Urinary free cortisol excretion in elderly persons with minor and major depression

Psychiatry Research 104 Ž2001. 39᎐47

Urinary free cortisol excretion in elderly persons with minor and major depression Albertine J. OldehinkelU , Marjan D. van den Berg, Frans Flentge, Antoinette L. Bouhuys, Gert J. ter Horst, Johan Ormel Department of Psychiatry, Uni¨ ersity of Groningen, P.O. Box 30001, 9700 RB Groningen, The Netherlands

Abstract Several studies have found that cortisol hypersecretion may occur in severely depressed patients who are characterized by melancholic features. On the other hand, illness chronicity seems to be related to low, rather than high, cortisol levels. This study aims to trace factors associated with 24-h urinary free cortisol levels in a sample of 23 elderly persons with major or minor depression and 21 non-depressed control subjects. Depressive episodes were subdivided according to severity and chronicity Ži.e. length and recurrence .. None of the depressed persons showed unusually high 24-h cortisol levels, and cortisol excretion was not elevated as compared with that in the control group, regardless of subtype of depression. The results suggest, however, that hyposecretion of cortisol may be a feature of chronic depressive episodes, especially in males. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Depressive disorder; Age; Sex; Chronic disease; Stress

1. Introduction Since the early 1960s, when the association of high cortisol levels with depression was first demonstrated Že.g. Gibbons and McHugh, 1963., hyperactivity of the hypothalamic-pituitaryadrenal ŽHPA. axis is a finding often reported in

U

Corresponding author. Tel.: q31-50-361-4550; fax: q3150-361-9722. E-mail address: [email protected] ŽA.J. Oldehinkel..

a subgroup of depressed patients Že.g. Carroll et al., 1976a,b; Stokes et al., 1984; Holsboer, 1988; Murphy, 1991; Maes et al., 1998.. On the other hand, several studies did not find a relation between major depression and elevated cortisol secretion Že.g. Schlechte et al., 1986; Anisman et al., 1999.. Dysthymia is not accompanied by elevations of cortisol and may even display reduced cortisol levels ŽThase and Howland, 1995; Licinio and Gold, 1997; Ravindran et al., 1997; Anisman et al., 1999.. This is consistent with the notion that relatively low levels of cortisol characteristi-

0165-1781r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 1 . 0 0 3 0 0 - 6

40

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

cally accompany chronic stress Že.g. Vingerhoets et al., 1996.. Low cortisol levels have also been found in post-traumatic stress disorders ŽPTSD. and chronic fatigue syndromes ŽCFS., irrespective of comorbid depressive illness ŽYehuda et al., 1990; Scott and Dinan, 1998.. These results suggest that cortisol hypersecretion only occurs in severely depressed patients with melancholic features, and that illness chronicity might be related to low, rather than high, cortisol levels. Studies on HPA-axis functioning in depression are often based on relatively homogeneous samples of severely depressed inpatients. Whereas this approach is justifiable and appropriate for many purposes, it does not provide information about cortisol levels found among mildly or moderately depressed persons in the general population. This study concerns cortisol excretion by elderly persons. Age has been found to be positively associated with cortisol secretion during depression ŽAsnis et al., 1981; Halbreich et al., 1984., especially in women ŽAkil et al., 1993. and severely depressed persons ŽJacobs et al., 1984.. However, Gotthardt et al. Ž1995. did not find age differences in basal cortisol levels between young and older depressed people. In the elderly, depressive states, although frequently associated with considerable suffering, relatively often do not meet the criteria for DSMIV major depression ŽErnst and Angst, 1995.. The prevalence of major depression in the community is approximately 2% and that of minor depression approximately 13% ŽBeekman et al., 1995.. It is, therefore, important to include persons with minor depressive symptoms when studying depression in later life. Studies comparing major and minor depression in the elderly suggest common vulnerability ŽVan den Berg et al., 2000. and common neurobiological substrates ŽKumar et al., 1998.. We investigated 24-h urinary free cortisol ŽUFC. levels in a sample of depressed and nondepressed elderly persons from the normal population and psychiatric outpatient clinics. We subdivided depression according to the severity Ži.e. minor vs. major. and chronicity of the episode. Chronicity was defined in two ways, namely ac-

cording to the length of the episode Žlonger vs. shorter than 2 years. and according to the recurrence of the episode. We hypothesize that: 䢇

䢇

䢇

depressed persons with melancholic features show elevated UFC excretion levels compared with control subjects; persons with non-melancholic non-chronic depressive episodes do not differ significantly from control subjects; and long-lasting Ži.e. longer than 2 years. or recurrent depressive episodes are associated with reduced levels of 24-h cortisol.

2. Methods 2.1. Subjects The study includes 23 depressed elderly subjects and 21 control subjects. The depressed cases were recruited from April 1996 until May 1998, as part of a more extensive study. Part of them Ž n s 8. were selected from participants of the Groningen Longitudinal Ageing Study ŽGLAS; Ormel et al., 1997, 1998., a community study of non-institutionalized persons who were aged 57 years or more in 1993; and part Ž n s 15. from mental health outpatient clinics. For a detailed description, see Van den Berg et al. Ž2000.. Depressed GLAS participants were traced by screening the eligible baseline population using the 15-item version of the Geriatric Depression Scale ŽGDS-15; Yesavage et al., 1982; Lesher and Berryhill, 1994.. In addition, general practitioners reported all GLAS baseline participants whom they identified as having depressive symptoms. Non-response on the screening questionnaire was 14.6%. Subjects with a GDS-15 score of 6 or more or with depressive symptoms according to their general practitioner were briefly interviewed by telephone Žnon-response 23.6%. to establish whether they had three or more depressive symptoms of at least subclinical severity. Those who did Ž n s 189. were put through a face-to-face interview. In addition to GLAS baseline participants, subjects were recruited from six outpatient

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

mental health clinics. If therapists judged elderly Ž55 years and older. patients to have a depressive disorder, they asked them for permission to pass on their name to the research staff. Of the 105 subjects whose names were passed on to us, 26.7% refused participation. In total, we administered 266 face-to-face interviews Ž189 to GLAS participants and 77 to mental health outpatients., of which 16 were discarded because of incomplete or unreliable data. To be included in the present study, subjects had to meet the below-described diagnostic criteria of DSM-IV major or minor depressive episode. These criteria were met in 132 subjects Ž68 GLAS participants, 64 mental health outpatients.. Furthermore, subjects had to be free of somatic conditions that could interfere with HPA-axis functioning, i.e. incontinence, asthmarbronchitis, gastrointestinal conditions, liver, gall bladder or kidney conditions, diabetes mellitus, thyroid gland disorder, Žconsequences of. stroke, chronic headache or migraine, chronic joint conditions Že.g. arthritis ., serious skin conditions, diseases of the central nervous system Že.g. Parkinson’s., cancer, and the use of corticosteroids or antibiotics; and should not have spoiled some of the 24-h urine. The total set of inclusion criteria were met in 23 persons, 8 originating from the GLAS study and 15 from mental health outpatient clinics. GLAS subjects and outpatients did not differ with respect to age Žmean age s 71.9 in GLAS vs. 71.8 in outpatients; t s 0.02, Ps 0.98. or severity of depression Žmean GDS-15 score s 7.8 in GLAS vs. 7.2 in outpatients; t s 0.37, Ps 0.72.. Control subjects were randomly selected from the GLAS population within either the lowest Žscore 0 or 1. or the highest Žscore 6 or more. quartile of the baseline neuroticism score on the Eysenck Personality Questionnaire ŽEysenck et al., 1985.. In total we interviewed 97 control subjects Ž52 with low and 45 with high neuroticism scores., of whom 22 were eligible for the present study, i.e. did not have any of the above-mentioned somatic conditions, were medication-free, and did not have a lifetime history of affective disorder. Stratified sampling on the basis of baseline neuroticism was done to study effects of psychological vulnerability to depression effi-

41

ciently but was irrelevant to the research questions dealt with in this article Žsubjects with high vs. low neuroticism scores did not differ with respect to 24-h UFC excretion; t s 0.81, Ps 0.46.. Preliminary analysis showed that one of the control subjects had an extremely high UFC value Žover 6.3 times the standard deviation higher than the mean.. Since this value greatly affected the results and could not be corrected satisfactorily by any transformation, it was removed from the dataset, leaving 21 control subjects. 2.2. Diagnosis Diagnostic assessment of the cases was based on the 10th version of the Present State Examination ŽPSE-10; Wing, 1996., administered by interviewers who were extensively trained by experienced staff members and maintained their skills in monthly booster sessions. The PSE-10, which is part of the Schedules for Clinical Assessment in Neuropsychiatry ŽSCAN; World Health Organization, 1992., generates diagnoses according to DSM-IV criteria ŽAmerican Psychiatric Association, 1994.. Diagnosis was assessed for the present state, that is, the month before the interview. We distinguished two categories of depression: DSM-IV major depressive episode and minor depressive episode according to research criteria defined in DSM-IV Žtwo to four symptoms including depressed mood, loss of interest, or loss of pleasure.. We did not use the diagnosis of dysthymia, because the distinction between dysthymic disorder and major depressive disorder in partial remission could not reliably be made in all cases. Furthermore, we wanted to examine the duration and the length of the episode separately. Therefore, diagnoses were made according to the symptoms present in the past month. The impairment criterion Žcriterion C. was not used in our diagnostic algorithms. Except for criterion C, our definition of major and minor depressive episode meets all DSM-IV criteria, i.e. the symptoms do not meet criteria for a mixed episode, they are not due to the direct physical effects of substance use or somatic illness, and they are not better accounted for by bereavement.

42

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

2.3. Cortisol Examination of urinary free cortisol ŽUFC. levels over a 24-h period is a simple and non-invasive method of estimating overall daily cortisol production. UFC levels have shown good agreement with plasma cortisol levels ŽStokes et al., 1984; Murphy, 1991. and have been found to covary with clinical changes ŽKling et al., 1994; Plotsky et al., 1998.. Subjects were provided with a container for urine collection and asked to collect all urine from 17.00 h one day to 17.00 h the next day. The volume of the 24-h urine ranged from 830 to 3780 ml and did not differ Ž Ps 0.20. between cases Žmean s 1815.5. and controls Žmean s 2040.2.. Urine was kept frozen at y20⬚C until assayed for cortisol. Cortisol was measured by radioimmunoassay ŽRIA. with locally prepared rabbit antiserum. Urinary cortisol was first purified on Sep-pack columns and isolated on Sephadex LH-20 columns. The intra-assay coefficient of variation was 8%, and the interassay variation was 13%. With this method, UFC levels of normal volunteers Žwithout adrenal gland dysfunction. have been found to range from 30 to 260 nmolr24 h, with most subjects having values between 50 and 100 nmolr24 h.

the Geriatric Depression Scale ŽGDS-15; Yesavage et al., 1982; Lesher and Berryhill, 1994., a 15-item depression questionnaire especially designed for the elderly with a score ranging from 0 to 15. The presence of somatic diseases in the year before the interview was assessed by means of a list of 18 diseases, concerning the respiratory system, cardiac system, gastrointestinal system, kidney, prostatic gland, endocrinological system, locomotor apparatus, neurological system, dermatological system and neoplasms. 2.5. Analysis Despite the hypotheses formulated in Section 1, the nature of this study is predominantly exploratory, and therefore all differences were tested two-tailed, with P-values - 0.05 considered statistically significant. Since we performed several statistical tests, the results may suffer from capitalization on chance: one would expect some 5% of the associations examined to be significant merely on the basis of chance. Therefore, it should be noted that a statistically significant result in this context does not have the same weight as significant results in an experimental design.

2.4. Other ¨ ariables 3. Results History of depression was gathered with a semi-structured interview specially developed for this study, which contained questions such as: when did the symptoms Ži.e. the depression symptoms as assessed with the PSE-10. start? Did they start suddenly or rather gradually? Since the start of the symptoms, have you had periods of 8 weeks or more where you had one or two symptoms at the most? Have you ever had periods like this one before? Control subjects were given an extensive description of a depressive episode according to our criteria and subsequently asked whether they had ever had such an episode in their lives Žthose who did were excluded from the analyses .. Chronic depression was defined as an episode that lasted for at least 2 years, consistent with the duration criterion for dysthymia, or as a recurrent episode. Severity of depression was assessed by

3.1. Sample characteristics Of all depressed cases, 47.8% Ž n s 11. had a major depression, of whom only one person met the criteria for melancholic depression; and 52.3% Ž n s 12. had a minor depression according to DSM-IV research criteria. Major depressive subjects used significantly more sedatives than minor depressive subjects Ž81.8% vs. 33.3%, Ps 0.03., whereas the use of antidepressants showed a trend in the same direction Žmajor depressives 81.8%, minor depressives 41.7%, Ps 0.09.. Control subjects were not put through a diagnostic interview to obtain DSM-IV diagnoses. However, mean scores on the Geriatric Depression Scale ŽGDS15. indicate that they had considerably fewer depressive symptoms than did cases Žcontrols: 0.4,

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

cases: 7.4, t s 9.3, P- 0.01.. Cases and controls did not differ with respect to age Žcases: mean s 71.8, range s 57᎐86; controls: mean s 69.3, range s 62᎐88, t s 1.1, Ps 0.29.. However, the percentage of females was significantly Ž ␹ 12 s 4.5, P s 0.04. higher in cases Ž65.2%. than in controls Ž33.3%.. 3.2. Urinary free cortisol (UFC) le¨ els 3.2.1. Cases ¨ s. controls The mean UFC level was 72.3 Žrange s 11.9᎐169.0. in the group of depressed cases, and 92.4 Žrange s 26.7᎐212.5. in the control subjects. Hence, overall UFC excretion tended to be lower in cases, but not significantly so Ž t s y1.69, Ps 0.10.. When the threshold value was set at 260 nmolr24 h, none of the subjects, neither controls nor cases, had abnormally high UFC levels. Because cases and controls differed with respect to gender, we checked whether UFC levels were different for males and females. Quite unexpectedly, depression appeared to be significantly related to decreased UFC secretion in males Žcases: mean s 59.9; controls: mean s 90.1, t s y2.25, Ps 0.04., but not in females Žcases: mean s 78.9; controls: mean s 96.8; t s y0.83, Ps 0.42.. UFC secretion was unrelated to age Žcases: r s 0.06, Ps 0.79; controls: r s 0.10, Ps 0.66.. Furthermore, neither use of antidepressants Žpredominantly selective serotonin reuptake inhibitors. nor use of sedatives Žbenzodiazepines derivatives. was related to UFC level Žantidepressants: t s 0.39, P s 0.70; sedatives: t s 0.41, Ps 0.69.. 3.2.2. Se¨ erity of depression UFC levels in minor depressions Žmean s 68.1, S.D.s 37.7. and major depressions Žmean s 76.9; S.D.s 41.5. were not significantly different Ž t s 0.53, Ps 0.60.. Table 1 represents the mean UFC levels by gender. In females, neither UFC levels in minor depressive episodes Ž t s y1.01, Ps 0.33. nor those in major depressive episodes Ž t s y0.72, Ps 0.72. differed significantly from levels in the control group. In males, on the other hand, UFC levels were significantly lower in major depressions Ž t s y2.38, P s 0.03.. The difference

43

between minor episodes and controls did not reach statistical significance Ž t s y1.48, Ps 0.16.. We hypothesized that persons with melancholic features would show elevated UFC levels compared with control subjects. Since only one person fulfilled all DSM-IV criteria for melancholic depression Ži.e. anhedonia or lack of reactivity to usually pleasurable stimuli, and at least three of the following symptoms: morning depression, early waking, psychomotor agitation or retardation, weight loss, and excessive guilt., we examined, within the group of cases, whether the number of melancholic symptoms, ranging from 0 to 5, was associated with UFC excretion. It was not Ž r s 0.17, Ps 0.43.. 3.2.3. Chronicity Chronicity of depression was defined according to the length Ži.e. shorter or longer than 2 years. of the episode and to psychiatric history, i.e. whether the present episode was the first ever or a recurrent episode. In 22% of the depressed persons, the present episode had lasted longer than 2 years, and in 61%, it was a recurrent episode. Length of episode was not related to recurrence Ž P s 0.99.. Furthermore, neither length nor recurrence of the depressive episode was associated with gender Žlength: Ps 0.99; recurrence: Ps 0.40., age Žlength: Ps 0.80; recurrence: Ps 0.98. or type of depression Žlength: Ps 0.16; recurrence: Ps 0.99.. Table 1 Urinary free cortisol levels for controls and cases subdivided according to severity and chronicity Group

Mean ŽS.D.. urinary free cortisol Žnmolr24 h. Males

Females

Controls

90.1 Ž27.2.

96.8 Ž60.6.

Minor episodes Major episodes

65.7 Ž43.1. 50.2 Ž21.0.

69.8 Ž38.8. 86.9 Ž43.8.

Short Ž- 2 years. episodes Long ŽG 2 years. episodes

62.1 Ž39.6. 53.1 Ž44.2.

82.3 Ž28.9. 65.1 Ž15.4.

First episodes Recurrent episodes

98.2 Ž34.9. 47.1 Ž27.0.

96.6 Ž49.5. 63.4 Ž23.4.

44

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

Whereas persons with a short episode and control subjects did not differ significantly from each other Ž t s y1.27, Ps 0.21., subjects with a longlasting depression had significantly lower UFC levels than control subjects Ž t s y2.62, Ps 0.02.. Similarly, UFC levels measured in first episodes did not differ from levels found in control subjects Ž t s 0.28, Ps 0.78., but levels in recurrent episodes were significantly lower Ž t s y2.98, P0.01.. Hence, regardless of their definition, chronic episodes were associated with decreased cortisol secretion. As Table 1 shows, the difference between chronic episodes and control subjects appeared to be larger in males Ž P- 0.10 for episode length, P- 0.01 for recurrence . than in females Žnon-significant differences in the expected direction.. In males, cortisol levels tended Ž Ps 0.08. to be reduced in short episodes as well, but not in first episodes Ž Ps 0.71.. Fig. 1 shows the mean UFC levels of the combined categories of length and recurrence of episode. There is a clear and significant Ž Ps 0.03. linear trend, ranging from short first episodes to long recurrent episodes. The effect of chronicity Ži.e. long-lasting andror recurrent episodes. was independent of medication use; we found reduced cortisol levels in

Fig. 1. Mean urinary free cortisol ŽUFC. levels by indicators of chronicity of depressive episode.

Table 2 Mean urinary free cortisol levels by use of medication and chronicity of depression

Short episodes Long episodes First episodes Recurrent episodes

Antidepressants

Sedatives

No

Yes

No

Yes

81.3 58.8 94.9 61.4

72.0 61.3 98.6 53.7

70.8 62.9 83.6 58.2

80.3 58.7 107.6 55.1

chronic episodes regardless of the use of antidepressants and sedatives ŽTable 2.. Since physical exercise has been found to stimulate the HPA axis Že.g. Rolandi et al., 1985; O’Connor and Corrigan, 1987., we further examined whether the effect of chronicity might be attributable to the fact that chronically depressed persons were less physically active. However, Žlack of. physical activity during the past month Ždefined as number of hours the respondents took a rest in the daytime. was not associated with cortisol excretion Ž r s y0.03, Ps 0.83..

4. Discussion This study examined correlates of 24-h free urinary cortisol ŽUFC. secretion in elderly subjects with and without depressive symptoms. We expected elevated UFC excretion in depressed persons with melancholic features, normal values in non-melancholic non-chronic depressives, and reduced cortisol levels in chronic Ži.e. with episodes longer than 2 years or recurrent episodes. depressives. Contrary to our hypothesis, we did not find abnormally high UFC outputs in any of the depressed persons; all had values below 260 nmolr24 h. Depressives with melancholic features did not have significantly increased UFC excretion compared with the control group. However, our hypotheses were corroborated in that we found an association of cortisol with chronicity: persons with a depressive episode lasting

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

longer than 2 years and persons with recurrent episodes showed lower UFC levels than other depressive persons and controls. This effect could not be ascribed to differences in age, depressive symptomatology, or mean physical activity. Rather unexpectedly, we found that the reduction of cortisol excretion was larger in males than in females. We are not aware of other studies reporting a comparable effect. Depressed women have been found to have higher cortisol levels than depressed men ŽAkil et al., 1993., which might compensate for the cortisol-reducing effect of chronicity in women. Similarly, cortisol levels have been found to increase with age in normal women but not in normal men ŽHalbreich et al., 1984., which might also act as a counterbalance. However, these postulations are both highly tentative. The fact that none of the depressed persons had strongly elevated levels of cortisol is remarkable in light of the often-found positive association of age and cortisol excretion in depressed patients ŽAsnis et al., 1981; Halbreich et al., 1984; Jacobs et al., 1984; Akil et al., 1993.. Since the age effect has been found to occur only in severe depressions ŽJacobs et al., 1984., the relative lack of severely depressed persons in our sample might explain our failure to find hypersecretion of cortisol among the cases. Whereas depressive disorders have been associated with hypersecretion of cortisol numerous times, the relation with cortisol hyposecretion is a less reported one. In a recent study, Anisman et al. Ž1999. found significantly reduced cortisol levels in persons with atypical depression and dysthymia who were characterized by mood reactivity, reversed neurovegetative symptoms, extreme fatigue and rejection sensitivity. Our small sample did not allow for examining atypical depressions properly. Provisional analyses suggested reduced cortisol levels in persons suffering from hyperphagia Žone of the reversed neurovegetative symptoms., but no significant associations with other atypical symptoms. Low cortisol rates have also been reported in patients with posttraumatic stress disorders ŽPTSD; Yehuda et al., 1990. and chronic fatigue syndromes ŽCFS; Scott and Dinan,

45

1998., regardless of whether they had a comorbid major depressive disorder. Hence, elderly persons with long-lasting or recurrent depressive symptoms might, endocrinologically, resemble PTSD or CFS patients. The similarity could be that both groups experience chronic stress, which has been associated with low cortisol Že.g. Eysenck, 1987; Kirschbaum and Hellhammer, 1994; Vingerhoets et al., 1996.. Chronic stress may lead to physiological adaptation in the form of heightened negative feedback sensitivity at the level of the hypothalamus or pituitary ŽYehuda et al., 1990.. To conclude, in this sample of elderly persons with minor or major depression, no one showed unusually high 24-h cortisol levels, and cortisol excretion was not elevated as compared with findings in control subjects, regardless of subtype of depression. However, the results suggest Žmild. hypofunction of the HPA axis in long-lasting and recurrent depressive episodes. The decrease in cortisol levels was largest in males. Since gender and chronicity of episode might be effect modifiers of the association between depression and cortisol secretion, it is recommended to take them into account in future studies.

Acknowledgements

This study was financed by grants from the Medical Science Foundation of the Dutch Organization for Scientific Research Ž904-57-068 and 904-57-069. and the Dutch government Žthrough NESTOR.. The data on the depressed patients were collected in collaboration with Els I. Brilman, M.A. Furthermore, we thank Gerda Bloem, Erwin H.A.M. Geerts, Ph.D., Roelie Nijzing, and Mieke van Schepen for their assistance during data collection; and the following mental health clinics for their willingness to recruit patients for this study: RIAGG Groningen, RIAGG Assen, Psychiatrische Universiteitskliniek Groningen, Ambulatorium Drachten, Medisch Centrum Leeuwarden, RIAGG Winschoten, and CGG Zuid.

46

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47

References American Psychiatric Association, 1994. Diagnostic and Statistical Manual of Mental Disorders, 4th ed. Author, Washington, DC. Akil, H., Haskett, R.F., Young, E.A., Grunhaus, L., Kotun, J., Weinberg, V., Greden, J., Watson, S.J., 1993. Multiple HPA profiles in endogenous depression: effect of age and sex on cortisol and beta-endorphin. Biological Psychiatry 33, 73᎐85. Anisman, H., Ravindran, A.V., Griffiths, J., Merali, Z., 1999. Endocrine and cytokine correlates of major depression and dysthymia with typical or atypical features. Molecular Psychiatry 4, 182᎐188. Asnis, G.M., Sachar, E.J., Halbreich, U., Nathan, R.S., Novacenko, H., Ostrow, L.C., 1981. Cortisol secretion in relation to age in major depression. Psychosomatic Medicine 43, 235᎐242. Beekman, A.T., Deeg, D.J., Van Tilburg, T., Smit, J.H., Hooijer, C., Van Tilburg, W., Kriegsman, D.M., 1995. Major and minor depression in later life: a study of prevalence and risk factors. Journal of Affective Disorders 36, 65᎐75. Carroll, B.J., Curtis, G.C., Davies, B.M., Mendels, J., Sugarman, A.A., 1976a. Urinary free cortisol excretion in depression. Psychological Medicine 6, 43᎐50. Carroll, B.J., Curtis, G.C., Mendels, J., 1976b. Neuroendocrine regulation in depression: II. Discrimination of depressed from non-depressed patients. Archives of General Psychiatry 33, 1051᎐1058. Ernst, C., Angst, J., 1995. Depression in old age. Is there a real decrease in prevalence? A review. European Archives of Psychiatry and Clinical Neuroscience 245, 272᎐287. Eysenck, H., 1987. Personality as a predictor of cancer and cardiovascular disease, and the application of behaviour therapy in prophylaxis. European Journal of Psychiatry 1, 29᎐41. Eysenck, S.B.G., Eysenck, H.J., Barrett, P., 1985. A revised version of the Psychotism Scale. Personality and Individual Differences 6, 21᎐29. Gibbons, J.L., McHugh, P.R., 1963. Plasma cortisol in depressive illness. Journal of Psychiatric Research 1, 162᎐171. Gotthardt, U., Schweiger, U., Fahrenberg, J., Lauer, C.J., Holsboer, F., Heuser, I., 1995. Cortisol, ACTH, and cardiovascular response to a cognitive challenge paradigm in aging and depression. American Journal of Physiology 268, R865᎐873. Halbreich, U., Asnis, G.M., Zumoff, B., Nathan, S., Shindledecker, R., 1984. Effect of age and sex on cortisol secretion in depressives and normals. Psychiatry Research 13, 221᎐229. Holsboer, F., 1988. Implications of altered limbic-hypothalamic-adrenocorticol ŽLHPA.-function for the neurobiology of depression. Acta Psychiatrica Scandinavica Suppl 341, 72᎐111. Jacobs, S., Mason, J., Kosten, T., Brown, S., Ostfeld, A., 1984. Urinary-free cortisol excretion in relation to age in acutely

stressed persons with depressive symptoms. Psychosomatic Medicine 46, 213᎐221. Kirschbaum, C., Hellhammer, D.H., 1994. Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology 19, 313᎐333. Kling, M.A., Geracioti, T.D., Licinio, J., Michelson, D., Oldfield, E.H., Gold, P.W., 1994. Effects of electroconvulsive therapy on the CRH-ACTH-cortisol system in melancholic depression: preliminary findings Žreview.. Psychopharmacology Bulletin 30, 489᎐494. Kumar, A., Jin, Z., Bilker, W., Udupa, J, Gottlieb, G., 1998. Late-onset minor and major depression: early evidence for common neuroanatomical substrates detected by using MRI. Proceedings of the National Academy of Sciences of the United States of America 95, 7654᎐7658. Lesher, E.L., Berryhill, J.S., 1994. Validation of the geriatric depression scale-short form among inpatients. Journal of Clinical Psychology 50, 256᎐260. Licinio, J., Gold, P.M., 1997. The neuroendocrinology of dysthymia. In: Licinio, J., Prilipko, L., Bolis, C.L. ŽEds.., Dysthymia in Neurological Disorders: Proceedings of WHO Meeting. World Health Organization, Geneva. Maes, M., Lin, A., Bonaccorso, S., Hunsel, F., van Gastel, A., van Delmeire, L., Biondi, M., Bosmans, E., Kenis, G., Sharpe, ´ S., 1998. Increased 24-hour urinary cortisol excretion in patients with post-traumatic stress disorder and patients with major depression, but not in patients with fibromyalgia. Acta Psychiatrica Scandinavica 98, 328᎐335. Murphy, B.E.P., 1991. Steroids and depression. Journal of Steroid Biochemistry and Molecular Biology 38, 537᎐559. O’Connor, P.J., Corrigan, D.L., 1987. Influence of short-term cycling on salivary cortisol levels. Medicine and Science in Sports and Exercise 19, 224᎐228. Ormel, J., Kempen, G.I., Deeg, D.J., Brilman, E.I., Sonderen, E., van Relyveld, J., 1998. Functioning, well-being, and health perception in late middle-aged and older people: comparing the effects of depressive symptoms and chronic medical conditions. Journal of the American Geriatric Society 46, 39᎐48. Ormel, J., Kempen, G.I., Penninx, B.W., Brilman, E.I., Beekman, A.T., van Sonderen, E., 1997. Chronic medical conditions and mental health in older people: disability and psychosocial resources mediate specific mental health effects. Psychological Medicine 27, 1065᎐1077. Plotsky, P.M., Owens, M.J., Nemeroff, C.B., 1998. Psychoneuroendocrinology of depression: hypothalamic-pituitaryadrenal axis. Psychoneuroendocrinology 21, 293᎐307. Ravindran, A.V., Merali, Z., Anisman, H., 1997. Dysthymia: a biological perspective. In: Licinio, J., Bolis, C.L., Gold, P. ŽEds., Dysthymia: From Clinical Neuroscience to Treatment. World Health Organization, Geneva. Rolandi, E., Reggiani, E., Franceschini, R., Bavastro, G., Messina, V., Odaglia, G., Barreca, T., 1985. Comparison of pituitary responses to physical exercise in athletes and sedentary subjects. Hormone Research 21, 209᎐213.

A.J. Oldehinkel et al. r Psychiatry Research 104 (2001) 39᎐47 Schlechte, J.A., Sherman, B.M, Pfohl, V., 1986. A comparison of adrenal cortical function in patients with depressive illness and Cushing’s disease. Hormone Research 23, 1᎐8. Scott, L.V., Dinan, T.G., 1998. Urinary free cortisol excretion in chronic fatigue syndrome, major depression and in healthy volunteers. Journal of Affective Disorders 47, 49᎐54. Stokes, P.E., Stoll, P.M., Koslow, S.H., Maas, J.W., Davis, J.M., Swann, A.C., Robins, E., 1984. Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. A multicenter study. Archives of General Psychiatry 41, 257᎐267. Thase, M.E., Howland, R.H., 1995. Biological processes in depression: an updated review. In: Beckham, E.E., Leber, W.R. ŽEds.., Handbook of Depression. Guilford Press, New York. Van den Berg, M.D., Oldehinkel, A.J., Brilman, E.I., Bouhuys, A.L., Ormel., J., 2000. Correlates of symptomatic, minor and major depression in the elderly. Journal of Affective Disorders 60, 87᎐95.

47

Vingerhoets, A.J.J.M., Ratliff-Crain, J., Jabaaij, L., Tilders, F.J.H., Moleman, P., Menges, L.J., 1996. Self-reported stressors, symptom complaints and psychobiological functioning. II: Psychoneuroendocrine variables. Journal of Psychosomatic Research 40, 191᎐203. Wing, J., 1996. SCAN and the PSE tradition. Social Psychiatry and Psychiatric Epidemiology 31, 50᎐54. World Health Organization, 1992. SCAN, Schedules for Clinical Assessment in Neuropsychiatry. Author, Geneva. Yehuda, R., Southwick, S.M., Nussbaum, G., Wahby, V., Giller, E.L., Mason, J.W., 1990. Low urinary cortisol excretion in patients with posttraumatic stress disorder. Journal of Nervous and Mental Disease 178, 366᎐369. Yesavage, J.A., Brink, T.L., Rose, T.L., Lum, O., Huang, V., Adey, M., Leirer, V.O., 1982. Development and validation of a geriatric depression screening scale: a preliminary report. Journal of Psychiatric Research 17, 37᎐49.