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Plasma dexamethasone concentration and cortisol response during manic episodes
Plasma Dexamethasone Concentration and Cortisol Response during Manic Episodes Frederick Cassidy, James C. Ritchie, and Bernard J. Carroll Background: Despite the widespread study of the dexamethasone suppression test (DST) in patients diagnosed with majordepression, it has been less wellstudied during manic and mixed stoles of bipolar disorder. Methods: Cortisol response to the administration of 1 mg of dexamethasone was studied ill 44 patients diagnosed bipolar disorder, . mallie (n :=:: 37) or mixed (n :=:: 7). Dexamethasone levels and cortisol responses were compared between tl.ese groups. Four patients initially meeting criteria for bipolar disorder. mixed. and 7 patients initially meeting criteria for bipolar disorder, mallie. all of whom were cbaracterized as DST nonsuppressors, were retested after remission, Results: Dexamethasone levels were lower and cortisol levels higherill those patients diagnosed bipolar disorder. mixed. An inverse correlation was found between logtransformed dexamethasone levels and log-tran.iormed cortisol levels at 3 PM (r :=:: -.619. p :s; .001) and 10 PM (r :=:: -.501, p :s; .00l). In those subjects retested after remission, dexamethasone levels were higher and cortisol levels lower than during the manic and mixed states. Conclusions: Disturbances in the hypothalamic-pituitary-adrenal axis are observed frequeml» during mixed states of bipolardisorder, but are also not uncommon in purely manic episodes. These changes appear to be state dependent and revert with treatment. Bioi Psychiatry 1998;43:747-754 © 1998 Society of Biological Psychiatry Key Words: Mania, bipolar, cortisol dexamethasone, HPA,DST
Introduction he dexamethasone suppression test (DST) has been widely studied and clinically administered in patients diagnosed with depression (Carroll et al 1981; Glassman et al 1987). The DSThas been less wen studied, however,
T
From the Department of Psychiatry and Behavioral Sciences. Duke University Medical Center. Durham. North Carolina: andJohnUmstead Hospital. Butner, North Carolina. Address reprint requests to Dr. F. Cassidy. Box 3414, DukeUniversity Medical Center. Durham, NC 27710. Received June 12. 1996; revised April 26. 1997; accepted May9. 1997.
© 1998 Society of Biological Psychiatry
in manic states of bipolar disorder, despite the conclusion that it may assist in the differential diagnosis of mania from schizophrenia (Glassman et al 1987) and the recognition of high rates of depression noted during manic states of bipolar disorder (Winokur et al 1969; Goodwin and Jamison 1990; Cassidy et al, in press). Reported frequencies of abnormal DSTs in mania have ranged from o to 70% (Table 1). Comparisons of those studies are complicated, however, by methodological differences (e.g., dexamethasone dosage, time of blood sampling). Few studies have reported the relative representation of mixed and pure manic states, which might also explain wide differences in reported rates of nonsuppression.
The DST and the Mixed State Only four studies of the DST in mania have reported on the relative inclusion of mixed vs. pure manic states. Evans and Nemeroff (1983) studied 7 patients who met DSM-III criteria for bipolar disorder, mixed, and 3 patients who met criteria for bipolar disorder, manic, All 7 diagnosed bipolar disorder, mixed, were nonsuppressors, whereas the 3 diagnosed bipolar disorder, manic, were suppressors. Krishnan et al (1983) reported on 10 manic patients who were nonsuppressors, All had some depressive features to their illness based on retrospective chart review. Godwin (1984) reported on 35 subjects who met DSM-III criteria for bipolar disorder, manic, and 5 subjects who met DSM-III criteria for bipolar disorder, mixed. The nonsuppression rate was60% for both groups. More recently Swann et al (1992) studied 16 drug-free manics, collecting cerebrospinal fluid (CSF) cortisol, urinary free cortisol, morning and evening cortisol, and postdexamethasone cortisol at 8:30 AM, 4:00 PM, and 10 PM. Theyreported highermorning andpostdexamethasone morning serum cortisols,as well as CSFcortisols, in those patients diagnosed with mixed mania using the criteria of an Affective Disorder Rating Scale score z 3 (Murphy et al 1982) and a Hamilton Depression Rating Scale> 15 (Hamilton 1960). They reported that 3 of 9 manics and 5 of 7 mixed manics were nonsuppressors at 8:30 AM after I mgdexamethasone overnight, in keeping with the growing consensus that positive DSTs are not specific to mixed manic states (Goodwin and Jamison 1990). 0006-3223/98/$19.00 PH S0006-3223(97)00274-6
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Table I. Frequencies of Abnormal DSTs during Manic Slates
Study Schlesser cl al (/9 KO) Hwu c l al (1987) Hwu and Lin (1990) Baumgartner Cl al (1986a) Kiriikc ct al (! ( 88) Hunt ct al (1989) Graham et al (/982) Slakes C( al (1984) and SW;J,Jlll et al (1992) Schmider et al ( )995) Godwin (1984) Rihmcr et al (! 983) Poirier ct al (1978) Evans and Nemeroff (19IlJ) Krishnan et al (1983) Copolov ct al (1989) CUITCI1l study data
1/
Frequency of DST nunsuppresslon in patients diagnosed with mania
71 %
ADRS score ;?: 3 and HDRS :> IS
60'i!-
60%
DSM·III
0'70
100% 100%"
43%
86%
19% JJ'il,"
-14 C/r 45'h,
50
46';~/'
16
50%
II
55%
40
60%
1(, 13 10 10 15
63% 69'7r
44
i ) <:;
12th-
IY
\I
Criteria for mixed mania
0%
(d
12 21 3
"pure" mania
Frequency of DST nonsupprcssion in patients diagnosed with "mixed" mania
Frequency of DST nonsupprcssion in patients diagnosed with
70'~'
DSM·III All had some dysphoric features
.1
50'7,
DSM·I/I·R
ADRS. Mfecli,'c Disorder Raring Scale: I!DRS. Hamill"n Deprcssinn Ralinf Scale. "The 2 patients who were inilially suppressing, switched to nonsupprcssing when fnllowed Inngitudinally. "Include" p'Jlienl, diagnosrcl "hj LOa rf~C1 i l'e disorder, manic lype. 'This study retrospectively reviewed Icaiurcsor mixed states ill p:Uient, who werenonsupprcssors. "Iligh rates or salivary enni", ' fnllnwing dcxumcthasonc administration were reponed, but are diflicull to directly compare withthe Mandnrdizcd DST'.
Dexamethasone Metabolism There has been increasing recognition of the importance of variability in dexamethasone metabolism for DST results. Age (Groden cr al 1986; Hunt et al 1989; Ritchie et al 1990b; Maes ct al 1990), sex (Tsuei cr al 1987; Baumgartner et al 1986b). and concurrent drug administration (Brooks ct al 1972; Haque ct al 1972; Meikle [982; Privitera et al 1982) may each affect dexamethasone metabolism. Some groups have reported lower dexamethasone levels in nonsuppressors in both depression (Hotsboer et al 1984, 1986a; Wiedemann and Holsboer 1987; Poland et al 1987; Maguire et al 1987; O'Sullivan et al 1989; Asnis et al 1989; Carson et al 1988; Maes et al 1990; Guthrie et al 1990) and across diagnostic lines (Arana et al 1984; Berger et al 1984; Johnson et al 1984; Morris et al 1986: Carr et al 1986). Others have not confirmed those dif.erences (Ritchie et ul 1990a; Maguire et al 1990). Baumgartner ct al (l986b) found a negative correlation between dexamethasone and cortisol levels in 12 schizophrenics and 3 manics ( r = - .63, df = 13. P < .0 I), but not in 34 depressives (I' = -. [ I, df 32, ns), Nonsignificant trends for [ower mean dexamethasone levels in endogenous/melancholic depressives compared to reactive/neurotic depressives have been reported (Carroll et al 1980; Maguire et al 1990). Differences in dexamethasone metabolism may also be state-dependent. Holsboer et al (1986b), Baumgartneret al (I 986b), and Maguire et al (1990) have reported that
plasma dexamethasone levels in the DST may rise with treatment. Poland et al (1 988) and Carroll et al (l980 ). however, found no change. The importance of dexamethasone levels prompted two groups independently to define dexamethasone "windows" for each postdexarnethasone collection point(Johnson et al 1984; Ritchie et al 1990a). Only those cortisol values with concurrent dexamethasone values falling within the defined "window" are considered valid.
Methods and Materials A DST (Carroll ct al 198I) was performed on 46 patients admitted to John Umstead Hospital who met DSM·III-R criteria fur a diagnosis of bipolar disorder, manic 01' mixed. On the day following the administration of 1 mg of dexamethasone at 10 PM, serum was collected at 3 PM and 10 I'M for determination of cortisol levels. Concurrent dexamethasone Icvcls were determined to verify if they fell within the windows set by Ritchie et aI (1990a). These arc defincd as a 3 PM dexamethasone level between 0.34 and 1.67 ng/mL and a 10 PM dexamethasone level between 0.10 and 0.91 nglmL. Exclusion criteria for valid DSTs were as listed by Carroll (1 984). In particular, patients were not concurrently treated with benzodiazepines or anticonvulsants. Patients were evaluated for manic symptomatology using a newly developed symptom rating instrument comprising 15 classical signs and symptoms of mania and five signs and symptoms of "mixed" mania (Cassidy et al, in press). Subjects were monitored clinically during the DST to assure they re-
DST in Bipolar Disorder
maincd manic. Those who did not (II = 2) were excluded from the analysis. Dexamethasone was administered on average onthe fourth to fifth hospital day (range 2nd-11th day). Nonsuppressing DSTs during mania were repeated following remission of manic symptoms to assess reversion. Patients treated with carbamazepine, a known source of false-positive DSTs (Privitera et al 1982). were excluded. Dexamethasone and cortisol assays were performed as previously described (Ritchie ct al 1990a). The coefficients of variation for the cortisol assay are 12.6% (intcrassay) and 6.4% (intraussay) for a cortisol-poor sample (2.6 I1g/dL), and 8.9% (intcrassay) and 5.6% dntraassay) for a cortisol-rich sample (10.15 IJ.g/dL). Theminimal detectable quantity of cortisol in the assay is 1.0 IJ.g/dL. The coefficients of variation for the dexamethasone assay at a level of0.52 ng/ml, arc 8% (intcrassay) and 4% (intraassay). The minimal detectable quantity of dcxarncthasonc in the assay is 0.02 nglmL. DSTs were characterized as nonsuppressing if either postdexamethasonc cortisol level was greater than 5 IJ.gldL. Therelationship between DSTstatus anddiagnosticgroup (bipolar disorder. manic or mixed) was analyzed with the Fisher Exact Test. Cortisol and dexamethasone levels were log-transformed because of inhomogeneity of variance, and differences were analyzed between those patients who met criteria for bipolar disorder, manic. and those patients who met criteria for bipolar disorder, mixed, using f tests. Differences between prc- and posttreatment Iog-transformed cortisol anddexamethasone levels were analyzed for those patients studied during mania and in remission using paired t tests. Pearson correlation coefficients were calculated for the log-transformed dexamethasone and log-transformed cortisolvalues foreach of thetime points within the entire cohort. A multiple regression analysis was conducted and partial correlations calculated to assess any interaction of age. sex, race. or body mass index with the cortisol and dexamethasone levels. Manic severity scores were calculated by determining the total of individual item scores from the mania rating instrument employed, excluding "mixed" signs and symptoms (depressed mood, lability, suicidality, anxiety. and guilt). The interrater reliability and validity of the scale is presented elsewhere (Cassidy et al, in press). In addition. a depressive subscalc comprising mixed signs and symptoms was defined as the sum of scores for dysphoric mood. lability. suicidality, anxiety. and guilt. Selection of which signs and symptoms to include was based on a previous factor analysis of manic signs and symptoms (Cassidy et al 1998). Severity and depressive subscale scores for the manic and mixed groups were compared with tests. Pearson correlation coefficients were also calculated to lest for an interaction of manic and depressive severity and cortisol and dexamethasone levels.
Results Patient Demographics Forty-six patients were diagnosed bipolar disorder, manic or mixed. Two patients had spontaneousremissions during
mOL PSYCHIATRY 19 9H ;4~ ;747-754
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the OST and were removed from the evaluation. Of the remaining 44 patients, 37 (84%) met DSM-IlI-R criteria for bipolar disorder, manic, and 7 (16%) for bipolar disorder, mixed, This is similar to the proportion of patients diagnosed bipolar disorder, manic and mixed, in our hospital (Cassidy et al 1997). Forty-three concurrent dexamethasone and cortisol levels were collected at 3 PM, and 42 at 10 PM, Results for I patient at 3 PM and 2 patients 10 PM were not obtained because of difficulties with phlebotomy or processing errors. The mean age of the patients diagnosed bipolar disorder. manic (38.5. SD 17.5) and those diagnosed bipolar disorder, mixed (46.1, SD 15.6) did not differ significantly (I = - 1.141, df = 42, P = .260). The sample comprised 17 blacks and 27 whites. Two male and 5 female subjects met criteria for bipolar disorder. mixed. and 23 male and 14 female subjects met criteria for bipolar disorder, manic. Mean mania severity scores for those patients diagnosed bipolar disorder, mixed (28.1, SD 9.8), and those diagnosed bipolar disorder, manic (32.2. SD 8.5). did not differ significantly (t = -1.145, df = 42. P = .259). As expected, differences in the depressive subscale scores between those patients diagnosed bipolar, manic (3.1 . SD 3.1). and those diagnosed bipolar, mixed (J2.J, SD 2.9), were significant (t = 7.077, df = 42, p < .001). Repeat DSTs were performed on I I nonsuppressors after recovery to assess reversion. These included 4 subjects initially diagnosed bir~lar disorder, mixed, and 7 subjects initially diagnosed b:.. Jar disorder. manic, Seven were female and 4 male, Eil,. ·.1 were white and 3 black. Their mean age was 42.3 (SD 17.0).
rhe DSr Sixteen of the 37 (43%) patients diagnosed bipolar disorder. manic, had one or both of the postdexamethasone cortisol samples greater than 5 IJ.g/dL and were characterized as nonsuppressors. Using the same criteria, 6 of the 7 (86%) patients diagnosed bipolar disorder, mixed, were also characterized as nonsuppressors. The Fisher Exact Test was significant for an association between DST status and diagnosis (p = .047). Log-transformed cortisol levels were significantly higher in those patients who met criteria for bipolar disorder, mixed. compared with those patients who met criteria for bipolar disorder, manic at 3 PM (t = 3.420, df = 4 I, p :S ,DO1) and 10PM (r = 2.207. df = 40. P :S .05) lime points (Figure 1). Means and standard deviations are given :0Table 2. Dexamethasonelevels were significantly lower in those patients who met criteria for bipolar disorder, mixed, at both 3 PM (t = -3.179, df = 41,p:S .005) and IO PM (t = -2.453, df = 40, P :S .02). Pearson correlation coefficients between log-transformed dexamethasone and
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Figure I. Cortisol <....gldL) and dexamethasone (pg/mL) levels at 3 and 10 PM for patients diagnosed bipolar disorder, manic, and bipolar disorder, mixed. Horizontal lines indicate eitherthreshold for cortisol escape or the defined dexamethasone window.
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OST in Bipolar Disorder
T(,1]c 2. Demographics and Mean Severity Scores and Cortisol (f.lgldL) and Dexamethasone (pg/mL) Levels for Patients Diagnosed Bipolar Disorder, Manic, and Bipolar Disorder. Mixed
Age (years) Weight (kg) Manic severity score Depressive subscale score 3 PM cortisol (llg1dL) 3 PM dexamethasone
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46.1 (15.6, 18-77) 77.4(15.3. 53.6--112.3) 32.2(8.5, 14-53) 3.1 (3.1.0-12)
38.5 (17.5, 20-73) 70.1 (15.1.47.7-88.2) 28.1 (9.8.19-45) 12.1 (2.9.9-17)
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ity and log-transformed dexamethasone levels were not significant at either time point. In contrast, there was a negative correlation between thedepressive subscale score and log-transformed dexamethasone level at 3 PM (r =: -.518. df =: 42, p < .001) and 10 PM (r =: -.394. df = 41, p < .01), and a positive correlation between the depressive score and the log-transformed cortisol level at 3 PM (r = .453, df =: 42. p = .002). A trend wasnoted for a positive correlation between the depressive subset score and the log-transformed cortisol levels at 10 I'M (r = ,286. df =: 41. p = .067). Body mass index, age, race, and sex did not have significant partial correlations with the hormonal measures. At 3:00 PM five of the seven plasma dexamethasone concentrations of those patients who met criteria for bipolar disorder, mixed. were below the defined window. Two were within the window. Similarly, at 10:00 PM three of the five values were below the defined window. Two were within the window. Among samples from those patients who metcriteria for bipolar disorder. manic, 25 of 36 samples collected at 3:00 PM fell within the defined windows. Of those I I that did not, four fell above and seven below the defined window. Similarly. 28 of 37 10:00 PM plasma dexamethasone values for those patients whometcriteria for bipolar disorder, manic, fell within the window. Three additional values fell above the window, and six below. A Fisher Exact Test was conducted comparing the number of samples below the window versus the number within or above thewindow during manic and mixed states. Five of the 7 (71 %) 3 PM samples of those patients diagnosed bipolar. mixed, were below the window. In contrast only seven of the 36 (19%) 3 PM samples of those patients diagnosed bipolar manic, werebelow the window. Likewise. three of the 5 (60%) 10 PM samples
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Figure 2. Cortisol (jJ..g/dL) vs, dexamethasone (pg/mL) levels at 3 PM and 10 PM for patients diagnosed bipolar disorder. manie (circles), and bipolar disorder. mixed (small diamonds). The horizontal lines indicate threshold for cortisol escape. The vertical lines indicate the dexamethasone window.
werebelow thedefined window in thebipolar mixed group, whereas only sixof 37 (16%) 10 PM samples were below the window in the bipolar manic group. The Fisher Exact Test was significant at 3 PM (p = .012) and showed a trend for significance at 10 PM (p = .057). Six of 11 nonsuppressing DSTs repeated to assess
752
IlIOL I'SYClIIATRY
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1998:43:7~7-7.'i4
reversion were suppressing. Paired 1 tests were significant for a decrease in cortisol levels at 3 PM (r :::: 2.897. df :::: 10, P :5 .02) and 10 PM (r = 6.414, df :::: 9, p :5 .001) following remission. Six of the eight 3 PM dexamethasone levels that fell below the window during the manic or mixed state, fell within the window at remission, while two remained below the window. The three that were within the window remained within the window. All five of the 10 PM dexamethasone levels that fell below the window during the manic or mixed state were within the window during remission. Two levels within the window during the manic slate fell below the window during remission, and three remained within the window, A Fisher Exact Test wasconducted comparing the number of samples below the window versus the number within or above the window. during the manic or mixed state and after remission, and was significant at 3 PM (p :::: .02) but not at 10 I'M (p :::: .175). Paired 1 tests were significant for an increase in dexamethasone levels at both 3 PM (I :::: -2.781, df:::: IO, P :5 .02) and 10 PM (I :::: -2.417, df :::: 9, P $ .05) following remission.
Discussion Our results are consistent with the studies we reviewed (Table I) and the conclusion of Goodwin and Jamison (J 990) that abnormal DSTs arc significantly more common in mixed manic states but not uncommon in pure manic states. Although the size of this mixed bipolar sample is small, thesedata indicate that patients who meet DSM-IlI-R criteria for bipolar disorder, mixed, have a high rate of DST nonsuppression (86% in our sample). Patients whomeet DSM-IIl-R criteria for bipolar disorder, manic, also have a nontrivial rate of escape (43% in our sample). The combined rate of nonsuppression in our sample was SQlfi., in keeping with those studies reviewed (Table I). These data also confirm the variability of dexamethasane levels among patients and the inlluence of this variation on cortisol suppression during the DST, as shown in Figure 2. Use of dexamethasone windows was suggested to take into account variability of hepatic metabolism and thereby provide more valid interpretation of DST cortisol results. While lower dexamethasone levels have been reported by some groups in nonsuppressors, an adequate explanation of this finding has never been established. There is direct and indirect evidence that differences in dexamethasone metabolism may relate to the particular diagnostic state. First. it is well established that patients diagnosed withmajordepression havehigherratesof nonsuppression thancontrols (Carroll et al 1981), and there are indications that nonsupprcssion may be associated with lower dexa-
mcthasone levels as reviewed above. Taken together, these observations are compatible with the hypothesis that patients diagnosed with major depression may have lower dexamethasone levels following its administration. Second, some of those studies we reviewed above have reported nonsignificant trends for lower dexamethasone levels in patients withendogenous depression compared to neurotic depression. Third,as previously noted, dexarncthusone levels may change in a state-dependent fashion within the same patient. Possible explanations for such state-dependent changes havebeen rarely offered. Holsboer et al (I986a)suggested a possible induction of hepatic enzymes in response to stress and hypcrcortisolernia, An alternate explanation focuses on directcentral nervous system (CNS) control of hepatic metabolism. Gustafsson et al (1980) suggested that a region of the brain including the anteriorperiventricular hypothalamic area and the suprachiasmatic nucleus are involved in hepatic steroid metabolism in male rats. Similar CNS-hepatk interactions have been studied and reviewed by Waxman (1988). Holsboer et al (1986b) also noted reports that the pituitary-adrenocortical unit influences several peripheral enzymes and suggested that exaggerated activity of the pituitary-adrenocortical unit mayaffectthose enzymes that metabolize dexamethasone. Our data are compatible with the view that dexamcthasone levels may vary in a state-dependent manner. Those patients who met criteria for bipolar disorder, manic, had higher dexamethasone levels than those diagnosed with bipolar disorder, mixed (Figure I). Dexamethasone levels tended to be the same or higher following remission of signs and symptoms of mania in those subjects who were initially nonsuppressors when compared with their initial levels. These increases corresponded with decreases in concurrent cortisol levels. A large number of dexamethasane levels in those patients who met criteria for bipolar disorder. mixed, were below the defined windows at 3 PM (II ::: 5 of?) and 10 PM (n ::: 3 of 5). again emphasizing the importance of dexamethasone levels. State-dependent alterations in dexamethasone metabolism arc potential confounds in the study of central hypnthalamic-pituirary-adreual (HPA) overdrive in affective disorders. The initial standardization of the DST was based on cortisol determinations following a l-mg dose of dexamethasone. Whether this disturbance results from purely central HPA overdrive, or a combination of this and secondary changes in dexamethasone metabolism, has littlebearing on the clinical application of the test,The use of dexamethasone windows (Johnson et al 1984; Ritchie et al 1990a), however, may provide a more direct view of central HPA suppression by controlling for the confound of peripheral dexamethasone metabolism. Furtherresearch
DST in Bipolar Disorder
mOL PSYCHIATRY 1998;43:747-754
studies arc indicated that focus directly on central HPA function. Supported in part by 5P3aMH4al59 and Raj MH39593 from NIMH.
References Arana GW. Workman Rl, Baldessarini Rl (1984): Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasone. Am J Psychiatry 141:1619-1620. Asnis GM, Harkavy Friedman 1M, Miller AH, Iqbal N, La ES, Cooper TB,ct al (1989): Plasma dexamethasone and cortisol levels in depressed outpatients. J Affec: Disord 16:5-10. Baumgartner A, Gruf K-l, Kurten I (l986a): Serial dexamethasonesuppression tests in psychiatric illness: PartI. A study in schizophrenia and mania. Psychiatry Res 18:9-23. Baumgartner A, Haack D, Vecsei P (l986b): Serial dexamethasone suppression test in psychiatric illness: Part III. The influence of intervening variables. Psychiatry Re.I' J 8:45-64. Berger M,Pirke K·M, Doerr P, Krieg 1-C, von Zerssen 0 (1984): The limited utility of the dexamethasone suppression test for the diagnostic process in psychiatry. Br J Psychiatry 145: 372-378. Brooks SM, Werk EE, Achennan Sl, Sullivan I, Thrasher K (1972): Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma. N Engl J Med 186:1125-1128. Carr V, Morris H, Gilliland 1 (1986): The effect of serum dexamethasone concentration in the dexamethasone suppression test. Bioi Psychiatry 21:735-743. Carroll Bl (1984): Dexamethasone suppression test. In: Hall RCW, Beresford TP, editors. Handbook l~r Psychiatric Diagnostic Procedures. New York: Spectrum Publication, pp 3-27. Carroll Bl, Schroeder K, Mukhopadhyay S, Greden lF, Feinberg M, Ritchie J, et al (1980): Plasma dexamethasone concentrations and cortisol suppression response in patients with endogenous depression. J cu« Endocrinol Ml'tab 51 :433437. Carroll Bl, Feinberg M, Greden lr, Tarika J, Albala AA, Haskell MB, et al (198\): A specific laboratory test for the diagnosis of melancholia. Arch Gel/ Psychiatry 38:15-22. Carson SW,Halbreich U. Yeh CM,Asnis G, Goldstein S (1988): Cortisol suppression per nanogram per milliliter of plasma dexamethasone in depressive and normal subjects. Bioi Psychiatry 24:569-577. Cassidy F, Murry E, Forest K, Carroll Bl (in press): Signs and symptoms of mania in mixed and pure episodes. J Affect Disord. Cassidy F, Forest K. Murry E, Carroll Bl (1998): A factor analysis of signs and symptoms in mania. Arch Gel/ PSyclliairy 55:23-32. : Cassidy F, Murry E, Forest K, Carroll 81 (1997): The performance of DSM·JII-R major depression criteria in the diagnosis of bipolar mixed states. J Affecl Disord47:79-81. Copolov DL, Rubin RT, Stuart GW, Poland RE, Mander Al,
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Sashidharan SP, et al (1989): Specificity of the salivary cortisol dexamethasone suppression test across psychiatric diagnoses. Bio! Psychiatry 25:873-879. Evans DL, Nemeroff CB (1983): The dexamethasone sU7'ljlrc~ sion testin mixed bipolar disorder. Am J Psychiatry I ~'. ' ,5· 617. Glassman AH, Arana GW, Baldessarini Rl, Brown WA, Carroll Bf, Davis JM, et al (APA Task Force 011 Laboratory Test in Psychiatry) (1987): The dexamethasone suppression test: An overview of its current status in psychiatry. Am J Psychiatry 144:1253-1262. Godwin CD (1984): The dexamethasone suppression lest in acute mania. J Ajjl'ct Disord 7:281-286. Goodwin FK, Jamison KR (1990): Manic-Depressive lllness. Baltimore: Williams & Wilkins. Graham PM, Booth 1, Boranga G, Galhenage S, Myers CM. Teoh CL,et Jl (1982): Thedexamethasone suppression test in mania. J Affect Disonl 4:201-211. Greden IF, Tiongco D, Haskett RF, Grunhaus L, Kotum 1 (1986): Interactions between depression and aging in HPA dysregulation. 41st Annual meeting of the Society of Biological Psychiatry, Abstract #155. Gustafsson I-A, Eneroth P, Hoekfell T, Mode A. Norstredt G, Skeu P (1980): Central control of hepatic steroid metabolism and "lactogenic" receptor. J Steroid Biochem 12: 1-15. Guthrie SK, Vartanian L, Grunhaus L, Hariharan M, Pande A, Haskett RF (1990): A longitudinal evaluation of dexamethasoneandcortisol plasma concentration in thedexamethasone suppression test before andduring treatment with antidepressant drugs. Acta Psychiatr Scand 82:427-432. Hamilton M (1960): A rating scale for depression. J Neurol Neurosurg Psychiatr» 23:56-62. Haque N, Thrasher K, Werk E. Knowles H, Sholiton 1 (1972): Studies on dexamethasone metabolism in man: Effect of diphenylhydantoin. J cu« Elldocrillol34:44-51. Ho!sboer F, Haack D, Gerken A. Vccsei P (1984): Plasma dexamethasone concentrations and differential suppression response of cortisol and corticosterone in depressives and controls. Bioi Psychiatry 19:281-291. Holsboer F, Wiedemann K, Boll E (l986a): Shortened dexamcthasone half-life in depressed dexamethasone nonsuppressol's. Arch Gen Psychiatry 43:813-815. Holsboer F, Wiedemann K, Gerken A, Boll E (1986b): The plasma dexamethasone variable in depression: Test-retest studies and early biophase '
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Kiriike N, lzumiya Y, Nishiwaki S. Maeda Y, Nagata T, Kawakita Y (1988): TRH test and DST in schizoaffectlve mania, mania and schizophrenia. Bioi Psychiatry 24:415422. Krishnan RR. Maltbie AA. Davidson RT (1983): Abnormal cortisol suppression in bipolar patients with simultaneous manic and depressive symptoms. Alii .I Psychiatty 140:203205. Maes M, Jacobs M-P, Suy E, Minner B, Rnus J (1990): Prediction of the DST results in depressives by means of urinary-free cortisol excretion, dexamethasone levels andage. Bioi Psychiatry 28:349-:157. Maguire KP, Schweitzer I. Biddle N. Bridge S, Tiller JWG (1987): The dexamethasone suppression test: Importance of (:examethasone concentrations. Bioi Psychiatry 22:957-967. Maguire KP, Tuckwell VM. Schweitzer I. Tiller JWG, Davies BM (1990): Dexamethasone kinetics in (kpressed patients before andafterclinical response. Psychoneuroendocrinology 15: 113-123. Meikle AW (1982): Dexamethasone suppression tests: Usefulness of simultaneous measurement of plasma cortisol and dexamethasone. Clill Endocrinol 16:401-408. Morris H,Carr V, Gilliland J, Hooper M (1986): Dexamethasone concern rations and the dexamethasone suppression test in psychiatric disorders. BI' J Psychiatry 148:66-69. Murphy DL, Pickar D, Aiierman IS (1982): Methods for the quantitative assessment of depressive andmanic behavior. In: Burdock EI,Sudilovsky A, Gershon S. editors. The Behavior of Psychiatric Patients.' Quantitative Techniques for Evaluatlon. New York: Marcel Dekker, pp 355-392. O'Sullivan BT, HuntGE, Johnson GF,Caterson ID (1989): The plasma dexamethasone window: Evidence supporting its usefulness to validate dexamethasone suppression testresults. Bioi Psychiatry 25:739-754. Poirier MF, Leo H, GayC. Del.uca HS (1978): Confirmation of abnormal DST results in manic patients. Am J Psychiatry 142:888. Poland RE, Rubin RT, Lesser 1M, Lane LA, Hart PJ (/987): Neuroendocrine aspects of primary endogenous depression: II. Serum dexamethasone concentration and hypothalamicpituitary-adrenal cortical activity as determinants of the dexamethasone suppression test response. Arch Gen Psychiatry 44:790 -795. Poland RE, Rubin RT. LeS,CI' 1M (1988): Serum dexamethasone
concentrations in endogenous depressives before, during and after treatment: Preliminary observations. Bioi Psychiatry 23:705-710. Privitera MR, Greden JF, Gardner RW, Ritchie JC, Carroll BJ (1982): Interference by carbamazepine with the dexamethasone suppression test. Bioi Psychiatry 17:611-619. Rihmer Z, Arato M, Gaszner P (1983): The dexamethasone suppression lest in manic-depressive and schizouffective patients. In: Pichot P, editor. Proceedings of the 7tl, World Congress of Psychiatry. New York: Plenum Press. Ritchie JC, Belkin BM,Krishnan KRR, NemeroffCB, Carroll BJ (1990a): Plasma dexamethasone concentrations and the dexamcthasone -unprcsslon test. Bioi Psychiatry 27:159-173. Ri'chie JC. Scot.h BS, Nemeroff CB, Carroll BJ (19';.lOb): The effect of age on DST status and plasma dexamethasone concentration in depressed patients. Bioi Psychiatry 27(suppl 9A):45A-46A. Schlesser MA, Winokur G. Sher-san 8M (1980): Hypothalamicpituitary-ndrenal axis activit> in depressive illness. Arch Gen P8)'clliarry 37:737"':143. Schmidcr J, Lammers C·H, Gotthardt U, Dettling M, Holsboer F, Heuser JE (1995): Combined dexamethasone/corticotropinreleasing hormone test in acute and remitted manic patients, in acutedepression, and in normal controls: I. BioiPsychiatry 38:797-802. Stokes PE, Stoll PM. Koslow SH, Maas JW. Davis JM. Swann AC. et al (1984): Pretreatment DST and hypothalamicpi tuitary-adrenal function in depressed patients and comparison groups. Arch Gen Psyclriatry 41 :257-267. Swann AC, Stokes PE, Secunda SK. Bowden CL, Berman N. Katz MM, et al (1992): Hypothalamic-pituitary-adrenocortical function in mixed and pure mania. Acta Psychiatr Sca/1{1 8~;;270-274.
Tsuei SE, Moore RO, Ashley JJ. Mcllridc WG (1987): Disposition of synthetic giucocorticoids: I. Pharmacokinetics of dexamethasone in healthy adults, J Pharmacokinet Biopharm 7:249-264. Waxman DJ (1938): Interactions of hepatic cytochromes P-450 with steroid hormones. Biochem Plrarmaco/37:71-84. Wiedemann K, Holsboer F (1987): Plasma dexamethasone kinetics during the DST after oral and intravenous administration of the test drug. Bioi Psychiatry 22:1340-1348. Winokur G, Clayton PJ, Reich T (I 969}: Mallie Depressive lllness. 51. Louis: Mosby.
Introduction he dexamethasone suppression test (DST) has been widely studied and clinically administered in patients diagnosed with depression (Carroll et al 1981; Glassman et al 1987). The DSThas been less wen studied, however,
T
From the Department of Psychiatry and Behavioral Sciences. Duke University Medical Center. Durham. North Carolina: andJohnUmstead Hospital. Butner, North Carolina. Address reprint requests to Dr. F. Cassidy. Box 3414, DukeUniversity Medical Center. Durham, NC 27710. Received June 12. 1996; revised April 26. 1997; accepted May9. 1997.
© 1998 Society of Biological Psychiatry
in manic states of bipolar disorder, despite the conclusion that it may assist in the differential diagnosis of mania from schizophrenia (Glassman et al 1987) and the recognition of high rates of depression noted during manic states of bipolar disorder (Winokur et al 1969; Goodwin and Jamison 1990; Cassidy et al, in press). Reported frequencies of abnormal DSTs in mania have ranged from o to 70% (Table 1). Comparisons of those studies are complicated, however, by methodological differences (e.g., dexamethasone dosage, time of blood sampling). Few studies have reported the relative representation of mixed and pure manic states, which might also explain wide differences in reported rates of nonsuppression.
The DST and the Mixed State Only four studies of the DST in mania have reported on the relative inclusion of mixed vs. pure manic states. Evans and Nemeroff (1983) studied 7 patients who met DSM-III criteria for bipolar disorder, mixed, and 3 patients who met criteria for bipolar disorder, manic, All 7 diagnosed bipolar disorder, mixed, were nonsuppressors, whereas the 3 diagnosed bipolar disorder, manic, were suppressors. Krishnan et al (1983) reported on 10 manic patients who were nonsuppressors, All had some depressive features to their illness based on retrospective chart review. Godwin (1984) reported on 35 subjects who met DSM-III criteria for bipolar disorder, manic, and 5 subjects who met DSM-III criteria for bipolar disorder, mixed. The nonsuppression rate was60% for both groups. More recently Swann et al (1992) studied 16 drug-free manics, collecting cerebrospinal fluid (CSF) cortisol, urinary free cortisol, morning and evening cortisol, and postdexamethasone cortisol at 8:30 AM, 4:00 PM, and 10 PM. Theyreported highermorning andpostdexamethasone morning serum cortisols,as well as CSFcortisols, in those patients diagnosed with mixed mania using the criteria of an Affective Disorder Rating Scale score z 3 (Murphy et al 1982) and a Hamilton Depression Rating Scale> 15 (Hamilton 1960). They reported that 3 of 9 manics and 5 of 7 mixed manics were nonsuppressors at 8:30 AM after I mgdexamethasone overnight, in keeping with the growing consensus that positive DSTs are not specific to mixed manic states (Goodwin and Jamison 1990). 0006-3223/98/$19.00 PH S0006-3223(97)00274-6
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11101. PSYCHIATIl T' IWH:4J:747-754
Table I. Frequencies of Abnormal DSTs during Manic Slates
Study Schlesser cl al (/9 KO) Hwu c l al (1987) Hwu and Lin (1990) Baumgartner Cl al (1986a) Kiriikc ct al (! ( 88) Hunt ct al (1989) Graham et al (/982) Slakes C( al (1984) and SW;J,Jlll et al (1992) Schmider et al ( )995) Godwin (1984) Rihmcr et al (! 983) Poirier ct al (1978) Evans and Nemeroff (19IlJ) Krishnan et al (1983) Copolov ct al (1989) CUITCI1l study data
1/
Frequency of DST nunsuppresslon in patients diagnosed with mania
71 %
ADRS score ;?: 3 and HDRS :> IS
60'i!-
60%
DSM·III
0'70
100% 100%"
43%
86%
19% JJ'il,"
-14 C/r 45'h,
50
46';~/'
16
50%
II
55%
40
60%
1(, 13 10 10 15
63% 69'7r
44
i ) <:;
12th-
IY
\I
Criteria for mixed mania
0%
(d
12 21 3
"pure" mania
Frequency of DST nonsupprcssion in patients diagnosed with "mixed" mania
Frequency of DST nonsupprcssion in patients diagnosed with
70'~'
DSM·III All had some dysphoric features
.1
50'7,
DSM·I/I·R
ADRS. Mfecli,'c Disorder Raring Scale: I!DRS. Hamill"n Deprcssinn Ralinf Scale. "The 2 patients who were inilially suppressing, switched to nonsupprcssing when fnllowed Inngitudinally. "Include" p'Jlienl, diagnosrcl "hj LOa rf~C1 i l'e disorder, manic lype. 'This study retrospectively reviewed Icaiurcsor mixed states ill p:Uient, who werenonsupprcssors. "Iligh rates or salivary enni", ' fnllnwing dcxumcthasonc administration were reponed, but are diflicull to directly compare withthe Mandnrdizcd DST'.
Dexamethasone Metabolism There has been increasing recognition of the importance of variability in dexamethasone metabolism for DST results. Age (Groden cr al 1986; Hunt et al 1989; Ritchie et al 1990b; Maes ct al 1990), sex (Tsuei cr al 1987; Baumgartner et al 1986b). and concurrent drug administration (Brooks ct al 1972; Haque ct al 1972; Meikle [982; Privitera et al 1982) may each affect dexamethasone metabolism. Some groups have reported lower dexamethasone levels in nonsuppressors in both depression (Hotsboer et al 1984, 1986a; Wiedemann and Holsboer 1987; Poland et al 1987; Maguire et al 1987; O'Sullivan et al 1989; Asnis et al 1989; Carson et al 1988; Maes et al 1990; Guthrie et al 1990) and across diagnostic lines (Arana et al 1984; Berger et al 1984; Johnson et al 1984; Morris et al 1986: Carr et al 1986). Others have not confirmed those dif.erences (Ritchie et ul 1990a; Maguire et al 1990). Baumgartner ct al (l986b) found a negative correlation between dexamethasone and cortisol levels in 12 schizophrenics and 3 manics ( r = - .63, df = 13. P < .0 I), but not in 34 depressives (I' = -. [ I, df 32, ns), Nonsignificant trends for [ower mean dexamethasone levels in endogenous/melancholic depressives compared to reactive/neurotic depressives have been reported (Carroll et al 1980; Maguire et al 1990). Differences in dexamethasone metabolism may also be state-dependent. Holsboer et al (1986b), Baumgartneret al (I 986b), and Maguire et al (1990) have reported that
plasma dexamethasone levels in the DST may rise with treatment. Poland et al (1 988) and Carroll et al (l980 ). however, found no change. The importance of dexamethasone levels prompted two groups independently to define dexamethasone "windows" for each postdexarnethasone collection point(Johnson et al 1984; Ritchie et al 1990a). Only those cortisol values with concurrent dexamethasone values falling within the defined "window" are considered valid.
Methods and Materials A DST (Carroll ct al 198I) was performed on 46 patients admitted to John Umstead Hospital who met DSM·III-R criteria fur a diagnosis of bipolar disorder, manic 01' mixed. On the day following the administration of 1 mg of dexamethasone at 10 PM, serum was collected at 3 PM and 10 I'M for determination of cortisol levels. Concurrent dexamethasone Icvcls were determined to verify if they fell within the windows set by Ritchie et aI (1990a). These arc defincd as a 3 PM dexamethasone level between 0.34 and 1.67 ng/mL and a 10 PM dexamethasone level between 0.10 and 0.91 nglmL. Exclusion criteria for valid DSTs were as listed by Carroll (1 984). In particular, patients were not concurrently treated with benzodiazepines or anticonvulsants. Patients were evaluated for manic symptomatology using a newly developed symptom rating instrument comprising 15 classical signs and symptoms of mania and five signs and symptoms of "mixed" mania (Cassidy et al, in press). Subjects were monitored clinically during the DST to assure they re-
DST in Bipolar Disorder
maincd manic. Those who did not (II = 2) were excluded from the analysis. Dexamethasone was administered on average onthe fourth to fifth hospital day (range 2nd-11th day). Nonsuppressing DSTs during mania were repeated following remission of manic symptoms to assess reversion. Patients treated with carbamazepine, a known source of false-positive DSTs (Privitera et al 1982). were excluded. Dexamethasone and cortisol assays were performed as previously described (Ritchie ct al 1990a). The coefficients of variation for the cortisol assay are 12.6% (intcrassay) and 6.4% (intraussay) for a cortisol-poor sample (2.6 I1g/dL), and 8.9% (intcrassay) and 5.6% dntraassay) for a cortisol-rich sample (10.15 IJ.g/dL). Theminimal detectable quantity of cortisol in the assay is 1.0 IJ.g/dL. The coefficients of variation for the dexamethasone assay at a level of0.52 ng/ml, arc 8% (intcrassay) and 4% (intraassay). The minimal detectable quantity of dcxarncthasonc in the assay is 0.02 nglmL. DSTs were characterized as nonsuppressing if either postdexamethasonc cortisol level was greater than 5 IJ.gldL. Therelationship between DSTstatus anddiagnosticgroup (bipolar disorder. manic or mixed) was analyzed with the Fisher Exact Test. Cortisol and dexamethasone levels were log-transformed because of inhomogeneity of variance, and differences were analyzed between those patients who met criteria for bipolar disorder, manic. and those patients who met criteria for bipolar disorder, mixed, using f tests. Differences between prc- and posttreatment Iog-transformed cortisol anddexamethasone levels were analyzed for those patients studied during mania and in remission using paired t tests. Pearson correlation coefficients were calculated for the log-transformed dexamethasone and log-transformed cortisolvalues foreach of thetime points within the entire cohort. A multiple regression analysis was conducted and partial correlations calculated to assess any interaction of age. sex, race. or body mass index with the cortisol and dexamethasone levels. Manic severity scores were calculated by determining the total of individual item scores from the mania rating instrument employed, excluding "mixed" signs and symptoms (depressed mood, lability, suicidality, anxiety. and guilt). The interrater reliability and validity of the scale is presented elsewhere (Cassidy et al, in press). In addition. a depressive subscalc comprising mixed signs and symptoms was defined as the sum of scores for dysphoric mood. lability. suicidality, anxiety. and guilt. Selection of which signs and symptoms to include was based on a previous factor analysis of manic signs and symptoms (Cassidy et al 1998). Severity and depressive subscale scores for the manic and mixed groups were compared with tests. Pearson correlation coefficients were also calculated to lest for an interaction of manic and depressive severity and cortisol and dexamethasone levels.
Results Patient Demographics Forty-six patients were diagnosed bipolar disorder, manic or mixed. Two patients had spontaneousremissions during
mOL PSYCHIATRY 19 9H ;4~ ;747-754
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the OST and were removed from the evaluation. Of the remaining 44 patients, 37 (84%) met DSM-IlI-R criteria for bipolar disorder, manic, and 7 (16%) for bipolar disorder, mixed, This is similar to the proportion of patients diagnosed bipolar disorder, manic and mixed, in our hospital (Cassidy et al 1997). Forty-three concurrent dexamethasone and cortisol levels were collected at 3 PM, and 42 at 10 PM, Results for I patient at 3 PM and 2 patients 10 PM were not obtained because of difficulties with phlebotomy or processing errors. The mean age of the patients diagnosed bipolar disorder. manic (38.5. SD 17.5) and those diagnosed bipolar disorder, mixed (46.1, SD 15.6) did not differ significantly (I = - 1.141, df = 42, P = .260). The sample comprised 17 blacks and 27 whites. Two male and 5 female subjects met criteria for bipolar disorder. mixed. and 23 male and 14 female subjects met criteria for bipolar disorder, manic. Mean mania severity scores for those patients diagnosed bipolar disorder, mixed (28.1, SD 9.8), and those diagnosed bipolar disorder, manic (32.2. SD 8.5). did not differ significantly (t = -1.145, df = 42. P = .259). As expected, differences in the depressive subscale scores between those patients diagnosed bipolar, manic (3.1 . SD 3.1). and those diagnosed bipolar, mixed (J2.J, SD 2.9), were significant (t = 7.077, df = 42, p < .001). Repeat DSTs were performed on I I nonsuppressors after recovery to assess reversion. These included 4 subjects initially diagnosed bir~lar disorder, mixed, and 7 subjects initially diagnosed b:.. Jar disorder. manic, Seven were female and 4 male, Eil,. ·.1 were white and 3 black. Their mean age was 42.3 (SD 17.0).
rhe DSr Sixteen of the 37 (43%) patients diagnosed bipolar disorder. manic, had one or both of the postdexamethasone cortisol samples greater than 5 IJ.g/dL and were characterized as nonsuppressors. Using the same criteria, 6 of the 7 (86%) patients diagnosed bipolar disorder, mixed, were also characterized as nonsuppressors. The Fisher Exact Test was significant for an association between DST status and diagnosis (p = .047). Log-transformed cortisol levels were significantly higher in those patients who met criteria for bipolar disorder, mixed. compared with those patients who met criteria for bipolar disorder, manic at 3 PM (t = 3.420, df = 4 I, p :S ,DO1) and 10PM (r = 2.207. df = 40. P :S .05) lime points (Figure 1). Means and standard deviations are given :0Table 2. Dexamethasonelevels were significantly lower in those patients who met criteria for bipolar disorder, mixed, at both 3 PM (t = -3.179, df = 41,p:S .005) and IO PM (t = -2.453, df = 40, P :S .02). Pearson correlation coefficients between log-transformed dexamethasone and
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OST in Bipolar Disorder
T(,1]c 2. Demographics and Mean Severity Scores and Cortisol (f.lgldL) and Dexamethasone (pg/mL) Levels for Patients Diagnosed Bipolar Disorder, Manic, and Bipolar Disorder. Mixed
Age (years) Weight (kg) Manic severity score Depressive subscale score 3 PM cortisol (llg1dL) 3 PM dexamethasone
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Bipolar disorder. mixed
46.1 (15.6, 18-77) 77.4(15.3. 53.6--112.3) 32.2(8.5, 14-53) 3.1 (3.1.0-12)
38.5 (17.5, 20-73) 70.1 (15.1.47.7-88.2) 28.1 (9.8.19-45) 12.1 (2.9.9-17)
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ity and log-transformed dexamethasone levels were not significant at either time point. In contrast, there was a negative correlation between thedepressive subscale score and log-transformed dexamethasone level at 3 PM (r =: -.518. df =: 42, p < .001) and 10 PM (r =: -.394. df = 41, p < .01), and a positive correlation between the depressive score and the log-transformed cortisol level at 3 PM (r = .453, df =: 42. p = .002). A trend wasnoted for a positive correlation between the depressive subset score and the log-transformed cortisol levels at 10 I'M (r = ,286. df =: 41. p = .067). Body mass index, age, race, and sex did not have significant partial correlations with the hormonal measures. At 3:00 PM five of the seven plasma dexamethasone concentrations of those patients who met criteria for bipolar disorder, mixed. were below the defined window. Two were within the window. Similarly, at 10:00 PM three of the five values were below the defined window. Two were within the window. Among samples from those patients who metcriteria for bipolar disorder. manic, 25 of 36 samples collected at 3:00 PM fell within the defined windows. Of those I I that did not, four fell above and seven below the defined window. Similarly. 28 of 37 10:00 PM plasma dexamethasone values for those patients whometcriteria for bipolar disorder, manic, fell within the window. Three additional values fell above the window, and six below. A Fisher Exact Test was conducted comparing the number of samples below the window versus the number within or above thewindow during manic and mixed states. Five of the 7 (71 %) 3 PM samples of those patients diagnosed bipolar. mixed, were below the window. In contrast only seven of the 36 (19%) 3 PM samples of those patients diagnosed bipolar manic, werebelow the window. Likewise. three of the 5 (60%) 10 PM samples
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werebelow thedefined window in thebipolar mixed group, whereas only sixof 37 (16%) 10 PM samples were below the window in the bipolar manic group. The Fisher Exact Test was significant at 3 PM (p = .012) and showed a trend for significance at 10 PM (p = .057). Six of 11 nonsuppressing DSTs repeated to assess
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CI al
1998:43:7~7-7.'i4
reversion were suppressing. Paired 1 tests were significant for a decrease in cortisol levels at 3 PM (r :::: 2.897. df :::: 10, P :5 .02) and 10 PM (r = 6.414, df :::: 9, p :5 .001) following remission. Six of the eight 3 PM dexamethasone levels that fell below the window during the manic or mixed state, fell within the window at remission, while two remained below the window. The three that were within the window remained within the window. All five of the 10 PM dexamethasone levels that fell below the window during the manic or mixed state were within the window during remission. Two levels within the window during the manic slate fell below the window during remission, and three remained within the window, A Fisher Exact Test wasconducted comparing the number of samples below the window versus the number within or above the window. during the manic or mixed state and after remission, and was significant at 3 PM (p :::: .02) but not at 10 I'M (p :::: .175). Paired 1 tests were significant for an increase in dexamethasone levels at both 3 PM (I :::: -2.781, df:::: IO, P :5 .02) and 10 PM (I :::: -2.417, df :::: 9, P $ .05) following remission.
Discussion Our results are consistent with the studies we reviewed (Table I) and the conclusion of Goodwin and Jamison (J 990) that abnormal DSTs arc significantly more common in mixed manic states but not uncommon in pure manic states. Although the size of this mixed bipolar sample is small, thesedata indicate that patients who meet DSM-IlI-R criteria for bipolar disorder, mixed, have a high rate of DST nonsuppression (86% in our sample). Patients whomeet DSM-IIl-R criteria for bipolar disorder, manic, also have a nontrivial rate of escape (43% in our sample). The combined rate of nonsuppression in our sample was SQlfi., in keeping with those studies reviewed (Table I). These data also confirm the variability of dexamethasane levels among patients and the inlluence of this variation on cortisol suppression during the DST, as shown in Figure 2. Use of dexamethasone windows was suggested to take into account variability of hepatic metabolism and thereby provide more valid interpretation of DST cortisol results. While lower dexamethasone levels have been reported by some groups in nonsuppressors, an adequate explanation of this finding has never been established. There is direct and indirect evidence that differences in dexamethasone metabolism may relate to the particular diagnostic state. First. it is well established that patients diagnosed withmajordepression havehigherratesof nonsuppression thancontrols (Carroll et al 1981), and there are indications that nonsupprcssion may be associated with lower dexa-
mcthasone levels as reviewed above. Taken together, these observations are compatible with the hypothesis that patients diagnosed with major depression may have lower dexamethasone levels following its administration. Second, some of those studies we reviewed above have reported nonsignificant trends for lower dexamethasone levels in patients withendogenous depression compared to neurotic depression. Third,as previously noted, dexarncthusone levels may change in a state-dependent fashion within the same patient. Possible explanations for such state-dependent changes havebeen rarely offered. Holsboer et al (I986a)suggested a possible induction of hepatic enzymes in response to stress and hypcrcortisolernia, An alternate explanation focuses on directcentral nervous system (CNS) control of hepatic metabolism. Gustafsson et al (1980) suggested that a region of the brain including the anteriorperiventricular hypothalamic area and the suprachiasmatic nucleus are involved in hepatic steroid metabolism in male rats. Similar CNS-hepatk interactions have been studied and reviewed by Waxman (1988). Holsboer et al (1986b) also noted reports that the pituitary-adrenocortical unit influences several peripheral enzymes and suggested that exaggerated activity of the pituitary-adrenocortical unit mayaffectthose enzymes that metabolize dexamethasone. Our data are compatible with the view that dexamcthasone levels may vary in a state-dependent manner. Those patients who met criteria for bipolar disorder, manic, had higher dexamethasone levels than those diagnosed with bipolar disorder, mixed (Figure I). Dexamethasone levels tended to be the same or higher following remission of signs and symptoms of mania in those subjects who were initially nonsuppressors when compared with their initial levels. These increases corresponded with decreases in concurrent cortisol levels. A large number of dexamethasane levels in those patients who met criteria for bipolar disorder. mixed, were below the defined windows at 3 PM (II ::: 5 of?) and 10 PM (n ::: 3 of 5). again emphasizing the importance of dexamethasone levels. State-dependent alterations in dexamethasone metabolism arc potential confounds in the study of central hypnthalamic-pituirary-adreual (HPA) overdrive in affective disorders. The initial standardization of the DST was based on cortisol determinations following a l-mg dose of dexamethasone. Whether this disturbance results from purely central HPA overdrive, or a combination of this and secondary changes in dexamethasone metabolism, has littlebearing on the clinical application of the test,The use of dexamethasone windows (Johnson et al 1984; Ritchie et al 1990a), however, may provide a more direct view of central HPA suppression by controlling for the confound of peripheral dexamethasone metabolism. Furtherresearch
DST in Bipolar Disorder
mOL PSYCHIATRY 1998;43:747-754
studies arc indicated that focus directly on central HPA function. Supported in part by 5P3aMH4al59 and Raj MH39593 from NIMH.
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