Higher postdexamethasone serum cortisol levels in agoraphobic than in nonagoraphobic panic disorder patients

BW~L ~YCW/ATR¥

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Higher Postdexamethasone Serum Cortisol vels in Agoraphobic Than in Nonagoraphobic P ic Disorder Patients Peter Westberg, Kjell Modigh, Pia Lisj6, and Elias Efiksson

The dexamethasone suppression test (DST) was performed in panic disorder (PD ) patients with (n = 32) or without (n = 31) agoraphobia and in normal controls (n = 49). Postdexamethasone serum cortisol &vels were significantly higher in agoraphabic PD patients (105.3 +. 19.3 nmol;L ) both when compared to PD patients without agoraphobia (47.3 +. 7.7 nmol/L; p < 0.01) and when compared to healthy controls (5t.7 +. 8.3 nmol/L; p < 0.01). The rate of nonsuppresso~-s (i.e., subjects displaying postdexame. thasone cortisol levels > 138 nmol/L) was 28% and 3% in agoraphobic and nonagoraphobic PD patients, resp.e~tively, and 12% in controls. In patients, the posMexamethasone cortisol levels did not correlate with the re:tuber of panic attacks per week, baseline anxiety as measured using the Hamilton Anxiety Scale, depressive symptoms as measured using the Montgomery.-,~sberg Depression scale, or duration of illness. Dam from eight patients in whom a second DST was performed after treatment with imipramine or domipramine for three months indicate that a marked reduction of the number of anxiety attacks is not necessarily accompanied by a normalization of a pathological DST. In conclusion, it is suggesied that the elevated pas~dexamethasone co~iso! &vels sometimes observed in agoraphobic PD patients are more closet.y related to the agoraphobic behavior than to the panic attacks per se.

Introduction Although severe agoraphobic avoidar,.e is common in panic disorder (PD) patients (~ein and Gorman i987), it is not an inevitable consequence of recurrent anxiety a~cks; thus, approximately one-third of PD patients do not display agoraphobia. To what extent the risk of developing agoraphobia as a complication of p ~ c disorder is correlated to the severity and frequency of the panic attacks is a matter of controversy (BuHer et al 1986; Noyes et al 1986; Ganellen et ai 1986; Coryell et aI 1989). Alternatively, proneness to develop agoraphobia as the result of repeated anxiety attacks may be caused by a specific genetic trait (Noyes et al 1986). The similarities between PD and depression, for example, with respect to the beneficial

From the Departments of Psychiatry~eurochemistry(PW, KM. PL) and Pbarmacology (EEL University of G~borg, ~ b o r g . Sweden. Address reprint requests to Elias Efiksson. Department of Pharmacology, Ua/versity of G6~borg. P.O.B. 33031. S-400 33 G6teborg, Sweden. Received May 24, 1990: revised February 23. |991. © 1991 Society of Biological Psychiatry

0006-3223/91/$03.50

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effects of antidepressant drugs (for ref see Breier et al 1986; Modigh 1987), have prompted many investigators to search for depression-related biological markers in PD patients (for ref see Roy-Byrne and Uhde 1985; Roy-Byme et al 1985; Eriksson 1988). Thus, a large body of data is today available regarding the outcome of the dexamethasone suppression test (DST) (Carroll 1982) in PD patients. Although the results of the different studies are not unanimous, most reports indicate that the frequency of dexamethasone nonsuppressors among PD patients is about 20%; that is, lower than among depressed patients (of which 50%-60% are nonsuppressors) but higher than among normal controls (of which generally less than 5% display abnormal DST results) (see Discussion). The determinants for a pathological DST in PD patients are not known. The present study was undertaken mainly in order to clarify to what extent postdexamethasone cortisol levels are different in agoraphobic as compared to nonagoraphobic PD patients. Moreover, ti~e putative importance of depressive sympton~s and the severity of anxiety for the outcome of DST in PD patients was investigated. Finall~,, in order to evaluate the possible state dependence of a pathological DST among PD patients, a second DST was perfortried in a number of PD patients after three months of treatment with either of the two antipanic drugs, imipramine or clomipramine. Materials and M e t h o d s Patients fulfilling the DSM-III-R criteria of PD with (n = 32) or without (n = 31) agoraphobia were recruited from a psychiatric outpatient clinic or via referrals from emergency rooms of somatic hospitals, other psychiatrists, or general practitioners. The diagnosis was confirmed by means of a structured interview performed by one of the participating psychiatrists; in addition symptoms of depression and anxiety were rated using the Montgomery-A, sberg Depression Scale (MADS) and the Hamilton Anxiety Scale (HAS), respectively. Patients with alcohol or drug abuse, other somatic or psychiatric illness (including major depression and dysthymia as defined in DSM-III-R), or verified or planned pregnancy were excluded from the study. As controls (n = 49) served members of the hospital staff, students, and firemen reporting no symptoms of psychiatric or somatic illness and taking no medication. The age and sex distributions were similar in the control group as compared to the group of PD patients (mean age of all patients: 33.2 _+ 1.'~ years; percentage of women among patients: 69.8; mean age of controls: 33.1 -4- 1.1 years; percentage of women among controls: 73.5). The mean age of agoraphobic PD patients was 31.4 +_ 1.5 and of nonagoraphobic PD patients 35.0 _ 1.5 (not significant); 75.0% of agoraphobic and 64.5% of nonagoraphobic PD patients were women. While none of the controls had ever suffered from major depression, 6 of the agoraphobic PD patients (19%) and 3 of the non-agoraphobic PD patients (10%) had previously in life had an episode of depressive disorder. All subjects participating in the study gave informed consent. The design of the study was accepted by the Ethical Committee of the University of G6teborg. Most patients participating in the present study also entered a placebo-controlled drug trial comprised of the drugs imipramine and clomipramine, the results of which will be presented elsewhere; the first DST was, however, performed before drug treatment was initiated. Patients consuming large amounts of anxiolytics were excluded from the drug trial as well as from the DST study; however, patients with only a moderate and irregular consumption of benzodiazepines (BZD) were allowed to participate. All these patients were asked to take as little BZD as possible; those who needed anxiolytic medication

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were switched from their regular anxiolytic drug to 5 mg tablet~ of d i a z e ~ ( ~ i m a t t y 3 per day) a few weeks before ~he DST was performed. The intake of BZD was carefully registered. Apart from th,.'s moderate consumption of anxiolytic ~ g s in some patients, all participants were totally free from any kind of medication at the time of the tint DST. In a small number of patients, a second DST was peffom-,ed after 3 months of treaunent with either clomipramine (n = 3) or imipram~ne (n = 5) (50-150 rag/day). The clinical effects of the treatment in these subjects were evaluated by means of the patient's recording of the number of panic attacks per week, and by rating of baseline anxiety by means of HAS. DST was performed by oral administration of dex~ethasone 1.0 mg at l0 PM followed by blood sampling at 4 aM on the following day. Comsol was an~yzed by a ~ i o i m munoassay from Farmos (Turku, Finland), the results of which is equivalen t to those of the widely used assay from Diagnostic Products Corpo~tion, Los Angeles, USA (cf., H~iilstr6m et al 1983). The lower detection limit of the assay was 5 nmoFL ~ d the interassay and intraassay variations were 5.0% and 2.2%, respectively. The cortisol analysis was performed blindly with respect to diagnosis. Cortiso| values are presented as nmol/L; the conversion factor for obtaining ttg/dL is 0.036. All values are given as mean with standard error. The statistical s i ~ f i c a n c e of differences between groups was analyzed by t-test (paired or unp~red), X2 test, or by analysis of variance followed by Fischer's PLSD-test. p < 0.05 was considered significant. Results Postdexamethasone plasma cortisol values in controls were 51.7 _ 8.3 nmo~L and in all PD patients (with or without agoraphobia) 76.8 ___ I1.1 nmoI/L (t = 1.7, DF = 110, p < 0.05; two-tailed t-test). Using postdexarnethasone cortisol levels exceeding 138 nmol/L as a definition of a pathological test (cf., Carroll 1982), 16% of patients and 12% of controls were nonsuppressors. All individual postdexamethasone cortisol levels are given in Table 1. When PD patients with (AG) and without (N-AG) agoraphobia were compared, ~ t dexamethasone plasma cortisol levels were found to be significantly higher in agoraphobic subjects (AG: 105.3 --- 19.3 nmol/L; N-AG: 47.3 -+ 7.7 nmo~L; PLSD = 48.5, df = i09, p < o.o1; ANOVA + Fischer PLSD-test) (Figure |). Moreover, agoraphobic PD patients, in contrast to nonagoraphobic PD subjects, displayed significantly higher postdexamethasone cortisol levels than controls (PLSD = 43.7, df = I ~ , p < 0.01; ANOVA + Fischer PLSD-test). Using 138 nmol/L as cut-point, 28% of patients with PD with agoraphobia and 3% of patients with PD without agoraphobia, respectively, were found to be nonsuppressors (X2 = 6.2, df = 1, p < 0.05; ×2 analysis). In contrast, neither the rate of agoraphobic nonsuppressors nor the rate of nonagoraphobic PD patients displaying pathological DST differed significantly from the rate of controls (16%) with postdexamethasone cortisoi levels exceeding 138 nmol/L. Agoraphobic and nonagoraphobic patients were compared with respect to the number of severe (AG: 4.9 + 1.5; N-AG: 3.3 - 1.0) as well as severe + moderate (AG: 11.5 _+ 4.3; N-AG: 5.0 -+ 0.6) panic attacks per week (as registered by the patient using a panic attack diary); the differences observed were, however, not statistically significant. In contrast, the baseline anxiety as measured using HAS was significantly higher in agoraphobic than in nonagoraphobic patients (AG: 12.5 -+ 1.0; N-AG: 8.2 - 1.1; t = 2.9, df = 60, p < 0.01; two-tailed t-test). The duration of illness was similar in the two

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Table 1. Individual Postdexameth~sone Serum Cortisol Values (nmol/L) in Controls and in Panic Disorder Patients with (FD + AG) or Without (PD) Agoraphobia Controls

PD + AG

PD

II 12 15 16 16 16 18 18 19 19 19 19 20 20 20 20 22 25 26 26 27 27 28 28 28 29 30 30 31 33 34 36 36 40 41 42 47 54 54 56 77 79 82 169 189 189 189 196 255

14 14 15 15 18 19 21 23 25 27 27 28 34 35 48 57 68 73 73 90 94 ! 14 117 158 195 205 206 231 258 304 358 406

15 15 16 16 17 18 19 19 23 25 26 28 30 30 31 31 32 34 38 43 43 52 60 60 63 69 73 81 106 134 220

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igg1:30:247-256

140 120

0 CONT

PD+AG

PD

Figure !. Individual postdexamethasone serum cortisol levels in healthy controls (CONT) (n = 49) and in panic disorder patients with (PD + AG) (n = 32)or without (PD) (n = 31) agoraphobia. The bars represent means with SEM. Cortisol levels in the PD + AG group differed si~ficantly from both other groups; * = p < 0.01.

groups (AG: 6.7 _+ 1.1 years; N-AG: 8.1 _ 1.5 years). Also, the two groups did not differ with respect to diazepam intake (AG: 6.6 +_ 1.8 diazepam 5 mg tablets/week; N-AG: 6.0 _+ 1.4 diazepam 5 mg tablets/week) or with respect to MADS scores (AG: 2.1 _+ 0.4; N-AG: 1.9 _ 0.5). In the patient group, postdexamethasone serum cortisol levels did not correlate to the number of severe (r 2 = 0.0003) or severe + moderate panic attacks/week = (r 2 = (;.026), HAS scores (r 2 = 0.0002), MADS scores (r 2 = 0.046), duration of illness (r 2 = 0.005) or BZD intake (r 2 = 0.021). Moreover, similar cortisol levels were observed in those 9 PD patients who had previously in life suffered from an episode of depression (75.2 _+ 25.6 nmol/L) as compared to those who had not (77.0 _ 12.3 nmoFL). In eight PD patients a second test was performed after 3 months of treatment with reduction of the number of panic attacks per week in most subjects; moreover, baseline anxiety as measured using HAS was reduced from to 9.5 - 1.2 to 2.6 _ 0.8 (t = 5.3, df = 6, p < 0.001, paired t-test). However, in most subjects this clinical improvement was not accompanied by a normalization of postdexamethasone serum cortisol levels (see Table 2). Thus, among the 7 patients in whom the drug treatment resulted in a marked reduction of panic attacks, the number of nonsuppressors (i.e., subjects displaying postdexamethasone cortisol values exceeding 138 nmol/L) was the same (i.e., 5) before and after clinical improvement.

Discussion In previous studies the rate of pathological DST as defined using a cut-point of 110 or i 38 nmol/L ( = 4 or 5 pLg/dL) in patients with panic attacks has differed from 0% (Curtis et al 1982; Lieberman et al 1983) to 75% (Grunhaus et al 1987); according to most studies, however, the rate of pathological tests in a group of PD patients is about 20%

252

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Table 2. The Effect of Treatmem with Either of the Two Antipanic Drugs lmipramine or Clomipramine for Three Months on the Number of Panic Attacks Per Week and Postdexamethasone Cortisol Levels, Respectively. in Eight Panic Disorder Patients with or Without Agoraphobia

Patient I (clom. agora) Before After Patient 2 (clom. agora) Before After Patient 3 (clom, agora) Before After Patient 4 (imi, agora) Before After Patient 5 (iali. agora) Before After Patient 6 (imi, non-agora) Before After Patient 7 (imi, non-agora) Before After Patient 8 (imi, non-agora) Before After

No. of panic attacks per week

Serum cacti.sol after dexamethasone (nmo~L)

> i0 0

23 I 139

2 O

406 326

2 0

2(}6 386

1 0

358 91

3 !

158 275

! 0

60 20

4 0

17 253

5 3

73 91

(see Table 2). Hence, our present finding of 16% nonsuppressors in the patient group is in line with previous investigations. In an attempt to disclose the determinants for a pathological DST in patients with panic attacks, postdexamethasone plasma cortisol levels were compared to the frequency of panic attacks and to the severity of baseline anxiety (as measured using HAS); however, neither of these two parameters correlated with the cortisol values. Thus, our present findings are in line with previous studies (Sheehan et al 1983; Coryell et al 1985; RoyByrne et al 1985; Faludi et al 1986; Judd et al 1987) indicating that the severity of illness is not a crucial factor with respect to cortisoi nonsuppression in PD patients. Also with respect to the occurrence of moderate depressive symptoms (as rated using MADS) no correlation with the outcome of the DST was found; again this finding is in line with previous studies (Sheehan et al 1983; Faludi et al 1986; Judd et al 1987). It should be pointed out, however, that no subjects with marked depressive symptomatology were included in the present investigation. In contrast to these negative findings, the comparison of PD patients with phobic avoidance with those without agoraphobia (as defined using the DSM-III-R criteria) revealed significantly higher cortisol levels in the former group, hence indicating that agoraphobia rather than the occurrence of panic attacks is associated with an inability to suppress cortisol release. Moreover, 9 out of 32 agoraphobic subjects but only one out

nmL PSVCmA~V

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Table 3. DST in Panic Disorder with or Without Agoraphobia Proportion of dexametha.__set~

Aulthors

PD with or without agoraplmbia

PD without ~. ag~ia

PD wi~.h agora~ 15% {|3) <~

Avery et al 1985 Bridges e! ai 1986 Bueno el al 1982 Coryell e| ai 1985 Coryeil el al 1989 Cottreaux el al 1984 Curtis el al 1982 Faludi el al 1986 Goldstein et al 1987 Grunhaus et al 1987

23% {35) 13% {15) 47% (15) 18% fSO) 26% (82) 20c~ (30) 0% {13) 17% (30) 13% (24) 75~ (8)

27% {22) ~

0% (6) 17% (23) "~ ~

~ (7*) 14% (7)

Judd et al 1987 Lieberman et al 1983

2 9 ~ (35) O ~ (I0) 10% (97)

~ 0 % {I0) --

2 9 % (35) --

Peterson et al 1985 Roy-Byrne et ai 1985 Sheehan el al 1983 Szid6czky el al 1986 Whiteford et al 1984 Total

38% 12% 35% 29%

(16) {51) (sO)

(21)

21% {572)

'~

~ 20% (49) ~

18% (50) 33% (33) 20%~ ( ~ )

'~

t@% (97") ~' 12% (51)

~ ~ 35% (40) ~

29% (21)

23% {150)

17% (323)

*Patients with other putative explanationsto a pathologicalDST {such as alcohol withdrawalor depression,)areexcluded.

of 31 nonagoraphobics displayed a pathological test result as defined by the 138 nmol/L cut-point. Previous studies on DST in PD patients have generally not provided any support for the assumption that agoraphobic patients more often display cortisol nonsuppression than do PD patients without agoraphobic behavior (see Table 3). However, the majority of these studies were not designed to address specifically the issue of a possible difference between agoraphobic and nonagoraphobic subjects; moreover, in most studies the number of subjects included has been considerably smaller than in the present investigation. interestin gly , in the iargest stu dy avauame u,om . ~. .v.,.a ~ ,~.^k:,. .vu.. . . . . ...... . . . .prc~:nung .. "~-- ~r""~'ldata ,.urn _ _ ~._.k and nonagoraphobic PD subjects, the rate of nonsuppressors was indeed somewhat larger among the agoraphobic subjects (33% versus 20%) (Coryell et al 1989). The concept of an overactivity in the hypothalamus-pituitm'y-adrenal (HPA) axis specifically associated to agoraphobia lends support also from studies by Kathol and co-workers (1988; 1989) sho~v,ng higher basal urinary cortisol levels in agoraphobic than in nonagoraphobic PD patients. The possibility that the difference between agoraphobic and nonagoraphobic PD patients with respect to postdexamethasone serum cortisol values in the present study is due to a difference in severity of anxiety rather than to the agoraphobia per se is refuted by the lack of correlation between plasma cortisol levels and the symptom rating (vide supra). BZD may influence the outcome of the DST (for ref see Weppner 1988); thus, the possibility that the intake of diazepam in some subjects has influenced the results obtained cannot be excluded. However, the consumption of BZD was similar in agoraphobic and nonagoraphobic subjects and could thus not explain the difference between

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groups. Moreover, only moderate doses of BZD, which should not be expected to interfere with the outcome of the DST, were allowed, and no correlation between diazepam intake and the outcome of DST was observed. In depressed patients, a pathological DST usually converts to normal on successful treatment with antidepressant drugs; hence, the DST is regarded as the prototype of a state dependent marker (Holsboer et al 1982; Maes et al 1986). In contrast, after three months of treatment with imipramine or clomipramine, a majority of these agoraphobic PD patients who displayed pathological DST results before medi~ation remained nonsuppressors in spite of the fact that they had dramatically improved with respect to frequency of panic attacks as well as baseline anxiety. Hence, the pathological DST observed in some PD patients with agoraphobia is obviously not secondary to the panic attacks; this conclusion is congruous with previous reports indicating that panic attacks per se do not elicit an increased activity of the HPA axis (Levin et al 1987). The lack of normalization of the DST in panic diso~er after successful drug treatment is also in line with a recent report by Coryell and co-workers (1989) showing similar DST results in PD patients before and during treatment with benzodiazepines (alprazolam or diazepam). When treating PD patients with antidepressants, it is well known that panic attacks disappear long before the agoraphobic behavior is fully remitted (Klein and Gorman 1987); indeed, although panic attacks and baseline anxiety were markedly reduced after 3 months of treatment, some patients still displayed some agoraphobic behavior at the time of the second DST. Thus, if elevated postdexamethasone cortisol levels are indeed specifically associated with phobic avoidance, the question of whether they constitute a state- or a trait~dependent marker warrants further investigations in which the slow declir,~ in agoraphobic behavior usually observed during long-term antipanic medication is compared with the outcome of repeated DSTs. In conclusion, the present data indicate that patients with panic attacks but without phobic avoidance do not differ from controls with respect to dexarnethasone-induced suppression of cortisol release. In contrast, agoraphobia appears associated with an HPA hyperactivity; to what extent this association is state or trait dependent should be the topic of further studies. This study was supported by grants from the Swedish Medical Research Council (04752 and 08668), the Swedish Society of Medicine, and by C1BA-GEIGY Pharma Division, Sweden.

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Curtis G, Cameron O, Nesse R (1982): The dexamethason¢ test in panic disorder ~ depressive disorder and agoraphobia. Am J P~chiat~ ,~ 139:1043-1~.

major

Eriksson E (1988): Biological markers in depression and panic disorder. In Svinkels .IA, Blijleven W (eds), Depression, a~t~ie~' and aggression. Houten, The Nether|ands: Medidact, pp 39-53. Faludi G, Kask6 M, Per6nyi A, Afar6 M, Eaton C (1986): The d e x ~ a s o n e test in panic di~rder and major depressive disorder. Biol Psychiat~" 21:1~8-10|4° Ganeilen RJ, Matutszas W, UhlenIuth EH, Glass R (1986): Panic disorder, agoraphobia and anxietyrelevants cognitive style. J Affect|re Disord I 1:219-225. Go|dstein S, Halbreich S, Asnis G, Endicott J, Alvir J ( 1987): The hypoth~c-pituitary-adrena| system in panic disorder. Am J P~'chiatry 144:1320-1323. Grunhaus L, Tiongco D, Haskett R, Greden .IF (1987): The dexan~t.hason¢ suppression test in inpatients with panic disorder or agoraphobia with panic attacks. Biol P~,chiatry 22:513-5 |7. Hiillstr6m T, Samuelsson S, Balldin .I, et al (1983): Abnormal dexamet.hasone suppression test in normal females. Br J Psychiatry 14:489-497. Holsboer F, Liebl R, Hofschuster E (1982): Repeated dexamethasone suppression test during depressive illness. J Affective Disord 4:93-101. .Iudd F, Norman G, Mclntyre I (1987): The dexamethasone suppression test m p ~ c disorder. Pharmacops). 'chiatry 20:99-101. Kathol RG, Noyes R, Lopez AL, Reich .IH (1988): Relationship of ~ free cot||sol levels in patients with panic disorder to symptoms of depression and agoraphobia. Psychiatry. Res 24:211221. Kathol RG, An|on R, Noyes R, Gehris T ( ! 989): Direct comparison of urinary free cortisol excretion in patients with depression and panic disorder. Biol Psychiatry 25:873-878. Klein DF, Gonnan JM (1987): A model of panic and agoraphobic development. Acta Psychiatr Scand 76:87-95. Levin AP, Doran AR, Liebowitz MR, et al (1987): P i t u i ~ adrenocorticfl unresponsiveness in lactate-inducod pa__~c. P~,chia~ Res 2!:23-32. Lieberman J, Brenner R, Lesser M, Coccaro E, Borenstein M, Kane J (1983): Dexanmthasone test in panic disorder patients. Am J Psychiatry 140:917-919. Maes M, DeRuyter M, Hobin P, Suy E (1986): Repeated dex~thasone suppression test in depressed patients. J Affect|re Disord 11 :|65-172. Modigh K (1987): Antidepressants in the treatment of p ~ c disorder Acta Psych|art Scand 76 (suppl 35): 57-71. Noyes R, Crowe R, Harris E, Hamra B, McChesney C, Chaudry D (1986): Relationship between panic disorder and agoraphobia. Arch Gen Psychiatry 43:227-232. Peterson GA, Ballenger JC, Cox DP, et al (1985): The dexamethasone suppression test in agoraphobia. J Clin Psychopharma:ol 5:!00-|03. Roy-Byrne P, Bierer L, Uhde T (1985): The dexamethasone test in panic disorder, comparison to normal controls. Bioi Psych|art) ' 2:1234-1237. Roy-Byrne PP, Uhde TW (1985): Pamc disorder and major depression: biological relationships. Psychopharmacol Bull 21:551-555.

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Sheehan D. Claycomb B, Surman O, Baer L, Coleman J, Gelles L (1983): Panic attacks and the dexame'hasone suppression test. Am J Psychiat~. 140:106. Sz:id6czky E, Rihmer Z, Arat6 M ( 1986): la~ue:~ce of hospital admission on DST results in patients with panic disorder. Am J Psychiatry 143:1315-1316. Weppner GJ (1988): The effect of benzodiazepine withdrawal on the dexamethasone suppression test. Acta Ps).,chiatr Scand 77:232-234. Whiteford HA, Evans L (1984): Agoraphobia and the dexamethasone suppression test: atypical depression? Aust NZ J Ps),chiatry 18:374-377.