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Serial dexamethasone suppression tests in psychiatric illness: Part I. A study in Schizophrenia and mania
Pswhiatr.1,
Reseamh,
18, 9-23
Elsevier
Serial Dexamethasone Suppression Tests in Psychiatric Illness: Part I. A Study in Schizophrenia and Mania Andreas Received 1985.
Baumgartner,
Klaus-Jbrgen
Gr’if,
and Irene
h4a.r 20, 1985; retsised version received Sepremher
Kiirten
IO, 1985; accepted September
27,
Abstract. Weekly dexamethasone suppression tests (DSTs) were performed in 15 patients with schizophrenia (n q 12) and mania (n = 3) until clinical response. At initial evaluation, 53.4% of the patients were nonsuppressors, and 93.3% showed nonsuppression at least once during the treatment period. There was a tendency for DST results to normalize coincident with clinical improvement, although single peaks of DST nonsuppression occurred in several patients irrespective of clinical course. The tests did not prove useful as predictors of recovery or relapse. DST nonsuppression occurred significantly more often in severely ill patients than in moderately ill patients or in patients after recovery, emphasizing the effects of nonspecific stress factors and/ or severity of illness on the DST. The cutoff point, established on the basis of DST results in 67 healthy controls, was lower than in other studies, and nonsuppression among healthy controls was associated with low dexamethasone serum levels. Key Words. Longitudinal Early escape
of plasma
cortisol
dexamethasone
suppression
concentrations
tests, schizophrenia,
in the dexamethasone
stress.
suppression
test
other psychiatric disorders (e.g., Carroll et al., 1976a, 1976b, 198 1; Carroll, 1982; Graham et al., 1982; Insel et al., 1982; Arana et al., 1983; Balldin et al., 1983; Abou-Saleh et al., 1984; Berger et al., 1984; Stokes et al., 1984). However, no consensus has yet been reached on the etiology of DST nonsuppression (e.g., Carroll, 1982; Berger et al., 1984) or its clinical relevance as a marker for endogenous depression (e.g., Baldessarini and Arana, 1985; Carroll, 1985; Keitner et al., 1985) or as a predictor of course, treatment outcome, or relapse in depressive illness (e.g., Greden et al., 1982, 1983). In some recent studies (e.g., Holsboer et al., 1982, 1983; Greden et al., 1983) in which the DST was conducted weekly in depressive patients, a trend toward normalization of the DST results preceding clinical recovery has been reported. These (DST)
has
frequently
been
reported
both
in endogenous
depression
and
An earlier version of this report was presented at the 137th Annual Meeting of the American Psychiatric Association, Los Angeles, May 5-l I, 1984. Andreas Baumgartner, M.D.. is at the Psychiatrische Klinik und Poliklinik. Klinikum Charlottenburg, Freie Universi&t Berlin. Klaus-Jiirgen Gt%f. M.D., is Associate Professor of Internal Medicine at the Medizinische Klinik und Poliklinik (Hormone Research Laboratory), Klinikum Charlottenburg. Irene K&en is Laboratory Assistant at the Hormone Research Laboratory, Klinikum Charlottenburg, Freie Universitat Berlin. Federal Republic of Germany, (Reprint requests to Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik. Klinikum Charlottenburg der Freien Universiiit Berlin, Eschenallee 3, 1000 Berlin 19. FRG.) 0165-1781
86 $03.50 @ 1986 Elsebier Science
Publishers
B.V.
10 results suggest that the DST might be a promising tool for monitoring the course of illness and predicting therapy response or relapse. Since DST nonsuppression in patients with diagnoses other than melancholia has been reported in an increasing number of studies, the question arises as to whether the pattern of DST results obtained in longitudinal studies in those diseases differs from that seen in endogenous depression. To our knowledge, only one study has been published on this issue: Myers (1984) found DST nonsuppression at least once in each of five chronic schizophrenic patients during a series of 12 weekly DSTs. The purpose of our study was to examine the pattern of weekly DST results in psychiatric patients with diagnoses other than depression. In a previous study we found a high nonsuppression rate in healthy volunteers after stress (Baumgartner et al., 1985). Ceulemans et al. (1985) also reported abnormal DST results in patients awaiting operation. Thus, we were interested in establishing whether stress due to severity of illness or other nonspecific stress factors such as hospital admission influenced DST results. We therefore included mainly severely ill patients in our study. Methods Patients. Fifteen patients, all hospitalized on our six nonresearch wards, were included in the study. Eight patients were female, seven male, and their mean age was 29.7 f 9.5 (range: 18-57) years. All patients were diagnosed by one psychiatrist (A.B.) according to Research Diagnostic Criteria (RDC) (Spitzer et al.. 1978), DSM-III (American Psychiatric Association, 1980) and ICD-9 (World Health Organization, 1978). Twelve met RDC for schizophrenia (probable or definite) and DSM-III criteria for schizophrenia (n = 6) or schizophreniform (n = 6) disorder (patient nos. l-12 in Table I). Eleven had paranoid schizophrenia, aud one had catatonic subtype. Nine patients had acute, two had subacute, and one had subchronic schizophrenia (RDC). None of them had a history of major depression. Three other patients met RDC for mania (bipolar 1, probable or definite) and DSM-III criteria for major affective disorder, manic episode (patient nos. 13-15, Table 1). None of the three patients had concomitant depressive symptoms. Additional criteria for inclusion in the study were : (1) a score > 6 on the Clinical Global Impressions Scale (CGI-II, severity item); (2) no history of severe weight loss before hospital admission (i.e., more than 20% of ideal body weight); (3) the absence of any serious medical illness; (4) no history of alcoholism or drug abuse; (5) no medication which might interfere with were evaluated by the DST (Carroll et al., 1981; Greden et al., 1983). All patients electroencephalogram (EEG). electrocardiogram (EKG), routine laboratory screening, and physical examination to exclude major physical illness. Nine patients did not complete the study. Five of these, who were in acute psychotic turmoil, refused either to take the dexamethasone or to give a blood sample at the initial DST. Four further patients left the hospital within the first 2 weeks. It was therefore necessary to include a total of 24 patients in order to obtain interpretable results for 15. Drug Treatment. In all patients, the initial DST was conducted 2-4 days after admission. Only two patients had not received medication before the first DST. In all other cases, immediate institution of neuroleptic treatment was considered necessary on hospitalization. Thus, the possibility of drug withdrawal effects influencing the initial DST was ruled out. Drug treatment methods, including specific medication and dosage, were determined on a clinical basis. All patients received neuroleptics. and in all but three patients, neuroleptic treatment was continued until discharge. Two of them (patient nos. 13 and 14 in Table I) were given lithium after neuroleptic withdrawal. and patient no. 7 received no further medication after week I. Two patients took tricyclic antidepressants (clomipramine and imipramine) for a brief period.
II Haloperidol, perazine, pipamperon, pimozide, thioridazine, fluperlapine, flusperilen, benperidol, flupentixol, and clozapine were the neuroleptic drugs given. Several patients were given biperiden as necessary. Thyrotropin-releasing hormone (TRH) tests were performed every 2 weeks in all patients on the day preceding the DST. The results are presented elsewhere (Baumgartner et al., 1986). More detailed information on demographic characteristics, diagnoses, the individual drug treatment, and the temporal relationship between drug treatment and DSTs is available from the authors on request. Ratings. All patients were rated according to the Clinical Global Impressions (CGIII, severity score) Scale (Guy and Bonato, 1970) the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960) on the day of the first DST. CGI severity ratings were then carried out weekly on the day of the DST until the patients showed clinical response. This was defined as a CGI score < 3. Clinical improvement was defined as a reduction > 1point on the CC1 severity scale. Relapse was defined as a CGI score > 6 in patients who had previously shown a response. All ratings were carried out by one observer (A.B.), who was unaware of all DST results until the patients responded clinically. Clinical
DSTs were conducted in 67 healthy controls (30 males, 37 females) to establish the optimal cutoff point between cortisol suppressors and nonsuppressors. The subjects’ mean age was 47.6 + 17.7 (range 26-80) years. Forty-seven of the controls were employees of the psychiatric clinic, and the DST was carried out under normal working conditions. Twenty retired volunteers (ages 63-80 years) who occasionally work for a drug research institute were also included in the study. None of the controls had a history of mental illness, showed signs of physical illness, or had received psychotropic medication in the last 3 months before the DST. Two retired volunteers were taking digitalis. Women on oral contraceptives were not included in the study. One woman was on a diet and had lost 12 kg in 8 weeks; she proved to be a suppressor. None of the others had lost weight before entering the study. Controls.
The DST was carried out by administering I mg of oral dexamethasone (Millicorten) at I I:00 p.m. A blood sample was collected at 4 p.m. on the following day. The nurses were instructed to ensure that the patients actually took the dexamethasone. Several times we ourselves had to ask the patients in acute psychotic turmoil to take the dexamethasone, particularly at the first administration, because they refused to take it from the nurses, although they had previously consented to do so. A commercial radioimmunoassay (RIA) kit (Cortisol-J-125, direct method, “Diagnostic Products Corporation”) was used for assay of cortisol. The lowest standard was 1 pg/dl; the highest was 50 pgi dl; and the sensitivity was 0.3 pg/ dl. Cross-reactivity for dexamethasone was 0.01%. Only prednisolone showed a cross-reactivity > 4%. The interassay coefficient of variation calculated from laboratory control samples taken from each assay over a 5-month period was 11%at a cortisol level of 3.3 kg/dl, 9% at 10.9 pg/dl, and 9% at 28.2 pg/dl. We also had 45 control samples evaluated, each under a different name, with three different cortisol levels, in order to test the “reliability” of the laboratory assistant, who had no knowledge of the results. The interassay coefficients of variation calculated for the groups of 15 samples were 3.5% at a cortisol level of 11.3 pg/dl, 4.4% at 3.2 pg/dl, and 8% at 0.7 pg/dl, respectively. DST.
Data Analysis. Where appropriate, values are given as mean f standard deviation (SD). As postdexamethasone cortisol values are not normally distributed even after logarithmic transformation, we used nonparametric tests for statistical evaluation. We applied the MannWhitney U test for the comparison of subgroups and the x2 test for dichotomous variables. It was not necessary to carry out Fisher-Yates correction for this sample (Camilli and Hopkins, 1979). Dexamethasone serum levels were normally distributed. We therefore applied the t test (two-tailed. for paired and unpaired samples) for comparison of subgroups with different
12
dexamethasone concentrations. In order to assess the relationship between postdexamethasone cortisol concentrations and clinical variables, we calculated Pearson’s r coefficient of correlation, which is insensitive even to extreme violations of the basic assumptions of normality (Havlicek and Peterson, 1977). For assessment of the temporal relationship between the normalization of DST results and clinical recovery, we also calcuated Pearson’s r coefficient of correlation between the DST results and CC1 severity scores of the same week, between the DST results of 1week and the CGI scores of the following week, and between the DST results of I week and the CGI scores obtained 2 weeks later. Due to the small number of measurements for each patient, however, the value of these calculations is limited. We therefore regard these results as additional information of descriptive value and not as evidence of statistical significance. We accepted p values < 0.05 as significant for all evaluations.
Table
1. Dexamethasone
suppression
test (DST)
responses
and Clinical
Patient no.
Weeks after initial DST
1
2
3
4
5
6
7 10.52 17)
0
5.72 (7)
21.02 171
6.72 16)
9.62 (7)
< 1 16)
1
< 1 14)
IO.02 (7)
19.42 (7)
< 1 15)
9.12 (3)2
2.52 (5)
4.32 (41
2
< 1 (312
10.52 (7)
21.02 (6)
1.4 12)
6.12 (312
< 1 (312
2.1
(7j
3
< 1 (3)
4 5
< 1 (2)2 < 1 (612
121
(5)
6
7
< 1 (312
8
< 1 (2)
9 10
(5)
11.52 (5)
< 1 (41
1.1 (3)2
< 1 (4) < 1 (3)2
-
(71
(2)
11 12 13 14 15 16 17 18
r = 0.93
r = 0.54
r = 0.97
r = 0.70
DST week 0
df = 3
df=8
df=4
df=4
CGI week0
p=O.O19
NS
p=O.OOl
NS
Pearson’s
r
r = 0.81
r = 0.39
r = 0.82
r = 0.53
DST week 0
df = 2
df=7
df=3
df = 3
CGI week +l
NS
NS
NS
NS
Pearson’s
r
r = 0.50
r-0.16
r = 0.52
r = 0.81
DST week 0
df = 1
df=6
df=2
df=2
CGI week +2
NS
NS
NS
NS
Pearson’s
r
1. Plasma cortisol 2 Nonsuppressors
levels in pg/dl and CGI-II scores in parentheses. and CGI scores in the week of clinical recovery
or relapse
12)
13
Results Cutoff Point. The mean postdexamethasone cortisol concentration for the group of 67 healthy controls was 1.19 * 0.58 pg/ dl (Fig. 1). We therefore fixed our cutoff point at 2.35 pg/ dl (mean + 2 SD). Three controls (4.5%) were nonsuppressors, and 64 were suppressors (95.5%). The nonsuppressors were aged 42,69, and 75 years, respectively. One was a physician, and the others were from the group of retired volunteers. Thus, no significant difference was found between the nonsuppression rate for the retired persons (age 63-80 years) and that for the hospital staff (age 26-60 years) (x2 2.03, df = 1, p > 0.1).The healthy controls over 63 years of age had slightly higher q
Global Impressions
(CGI) severity scores1 Patient no.
8
9
10
11
3.72 (8)
1.9 (6,
< 1 (6) 12.72 (7)
~1
9.52 (6)
< 1 (51
Mean cortisol CGI
13
14
15
(61
1.2 (7)
2.1 (6)
6.12 17)
5.7
6.6
15
12
n
6.82 (8)
(5)
cl
15)
2.0 (7)
1.4 (5)
~1
(6)
4.7
5.4
15
cl
(4)
< 1 (3)2 1.3 (6)
(4)
< 1 14)
< 1 161
1.3 (5)
14)
3.3
4.3
15
(5)
~1
(312
(4)
1.1 (5)
1.2 (5)
(2)2
1.8
3.9
12
cl
(51
(4)
-=z 1 (5)
-
1.0
3.6
8
~1
(3)2
1.1 (4)
1.5 (4)
1.0
4.0
7
4.12 (4)
9.82 (5)
1.1 (5)
1.8 (3)
2.0 (3)
(2)
<1
(4)
~1
(312
(4)
8.22 (4, (4)
(4)
(5)
(5)
2.1 (3)
(51
2.1 (2)
15.12 (8,
4.22 (2)
< 1 (4)
~1
-
1.5 (3)2
13.02 (4) -
(5)
(6)
(61
1.6 (51
Discharged
151
15)
1.1 (61
(6)
15)
Monitoring stopped r=
r= 0.76
r=
0.21
df = 4
df=3
df=
10
NS
NS
NS
r=
0.50
-0.08
r=
df=3
df=
NS
NS
r= df= NS
0.50
r=
2
df= NS
0.20 2
-0.23 1
r = 0.50
r =-0.55
df=
df=9
df=4
NS
p=
0.002 0.80
p=
17 0.025
r = 0.95
r = 0.05
r =-0.63
r=
df= 8
df=
df=8
df=
NS
NS
p = 0.048
NS
r=
r= df= NS
-0.17
-0.23 8
16
r=
0.20
df=
15
NS
3
r = 0.49
r=
df=7
df=2
NS
NS
0.48
14 Fig. 1. Postdexamethasone cortisol concentrations in healthy controls and in patients with schizophrenia and mania at 4 p.m. Healthy controls
I---n = 67
Cort~sol24 Wdll 22
1 md Mama P
her chcal
n
,=13' _
575' 569
1
rerponre 24 Cortisol (mIdI)
-22
.
20
-20
16 1
-18
16
-16
14
-14
. 1
12-I
.
10
.
. iI 1
8-l 6 5
4 235 2
0.
-12 -10
119tO58
0
.... -*::L ................ i ::::::s::::::::::
-.-
postdexamethasone cortisol levels (mean 1.4 ?r 0.7 pg/ dl) than those younger than 60 years (mean I. 1 f 0.6 pg/dl), but this difference was not statistically significant (Mann-Whitney Ii 27 1,p > 0.05, NS). The correlation between postdexamethasone cortisol values and age in all healthy volunteers was also not significant (r = 0.20, df= 65). The mean dexamethasone level of 44 healthy controls was 112.4 f 57.3 (range 38-275) ngjdl. The mean dexamethasone level of all healthy subjects with cortisol levels > 1 pug/ dl was 82.7 f 39.2 ng/ dl, whereas that of all volunteers with a DST result < 1 pg/dl was 128.7 k 6 1.3 ng/ dl. This difference was statistically significant (t 2.75, df= 42,~ < 0.005). The dexamethasone levels of the three nonsuppressors among our healthy subjects were 25 ng/ dl, 52 ng/ dl, and 106 ng/ dl, respectively. Dexamethasone was detected in all serum samples of the healthy subjects, and the lowest concentration that led to suppression of cortisol to a value < 1 pg/ dl was 38 ng/ dl. Detailed results of dexamethasone investigations in healthy controls will be presented in a later report. q
q
Comparison Between Suppressors and Nonsuppressors. The distribution of postdexamethasone cortisol values is shown in Fig. I. At the initial DST, eight patients (53.4%) exhibited nonsuppression, and after clinical response two patients (15.3%) showed elevated postdexamethasone cortisol levels. Both of them had shown suppression at the first DST (patient nos. 6 and 14, Table I). Thus, the nonsuppression rate for the patients following admission and that for the healthy controls differed
15
significantly (x2 25.1, df 1, p < 0.001). However, the DST results obtained in patients after recovery did not differ significantly from those for the healthy volunteers (x2 = 2.0, df = 1,p > 0.1, NS). Even if we set a more “conservative” cutoff point (e.g., 5 pg/dl according to Carroll et al., 1981), the nonsuppression rate of the patients following admission (46.4%) again differed significantly from that of the healthy controls (x2 = 34.1, df = 1,p < 0.00 1). When we included not only the first DST but all results obtained over the entire study period, we obtained a rate of 93.3% of patients showing nonsuppression at least once (86.7% with the cutoff point at q
q
5 ygldl). Longitudinal Pattern of DST Results. The relationships between weekly DST results and CGI severity scores are shown in Tables 1 and 2, and in Fig. 2. There was an obvious decrease in the mean postdexamethasone cortisol concentrations during treatment. This decrease was associated with a similar progressive reduction in the mean CGI scores. The correlation (Pearson’s r) between mean weekly cortisol concentrations and mean CGI scores obtained simultaneously was r 0.95 @ < 0.01) in the first 5 weeks (Table I and Fig. 2). Normalization of initially abnormal DST results occurred at the same time as, or 1-4 weeks before, clinical recovery (Table 2~). Only in one patient did the DST result fail to return to normal until 1 week after clinical recovery (patient no. 5). The question as to whether normalization of the DST results occurs before, simultaneously with, or after clinical recovery, however, depends on the clinical response criteria and the specified cutoff point, factors that differ from study to study. In other words, the higher the cutoff point and the lower the scores required for clinical response, the sooner before clinical recovery DST results normalize. To obtain additional information on the best temporal relationship between the two variables, we also calculated Pearson’s r coefficient between the DST results and CGI scores of the same week, the DST values of one week and CGI scores of the following week, and between DST results of one week and CGI scores obtained 2 weeks later. This was possible for nine patients. In three of these patients, the best correlation was obtained on comparison of the DST results and CGI ratings for the same weeks, and in no patient was there a significant correlation between the DST of one week and the CGI score of one of the two following weeks. In six patients there was no significant correlation between the two variables at all (Table 1). Thus, although, according to the response criteria applied, the DST normalizations preceded clinical recovery, the statistical analysis failed to confirm such a temporal relationship. The relationships between DST results and CGI scores in patients with nonsuppression during treatment are shown in Tables 2a and 26. With regard to whether DST normalization could be helpful in predicting subsequent drug response, we looked at CGI scores in the week of DST normalization (Table 24. Eleven patients had already shown clinical improvement in the week of DST normalization, and in only three patients did the DST values return to normal without corresponding clinical improvement. Thus, in most of the patients, DST normalization was superfluous as a predictor of clinical recovery because clinical improvement was already obvious before the DST results were known. The only patient (no. 3) who relapsed exhibited cortisol suppression both before and during the relapse. Thus, in this case, the DST was of no help in predicting the relapse. q
16 Table a.
2. Changes
in DST results
related
to clinical
8 (Patient nos. 1, 3, 4, 5, 7, 8, 11, 15)
DST normalization in nonsuppressors at initial evaluation
Normalization
of DST results coinciding
Normalization
of DST results before clinical
Normalization
b.
with clinical
recovery
2 (Patient
nos. 3, 7)
1 week
1 (Patient
no. 1)
2 weeks
2
3 weeks
1 (Patient
4 weeks
1 [Patient
no. 4)
1 (Patient
no. 5)
recovery:
of DST results 1 week after clinical
Patients with nonsuppression during treatment:
recovery
arising
Change
in DST results coinciding
with relapse
Change
in DST results coinciding
with increase
condition
i Patient nos. 11, 14) nos. 8)
6 (Patient nos. 2, 6, 10, 12, 13, 14) 0 in CGI score
2 (Patient
nos. 10, 131
by at least 1 point Change
in DST results without
in clinical
coinciding
Change
in DST results as a predictor
Change
in DST results in spite of decrease
CGI severity
c.
change
4 (Patient
of clinical
0
relapse
in the
1 (Patient
of DST results before clinical
DST not normalized DST normalization clinical Chance
d.
no. 6)
score by at least 1 point
DST normalization in patients with nonsuppression arising during treatment:
Normalization
nos. 2, 12, 13, 14)
condition
in spite of clinical without
coinciding
6 (Patient nos. 2, 6, 10, 12, 13, 14)
1 week
1 [Patient
2 weeks
1 (Patient
no. 10)
recovery
1 (Patient
no. 6)
or subsequent
2 (Patient
nos.
1 (Patient
no. 14)
recovery
no. 21
12, 13
recovery to nonsuppression
after recovery
and before discharqe
Clinical improvement as shown by decrease in CGI severity score by at least 1 point in the week of DST normalization1 No clinical improvement of DST normalization
1. Mean improvement
in the week
on the CGI severity
11
3
scale in the week of DST normalization:
1.72 points [range l-31
DST Results and Severity of Illness. The correlation (Pearson’s r ) between the initial DST results and CC1 scores of all patients was not significant (r = 0.38, df= 13, NS). A significant correlation would hardly be expected, however, since only patients with CGI scores of 6-8 were included and, moreover, our population was small. If interindividual and intraindividual data are considered together, the correlation between all CGI scores and all DST results in all patients is significant (r 0.43, df= 98, p < 0.01). It should be borne in mind that in this calculation different numbers of measurements are being compared for each patient. We therefore calculated this correlation for the first 3 weeks only and again obtained a significant correlation (r 0.40, df= 43, p < 0.01). We also calculated the percentages of nonsuppressors at various levels of severity of illness. We divided the patients into three groups according to their CGI scores: group I consisted of patients with CGI scores of 2 or 3 (clinical q
q
17
Fig. 2. Mean (+ SD) cortisol concentrations (bars) and mean Clinical Impressions (CGI) scores (connected dots) for the total sample. Plasma Cortisol (ccsidl) 12
Global
CGI Score 7 T
8
6
I
wk0 (n=15)
wk 1 (n=15)
wk 2 (n=15)
Values are given for the first 4 weeks of treatment
\
T
wk 3
wk4
(n=12)
(n=8)
t
after response
(n=13) and for the week after clinical
recovery.
responders); group 2 contained all the moderately and distinctly ill patients (CGI 4-6); and group 3 encompassed the severely ill patients (CGI 7 and 8). All DST evaluations for all patients were included in the calculation (Fig. 3). The x* test revealed no significant differences between the nonsuppression rates for the clinical responders (1 1.5%) and those for the moderately and distinctly ill patients (16.9%; x* 0.29, d’= I, p > 0.5, NS). The nonsuppression rate for the severely ill patients (80%) however, differed significantly from that for the two other groups combined (15.3%; x2 = 26.1, df I, p < 0.001). To sum up, we were able to show a good correlation between DST results and severity scores when both interindividual and intraindividual data were taken into account. Nonetheless, it should be borne in mind that severity of illness alone is not related to DST nonsuppression in all cases, as single peaks of abnormal DST results occurred in some patients without a corresponding change on the CGI scale. q
q
DST Results and Clinical Symptomatology. The mean HRSD score for all patients at the time of the initial DST was 13 * 6.2 (range 3-23). There was no significant correlation between postdexamethasone cortisol concentrations and either the HRSD scores (r 0.086) or the anxiety/depression syndrome score on the BPRS (r = -0.086). There was a good correlation between the two rating scales for depressive symptomatology (r = 0.77, df = 13,~ < 0.01) and also a significant correlation between both the thought disturbance syndrome score (r = 0.65, df= 13, p < 0.01) and the activation syndrome score (r 0.72, df = 13, p < 0.01) and the postdexamethasone q
q
18 Fig. 3. Nonsuppression rates and severity of illness in patients with schizophrenia and mania, calculated from all measurements during entire study period (n = 100) % Nonsuppressors 100 90
80 70
i
60 50 40
30
-I
20 -
3 (n=17)
2 (n=9) ClInical
Global
4 (n=19)
6 5 (n=25)in=15)
lmpresslons
(CGI
(n=12)
II) Severity
(n=3) Scores
cortisol levels. There was no significant correlation for the anergia suspiciousness syndromes (r 0.48 and r = 0.25, respectively).
or hostile-
q
DST and Clinical Outcome. Thirteen of the 15 patients responded clinically within 6 weeks. They had both normal (n = 5) and abnormal (n = 8) DST results at the initial evaluation. The two patients who did not respond clinically (no. 12 and no. 13) showed suppression at the initial evaluation, but both exhibited nonsuppression several times during the treatment period. Thus, the DST had no predictive value for the response to neuroleptic drugs in our patients. Discussion The Cutoff Point. The low incidence of nonsuppression among our healthy controls and the resultant low cutoff point might be partly due to the differences between laboratories. Meltzer and Fang (1983) reported a sixfold range in cortisol concentrations at a 95% confidence level between different laboratories working with different methods. These observations have since been confirmed by other authors (Wilens et al., 1983; Wood et al., 1983; Rubin and Poland, 1984; Ritchie et al., 1985). Therefore it must be emphasized that the cortisol measurements conducted by individual laboratories are only relative quantities and that it is thus impossible to compare results obtained by different methods. The quality of our cortisol evaluations has been
19 carefully controlled (see above). Even in the low range of 0.7 pg/dl, the interassay coefficient of variation was only 8%. Furthermore, 11 of 13 patients who finally responded clinically showed postdexamethasone cortisol values < 2.35 pg/dl, indicating that our cortisol measurements were consistent within the study and confirming the validity of the low cutoff point. Three other studies are known to us in which RIA kits from the Diagnostic Products Corporation were also used for measuring cortisol. In the study by Graham et al. (1982), none of the 20 healthy controls showed postdexamethasone cortisol levels > 1.85 pg/ dl (mean 1.20 pg/ dl) at 4:00 p.m.; the results thus do not differ from our own. However, Graham et al. (1982) used a 2 mg dose of dexamethasone. Hallstrom et al. (1983) and Lowy et al. (1984) who used the same RIA kit, reported much higher postdexamethasone cortisol values in their healthy controls. Stokes et al. (1984) reported nonsuppression rates in healthy controls (calculated from a blood sample collected at 8:30 a.m.) that ranged between 0% and 25% at different diagnostic centers. The results of our dexamethasone serum level investigations suggest that these differences could be at least partly due to differences in the pharmacokinetics of dexamethasone in healthy controls. Other authors have also reported a possible influence of dexamethasone levels on DST results (Arana et al., 1984; Berger et al., 1984; Johnson et al., 1984). Nevertheless, nonsuppression among our healthy controls cannot simply be related to low dexamethasone serum levels, as in two nonsuppressors the dexamethasone levels were higher than the lowest level that produced complete cortisol suppression in other controls investigated. It is possible that interindividual differences in the sensitivity of the hypothalamic-pituitary-adrenal axis to influences that lead to negative feedback mechanisms are responsible for this phenomenon. Finally, our low cutoff point might also be due to the fact that it was set by comparing healthy volunteers with all patients, irrespective of diagnosis. The few authors who have set their own cutoff levels have often compared melancholic patients with patients with other diagnoses (e.g., Carroll et al., 1981) in order to achieve the greatest diagnostic specificity. However, control patients with different diagnoses (i.e., other than melancholia) might have elevated postdexamethasone cortisol levels themselves, as was the case with the patients in this study. This factor would result in a higher cutoff point, because the two groups being compared both showed pathologically high cortisol values. We therefore suggest that in order to differentiate between normal and pathological results, healthy controls should be compared with the entire patient group without regard to diagnosis. Diagnostic Specificity of the DST. As regards use of the DST as a diagnostic tool, our results raise some doubts about the specificity of the DST for endogenous depression. The findings of hypercortisolism in schizophrenia and mania are, however, nothing new. In an early report, Sachar et al. (1970) found significantly elevated urinary 17-hydroxycorticosteroid excretion levels in four schizophrenic patients during acute psychotic turmoil, which is consistent with the findings in this study. Dexamethasone resistance has also been found in many recent studies in which the DST was employed in mania and schizophrenia. Dewan et al. (1982) found 30% nonsuppressors in 20 nondepressed chronic schizophrenics, and Haskett et al. (1984) reported 100% nonsuppression in five schizophrenic patients immediately after hospitalization. Berger et al. (1984) found 30.4% nonsuppression in 23 schizophrenic
20 patients, and Herz et al. (1985) reported 11 nonsuppressors out of 15 acute schizophrenic patients. The results obtained by Myers (1984) in weekly DSTs in chronic schizophrenics have already been quoted above. Evans and Nemeroff (1983) and Krishnan et al. (1983) found high nonsuppression rates in mixed bipolar disorders only, whereas Arana et al. (1983) and Graham et al. (1982) reported a high incidence of abnormal DST results in manic patients without concomitant dysphoric symptoms. Godwin et al. (1984) found DST nonsuppression in six out of nine bipolar patients both in depression and in the manic phase. Other workers have failed to find nonsuppression in schizophrenia and mania (Schlesser et al., 1980; Carroll et al., 198 1; Evans et al., 1983). In most of these studies, however, control patients were not rated for severity of illness. The different results could thus be due to the fact that the DSTs were performed in patients who were not comparable as regards severity of illness. Fig. 3 showed that there were significant differences between the nonsuppression rates for the group of severely ill and the group of moderately and distinctly ill patients, a finding that emphasizes the importance of rating control patients for severity. Carroll et al. (19766) suggested that in order to improve the diagnostic specificity of the DST, newly admitted psychotic patients should not be tested immediately after hospitalization. In our patients, however, abnormal DST results did not occur at the first DST evaluation only, but in 10 out of 15 patients at least one more time in the further course of the episode. Thus, even if patients were not tested sooner than 1 week after admission, the final nonsuppression rate for schizophrenic and manic patients would still be 66%. Use of Weekly DSTs in Schizophrenia and Mania. In our study, the DST was of no value as a predictor of clinical course and treatment outcome. In about half of the patients, the DST results returned to normal several weeks before clinical recovery. Most of the patients, however, already showed clinical improvement in the week of DST normalization, indicating subsequent clinical recovery. Thus DST normalization had no relevance as regards maintenance or changes in drug treatment. DST results did not predict relapse, and in several patients nonsuppression occurred without corresponding or following changes in clinical state, making clinical decisions based on DST results even more problematic. The high nonsuppression rate in our patients was clearly related to severity of illness. It is not yet possible to come to any definite conclusions as to whether in schizophrenia and mania the severity of illnesses in itself is the primary factor activating the HPA axis, or whether secondary nonspecific factors, such as stress, are responsible for the abnormal DST results. As an important influence of stress on the DST in healthy volunteers has been shown in some studies (e.g., Baumgartner et al., 1985; Ceulemans et al,, 1985), the possibility cannot be excluded that DST nonsuppression in patients is also due to secondary stress factors related to severity of illness. As regards a possible influence of drugs in our patients, most of them were receiving high doses of neuroleptics at all DST evaluations. According to Carroll et al. (198 I), neuroleptics do not affect DST results, but surprisingly little investigation seems to have been done on this issue. We shall discuss this problem in Part III of this report. There is evidence that a considerable number of other variables might influence DST results: weight loss (Berger et al., 1984) dexamethasone serum levels Clinical
21 (Arana et al., 1984), age (Halbreich et al., 1984) length of episode (Sashidharan et al., 1984) time and frequency of blood samples (Sherman et al., 1984) and, of course, diagnosis (Carroll, 1982). We therefore also performed weekly DSTs in 35 patients with major depression and will present the results in Part II of this report. A discussion of the role of diagnosis and an investigation of the influence of nonspecific intervening variables are included in Part III. References Abou-Saleh.
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22 Evans, D.L., and Nemeroff, C.B. The dexamethasone suppression test in mixed bipolar disorder. American Journal of Psychiatry, 140, 6 15 (1983). Godwin, C.D., Greenberg, L.C., Shukla, S. Consistent dexamethasone suppression test results with mania and depression in bipolar illness. American Journal ofPsychiatry, 141, 1263 (1984).
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Haskett, R.F., Zis, A.P., and Albala, A.A. Clinical use of the dexamethasone suppression test. Presented at the 137th Annual Meeting of the American Psychiatric Association, Los Angeles, CA, May 5-11 (1984). Havlicek, L.L., and Peterson, N.L. Effect of the violation of assumptions upon significance levels of the Pearson r. Psychological Bulletin, 84,373 (1977). Herz, M.I.. Fava, G., Molnar. G., and Edwards, L. The dexamethasone suppression test in newly hospitalized schizophrenic patients. American Journal of Psychiutry, 142, 127 (1985). Holsboer, F., Liebl, R., and Hofschuster, E. Repeated dexamethasone suppression tests during depressive illness. Journal of Affective Disorders, 4, 93 (1982). Holsboer, F., Steiger. A.. and Maier, W. Four cases of reversion to abnormal dexamethasone suppression test response as indicator of clinical relapse: A preliminary report. Biological Ps_vchiutr_v, 18, 91 1 (1983). Insel, T.R., Kalin. N.H., Guttmacher, L.B., Cohen, R.M., and Murphy, D.L. The dexamethasone suppression test in patients with primary obsessive compulsive disorder. Psychiurry
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Johnson, G.F., Hunt, G., Kerr, K.. and Caterson, 1. Dexamethasone suppression test (DST) and plasma dexamethasone levels in depressed patients. Psychiatry Research, 13, 305 (1984). Keitner, G.I., Haier, R.J., Quails, B.C., Brown, W.A., and McKendall, M.J. Diagnostic heterogeneity and the DST in consecutive psychiatric admissions. Psychiurr.p Research, 14,215 (1985). Krishnan, R.R., Maltbie, A.A., and Davidson, J.R.T. Abnormal cortisol suppression in bipolar patients with simultaneous manic and depressive symptoms. American Journal of Psychiatry,
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Meltzer, H.Y., and Fang, V.S. Cortisol determination and the dexamethasone suppression test. Archives qf General Psychiatry. 40, 501 (1983). Myers, E.D. Serial dexamethasone suppression tests in male chronic schizophrenic patients. American
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141, 904 (1984).
23
Ritchie, J.C., Carroll, B.J., Olton. P.R., Shively, V., and Feinberg, determination for the dexamethasone suppression test. Archives ofGenera
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Spitzer, R.L., Endicott, J., and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35, 773 (1978). Stokes, P.E., Stall, 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 Psychiatry, 41,257 (1984). Wilens, T.E.. Arana, G.W., Baldessarini, R.J., and Cremens, C. Comparison of solid-phase radioimmunoassay and competitive protein binding method for postdexamethasone cortisol levels in psychiatric patients. Psychiatry Research, 8, 199 (1983). Wood, K., Horwood, J., and Coppen, A. Technique and accuracy of the dexamethasone suppression test. Archives of General Pschiatry, 40, 585 (1983). World Health Organization. Mentul Disorders: Glossary and Guide to Their Classification in Accordance With the 9th Revision of the International Classification of Diseases. WHO, Geneva ( 1978).
Reseamh,
18, 9-23
Elsevier
Serial Dexamethasone Suppression Tests in Psychiatric Illness: Part I. A Study in Schizophrenia and Mania Andreas Received 1985.
Baumgartner,
Klaus-Jbrgen
Gr’if,
and Irene
h4a.r 20, 1985; retsised version received Sepremher
Kiirten
IO, 1985; accepted September
27,
Abstract. Weekly dexamethasone suppression tests (DSTs) were performed in 15 patients with schizophrenia (n q 12) and mania (n = 3) until clinical response. At initial evaluation, 53.4% of the patients were nonsuppressors, and 93.3% showed nonsuppression at least once during the treatment period. There was a tendency for DST results to normalize coincident with clinical improvement, although single peaks of DST nonsuppression occurred in several patients irrespective of clinical course. The tests did not prove useful as predictors of recovery or relapse. DST nonsuppression occurred significantly more often in severely ill patients than in moderately ill patients or in patients after recovery, emphasizing the effects of nonspecific stress factors and/ or severity of illness on the DST. The cutoff point, established on the basis of DST results in 67 healthy controls, was lower than in other studies, and nonsuppression among healthy controls was associated with low dexamethasone serum levels. Key Words. Longitudinal Early escape
of plasma
cortisol
dexamethasone
suppression
concentrations
tests, schizophrenia,
in the dexamethasone
stress.
suppression
test
other psychiatric disorders (e.g., Carroll et al., 1976a, 1976b, 198 1; Carroll, 1982; Graham et al., 1982; Insel et al., 1982; Arana et al., 1983; Balldin et al., 1983; Abou-Saleh et al., 1984; Berger et al., 1984; Stokes et al., 1984). However, no consensus has yet been reached on the etiology of DST nonsuppression (e.g., Carroll, 1982; Berger et al., 1984) or its clinical relevance as a marker for endogenous depression (e.g., Baldessarini and Arana, 1985; Carroll, 1985; Keitner et al., 1985) or as a predictor of course, treatment outcome, or relapse in depressive illness (e.g., Greden et al., 1982, 1983). In some recent studies (e.g., Holsboer et al., 1982, 1983; Greden et al., 1983) in which the DST was conducted weekly in depressive patients, a trend toward normalization of the DST results preceding clinical recovery has been reported. These (DST)
has
frequently
been
reported
both
in endogenous
depression
and
An earlier version of this report was presented at the 137th Annual Meeting of the American Psychiatric Association, Los Angeles, May 5-l I, 1984. Andreas Baumgartner, M.D.. is at the Psychiatrische Klinik und Poliklinik. Klinikum Charlottenburg, Freie Universi&t Berlin. Klaus-Jiirgen Gt%f. M.D., is Associate Professor of Internal Medicine at the Medizinische Klinik und Poliklinik (Hormone Research Laboratory), Klinikum Charlottenburg. Irene K&en is Laboratory Assistant at the Hormone Research Laboratory, Klinikum Charlottenburg, Freie Universitat Berlin. Federal Republic of Germany, (Reprint requests to Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik. Klinikum Charlottenburg der Freien Universiiit Berlin, Eschenallee 3, 1000 Berlin 19. FRG.) 0165-1781
86 $03.50 @ 1986 Elsebier Science
Publishers
B.V.
10 results suggest that the DST might be a promising tool for monitoring the course of illness and predicting therapy response or relapse. Since DST nonsuppression in patients with diagnoses other than melancholia has been reported in an increasing number of studies, the question arises as to whether the pattern of DST results obtained in longitudinal studies in those diseases differs from that seen in endogenous depression. To our knowledge, only one study has been published on this issue: Myers (1984) found DST nonsuppression at least once in each of five chronic schizophrenic patients during a series of 12 weekly DSTs. The purpose of our study was to examine the pattern of weekly DST results in psychiatric patients with diagnoses other than depression. In a previous study we found a high nonsuppression rate in healthy volunteers after stress (Baumgartner et al., 1985). Ceulemans et al. (1985) also reported abnormal DST results in patients awaiting operation. Thus, we were interested in establishing whether stress due to severity of illness or other nonspecific stress factors such as hospital admission influenced DST results. We therefore included mainly severely ill patients in our study. Methods Patients. Fifteen patients, all hospitalized on our six nonresearch wards, were included in the study. Eight patients were female, seven male, and their mean age was 29.7 f 9.5 (range: 18-57) years. All patients were diagnosed by one psychiatrist (A.B.) according to Research Diagnostic Criteria (RDC) (Spitzer et al.. 1978), DSM-III (American Psychiatric Association, 1980) and ICD-9 (World Health Organization, 1978). Twelve met RDC for schizophrenia (probable or definite) and DSM-III criteria for schizophrenia (n = 6) or schizophreniform (n = 6) disorder (patient nos. l-12 in Table I). Eleven had paranoid schizophrenia, aud one had catatonic subtype. Nine patients had acute, two had subacute, and one had subchronic schizophrenia (RDC). None of them had a history of major depression. Three other patients met RDC for mania (bipolar 1, probable or definite) and DSM-III criteria for major affective disorder, manic episode (patient nos. 13-15, Table 1). None of the three patients had concomitant depressive symptoms. Additional criteria for inclusion in the study were : (1) a score > 6 on the Clinical Global Impressions Scale (CGI-II, severity item); (2) no history of severe weight loss before hospital admission (i.e., more than 20% of ideal body weight); (3) the absence of any serious medical illness; (4) no history of alcoholism or drug abuse; (5) no medication which might interfere with were evaluated by the DST (Carroll et al., 1981; Greden et al., 1983). All patients electroencephalogram (EEG). electrocardiogram (EKG), routine laboratory screening, and physical examination to exclude major physical illness. Nine patients did not complete the study. Five of these, who were in acute psychotic turmoil, refused either to take the dexamethasone or to give a blood sample at the initial DST. Four further patients left the hospital within the first 2 weeks. It was therefore necessary to include a total of 24 patients in order to obtain interpretable results for 15. Drug Treatment. In all patients, the initial DST was conducted 2-4 days after admission. Only two patients had not received medication before the first DST. In all other cases, immediate institution of neuroleptic treatment was considered necessary on hospitalization. Thus, the possibility of drug withdrawal effects influencing the initial DST was ruled out. Drug treatment methods, including specific medication and dosage, were determined on a clinical basis. All patients received neuroleptics. and in all but three patients, neuroleptic treatment was continued until discharge. Two of them (patient nos. 13 and 14 in Table I) were given lithium after neuroleptic withdrawal. and patient no. 7 received no further medication after week I. Two patients took tricyclic antidepressants (clomipramine and imipramine) for a brief period.
II Haloperidol, perazine, pipamperon, pimozide, thioridazine, fluperlapine, flusperilen, benperidol, flupentixol, and clozapine were the neuroleptic drugs given. Several patients were given biperiden as necessary. Thyrotropin-releasing hormone (TRH) tests were performed every 2 weeks in all patients on the day preceding the DST. The results are presented elsewhere (Baumgartner et al., 1986). More detailed information on demographic characteristics, diagnoses, the individual drug treatment, and the temporal relationship between drug treatment and DSTs is available from the authors on request. Ratings. All patients were rated according to the Clinical Global Impressions (CGIII, severity score) Scale (Guy and Bonato, 1970) the Brief Psychiatric Rating Scale (BPRS) (Overall and Gorham, 1962) and the 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960) on the day of the first DST. CGI severity ratings were then carried out weekly on the day of the DST until the patients showed clinical response. This was defined as a CGI score < 3. Clinical improvement was defined as a reduction > 1point on the CC1 severity scale. Relapse was defined as a CGI score > 6 in patients who had previously shown a response. All ratings were carried out by one observer (A.B.), who was unaware of all DST results until the patients responded clinically. Clinical
DSTs were conducted in 67 healthy controls (30 males, 37 females) to establish the optimal cutoff point between cortisol suppressors and nonsuppressors. The subjects’ mean age was 47.6 + 17.7 (range 26-80) years. Forty-seven of the controls were employees of the psychiatric clinic, and the DST was carried out under normal working conditions. Twenty retired volunteers (ages 63-80 years) who occasionally work for a drug research institute were also included in the study. None of the controls had a history of mental illness, showed signs of physical illness, or had received psychotropic medication in the last 3 months before the DST. Two retired volunteers were taking digitalis. Women on oral contraceptives were not included in the study. One woman was on a diet and had lost 12 kg in 8 weeks; she proved to be a suppressor. None of the others had lost weight before entering the study. Controls.
The DST was carried out by administering I mg of oral dexamethasone (Millicorten) at I I:00 p.m. A blood sample was collected at 4 p.m. on the following day. The nurses were instructed to ensure that the patients actually took the dexamethasone. Several times we ourselves had to ask the patients in acute psychotic turmoil to take the dexamethasone, particularly at the first administration, because they refused to take it from the nurses, although they had previously consented to do so. A commercial radioimmunoassay (RIA) kit (Cortisol-J-125, direct method, “Diagnostic Products Corporation”) was used for assay of cortisol. The lowest standard was 1 pg/dl; the highest was 50 pgi dl; and the sensitivity was 0.3 pg/ dl. Cross-reactivity for dexamethasone was 0.01%. Only prednisolone showed a cross-reactivity > 4%. The interassay coefficient of variation calculated from laboratory control samples taken from each assay over a 5-month period was 11%at a cortisol level of 3.3 kg/dl, 9% at 10.9 pg/dl, and 9% at 28.2 pg/dl. We also had 45 control samples evaluated, each under a different name, with three different cortisol levels, in order to test the “reliability” of the laboratory assistant, who had no knowledge of the results. The interassay coefficients of variation calculated for the groups of 15 samples were 3.5% at a cortisol level of 11.3 pg/dl, 4.4% at 3.2 pg/dl, and 8% at 0.7 pg/dl, respectively. DST.
Data Analysis. Where appropriate, values are given as mean f standard deviation (SD). As postdexamethasone cortisol values are not normally distributed even after logarithmic transformation, we used nonparametric tests for statistical evaluation. We applied the MannWhitney U test for the comparison of subgroups and the x2 test for dichotomous variables. It was not necessary to carry out Fisher-Yates correction for this sample (Camilli and Hopkins, 1979). Dexamethasone serum levels were normally distributed. We therefore applied the t test (two-tailed. for paired and unpaired samples) for comparison of subgroups with different
12
dexamethasone concentrations. In order to assess the relationship between postdexamethasone cortisol concentrations and clinical variables, we calculated Pearson’s r coefficient of correlation, which is insensitive even to extreme violations of the basic assumptions of normality (Havlicek and Peterson, 1977). For assessment of the temporal relationship between the normalization of DST results and clinical recovery, we also calcuated Pearson’s r coefficient of correlation between the DST results and CC1 severity scores of the same week, between the DST results of 1week and the CGI scores of the following week, and between the DST results of I week and the CGI scores obtained 2 weeks later. Due to the small number of measurements for each patient, however, the value of these calculations is limited. We therefore regard these results as additional information of descriptive value and not as evidence of statistical significance. We accepted p values < 0.05 as significant for all evaluations.
Table
1. Dexamethasone
suppression
test (DST)
responses
and Clinical
Patient no.
Weeks after initial DST
1
2
3
4
5
6
7 10.52 17)
0
5.72 (7)
21.02 171
6.72 16)
9.62 (7)
< 1 16)
1
< 1 14)
IO.02 (7)
19.42 (7)
< 1 15)
9.12 (3)2
2.52 (5)
4.32 (41
2
< 1 (312
10.52 (7)
21.02 (6)
1.4 12)
6.12 (312
< 1 (312
2.1
(7j
3
< 1 (3)
4 5
< 1 (2)2 < 1 (612
121
(5)
6
7
< 1 (312
8
< 1 (2)
9 10
(5)
11.52 (5)
< 1 (41
1.1 (3)2
< 1 (4) < 1 (3)2
-
(71
(2)
11 12 13 14 15 16 17 18
r = 0.93
r = 0.54
r = 0.97
r = 0.70
DST week 0
df = 3
df=8
df=4
df=4
CGI week0
p=O.O19
NS
p=O.OOl
NS
Pearson’s
r
r = 0.81
r = 0.39
r = 0.82
r = 0.53
DST week 0
df = 2
df=7
df=3
df = 3
CGI week +l
NS
NS
NS
NS
Pearson’s
r
r = 0.50
r-0.16
r = 0.52
r = 0.81
DST week 0
df = 1
df=6
df=2
df=2
CGI week +2
NS
NS
NS
NS
Pearson’s
r
1. Plasma cortisol 2 Nonsuppressors
levels in pg/dl and CGI-II scores in parentheses. and CGI scores in the week of clinical recovery
or relapse
12)
13
Results Cutoff Point. The mean postdexamethasone cortisol concentration for the group of 67 healthy controls was 1.19 * 0.58 pg/ dl (Fig. 1). We therefore fixed our cutoff point at 2.35 pg/ dl (mean + 2 SD). Three controls (4.5%) were nonsuppressors, and 64 were suppressors (95.5%). The nonsuppressors were aged 42,69, and 75 years, respectively. One was a physician, and the others were from the group of retired volunteers. Thus, no significant difference was found between the nonsuppression rate for the retired persons (age 63-80 years) and that for the hospital staff (age 26-60 years) (x2 2.03, df = 1, p > 0.1).The healthy controls over 63 years of age had slightly higher q
Global Impressions
(CGI) severity scores1 Patient no.
8
9
10
11
3.72 (8)
1.9 (6,
< 1 (6) 12.72 (7)
~1
9.52 (6)
< 1 (51
Mean cortisol CGI
13
14
15
(61
1.2 (7)
2.1 (6)
6.12 17)
5.7
6.6
15
12
n
6.82 (8)
(5)
cl
15)
2.0 (7)
1.4 (5)
~1
(6)
4.7
5.4
15
cl
(4)
< 1 (3)2 1.3 (6)
(4)
< 1 14)
< 1 161
1.3 (5)
14)
3.3
4.3
15
(5)
~1
(312
(4)
1.1 (5)
1.2 (5)
(2)2
1.8
3.9
12
cl
(51
(4)
-=z 1 (5)
-
1.0
3.6
8
~1
(3)2
1.1 (4)
1.5 (4)
1.0
4.0
7
4.12 (4)
9.82 (5)
1.1 (5)
1.8 (3)
2.0 (3)
(2)
<1
(4)
~1
(312
(4)
8.22 (4, (4)
(4)
(5)
(5)
2.1 (3)
(51
2.1 (2)
15.12 (8,
4.22 (2)
< 1 (4)
~1
-
1.5 (3)2
13.02 (4) -
(5)
(6)
(61
1.6 (51
Discharged
151
15)
1.1 (61
(6)
15)
Monitoring stopped r=
r= 0.76
r=
0.21
df = 4
df=3
df=
10
NS
NS
NS
r=
0.50
-0.08
r=
df=3
df=
NS
NS
r= df= NS
0.50
r=
2
df= NS
0.20 2
-0.23 1
r = 0.50
r =-0.55
df=
df=9
df=4
NS
p=
0.002 0.80
p=
17 0.025
r = 0.95
r = 0.05
r =-0.63
r=
df= 8
df=
df=8
df=
NS
NS
p = 0.048
NS
r=
r= df= NS
-0.17
-0.23 8
16
r=
0.20
df=
15
NS
3
r = 0.49
r=
df=7
df=2
NS
NS
0.48
14 Fig. 1. Postdexamethasone cortisol concentrations in healthy controls and in patients with schizophrenia and mania at 4 p.m. Healthy controls
I---n = 67
Cort~sol24 Wdll 22
1 md Mama P
her chcal
n
,=13' _
575' 569
1
rerponre 24 Cortisol (mIdI)
-22
.
20
-20
16 1
-18
16
-16
14
-14
. 1
12-I
.
10
.
. iI 1
8-l 6 5
4 235 2
0.
-12 -10
119tO58
0
.... -*::L ................ i ::::::s::::::::::
-.-
postdexamethasone cortisol levels (mean 1.4 ?r 0.7 pg/ dl) than those younger than 60 years (mean I. 1 f 0.6 pg/dl), but this difference was not statistically significant (Mann-Whitney Ii 27 1,p > 0.05, NS). The correlation between postdexamethasone cortisol values and age in all healthy volunteers was also not significant (r = 0.20, df= 65). The mean dexamethasone level of 44 healthy controls was 112.4 f 57.3 (range 38-275) ngjdl. The mean dexamethasone level of all healthy subjects with cortisol levels > 1 pug/ dl was 82.7 f 39.2 ng/ dl, whereas that of all volunteers with a DST result < 1 pg/dl was 128.7 k 6 1.3 ng/ dl. This difference was statistically significant (t 2.75, df= 42,~ < 0.005). The dexamethasone levels of the three nonsuppressors among our healthy subjects were 25 ng/ dl, 52 ng/ dl, and 106 ng/ dl, respectively. Dexamethasone was detected in all serum samples of the healthy subjects, and the lowest concentration that led to suppression of cortisol to a value < 1 pg/ dl was 38 ng/ dl. Detailed results of dexamethasone investigations in healthy controls will be presented in a later report. q
q
Comparison Between Suppressors and Nonsuppressors. The distribution of postdexamethasone cortisol values is shown in Fig. I. At the initial DST, eight patients (53.4%) exhibited nonsuppression, and after clinical response two patients (15.3%) showed elevated postdexamethasone cortisol levels. Both of them had shown suppression at the first DST (patient nos. 6 and 14, Table I). Thus, the nonsuppression rate for the patients following admission and that for the healthy controls differed
15
significantly (x2 25.1, df 1, p < 0.001). However, the DST results obtained in patients after recovery did not differ significantly from those for the healthy volunteers (x2 = 2.0, df = 1,p > 0.1, NS). Even if we set a more “conservative” cutoff point (e.g., 5 pg/dl according to Carroll et al., 1981), the nonsuppression rate of the patients following admission (46.4%) again differed significantly from that of the healthy controls (x2 = 34.1, df = 1,p < 0.00 1). When we included not only the first DST but all results obtained over the entire study period, we obtained a rate of 93.3% of patients showing nonsuppression at least once (86.7% with the cutoff point at q
q
5 ygldl). Longitudinal Pattern of DST Results. The relationships between weekly DST results and CGI severity scores are shown in Tables 1 and 2, and in Fig. 2. There was an obvious decrease in the mean postdexamethasone cortisol concentrations during treatment. This decrease was associated with a similar progressive reduction in the mean CGI scores. The correlation (Pearson’s r) between mean weekly cortisol concentrations and mean CGI scores obtained simultaneously was r 0.95 @ < 0.01) in the first 5 weeks (Table I and Fig. 2). Normalization of initially abnormal DST results occurred at the same time as, or 1-4 weeks before, clinical recovery (Table 2~). Only in one patient did the DST result fail to return to normal until 1 week after clinical recovery (patient no. 5). The question as to whether normalization of the DST results occurs before, simultaneously with, or after clinical recovery, however, depends on the clinical response criteria and the specified cutoff point, factors that differ from study to study. In other words, the higher the cutoff point and the lower the scores required for clinical response, the sooner before clinical recovery DST results normalize. To obtain additional information on the best temporal relationship between the two variables, we also calculated Pearson’s r coefficient between the DST results and CGI scores of the same week, the DST values of one week and CGI scores of the following week, and between DST results of one week and CGI scores obtained 2 weeks later. This was possible for nine patients. In three of these patients, the best correlation was obtained on comparison of the DST results and CGI ratings for the same weeks, and in no patient was there a significant correlation between the DST of one week and the CGI score of one of the two following weeks. In six patients there was no significant correlation between the two variables at all (Table 1). Thus, although, according to the response criteria applied, the DST normalizations preceded clinical recovery, the statistical analysis failed to confirm such a temporal relationship. The relationships between DST results and CGI scores in patients with nonsuppression during treatment are shown in Tables 2a and 26. With regard to whether DST normalization could be helpful in predicting subsequent drug response, we looked at CGI scores in the week of DST normalization (Table 24. Eleven patients had already shown clinical improvement in the week of DST normalization, and in only three patients did the DST values return to normal without corresponding clinical improvement. Thus, in most of the patients, DST normalization was superfluous as a predictor of clinical recovery because clinical improvement was already obvious before the DST results were known. The only patient (no. 3) who relapsed exhibited cortisol suppression both before and during the relapse. Thus, in this case, the DST was of no help in predicting the relapse. q
16 Table a.
2. Changes
in DST results
related
to clinical
8 (Patient nos. 1, 3, 4, 5, 7, 8, 11, 15)
DST normalization in nonsuppressors at initial evaluation
Normalization
of DST results coinciding
Normalization
of DST results before clinical
Normalization
b.
with clinical
recovery
2 (Patient
nos. 3, 7)
1 week
1 (Patient
no. 1)
2 weeks
2
3 weeks
1 (Patient
4 weeks
1 [Patient
no. 4)
1 (Patient
no. 5)
recovery:
of DST results 1 week after clinical
Patients with nonsuppression during treatment:
recovery
arising
Change
in DST results coinciding
with relapse
Change
in DST results coinciding
with increase
condition
i Patient nos. 11, 14) nos. 8)
6 (Patient nos. 2, 6, 10, 12, 13, 14) 0 in CGI score
2 (Patient
nos. 10, 131
by at least 1 point Change
in DST results without
in clinical
coinciding
Change
in DST results as a predictor
Change
in DST results in spite of decrease
CGI severity
c.
change
4 (Patient
of clinical
0
relapse
in the
1 (Patient
of DST results before clinical
DST not normalized DST normalization clinical Chance
d.
no. 6)
score by at least 1 point
DST normalization in patients with nonsuppression arising during treatment:
Normalization
nos. 2, 12, 13, 14)
condition
in spite of clinical without
coinciding
6 (Patient nos. 2, 6, 10, 12, 13, 14)
1 week
1 [Patient
2 weeks
1 (Patient
no. 10)
recovery
1 (Patient
no. 6)
or subsequent
2 (Patient
nos.
1 (Patient
no. 14)
recovery
no. 21
12, 13
recovery to nonsuppression
after recovery
and before discharqe
Clinical improvement as shown by decrease in CGI severity score by at least 1 point in the week of DST normalization1 No clinical improvement of DST normalization
1. Mean improvement
in the week
on the CGI severity
11
3
scale in the week of DST normalization:
1.72 points [range l-31
DST Results and Severity of Illness. The correlation (Pearson’s r ) between the initial DST results and CC1 scores of all patients was not significant (r = 0.38, df= 13, NS). A significant correlation would hardly be expected, however, since only patients with CGI scores of 6-8 were included and, moreover, our population was small. If interindividual and intraindividual data are considered together, the correlation between all CGI scores and all DST results in all patients is significant (r 0.43, df= 98, p < 0.01). It should be borne in mind that in this calculation different numbers of measurements are being compared for each patient. We therefore calculated this correlation for the first 3 weeks only and again obtained a significant correlation (r 0.40, df= 43, p < 0.01). We also calculated the percentages of nonsuppressors at various levels of severity of illness. We divided the patients into three groups according to their CGI scores: group I consisted of patients with CGI scores of 2 or 3 (clinical q
q
17
Fig. 2. Mean (+ SD) cortisol concentrations (bars) and mean Clinical Impressions (CGI) scores (connected dots) for the total sample. Plasma Cortisol (ccsidl) 12
Global
CGI Score 7 T
8
6
I
wk0 (n=15)
wk 1 (n=15)
wk 2 (n=15)
Values are given for the first 4 weeks of treatment
\
T
wk 3
wk4
(n=12)
(n=8)
t
after response
(n=13) and for the week after clinical
recovery.
responders); group 2 contained all the moderately and distinctly ill patients (CGI 4-6); and group 3 encompassed the severely ill patients (CGI 7 and 8). All DST evaluations for all patients were included in the calculation (Fig. 3). The x* test revealed no significant differences between the nonsuppression rates for the clinical responders (1 1.5%) and those for the moderately and distinctly ill patients (16.9%; x* 0.29, d’= I, p > 0.5, NS). The nonsuppression rate for the severely ill patients (80%) however, differed significantly from that for the two other groups combined (15.3%; x2 = 26.1, df I, p < 0.001). To sum up, we were able to show a good correlation between DST results and severity scores when both interindividual and intraindividual data were taken into account. Nonetheless, it should be borne in mind that severity of illness alone is not related to DST nonsuppression in all cases, as single peaks of abnormal DST results occurred in some patients without a corresponding change on the CGI scale. q
q
DST Results and Clinical Symptomatology. The mean HRSD score for all patients at the time of the initial DST was 13 * 6.2 (range 3-23). There was no significant correlation between postdexamethasone cortisol concentrations and either the HRSD scores (r 0.086) or the anxiety/depression syndrome score on the BPRS (r = -0.086). There was a good correlation between the two rating scales for depressive symptomatology (r = 0.77, df = 13,~ < 0.01) and also a significant correlation between both the thought disturbance syndrome score (r = 0.65, df= 13, p < 0.01) and the activation syndrome score (r 0.72, df = 13, p < 0.01) and the postdexamethasone q
q
18 Fig. 3. Nonsuppression rates and severity of illness in patients with schizophrenia and mania, calculated from all measurements during entire study period (n = 100) % Nonsuppressors 100 90
80 70
i
60 50 40
30
-I
20 -
3 (n=17)
2 (n=9) ClInical
Global
4 (n=19)
6 5 (n=25)in=15)
lmpresslons
(CGI
(n=12)
II) Severity
(n=3) Scores
cortisol levels. There was no significant correlation for the anergia suspiciousness syndromes (r 0.48 and r = 0.25, respectively).
or hostile-
q
DST and Clinical Outcome. Thirteen of the 15 patients responded clinically within 6 weeks. They had both normal (n = 5) and abnormal (n = 8) DST results at the initial evaluation. The two patients who did not respond clinically (no. 12 and no. 13) showed suppression at the initial evaluation, but both exhibited nonsuppression several times during the treatment period. Thus, the DST had no predictive value for the response to neuroleptic drugs in our patients. Discussion The Cutoff Point. The low incidence of nonsuppression among our healthy controls and the resultant low cutoff point might be partly due to the differences between laboratories. Meltzer and Fang (1983) reported a sixfold range in cortisol concentrations at a 95% confidence level between different laboratories working with different methods. These observations have since been confirmed by other authors (Wilens et al., 1983; Wood et al., 1983; Rubin and Poland, 1984; Ritchie et al., 1985). Therefore it must be emphasized that the cortisol measurements conducted by individual laboratories are only relative quantities and that it is thus impossible to compare results obtained by different methods. The quality of our cortisol evaluations has been
19 carefully controlled (see above). Even in the low range of 0.7 pg/dl, the interassay coefficient of variation was only 8%. Furthermore, 11 of 13 patients who finally responded clinically showed postdexamethasone cortisol values < 2.35 pg/dl, indicating that our cortisol measurements were consistent within the study and confirming the validity of the low cutoff point. Three other studies are known to us in which RIA kits from the Diagnostic Products Corporation were also used for measuring cortisol. In the study by Graham et al. (1982), none of the 20 healthy controls showed postdexamethasone cortisol levels > 1.85 pg/ dl (mean 1.20 pg/ dl) at 4:00 p.m.; the results thus do not differ from our own. However, Graham et al. (1982) used a 2 mg dose of dexamethasone. Hallstrom et al. (1983) and Lowy et al. (1984) who used the same RIA kit, reported much higher postdexamethasone cortisol values in their healthy controls. Stokes et al. (1984) reported nonsuppression rates in healthy controls (calculated from a blood sample collected at 8:30 a.m.) that ranged between 0% and 25% at different diagnostic centers. The results of our dexamethasone serum level investigations suggest that these differences could be at least partly due to differences in the pharmacokinetics of dexamethasone in healthy controls. Other authors have also reported a possible influence of dexamethasone levels on DST results (Arana et al., 1984; Berger et al., 1984; Johnson et al., 1984). Nevertheless, nonsuppression among our healthy controls cannot simply be related to low dexamethasone serum levels, as in two nonsuppressors the dexamethasone levels were higher than the lowest level that produced complete cortisol suppression in other controls investigated. It is possible that interindividual differences in the sensitivity of the hypothalamic-pituitary-adrenal axis to influences that lead to negative feedback mechanisms are responsible for this phenomenon. Finally, our low cutoff point might also be due to the fact that it was set by comparing healthy volunteers with all patients, irrespective of diagnosis. The few authors who have set their own cutoff levels have often compared melancholic patients with patients with other diagnoses (e.g., Carroll et al., 1981) in order to achieve the greatest diagnostic specificity. However, control patients with different diagnoses (i.e., other than melancholia) might have elevated postdexamethasone cortisol levels themselves, as was the case with the patients in this study. This factor would result in a higher cutoff point, because the two groups being compared both showed pathologically high cortisol values. We therefore suggest that in order to differentiate between normal and pathological results, healthy controls should be compared with the entire patient group without regard to diagnosis. Diagnostic Specificity of the DST. As regards use of the DST as a diagnostic tool, our results raise some doubts about the specificity of the DST for endogenous depression. The findings of hypercortisolism in schizophrenia and mania are, however, nothing new. In an early report, Sachar et al. (1970) found significantly elevated urinary 17-hydroxycorticosteroid excretion levels in four schizophrenic patients during acute psychotic turmoil, which is consistent with the findings in this study. Dexamethasone resistance has also been found in many recent studies in which the DST was employed in mania and schizophrenia. Dewan et al. (1982) found 30% nonsuppressors in 20 nondepressed chronic schizophrenics, and Haskett et al. (1984) reported 100% nonsuppression in five schizophrenic patients immediately after hospitalization. Berger et al. (1984) found 30.4% nonsuppression in 23 schizophrenic
20 patients, and Herz et al. (1985) reported 11 nonsuppressors out of 15 acute schizophrenic patients. The results obtained by Myers (1984) in weekly DSTs in chronic schizophrenics have already been quoted above. Evans and Nemeroff (1983) and Krishnan et al. (1983) found high nonsuppression rates in mixed bipolar disorders only, whereas Arana et al. (1983) and Graham et al. (1982) reported a high incidence of abnormal DST results in manic patients without concomitant dysphoric symptoms. Godwin et al. (1984) found DST nonsuppression in six out of nine bipolar patients both in depression and in the manic phase. Other workers have failed to find nonsuppression in schizophrenia and mania (Schlesser et al., 1980; Carroll et al., 198 1; Evans et al., 1983). In most of these studies, however, control patients were not rated for severity of illness. The different results could thus be due to the fact that the DSTs were performed in patients who were not comparable as regards severity of illness. Fig. 3 showed that there were significant differences between the nonsuppression rates for the group of severely ill and the group of moderately and distinctly ill patients, a finding that emphasizes the importance of rating control patients for severity. Carroll et al. (19766) suggested that in order to improve the diagnostic specificity of the DST, newly admitted psychotic patients should not be tested immediately after hospitalization. In our patients, however, abnormal DST results did not occur at the first DST evaluation only, but in 10 out of 15 patients at least one more time in the further course of the episode. Thus, even if patients were not tested sooner than 1 week after admission, the final nonsuppression rate for schizophrenic and manic patients would still be 66%. Use of Weekly DSTs in Schizophrenia and Mania. In our study, the DST was of no value as a predictor of clinical course and treatment outcome. In about half of the patients, the DST results returned to normal several weeks before clinical recovery. Most of the patients, however, already showed clinical improvement in the week of DST normalization, indicating subsequent clinical recovery. Thus DST normalization had no relevance as regards maintenance or changes in drug treatment. DST results did not predict relapse, and in several patients nonsuppression occurred without corresponding or following changes in clinical state, making clinical decisions based on DST results even more problematic. The high nonsuppression rate in our patients was clearly related to severity of illness. It is not yet possible to come to any definite conclusions as to whether in schizophrenia and mania the severity of illnesses in itself is the primary factor activating the HPA axis, or whether secondary nonspecific factors, such as stress, are responsible for the abnormal DST results. As an important influence of stress on the DST in healthy volunteers has been shown in some studies (e.g., Baumgartner et al., 1985; Ceulemans et al,, 1985), the possibility cannot be excluded that DST nonsuppression in patients is also due to secondary stress factors related to severity of illness. As regards a possible influence of drugs in our patients, most of them were receiving high doses of neuroleptics at all DST evaluations. According to Carroll et al. (198 I), neuroleptics do not affect DST results, but surprisingly little investigation seems to have been done on this issue. We shall discuss this problem in Part III of this report. There is evidence that a considerable number of other variables might influence DST results: weight loss (Berger et al., 1984) dexamethasone serum levels Clinical
21 (Arana et al., 1984), age (Halbreich et al., 1984) length of episode (Sashidharan et al., 1984) time and frequency of blood samples (Sherman et al., 1984) and, of course, diagnosis (Carroll, 1982). We therefore also performed weekly DSTs in 35 patients with major depression and will present the results in Part II of this report. A discussion of the role of diagnosis and an investigation of the influence of nonspecific intervening variables are included in Part III. References Abou-Saleh.
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Haskett, R.F., Zis, A.P., and Albala, A.A. Clinical use of the dexamethasone suppression test. Presented at the 137th Annual Meeting of the American Psychiatric Association, Los Angeles, CA, May 5-11 (1984). Havlicek, L.L., and Peterson, N.L. Effect of the violation of assumptions upon significance levels of the Pearson r. Psychological Bulletin, 84,373 (1977). Herz, M.I.. Fava, G., Molnar. G., and Edwards, L. The dexamethasone suppression test in newly hospitalized schizophrenic patients. American Journal of Psychiutry, 142, 127 (1985). Holsboer, F., Liebl, R., and Hofschuster, E. Repeated dexamethasone suppression tests during depressive illness. Journal of Affective Disorders, 4, 93 (1982). Holsboer, F., Steiger. A.. and Maier, W. Four cases of reversion to abnormal dexamethasone suppression test response as indicator of clinical relapse: A preliminary report. Biological Ps_vchiutr_v, 18, 91 1 (1983). Insel, T.R., Kalin. N.H., Guttmacher, L.B., Cohen, R.M., and Murphy, D.L. The dexamethasone suppression test in patients with primary obsessive compulsive disorder. Psychiurry
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Johnson, G.F., Hunt, G., Kerr, K.. and Caterson, 1. Dexamethasone suppression test (DST) and plasma dexamethasone levels in depressed patients. Psychiatry Research, 13, 305 (1984). Keitner, G.I., Haier, R.J., Quails, B.C., Brown, W.A., and McKendall, M.J. Diagnostic heterogeneity and the DST in consecutive psychiatric admissions. Psychiurr.p Research, 14,215 (1985). Krishnan, R.R., Maltbie, A.A., and Davidson, J.R.T. Abnormal cortisol suppression in bipolar patients with simultaneous manic and depressive symptoms. American Journal of Psychiatry,
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Meltzer, H.Y., and Fang, V.S. Cortisol determination and the dexamethasone suppression test. Archives qf General Psychiatry. 40, 501 (1983). Myers, E.D. Serial dexamethasone suppression tests in male chronic schizophrenic patients. American
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23
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