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Clinical variables and hypothalamic-pituitary-adrenal function in depression
Journal of Affective Disorders, 12 (1987) 219-221
219
Elsevier JAD 00457
Clinical variables and hypothalamic-pituitary-adrenal function in depression The i m p o r t a n c e of m o o d reactivity Carmen Z. Lemus 1, Gregory M. Asnis 1, Uriel Halbreich 2, Jill M. Harkavy Friedman 1, Herman M. Van Praag 1, Eileen Rubinson i and Jacques Eisenberg 1 l Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, N Y and 2 State University of New York at Buffalo, Buffalo, NY, U.S.A.
(Received 5 January 1987) (Accepted 21 March 1987)
Summary Forty outpatients with major depressive disorder were studied with the 1 mg DST and the Afternoon Cortisol Test. No relationship was found between hypothalamic-pituitary-adrenal (HPA) axis function and Research Diagnostic Criteria subtypes of depression, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. Patients with mood reactivity had lower cortisol values on all assessments. The data suggest that the presence of mood reactivity may be useful as a predictor of normal H P A function in depression.
K e y words." Depression; Mood reactivity; Hypothalamic-pituitary-adrenal (HPA) axis function; Cortisol
values; (Afternoon Cortisol Test)
Introduction
Hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis is a finding consistently reAddress for correspondence: Carmen Z. Lemus, Hillside Hospital, Research Department, P.O. Box 38, Glen Oaks, NY 11004, U.S.A. Supported in part by NIMH Grants MH RO1-37111 and MH RO1-38807. Presented in part at the 25th Annual Meeting of the American College of Neuropsychopharmacology,Washington, DC, December 1986.
ported in a subgroup of depressed patients (Sachar et al. 1970; Stokes et al. 1975). The relationship between clinical features of depression and H P A axis hyperactivity is a question that remains unanswered. Investigators have tried to define the clinical profile of this population, but results have been contradictory (Asnis et al. 1982; Mendlewicz et al. 1982; Schatzberg et al. 1983; Kocsis et al. 1985). Thus, we decided to study H P A axis function in a group of patients with major depressive disorder (MDD), placing particular emphasis on diagnostic subtypes. We
0165-0327/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
220 included reactivity of mood as one of the variables examined. Although not considered a depressive subtype per se, reactivity is the essential feature found in a subgroup of patients, atypical depressives, noted to have different clinical presentation and treatment response (Liebowitz et al. 1981). To broaden our evaluation of the H P A axis we used two different methods of assessing cortisol secretion: the Afternoon Cortisol Test to determine basal plasma cortisol and the 1 mg DST to identify resistance to feedback suppression. Methods
Forty outpatients (10 men, 30 women, mean age 45.4, SD 16.1 years) participated in this study after giving written informed consent. They were evaluated with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978) and given a diagnosis of M D D by Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). They were further classified into depressive subtypes by RDC. Reactivity, as defined by item 350 of the SADS (' the extent to which temporary improvement in mood is associated with positive environmental events') was assessed for each subject. Those who were very responsive, usually responsive or often responsive to environmental events during the worst week of their depressive episode were considered to be reactive. Severity of depression was determined by the Extracted H a m ilton Depression Scale (Endicott et al. 1981), with a mean score of 23.9, SD 6.7, range 13-41. All subjects were free of psychotropic drugs for a minimum of 10 days prior to the study, did not have alcohol or drug abuse in the previous six months, and had no history of endocrine disease. A physical examination, complete laboratory admission survey including thyroid function tests, and E C G were normal on all subjects.
Endocrine assessments For determination of basal plasma cortisol we used the Afternoon ( 1 - 4 p.m.) Cortisol Test, which is an integrated measure of plasma cortisol secretion from 13.00-16.00 h. It has been shown to be highly correlated to the mean 24-h plasma cortisol in depressives (Halbreich et al. 1985) and normals (Halbreich et al. 1982). An angiocatheter was in-
serted in a forearm vein at 12.00 h and blood was continuously drawn from 13.00-16.00 h. Samples were immediately centrifuged and plasma frozen at - 2 0 ° C to await determination of the cortisol level. Subjects remained supine during the test. All ate breakfast at 7.30 h and a light lunch at 10.30 h; no snacks or naps were permitted. Cortisol secretion was defined here as a mean 1 - 4 p.m. plasma cortisol level > 13.5/~g/dl (greater than 2 SD of the mean plasma cortisol level for 61 normal controls, 7.8, SD 2.8/zg/dl). On a subsequent day the 1 mg DST was administered. Dexamethasone 1 mg was given orally at 23.00 h with a blood sample for plasma cortisol being drawn the next day at 16.00 h. Non-suppression was defined as a plasma post-dexamethasone cortisol level > 5 /xg/dl. Cortisol levels were determined by a homologous double antibody radioimmunoassay using reagents purchased from Diagnostic Products Corporation (Los Angeles, CA), with an inter-assay and intra-assay coefficient of variation of 9% and 2%, respectively. Fisher exact tests (2-tailed), or chi-square when appropriate, were used to evaluate rates of dexamethasone non-suppression and cortisol hypersecretion within each diagnostic subtype. Student's t-tests were used for continuous variables. Post-dexamethasone cortisol values were logtransformed to better fit a normal distribution (Carroll et al. 1972). Results
Endogenous depressives had higher log postdexamethasone cortisol levels when compared to the non-endogenous group ( t = - 2 . 0 9 , df 38, P < 0.04). N o n e of the other subtypes differed with respect to age, severity of illness, rates of non-suppression to dexamethasone or cortisol hypersecretion. Non-reactivity of mood was significantly associated with resistance to dexamethasone suppression (Fisher exact test, P < 0.04). There were also significant differences between reactive and nonreactive patients on measures of basal plasma cortisol secretion (t = 2.32, df 38, P < 0.02), mean post-dexamethasone cortisol levels (t = 3.47, df 29.4, P < 0.002), and log post-dexamethasone
221
cortisol (t = 2.82, df 38, P < 0.007), with reactive patients showing lower cortisol values on all assessments. In view of the fact that endogenous was the only R D C subtype presenting with H P A abnormalities, and because traditionally endogenous patients have been thought to have alterations in physiology, we evaluated the effect of mood reactivity on these subjects. Within this group there was a significant difference between reactive and non-reactive subjects with respect to log post-dexamethasone cortisol (t = 2.32, df 16.9, P < 0.03), mean post-dexamethasone cortisol (t = 2.90, df 21.2, P < 0.008) and basal cortisol (t = 3.03, df 17.8, P < 0.007). Discussion
This study finds no relationship between HPA axis hyperactivity and clinical subtypes of depression as defined by RDC, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. The subtypes psychotic, incapacitated and retarded were not analyzed due to the small numbers in each group. Our main finding is the relative absence of HPA axis abnormalities in patients presenting with reactive mood. Patients with mood reactivity had significantly lower post-dexamethasone cortisol levels and mean 1 - 4 p.m. basal plasma cortisol. In fact, they rarely had an HPA disturbance (one of 12 reactive patients had HPA disturbance vs. 11 of 28 non-reactive patients). To further evaluate the influence of mood reactivity on HPA function we examined its effect on endogenous depressives, a subgroup of patients expected to have biological abnormalities. In our sample, of 24 endogenously depressed subjects, the five patients who were endogenous and reactive had no biological abnormalities, while ten of the 19 patients who were endogenous and non-reactive had abnormalities of the HPA axis. Our findings emphasize the need to carefully define the characteristics of the mood in studies of major depression. The persistence and intensity of the depressed mood, as well as the presence or absence of reactivity, may affect the results of biological studies in this population. Additional data are needed to confirm the value of mood reactivity as a predictor of normal HPA axis func-
tion in depression. Since mood reactivity is the essential feature for the diagnosis of atypical depression, studies of the HPA axis in this group may be useful in clarifying this issue. References Asnis, G.M., Halbreich, U., Nathan, R.S., Ostrow, L., Novacenko, H., Endicott, J. and Sachar, E.J., The dexamethasone suppression test in depressive illness: clinical correlates, Psychoneuroendocrinology, 7 (1982) 295-301. Carrol, B.J., Control of plasma cortisol levels in depression: studies with the dexamethasone suppression test. In: B. Davies, B.J. Carroll and R.M. Mowbray (Eds.), Depressive Illness: Some Research Studies, Charles C. Thomas, Springfield, IL, 1972, pp. 87-148. Endicott, J. and Spitzer, R.L., A diagnostic interview: the schedule for affective disorders and schizophrenia, Arch. Gen. Psychiatry, 35 (1978) 837-844. Endicott, J., Cohen, J., Nee, J., Fleiss, J., and Sarantakos, S., Hamilton depression rating scale: extracted form and change versions of the Schedule for affective disorders and schizophrenia, Arch. Gen. Psychiatry, 38 (1981) 98-108. Halbreich, U., Zumoff, B., Kream, J. and Fukushima, D.K., The mean 1-4 pm plasma cortisol concentration as a diagnostic test for hypercortisolism, J. Clin. Endocr. Metab., 54 (1982) 1262-1264. Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B. and Nathan, R.S., Cortisol secretion in endogenous depression, I. Basal plasma levels, Arch. Gen. Psychiatry, 42 (1985) 904-908. Kocsis, J.H., Davis, J.M., Katz, M.M., Koslow, S.H., Stokes, P.E., Casper, R. and Redmond, D.E., Depressive behavior and hyperactive adrenocortical function, Am. J. Psychiatry, 142 (1985) 1291-1298. Liebowitz, M.R., Quitkin, F.M., Stewart, J.W., McGrath, P.J., Harrison, W., Schwartz, D., Rabkin, J., Tricano, E. and Klein, D.F., Phenelzine and imipramine in atypical depression, Psychopharm. Bull., 17 (1981) 159-161. Mendlewicz, J., Charles, G. and Franckson, J.M., The Dexamethasone Suppression Test in affective disorder: relationship to. clinical and genetic subgroups, Br. J. Psychiatry, 141 (1982) 464-470. Sachar, E.J., Hellman, L., Fukushima, D. and Gallagher, T., Cortisol production in depressive illness, Arch. Gen. Psychiatry, 23 (1970) 289-298. Schatzberg, A.F., Rothschild, A.J., Stahl, J.B., Bond, T.C., Rosenbaum, A.H., Lofgren, S.B., MacLaughlin, R.A., Sullivan, M.A. and Cole, J.O., The dexamethasone suppression test: identification of subtypes of depression, Am. J. Psychiatry, 140 (1983) 88-91. Spitzer, R.L., Endicott, J. and Robins, E., Research diagnostic criteria: rationale and reliability, Arch. Gen. Psychiatry, 35 (1978) 773-782. Stokes, P.E., Pick, G.R., Stoll P.M. and Nunn, W.O., Pituitary-adrenal function in depressed patients: resistance to dexamethasone suppression, Psychiatr. Res., 12 (1975) 271-281.
219
Elsevier JAD 00457
Clinical variables and hypothalamic-pituitary-adrenal function in depression The i m p o r t a n c e of m o o d reactivity Carmen Z. Lemus 1, Gregory M. Asnis 1, Uriel Halbreich 2, Jill M. Harkavy Friedman 1, Herman M. Van Praag 1, Eileen Rubinson i and Jacques Eisenberg 1 l Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, N Y and 2 State University of New York at Buffalo, Buffalo, NY, U.S.A.
(Received 5 January 1987) (Accepted 21 March 1987)
Summary Forty outpatients with major depressive disorder were studied with the 1 mg DST and the Afternoon Cortisol Test. No relationship was found between hypothalamic-pituitary-adrenal (HPA) axis function and Research Diagnostic Criteria subtypes of depression, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. Patients with mood reactivity had lower cortisol values on all assessments. The data suggest that the presence of mood reactivity may be useful as a predictor of normal H P A function in depression.
K e y words." Depression; Mood reactivity; Hypothalamic-pituitary-adrenal (HPA) axis function; Cortisol
values; (Afternoon Cortisol Test)
Introduction
Hyperactivity of the hypothalamic-pituitaryadrenal (HPA) axis is a finding consistently reAddress for correspondence: Carmen Z. Lemus, Hillside Hospital, Research Department, P.O. Box 38, Glen Oaks, NY 11004, U.S.A. Supported in part by NIMH Grants MH RO1-37111 and MH RO1-38807. Presented in part at the 25th Annual Meeting of the American College of Neuropsychopharmacology,Washington, DC, December 1986.
ported in a subgroup of depressed patients (Sachar et al. 1970; Stokes et al. 1975). The relationship between clinical features of depression and H P A axis hyperactivity is a question that remains unanswered. Investigators have tried to define the clinical profile of this population, but results have been contradictory (Asnis et al. 1982; Mendlewicz et al. 1982; Schatzberg et al. 1983; Kocsis et al. 1985). Thus, we decided to study H P A axis function in a group of patients with major depressive disorder (MDD), placing particular emphasis on diagnostic subtypes. We
0165-0327/87/$03.50 © 1987 Elsevier Science Publishers B.V. (Biomedical Division)
220 included reactivity of mood as one of the variables examined. Although not considered a depressive subtype per se, reactivity is the essential feature found in a subgroup of patients, atypical depressives, noted to have different clinical presentation and treatment response (Liebowitz et al. 1981). To broaden our evaluation of the H P A axis we used two different methods of assessing cortisol secretion: the Afternoon Cortisol Test to determine basal plasma cortisol and the 1 mg DST to identify resistance to feedback suppression. Methods
Forty outpatients (10 men, 30 women, mean age 45.4, SD 16.1 years) participated in this study after giving written informed consent. They were evaluated with the Schedule for Affective Disorders and Schizophrenia (SADS) (Endicott and Spitzer 1978) and given a diagnosis of M D D by Research Diagnostic Criteria (RDC) (Spitzer et al. 1978). They were further classified into depressive subtypes by RDC. Reactivity, as defined by item 350 of the SADS (' the extent to which temporary improvement in mood is associated with positive environmental events') was assessed for each subject. Those who were very responsive, usually responsive or often responsive to environmental events during the worst week of their depressive episode were considered to be reactive. Severity of depression was determined by the Extracted H a m ilton Depression Scale (Endicott et al. 1981), with a mean score of 23.9, SD 6.7, range 13-41. All subjects were free of psychotropic drugs for a minimum of 10 days prior to the study, did not have alcohol or drug abuse in the previous six months, and had no history of endocrine disease. A physical examination, complete laboratory admission survey including thyroid function tests, and E C G were normal on all subjects.
Endocrine assessments For determination of basal plasma cortisol we used the Afternoon ( 1 - 4 p.m.) Cortisol Test, which is an integrated measure of plasma cortisol secretion from 13.00-16.00 h. It has been shown to be highly correlated to the mean 24-h plasma cortisol in depressives (Halbreich et al. 1985) and normals (Halbreich et al. 1982). An angiocatheter was in-
serted in a forearm vein at 12.00 h and blood was continuously drawn from 13.00-16.00 h. Samples were immediately centrifuged and plasma frozen at - 2 0 ° C to await determination of the cortisol level. Subjects remained supine during the test. All ate breakfast at 7.30 h and a light lunch at 10.30 h; no snacks or naps were permitted. Cortisol secretion was defined here as a mean 1 - 4 p.m. plasma cortisol level > 13.5/~g/dl (greater than 2 SD of the mean plasma cortisol level for 61 normal controls, 7.8, SD 2.8/zg/dl). On a subsequent day the 1 mg DST was administered. Dexamethasone 1 mg was given orally at 23.00 h with a blood sample for plasma cortisol being drawn the next day at 16.00 h. Non-suppression was defined as a plasma post-dexamethasone cortisol level > 5 /xg/dl. Cortisol levels were determined by a homologous double antibody radioimmunoassay using reagents purchased from Diagnostic Products Corporation (Los Angeles, CA), with an inter-assay and intra-assay coefficient of variation of 9% and 2%, respectively. Fisher exact tests (2-tailed), or chi-square when appropriate, were used to evaluate rates of dexamethasone non-suppression and cortisol hypersecretion within each diagnostic subtype. Student's t-tests were used for continuous variables. Post-dexamethasone cortisol values were logtransformed to better fit a normal distribution (Carroll et al. 1972). Results
Endogenous depressives had higher log postdexamethasone cortisol levels when compared to the non-endogenous group ( t = - 2 . 0 9 , df 38, P < 0.04). N o n e of the other subtypes differed with respect to age, severity of illness, rates of non-suppression to dexamethasone or cortisol hypersecretion. Non-reactivity of mood was significantly associated with resistance to dexamethasone suppression (Fisher exact test, P < 0.04). There were also significant differences between reactive and nonreactive patients on measures of basal plasma cortisol secretion (t = 2.32, df 38, P < 0.02), mean post-dexamethasone cortisol levels (t = 3.47, df 29.4, P < 0.002), and log post-dexamethasone
221
cortisol (t = 2.82, df 38, P < 0.007), with reactive patients showing lower cortisol values on all assessments. In view of the fact that endogenous was the only R D C subtype presenting with H P A abnormalities, and because traditionally endogenous patients have been thought to have alterations in physiology, we evaluated the effect of mood reactivity on these subjects. Within this group there was a significant difference between reactive and non-reactive subjects with respect to log post-dexamethasone cortisol (t = 2.32, df 16.9, P < 0.03), mean post-dexamethasone cortisol (t = 2.90, df 21.2, P < 0.008) and basal cortisol (t = 3.03, df 17.8, P < 0.007). Discussion
This study finds no relationship between HPA axis hyperactivity and clinical subtypes of depression as defined by RDC, with the exception of higher log post-dexamethasone cortisol levels in endogenous depressives. The subtypes psychotic, incapacitated and retarded were not analyzed due to the small numbers in each group. Our main finding is the relative absence of HPA axis abnormalities in patients presenting with reactive mood. Patients with mood reactivity had significantly lower post-dexamethasone cortisol levels and mean 1 - 4 p.m. basal plasma cortisol. In fact, they rarely had an HPA disturbance (one of 12 reactive patients had HPA disturbance vs. 11 of 28 non-reactive patients). To further evaluate the influence of mood reactivity on HPA function we examined its effect on endogenous depressives, a subgroup of patients expected to have biological abnormalities. In our sample, of 24 endogenously depressed subjects, the five patients who were endogenous and reactive had no biological abnormalities, while ten of the 19 patients who were endogenous and non-reactive had abnormalities of the HPA axis. Our findings emphasize the need to carefully define the characteristics of the mood in studies of major depression. The persistence and intensity of the depressed mood, as well as the presence or absence of reactivity, may affect the results of biological studies in this population. Additional data are needed to confirm the value of mood reactivity as a predictor of normal HPA axis func-
tion in depression. Since mood reactivity is the essential feature for the diagnosis of atypical depression, studies of the HPA axis in this group may be useful in clarifying this issue. References Asnis, G.M., Halbreich, U., Nathan, R.S., Ostrow, L., Novacenko, H., Endicott, J. and Sachar, E.J., The dexamethasone suppression test in depressive illness: clinical correlates, Psychoneuroendocrinology, 7 (1982) 295-301. Carrol, B.J., Control of plasma cortisol levels in depression: studies with the dexamethasone suppression test. In: B. Davies, B.J. Carroll and R.M. Mowbray (Eds.), Depressive Illness: Some Research Studies, Charles C. Thomas, Springfield, IL, 1972, pp. 87-148. Endicott, J. and Spitzer, R.L., A diagnostic interview: the schedule for affective disorders and schizophrenia, Arch. Gen. Psychiatry, 35 (1978) 837-844. Endicott, J., Cohen, J., Nee, J., Fleiss, J., and Sarantakos, S., Hamilton depression rating scale: extracted form and change versions of the Schedule for affective disorders and schizophrenia, Arch. Gen. Psychiatry, 38 (1981) 98-108. Halbreich, U., Zumoff, B., Kream, J. and Fukushima, D.K., The mean 1-4 pm plasma cortisol concentration as a diagnostic test for hypercortisolism, J. Clin. Endocr. Metab., 54 (1982) 1262-1264. Halbreich, U., Asnis, G.M., Shindledecker, R., Zumoff, B. and Nathan, R.S., Cortisol secretion in endogenous depression, I. Basal plasma levels, Arch. Gen. Psychiatry, 42 (1985) 904-908. Kocsis, J.H., Davis, J.M., Katz, M.M., Koslow, S.H., Stokes, P.E., Casper, R. and Redmond, D.E., Depressive behavior and hyperactive adrenocortical function, Am. J. Psychiatry, 142 (1985) 1291-1298. Liebowitz, M.R., Quitkin, F.M., Stewart, J.W., McGrath, P.J., Harrison, W., Schwartz, D., Rabkin, J., Tricano, E. and Klein, D.F., Phenelzine and imipramine in atypical depression, Psychopharm. Bull., 17 (1981) 159-161. Mendlewicz, J., Charles, G. and Franckson, J.M., The Dexamethasone Suppression Test in affective disorder: relationship to. clinical and genetic subgroups, Br. J. Psychiatry, 141 (1982) 464-470. Sachar, E.J., Hellman, L., Fukushima, D. and Gallagher, T., Cortisol production in depressive illness, Arch. Gen. Psychiatry, 23 (1970) 289-298. Schatzberg, A.F., Rothschild, A.J., Stahl, J.B., Bond, T.C., Rosenbaum, A.H., Lofgren, S.B., MacLaughlin, R.A., Sullivan, M.A. and Cole, J.O., The dexamethasone suppression test: identification of subtypes of depression, Am. J. Psychiatry, 140 (1983) 88-91. Spitzer, R.L., Endicott, J. and Robins, E., Research diagnostic criteria: rationale and reliability, Arch. Gen. Psychiatry, 35 (1978) 773-782. Stokes, P.E., Pick, G.R., Stoll P.M. and Nunn, W.O., Pituitary-adrenal function in depressed patients: resistance to dexamethasone suppression, Psychiatr. Res., 12 (1975) 271-281.