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corticotropin-releasing hormone test in acute and remitted manic patients, in acute depression, and in normal controls: I
Combined Dexamethasone/Corticotropin-Releasing Hormone Test in Acute and Remitted Manic Patients, in Acute Depression, and in Normal Controls: I Jiirgen Schmider, Claas-H. Lammers, Ulrike Gotthardt, Michael Dettling, Florian Holsboer, and Isabella J.E. Heuser
Hypothalamic-pituitary-adrenal system (HPA)-function in patients with mania (n = 11), depression (n = 11, unipolar) and in control subjects (n = 11) was studied; six of the acutely manic patients were reevaluated after a symptom-free interval of at least 6 months. The combined dexamethasone-suppression/human CRH-challenge test was used to probe HPAsystem function. After CRH and dexamethasone pretreatment, A CTH and cortisol release were significantly increased in both manic and depressed patients in comparison to the control group. In the remitted patients with mania, a significant decrease in hormonal release after DEX and CRH was evident when compared to the acute manic episode, but the degree of CRH-stimulated hormone secretion in these remitted patients was still significantly larger than in normal controls. This study demonstrates that acute and remitted manic episodes are associated with a profoundly dysregulated HPA-system activity.
Key Words: HPA system, mania, depression, mania remission, DEX/CRH test BIOL PSYCHIATRY1995;38:797-802
Introduction In 1975, Stokes and co-workers were the first to report an increased percentage of escape from cortisol suppression in patients with depression who had undergone a dexamethasone suppression test (DST). Following this report, Carroll and co-workers (1981) suggested that the DST might be a useful tool to identify patients with the melancholic subtype of depression. However, later studies of the hypothalamic-pituitary-adrenal (HPA) system From the Max Planck Institute of Psychiatry, Munich, Germany. Address reprint requests to Isabella J.E. Heuser M.D., Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse 10, 80804 Munich, Germany. Received March 7, 1994; revised December 29, 1994.
© 1995 Society of Biological Psychiatry
found that the alterations in regulation do not seem to be linked to any particular type of depression, but rather reflect a state-dependent, severity of disease-related neuroendocrine sign of the stress-responsive HPA system during depression (Holsboer et al 1982, 1992; Greden et al 1983). Nevertheless, these original DST reports have prompted intensive research of HPA system physiology and pathophysiology in various stressful conditions and in patients with different psychiatric disorders (for review, see Arana and Baldessarini 1987). We have explored the mechanisms underlying DST nonsuppression by combining the DST procedure with another endocrine test that probes the integrity of the HPA system, the corticotropin-releasing hormone (CRH) chal0006-3223/95/$09.50 SSD1 0006-3223(95)00064-N
798
BIOLPSYCHIATRY
J. Schmider et al
1995;38:797-802
lenge test (combined dexamethasone suppression/human CRH challenge; DEX/CRH; von Bardeleben and Holsboer 1989). This test has revealed that in comparison to normal controls, depressed patients release significantly more ACTH and/or cortisol after additional CRH stimulation despite elevated cortisol concentrations after DEX. This finding is best explained by assuming that episodes of glucocorticoid hypersecretion, as they occur during severe depression, result in a refractoriness of the HPA system feedback loop (possibly at suprapituitary levels) to the glucocorticoid (GC) signal. The DEX/CRH test has recently also been used to differentiate Cushing's syndrome from pseudo-Cushing's states (Yanovski et al 1993). There is a surprising paucity of studies of glucocorficoid regulation in patients with mania: the psychopathological "flip side" of depression. This is probably due to the fact that acutely manic patients are difficult to enroll in clinical research protocols. The aim of this study was to assess HPA axis system function in patients with an acute manic episode and during remission utilizing the DEX/CRH test procedure. Neuroendocrine test outcomes of these patients were compared to those of age-matched depressed patients and normal controls.
had decided to discontinue their medication 2 and 4 months, respectively, prior to retesting. All depressed patients were medication-free for at least 1 week prior to the study. The mean Hamilton Depression rating scale score (21 item version; HDRS; Hamilton 1962) was 30 +-- 4.6. None of the patients abused alcohol or any other drug except for nicotine, but only patients who smoked fewer than 10 cigarettes per day were included in the study. However, smoking was not permitted during DEX/CRH testing.
Normal Controls Eleven healthy volunteers, eight men and three women (mean age: 38 --- 15 years) with no personal or family history of neurological or psychiatric disorders served as control subjects. All of these individuals were medicationfree for at least 6 months and a thorough physical examination and laboratory studies yielded no sign of pathology.
DEX/CRH Test
Subjects and Methods Patients Seven men and four women (mean age ___ SD: 39 ___ 17 years) with a Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R) diagnosis (American Psychiatric Association 1987) of an acute manic episode and three men and eight women with a DSM-III-R diagnosis of major depression (40 - 16 years) participated in the study after giving informed consent. One of the manic patients had never been treated with psychotropic drugs; four had not received any medication for at least 1 week prior to the study; one was currently medicated with clozapine; one with clozapine and lorazepam; one with clozapine and perazine; two were receiving a combination of lithium, carbamazepine and lorazepam; and one was receiving haloperidol, lithium, and carbamazepine. Mean mania rating scale score (MRS; Bech et al 1978) was 22 ___ 5 and the mean brief psychiatric rating scale score (BPRS; Overall and Gorham 1962) was 47 __+8. Degree of severity of mania was similar in untreated (MRS 23 ___ 4) and treated (23 ___2) patients. In six of the patients with acute mania a follow-up DEX/CRH test was done after a minimum symptomfree interval of 6 months, at which time their mean MRS score was 1 _+ 1.3. None of these patients in remission had any depressive or psychotic symptoms or complaints. Two of these patients were taking carbamazepine, two lithium, and the remaining two
The test was performed as previously described in detail (von Bardeleben and Holsboer 1989). Five to 8 days after hospitalization all participants received an oral dose of 1.5 mg dexamethasone at 11 PM. At 1:30 PM on the following day they rested supine on a bed in a single room where they were observed by a video system with a monitor located in the adjacent laboratory unit. An intravenous forearm catheter was connected to tubing and passed through a soundproof lock in the wall into the laboratory. Heart rate and blood pressure were monitored automatically throughout the study. Blood samples were drawn through the tubing at time points shown in Figure 1. At 3 PM 100 p~g human CRH (Bissendorf Peptide, Wedemark, Germany) reconstituted in 1 ml 0.02% HCI in 0.9 saline was infused within 30 s.
Analytical Methods Plasma ACTH was measured by immunoradiometric assay, using a conunercial kit (Nichols Institute, San Juan Capistrano, CA). The intraassay variability was less than 8% at an average concentration of 11 pmol/L, and the interassay variability was less than 8% with a lower limit of detection at 1 pmol/L. Cortisol was measured using a commercial radioimmunoassay (ICN, Cersa, CA). The inter- and intraassay coefficients of variation were below 7% respectively. The lower limit of detection was 2.8 nmol/L.
DEX/CRH Test of HPA in Mania: I
BIOLPSYCHIATRY 1995;38:797- 802
ACTH (pmol/L)
CORTISOL (nmol/L)
12
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400
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'
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"
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TIME DEPRESSION, ACUTE
- - l - MANIA, ACUTE
7100'
1
I
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--o- C O N T R O L
Figure 1. ACTH and cortisol secretion during DEX/CRH test in patients with acute mania (n = 11), acute depression (n = 11), and controls (n = 11) (mean -+ SEM).
Data Analysis After CRH infusion cortisol and ACTH responses were computed as the areas under the concentration-time course curve (AUC), using the trapezoidal integration corrected for baseline. The maximum hormone responses after CRH administration (time between 3 and 6 PM) are reported as PEAK. The mean value for the samples between 2 and 3 PM was calculated and is reported as BASAL concentration. Dexamethasone suppression test (DST) status was determined according to the highest plasma cortisol concentration between 2 and 3 OM, with a cutoff at 110 nmol/L to define nonsuppression, as established by the normative data base of our laboratory. Group means were compared using nonparametric tests (Kruskal-Wallis) for analysis of variance, followed by Mann-Whitney U test to determine local effects. Correlations among variables were analyzed using Spearman's correlation. Patients with mania and in remission were compared using the Wilcoxon signed-rank test for paired samples.
Statistical significance was set at a p value < 0.05 (two-tailed). Results are reported as means -+ standard deviation (SD) and data in figures are presented as means ___ standard error of the mean (SEM),
Results BASAL cortisol and BASAL ACTH concentrations were significantly (p < 0.05) increased in depressed and manic patients compared to healthy controls (Tables 1, 2). Fifty-five percent (6/11) of the acutely manic patients, 73% (8/11) of the depressed patients, and none of the controls escaped cortisol suppression after DEX. After CRH administration, manic and depressed patients had a significantly (p < 0.05) increased secretory activity, as reflected by larger AUCs for both ACTH and cortisol compared to the age-matched normal controls (Table 1; Fig. 1). Although only a small group of six patients in remission with mania agreed to be reinvestigated, there was a highly significant change in cortisol and ACTH-release pattern
Table 1. Cortisol Response (nmol/L) during DEX/CRH Test BASAL Patients with mania, acute (n = 11) Patients with depression (n = 11) Patients with mania, remitted (n = 6) Normal controls (n = 11)
127.6 226.4 60.4 20.4
--- 100.0" +_ 174.4" _ 94.39*** -+ 7.8
PEAK 397.7 488.7 217.8 73.5
- 286.1" + 277.7* _+ 195.0"** _ 73.3
AUC 24,202 14,355 10,875 4,617
--- 28,181 _ 31,110 _+ 16,154"* _+ 6,331
BASAL, mean value between 2 and 3 I,M; PEAK, maximum hormone response after CRH administration (time between 3 and 6 PM), AUC, area under the concentration-time course curve after CRH corrected for baseline, Mean +- SD. *Significant vs. normal controls (p < 0,01). **Significant vs. the corresponding data of these six patients with acute mania (p < 0.05). ***Significant vs. the corresponding data of these six patients with acute mania (p < 0.01).
800
BIOL PSYCHIATRY 1995;38:797-802
J. S c h m i d e r e t al
Table 2. ACTH Response (pmol/L) during DEX/CRH Test
Patients with mania, acute (n = 11) Patients with depression (n = 11) Patients with mania, remitted (n = 6) Normal controls (n = 11)
BASAL
PEAK
AUC
2.9 _+ 1.5"* 3.4 "!"-i.2'** 2.3 ___1.2"**** 1.2 --- 0.3
9.2 +_5.2* 8.1 - 3.0*** 6.1 _+3.8***** 3.7 --- 1.7
415 +- 393 237 -+ 206 257 +_ 365**** 245 + 192
*Significant vs. normal controls (p < 0,05). **Significant vs. normal controls (p < 0.01). ***Significant vs. normal controls (p < 0.001). ****Significant vs. the corresponding data of these 6 patients with acute mania (17 < 0.05). *****Significant vs. the corresponding data of these 6 patients with acute mania (p < 0.01).
compared to that of these patients during the acute episode. These changes were reflected in smaller values for all parameters (BASAL, PEAK, AUC; Tables 1, 2; Fig. 2). However, in comparison to healthy controls, manic patients in remission still had significantly larger AUCs after additional C R H administration, but similar BASAL hormone concentrations (see Tables 1 and 2). Pituitary-adrenal ratios (PAR = AUC ACTH/AUC cortisol) did not differ between patients with acute mania and depression (1.7 × 10 -2 vs. 1.65 × 10-2), but were nearly half the ratio of patients with mania in remission (2.9 × 10 -2) and one-third of PAR of controls (5.3 × 10-2). The degree of severity of mania (MRS scores) in the acutely ill patients was positively correlated with AUCs of cortisol (r = 0.7; p < 0.05) and ACTH (r = 0.6; p < 0.05). Taken together, in 82% (8/11) of the acutely manic patients and in 91% (10/11) of the acutely depressed patients DEX/CRH test outcome reflected an inability to suppress cortisol adequately after DEX when further challenged with CRH (PEAK cortisol secretion after CRH > 110 nmol/L) Also, in 50% (3/6) of the manic patients in
ACTH
(pmol/L)
remission neuroendocrine testing unmasked a persisting HPA system dysregulation.
Discussion The findings of this study demonstrate that both patients with acute or remitted mania and patients with depression have alterations of the HPA system. Contrary to previous reports that patients with mania have a lesser prevalence of hypercortisolemia and abnormal HPA system test outcome in comparison to controls (Carroll 1979; Cookson et al 1985; Kennedy et al 1989), we found that manic patients had HPA system changes comparable with those seen in patients with depression. After remission of manic symptoms, HPA system function, as assessed by the DEX/CRH test, "normalized" with regard to BASAL hormone secretion, whereas post-CRH hormone release still reflected profound HPA system dysregulation despite psychopathological remission. Hormone release after CRH stimulation and DEX pretreatment correlated positively with MRS score in patients with an acute manic episode. This
C O R T I S O L (nmol/L)
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8
300
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100
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//
~
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.
,
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,
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- - 1 - - MANIA, ACUTE
0
}/
I
1400
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I
'
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1600
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I
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---43--- MANIA, R E M I T T E D
Figure 2. ACTH and cortisol secretion during DEX/CRH test of patients with acute mania and in remission (mean --. SEM).
DEX/CRH Test of HPA in Mania: I
suggests that the degree of severity of psychopathology and the degree of neuroendocrine alteration are not independent of each other. However, the causal relationship is still not understood. It seems unlikely that the antimanic medication taken by quite a few of the patients caused the observed HPA system activation. If anything, one would expect that these compounds, especially those acting at the GABA-receptor complex, dampen HPA system drive as has been shown in animal and human studies (Lesch et al 1991; Torpy et al 1994). WhaUey et al (1989) reported significant basal hypercortisolemia in 57 psychiatric patients, regardless of diagnosis (26 schizophrenic, 10 major depressive, 9 schizoaffective, manic subtype, and 12 manic), compared to 35 control subjects. Taken together with the findings of Lammers et al (1995), who used the DEX/CRH test in 24 patients with schizophrenia, and of Schreiber et al (unpublished), who studied 14 patients with panic disorder by applying the DEX/CRH test, it is suggested that changes in HPA system function are indeed a neuroendocrine sign in psychiatric patients, independent of a specific psychopathological presentation. There is some evidence that an increase in the activity of the dopaminergic system occurs in manic patients, whereas a hypoactivity of this system may prevail in depression (for review, see Diehl and Gershon 1992). If this holds true, we can conclude from our present data that dopaminergic activity in humans (as has been shown in experimental animals) does not play a major part in the modulation of the activity of the HPA system as determined by DEX/CRH testing, since those patients with a presumed decreased activity of the dopaminergic system (depression) had DEX/CRH test outcomes similar to those of the manic patients. Furthermore, our group has shown that changes in HPA system function are also present in normal human aging and in humans subjected to repeated episodes of physical
BIOLPSYCHIATRY 1995;38:797-802
801
stress, such as competitive athletic activity (Heuser et al 1991, 1994). Thus, it appears that, with the DEX/CRH test, "adaptive" states of the organism to acute and/or frequently repeated stressful situations are possible to detect. In the case of affective or psychotic illnesses, dysregulation of the HPA system associated with increased severity of illness can be considered a neuroendocrine sign of these disorders. In the case of mentally and physically healthy elderly humans or in athletes, it probably constitutes a sign of adaptation to age- and lifestyleassociated changes of central nervous system components of the HPA system. Pituitary-adrenal ratios were lower in acutely ill patients, meaning that after CRH administration a smaller amount of ACTH was needed to release a certain quantity of cortisol. This might indicate that during the course of an affective episode the adrenals become more sensitive to ACTH stimulation, since even after psychopathological remission this increased adrenal sensitivity had not normalized. This is in line with the observation by Nemeroff and co-workers (1992), who reported enlargement of the adrenal glands in depressed patients in comparison to controls. If in our study the DST alone had been used, only 55% of patients with mania and 73% of depressed patients would have been detected to have an altered HPA system function. Additional CRH stimulation (DEX/CRH test) unmasked hormonal dysfunction in another 20-30% of the acutely ill patients and in almost 50% of the manic patients in remission. Thus, it appears that the DEX/CRH test reflects more reliably the endocrine "inprints" that outlast the acute phase in patients with affective disorders than the standard DST. Our findings strengthen the notion that affectively ill patients, regardless of their psychopathological syndrome, have a profoundly altered HPA system regulation.
References American Psychiatric Association (1987): Diagnostic and Statistical Manual of Mental Disorders, third edition revised. Washington, DC: APA. Arana GW, Baldessarini RJ (1987): Clinical use of the dexamethasone suppression test in psychiatry. In Meltzer HY (ed), Psychopharmacology: The Third Generation of Progress.
New York: Raven Press, pp 609-615. Bech P, Rafaelsen OJ, Kramp P, Bolwig TG (1978): The mania rating scale: Scale construction and inter-observer agreement. Neuropharmacology 17:430-431. Carroll BJ (1979): Neuroendocrine function in mania. In Shopsin B (ed), Manic Illness. New York: Raven Press, pp 163-176. Carroll BJ, Feinberg M, Greden JF, et al (1981): A specific laboratory test for the diagnosis of melancholia: Standardiza-
tion, validation, and clinical utility. Arch Gen Psychiatry 38:15-22. Cookson JC, Silverstone T, Williams S, Besser GM (1985): Plasma cortisol levels in mania: Associated clinical ratings and changes during treatment with haloperidol. Br J Psychiatry 146:498-502. Diehl DJ, Gershon S (1992): The role of dopamine in mood disorders. Compr Psychiatry 33:115-120. Greden JF, Gardner R, King D, Grunhaus L, Carroll BJ, Kronfold Z (1983): Dexamethasone suppression tests in antidepressant treatment of melancholia--the process of normalization and test-retest reproductability. Arch Gen Psychiatry 40:493-500. Hamilton M (1962): A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56-62.
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Heuser liE, Gotthardt U, Schweiger U, Schmider J, Lammers C-H, Dettling M, Holsboer F (1994): Age-associated changes of pituitary-adrenocortical hormone regulation in humans: importance of gender. Neurobiol Aging 15:227-231. Heuser LIE, Wark H-J, Keul J, Holsboer F (1991): Hypothalamic-pituitary-adrenal axis function in elderly endurance athletes. J Clin Endocrinol Metab 73:485-488. Holsboer F, Liebl R, Hofschuster E (1982): Repeated dexamethasone suppression test during depressive illness. Normalization of test result compared with clinical improvement. J Affect Disord 4:93--101. Holsboer F, Spengler D, Heuser I (1992): The role of corticotropin-releasing hormone in the pathogenesis of Cushing's disease, anorexia nervosa, alcoholism, affective disorders and dementia. Prog Brain Res 93:385-417. Kennedy SH, Tighe S, McVey G, Grown GM (1989): Melatonin and cortisol "switches" during mania, depression, and euthymia in a drug-free bipolar patient. J Nerv Ment Dis 177:300303. Lammers C-H, Garcia-Borreguero D, Schmider J, Gotthardt U, Dettling M, Holsboer F, Heuser IJE (1995): Combined dexamethasone test in patients with schizophrenia and corticotropin-releasing hormone normal controls: 1I. Biol Psychiatry 38:803-807. Lesch KP, Aulakh CS, Tolliver TJ, Hill JL, Murphy DL (1991): Differential effects of long-term lithium and carbamazepine administration on G~,~ and Gi,~ protein in rat brain. Eur J Pharmacol 207:355-359.
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Nemeroff CB, Krishnan RR, Reed D, Leder R, Beam C, Dunnick NR (1992): Adrenal gland enlargement in major depression. A computed tomographic study. Arch Gen Psychiatry 49: 384-387. Overall JE, Gorham DR (1962): The Brief Psychiatric Rating Scale. Psychol Rep 10:799-812. Stokes PE, Pick GR, Stoll PM, Nunn WD (1975): Pituitaryadrenal function in depressed patients: Resistance to dexamethasone suppression. J Psychiatry Res 12:271-281. Torpy DJ, Grice JE, Hockings GI, Waiters MM, Crosbie GV, Jackson RV (1994): Alprazolam attenuates vasopressin-stimulated adrenocorticotropin and cortisol release: Evidence for synergy between vasopressin and corticotropin-releasing hormone in humans. J Clin Endocrinol Metab 79:140-144. yon Bardeleben U, Holsboer F (1989): Cortisol response to a combined dexamethasone/human corticotropin-releasing hormone challenge in patients with depression. J Neurorendocrinol 1:485-488. Whalley LJ, Christie JE, Blackwood DHR, Bennie J, Dick H, Blackburn IM, Fink G (1989): Disturbed endocrine function in the psychoses I: Disordered homeostasis or disease process? Br J Psychiatry 155:455-461. Yanovski JA, Cutler GB, Chrousos GP, Nieman LK (1993): Corticotropin-releasing hormone stimulation following lowdose dexamethasone administration. A new test to distinguish Cushing's syndrome from pseudo-Cushing's states. JAMA 269:2232-2238.
Hypothalamic-pituitary-adrenal system (HPA)-function in patients with mania (n = 11), depression (n = 11, unipolar) and in control subjects (n = 11) was studied; six of the acutely manic patients were reevaluated after a symptom-free interval of at least 6 months. The combined dexamethasone-suppression/human CRH-challenge test was used to probe HPAsystem function. After CRH and dexamethasone pretreatment, A CTH and cortisol release were significantly increased in both manic and depressed patients in comparison to the control group. In the remitted patients with mania, a significant decrease in hormonal release after DEX and CRH was evident when compared to the acute manic episode, but the degree of CRH-stimulated hormone secretion in these remitted patients was still significantly larger than in normal controls. This study demonstrates that acute and remitted manic episodes are associated with a profoundly dysregulated HPA-system activity.
Key Words: HPA system, mania, depression, mania remission, DEX/CRH test BIOL PSYCHIATRY1995;38:797-802
Introduction In 1975, Stokes and co-workers were the first to report an increased percentage of escape from cortisol suppression in patients with depression who had undergone a dexamethasone suppression test (DST). Following this report, Carroll and co-workers (1981) suggested that the DST might be a useful tool to identify patients with the melancholic subtype of depression. However, later studies of the hypothalamic-pituitary-adrenal (HPA) system From the Max Planck Institute of Psychiatry, Munich, Germany. Address reprint requests to Isabella J.E. Heuser M.D., Max Planck Institute of Psychiatry, Clinical Institute, Kraepelinstrasse 10, 80804 Munich, Germany. Received March 7, 1994; revised December 29, 1994.
© 1995 Society of Biological Psychiatry
found that the alterations in regulation do not seem to be linked to any particular type of depression, but rather reflect a state-dependent, severity of disease-related neuroendocrine sign of the stress-responsive HPA system during depression (Holsboer et al 1982, 1992; Greden et al 1983). Nevertheless, these original DST reports have prompted intensive research of HPA system physiology and pathophysiology in various stressful conditions and in patients with different psychiatric disorders (for review, see Arana and Baldessarini 1987). We have explored the mechanisms underlying DST nonsuppression by combining the DST procedure with another endocrine test that probes the integrity of the HPA system, the corticotropin-releasing hormone (CRH) chal0006-3223/95/$09.50 SSD1 0006-3223(95)00064-N
798
BIOLPSYCHIATRY
J. Schmider et al
1995;38:797-802
lenge test (combined dexamethasone suppression/human CRH challenge; DEX/CRH; von Bardeleben and Holsboer 1989). This test has revealed that in comparison to normal controls, depressed patients release significantly more ACTH and/or cortisol after additional CRH stimulation despite elevated cortisol concentrations after DEX. This finding is best explained by assuming that episodes of glucocorticoid hypersecretion, as they occur during severe depression, result in a refractoriness of the HPA system feedback loop (possibly at suprapituitary levels) to the glucocorticoid (GC) signal. The DEX/CRH test has recently also been used to differentiate Cushing's syndrome from pseudo-Cushing's states (Yanovski et al 1993). There is a surprising paucity of studies of glucocorficoid regulation in patients with mania: the psychopathological "flip side" of depression. This is probably due to the fact that acutely manic patients are difficult to enroll in clinical research protocols. The aim of this study was to assess HPA axis system function in patients with an acute manic episode and during remission utilizing the DEX/CRH test procedure. Neuroendocrine test outcomes of these patients were compared to those of age-matched depressed patients and normal controls.
had decided to discontinue their medication 2 and 4 months, respectively, prior to retesting. All depressed patients were medication-free for at least 1 week prior to the study. The mean Hamilton Depression rating scale score (21 item version; HDRS; Hamilton 1962) was 30 +-- 4.6. None of the patients abused alcohol or any other drug except for nicotine, but only patients who smoked fewer than 10 cigarettes per day were included in the study. However, smoking was not permitted during DEX/CRH testing.
Normal Controls Eleven healthy volunteers, eight men and three women (mean age: 38 --- 15 years) with no personal or family history of neurological or psychiatric disorders served as control subjects. All of these individuals were medicationfree for at least 6 months and a thorough physical examination and laboratory studies yielded no sign of pathology.
DEX/CRH Test
Subjects and Methods Patients Seven men and four women (mean age ___ SD: 39 ___ 17 years) with a Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised (DSM-III-R) diagnosis (American Psychiatric Association 1987) of an acute manic episode and three men and eight women with a DSM-III-R diagnosis of major depression (40 - 16 years) participated in the study after giving informed consent. One of the manic patients had never been treated with psychotropic drugs; four had not received any medication for at least 1 week prior to the study; one was currently medicated with clozapine; one with clozapine and lorazepam; one with clozapine and perazine; two were receiving a combination of lithium, carbamazepine and lorazepam; and one was receiving haloperidol, lithium, and carbamazepine. Mean mania rating scale score (MRS; Bech et al 1978) was 22 ___ 5 and the mean brief psychiatric rating scale score (BPRS; Overall and Gorham 1962) was 47 __+8. Degree of severity of mania was similar in untreated (MRS 23 ___ 4) and treated (23 ___2) patients. In six of the patients with acute mania a follow-up DEX/CRH test was done after a minimum symptomfree interval of 6 months, at which time their mean MRS score was 1 _+ 1.3. None of these patients in remission had any depressive or psychotic symptoms or complaints. Two of these patients were taking carbamazepine, two lithium, and the remaining two
The test was performed as previously described in detail (von Bardeleben and Holsboer 1989). Five to 8 days after hospitalization all participants received an oral dose of 1.5 mg dexamethasone at 11 PM. At 1:30 PM on the following day they rested supine on a bed in a single room where they were observed by a video system with a monitor located in the adjacent laboratory unit. An intravenous forearm catheter was connected to tubing and passed through a soundproof lock in the wall into the laboratory. Heart rate and blood pressure were monitored automatically throughout the study. Blood samples were drawn through the tubing at time points shown in Figure 1. At 3 PM 100 p~g human CRH (Bissendorf Peptide, Wedemark, Germany) reconstituted in 1 ml 0.02% HCI in 0.9 saline was infused within 30 s.
Analytical Methods Plasma ACTH was measured by immunoradiometric assay, using a conunercial kit (Nichols Institute, San Juan Capistrano, CA). The intraassay variability was less than 8% at an average concentration of 11 pmol/L, and the interassay variability was less than 8% with a lower limit of detection at 1 pmol/L. Cortisol was measured using a commercial radioimmunoassay (ICN, Cersa, CA). The inter- and intraassay coefficients of variation were below 7% respectively. The lower limit of detection was 2.8 nmol/L.
DEX/CRH Test of HPA in Mania: I
BIOLPSYCHIATRY 1995;38:797- 802
ACTH (pmol/L)
CORTISOL (nmol/L)
12
600-
799
100~pgCRH
10 100
400
8 6-
200
4 2 o
H ,
'
1400
'
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1
I
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I
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I
15100 1600
"'
TIME DEPRESSION, ACUTE
- - l - MANIA, ACUTE
7100'
1
I
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TIME
--o- C O N T R O L
Figure 1. ACTH and cortisol secretion during DEX/CRH test in patients with acute mania (n = 11), acute depression (n = 11), and controls (n = 11) (mean -+ SEM).
Data Analysis After CRH infusion cortisol and ACTH responses were computed as the areas under the concentration-time course curve (AUC), using the trapezoidal integration corrected for baseline. The maximum hormone responses after CRH administration (time between 3 and 6 PM) are reported as PEAK. The mean value for the samples between 2 and 3 PM was calculated and is reported as BASAL concentration. Dexamethasone suppression test (DST) status was determined according to the highest plasma cortisol concentration between 2 and 3 OM, with a cutoff at 110 nmol/L to define nonsuppression, as established by the normative data base of our laboratory. Group means were compared using nonparametric tests (Kruskal-Wallis) for analysis of variance, followed by Mann-Whitney U test to determine local effects. Correlations among variables were analyzed using Spearman's correlation. Patients with mania and in remission were compared using the Wilcoxon signed-rank test for paired samples.
Statistical significance was set at a p value < 0.05 (two-tailed). Results are reported as means -+ standard deviation (SD) and data in figures are presented as means ___ standard error of the mean (SEM),
Results BASAL cortisol and BASAL ACTH concentrations were significantly (p < 0.05) increased in depressed and manic patients compared to healthy controls (Tables 1, 2). Fifty-five percent (6/11) of the acutely manic patients, 73% (8/11) of the depressed patients, and none of the controls escaped cortisol suppression after DEX. After CRH administration, manic and depressed patients had a significantly (p < 0.05) increased secretory activity, as reflected by larger AUCs for both ACTH and cortisol compared to the age-matched normal controls (Table 1; Fig. 1). Although only a small group of six patients in remission with mania agreed to be reinvestigated, there was a highly significant change in cortisol and ACTH-release pattern
Table 1. Cortisol Response (nmol/L) during DEX/CRH Test BASAL Patients with mania, acute (n = 11) Patients with depression (n = 11) Patients with mania, remitted (n = 6) Normal controls (n = 11)
127.6 226.4 60.4 20.4
--- 100.0" +_ 174.4" _ 94.39*** -+ 7.8
PEAK 397.7 488.7 217.8 73.5
- 286.1" + 277.7* _+ 195.0"** _ 73.3
AUC 24,202 14,355 10,875 4,617
--- 28,181 _ 31,110 _+ 16,154"* _+ 6,331
BASAL, mean value between 2 and 3 I,M; PEAK, maximum hormone response after CRH administration (time between 3 and 6 PM), AUC, area under the concentration-time course curve after CRH corrected for baseline, Mean +- SD. *Significant vs. normal controls (p < 0,01). **Significant vs. the corresponding data of these six patients with acute mania (p < 0.05). ***Significant vs. the corresponding data of these six patients with acute mania (p < 0.01).
800
BIOL PSYCHIATRY 1995;38:797-802
J. S c h m i d e r e t al
Table 2. ACTH Response (pmol/L) during DEX/CRH Test
Patients with mania, acute (n = 11) Patients with depression (n = 11) Patients with mania, remitted (n = 6) Normal controls (n = 11)
BASAL
PEAK
AUC
2.9 _+ 1.5"* 3.4 "!"-i.2'** 2.3 ___1.2"**** 1.2 --- 0.3
9.2 +_5.2* 8.1 - 3.0*** 6.1 _+3.8***** 3.7 --- 1.7
415 +- 393 237 -+ 206 257 +_ 365**** 245 + 192
*Significant vs. normal controls (p < 0,05). **Significant vs. normal controls (p < 0.01). ***Significant vs. normal controls (p < 0.001). ****Significant vs. the corresponding data of these 6 patients with acute mania (17 < 0.05). *****Significant vs. the corresponding data of these 6 patients with acute mania (p < 0.01).
compared to that of these patients during the acute episode. These changes were reflected in smaller values for all parameters (BASAL, PEAK, AUC; Tables 1, 2; Fig. 2). However, in comparison to healthy controls, manic patients in remission still had significantly larger AUCs after additional C R H administration, but similar BASAL hormone concentrations (see Tables 1 and 2). Pituitary-adrenal ratios (PAR = AUC ACTH/AUC cortisol) did not differ between patients with acute mania and depression (1.7 × 10 -2 vs. 1.65 × 10-2), but were nearly half the ratio of patients with mania in remission (2.9 × 10 -2) and one-third of PAR of controls (5.3 × 10-2). The degree of severity of mania (MRS scores) in the acutely ill patients was positively correlated with AUCs of cortisol (r = 0.7; p < 0.05) and ACTH (r = 0.6; p < 0.05). Taken together, in 82% (8/11) of the acutely manic patients and in 91% (10/11) of the acutely depressed patients DEX/CRH test outcome reflected an inability to suppress cortisol adequately after DEX when further challenged with CRH (PEAK cortisol secretion after CRH > 110 nmol/L) Also, in 50% (3/6) of the manic patients in
ACTH
(pmol/L)
remission neuroendocrine testing unmasked a persisting HPA system dysregulation.
Discussion The findings of this study demonstrate that both patients with acute or remitted mania and patients with depression have alterations of the HPA system. Contrary to previous reports that patients with mania have a lesser prevalence of hypercortisolemia and abnormal HPA system test outcome in comparison to controls (Carroll 1979; Cookson et al 1985; Kennedy et al 1989), we found that manic patients had HPA system changes comparable with those seen in patients with depression. After remission of manic symptoms, HPA system function, as assessed by the DEX/CRH test, "normalized" with regard to BASAL hormone secretion, whereas post-CRH hormone release still reflected profound HPA system dysregulation despite psychopathological remission. Hormone release after CRH stimulation and DEX pretreatment correlated positively with MRS score in patients with an acute manic episode. This
C O R T I S O L (nmol/L)
12-
500
10 400 100
100#gCR. T~
8
300
rr
6-
200 4-
100
2-
0
//
~
1400
.
,
1500
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,
--
1600
1700
2300 H PREVIOUS NIGHT 1.5 rag DEXAMETHASONE
.
,
1800 TIME
- - 1 - - MANIA, ACUTE
0
}/
I
1400
'
I
'
1500
l
1600
'
I
1700
'
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1800 TIME
---43--- MANIA, R E M I T T E D
Figure 2. ACTH and cortisol secretion during DEX/CRH test of patients with acute mania and in remission (mean --. SEM).
DEX/CRH Test of HPA in Mania: I
suggests that the degree of severity of psychopathology and the degree of neuroendocrine alteration are not independent of each other. However, the causal relationship is still not understood. It seems unlikely that the antimanic medication taken by quite a few of the patients caused the observed HPA system activation. If anything, one would expect that these compounds, especially those acting at the GABA-receptor complex, dampen HPA system drive as has been shown in animal and human studies (Lesch et al 1991; Torpy et al 1994). WhaUey et al (1989) reported significant basal hypercortisolemia in 57 psychiatric patients, regardless of diagnosis (26 schizophrenic, 10 major depressive, 9 schizoaffective, manic subtype, and 12 manic), compared to 35 control subjects. Taken together with the findings of Lammers et al (1995), who used the DEX/CRH test in 24 patients with schizophrenia, and of Schreiber et al (unpublished), who studied 14 patients with panic disorder by applying the DEX/CRH test, it is suggested that changes in HPA system function are indeed a neuroendocrine sign in psychiatric patients, independent of a specific psychopathological presentation. There is some evidence that an increase in the activity of the dopaminergic system occurs in manic patients, whereas a hypoactivity of this system may prevail in depression (for review, see Diehl and Gershon 1992). If this holds true, we can conclude from our present data that dopaminergic activity in humans (as has been shown in experimental animals) does not play a major part in the modulation of the activity of the HPA system as determined by DEX/CRH testing, since those patients with a presumed decreased activity of the dopaminergic system (depression) had DEX/CRH test outcomes similar to those of the manic patients. Furthermore, our group has shown that changes in HPA system function are also present in normal human aging and in humans subjected to repeated episodes of physical
BIOLPSYCHIATRY 1995;38:797-802
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stress, such as competitive athletic activity (Heuser et al 1991, 1994). Thus, it appears that, with the DEX/CRH test, "adaptive" states of the organism to acute and/or frequently repeated stressful situations are possible to detect. In the case of affective or psychotic illnesses, dysregulation of the HPA system associated with increased severity of illness can be considered a neuroendocrine sign of these disorders. In the case of mentally and physically healthy elderly humans or in athletes, it probably constitutes a sign of adaptation to age- and lifestyleassociated changes of central nervous system components of the HPA system. Pituitary-adrenal ratios were lower in acutely ill patients, meaning that after CRH administration a smaller amount of ACTH was needed to release a certain quantity of cortisol. This might indicate that during the course of an affective episode the adrenals become more sensitive to ACTH stimulation, since even after psychopathological remission this increased adrenal sensitivity had not normalized. This is in line with the observation by Nemeroff and co-workers (1992), who reported enlargement of the adrenal glands in depressed patients in comparison to controls. If in our study the DST alone had been used, only 55% of patients with mania and 73% of depressed patients would have been detected to have an altered HPA system function. Additional CRH stimulation (DEX/CRH test) unmasked hormonal dysfunction in another 20-30% of the acutely ill patients and in almost 50% of the manic patients in remission. Thus, it appears that the DEX/CRH test reflects more reliably the endocrine "inprints" that outlast the acute phase in patients with affective disorders than the standard DST. Our findings strengthen the notion that affectively ill patients, regardless of their psychopathological syndrome, have a profoundly altered HPA system regulation.
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