Psychoneuroendocrinology, Vol. 15, No. 1, pp. 59--68, 1990 0306-4530/90 $3.00 + 0.00 Printed in Great Britain @1990 Pergamon Press pie MONONUCLEAR LEUKOCYTE GLUCOCORTICOID RECEPTOR BINDING CHARACTERISTICS AND DOWN-REGULATION IN MAJOR DEPRESSION A. WASSEF, 1 E. M. SMITH, 1,2 R. M. ROSE, 1 R. GARDNER) H. NGUYEN, 1 and W. J. MEYER 1 Psychiatric Clinical Research Center and Departments of 1Psychiatry and Behavioral Sciences and 2Microbiology, The University of Texas Medical Branch, Galveston, Texas, USA (Received 5 December 1988; Infinal form 2 October 1989) SUMMARY Some patients with major depressive disorder (MDD) have elevated plasma cortisol concentrations and show failure to suppress cortisol secretion upon administration of dexamethasone (DEX), yet they do not have Cushingoid features. To study whether this represents glucocorticoid (GC) resistance, [3H]-DEX-binding assays were used to measure, in vitro, the GC receptor affinity (1/Kd) and number (Bmax) in mononuclear leukocytes of 11 MDD patients and 15 control subjects. No receptor abnor- malities were detected in the MDD group; thus any cellular defect leading to a lack of responsiveness to GC in the MDD patients, if present, probably lies beyond the initial receptor binding. DEX (1.0 mg orally) was administered to study in vivo GC receptor down-regulation. Compared to the control group, fewer depressed subjects down-regulated Bmax after DEX. By paired t-test, Bmax decreased significantly in the control group but not in the depressed group. Receptor number on the control day did not correlate significantly with the degree of receptor down-regulation, severity of depression or cortisol concentrations across all the subjects. These results do not lend support to previous reports suggesting that GC resistance in MDD results from a GC receptor-binding abnormality, and they emphasize the importance of considering receptor studies in the context of GC-mediated cell processes in order to identify the exact cellular defect(s) leading to GC resistance. INTRODUCTION ABNORMALGLUCOCORTICOID (GC) concentrations in some patients with major depressive disorder (MDD) have long been recognized. Elevated cortisol concentrations have been documented in blood (Ferguson et al., 1964; Gibbons, 1964; Sachar et al., 1970; 1973; Carpenter & Bunney, 1971; Carroll, 1972) and cerebmspinal fluid (Carroll et al., 1976; Traskman et al., 1980). Further, the circadian patterns of plasma cortisol was reported by some investigators to be abnormal (Carroll, 1972; Sachar et al., 1973), though these conclusions have been questioned by Rubin et al., 1987. The elevated endogenous GC may be ineffective in lowering GC secretion; there is early cortisol escape from dexamethasone (DEX) suppression in 30-50% of MDD patients (for review see Arana, 1985). Despite elevated cortisol concentrations, patients with MDD do not develop clinical features of Cushing's syndrome; at most, they develop only minor changes in blood chemistry (Reus & Miner, 1985). Schlechte et al. (1986) suggested that depressed patients Correspondence to be addressed to: Walter J. Meyer, III, M.D. Psychiatric Clinical Research Center, Department of Psychiatry and Behavioral Sciences - D29, University of Texas Medical Branch, Galveston TX 77550-2777, USA. 59