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associated

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of thyroid function

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Morley JE, Brammer GL, Sharp B, Yamada T, Yuwiler A, Hershman JM (1981): Neurotransmitter control of hypothalamic-pituitary-thyroid function in rats. Eur J Pharmacol 70:263-27 1.

patients.

References Benaim S, Page C (1984): The prognostic significance of lithium induced hypothyroidism and the importance of a positive thyroid antibody titre in recurrent affective illness. Proceedings of the CINP, abstract no. F-182. Fischetti B (1962): Pharmacological influences on thyroid activity. Arch ltal Sci Pharmacol 12:33109. Kirkegaard C, Faber J (1981): Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression. Acta Endocrinol 96: 199-207. Linnoila M, Leppaluoto J, Seppala T, Ranta T (1977): Serum gonadotrophin and TSH levels after tricyclic antidepressants in healthy males. Acfa Pharmacol Toxic01 4 I :285-288. Linnoila M, Gold P. Potter WZ, Wehr TA (1981): Tricyclic antidepressants do not alter thyroid hormone levels in patients suffering from a major affective disorder. Psychiatry Res 4:357-360. McDaniel KD (1986): Clinical pharmacology of monoamine oxidase inhibitors. Clin Neuropharmacol 91207-234.

Post RM, Ballenger JC, Uhde TW, Bunney WE Jr (1984): Efficacy of carbamazepine in manic-depressive illness: Implications for underlying mechanisms. In Post RM, Ballenger JC (eds), Neurobiology of Mood Disorders. Baltimore: Williams & Wilkins, pp 777-816. Prange AJ Jr, Bakewell WE (1966): Effect of imipramine and reserpine on body size in euthyroid and hyperthyroid growing rats. J Pharmacol Exp Ther 151:409-412. Roy-Byrne PP, Joffe RT, Uhde TW, Post RM (1984): Effects of carbamazepine on thyroid function in affectively ill patients: Clinical and theoretical implications. Arch Gen Psychiatry 41:1150-l 153. Schlinger JL, Kapfer MT, Singer L, Stephan F (1980): The action of clomipramine on thyroid function. Horm Metab Res 121481-482. Whybrow PC, Coppen A, Prange AJ Jr, Noguera R, Bailey JE (1972): Thyroid function and the response to liothyronine in depression. Arch Gen Psychiatry 26~242-245.

The Plasma Dexamethasone “Window” and the Dexamethasone Suppression Test in Depression Gordon F. Johnson, Glenn Hunt, Kristin Kerr, and Ian Caterson

Introduction Disturbance of feedback control of glucocorticoid secretion, as evidenced by cortisol escape from suppression following dexamethasone From the Depanment of Psychiatry, University of Sydney (G.F.J., G.H.), and the Department ofEndocrinology. Royal Prince Alfred Hospital (K.K., I.C.), Camperdown, Australia. Address reprint requests to Dr. G. F. Johnson, Department of Psychiatry, University of Sydney, Sydney, N.S.W. 2006, Australia. Received October 1. 1986, revised December 7, 1986. C

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administration, has been widely reported in patients with depression (Arana et al. 1985). Although such changes may reflect altered limbic or hypothalamic-pituitary function, recent reports have firmly established that availability of dexamethasone is an important intervening variable determining cortisol response. Plasma dexamethasone concentrations following oral administration show wide individual variation, with a curvilinear negative correlation between OOGf-3223/871$03.50

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plasma dexamethasone and plasma cortisol. Significant differences in plasma dexamethasone concentrations are evident between Dexamethasone Suppression Test (DST) suppressors and nonsuppressors at all sampling times (8:00 AM, 4:00 PM, and 11:OO PM) (Arana et al. 1984; Johnson et al. 1984; Carr et al. 1986; Holsboer et al. 1986). Marked variation is evident in the sensitivity and specificity of the DST at different plasma dexamethasone concentrations (Johnson et al. 1986). To more accurately define the range of plasma dexamethasone concentrations that will allow reliable interpretation of hypothalamic-pituitary-adrenal (HPA) axis disinhibition, a prospective dose-response study, using sequential administration of 1.O mg and 0.5 mg oral dexamethasone , is reported.

Methods Patients included in the study were selected from admissions to the Affective Disorders Unit, Royal Prince Alfred Hospital. On entry into the study, all patients underwent a baseline observation and drug wash-out period of 3-7 days. Patients who required continuing drug treatment of immediate commencement of antidepressants or electroconvulsive therapy (ECT) were excluded from the study. Standard exclusion criteria included medical illnesses, drug or alcohol abuse, or other drugs likely to interfere with the DST. Diagnoses were made using Research Diagnostic Criteria (RDC), following interview with the Schedule for Affective Disorders and Schizophrenia (SADS). Nine patients met RDC criteria for major depression (6 endogenous and 3 probable endogenous). There were 8 nondepressed psychiatric patients (2 schizophrenia, 2 personality disorder, 2 bipolar in remission, 1 each mania and panic disorder). Hamilton Rating Scale scores (21 items) were greater than 17 in all patients with major depression and less than 17 in all psychiatric controls. Nine normal control subjects comprising medical and other staff, free of psychiatric and medical illness, volunteered for the study.

Dexamethasone, 0.5 mg or 1 .O mg, was administered in a randomized crossover design. Blood samples were obtained at 4:00 PM on day 1 and at 8:00 AM and 4:00 PM on days 2, 3, and 4 for plasma cortisol and dexamethasone. Dexamethasone was administered at 1l:OO PM on day 1 and day 3. Plasma cortisol levels returned to predexamethasone levels prior to the subsequent dexamethasone dose in all cases. Plasma cortisol was measured by radioimmunoassay (RIA) (Clinical Assays, Cambridge, MA). The intra- and interassay coefficients of variation were less than 10%. Dexamethasone was also measured by RIA. The standard used was 1,4.pregnan-9-fluoro-16x-methyl-11 B, 17a, 21 triol-3 20 dione (Steraloids, Wilton, NH) and the tracer was dexamethasone [6,7-‘H(N)] (New England Nuclear, Boston, MA). The antiserum to dexamethasone was from RIA-Labor (Heidelberg, Germany). The intra- and interassay coefficients of variation were
Results The mean plasma dexamethasone concentrations at 8:00 AM and 4:OO PM following either 1 mg or 0.5 mg dexamethasone were similar in normal subjects, patients with major depression, and psychiatric controls. However, there were significant differences in mean plasma dexamethasone concentrations between suppressors and nonsuppressors after 1 mg dexamethasone at 8:00 AM (10.4 t 3.3 versus 6.8 + 1.3 nmol/liter; F, , ,24j = 6.32, p < 0.02) and 4:00 PM (3.7 4 1.6 versus 2.1 ? 0.9 nmol/liter; F = 5.90, p < 0.05) and after 0.5 mg dexamethasone at 4:00 PM (2.6 ? 0.8 versus 1.6 ? 0.9 nmol/liter; F = 9.98, p < 0.002). The range of plasma dexamethasone concentrations and plasma cortisol at 4:OO PM following 0.5 mg and 1 .O mg dexamethasone administration for all subjects is shown in Figure 1. Plasma

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Figure 1. Plasma cortisol and dexamethasone concentrations 17 hr (4:OO PM) after dexamethasone (1.0 and 0.5 mg) in normal controls (n = 9), nondepressed psychiatric controls (n = 8), and patients with major depression (n = 9). The solid curvilinear lines were the visual fit of the 95% confidence intervals for the data obtained from the normal controls and nondepressed patients. Dexamethasone concentrations above 4 nmol/liter and below 2 nmol/liter (vertical dotted lines) were associated with cortisol suppression and nonsuppression, respectively, in all 3 groups. The horizontal dotted line indicates the criterion of cortisol used to define nonsuppression over the range of plasma dexamethasone concentrations as shown.

dexamethasone concentrations above 2 nmovliter appear to be necessary to obtain reliable suppression of plasma cortisol in normal subjects and nondepressed psychiatric controls. At 8:00 AM (data not shown), reliable suppression of plasma cortisol was achieved with plasma dexamethasone levels greater than 5 nmol/liter. All subjects whose plasma levels were below 5 nmol/liter at 890 AM showed plasma levels below 2 nmol/liter at 4:OO PM. Failure to suppress plasma cortisol despite minimum adequate plasma dexamethasone levels occurred in 5 depressed patients. In all subjects, levels above 4 nmolkter were associated with plasma cortisol suppression. The relationship between DST response (nonsuppression or suppression) and plasma

dexamethasone levels at 0.5 mg and 1.O mg for each subject at 8:00 AM and 4 PM is shown in Figure 2A and B. At 8:00 AM with the 0.5-mg test, similar rates of nonsuppression were found in depressed patients and psychiatric controls with plasma levels below 5 nmol/liter. At 4:00 PM, rates of nonsuppression are similar for depressed patients and nondepressed psychiatric controls, with plasma levels of dexamethasone below 2 nmol/liter with either or both the 0.5 mg or 1-mg test. Abnormal “suppressibility” of plasma cortisol with the high levels of dexamethasone greater than 11 nmoVliter at 8:00 AM or 4 nmol/liter at 4:00 PM is suggested in depressed patients who were nonsuppressors at lower plasma dexamethasone concentrations.

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These contrast with the psychiatric control subjects, whose DST status did not change despite similar differences in plasma dexamethasone concentrations obtained with the two tests.

Discussion In normal subjects, plasma dexamethasone concentrations above 5 nmol/liter at 8:00 AM (9 hr following dexamethasone administration) are reported to be required to adequately suppress plasma cortisol (Meikle et al. 1975). However, minimal plasma dexamethasone levels required to maintain suppression at later time points have not been examined systematically. This study involved two doses (0.5 and 1.0 mg) of dexamethasone. and reliable suppression of plasma cortisol in normal subjects and nondepressed psychiatric patients was obtained with plasma dexamethasone levels above 5 nmol/liter (196 ng/dl) at 8:00 AM and above 2 nmol/liter (79 ng/dl) at 4:00 PM. Failure to achieve these minimum nlasma dexamethasone levels was associated with similar rates of nonsuppression in depressed and nondepressed psychiatric patients, considerably reducing the specificity of the test. Abnormal “suppressibility” was also suggested in some depressed patients and was associated with high levels of plasma dexamethasone. This result is consistent with previous reports showing a precipitous fall in sensitivity of the test with high plasma dexamethasone levels (Johnson et al. 1984, 1986). Controlling for plasma dexamethasone concentrations by selecting a test result associated with a plasma level that fell within a “window” of 5-l 1 nmol/liter at 8:00 AM or 2-4 nmol/liter at 4:OO PM on either test offers a satisfactory balance between sensitivity and specificity. Moreover, the significant differences in plasma dexamethasone concentrations between suppressors and nonsuppressors are no longer evident, ensuring that cortisol escape reflects central factors associated with depression and not peripheral mechanisms responsible for the

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availability of dexamethasone. These figures are based on a small number of patients and need to be confirmed in a larger sample. In this study, the 0.5-mg dexamethasone dose frequently failed to achieve adequate plasma concentrations, with resulting low specificity. Although the I-mg test provided a more satisfactory range of plasma dexamethasone concentrations, some subjects failed to achieve adequate levels. In such cases, a 1.5-mg or 2-mg test would be more appropriate. Therefore, without knowledge of the plasma dexamethasone concentrations, it is not possible to reliably interpret DST response.

References Arana GW, Workman RJ, Baldessarini RJ (1984): Association between low plasma levels of dexamethasone and elevated levels of cortisol in psychiatric patients given dexamethasonc. Am J Psy chiarry 141:1619-1620. Arana GW. Baldessarini RJ, Omsteen M (1985): The Dexamethasone Suppression Test for diagnosis and prognosis in psychiatry. Arch Gen Psychicup 42:1193-1204. Carr V, Morris H, Gilliland J (1986): The effect of serum dexamethasone concentrations in the Dexamethasone Suppression Test. Biol Psyrhiat~ 21:135-743. Holsboer F, Wiedemann K, Gerken A, Boll E (1986): The plasma dexamethasone variable in depression: Test-retest studies and early biophase kinetics. Psychiat~ Res 17:97-l 03. Johnson GFS, Hunt G, Kerr K, Caterson I (1984): Dexamethasone Suppression Test (DST) and plasma dexamethasone levels in depressed patients. P,sychiaq Res 13:305-313. Johnson GFS, Hunt G, Kerr K. Caterson I (1986): Plasma dexamethasone concentrations and the Dexamethasone Suppression Test. Proceedings of the IVth World Congress on Biological Psychiufry, Philadelphia. New York: Elsevier. Meikle AW, Lagerquist LG, Tyler FH. (1975): Apparently normal pituitary adrenal suppressibility in Cushing’s syndrome: Dexamethasone metabolism and plasma levels. J Lab C/in Med 86:472-478.