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Relationship of urinary free cortisol levels in patients with panic disorder to symptoms of depression and agoraphobia
Qwhiatry Elsevier
Rrsuarch,
24, 2 I I-22
211
I
Relationship of Urinary Free Cortisol With Panic Disorder to Symptoms Agoraphobia Roger G. Kathol,
Russell
Levels in Patients of Depression and
Noyes, Jr., Ana L. Lopez, and James
Rec,ei\ted h4a.v 18, 1987; revised version received August 28. 1987; accepted
H. Reich
October 10, 1~87.
Abstract. Sixty-five patients with panic disorder and 37 matched controls collected 24-hour urine specimens for measurement of urinary free cortisol. Although patients with panic disorder had significantly higher urinary free cortisol levels than control subjects, this difference was accounted for by panic disorder patients with concomitant depression, agoraphobia, or both. Urinary free cortisol excretion was not related to the age of onset of panic disorder, the number of spontaneous panic attacks, or the degree of impairment associated with the disorder. They were related, however, to the level of symptoms on both the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety in the entire group of panic patients, but this relationship disappeared when those patients with the complications of agoraphobia and depression were excluded. These data suggest that, as with primary depression, depression secondary to panic disorder, as well as to agoraphobia in panic disorder patients, is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis. Key Words. Panic disorder, disorder.
urinary free cortisol,
agoraphobia,
depression,
anxiety
For years it has been known that urinary glucocorticoid excretion can be used as a reflection of acute psychological or physical stress (Schwartz and Shields, 1954, 1956; Espiner, 1966; Mason, 1968). Measurement of urinary or plasma corticosteroids in situations typified as subacute, however, have not demonstrated the elevations typically present in acute situations (Schwartz and Shields, 1956; Bourne et al., 1967; Blumenfield et al., 1970; Hofer et al., 1972; Gorzynski et al., 1980). More recently, Mason et al. (1986) measured urinary free cortisol levels in various psychiatric conditions. Interestingly, patients with posttraumatic stress disorder, typified by chronic psychological stress related to prior life experiences, did not demonstrate an elevation of urinary free cortisol and, in fact, demonstrated lower levels than patients with both affective and psychotic disorders. Urinary glucocorticoid excretion has been most widely studied in patients with primary affective disorder (Carroll et al., 1976; Milln et al., 1981; Rosenbaum et al., 1983a; Stokes et al., 1984). These studies have demonstrated that patients with active primary affective disorder have elevated glucocorticoid excretion in comparison to a
Roger G. Kathol. M.D., 6.A.C.P.. ia Associate Professor of Psychiatry and Internal Medicine, and Director of Medical Psychiatry Unit; Russell Noyes, Jr., M.D., is Professor of Psychiatry; Ana L. Lope/, B.S.. is Research AssIstant. University of Iowa, Iowa City, IA. James H. Reich, M.D.. is Assistant Professor of Psychiatry. Brockton VA Medical Center, Brockton, MA. (Reprint requests lo Dr. R.G. Kathol, Dept. of Psychiatry, University of Iowa, 500 Newton Rd., Iowa City, IA 52242. USA.) Ol65-1781/88/$03.50
@ 1988 Elsevier Scientific
Publishers Ireland
Ltd.
212 control population. Studies by both Berger et al. (1982) and Mason et al. (1986) have demonstrated that this elevation in glucocorticoid excretion diminishes as clinical improvement occurs; a recent report by Kathol(l985), however, suggests that return to control levels may not occur in some patients. Measurement of urinary glucocorticoids has not been nearly so extensively studied in patients with primary anxiety. In a series of studies in the 195Os, Persky et al. ( 1956, 1959~1, 19596) measured urinary hydroxycorticosteroid excretion in normal subjects and anxious patients. In these studies, it was demonstrated that patients with symptoms of anxiety had significantly elevated urinary hydroxycorticoid excretion when compared to a control population. However, sub.jects in these studies were drawn from a mixed population of psychiatric patients who had demonstrated anxiety-type behavior while hospitalized. These results cannot be considered equivalent to those which might be found in patients with primary anxiety disorder. More recently Rosenbaum et al. (19836) were unable to find a difference between 22 patients with generalized anxiety disorder and a group of 22 nonanxious volunteers. These findings suggest that chronic anxiety disorders do not result in an increase in urinary glucocorticoid excretion, but that when anxiety symptoms accompany other psychiatric conditions, excretion may be increased. As a part of a treatment study of diazepam, alprazolam, and placebo in patients with primary anxiety, and specifically panic disorder, we decided to explore further the relationship of urinary free cortisol (U FC) levels in 65 unmedicated panic disorder patients and 37 controls.
Methods Subjects. Ninety-one patients identified by advertisement were screened using the Structured Clinical Interview for DSM-//I (SCID) (Spitrer and Williams, 1982) and met DSM-//l-K 1985) criteria for panic disorder. In addition. all panic (American Psychiatric Association, patients were required to have had at least one panic attack per week. All patients wet-c between the ages of 19 and 62 and in good physical health. Patients who were pregnant, lactating, psychotic, suicidal, demented, or who had a history of epilepsy, seizures, bipolar or melancholic depression, obsessive-compulsive disorder, alcohol dependency, or who were taking a- or /3-adrenergic blockers were excluded. Eighteen of the 91 patients were excluded because they were on medication which could potentially interfere with measurement of urinary cortisol levels (birth control pills, glucocorticoids. or centrally acting hypertensive medications). Eight additional patients were excluded because they did not submit complete 24-hour urine specimens. A total of 65 patients (35 males and 30 females) with a mean age of 40 (SD Y.6) were included in the study. Twenty-nine met criteria for concurrent agoraphobia, while 14 met criteria for concurrent secondary ma.jor depression in addition to panic disorder. Subject5 with major depression were included if panic disorder preceded the onset of depression and dominated the clinical picture. Sixty-two control subjects were identified by advertisement and screened with the Schedule for Schizophrenia and Affective Disorders-Lifetime Version (Spitter and Endicott. 1975). After this screening, 40 medically healthy controls remained who were free from past or present psychiatric illness. It was necessary to exclude three control subjects who failed to submit complete urine collections. Thirty-seven medication-free controls (I9 males and IX females) with a mean age of 35 (SD I I. I) years (range 23-60 years) entered the study. Procedures.
of alprazolam,
The patients were participants in a double-blind, placebo-controlled comparison dia/epam, and placebo. In addition to the SCIL), patients were assessed using the
213 Carroll Rating Scale for Depression (Carroll et al., 1981), the Hamilton Rating Scale for Anxiety (H RSA) (Hamilton, 1959), and the Hamilton Rating Scale for Depression ( H RSD) (Hamilton, 1960). The age of onset and frequency of panic attacks were recorded on a Panic Attack Scale developed for the treatment study, and ratings of impairment were made on an I l-point visual analog Disability Scale for work, social life and leisure activities, and family life and home responsibilites (Table I). Patients who met criteria for panic disorder were further subdivided into those with extensive phobic avoidance (agoraphobia), limited phobic avoidance, and uncomplicated or no phobic avoidance. To be placed in the agoraphobic group, patients had to have generalized travel restrictions, often need a companion away from home, or have a markedly altered life style, while those in the limited phobic avoidance group required significant phobic avoidance or endurance despite intense anxiety. Thirty-three patients were taking psychotropic medication up to 2 weeks before the trial began. Those still on medications were instructed to discontinue them I week before collection of the 24-hour urine specimen. All except one were withdrawn from a benzodiazepine, while two were withdrawn from a tricyclic antidepressant. Control subjects were screened through the exclusion process described above and then given the Carroll Rating Scale for Depression (Carroll et al., 1981). Once this was completed, a 24-hour urine specimen for U FC measurement was collected. Patients and control subjects were given detailed written and verbal instructions on how to collect 24-hour urine specimens for UFC measurement. The subjects were told that it was important for the sample to be complete and that we preferred to know that a single void was missed and not use the collection in our analysis rather than use an incomplete sample. When possible, the participants were encouraged to retry a collection. Subjects were cooperative with this request. The measurement of 24-hour creatinine excretion was used as an additional safeguard to ensure that only complete specimens were compared. Those patients with 24-hour creatinine levels below 450 mg and in whom there was a significant discrepancy in 24-hour
Table 1. Demographic
characteristics
of sample
Controls
Panic disorder patients Total n = 65
n = 37
tyears J
Age
35.0211 .o
Carroll score Age
2.02 1.91
of PD onset
D n=
14
4O.OT9.6
39.7+10.3
17.8?9.51
26.41 7.12
ND n = 51 40.0+9.5
A n = 29
NA n = 36
41.0?11.4
39.157.9
15.418.72
19.6+ 9.6
16.529.3
29.7+
8.5
27.629.0
25.42
29.5k7.5
3.218.7
4.42
6.2
2.9k9.3
17.4k6.1
22.32
5.33
16.155.73
27.7M.7
9.9
Spontaneous
in last week
attacks
HRSD
score
Level
of social
disability* HRSA
5.5k2.9
score
18.9f8.7
7.11ir 2.5 25.12
6.15
5.3t12.7 18.8?
6.8
1521.5 16.315.4
5.122.8
7.Oi
2.44
4.422.84
17.228.65
21.32
9.76
16.927.56
Note. Cells wth the same superscript number are significantly different. D = depressed. ND = nondepressed. A agoraphobic. NA = nonagoraphoblc. PD = panic disorder. Carroll = Carroll Rating Scale for Depression. HRSD = Hamilton Rating Scale for Depresston. HRSA = Hamllton Rahng Scale for Anxiety.
=
‘A higher score Indicates 1.p~0.0001. 2. p <. 0.0001. 3. p c 0.0005. 4. p <: 0.002. 5. p <: 0.0001. 6. D q. 0.04.
greater
disability
214 creatinine excretion from other specimens submitted during a treatment followup phase of this study were excluded from analysis. The patients and control subjects refrigerated the UFC samples after collection and returned them for storage at -20” C within 3 days of collection.
Assays. Twenty-four-hour urinary creatinine levels were measured by the Schafe method (Henry, 1964). UFC levels were determined by radioimmunoassay (RIA) on extracted samples using a double antibody technique (Hsu and Bledsoe, 1969). The intra- and interassay coefficients of variation were 5.5 and 9.9%, respectively. The results were reported aspg/gcreatinine to correct for differences in body mass among subjects (Streeten et al., 1969). The assays were performed by a person without knowledge of the diagnosis of the individuals involved. Statistical Analysis. A comparison of dichotomous parametric data was performed by using Student’s I test. Comparison of parametric data on three or more groups was performed by 2-way analysis of variance (ANOVA). When differences were identified, post hoc testing was performed with the Duncan Multiple Range Test. Linear regression was used to correlate U FC levels with other clinical variables. When appropriate, log transformation was performed to correct for nonnormally distributed data. Variance was expressed as standard deviation. Results Patients with panic disorder (29.3 f 13.0 pg/ g creatinine) had significantly higher U FC levels (t = 3.25, @= 100, p = 0.002) than control sub.jects (22.0 k 10.3 pg/g creatinine) (see Fig. 1). When the patients with panic disorder were divided, agoraphobic (34.1 + 13.9 /*g/g creatinine) and nonagoraphobic (25.5 + 11.0 pg/g creatinine) subgroups
Fig. 1. Scattergram of urinary free cortisol (UFC) levels in patients with panic disorder and controls 60
y
1
so]
e 3 4o
t=3.246* p=D.o02
0
uo
0
0
SO-1
8
0
40-
- 0%
QJo
50-l
0
40-
08 e 3
30-
30-
zo-
zo-
lo-
lo-
2 “0””
30zo-
0
lo-
0
Panic Disorder Patients C=contmls PD=ponk disordw l
Patients
(all)
A-ogomphobk NA=non-agomphoblc D=dmpmas.d; Nlknon-depnsrmd
based on log,, tmn8fommd data.
with panic disorder
are subdIvIded
into those wtth and wlthout
depression
and agoraphobia
215 both had levels significantly higher than controls (F = 9.4, df = 2, p = 0.002). Patients with agoraphobia also had significantly higher UFC levels than those who were not agoraphobic when examined independently (see Fig. 1). When nonagoraphobic panic patients were divided into those with limited phobic avoidance (n = 2 1) and those with none (n = 15), no stepwise increase in UFC levels could be found (24.4 f 9.6 vs. 26.9 k 13.0 pg/ g creatinine, respectively). Panic disorder patients with concurrent depression (35.3 + 16.6 pg/g creatinine) had significantly higher UFC levels (F= 7.0, df= 2, p 0.001) than controls and tended toward higher levels than panic disorder patients without depression (27.7 + 11.5 pg/ g creatinine) (see Fig. 1). The eight panic disorder patients in whom both agoraphobia and depression were present constituted a group with the highest UFC levels (38.1 f 20.3 pg/g creatinine), while those with either depression (3 1.6 + 10.4 pg/ g creatinine) or agoraphobia (32.6 + 10.8 pg/ g creatinine) but not both constituted a middle group. Panic disorder patients without either accompanying depression or agoraphobia (24.2 f 10.9 pg/g creatinine) had UFC levels similar to those of controls (t = 0.9, df = 64, p = 0.39) (see Fig. 2). q
Fig. 2. Urinary free cortisol (UFC) levels in subgroups patients with or without agoraphobia or depression
of panic disorder
60
50
T
T
I-
I-
ia l-
aI-
D 8)
C=contmlr. Panic Oi~ordw Patlwtr: NO=non-dapnrred; O=doprw*d. Groups with thesame < 0.001 ‘.
A/ND (~5221)
Nknon-agomphoblc:
letter ra, b, c.d~ areslgnificantlydifferent
NA/D
(~=6)
A=agomphobic:
at theconfldencelevelp<0.05
1Fz5.4, df=4.p
UFC levels correlated most closely with the HRSD (see Fig. 3). There was also a strong correlation with the HRSA (r 0.35, r-2 = 0.12, p = 0.004). When anxiety questions were deleted from the HRSD (items 9, IO, and 11; mean score for patients with panic disorder = 10.9 + 5.4) a significant correlation with UFC levels remained (r 0.34, t-2 0.12, p = 0.005). When panic patients with thecomplications ofagoraphobia, depression, or both were deleted before correlation with the HRSA and the HRSD q
q
216
Fig. 3. Correlation of urinary free cortisol (UFC) depression scores in panic disorder patients.
levels
with
Hamilton
80
1
t=O.S60 p=o.o03 0
0
0
I
I
I
I
10
20
30
40
Hamilton Depression
Scale
scores, the relationship of these indices of severity and UFC excretion was lost (r = -0.04, r2 = 0.002, p = 0.8, and r = -0.15,r’ = 0.02, p = 0.4, respectively). UFC levels were not correlated with the age of onset of panic disorder, the number of spontaneous panic attacks during the past week, or the degree of social, work, or family/ home disability experienced by the patient. Further, there was no effect of gender or age on U FC levels either in controls or patients with panic disorder. Patients who had been taken off psychotropic medications before urine collection had UFC levels (3 1.O 2 13.8 pg/ g creatinine) significantly higher than those of controls (F= 5.15, d/‘= 2, p 0.008). When patients were divided into those with complicated and uncomplicated panic disorder, however,the presence of agoraphobia and depression influenced the UFC levels more than did medication withdrawal status (Table 2). q
Table 2. Urinary free cortisol levels in relationship comolication of manic disorder Controls 31.0i13.81
withdrawal
I n=33 I Off
and
Panic disorder patients Total
Drug
to drug withdrawal
D
ND
36.41-17.9
29.0211.7
tn=9r
( n=24
A 35.5k15.72
)
NA 26.2~
9.82
tn=17)
ln=161
31.1+11.3
24.9212.2
medlcatlon
before
study
21.8+10.21
I n=37
27.1212.1
I
t n=31 I
33.5k15.7
25.9k11.2
In=51
tn=26,
Note. Cells wth the same superscript number were slgnlflcantly dtfferent. Urinary free cortlsol levels are expressed as rg/g creatine + SD.
in=ll)
j n=20,
See note to Table 1 forabbrevtations.
1. F = 5.15, df = 2. p = 0.008. Duncan p < 0.05 icontrol vs. total withdrawal 2. I 2.08. df = 29, &I < 0.05.
vs. total off medication,
217 Patients who had been taken off psychotropic medication, as might be expected, also had significantly higher HRSA scores(tz4.4, o’f=63,p=O.O0004)and HRSD scores(t = 3.5, elf= 6 I, p = 0.0009) than those who had not been on medication before inclusion in the study.
Discussion The ma.jor finding in this study is that patients with panic disorder had higher UFC levels than did matched control subjects. In great part, this difference was explained by patients with panic disorder complicated by agoraphobia or depression or both. The difference in UFC levels was neither associated with the frequency of spontaneous panic attacks per week nor with the degree of disability. Rather, the degree of the symptoms of anxiety and depression significantly predicted U FC levels if patients with depression and/ or agoraphobia were not deleted. It is not unexpected that patients with coexistent depression were found to have higher UFC levels than did panic disorder patients without depression since similar UFC levels are seen in patients with primary affective disorder (Carroll et al., 1976; Milln et al., 1981; Rosenbaum et al., 1983~1; Stokes et al., 1984; Anton, 1987). Our results show that abnormalities of the hypothalamic-pituitary-adrenal axis occur in patients with secondary affective disorder as well. Since patients with uncomplicated panic disorder do not have UFC levels significantly different from those of control subjects, it suggests that anxiety symptoms have a less significant influence on UFC change than depressive symptoms. Panic patients with agoraphobia also demonstrated significantly higher U FC levels than controls. This finding was not explained entirely by the coexistence of depression in agoraphobic patients, as can be seen in Fig. 2. Agoraphobic patients had UFC levels higher than controls even after depressed patients were removed from this group. However, when panic patients with both depression and agoraphobia were examined separately, their UFC levels were elevated above those with either agoraphobia or depression alone. In fact, there appeared to be an additive effect of these two complications of panic disorder on UFC excretion. It is possible that the differences in UFC excretion between patients and controls could be related to benzodiazepine withdrawal (only a 7-day washout) or to increased symptoms related to discontinuation of medication. Our results, however, suggest that these possibilities are not likely to be major factors since there were no differences in UFC levels between panic disorder patients or subcategories thereof on and off medication at study onset. Furthermore, differences in UFC excretion between depressed and nondepressed and between agoraphobic and nonagoraphobic patients still appeared or showed a trend in the appropriate direction even when medication withdrawal status was controlled for. While the number of symptoms of anxiety and depression correlated with UFC levels in panic patients as a whole, there is no such relationship with symptoms of phobic avoidance. If progression from panic disorder without phobic avoidance to limited phobic avoidance to agoraphobia can be used as an indication of severity, there was not a stepwise progression in U FC levels related to this. Rather, something about the state of agoraphobia itself led to an alteration in UFC excretion. This is further supported by the fact that patients with panic uncomplicated by agoraphobia and/ or depression did not show a correlation of the numbers
218 of symptoms of anxiety and depression, as identified in the HRSA and HRSD, to U FC levels. Our results are not directly comparable to either those of Persky (1962) or those of Rosenbaum et al. (19836). Persky identified a subgroup of “anxious patients” and measured urinary hydroxycorticoid excretion. The anxious patients in his studies were actually patients with a variety of psychiatric conditions in which symptoms of anxiety were prominent (Persky et al., 19.56, 1959a, 19596). He did not report what primary psychiatric conditions these patients had. Consequently, his findings are not possible to interpret in terms of diagnostic categories. Since many of these patients could have had depression, the differences in hydroxycorticoid excretion could have reflected findings related to depression rather than anxiety. Rosenbaum et al. (19836) measured UFC levels in 22 patients with primary generalized anxiety disorder and 22 controls. In that study, which was performed in an internal medicine outpatient clinic, patients and control subjects did not differ significantly. Even the patients who had secondary major depression did not show elevated UFC excretion. It is interesting, however, that the only patient with an elevated UFC level was depressed. Since Rosenbaum et al. (19836) studied generalized anxiety disorder and did not subcategorize their patients into those with and without panic attacks, our results are not directly comparable to theirs. Our patients with uncomplicated panic disorder, however, do resemble those described by Rosenbaum et al. (1983b) in having UFC levels that do not differ significantly from those of controls. The severity of anxiety symptoms, as measured by H RSA, in the two studies was similar (mean anxiety score: 19 vs. 18). UFC assays vary significantly from institution to institution (Murphy et al., 1981), making it impossible to compare the levels reported in this study with those reported by other investigators, even though a similar assay methodology was used. Since UFC levels in patients with primary depression have not been compared to those found in patients with agoraphobia or secondary depression, it is impossible to know whether the magnitude of UFC change is similar. The etiology of increased UFC excretion in patients with panic disorder, and specifically those with associated depression and agoraphobia, is uncertain. It could be that the degree of symptoms present, whether symptoms of anxiety or depression, provokes the adrenergic response to increase the level of cortisol excretion. The lack of correlation of the HRSD and HRSA scores with UFC levels in panic patients without the complications of agoraphobia and depression, however, suggests that a graded adrenergic response with alteration in cortisol excretion occurs only after a certain threshold of symptomatology is reached. Another possibility is that symptoms associated with agoraphobia and/ or depression lead to an alteration in U FC levels. For instance, weight loss, seen in patients with primary depression, is associated with an alteration in the function of the hypothalamic-pituitary-adrenal axis (Berger et al., 1983; Krishnan et al., 1985; Fichter and Pirke, 1986; Pfohl et al., 1986). This or other symptoms associated with the complications of agoraphobia and depression, but not panic disorder alone, could result in elevated UFC excretion. Vegetative disturbances that occur in agoraphobia as well as
219 depression might contribute to these elevations and explain why there is an additive effect of the two syndromes on UFC levels in some patients. There is a high incidence of depression in patients with agoraphobia (Bowen and Kohut, 1979; Breier et al., 1984). It is possible that there is a common underlying defect in corticosteroid metabolism that accounts for the identification of elevated UFC excretion and perhaps the production of depressive symptoms in patients with agoraphobia. Such a hypothesis is consistent with the report of Grunhaus et al. (1987a), who not only found an increase in DST nonsuppression in patients with simultaneous panic disorder and depression but also found such an increase in inpatients with panic disorder or agoraphobia with panic attacks (Grunhaus et al., 19876). Unfortunately, these investigators did not separate patients with uncomplicated panic disorder from those with panic disorder complicated by agoraphobia. In another study describing DST changes in outpatients with agoraphobia with panic attacks, no such differences were found (Curtis et al., 1982). Our study represents a preliminary step in understanding the influence of panic symptoms on UFC excretion. Further investigation of the influence of agoraphobia on hypothalamic-pituitary-adrenal axis function appears warranted. Acknowledgments. This work was partially supported by Clinical Research Centers Program Grant RR59 and partially by the Upjohn Company. The authors thank Janelle Gabel and Tim Gehris for their assistance in data collection and sample analysis and Betty Stevens for assistance in preparation of the manuscript.
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21, I53 (1959).
221
Pfohl, B., Coryell, W., Stan@, D., and Zimmerman, M. Body weight and reported versus measured weight loss as confounders of thedexamethasone suppression test. Bio/ogicd P.syhiatry, 21, 93 I (1986). Rosenbaum, A.H., Maruta, T., Schatzberg. A.F., Orsulak. f’.J., Jiang, N.-S., Cole, J.O.. and Schildkraut, J.J. Toward a biochemical classification of depressive disorders: VII. Urinary free cortisol and urinary M HPG in depressions. Anwricun Journd qf P.cwhiurry, 140,3 I4 ( 1983~). Rosenbaum, A.H., Wells, L.A. , Schatrberg, A.F., Jiang, N.-S.. Jost, F.A. III, Maruta, T., and Cross, P.D. Urinary free cortisol levels in anxiety. Ps,~c~hoso,~~u/ic~.s. 24, X35 (19836). Schwartz, T.B., and Shields, D.R. Emotional tension and excretion of corticoids and creatinine. Anwrican Journal qf Mtdicinr. 16, 608 (1954). Schwartz, T.B.. and Shields, D.R. Urinary excretion of formaldehydogenic steroids and creatinine: A reflection of emotional tension. Ps,~cho.somutic~ Meclicim, 18, I59 (1956). Spitzer, R.L., and Endicott, J. Schedule,for A,[fkctivr Disorders und Schizophrmiu. New York State Psychiatric Institute, New York (1975). Spitzer. R.L., and Williams. B.W. Srrucrurd Clinicd IntrrrGc~,/tir DSM-III. New York State Psychiatric Institute, New York (1982). 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. Archiws of’ Grnrrul Rv,whiu[rjx, 41, 257 ( 19X4). Streeten, D.H.P., Stevenson, C.T., Dalakos. T.G., Nicholas, J.J.. Dennick, L.G., and Feller-man, H. The diagnosis of hypercortisolism: Biochemical criteria differentiating patients from lean and obese normal subjects and from females on oral contraceptives. Journal o/ Clinid Endwrinolog~~. 29, I I9 I ( 1969).
Rrsuarch,
24, 2 I I-22
211
I
Relationship of Urinary Free Cortisol With Panic Disorder to Symptoms Agoraphobia Roger G. Kathol,
Russell
Levels in Patients of Depression and
Noyes, Jr., Ana L. Lopez, and James
Rec,ei\ted h4a.v 18, 1987; revised version received August 28. 1987; accepted
H. Reich
October 10, 1~87.
Abstract. Sixty-five patients with panic disorder and 37 matched controls collected 24-hour urine specimens for measurement of urinary free cortisol. Although patients with panic disorder had significantly higher urinary free cortisol levels than control subjects, this difference was accounted for by panic disorder patients with concomitant depression, agoraphobia, or both. Urinary free cortisol excretion was not related to the age of onset of panic disorder, the number of spontaneous panic attacks, or the degree of impairment associated with the disorder. They were related, however, to the level of symptoms on both the Hamilton Rating Scale for Depression and the Hamilton Rating Scale for Anxiety in the entire group of panic patients, but this relationship disappeared when those patients with the complications of agoraphobia and depression were excluded. These data suggest that, as with primary depression, depression secondary to panic disorder, as well as to agoraphobia in panic disorder patients, is associated with hyperactivity of the hypothalamic-pituitary-adrenal axis. Key Words. Panic disorder, disorder.
urinary free cortisol,
agoraphobia,
depression,
anxiety
For years it has been known that urinary glucocorticoid excretion can be used as a reflection of acute psychological or physical stress (Schwartz and Shields, 1954, 1956; Espiner, 1966; Mason, 1968). Measurement of urinary or plasma corticosteroids in situations typified as subacute, however, have not demonstrated the elevations typically present in acute situations (Schwartz and Shields, 1956; Bourne et al., 1967; Blumenfield et al., 1970; Hofer et al., 1972; Gorzynski et al., 1980). More recently, Mason et al. (1986) measured urinary free cortisol levels in various psychiatric conditions. Interestingly, patients with posttraumatic stress disorder, typified by chronic psychological stress related to prior life experiences, did not demonstrate an elevation of urinary free cortisol and, in fact, demonstrated lower levels than patients with both affective and psychotic disorders. Urinary glucocorticoid excretion has been most widely studied in patients with primary affective disorder (Carroll et al., 1976; Milln et al., 1981; Rosenbaum et al., 1983a; Stokes et al., 1984). These studies have demonstrated that patients with active primary affective disorder have elevated glucocorticoid excretion in comparison to a
Roger G. Kathol. M.D., 6.A.C.P.. ia Associate Professor of Psychiatry and Internal Medicine, and Director of Medical Psychiatry Unit; Russell Noyes, Jr., M.D., is Professor of Psychiatry; Ana L. Lope/, B.S.. is Research AssIstant. University of Iowa, Iowa City, IA. James H. Reich, M.D.. is Assistant Professor of Psychiatry. Brockton VA Medical Center, Brockton, MA. (Reprint requests lo Dr. R.G. Kathol, Dept. of Psychiatry, University of Iowa, 500 Newton Rd., Iowa City, IA 52242. USA.) Ol65-1781/88/$03.50
@ 1988 Elsevier Scientific
Publishers Ireland
Ltd.
212 control population. Studies by both Berger et al. (1982) and Mason et al. (1986) have demonstrated that this elevation in glucocorticoid excretion diminishes as clinical improvement occurs; a recent report by Kathol(l985), however, suggests that return to control levels may not occur in some patients. Measurement of urinary glucocorticoids has not been nearly so extensively studied in patients with primary anxiety. In a series of studies in the 195Os, Persky et al. ( 1956, 1959~1, 19596) measured urinary hydroxycorticosteroid excretion in normal subjects and anxious patients. In these studies, it was demonstrated that patients with symptoms of anxiety had significantly elevated urinary hydroxycorticoid excretion when compared to a control population. However, sub.jects in these studies were drawn from a mixed population of psychiatric patients who had demonstrated anxiety-type behavior while hospitalized. These results cannot be considered equivalent to those which might be found in patients with primary anxiety disorder. More recently Rosenbaum et al. (19836) were unable to find a difference between 22 patients with generalized anxiety disorder and a group of 22 nonanxious volunteers. These findings suggest that chronic anxiety disorders do not result in an increase in urinary glucocorticoid excretion, but that when anxiety symptoms accompany other psychiatric conditions, excretion may be increased. As a part of a treatment study of diazepam, alprazolam, and placebo in patients with primary anxiety, and specifically panic disorder, we decided to explore further the relationship of urinary free cortisol (U FC) levels in 65 unmedicated panic disorder patients and 37 controls.
Methods Subjects. Ninety-one patients identified by advertisement were screened using the Structured Clinical Interview for DSM-//I (SCID) (Spitrer and Williams, 1982) and met DSM-//l-K 1985) criteria for panic disorder. In addition. all panic (American Psychiatric Association, patients were required to have had at least one panic attack per week. All patients wet-c between the ages of 19 and 62 and in good physical health. Patients who were pregnant, lactating, psychotic, suicidal, demented, or who had a history of epilepsy, seizures, bipolar or melancholic depression, obsessive-compulsive disorder, alcohol dependency, or who were taking a- or /3-adrenergic blockers were excluded. Eighteen of the 91 patients were excluded because they were on medication which could potentially interfere with measurement of urinary cortisol levels (birth control pills, glucocorticoids. or centrally acting hypertensive medications). Eight additional patients were excluded because they did not submit complete 24-hour urine specimens. A total of 65 patients (35 males and 30 females) with a mean age of 40 (SD Y.6) were included in the study. Twenty-nine met criteria for concurrent agoraphobia, while 14 met criteria for concurrent secondary ma.jor depression in addition to panic disorder. Subject5 with major depression were included if panic disorder preceded the onset of depression and dominated the clinical picture. Sixty-two control subjects were identified by advertisement and screened with the Schedule for Schizophrenia and Affective Disorders-Lifetime Version (Spitter and Endicott. 1975). After this screening, 40 medically healthy controls remained who were free from past or present psychiatric illness. It was necessary to exclude three control subjects who failed to submit complete urine collections. Thirty-seven medication-free controls (I9 males and IX females) with a mean age of 35 (SD I I. I) years (range 23-60 years) entered the study. Procedures.
of alprazolam,
The patients were participants in a double-blind, placebo-controlled comparison dia/epam, and placebo. In addition to the SCIL), patients were assessed using the
213 Carroll Rating Scale for Depression (Carroll et al., 1981), the Hamilton Rating Scale for Anxiety (H RSA) (Hamilton, 1959), and the Hamilton Rating Scale for Depression ( H RSD) (Hamilton, 1960). The age of onset and frequency of panic attacks were recorded on a Panic Attack Scale developed for the treatment study, and ratings of impairment were made on an I l-point visual analog Disability Scale for work, social life and leisure activities, and family life and home responsibilites (Table I). Patients who met criteria for panic disorder were further subdivided into those with extensive phobic avoidance (agoraphobia), limited phobic avoidance, and uncomplicated or no phobic avoidance. To be placed in the agoraphobic group, patients had to have generalized travel restrictions, often need a companion away from home, or have a markedly altered life style, while those in the limited phobic avoidance group required significant phobic avoidance or endurance despite intense anxiety. Thirty-three patients were taking psychotropic medication up to 2 weeks before the trial began. Those still on medications were instructed to discontinue them I week before collection of the 24-hour urine specimen. All except one were withdrawn from a benzodiazepine, while two were withdrawn from a tricyclic antidepressant. Control subjects were screened through the exclusion process described above and then given the Carroll Rating Scale for Depression (Carroll et al., 1981). Once this was completed, a 24-hour urine specimen for U FC measurement was collected. Patients and control subjects were given detailed written and verbal instructions on how to collect 24-hour urine specimens for UFC measurement. The subjects were told that it was important for the sample to be complete and that we preferred to know that a single void was missed and not use the collection in our analysis rather than use an incomplete sample. When possible, the participants were encouraged to retry a collection. Subjects were cooperative with this request. The measurement of 24-hour creatinine excretion was used as an additional safeguard to ensure that only complete specimens were compared. Those patients with 24-hour creatinine levels below 450 mg and in whom there was a significant discrepancy in 24-hour
Table 1. Demographic
characteristics
of sample
Controls
Panic disorder patients Total n = 65
n = 37
tyears J
Age
35.0211 .o
Carroll score Age
2.02 1.91
of PD onset
D n=
14
4O.OT9.6
39.7+10.3
17.8?9.51
26.41 7.12
ND n = 51 40.0+9.5
A n = 29
NA n = 36
41.0?11.4
39.157.9
15.418.72
19.6+ 9.6
16.529.3
29.7+
8.5
27.629.0
25.42
29.5k7.5
3.218.7
4.42
6.2
2.9k9.3
17.4k6.1
22.32
5.33
16.155.73
27.7M.7
9.9
Spontaneous
in last week
attacks
HRSD
score
Level
of social
disability* HRSA
5.5k2.9
score
18.9f8.7
7.11ir 2.5 25.12
6.15
5.3t12.7 18.8?
6.8
1521.5 16.315.4
5.122.8
7.Oi
2.44
4.422.84
17.228.65
21.32
9.76
16.927.56
Note. Cells wth the same superscript number are significantly different. D = depressed. ND = nondepressed. A agoraphobic. NA = nonagoraphoblc. PD = panic disorder. Carroll = Carroll Rating Scale for Depression. HRSD = Hamilton Rating Scale for Depresston. HRSA = Hamllton Rahng Scale for Anxiety.
=
‘A higher score Indicates 1.p~0.0001. 2. p <. 0.0001. 3. p c 0.0005. 4. p <: 0.002. 5. p <: 0.0001. 6. D q. 0.04.
greater
disability
214 creatinine excretion from other specimens submitted during a treatment followup phase of this study were excluded from analysis. The patients and control subjects refrigerated the UFC samples after collection and returned them for storage at -20” C within 3 days of collection.
Assays. Twenty-four-hour urinary creatinine levels were measured by the Schafe method (Henry, 1964). UFC levels were determined by radioimmunoassay (RIA) on extracted samples using a double antibody technique (Hsu and Bledsoe, 1969). The intra- and interassay coefficients of variation were 5.5 and 9.9%, respectively. The results were reported aspg/gcreatinine to correct for differences in body mass among subjects (Streeten et al., 1969). The assays were performed by a person without knowledge of the diagnosis of the individuals involved. Statistical Analysis. A comparison of dichotomous parametric data was performed by using Student’s I test. Comparison of parametric data on three or more groups was performed by 2-way analysis of variance (ANOVA). When differences were identified, post hoc testing was performed with the Duncan Multiple Range Test. Linear regression was used to correlate U FC levels with other clinical variables. When appropriate, log transformation was performed to correct for nonnormally distributed data. Variance was expressed as standard deviation. Results Patients with panic disorder (29.3 f 13.0 pg/ g creatinine) had significantly higher U FC levels (t = 3.25, @= 100, p = 0.002) than control sub.jects (22.0 k 10.3 pg/g creatinine) (see Fig. 1). When the patients with panic disorder were divided, agoraphobic (34.1 + 13.9 /*g/g creatinine) and nonagoraphobic (25.5 + 11.0 pg/g creatinine) subgroups
Fig. 1. Scattergram of urinary free cortisol (UFC) levels in patients with panic disorder and controls 60
y
1
so]
e 3 4o
t=3.246* p=D.o02
0
uo
0
0
SO-1
8
0
40-
- 0%
QJo
50-l
0
40-
08 e 3
30-
30-
zo-
zo-
lo-
lo-
2 “0””
30zo-
0
lo-
0
Panic Disorder Patients C=contmls PD=ponk disordw l
Patients
(all)
A-ogomphobk NA=non-agomphoblc D=dmpmas.d; Nlknon-depnsrmd
based on log,, tmn8fommd data.
with panic disorder
are subdIvIded
into those wtth and wlthout
depression
and agoraphobia
215 both had levels significantly higher than controls (F = 9.4, df = 2, p = 0.002). Patients with agoraphobia also had significantly higher UFC levels than those who were not agoraphobic when examined independently (see Fig. 1). When nonagoraphobic panic patients were divided into those with limited phobic avoidance (n = 2 1) and those with none (n = 15), no stepwise increase in UFC levels could be found (24.4 f 9.6 vs. 26.9 k 13.0 pg/ g creatinine, respectively). Panic disorder patients with concurrent depression (35.3 + 16.6 pg/g creatinine) had significantly higher UFC levels (F= 7.0, df= 2, p 0.001) than controls and tended toward higher levels than panic disorder patients without depression (27.7 + 11.5 pg/ g creatinine) (see Fig. 1). The eight panic disorder patients in whom both agoraphobia and depression were present constituted a group with the highest UFC levels (38.1 f 20.3 pg/g creatinine), while those with either depression (3 1.6 + 10.4 pg/ g creatinine) or agoraphobia (32.6 + 10.8 pg/ g creatinine) but not both constituted a middle group. Panic disorder patients without either accompanying depression or agoraphobia (24.2 f 10.9 pg/g creatinine) had UFC levels similar to those of controls (t = 0.9, df = 64, p = 0.39) (see Fig. 2). q
Fig. 2. Urinary free cortisol (UFC) levels in subgroups patients with or without agoraphobia or depression
of panic disorder
60
50
T
T
I-
I-
ia l-
aI-
D 8)
C=contmlr. Panic Oi~ordw Patlwtr: NO=non-dapnrred; O=doprw*d. Groups with thesame < 0.001 ‘.
A/ND (~5221)
Nknon-agomphoblc:
letter ra, b, c.d~ areslgnificantlydifferent
NA/D
(~=6)
A=agomphobic:
at theconfldencelevelp<0.05
1Fz5.4, df=4.p
UFC levels correlated most closely with the HRSD (see Fig. 3). There was also a strong correlation with the HRSA (r 0.35, r-2 = 0.12, p = 0.004). When anxiety questions were deleted from the HRSD (items 9, IO, and 11; mean score for patients with panic disorder = 10.9 + 5.4) a significant correlation with UFC levels remained (r 0.34, t-2 0.12, p = 0.005). When panic patients with thecomplications ofagoraphobia, depression, or both were deleted before correlation with the HRSA and the HRSD q
q
216
Fig. 3. Correlation of urinary free cortisol (UFC) depression scores in panic disorder patients.
levels
with
Hamilton
80
1
t=O.S60 p=o.o03 0
0
0
I
I
I
I
10
20
30
40
Hamilton Depression
Scale
scores, the relationship of these indices of severity and UFC excretion was lost (r = -0.04, r2 = 0.002, p = 0.8, and r = -0.15,r’ = 0.02, p = 0.4, respectively). UFC levels were not correlated with the age of onset of panic disorder, the number of spontaneous panic attacks during the past week, or the degree of social, work, or family/ home disability experienced by the patient. Further, there was no effect of gender or age on U FC levels either in controls or patients with panic disorder. Patients who had been taken off psychotropic medications before urine collection had UFC levels (3 1.O 2 13.8 pg/ g creatinine) significantly higher than those of controls (F= 5.15, d/‘= 2, p 0.008). When patients were divided into those with complicated and uncomplicated panic disorder, however,the presence of agoraphobia and depression influenced the UFC levels more than did medication withdrawal status (Table 2). q
Table 2. Urinary free cortisol levels in relationship comolication of manic disorder Controls 31.0i13.81
withdrawal
I n=33 I Off
and
Panic disorder patients Total
Drug
to drug withdrawal
D
ND
36.41-17.9
29.0211.7
tn=9r
( n=24
A 35.5k15.72
)
NA 26.2~
9.82
tn=17)
ln=161
31.1+11.3
24.9212.2
medlcatlon
before
study
21.8+10.21
I n=37
27.1212.1
I
t n=31 I
33.5k15.7
25.9k11.2
In=51
tn=26,
Note. Cells wth the same superscript number were slgnlflcantly dtfferent. Urinary free cortlsol levels are expressed as rg/g creatine + SD.
in=ll)
j n=20,
See note to Table 1 forabbrevtations.
1. F = 5.15, df = 2. p = 0.008. Duncan p < 0.05 icontrol vs. total withdrawal 2. I 2.08. df = 29, &I < 0.05.
vs. total off medication,
217 Patients who had been taken off psychotropic medication, as might be expected, also had significantly higher HRSA scores(tz4.4, o’f=63,p=O.O0004)and HRSD scores(t = 3.5, elf= 6 I, p = 0.0009) than those who had not been on medication before inclusion in the study.
Discussion The ma.jor finding in this study is that patients with panic disorder had higher UFC levels than did matched control subjects. In great part, this difference was explained by patients with panic disorder complicated by agoraphobia or depression or both. The difference in UFC levels was neither associated with the frequency of spontaneous panic attacks per week nor with the degree of disability. Rather, the degree of the symptoms of anxiety and depression significantly predicted U FC levels if patients with depression and/ or agoraphobia were not deleted. It is not unexpected that patients with coexistent depression were found to have higher UFC levels than did panic disorder patients without depression since similar UFC levels are seen in patients with primary affective disorder (Carroll et al., 1976; Milln et al., 1981; Rosenbaum et al., 1983~1; Stokes et al., 1984; Anton, 1987). Our results show that abnormalities of the hypothalamic-pituitary-adrenal axis occur in patients with secondary affective disorder as well. Since patients with uncomplicated panic disorder do not have UFC levels significantly different from those of control subjects, it suggests that anxiety symptoms have a less significant influence on UFC change than depressive symptoms. Panic patients with agoraphobia also demonstrated significantly higher U FC levels than controls. This finding was not explained entirely by the coexistence of depression in agoraphobic patients, as can be seen in Fig. 2. Agoraphobic patients had UFC levels higher than controls even after depressed patients were removed from this group. However, when panic patients with both depression and agoraphobia were examined separately, their UFC levels were elevated above those with either agoraphobia or depression alone. In fact, there appeared to be an additive effect of these two complications of panic disorder on UFC excretion. It is possible that the differences in UFC excretion between patients and controls could be related to benzodiazepine withdrawal (only a 7-day washout) or to increased symptoms related to discontinuation of medication. Our results, however, suggest that these possibilities are not likely to be major factors since there were no differences in UFC levels between panic disorder patients or subcategories thereof on and off medication at study onset. Furthermore, differences in UFC excretion between depressed and nondepressed and between agoraphobic and nonagoraphobic patients still appeared or showed a trend in the appropriate direction even when medication withdrawal status was controlled for. While the number of symptoms of anxiety and depression correlated with UFC levels in panic patients as a whole, there is no such relationship with symptoms of phobic avoidance. If progression from panic disorder without phobic avoidance to limited phobic avoidance to agoraphobia can be used as an indication of severity, there was not a stepwise progression in U FC levels related to this. Rather, something about the state of agoraphobia itself led to an alteration in UFC excretion. This is further supported by the fact that patients with panic uncomplicated by agoraphobia and/ or depression did not show a correlation of the numbers
218 of symptoms of anxiety and depression, as identified in the HRSA and HRSD, to U FC levels. Our results are not directly comparable to either those of Persky (1962) or those of Rosenbaum et al. (19836). Persky identified a subgroup of “anxious patients” and measured urinary hydroxycorticoid excretion. The anxious patients in his studies were actually patients with a variety of psychiatric conditions in which symptoms of anxiety were prominent (Persky et al., 19.56, 1959a, 19596). He did not report what primary psychiatric conditions these patients had. Consequently, his findings are not possible to interpret in terms of diagnostic categories. Since many of these patients could have had depression, the differences in hydroxycorticoid excretion could have reflected findings related to depression rather than anxiety. Rosenbaum et al. (19836) measured UFC levels in 22 patients with primary generalized anxiety disorder and 22 controls. In that study, which was performed in an internal medicine outpatient clinic, patients and control subjects did not differ significantly. Even the patients who had secondary major depression did not show elevated UFC excretion. It is interesting, however, that the only patient with an elevated UFC level was depressed. Since Rosenbaum et al. (19836) studied generalized anxiety disorder and did not subcategorize their patients into those with and without panic attacks, our results are not directly comparable to theirs. Our patients with uncomplicated panic disorder, however, do resemble those described by Rosenbaum et al. (1983b) in having UFC levels that do not differ significantly from those of controls. The severity of anxiety symptoms, as measured by H RSA, in the two studies was similar (mean anxiety score: 19 vs. 18). UFC assays vary significantly from institution to institution (Murphy et al., 1981), making it impossible to compare the levels reported in this study with those reported by other investigators, even though a similar assay methodology was used. Since UFC levels in patients with primary depression have not been compared to those found in patients with agoraphobia or secondary depression, it is impossible to know whether the magnitude of UFC change is similar. The etiology of increased UFC excretion in patients with panic disorder, and specifically those with associated depression and agoraphobia, is uncertain. It could be that the degree of symptoms present, whether symptoms of anxiety or depression, provokes the adrenergic response to increase the level of cortisol excretion. The lack of correlation of the HRSD and HRSA scores with UFC levels in panic patients without the complications of agoraphobia and depression, however, suggests that a graded adrenergic response with alteration in cortisol excretion occurs only after a certain threshold of symptomatology is reached. Another possibility is that symptoms associated with agoraphobia and/ or depression lead to an alteration in U FC levels. For instance, weight loss, seen in patients with primary depression, is associated with an alteration in the function of the hypothalamic-pituitary-adrenal axis (Berger et al., 1983; Krishnan et al., 1985; Fichter and Pirke, 1986; Pfohl et al., 1986). This or other symptoms associated with the complications of agoraphobia and depression, but not panic disorder alone, could result in elevated UFC excretion. Vegetative disturbances that occur in agoraphobia as well as
219 depression might contribute to these elevations and explain why there is an additive effect of the two syndromes on UFC levels in some patients. There is a high incidence of depression in patients with agoraphobia (Bowen and Kohut, 1979; Breier et al., 1984). It is possible that there is a common underlying defect in corticosteroid metabolism that accounts for the identification of elevated UFC excretion and perhaps the production of depressive symptoms in patients with agoraphobia. Such a hypothesis is consistent with the report of Grunhaus et al. (1987a), who not only found an increase in DST nonsuppression in patients with simultaneous panic disorder and depression but also found such an increase in inpatients with panic disorder or agoraphobia with panic attacks (Grunhaus et al., 19876). Unfortunately, these investigators did not separate patients with uncomplicated panic disorder from those with panic disorder complicated by agoraphobia. In another study describing DST changes in outpatients with agoraphobia with panic attacks, no such differences were found (Curtis et al., 1982). Our study represents a preliminary step in understanding the influence of panic symptoms on UFC excretion. Further investigation of the influence of agoraphobia on hypothalamic-pituitary-adrenal axis function appears warranted. Acknowledgments. This work was partially supported by Clinical Research Centers Program Grant RR59 and partially by the Upjohn Company. The authors thank Janelle Gabel and Tim Gehris for their assistance in data collection and sample analysis and Betty Stevens for assistance in preparation of the manuscript.
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