychomotor
Decreased Terminal
physical
retardation activity
insomnia
Diurnal
variation
Worthlessness Lack
of
responsiveness
Decreased Psychic 1 Total
work
and
during activities
anxiety number of HamIlton
intervlew
Suppressors (n = 27) (Adjusted mean + SD) 39.2
on by
t
p
+ 10.7
1.77
0.084
1.1
t
0.8
0.5
i
0.8
2.60
0.012
2.4
+_ 0.7
2.0
t
0.7
2.16
0.036
1 2 +
0.8
0.7
t
0.8
2.06
0.044
1.2
i-
0.9
0.7
-t
0.9
1.98
0.053
2.4
i
1.2
1.72
1.2
1.84
0.071
0.5
+
0.6
0.2
?
0.6
1.79
0.080
2.9
+-
0.8
2.5
i
0.8
1.74
0.089
2.5
i
1.2
1.9 i
1.2
1.69
0.098
Items = 32 Only those Items with
p < 0 10
are shown
Discussion This study indicates that there is a robust association between the degree of cortisol resistance to dexamethasone and noradrenergic turnover as assessed by plasma MHPG in patients with major depression. In addition. use of the DSTcutoff criterion empirically developed by Carroll et al. (198 I) reveals that dexamethasone nonsuppressors have significantly higher plasma M H PC levels than either suppressors or normal controls. The observed association between HPA and noradrenergic turnover does not appear to be due to some intervening clinical variable (e.g.. age or benzodia7epine use), as it persists even when such Lariables are statistically controlled.
II
These findings are consistent with the report of Jimerson et al. (1983) demonstrating a positive correlation between plasma cortisol and plasma MHPG levels after dexamethasone administration in a sample of I5 patients, as well as with other studies indicating positive correlations between cortisol secretion and various measures of noradrenergic turnover in depression. Stokes et al. (198 1) reported a strong positive correlation of baseline plasma cortisol levels with urinary and cerebrospinal fluid (CSF) MHPG in both depressed and normal subjects. Rosenbaum et al. (1983) found a positive association between urinary MHPG and cortisol levels in depressed patients. Davis et al. (1984) have reported a positive relationship between CSF CRF and MHPG in depressives, but a negative correlation between these measures in schizophrenic and normal subjects. Three major etiologic hypotheses can be offered to account for the observed association between noradrenergic turnover and HPA hyperactivity. One is that activation of the two systems occurs in a simultaneous but independent manner. This could occur either as a result of abnormal function in some third neurotransmitter system (Rosenbaum et al.. 1983). or as a consequence of nonspecific illness-related stresses in depression (Jimerson et al., 1983). Evidence in support of the latter possibility includes findings of increased peripheral sympathetic nervous system function in some depressed patients (Wyatt et al., 197 I; Esler et al., 1982; Lake et al., 1982) and higher plasma norepinephrine and epinephrine levels in dexamethasone nonsuppressors than suppressors (Barnes et al., 1983). A second hypothesis is that HPA hyperactivity directly increases noradrenergic turnover. In laboratory animals, both CRF and ACTH have been shown to increase firing of the locus ceruleus, the major norepinephrine system in the brain (Olpe and Jones. 1982; Valentino et al, 1983). Recent clinical studies suggesting elevated levels of CRF and ACTH in some depressed patients (Kahn et al., 1982; Reus et al., 1982; Demisch et al.. 1983; Gold et al., 1984) are consistent with this mechanism. A third major hypothesis is that elevated MHPG levels reflect a primary abnormality of the noradrenergic system which causes H PA hyperactivity. Consistent with this is a recent report in which the differential M H PC and cortisol responses to clonidine in healthy subjects and depressed patients were interpreted as reflecting abnormal noradrenergic receptor sensitivity (Siever et al., 1984). One possibility is that the hypothesized primary abnormality may result in a net increase in noradrenergic input to the pituitary. Recent work indicates that stimulation of o-and P-adrenergic receptors of the pituitary corticotroph ceils results in release of ACTH (Raymond et al.. 1981; Mezey et al., 1983). Increased presynaptic noradrenergic activity. as may be reflected in increased M H PC, could cause increased stimulation of the postsynaptic adrenergic receptors resulting in increased release of ACTH. This could account for the positive correlation identified between plasma free M H PC and cortisol in the present study. Another possibility is that the association between increased MHPG levels and HPA activity may be due to a net decrease in noradrenergic function centrally, such as in the hypothalamus where norepinephrine is inhibitory to CRF release (Weiner and Ganong, 1978). MHPG levels might then be increased because postsynaptic noradrenergic receptors in the hypothalamus are subsensitive. and consequently the long-loop negative feedback mechanism (Fuller et al.. 1978) regulating presynaptic noradrenergic activity is decreased. In this model,
12 HPA hyperactivity would result from a decrease in the central inhibition of the HPA axis by the postsynaptic noradrenergic receptors. Unfortunately, the design of the present study does not allow us to make a definitive choice among the three competing major hypotheses. We also found age, frequency of cortisol sampling, and benzodiazepine use to be significantly correlated with postdexamethasone cortisol levels. Several previous studies have documented positive correlations of various measures of cortisol secretion with age (Asnis et al., 1981; Oxenkrug et al.. 1983; Stokes et al.. 1984) and postdexamethasone cortisol sampling frequency (Sherman et al.. 1984). Multiple regression analysis showed that age and sampling frequency had a negligible independent association with cortisol level in the present sample when other variables were accounted for. The relationship between benzodiazepine use and cortisol level, however, appeared to persist after multiple regression, even though it did not quite reach statistical significance. Carroll (1982) suggested that benzodiazepines caused elevated postdexamethasone cortisol levels by inducing metabolism of dexamethasone. The positive correlation in our study could be accounted for by the fact that nonsuppressors, who were more likely to have terminal insomnia. psychic anxiety, and a higher HRSD total score (Table 3), were more likely to have received benzodiazepines for management of these symptoms. The DST did not reliably distinguish between DSM-III melancholic and nonmelancholic major depressives in this sample of research patients. With 6lYp of melancholies and 397~ of nonmelancholics judged nonsuppressors, sensitivity of the DST for melancholia was 6 I Yo,specificity 58% and diagnostic confidence 6 1%. These findings underscore the need to consider the population to which the DST is applied in assessing its diagnostic utility. We found positive correlations between the degree of dexamethasone resistance and the specific HRSD-rated symptoms of observed psychomotor retardation, lack of responsiveness during the interview. diminished work and activities. and weight loss. Similarly. nonsuppressors had significantly higher ratings than suppressors on observed psychomotor retardation, terminal insomnia, lack of responsiveness during the interview. and total HRSD score. with differences in seven additional items approaching statistical significance (Table 3). Controlling for MHPG did not substantially alter these findings (Table 4). suggesting that the symptomatic differences were primarily related to HPA dysfunction. Previous studies have also found dexamethasone nonsuppression to be associated with the HRSD items of terminal insomnia. psychic anxiety, and psychomotor retardation, and with severity of illness as measured by total HRSD score (Davis et al., 198 I; Kasper and Beckmann, 1983; Nasr and Gibbons, 1983). we found evidence of a strong positive association between In summary, noradrenergic turnover and dexamethasone nonsuppression in 64 depressed patients. Depressed nonsuppressors had higher baseline MHPG levels than either depressed suppressors or nondepressed healthy controls. Dexamethasone resistance was associated with increased severity of some depressive symptoms as assessed by the HRSD. Our findings indicate that hyperactivity of the HPA in depressed patients is associated with an abnormality in noradrenergic regulation manifested by increased norepinephrine turnover.
References Psychiatric Association. DSM-III: Diagnostic and Statistical Manual qf’ Menral 3rd ed. APA, Washington, DC (1980). Asnis, G.M., Sachar. E.J., Halbreich, V., Nathan. R.S., Novacenko, H., and Ostrow, L.C. Cortisol secretion in relation to age in major depression. Ps,,chosomatic Medicine, 43, 235
American
Disorders.
(1981).
Barnes, R.F.. Veith, R.C.. Borson, S.. Verhey. J.. Raskind, M.A.. and Halter, J.B. High levels of plasma catecholamines in dexamethasone-resistant depressed patients, American Journal
of Ps~~chiarr~~. 140, 1623 (1983).
Blombery. P.A., Kopin. LJ.. Gordon, E.K., Markey, S.P., and Ebert, M.H. Conversion of M HPG to vanillylmandelic acid: Implications for the importance of urinary M HPG. Archives qf Genera/
Psychiarr!,,
Bunney, Archives
37, 1098 ( 1980).
W.E.. Jr.. and Davis, J.M. yf’ Genera/
Carroll.
Norepinephrine
in depressive
reactions:
A review.
Ps~~chiarry. 13, 483 ( 1965).
B.J. The dexamethasone
suppression
test for melancholia.
British
Journal
of
Ps~~chiatr~~. 140, 292 (1982).
Carroll, B.J., Feinberg, M., Greden, J.F., Tarika, J., Albala, A.A., Haskett, R.F., James, N. MCI.. Kronfol, Z.. Lohr. N., Steiner, M., de Vigne. J.P., and Young, E. A specific laboratory test for the diagnosis of melancholia. Archives qf Genera/ Psychiatry. 38, I5 (198 I). Charney. D.S.. Heninger, G.R.. and Breier. A. Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Archives qJ‘ General P.y~~chiarr,~,41, 75 I (1984). Charney, D.S.. Heninger. G.R.. Sternberg, D.E.. Redmond, D.E., Leckman. J.F., Maas, J.W.. and Roth, R. Presynaptic adrenergic receptor sensitivity in depression: The effect of long-term desipramine treatment. Archives qf’ Genera/ P.y_r,chiafry, 38, I334 (198 I). Checkley. S.A. Corticosteroid and growth hormone responses to methylamphetamine in depressive illness. fs~~chological Medicine, 9, 107 (1979). Davis, K.L.. Davis. B.M.. Mohs. R.C., Math& A.A., Vale, W., and Krieger, D. CSF corticotropin releasing factor in neuropsychiatric disease. (Abstract) Presented at the Annual Meeting of the American Psychiatric Association, Los Angeles. May IO (1984). Davis, K.L.. Hollister. L.E.. Math& A.A., Davis, B.M., Rothpearl, A.B., Faull, K.F., Hsieh, J.Y.K.. Barchas. J.D., and Berger, P.A. Neuroendocrine and neurochemical measurements in depression. American Journal of Pswhiarry, 138, I555 (198 I). Dekirmenjian, H.. and Maas, J.W. 3-Methoxy-4-hydroxyphenylethylene glycol in plasma. Clinica Chimica
Acra, 52, 203 (1974).
Demisch. suppression
K.. Demisch. L., Bochnik, H.J.. and Schulz, F. Comparison of the ACTH test and dexamethasone suppression test in depressed patients. American Journal qf‘ Ps~~chiarry. 140, I5 I I ( 1983). DeMoor. P.. Steeno, 0.. Raskin. M.,and Hendrikx, A. Afluorometricdeterminationoffree plasma I I-hydroxycorticosteroids in man. Acra Endoc,rino/ogica, 33, 297 (1960). Dixon, W.J.. Brown. M.B., Engelman. L.. Frane. J.W., Hill, M.A., Jennrich. R.I., and Toporek. J.D. BMDP Sratisrical Sqf/Lvare: 1983 Printing With Additions. University of California Press. Berkeley (1983). Elsworth. J.D.. Redmond. D.E.. Jr.. and Roth. R.H. Plasma and cerebrospinal fluid 3methoxy-4-hydroxyphenylethylene glycol (M H PG) as indices of brain norepinephrine metabolites in primates. Brain Research. 235, I I5 (1982). Esler, M.. Turbott. J., Schwartz, R., Leonard, P.. Bubik, A., Skews. H., and Jackman, G. The peripheral kinetics of norepinephrine in depressive illness. Archives ofGenera/ fs_vchiatry, 39, 295 (1982).
Fuller, R.W.. Snoddy. H.D.. and Perry, K.W. concentration and turnover in rat brain and Pharrnacod~~namie,
231, 30 (1978).
Effect of prazosin on norepinephrine heart. Archives Inrernationales de
14
Gold, P.W., Chrousos. G.. Kellner. C.. Post. R.. Roy. A., Augerinos. P.. Schulte. H., Oldfield, E., and Loriaux, D.L. Psychiatric implications of basic and clinical studies with corticotropin releasing factor. American Journal of f.swhiatr~~, 141, 619 (1984). Hamilton, M. A rating scale for depression. Journal of Neurolog~~. ,Yeuro.surXer~~ and P~yhiarr~~,
23, 56 ( 1960).
Heath, D.F. Normal or log normal: Appropriate distributions. Nature, 213, I I59 (1967). Jimerson, D.C.. Ballenger. J.C., Lake. C.R.. Post, R.M., Goodwin. F.K.. and Kopin, I.J. Plasma and CSF MHPG in normals. P.s~,c,hopharrnac,olo~~, Bullerin, 17, 86 (198 I). Jimerson. D.C., Insel. T.R., Reus, V.I.. and Kopin. 1.J. Increased plasma M HPG in dexamethasone-resistant depressed patients. Architses of General PsJ,chiatr>,, 40, 173 ( 1983). Kalin, N.H., Weiler. S.J.. and Shelton. S.E. Plasma ACTH and cortisol concentrations before and after dexamethasone. f?s~~chia/r~~Researc,h, 7, 87 (1982). Karoum, F., Mayer-Schwing. J., Potkin. S.G., and Wyatt, R.J. Presence of free sulfate and glucuronide conjugated MHPG in human brain, cerebrospinal fluid and plasma. Brain Research,
125, 333 (1977).
Kasper, approach:
S.. and Beckmann. H. Dexamethasone suppression test in a pluridiagnostic Its relationship to psychopathological and clinical variables. Acra Ps~~chiatrica Scandinavica, 68, 3 I ( 1983). Kopin, I.J., Jimerson. D.C., Markey, S.P.. Ebert. M.H., and Polinsky. R.J. Disposition and metabolism of M H PG in humans: Application to studies in depression. Pharmac,opsl’c,hia/rl,. 17, 3 (1984).
Lake, C.R.. Pickar, D.. Ziegler. M.G.. Lipper, S.. Slater, S., and Murphy. D.L. High plasma norepinephrine levels in patients with major affective disorder. American Journul of’ Psyhiarr.v,
139, I3 I5
( 1982).
l.eckman. J.F.. and systems and emerging
Maas. J.W. Plasma MHPG: Relationship to brain noradrenergic In: Post, R.M., and Ballenger. J.C.. eds. clinical applications. Neurohiologv qf Mood Disorders. Williams & Wilkins. Baltimore (1984). Maas. J.W., Hattox. S.E.. Landis. D.H.. and Roth. R.H. The determination of a brain arteriovenous difference for 3-methoxy-4-hydroxy-phenylethyleneglycol (M H PG). Brain Research, 118, I67 ( 1976). Mattingly, D. A simple fluorimetric method for the estimation of free I I-hydroxycorticoids in human plasma. Journal of Clinical fatholog~~, 15, 374 (1962). Mezey, E.. Reisine. T.D., Palkovits, M.. Brownstein, M.J.. and Axelrod. J. Direct stimulation of beta-2-adrenergic receptors in rat anterior pituitary induces the release of adrenocorticotropin in vivo. Proceedings qf the National Academy qf Sc,ience.s qfthe Uninired States cf America.
80, 6728 (1983).
Nasr, S.J., and Gibbons, R.D. Depressive symptoms associated with dexamethasone resistance. Ps~~chiarr,~ Research, 10, I83 (1983). Olpe, H.R.. and Jones, R.S.G. Excitatory effects of ACTH in noradrenergic neurons of the locus coeruleus in the rat. Brain Research, 251, 177 (1982). Oxenkrug, G.F.. Nunzio. P., McIntyre. I.M.. Branconnier. R.J., Stanley. M.. and Gershon. S. Aging and cortisol resistance to suppression by dexamethasone: A positive correlation. Ps_vchiafry Research. 10, 125 (1983). Raymond, V.. Lepine. J.. Giguere. V., Lissitrky. J.C., Cote. J.. and Labrie. F. Parallel stimulation of ACTH. B-LPH + P-endorphinand (Y-MSH release by a-adrenergicagents in rat anterior pituitary cells in culture. Molecular and Cellular Endocrinology,, 22, 295 (1981). Rees, L.. Butler, P.W.P.. Gosling. C., and Besser, G.M. Adrenergic blockade and the corticosteroid and growth hormone responses to methylamphetamine. Nature, 228,565 ( 1970). Reus, V.I.. Joseph, M.S.. and Dallman, M.F. ACTH levels after dexamethasone suppression test in depression. The New, England Journal of Medicine. 306, 238 (1982). Rosenbaum, A.H., Marata. T.. Schatzberg. A. F.. Orsulak, P.J.. Jiang, N.S.. Cole, J.O.. and Schildkraut. J.J. Toward a biochemical classification ofdepressivedisorders: VII. Urinary free cortisol and urinary M HPG in depression. American Journal qf‘ P.sj,c,hiarrj., 140, 3 I4 ( 1983).
15
Sachar, E.J., Halbreich, U., Asnis, G.M., Nathan, R.S., Halpern, F.S., and Ostrow, L. Paradoxical cortisol responses to dextroamphetamine in endogenous depression. Archives of General Psychiatry, 38, I 113 ( I98 1). Schildkraut, J.J., and Kety, S.S. Biogenic amines and emotion. Science. 156, 21 (1967). Sherman, B., Pfohl, B., and Winokur, G. Circadian analysis of plasma cortisol levels before and after dexamethasone administration in depressed patients. Archives of General Psychiatry, 41,27
I (1984).
Siever, L.J., Uhde, T.W.. Jimerson, D.C., Post, R.M., Lake, C.R., and Murphy, D.L. Plasma cortisol responses to clonidine in depressed patients and controls. Archives of Generul Psychiatry,
41, 63 (1984).
Stokes, P.E., Frazer, A., and Casper, R. Unexpected neuroendocrine-transmitter relationships. Psychopharmacology Bulletin. 17, 72 (198 I). Stokes, P.E., Stoll, P.M., Koslow, S.H., Maas. J. W., Davis, J.M., Swann, A.C., and Robins, E. Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. Archives of General Psvchiurry, 41,257 (1984). Valentino, R.J., Foote, S.L., and Aston-Jones, G. Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Bruin Research, 270,363 (1983). Weiner, R.I., and Ganong, W.F. Role of brain monoamines and histamine in regulation of anterior pituitary secretion. Physiological Reviews, 58, 905 (1978). Wyatt, R.J., Portnoy, B., Kupfer, D.J., Snyder, F., and Engelman, K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Archives of General Psychiarry, 24, 63 ( 197 I).
15, 5- I5
5
Elsevier
Noradrenergic Function and the Dexamethasone in Depression A. Lawrence Rubin, Lawrence George R. Heninger
H. Price,
Cortisol
Dennis
Received June 29. 1984; revised version received November 1984.
S. Charney,
Response
to
and
26, 1984; accepted December 20,
Abstract. Abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis and the noradrenergic system have been reported in depression. To study possible interrelations between these two systems, plasma free 3-methoxy-4-hydroxyphenylglycol (MPHG) was compared with the cortisol response to dexamethasone in 64 depressed patients. Postdexamethasone cortisol nonsuppressors had higher baseline plasma free MHPG values than did cortisol suppressors. Increased severity of some depressive symptoms was associated with increased postdexamethasone cortisol levels. These results indicate that depressed patients with dexamethasone nonsuppression have increased noradrenergic turnover. Key Words. Norepinephrine, dexamethasone 3-methoxy-4-hydroxyphenylglycol (MHPG).
suppression cortisol.
test. depression,
It has been suggested that the hypersecretion of cortisol seen in depression might reflect an underlying noradrenergic deficiency (Schildkraut and Kety, 1967; Bunney and Davis, 1965; Checkley, 1979; Sachar et al., 1981). This hypothesis is based on research in laboratory animals indicating that norepinephrine inhibits adrenocorticotropic hormone (ACTH) secretion by inhibiting corticotropin-releasing factor (CRF) release within the hypothalamus (Weiner and Ganong, 1978). Other preclinical investigations, however, have indicated excitatory actions of the noradrenergic system on the hypothalamic-pituitary-adrenal (HPA) axis (Rees et al., 1970; Weiner and Ganong, 1978; Raymond et al., 1981; Mezey et al., 1983). Several clinical studies seem to be consistent with this excitatory effect in demonstrating positive correlations between cortisol secretion and measures of noradrenergic function (Stokes et al., 198 I; Jimerson et al., 1983; Rosenbaum et al., 1983). However, most studies have involved relatively small patient samples or have not systematically controlled several clinical factors that might affect noradrenergic and HPA function. In the present study, we examined the relationship between norepinephrine turnover and HPA function in a large sample of depressed patients who were
A. Lawrence Rubin. M.D., is Postdoctoral Fellow; Lawrence H. Price, M.D., and Dennis S. Charney. M.D.. are Assistant Professors of Psychiatry; and George R. Heninger, M.D., is Professor of Psychiatry, Yale University School of Medicine and The Connecticut Mental Health Center, Ribicoff Research Facilities. New Haven, CT. Dr. Rubin is currently at Falkirk Hospital. P.O. Box 194. Central Valley. NY 10917. (Reprint requests to Dr. L.H. Price, The Connecticut Mental Health Center, 34 Park St., Rm. 358, New Haven. CT 06508. USA.) 0165-1781
85 $03.30 % 1985 Elsevier Science Publishers
B.V.
6
participating
in controlled
clinical
studies
of noradrenergic
function
using a challenge
paradigm as previously reported (Charney et al.. 198 I, 1984). Noradrenergic turnover was assessed by measurement of plasma free Smethoxy-4-hydroxyphenylglycol (MHPG). Plasma MHPG correlates with more direct measures of brain norepinephrine 1982),
turnover
suggesting
(Karoum that
it may
et al.,
1977; Jimerson
serve
as a valid
index
et al..
1981; Elsworth
of central
et al.,
noradrenergic
metabolism (Leckman and Maas. 1984). even though a substantial proportion of plasma M HPG appears to be derived from peripheral sources (Blombery et al. 1980; Kopin et al.. 1984). HPA activity was assessed by measurement of plasma cortisol following oral administration of dexamethasone (Carroll et al., 1981). in addition. depressive symptomatology was assessed using a modified version of the Hamilton Rating Scale for Depression (Hamilton. 1960).
Methods Subjects. Sixty-four depressed patients (3 I male. 33 female; mean age. 41.X + SD 13.4 years: age range. 18-68 years) participated in this study. Forty-one patients were hospitalired on the Clinical Research Unit of the Connecticut Mental Health Center and 23 were treated as outpatients at the same facility. All patients met DSM-//I criteria (American Psychiatric Association, 1980) for major depression; 60 were unipolar and 4 were bipolar. Unipolar DSM-//I depressive subtypes were as follows: 29 nonmelancholic. 21 nonpsqchotic melancholic. and IO psychotIc melancholic. The bipolar L>SM-///depressive subtypes included 2 nonmelancholic, I nonpsychotic melancholic. and I psychotic melancholic. As there were no significant differences between unipolar and bipolar patients on postdexamethasone cortisol measures or plasma M H PC, the two groups were combined according 10 LIShf-l/l subtype. Similarly, psychotic and nonpsychotic melancholic patients were combined because of the lack of cortisol differences between these groups. All patients were free of significant medical problems as determined by a complete medical and neurological examination. including ECG and laboratory tests of renal, hepatic. pancreatic. hematopoetic. and thyroid function. A modified 32-item Hamilton Rating Scale for Depression (HRSD) was completed by trained psychiatric research nurses within 8 days of the M H PG samplings. The nurse raters were unaware of results of the plasma cortisol and M H PC; determmatlons. The mean pretreatment total HRSD score was 41.9 f SD 10.X. Procedures. A dexamethasone suppression test (DST) was administered to all patients (Carroll et al.. 1981). Dexamethasone. I mg. was given orall) at I I p.m.. and blood was drawn for cortisol determination the following day. al 4 p.m. and I I p.m. for inpatients and at 4 p.m. only for outpatients. Fifty-one patients were tested before beginning antidepressant treatment. and I3 patients were being treated with antidepressants and/or neuroleptics at the time of the DST. Since it has been reported that the DST is unaffected by antidepressant or neuroleptic use (Carroll et al., 1981). the results of these two groups were combined. Patients were judged nonsuppressors if any postdexamethasone plasma cortisol level was 2 5 pg;dl (Carroll et al.. 19X1). For determination of plasma cortisol. 5 cc of blood was collected in a hepariniled tube. Plasma was separated and stored at -20°C until assayed. Cortisol concentrations were measured by a fluorometric assay (DeMoor et al.. 1960; Mattingly. 1962). with an intra-assay coefficient of variation of 3Fc and an interassay coefficient of variation of 8C; (R.K. Donabedian. M.D.. personal communication). At the time blood samples for MHPG were obtained. 52 subjects had been free of psychotropic medication (except for benrodiarepine hypnotics) for at least 2 weeks, X subjects had been medication-free between 2 weeks and 7 days. and 4 subjects had been off medication for only 7 days. The correlation between days off medication and MHPG was not significant (r = -0.17. p > 0. IO). Beginning at X:30 a.m.. two baseline blood samples were obtained I5
7
minutes apart on each of two noradrenergic challenge days. Thus. four determinations of baseline MHPG were obtained. The mean of the four MHPG values was used to calculate “baseline M HPG.” The mean time interval between the two test days was 5.5 days (range, I to 18 days). Patients were instructed to adhere to a vanillylmandelic acid exclusion diet for 3 days before each M H PG test day. The DST was given at least I day before M H PC sampling (mean lO.2+ 8.0days) in 51 patientsandafter MHPG sampling(mean 12.5 f 20.7days)in I3 patients. All patients were in the same clinical state at the time of the DST and MHPG sampling. For determination of plasma free M H PG. blood samples were kept on ice for a maximum of 2 hours before separation of plasma in a refrigerated centrifuge. Each blood sample yielded two l-ml aliquots of plasma. Sodium metabisulfite (0.5 mg) and deuterated MHPG (200 ng) were added to each plasma aliquot. The plasma specimens then were frozen at -7O’C until assay. Preparation of the sample was carried out according to a modified version of the method of Dekirmenjian and Maas (1974). Quantitation of the plasma free MHPG was carried out by selected ion monitoring, as described elsewhere (Maas et al., 1976). using a quadrupole mass spectrometer equipped with a gas chromatographic inlet system. To reduce the variance in method, plasma specimens were assayed in duplicate. The individual values reported for each specimen were the means of these two determinations. The intra-assay and interassay coefficients of variation for this method are 6%, and II’%, respectively. Peak postdexamethasone cortisol values were used to assess dexamethasone resistance (Carroll et al.. 198 I). The cortisol values were log-transformed to obtain a normal distribution (Heath, 1967). On the basis of previous clinical studies, measures of dexamethasone resistance were examined with respect to the following variables in addition to baseline MHPG: age, days free of psychotropic medication before initial MHPG sampling, days between DSTand MH PC; sampling, sex. diagnosis of melancholia (yes; no), and benzodiazepine use within 24 hours of the DST (yes,‘no). Although inpatients were more likely than outpatients to be nonsuppressors (~2= 4.05-p < 0.05), this difference disappeared when we controlled for the difference in cortisol sampling frequency between the two groups (once, at 4 p.m. for outpatients vs. twice, at 4 p.m. and I I p.m.. for inpatients). Consequently, postdexamethasone cortisol sampling frequency was included as an independent variable in the analysis, but inpatient vs. outpatient status was not. Analysis. Pearson’s product-moment and point biserial coefficients were used for bivariate correlations involving continuous and dichotomous variables, respectively. The PI R program of the BM DP series (Dixon et al.. 1983) was used to perform multiple linear regression of cortisol on these same variables. Differences between dexamethasone suppressors and nonsuppressors were examined using nonpaired I tests and x? analysis with Yates’correction, as appropriate. All tests of significance were two-tailed. Statistical
Results There was a significant positive correlation between peak postdexamethasone cortisol and baseline plasma MHPG (r = 0.50,~ < 0.0001) (Table 1). The degree of relationship between these two measures is illustrated in Fig. 1. Cortisol levels were also positively correlated with benzodiazepine use (r = 0.33,~
8 (r = 0.52 vs.
given within 7 days or greater than 7 days before or after M HPG sampling r q 0.50). Table 1. Multiple regression plasma MHPG and clinical
analysis1 variables
of postdexamethasone
MHPG Benzodiazepine Cortisol Age Sex
frequency
ionce/twice;
I male/female)
Diagnosis
of melancholia
Days drug Days
use iyes/no,
sampling
free
between
before
[yes/no
on
Multiple regression2
Correlation with postdexamethasone cortisol
Variables
cortisol
Standardized coefficient
t
0.5023
0.352
2.85
0.006
0.3254
0.214
1.81
0.075
0.3004
0.099
0.79
NS
0.2915 0.208
0.096
0.81 -
NS -
P
0.131
MHPG
-0 120
DST and MHPG
0.087
1. Multiple regression analysis includes first 4 variables; analysts using all 8 variables did not yield substantially different results 2. Multiple r = 0.54, F = 5.97; df = 4. 58; p < 0 0004 3. p < 0.0001. 4. p < 0.01. 5. D < 0.02.
Fig. 1. Peak depressed
postdexamethasone patients (n = 64)
cortisol
levels
I6 [
$
and plasma
free
MHPG
in
0 0
14.
\
312’
*
.
0
r L-
.
M..
I
I
. --L-
30
40
PLASMA Open circles 101 are nonsuppressors,
.
20
I
IO
-
0
00
FREE MHPG
~~~~
_I~___ 50
--1-l 60
70
(ng/ml)
closed circles 1.1 are suppressors
Thirty-three of the 64 patients (52Yc) were nonsuppressors. Table 2 shows that nonsuppressors had significantly higher baseline M H PG values (I 3.52. p < 0.0008) and were significantly older (t 2.89, p < 0.005) than suppressors. Comparison with plasma MHPG values (mean. 3.4 k SD 0.7 ng: ml) in a group of 20 normal controls, as determined in this laboratory using identical procedures (Charney et al.. 1984). showed nonsuppressors to have significantly higher levels (r = 2.87, p < 0.006). q
q
9
Nonsuppressors were significantly f SD 9.1 years; t = 2.15, p < 0.036) Nonsuppressors continued to have age was controlled for by analysis difference in M H PC levels between
older than normal controls (mean age, 39.3 but did not significantly differ in sex distribution. significantly higher plasma MHPG values when of covariance (t = 2.02, p < 0.048). There was no suppressors and normals.
Table 2. Differences between dexamethasone nonsuppressors pressors on plasma MHPG and clinical variables1 Nonsuppressors (Mean f SD) MHPG Age
ing/ml/
4.142
Iyears I
Hamilton
total
Days drug
46.2 score
free before
Days between
MHPG
1.13
Diagnosis Cortisol
of melancholia
sampling
frequency
Sex
3.27-t
(n=331
37.1 f
12.7
45.0
+
9.4
65.2
2191.0
in=
k
(n = 321
7.2
(n-26)
6.7
No. use
\n=331
?
DST and MHPG
Benzodiazepine
Suppressors (Mean f SD)
291
0.82 (n = 31)
0.001 0.005
(n = 27)
2.16
0.035
(n =27)
0.87
NS
jn = 31)
0.87
NS
38.9 + 11.3
Nonsuppressors
Suppressors
~2
p
3.18
0.075
2.23
NS
4.05
0.044
2.22
NS
Yes
21
14
7
No
42
18
24
Yes
33
20
13
No
31
13
18
Once
23
8
15
Twice
41
25
16
Male
23
9
14
Female
41
24
17
1. Data on some measures unavailable for all
64
P
2.89
in = 31)
3.9 IL 20.0
t 3.52
12.6
114.2 2225.5
and sup-
patients
Relationships between the cortisol response to dexamethasone and HRSD ratings were also examined. Postdexamethasone cortisol values were positively correlated with 4 of the 32 H RSD items: observed psychomotor retardation (r = 0.47,~ < 0.0004), lack of responsiveness during the interview (r=0.38.p< O.OOS),weight loss (r = 0.30,~ < 0.03). and diminished work and activities (r = 0.27, p < 0.05). Correlations with terminal insomnia (r < 0.25, p < 0.08) and total HRSD score (r = 0.25, p < 0.08) approached significance. Comparison of nonsuppressors and suppressors by t test (Table 3) revealed that nonsuppressors had significantly higher ratings on the HRSD total score (t 2.16, p < 0.035). observed psychomotor retardation (t = 3.26, p < 0.002). terminal insomnia (t = 2.65, p < 0.01). and lack of responsiveness during the interview (t = 2. IO, p < 0.042). Closely approaching significance were higher ratings for nonsuppressors on diurnal variation (t = I .98, p < 0.053), psychic anxiety (t = I .97, p < 0.055). and decreased physical activity (t = I .97, p < 0.055). Analysis of covariance was used to examine the possibility that differences in MHPG between nonsuppressors and suppressors might account for the HRSD differences (Table 4). Controlling for M HPG eliminated loss of sex drive, helplessness, and weight loss from the list of nearly significant H RSD items, but added worthlessness. Effects on most of the other items were minimal. q
Table 3. Differences between Rating Scale for Depression
Hamilton Total
item
44.0 psychomotor
Terminal
retardation
insomnia
of
and suppressors
Nonsuppressors (n = 26) (Mean + SD)
score
Observed
Lack
nonsuppressors items1
responsiveness
during
interview
Suppressors (n = 27) (Mean&SD)
on Hamilton
t
p
I
9.4
38.9
i- 11.3
2.16
0.035
1 2
I
0.8
0.4
i
0.8
3.26
0.002
1 2
i
0.8
0.7
+
0.8
2.65
0.01
0.5
+
0.7
0.2
?
0.4
2.10
0.42
Diurnal
variation
1.2
i
0.9
0.7
i
0.8
1.98
0.053
Psychic
anxiety
2.5
i
1.0
1.9 i
1.3
1.97
0.055 0.055
Decreased
physical
Decreased
work
Loss
of
sex
activity
and
activities
drive
2 4
t
0.6
2.0
?I
0.7
1.97
2.9
t
0.7
2.5
+
0.8
1.93
0.059
1.5
-t
0.7
1.1 t
0.9
1.93
0.059
Helplessness
2.1
+
1.1
1.6
?
0.9
1.83
0.073
Weight
0.5
?
0.8
0.2
+
0.5
1.80
0.077
loss
1 Total
number
of Hamilton
items
= 32. Only
those
Items
wth
p 5 0 10 are shown
Table 4. Adjusted differences between nonsuppressors and suppressors Hamilton Rating Scale for Depression items (controlling for MHPG analysis of covariance)l
Hamilton Total
Nonsuppressors (n = 26) (Adjusted mean f SD)
item
score
Observed
44 7 -t 10.7 psychomotor
Decreased Terminal
physical
retardation activity
insomnia
Diurnal
variation
Worthlessness Lack
of
responsiveness
Decreased Psychic 1 Total
work
and
during activities
anxiety number of HamIlton
intervlew
Suppressors (n = 27) (Adjusted mean + SD) 39.2
on by
t
p
+ 10.7
1.77
0.084
1.1
t
0.8
0.5
i
0.8
2.60
0.012
2.4
+_ 0.7
2.0
t
0.7
2.16
0.036
1 2 +
0.8
0.7
t
0.8
2.06
0.044
1.2
i-
0.9
0.7
-t
0.9
1.98
0.053
2.4
i
1.2
1.72
1.2
1.84
0.071
0.5
+
0.6
0.2
?
0.6
1.79
0.080
2.9
+-
0.8
2.5
i
0.8
1.74
0.089
2.5
i
1.2
1.9 i
1.2
1.69
0.098
Items = 32 Only those Items with
p < 0 10
are shown
Discussion This study indicates that there is a robust association between the degree of cortisol resistance to dexamethasone and noradrenergic turnover as assessed by plasma MHPG in patients with major depression. In addition. use of the DSTcutoff criterion empirically developed by Carroll et al. (198 I) reveals that dexamethasone nonsuppressors have significantly higher plasma M H PC levels than either suppressors or normal controls. The observed association between HPA and noradrenergic turnover does not appear to be due to some intervening clinical variable (e.g.. age or benzodia7epine use), as it persists even when such Lariables are statistically controlled.
II
These findings are consistent with the report of Jimerson et al. (1983) demonstrating a positive correlation between plasma cortisol and plasma MHPG levels after dexamethasone administration in a sample of I5 patients, as well as with other studies indicating positive correlations between cortisol secretion and various measures of noradrenergic turnover in depression. Stokes et al. (198 1) reported a strong positive correlation of baseline plasma cortisol levels with urinary and cerebrospinal fluid (CSF) MHPG in both depressed and normal subjects. Rosenbaum et al. (1983) found a positive association between urinary MHPG and cortisol levels in depressed patients. Davis et al. (1984) have reported a positive relationship between CSF CRF and MHPG in depressives, but a negative correlation between these measures in schizophrenic and normal subjects. Three major etiologic hypotheses can be offered to account for the observed association between noradrenergic turnover and HPA hyperactivity. One is that activation of the two systems occurs in a simultaneous but independent manner. This could occur either as a result of abnormal function in some third neurotransmitter system (Rosenbaum et al.. 1983). or as a consequence of nonspecific illness-related stresses in depression (Jimerson et al., 1983). Evidence in support of the latter possibility includes findings of increased peripheral sympathetic nervous system function in some depressed patients (Wyatt et al., 197 I; Esler et al., 1982; Lake et al., 1982) and higher plasma norepinephrine and epinephrine levels in dexamethasone nonsuppressors than suppressors (Barnes et al., 1983). A second hypothesis is that HPA hyperactivity directly increases noradrenergic turnover. In laboratory animals, both CRF and ACTH have been shown to increase firing of the locus ceruleus, the major norepinephrine system in the brain (Olpe and Jones. 1982; Valentino et al, 1983). Recent clinical studies suggesting elevated levels of CRF and ACTH in some depressed patients (Kahn et al., 1982; Reus et al., 1982; Demisch et al.. 1983; Gold et al., 1984) are consistent with this mechanism. A third major hypothesis is that elevated MHPG levels reflect a primary abnormality of the noradrenergic system which causes H PA hyperactivity. Consistent with this is a recent report in which the differential M H PC and cortisol responses to clonidine in healthy subjects and depressed patients were interpreted as reflecting abnormal noradrenergic receptor sensitivity (Siever et al., 1984). One possibility is that the hypothesized primary abnormality may result in a net increase in noradrenergic input to the pituitary. Recent work indicates that stimulation of o-and P-adrenergic receptors of the pituitary corticotroph ceils results in release of ACTH (Raymond et al.. 1981; Mezey et al., 1983). Increased presynaptic noradrenergic activity. as may be reflected in increased M H PC, could cause increased stimulation of the postsynaptic adrenergic receptors resulting in increased release of ACTH. This could account for the positive correlation identified between plasma free M H PC and cortisol in the present study. Another possibility is that the association between increased MHPG levels and HPA activity may be due to a net decrease in noradrenergic function centrally, such as in the hypothalamus where norepinephrine is inhibitory to CRF release (Weiner and Ganong, 1978). MHPG levels might then be increased because postsynaptic noradrenergic receptors in the hypothalamus are subsensitive. and consequently the long-loop negative feedback mechanism (Fuller et al.. 1978) regulating presynaptic noradrenergic activity is decreased. In this model,
12 HPA hyperactivity would result from a decrease in the central inhibition of the HPA axis by the postsynaptic noradrenergic receptors. Unfortunately, the design of the present study does not allow us to make a definitive choice among the three competing major hypotheses. We also found age, frequency of cortisol sampling, and benzodiazepine use to be significantly correlated with postdexamethasone cortisol levels. Several previous studies have documented positive correlations of various measures of cortisol secretion with age (Asnis et al., 1981; Oxenkrug et al.. 1983; Stokes et al.. 1984) and postdexamethasone cortisol sampling frequency (Sherman et al.. 1984). Multiple regression analysis showed that age and sampling frequency had a negligible independent association with cortisol level in the present sample when other variables were accounted for. The relationship between benzodiazepine use and cortisol level, however, appeared to persist after multiple regression, even though it did not quite reach statistical significance. Carroll (1982) suggested that benzodiazepines caused elevated postdexamethasone cortisol levels by inducing metabolism of dexamethasone. The positive correlation in our study could be accounted for by the fact that nonsuppressors, who were more likely to have terminal insomnia. psychic anxiety, and a higher HRSD total score (Table 3), were more likely to have received benzodiazepines for management of these symptoms. The DST did not reliably distinguish between DSM-III melancholic and nonmelancholic major depressives in this sample of research patients. With 6lYp of melancholies and 397~ of nonmelancholics judged nonsuppressors, sensitivity of the DST for melancholia was 6 I Yo,specificity 58% and diagnostic confidence 6 1%. These findings underscore the need to consider the population to which the DST is applied in assessing its diagnostic utility. We found positive correlations between the degree of dexamethasone resistance and the specific HRSD-rated symptoms of observed psychomotor retardation, lack of responsiveness during the interview. diminished work and activities. and weight loss. Similarly. nonsuppressors had significantly higher ratings than suppressors on observed psychomotor retardation, terminal insomnia, lack of responsiveness during the interview. and total HRSD score. with differences in seven additional items approaching statistical significance (Table 3). Controlling for MHPG did not substantially alter these findings (Table 4). suggesting that the symptomatic differences were primarily related to HPA dysfunction. Previous studies have also found dexamethasone nonsuppression to be associated with the HRSD items of terminal insomnia. psychic anxiety, and psychomotor retardation, and with severity of illness as measured by total HRSD score (Davis et al., 198 I; Kasper and Beckmann, 1983; Nasr and Gibbons, 1983). we found evidence of a strong positive association between In summary, noradrenergic turnover and dexamethasone nonsuppression in 64 depressed patients. Depressed nonsuppressors had higher baseline MHPG levels than either depressed suppressors or nondepressed healthy controls. Dexamethasone resistance was associated with increased severity of some depressive symptoms as assessed by the HRSD. Our findings indicate that hyperactivity of the HPA in depressed patients is associated with an abnormality in noradrenergic regulation manifested by increased norepinephrine turnover.
References Psychiatric Association. DSM-III: Diagnostic and Statistical Manual qf’ Menral 3rd ed. APA, Washington, DC (1980). Asnis, G.M., Sachar. E.J., Halbreich, V., Nathan. R.S., Novacenko, H., and Ostrow, L.C. Cortisol secretion in relation to age in major depression. Ps,,chosomatic Medicine, 43, 235
American
Disorders.
(1981).
Barnes, R.F.. Veith, R.C.. Borson, S.. Verhey. J.. Raskind, M.A.. and Halter, J.B. High levels of plasma catecholamines in dexamethasone-resistant depressed patients, American Journal
of Ps~~chiarr~~. 140, 1623 (1983).
Blombery. P.A., Kopin. LJ.. Gordon, E.K., Markey, S.P., and Ebert, M.H. Conversion of M HPG to vanillylmandelic acid: Implications for the importance of urinary M HPG. Archives qf Genera/
Psychiarr!,,
Bunney, Archives
37, 1098 ( 1980).
W.E.. Jr.. and Davis, J.M. yf’ Genera/
Carroll.
Norepinephrine
in depressive
reactions:
A review.
Ps~~chiarry. 13, 483 ( 1965).
B.J. The dexamethasone
suppression
test for melancholia.
British
Journal
of
Ps~~chiatr~~. 140, 292 (1982).
Carroll, B.J., Feinberg, M., Greden, J.F., Tarika, J., Albala, A.A., Haskett, R.F., James, N. MCI.. Kronfol, Z.. Lohr. N., Steiner, M., de Vigne. J.P., and Young, E. A specific laboratory test for the diagnosis of melancholia. Archives qf Genera/ Psychiatry. 38, I5 (198 I). Charney. D.S.. Heninger, G.R.. and Breier. A. Noradrenergic function in panic anxiety: Effects of yohimbine in healthy subjects and patients with agoraphobia and panic disorder. Archives qJ‘ General P.y~~chiarr,~,41, 75 I (1984). Charney, D.S.. Heninger. G.R.. Sternberg, D.E.. Redmond, D.E., Leckman. J.F., Maas, J.W.. and Roth, R. Presynaptic adrenergic receptor sensitivity in depression: The effect of long-term desipramine treatment. Archives qf’ Genera/ P.y_r,chiafry, 38, I334 (198 I). Checkley. S.A. Corticosteroid and growth hormone responses to methylamphetamine in depressive illness. fs~~chological Medicine, 9, 107 (1979). Davis, K.L.. Davis. B.M.. Mohs. R.C., Math& A.A., Vale, W., and Krieger, D. CSF corticotropin releasing factor in neuropsychiatric disease. (Abstract) Presented at the Annual Meeting of the American Psychiatric Association, Los Angeles. May IO (1984). Davis, K.L.. Hollister. L.E.. Math& A.A., Davis, B.M., Rothpearl, A.B., Faull, K.F., Hsieh, J.Y.K.. Barchas. J.D., and Berger, P.A. Neuroendocrine and neurochemical measurements in depression. American Journal of Pswhiarry, 138, I555 (198 I). Dekirmenjian, H.. and Maas, J.W. 3-Methoxy-4-hydroxyphenylethylene glycol in plasma. Clinica Chimica
Acra, 52, 203 (1974).
Demisch. suppression
K.. Demisch. L., Bochnik, H.J.. and Schulz, F. Comparison of the ACTH test and dexamethasone suppression test in depressed patients. American Journal qf‘ Ps~~chiarry. 140, I5 I I ( 1983). DeMoor. P.. Steeno, 0.. Raskin. M.,and Hendrikx, A. Afluorometricdeterminationoffree plasma I I-hydroxycorticosteroids in man. Acra Endoc,rino/ogica, 33, 297 (1960). Dixon, W.J.. Brown. M.B., Engelman. L.. Frane. J.W., Hill, M.A., Jennrich. R.I., and Toporek. J.D. BMDP Sratisrical Sqf/Lvare: 1983 Printing With Additions. University of California Press. Berkeley (1983). Elsworth. J.D.. Redmond. D.E.. Jr.. and Roth. R.H. Plasma and cerebrospinal fluid 3methoxy-4-hydroxyphenylethylene glycol (M H PG) as indices of brain norepinephrine metabolites in primates. Brain Research. 235, I I5 (1982). Esler, M.. Turbott. J., Schwartz, R., Leonard, P.. Bubik, A., Skews. H., and Jackman, G. The peripheral kinetics of norepinephrine in depressive illness. Archives ofGenera/ fs_vchiatry, 39, 295 (1982).
Fuller, R.W.. Snoddy. H.D.. and Perry, K.W. concentration and turnover in rat brain and Pharrnacod~~namie,
231, 30 (1978).
Effect of prazosin on norepinephrine heart. Archives Inrernationales de
14
Gold, P.W., Chrousos. G.. Kellner. C.. Post. R.. Roy. A., Augerinos. P.. Schulte. H., Oldfield, E., and Loriaux, D.L. Psychiatric implications of basic and clinical studies with corticotropin releasing factor. American Journal of f.swhiatr~~, 141, 619 (1984). Hamilton, M. A rating scale for depression. Journal of Neurolog~~. ,Yeuro.surXer~~ and P~yhiarr~~,
23, 56 ( 1960).
Heath, D.F. Normal or log normal: Appropriate distributions. Nature, 213, I I59 (1967). Jimerson, D.C.. Ballenger. J.C., Lake. C.R.. Post, R.M., Goodwin. F.K.. and Kopin, I.J. Plasma and CSF MHPG in normals. P.s~,c,hopharrnac,olo~~, Bullerin, 17, 86 (198 I). Jimerson. D.C., Insel. T.R., Reus, V.I.. and Kopin. 1.J. Increased plasma M HPG in dexamethasone-resistant depressed patients. Architses of General PsJ,chiatr>,, 40, 173 ( 1983). Kalin, N.H., Weiler. S.J.. and Shelton. S.E. Plasma ACTH and cortisol concentrations before and after dexamethasone. f?s~~chia/r~~Researc,h, 7, 87 (1982). Karoum, F., Mayer-Schwing. J., Potkin. S.G., and Wyatt, R.J. Presence of free sulfate and glucuronide conjugated MHPG in human brain, cerebrospinal fluid and plasma. Brain Research,
125, 333 (1977).
Kasper, approach:
S.. and Beckmann. H. Dexamethasone suppression test in a pluridiagnostic Its relationship to psychopathological and clinical variables. Acra Ps~~chiatrica Scandinavica, 68, 3 I ( 1983). Kopin, I.J., Jimerson. D.C., Markey, S.P.. Ebert. M.H., and Polinsky. R.J. Disposition and metabolism of M H PG in humans: Application to studies in depression. Pharmac,opsl’c,hia/rl,. 17, 3 (1984).
Lake, C.R.. Pickar, D.. Ziegler. M.G.. Lipper, S.. Slater, S., and Murphy. D.L. High plasma norepinephrine levels in patients with major affective disorder. American Journul of’ Psyhiarr.v,
139, I3 I5
( 1982).
l.eckman. J.F.. and systems and emerging
Maas. J.W. Plasma MHPG: Relationship to brain noradrenergic In: Post, R.M., and Ballenger. J.C.. eds. clinical applications. Neurohiologv qf Mood Disorders. Williams & Wilkins. Baltimore (1984). Maas. J.W., Hattox. S.E.. Landis. D.H.. and Roth. R.H. The determination of a brain arteriovenous difference for 3-methoxy-4-hydroxy-phenylethyleneglycol (M H PG). Brain Research, 118, I67 ( 1976). Mattingly, D. A simple fluorimetric method for the estimation of free I I-hydroxycorticoids in human plasma. Journal of Clinical fatholog~~, 15, 374 (1962). Mezey, E.. Reisine. T.D., Palkovits, M.. Brownstein, M.J.. and Axelrod. J. Direct stimulation of beta-2-adrenergic receptors in rat anterior pituitary induces the release of adrenocorticotropin in vivo. Proceedings qf the National Academy qf Sc,ience.s qfthe Uninired States cf America.
80, 6728 (1983).
Nasr, S.J., and Gibbons, R.D. Depressive symptoms associated with dexamethasone resistance. Ps~~chiarr,~ Research, 10, I83 (1983). Olpe, H.R.. and Jones, R.S.G. Excitatory effects of ACTH in noradrenergic neurons of the locus coeruleus in the rat. Brain Research, 251, 177 (1982). Oxenkrug, G.F.. Nunzio. P., McIntyre. I.M.. Branconnier. R.J., Stanley. M.. and Gershon. S. Aging and cortisol resistance to suppression by dexamethasone: A positive correlation. Ps_vchiafry Research. 10, 125 (1983). Raymond, V.. Lepine. J.. Giguere. V., Lissitrky. J.C., Cote. J.. and Labrie. F. Parallel stimulation of ACTH. B-LPH + P-endorphinand (Y-MSH release by a-adrenergicagents in rat anterior pituitary cells in culture. Molecular and Cellular Endocrinology,, 22, 295 (1981). Rees, L.. Butler, P.W.P.. Gosling. C., and Besser, G.M. Adrenergic blockade and the corticosteroid and growth hormone responses to methylamphetamine. Nature, 228,565 ( 1970). Reus, V.I.. Joseph, M.S.. and Dallman, M.F. ACTH levels after dexamethasone suppression test in depression. The New, England Journal of Medicine. 306, 238 (1982). Rosenbaum, A.H., Marata. T.. Schatzberg. A. F.. Orsulak, P.J.. Jiang, N.S.. Cole, J.O.. and Schildkraut. J.J. Toward a biochemical classification ofdepressivedisorders: VII. Urinary free cortisol and urinary M HPG in depression. American Journal qf‘ P.sj,c,hiarrj., 140, 3 I4 ( 1983).
15
Sachar, E.J., Halbreich, U., Asnis, G.M., Nathan, R.S., Halpern, F.S., and Ostrow, L. Paradoxical cortisol responses to dextroamphetamine in endogenous depression. Archives of General Psychiatry, 38, I 113 ( I98 1). Schildkraut, J.J., and Kety, S.S. Biogenic amines and emotion. Science. 156, 21 (1967). Sherman, B., Pfohl, B., and Winokur, G. Circadian analysis of plasma cortisol levels before and after dexamethasone administration in depressed patients. Archives of General Psychiatry, 41,27
I (1984).
Siever, L.J., Uhde, T.W.. Jimerson, D.C., Post, R.M., Lake, C.R., and Murphy, D.L. Plasma cortisol responses to clonidine in depressed patients and controls. Archives of Generul Psychiatry,
41, 63 (1984).
Stokes, P.E., Frazer, A., and Casper, R. Unexpected neuroendocrine-transmitter relationships. Psychopharmacology Bulletin. 17, 72 (198 I). Stokes, P.E., Stoll, P.M., Koslow, S.H., Maas. J. W., Davis, J.M., Swann, A.C., and Robins, E. Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. Archives of General Psvchiurry, 41,257 (1984). Valentino, R.J., Foote, S.L., and Aston-Jones, G. Corticotropin-releasing factor activates noradrenergic neurons of the locus coeruleus. Bruin Research, 270,363 (1983). Weiner, R.I., and Ganong, W.F. Role of brain monoamines and histamine in regulation of anterior pituitary secretion. Physiological Reviews, 58, 905 (1978). Wyatt, R.J., Portnoy, B., Kupfer, D.J., Snyder, F., and Engelman, K. Resting plasma catecholamine concentrations in patients with depression and anxiety. Archives of General Psychiarry, 24, 63 ( 197 I).