Psychological Medicine, 1976, 6, 43-50

Urinary free cortisol excretion in depression BERNARD J. CARROLL,1 GEORGE C. CURTIS, B. M. DAVIES, J. MENDELS AND A. ARTHUR SUGERMAN From the University of Michigan, Ann Arbor, the University of Melbourne, Parkville, Victoria, Australia, the Veterans Administration Hospital, Philadelphia, and the Carrier Clinic, Belle Mead, N.J.

Urinary free cortisol (UFC) excretion was determined in 60 depressed inpatients and in 35 psychiatric inpatients with other disorders. The depressed patients had high daily UFC values, while the other patients excreted normal amounts. Over 40 % of the depressed patients had UFC excretions in the range seen in Cushing's disease, while only 6 % of the other patients excreted such high amounts of cortisol. Age and sex differences did not account for the results. Among the depressed patients those with depressive neuroses excreted less than unipolar or bipolar depressives. Following treatment, more normal UFC excretion was found in depressed patients. The estimation of UFC and its clinical utility are discussed in detail. UFC determination is a simple and informative indicator of adrenal cortical activation and its application to psychoendocrine studies is recommended. SYNOPSIS

In patients suffering from depressive illnesses increased adrenal cortical activity is frequently observed. Plasma cortisol levels are elevated (Carroll, 1972); the secretion rates of cortisol and corticosterone are raised, sometimes to the range seen in Cushing's disease (Gibbons, 1964, 1966; Sachar et al, 1970, 1973; Carpenter & Bunney, 1971) and the urinary excretion of cortisol metabolites is greater than control or recovered values in many but not all reported studies (Sachar 1967a; Fullerton et al., 1968; Sclare & Grant, 1971). These findings are of interest, in view of the clinical association between mood disorders and pituitary-adrenal diseases (Rubin & Mandell, 1966; Gibbons, 1974), but they have not generally been of use in the diagnosis or management of depressed patients. In the routine clinical situation it is not feasible to measure cortisol secretion rates by isotope dilution techniques or by frequent blood sampling through an indwelling venous catheter for 24 h. Plasma cortisol values obtained during the night are more useful than daytime values in separating depressed * Address for reprints: Dr B. J. Carroll, Mental Health Research Institute, University of Michigan, Ann Arbor, Michigan, 48104, U.S.A.

patients from recovered or control subjects (Doig et al, 1966; Knapp et al., 1967; Butler & Besser, 1968; Sachar et al, 1973). Because of the episodic nature of cortisol release in man (Hellman et al, 1970; Krieger et al, 1971), however, infrequent blood samples, even at night, give only limited information. Urinary measures of adrenal cortical function have the advantage of providing an indication of cortisol secretion over time and could potentially yield more information than can be obtained from occasional blood samples. In most psychoendocrine studies of depression urinary 17hydroxycorticosteroid (17-OHCS) excretion has been measured. Less frequently urinary 17-ketogenic (oxogenic) corticosteroid (17-KGS) excretion has been determined (Kurland, 1964; Sachar, 1967ft). The urinary 17-OHCS excretion reflects less than 50 % of total cortisol secretion (Cope & Black, 1959; James & Landon, 1968), it is affected by a large number of factors (Poe et al, 1970) and it does not always correlate well with plasma 17-OHCS levels (Curtis et al, 1970). For many years the measurement of urinary free cortisol (UFC) excretion has been recommended by clinical endocrinologists (Cope & Black, 1959) as a better indicator of adrenal

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Bernard J. Carroll and others

cortical activation than 17-OHCS or 17-KGS excretion. This report describes our experience with UFC determinations in depressed and other psychiatric inpatients. METHODS

A competitive-protein-binding (CPB) method (Murphy, 1968) was used to measure UFC excretion in 24-hour urine samples obtained between 2 and 8 days after admission of the patients to hospital. The laboratory procedure was modified slightly by the use of corticosterone rather than hydrocortisone as the tracer, by the use offlorisilrather than Fuller's earth as the adsorbent, and by the use of double rather than single aliquots of the dichloromethane extracts. These modifications improved the performance of the assay in our hands and have been adopted by other workers (Beardwell et al., 1968; Hsu & Bledsoe, 1970). In every assay two doses of sample extract, each in duplicate, were carried through the quantitation procedure to yield a quadruplicate estimate for every sample; the mean of all four values was recorded. The coefficient of variation between assays was 10 % and within assays was 8 %. For statistical computations the UFC values were log-transformed since this variable is known to be distributed in a log-normal manner (Carroll, 1972). Accordingly, this procedure gives a geometric mean and a standard deviation range rather than a simple standard deviation (Gaddum, 1945; Heath, 1967). Student's / values are two-tailed.

depressed patients aged over 45 years were compared separately with 12 age- and sex-matched depressed patients. In this subgroup the depressed subjects had a mean age of 56 years and the non-depressed subjects a mean age of 59 years (/ = 016, n.s.). The patients were diagnosed by two psychiatrists in each unit. All depressed patients were experiencing a primary mood disturbance in the absence of schizophrenia, alcoholism, organic brain disease or personality disorder. Patients with unipolar depression, bipolar depression and depressive neurosis are included in the depressed group. Depressive neurosis rather than unipolar depression was diagnosed when clear psychological precipitants were present which resulted in a clinical picture of dysphoria responsive to environmental changes. These patients were treated primarily by psychotherapy and displayed few of the traditional physiologic symptoms of depression (such as retardation, agitation, early waking, anorexia and weight loss). The non-depressed group was made up of 23 schizophrenic patients, all but one experiencing an acute psychotic episode, eight patients with anxiety neuroses, three with sociopathic personality disorders and one with Korsakoff's psychosis. Women who were pregnant or taking oral contraceptives were not included. The patients studied in Melbourne and Philadelphia were drug-free except for nitrazepam or chloral hydrate received as a hypnotic; the Carrier Clinic patients were receiving tricyclic antidepressants and trifluoperazine; the patients studied in Ann Arbor were receiving chloral hydrate or flurazepam as a hypnotic and occasionally diazepam during the day.

PATIENTS

A total of 95 patients has been studied, of whom 60 suffered from depressive disorders while 35 received other diagnoses. They were admitted as inpatients to the following units: The Royal Melbourne Hospital and/or the Parkville Psychiatric Unit (21 depressed, 10 non-depressed); the Affective Diseases Research Unit, V.A. Hospital, Philadelphia (7 depressed, 3 non-depressed); the Carrier Clinic, Belle Mead, New Jersey (8 depressed); and the Neuropsychiatric Institute, University of Michigan Medical Center (24 depressed, 22 non-depressed). The depressed patients (24 males, 36 females) had a mean age of 55 (S.D. 14) years while the non-depressed patients (20 males, 15 females) had a mean age of 35 (S.D. 17) years: this age difference was significant (r = 601; P < 0001) and corresponds with the known age distribution of depressed and nondepressed general psychiatric inpatients. In view of this age difference in the total patient sample 12 non-

RESULTS

The depressed patients as a group had a higher UFC excretion than the non-depressed patients. The mean value of 90-1 fig for the depressives (Table 1) is significantly above the mean of 48-6/*g for the non-depressed group (/ = 5-18; d.f. = 93; P < 0-0001). By comparison with other studies of UFC excretion using closely similar techniques the non-depressed group had normal UFC excretion (Table 1). The upper normal limit of daily UFC excretion is approximately 100 /ig. Only one of 24 convalescent patients studied by Beardwell et al. (1968) and three of 57 normal, hypertensive or chronically ill patients studied by Murphy (1968) excreted more than this amount of cortisol in 24 h. In the present study 26 of the 60 depressed

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Urinary free cortisol excretion in depression TABLE 1

TABLE 2

URINARY FREE CORTISOL ( U F C ) EXCRETION (/ig/24 h) IN DEPRESSED, NON-DEPRESSED AND CONTROL SUBJECTS

AGE AND URINARY FREE CORTISOL ( U F C ) EXCRETION

Subjects Investigator This study This study

Depressed (60) Non-depressed (35) Beardwell el al. Convalescent medical (24) (1968) f Normal (23) Murphy (1968) < Hypertensive (16) l_Cnronic illness

Mean UFC

Range

901 48-6

25-8-261 3-6-163-8

41-9

0-146

48 42 53

10-146 10-90 20-100

Otg/24 h) Age (n) (years)

Mean UFC

range

11-20(5) 21-30 (21) 31-40(6) 41-50(19) 51-60(21) 61-70(13) 71-80 (10)

44-6 53-5 67-6 931 78-3 75-3 98-8

19-3-103-3 25-2-113-9 30-4-150-1 61 -1-42-0 44-7-137-2 41-2-137 4 51-6-159-5

yiof

patients (43%) had a UFC excretion above 100 fig, while only 2 of the 35 non-depressed patients (6 %) excreted 100 /ig or more (x2 = 19-96; P < 0-0001). The difference between the two patient groups was not related to urinary volume differences. For the depressed patients mean urine volume was 1-306 1 and for the non-depressed patients it was 1-385 1. For the entire group there was no significant correlation between UFC excretion and urine volume (/• = +0-13). The correlation in each sub-group also was not significant (r = +0-17 for depressed; r = +0-10 for nondepressed). The non-depressed patients were, as noted, considerably younger than the depressives. For the total patient group an apparent effect of age on UFC excretion was seen (Table 2). Since most of the younger patients were not depressed these results are difficult to interpret. Accordingly, older non-depressed patients were matched for age and sex with depressed patients as described earlier. Twelve non-depressed patients with a mean age of 59 years had a mean UFC excretion of 49-4 fig/24 h while the twelve matched depressed patients excreted a mean of 96-6 /^g/24 h. These figures are very close to those for the entire patient group (Table 1) and indicate that the age effect seen in Table 2 is related only to the high proportion of non-depressed patients in the younger age groups. Other workers also have noted no effect of age on UFC excretion in adults between 21 and 50 years old (Juselius & Kenny, 1974). Since the sex distribution differed between the depressed and non-depressed groups this variable also has been examined for an effect on UFC

S.D.

TABLE 3 DETAILS OF URINARY FREE CORTISOL RESULTS (/(g/24 h) IN THREE LABORATORIES (MEAN VALUES)

Depressed

Non-depressed

1040(21) 84-2 (24) 87-8 (7) 630 (8)

390 (10) 55-2 (22) 41-8(3)

Location Melbourne Ann Arbor Philadelphia Carrier Clinic

001 001 004

excretion. Considering the entire patient group, the 51 females had a mean UFC excretion of 70-4 /