The hypothalamic-pituitary-thyroid axis in depressive patients and healthy subjects in relation to the hypothalamic-pituitary-adrenal axis

7

Psychiatry Research, 47:7-21

Elsevier

The Hypothalamic-Pituitary-Thyroid Patients and Healthy Subjects Hypothalamic-Pituitary-Adrenal Bengt F. Kjellman, Bertil Kagedal Received

February

Las-HAkan

Axis in Depressive in Relation to the Axis

Thorell, Tina Orhagen,

8. 1991; revised version received

December

Giacomo

d’Elia, and

7, 1992; accepted January 5, 1993.

Abstract. Serum levels of thyroid stimulating hormone (TSH), triiodothyronine (T3), free TJ index (ff~i), thyroxine (Tb), and free T4 index (ff,;) were measured before and after administration of I mg of dexamethasone in 54 depressive patients and 54 matched healthy subjects. A followup study at a mean of 2 years was performed in 28 patients in remission. Basal TSH levels were lower and t’T4, levels were higher in major depressive patients compared with healthy subjects. After dexamethasone administration, there was no significant change in any of the hormones in a subgroup of 46 major depressive patients in contrast to matched healthy subjects, who showed a significant decrease in the levels of TSH, TJ, and lT3;. The magnitude of the TSH response to dexamethasone in the major depressive patients was related to the level of nocturnal urinary cortisol excretion and pathological dexamethasone suppression test results. The level of TSH in depressive patients found in the healthy

during remission subjects.

Key Words. Affective hormones, cortisol.

disorder,

did

not

return

dexamethasone

to levels

suppression

similar

test,

to those

thyroid

The most consistently reported changes in the function of the hypothalamicpituitary-thyroid (HPT) axis in depressive states are low thyroid stimulating hormone (TSH) levels (Weeke and Weeke, 1980; Kijne et al., 1982; Kjellman et al., 1984; Unditn et al., 1986) and “blunted” secretion of TSH in response to thyrotropin releasing hormone (TRH) stimulation (Kirkegaard et al., 1978; Extein et al., 1981; Loosen and Prange, 1982; Kjellman et al., 1985; Unden et al., 1986). Regarding the thyroid hormones thyroxine (T4) and triiodothyronine (Tj), the findings are more inconsistent (Kirkegaard and Farber, 1981; Spratt et al., 1982; Kjellman et al., 1983; Orsulak et al., 1985; Unditn et al., 1986; Baumgartner et al., 1988). Increased levels of

At the time that the present article was submitted for publication. Bengt F. Kjellman, M.D., Ph.D.. was Psychiatrist and Assistant Professor, Department of Psychiatry, St. Gorans Hospital, Stockholm. LarsHlkan Thorell, Dr. Med. Sci., Ph.D., was Research Psychologist; Tina Orhagen, Dr. Med. Sci., Ph. D., was Research Nurse: and Giacomo d’Elia, M.D., Ph.D.. was Psychiatrist and Professor, Department of Psychiatry, Faculty of Health Sciences, Linkoping. Bertil Kagedal, M.D.. Ph.D., was Chemist and Assistant Professor, Department of Clinical Chemistry, University Hospital, Linkoping, Sweden. (Reprint requests to Dr. B.F. Kjellman, Dept. of Psychiatry, St. Gorans Hospital, S-l 12 81 Stockholm, Sweden.) 0165-I 781: 938 $06.00 @ 1993 Elsevier Scientific

Publishers

Ireland

Ltd.

8 the metabolically inert reversed T3 have been found in serum and cerebrospinal fluid in depressive patients (Kjellman et al., 1983; Linnoila et al., 1983). Dysregulation of the hypothalamic-pituitary-adrenocortical (HPA) axis in depressive patients has been extensively studied. The main findings have been of elevated cortisol levels, often during the night (Sachar et al., 1973; Thorell et al., 1988) and of a relative resistance of cortisol suppression to dexamethasone administration (Carroll, 1982; Berger et al., 1984; Thorell et al., 1988). Relationships between changes of the HPA and HPT axes in depressive patients have been shown to be weak (Kirkegaard and Carroll, 1980; Extein et al., 1981; d’Haenen et al., 1984; Dam et al., 1986). Recently, however, diverse responses of the HPT axis to dexamethasone administration in depressive patients as compared with healthy subjects have been reported (Rupprecht et al., 1989). Alterations in HPT hormones subsequent to dexamethasone administration were more prominent in melancholic patients than in other depressed patients (Rush et al., 1983). The aims of the present study were to investigate the function of the HPT axis in relation to the function of the HPA axis in depressive patients and in healthy subjects with regard to the following questions: (1) Are the basal levels of HPT hormones similar in groups of depressive patients and healthy subjects? (2) Are basal levels of HPT hormones unrelated to nocturnal cortisol in urine and morning cortisol in serum? (3) Are levels of HPT hormones unchanged subsequent to a standard test dose of dexamethasone in groups of depressive patients and healthy subjects? (4) If there are postdexamethasone changes in levels of HPT hormones, are the changes unrelated to the basal hormone levels? (5) If there are postdexamethasone changes in levels of HPT hormones, are the changes similar in groups of depressive patients and healthy subjects? (6) Are basal levels and possible postdexamethasone changes in levels of HPT hormones unrelated to the outcome of the dexamethasone suppression test? (7) Are basal and possible postdexamethasone changes in levels of hormones the same during clinical recovery as they are during depression? Methods The original group of subjects comprised 59 depressive patients at the Psychiatric Department of the University Hospital in Linkoping, Sweden, and 59 healthy subjects individually matched for age and sex. The healthy subjects were randomly sampled from the hospital staff population (n > 7,000). The subjects have been described in detail previously (Thorell, 1987; Thorell et al., 1987; Thorell and d’Elia, 1988). Because of missing data on TSH or thyroid hormones and TSH values outside the reference limit, the number of subjects in each group was confined to 54.3 I women and 23 men. The mean age of the patients was 42.6 (SD = 13. I) years and that of the healthy subjects was 42.9 (SD = 13.2) years. Fifteen patients were drug free (they had not taken antidepressant medication for more than 4 weeks and sedatives for more than 1 week). They were individually age-matched to 15 patients who had been receiving antidepressant medication for at least I month. The sex distributions were similar in the groups. Subjects.

Diagnostic Classification. At admission, eight patients suffered from a dysthymic disorder (DD) and 46 from a major depressive episode (MDE) (45 unipolar and I bipolar), including I9 patients with melancholia (MDEm) according to DSM-III criteria (American Psychiatric Association, 1980). The revised version of DSM-II/ was not available at the time of the study.

9

Depressive Symptomatology. Symptoms were rated according to the Comprehensive Psychopathological Rating Scale (CPRS) for depression (Asberg et al., 1978). Results from this scale are not presented in this study. The overall psychological disturbance was estimated by means of the Global Assessment Scale (GAS; Endicott et al., 1976). The scores range from zero (lowest level of function) to 100. Followup 36 months followup, from the recovery assessment

During the Period of Remission. The followup assessment was performed 3 to (mean = 24.2) after the investigation during the depressive episode. At the time of 10 patients refused to be investigated a second time, three had died, five had moved region or were otherwise unavailable, and eight did not meet the criterion for (a GAS score > 51). The number of patients who remained for the followup was 28.

HPA Variables. Concentrations of cortisol in urine and serum were determined by radioimmunoassay with the use of reagents (Immophase) from Corning Medical (Medfield, MA, USA). Measurements were made of nocturnal urinary cortisol (Cortisol U,). The subject was instructed to empty the bladder at 10 p.m. This urine was not saved. The subjects collected urine during the night until 8 a.m. the following morning or just after getting up in the morning, when the final urine sample was collected. The level of creatinine in urine was measured to control for a reliable urinary sampling. From this measurement, a hypothetical 24-hour excretion of creatinine was calculated for each subject. Subjects with a 24-hour excretion of creatinine less than the lower limit of normal (9.7 mmo1/24 hours for men and 8.8 mmol/24 hours for women) were excluded from the calculations. Nocturnal urinary cortisol was correctly sampled in 47 patients and 37 healthy subjects. Morning serum cortisol (Cortisol S,) measurements were made at 8 a.m. in 50 patients and 50 matched healthy subjects. To normalize the distributions, the urinary cortisol-creatinine ratio was expressed as log, of the ratio between the total amount of cortisol in nmol and the total amount of creatinine in mmol; the serum cortisol concentrations were expressed in log, of nmol/l (Thorell et al., 1988). In the dexamethasone suppression test (DST), a I-mg dose of dexamethasone (Decadrons, MSD) was orally administered at 10 p.m. An abnormal DST result was defined as a critical level of more than 200 nmol/l cortisol in serum in at least one of the blood samples taken at 8 a.m. or 4 p.m. during the following day. HPT Variables. Serum concentrations of TSH were determined by time-resolved fluorimmunoassay with reagents (Delfia TSH) from LKB Wallac (Turku, Finland). TSH was expressed in units of mu/l. Measurements of T4 were made with a modification of the competitive protein binding technique described by Seligson and Seligson (1972). Total serum concentrations of T3 were determined by radioimmunoassay with reagents from Farmos Diagnostika (Oulunsalo, Finland). T4 and T3 were expressed in nmol/l. The serum T3 uptake test was performed according to Nosslin (1965). The values for the T3 uptake test were used to calculate a free T, index: (ffdi) = (thyroxine X triiodothyronine uptake)/ 100. The ff,;, an indirect estimate of the free T4 concentration was first proposed by Clark and Horn (1965) although they used protein bound iodine instead of T4 in the calculations. Similarly, a free T, index (ff3;) was proposed by Solomon et al. (1976) as an indirect estimate of the free T, concentration. Changes in HPT hormones after dexamethasone (ATSH, AT3, Affji, AT4, and Aff4;) were the basal levels at 8 a.m. minus the levels at 8 a.m. the next day, 10 hours after the dexamethasone administration. Due to the introduction of new laboratory routines for thyroid hormones between the measurements during depression and in remission, only the TSH results are reported. Investigation Procedures. Each investigation was carried out over 3 days. Day 1 included information to the subjects, diagnostic classification, clinical ratings, and ascertainment of informed consent. In addition, urine sampling began for nocturnal urinary cortisol

10

measurements.

On day 2, venous blood was sampled at 8 a.m. for basal concentrations of and cortisol in serum. Body weight and body height were recorded. At 10 p.m., dexamethasone was administered. At 8 a.m. on day 3, postdexamethasone blood levels were measured of TSH, thyroid hormones, and cortisol; at 4 p.m, another measurement of cortisol was made for the DST. TSH, thyroid

hormones,

Statistical Procedures and Analyses. The hypotheses included a number of dependent variables (HPT hormones), independent variables (diagnosis, measures of cortisol, and DST result), and potentially confounding variables (age, gender, and basal levels of HPT hormones). One- and two-factor multivariate analyses of variance (MANOVAs) and covariance (MANCOVAs) constituted the primary statistical methods in the study. When inappropriate, one- or two-factor univariate analyses of variance (ANOVAs) or covariance (ANCOVAs) were used instead. Repeated measures designs were used when repetitive assessments of covariates were not necessary. Where appropriate, univariate hypotheses were combined to form a single multivariate hypothesis, two one-factor hypotheses were combined to form one two-factor hypothesis, confounding continuous variables were used as covariates, and interaction terms were included, all under one model. The models were then entered into preliminary analyses. Potential confounding variables and interaction terms that did not contribute stgnificantly were removed from the models and the modified models were retested to obtain the final result. Wherever possible. the statistical effects of age and gender were controlled by individual matching of subjects instead of by statistical methods. In all tests. the rejection limit was set to a = 0.05. In the multivariate analyses. Wilks’ y was used as the test parameter. Post hoc analyses used the Fisher Protected I.east Square Difference test. The fi coefficients from the ANOVAs between covariates and dependent variables were used as indicators of the direction of their relationships. Pearson’s productmoment correlation coefficients were used in correlation analyses. When ~2 tests were applied. they were corrected for ties. In contrast to the distributions of the HPT hormones. those o( cortisol in serum and urine were strongly skewed, so these measures were transformed by the natural logarithm for statistical reasons.

Results The results for HPA hormones

have been published

previously

(Thorell

et al.. 1988).

Basal Levels of HPT Hormones vs. Medication. There was no statistically significant effect of medication on the levels of HPT hormones according to a one-factor MANOVA that was controlled for age by individual matching and for gender by group matching (drug-free vs. medicated patients: n = lSf15: F= I .63: df= 5, 24; p = NS). Levels of HPT Hormones vs. Diagnosis and Cortisol. A one-factor MANOVA showed a significant statistical overall effect of MDE on HPT variables but not for melancholia or dysthymia (patients with MDE vs. healthy subjects: 17 = 46+46; F = 2.46; @= 5. 83; p = 0.04: patients with melancholia vs. healthy subjects: n = 19+19; F= 1.41; #= 5, 32; /> = NS; patients with dysthymic disorder vs. healthy subjects: n = 8+8; F = 3.12; ~/f = 5. IO; p = NS). Subsequent ANOVA showed that patients with MDE had significantly lower TSH and higher tT4i basal levels than the individually matched healthy subjects (Table I). Fig. I ylt;ents the results for the total number of individuals in the diagnostic and the healthy groups. Basal

II

Table 1. Basal levels of TSH, T3, fTsi, T4, and ff4i in relation to major depressive episode (MDE) compared with individually matched healthy subiects (HS) MDE (n = 46) TSH

(mu/l)

TJ (nmolil)

f-r31 Tq (nmolil)

f-rs

Mean

(n !:6)

1.93

2.75

SD

1.32

1.19

Mean

1.97

1.91

SD

0.38

0.39

Mean

1.97

1.88

SD

0.36

0.38

Mean

96.0

89.3

SD

21.7

17.6

Mean

96.7

87.9

SD

24.0

14.7

(df =: $0)

P

9.86

0.002

0.50

NS

1.23

NS

2.64

NS

4.48

0.037

Note. F from one-factor analysis of variance. TSH = thyroid stimulating hormone. T1 = triiodothyronine. index. T4 = thyroxine. fl.~ = free TA index.

fTa = free T)

Fig. 1a. Means and SDS of basal (Basal) and postdexamethasone (Post) levels of thyroid stimulating hormone (TSH) in healthy subjects (HS) (n = 46) and in patients with major depressive episode (MDE) (n = 46), melancholia (MDE,) (n = 19), and dysthymic disorder (DD) (n = 6) TSH, @J/L

Banal Post B~IVN~Post Basal Poet Basal Post MDE HS MDEm DD

Fig. lb. Means and SDS of basal (Basal) and postdexamethasone (Post) levels of triiodothyronine (T3) in healthy subjects (HS) (n = 46) and in patients with major depressive episode (MDE) (n = 46) melancholia (MDE,,,) (n = 19), and dysthymic disorder (DD) (n = 6)

Balal Pod HS

Banal Poat Basal Poet Balal Post MDE MDEm DD

12 Fig. lc. Means and SDS of basal (Basal) and postdexamethasone (Post) levels of free triodothyronine index (ffsi) in healthy subjects (HS) (n= 46) and in patients with major depressive episode (MDE) (n = 46), melancholia (MDEm) (n = 19), and dysthymic disorder (DD) (n = 8) tT3i,nmol/L

1

I&f-f cl Q l-8

I

I

I

I

I

I

I

Bad Po#t Bud Pat Burl Post BIMI Pant MDEm DD MDE HS

Fig. Id. Means and SDS of basal (Basal) and postdexamethasone (Post) levels of thyroxine (T4) in healthy subjects (HS) (n = 46) and in patients with major depressive episode (MDE) (n = 46), melancholia (MDE,) (n = 19), and dysthymic disorder (DD) (n = 8) T,,, nmol/L 130 -

‘::R

ff Bed

Pat HS

fi

f:

Burl Poet Basal Post Banal Pod MDEm DD MDE

Fig. le. Means and SDS of basal (Basal) and postdexamethasone (Post) levels of free thyroxine index (fT4i) in healthy subjects (HS) (n= 46) and in patients with major depressive episode (MDE) (n = 46), melancholia (MDE,) (n= 19), and dysthymic disorder (DD) (n= 8) fT,i, nmoVL 130 110 90 70

Ii I

Baaal Post HS

I

I

I

Basal Poet Bllll Post DD MDEm

13 Postdexamethasone Changes in Levels of HPT Hormones vs. Diagnosis. There was no significant postdexamethasone change in any of the HPT hormones in the MDE group (basal vs. postdexamethasone levels: n = 46-l-46; F = 1.15; df = 5, 86;~ = NS) in contrast to the significant changes found in the healthy subjects (basal vs. postdexamethasone levels: n = 46-t-46; F = 4.63; df = 5, 86; p = 0.0009) according to one-factor repeated measures MANOVA. Subsequent ANOVA showed significant decreases in the healthy group for TSH (F= 8.58,~ = 0.004), T3 (F= 7.28,p= 0.008) and ff3i (F= 11.98,~ =0.0008) (Fig. 1). Differences between patients with MDE and individually matched healthy subjects were significant for AfTji, AT4, and Aff4i when the respective basal levels of each HPT hormone and cortisol U, were taken into account (Table 2, Fig. 1). All the basal HPT-hormone levels were significantly related to their change-the higher the basal level, the greater the change (Table 2, Fig. 1). Cortisol U, was significantly related to ATSH (r = -0.38, df = 52, p = 0.004)-the higher the nocturnal urinary cortisol level, the smaller the changes in the TSH levels (see also Table 2). Cortisol S, was not significantly related to basal and postdexamethasone changes in HPT hormones. There was no significant difference in ATSH between patients with melancholia and individually matched healthy subjects ( F = 1.5 1; df = 1, 35; p = NS). However, the cutoff limit of an 80% postdexamethasone reduction of TSH used by Rupprecht et al. (1989) discriminated significantly melancholic patients from matched healthy subjects (patients below the 80% limit [n = 141 and above [n = 51 vs. healthy subjects below the limit [n = 61 and above [n = 121: ~2 = 4.54, df = 1, p = 0.033). Basal Levels and Postdexamethasone Changes of HPT Hormones vs. Outcome of the DST. One-factor MANOVA showed a nonsignificant relationship between DST outcome and the basal levels of the HPT hormones (MDE patients with normal vs. pathological DST results: n = 29f16; F= 1.19; df = 5,4O;p = NS). Significant statistical effects of gender and age were found, but their interactions with the DST findings were insignificant, so they were withdrawn from the analysis. One-factor ANCOVA with the basal level of TSH and cortisol U, as covariates showed that ATSH was significantly smaller in MDE patients with a pathological DST result than in those with a normal result (Table 3). The postdexamethasone changes in the thyroid hormones were not significantly related to the outcome of the DST (Table 3). Basal Levels and Postdexamethasone Changes of TSH in Remission. TSH was the only HPT hormone measured at followup in remission. The basal TSH level did not change significantly in remission. It was still significantly different from that of the healthy subjects (Table 4, Fig. 2~). The ATSH value was not significantly different in remission from the ATSH value during depression or in healthy subjects when the basal level of TSH was taken into account (Table 4, Fig. 26). A one-factor ANOVA showed a significant decrease in cortisol U, in remission (p = 0.001, post hoc Fisher Protected Least Square Difference) to levels similar to those of the matched healthy subjects (Table 4). A two-factor ANOVA of the effect of the DST in 27 patients with complete DST results during depression and in remission showed no statistically significant effect on ATSH (Fig. 2~).

9.5 3.9 10.8

-1.6

14.9

Mean

SD

2.1

-2.2

13.3

0.39

0.44

Mean

0.25

0.07

Mean

SD

SD

0.40

0.43

SD

1.06 0.20

0.65

0.04

Mean

Mean

SD

5.61

4.41

4.95

2.76

0.020

0.039

0.029

NS

0.18

0.18

0.61

7.29

8.90

37.44

20.75

56.38

0.47

(c&66)

P 0.42

0.008

0.004

<0.0001

<0.0001

<0.0001

p

Basallevel of hormone P

-0.30

-0.07

-0.10

-0.09

-0.29

0.02

0.00

3.41

2.83

7.78

&,66)

CortisolUn p

NS

NS

NS

NS

0.007

Note. The F value is from one-factor analysis of covariance; the X coefficient is from the regresslon model of the variable on the covanate. TSH = thyroid stimulating hormone. TB = trliodothyronine. fT3, = free TJ index. T4 = thyroxine. fl,, = free T4 Index.

Aff41

AT4 (nmolil)

AfTa,

AT3 (nmolil)

ATSH (mu/l)

p NS

0.68

2.46

MDEX HS (n= 46) (&66)

HS

0.44

(n= 46)

MDE

Sourceof variance

Table 2. Postdexamethasone changes in TSH, T3, ffsi, T4, and fT4i in patients with major depressive episode (MDE) and individually matched healthy subjects (HS) when basal levels of the corresponding hormone and nocturnal urinary cortisol (cortisol U,) were taken into account

(mu/l)

-5.6 20.8

-0.03

10.1

Mean

SD

0.48 -5.5

0.09 0.36

0.05

Mean

SD 17.0

0.36

0.47

-1 .o

0.05

0.03

Mean

SD

10.6

0.61

0.66

SD

SD

0.26

0.57

Mean

Mean

(n= 16)

(n=29)

2.27

1.77

0.06

0.02

4.79

(&I)

NS

NS

NS

NS

0.034

P

Normal*pathological

0.17

0.16

0.52

0.30

0.34

P

2.09

2.42

10.22

3.65

59.87

(c&l)

NS

NS

0.003

-5.28

-3.78

-0.15

-0.08

-0.23

<0.0001 NS

P

p

Basal level of hormone

1.05

0.51

2.87

1.12

3.42

(&4l)

Cortisol U,

NS

NS

NS

NS

NS

p

Note. The F value is from one-factor analysis of covariance; the fl coefficient is from the regression model of the dependent variable on the covariate. TSH = thyroid stimulating hormone. T3 = triiodothyronine. ffs, = free TJ index. Tq = thyroxine. fr4, = free Ts Index.

An41

A (nmolil)

An31

AT3 (nmol/l)

ATSH

Pathology

Normal

Source of variance

Table 3. Postdexamethasone changes in TSH, Ts, fTs(, T4, and fT4i relation to the outcome of the dexamethasone suppression test when basal levels of corresponding hormone and nocturnal urinary cortisol (cortisol U,) were taken into account

3.13

0.56

2.06

0.59

0.69

1.50

24

28

28

2.54

0.80

2.27

0.79

0.65

1.20

SD

24

28

28

n

1. The F value is from one-factor analysis of vanance. 2. The F value IS from one-factor analysis of covariance with basal level of TSH as the covariate. 3. Post hoc tests by Fisher’s Protected Least Sigmficant Difference.

Note. TSH = thyroid stimulating hormone.

Cortisol U,

24

28

ATSH

(mU/l)

28

TSH (mU/l)

n

Mean

SD

Mean

n

In remission (R)

During depression (D)

MDE

0.53

1.47

1.02

2.56

2.29

SD

3.20

Mean

HS

0.004 0.003 NS

D vs. HS3 R vs. HS3

0.003 D vs. R3

2,69

R vs. HS3 2.28

NS

D vs. HS3

D vs. HS’

NS 0.011

D vs. R3

0.054

0.046

R vs. HS3 D vs. R vs. HS*

NS

2,78

P 0.036 0.016

1.25

df 2,81

D vs. HS3

3.47

F

D vs. R3

D vs. R vs. HS’

Comparisons

Table 4. Basal level of TSH, ATSH, and basal level of nocturnal urinary cortisol (cortisol U,) in patients with major depressive episode (MDE) during depression (D) and the same patients in remission (R) and individually matched healthy subjects (HS)

17

Fig. 2a. Means and SD of basal. thyroid stimulating hormone (TSH)in patien its with major depressive episode (MDE) during depression, in the same patients in a period of remission, and in individually matched healthy subjects (n = 28) TSH, mu/L 4

Remlesion Deprenslon Patlcab with MDE

Healthy IubJecb

Fig. 2b. Means and SDS of postdexamethasone change in thyroid stimulating hormone (ATSH)in patients with major depressive episode (MDE) during depression, in the same patients during a period of remission, a;;~~in$$dually matched healthy subjects (n = 28) 31

,

Depression Remlesion Pntieab with MDE

Healthy subJecb

Fig. 2c. Means and SDS of postdexamethasone change in thyroid stimulating hormone (ATSH) in 27 patients with normal (n = 20) or pathologic results from the dexamethasone suppression test (DST) during a major depressive episode (MDE) and the same patients in a period of remission (n = 27) and in individually matched healthy subjects (n = 27) ATSH, mu/L

I 1

0

Norm Path Norm Path Depression Remission Patients with MDE The classification

into normal or pathological depressive episode.

I I Norm

Path

Healthy subjects

DST results was based on the DST carried out in the patients during the

18

Discussion The main results were as follows: (1) The basal TSH levels were lower and the ffdi levels were higher than those in the healthy subjects only in the patients with MDE. (2) The differences were unrelated to levels of cortisol in urine and serum. (3) TSH, TJ, and ff3i decreased significantly after dexamethasone in the healthy subjects, but there were no significant postdexamethasone changes in HPT hormones in the patients with MDE, dysthymia, or melancholia. (4) The postdexamethasone changes in all the HPT hormones were significantly related to their basal levels. The ATSH value was significantly inversely related to the nocturnal level of cortisol in urine. (5) When the basal levels of the HPT hormones were held constant, the levels of the thyroid hormone measures of fT3i, T4, and ff4i decreased following dexamethasone administration significantly more in the healthy group than in the MDE group; in the latter group, the postdexamethasone levels of T4 and fT4i even tended to increase. A classification into postdexamethasone TSH reducers and nonreducers differentiated melancholic patients from healthy subjects. (6) The ATSH was significantly smaller in those with a pathological DST outcome than in those with a normal outcome. There was no significant indication of normalization of the basal TSH levels or ATSH in remission in contrast to the nocturnal urinary cortisol level. Low TSH levels in depressive patients have been reported previously by some groups (Weeke and Weeke, 1980; Kijne et al., 1982; Kjellman et al., 1984). Higher ff4i levels in depressive patients than in control subjects have also been reported by some groups (Kirkegaard and Farber, 1981; Baumgartner et al., 1988) but not by others (Loosen and Prange, 1982; Kjellman et al., 1983; Unden et al., 1986). In the present study, the differences in TSH and ff4i could not be attributed to antidepressant medication. These results are in accord with current theories of primary increases in HPT axis activity in the depressive state and secondary downregulation of the thyrothropes in the pituitary. Further, as a result of downregulation and feedback mechanisms, the TSH levels are lowered, the TSH response to the TRH stimulation is blunted, and the fT4i levels are increased or normal. Previous studies have failed to demonstrate altered TSH levels in healthy subjects subsequent to administration of I mg of oral dexamethasone (Copinschi et al., 1975) or 4 mg of oral dexamethasone and 1 mg i.v. administration of dexamethasone (Besser et al., 1971). In the present study, however, the administration of dexamethasone was followed by significantly reduced TSH. In addition, the levels of TJ. and fT3i were also significantly reduced. There were, however, no significant changes in the levels of HPT hormones in the major depressive patients. There were significant differences in ATSH, AfTji, AT4, and Aff4i between the patients with MDE and the healthy subjects. The T4 levels even tended to increase in the patients following dexamethasone administration in contrast to the lowered levels of the healthy subjects. Rupprecht et al. (1989) also reported a significantly lesser degree of TSH reduction in 14 depressive patients. In accordance with that report, a cutoff limit of 80% postdexamethasone reduction of TSH significantly discriminated melancholic patients from matched healthy subjects in the current study.

19 Basal TSH levels in the patients with pathological DST results were similar to those in the patients with normal DST results, while the ATSH value was significantly smaller in patients with pathological DST results. The DST nonsuppressors displayed, in fact, the smallest TSH reduction observed in any of the patient groups in this study. Low TSH levels have been viewed as a partial explanation for blunted TSH responses to TRH stimulation in these patients (Kjellman et al., 1985; Maes et al., 1989). The data further indicate that the small response may be related to higher cortisol levels (dexamethasone -I endogenous cortisol) in patients who are resistent to suppression. A relationship between levels of cortisol and TSH is supported in this study by the negative correlation between nocturnal urinary cortisol and ATSH. These results are in contrast to those referred to in the review by Baumgartner et al. (1988) that the majority of studies did not report any negative correlations between cortisol measured by different methods, including DST and 24-hour urinary cortisol, and ATSH. The findings discussed in this paragraph indicate that a small TSH response to dexamethasone may be related to elevated levels of nocturnal cortisol. However, elevated cortisol levels may only be partial factors influencing the postdexamethasone TSH response since significantly smaller TSH response was found in patients at a 2-year followup in remission than in matched healthy subjects despite a completely normalized mean nocturnal urinary cortisol level. Incomplete normalization of the function of the HPT axis in remission has previously been reported by Baumgartner et al. (1988). They found that ATSH levels subsequent to TRH stimulation may return to normal after being blunted, remain blunted, or even become blunted after recovery. The results of the present study indicate differences in function of the HPT axis in major depressed patients compared with healthy subjects and dysthymic patients. The dysfunction is observed in basal TSH levels and in changes in TSH and thyroid hormones subsequent to dexamethasone administration. Acknowledgments. The authors thank Maude Mansfield (R.N.) for collecting the blood samples and for other valuable assistance. The Medical Research Fund of the County of ostergtitland, Sweden, provided support.

References Psychiatric Association. DSM-III: Diagnostic and Statistic Manual for Mental Washington, DC: American Psychiatric Press, 1980. &berg, M.; Perris, C.; Schalling, D.; and Sedvall, G. The CPRS-Development and applications of a psychiatric rating scale. Acta Psychiatrica Scandinavica, Suppl. 271, 1978. Baumgartner, A.; Gr%f, K.-J.; Kiirten, I.; and Meinhold, H. The hypothalamic-pituitarythyroid axis in psychiatric patients and healthy subjects: Parts 1-4. Psychiatry Research, American

Disorders.

24:271-332,

1988.

Berger, M.; Pirke, K.M.; and Doerr, P. The limited suppression test for the diagnostic process in psychiatry. 145:372-382,

Endocrinology, Psychiatry,

of the dexamethasone Journal

of Psychiatry,

1984.

Besser, G.M.; Ratcliffe, J.G.; Kilborn, J.R.; Urmston, between thyrotropin, corticotropin and growth hormone Carroll,

utility British

5 1:699-706,

197

1982.

Hall, R. Interaction in man. Journal of

I.

B.J. The dexamethasone 140:292-304,

B.J.; and secretion

suppression

test for melancholia.

British

Journal

of

20 Clark, F., and Horn, D.B. Assessment of thyroid function by the combined protein-bound iodine and resin uptake of I3tI-triiodothyronine. Journal Endocrinology

and Metabolism,

25139-45,

use of serum of Clinical

1965.

Copinschi, G.; L’Hermite, M.; Leclercq, R.; Golstein, J.; Vanhaels, L.; Virasoro, E.; and Robyn, C. Effects of glucocortoids on pituitary hormonal responses to hypoglycemia: Inhibition of prolactin release. Journal of Clinical Endocrinology and Metabolism, 40:442449,

1975.

Dam, K.; Mellerup E.T.; and Rafaelsen, O.J. The TRH stimulation test and the dexamethasone suppression test in depression. Psychiatry Research, 17:309-316, 1986. d’Haenen, H.; Kaufman, L.; DeNeert, P.; Cornet C.; and Raets, I. The correlation of the dexamethasone suppression test and thyrotropin-releasing hormone test results in different subtypes of depression. Acta Psychiatrica Scandinavica, 84:218-234, 1984. Endicott, J.; Spitzer, R.L.; Fleiss, J.L.; and Cohen, J. The Global Assessment Scale: A procedure for measuring overall severity of psychiatric disturbance. Archives of General Psychiatry,

33:766-771,

1976.

Extein, I.; Pottash, A.L.C.; and Gold, M.S. Relationship of thyrotropin-releasing hormone test and dexamethasone suppression test abnormalities in unipolar depression. Psyc’hiatr> Research, 4:49-53, 198 1. Kijne, B.; Aggernaes, H.; Fog-Moller, F.; Harrestrup Andersen, H.; Nissen, J.; Kirkegaard, C.; and Bjorum, N. Circadian variation of serum thyrotropin in endogenous depression. Psychiatry

Research,

6:277-282,

1982.

Kirkegaard, C.; Bjorum, N.; Cohn, D.; and hormone (TRH) stimulation test in manic-depressive 35:1017-1023,

Lauridsen, U.B. Thyrotropin-releasing illness. Archives of General Psychiatry.

1978.

Kirkegaard, C., and Carroll, B.J. Dissociation of TSH and adrenocortical disturbances in endogenous depression. Psychiatry Research, 3:253-264, 1980. Kirkegaard, C., and Farber, J. Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression. Acta Endocrinologica (Copenhagen), 96: 199-207, 1981. Kjellman, B.F.; Beck-Friis, J.; Ljunggren, J.-G.; Unden. F.; and Wetterberg, L. Twentyfour hour serum levels of TSH in affective disorders. Acta Ps.whiatrica Scandinavicu, 69:491502,

1984.

Kjellman, B.F.; Ljunggren, J.G.; Beck-Friis, J.; and Wetterberg, L. Reversed 7, levels in affective disorders. Psychiatry Research, 10: I-9, 1983. Kjellman, B.F.; Ljunggren, J.-G.; Beck-Friis, J.; and Wetterberg, L. Effect of TRH on TSH and prolactin levels in affective disorders. Psychiatry Research, 14:353-363, 1985. B.A.; Maleinen, T.; and Rubinow, D. CSF Linnoila, M.; Cowdry, R.; Lamberg, triiodothyronine (rT3) levels in patients with affective disorders. Biological Psjchiatr,,, 18:1489-1492,

1983.

Loosen, P.T., and Prange, A.J. Serum thyrotropin hormone in psychiatric patients: A review. American

response Journul

to thyrotropin of P.sychiutr.v,

releasing 139:405-416,

1982.

Maes, M.; Vandewoude, M.; Maes, L.; Schotte, C.; and Cosyns, P. A revised interpretation of the TRH test results in female depressed patients. Journal of A.ffective Disorders. l6:203213,

1989.

Nosslin,

test (T, test) with Sephadex. 17(Suppl. 86): 177. 1965. Orsulak, P.J.; Crowley, G.; Schlesser, M.A.; Giles. D.: Fairchild, C.; and Rush, A.J. Free triiodothyronine (T,) and thyroxine (T,) in a group of unipoiar depressed patients and normal subjects. Biological Psychiatry, 20: 1047-1057, 1985. Rupprecht, R.; Rupprecht, C.; Rupprecht. M.; Noder, M.; and Mahlstedt, J. Triiodothyronine, thyroxine, and TSH response to dexamethasone in depressed patients and normal controls. Biological Psychiatry, 25:22-32. 1989.

Scandinavian

B. A simplified Journal

technique

for the triiodothyronine

of Clinical and Laboratory

Investigation,

21

Rush, A.J.; Schlesser, M.A.; Roffwarg, H.P.; Giles, D.E.; Orsulak, P.J.; and Fairchild, C. Relationships among the TRH, REM latency, and dexamethasone suppression tests: Preliminary findings. Journal of Clinical Psychiatry, 44:23-29, 1983. Sachar, E.J.; Hellman, L.; Roffwarg, H.; Halpern, F.; Fukushima, D.; and Gallagher, T. Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Archives of General Psychiatry, 28: 19-24, 1973. Seligson, H., and Seligson, D. Measurement of thyroxine by competitive protein binding. Clinica Chimica Acta, 38:199-205, 1972. Solomon, D.H.; Benotti, J.; DeGroot, L.J.; Greer, M.A.; Oppenheimer, J.H.; Pileggi, P.J.; Robbins, J.; Selenkow, H.A.; Sterling, K.; and Volpe, R. Revised nomenclature for tests of thyroid hormones in serum. Journal of Clinical Endocrinology and Metabolism, 42:595-598, 1976. Spratt, D.I.; Pont, A.; Miller, M.B.; McDoughall, I.R.; Bayer, M.F.; and McLaughlin, W.T. Hyperthyroxinemia in patients with acute psychiatric disorders. American Journal of Medicine, 73:41-48, 1982. Thorell, L.-H. Electrodermal activity in depressive patients. Its relationship to symptomatology, suicidal behaviour, cortisol dysregulation, and clinical recovery. Linkoping, Sweden: Linkoping University (Medical dissertation no. 249), 1987. Thorell, L.-H., and d’Elia, G. Electrodermal activity in depressive patients in remission and in matched healthy subjects. Acta Psychiatrica Scandinavica, 78:247-253, 1988. Thorell, L.-H.; Kjellman, B.F.; and d’Elia, G. Electrodermal activity in antidepressant medicated and unmedicated depressive patients and in matched healthy subjects. Acta Psychiatrica Scandinavica, 76:684-692, 1987. Thorell, L.-H.; Kjellman, B.F.; d’Elia, G.; and Klgedal, B. Electrodermal activity in relation to cortisol dysregulation in depressive patients. Acta Psychiatrica Scandinavica, 78:743-753, 1988. Unden, F.; Ljunggren, J.-G.; Kjellman, B.F.; Beck-Friis, J.; and Wetterberg, L. Twentyfour hour serum levels and decreased TSH response to TRH in affective disorders. Acta Psychiatrica Scandinavica, 73:358-365, 1986. Weeke, A., and Weeke, J. The 24-hour pattern of serum TSH in patients with endogenous depression. Acta Psychiatrica Scandinavica, 62:69-74, 1980.