Neuroendocrine challenge tests in depression: a study of growth hormone, TRH and cortisol release

Journal of Affective

Disorders,

18 (1990) 229-234

229

Elsevier

JAD

00686

Neuroendocrine challenge tests in depression: a study of growth hormone, TRH and cortisol release Siobhan Departmeni

Barry and Timothy

G. Dinan

of Psychiatry, St. James’s Hospital, Dublin 8, Republic of Ireland (Received (Revision

7 February

1989)

received 20 July 1989)

(Accepted

1 August 1989)

Summary Thirty

drug-free

patients

fulfilling

the DSM-III

criteria

for major

depression

serially

underwent

the

dexamethasone suppression test (DST), thyroid stimulating hormone (TSH) test and a growth hormone (GH) challenge test with oral desipramine. Fifty-three per cent of the sample showed a blunted GH response, 47% were DST non-suppressors while 26% had a blunted TSH response. Eighty per cent of patients showed some biological abnormality. There was no clear association between any of these abnormalities. Neither was there any association between the neuroendocrine parameters studied and the severity of depression or patient gender. There was a trend for increasing GH blunting and DST non-suppression

with increasing

Key words: Neuroendocrine

age.

challenge

tests;

Depression;

Introduction

disorder proposes that some, if not all, depressions are associated with an absolute or relative de-

Lecturer,

for correspondence: Department

Dublin 8, Republic 016%0327/90/$03.50

hormone;

TRH;

Cortisol

ficiency of catecholamines, particularly NA, at functionally important receptor sites in the brain

Much of the biological literature on depression concerns the monoamine neurotransmitters noradrenaline (NA), dopamine (DA) and serotonin (5HT). The catecholamine hypothesis of affective

Address

Growth

of

Siobhan

Psychiatry,

St.

Barry,

MRCPsych.,

James’s

Hospital,

of Ireland. 0 1990 Elsevier

Science

Publishers

(Schildkraut, 1965). NA innervation of the forebrain derives largely from the locus coeruleus via the dorsal bundle. NA innervation of the hypothalamus arises mainly from the more caudal cell groups projecting through the central tegmental tract (Willner, 1985). The paraventricular nucleus and the median eminence which play a major role in the hypothalamic regulation of pituitary neuroendocrine function are intimately interconnected with the ventral NA bundle cell groups. Consequently, the ventral bundle is thought to have an important influence on neuroendocrine function (Sawchenko, 1982).

B.V. (Biomedical

Division)

230

NA systems are involved in a variety of neuroendocrine effects (Ettigi and Brown, 1977; Risch et al., 1981). NA exerts a tonic inhibitory effect over

the

hypothalamic-pituitary-adrenal

(HPA)

We have found that normal healthy subjects when given a challenge dose of desipramine (1 mg/kg body weight) increase their serum GH levels by at least 5 mU/l above baseline and this value offers the best discrimination

axis which is probably mediated by the ventral bundle. A substantial percentage of patients with

pressives

endogenous

report

depression

exhibit

characteristic

dis-

(Dinan

describes

and

between Barry,

controls

1989).

the simultaneous

and de-

The

present

investigation

of

turbances of HPA function. Cortisol secretion is excessive and resistant to normal feedback inhibition (Pepper and Krieger, 1984) as demonstrated

DST, TSH and GH responses to pharmacological challenges carried out in patients fulfilling the DSM-III criteria for major depressive disorder

by the dexamethasone suppression (Carroll et al., 1981). The thyroid stimulating hormone

(American

test

(DST)

(TSH)

re-

sponse to thyrotropin releasing hormone (TRH), the TSH test, has been described as impaired in 25% of depressed euthyroid patients (Loosen and Prange, 1982). It is suggested that 5HT inhibits the release of TRH (Ettigi and Brown, 1977; Banki and Arato, 1983). However, low NA activity has

Psychiatric

Association,

1980).

Methodology We studied 19 inpatients and 11 outpatients (20 female and 10 male) who were suffering from DSM-III major depressive disorder (for characteristics

see Table

1). All patients

were

drug-free,

of

either not yet having commenced treatment or subject to a 16day wash-out of psychotropic

TSH blunting (Reichlin, 1975; Extein et al., 1982). Overall, it seems likely that a blunted TSH re-

medication. Temazepam was allowed as a hypnotic. Twenty-one of the patients had received no

sponse

psychotropic medication in the previous 6 months. Premenopausal women were tested midway through their menstrual cycle and those taking

also

been

implicated

to the TRH

the central itary-thyroid

as a possible

challenge

reflects

mediator

a defect

in

regulation of the hypothalamic-pitu(HPT) axis but no precise explana-

tion implicating a specific neurotransmitter or neurotransmitters has yet been verified. Depressed patients show some evidence of altered NA receptor function in that the responsiveness of postsynaptic (Ye receptors appears to be reduced (Matussek et al., 1980). Direct assessment of human receptor function is, in practice, quite difficult. Central receptor function can be indirectly measured pharmacological

by neuroendocrine responses to probes. NA influences have been

demonstrated for the release of growth hormone (GH) (La1 et al., 1975) using a selective 0~~agonist, clonidine. There is considerable evidence from animal work to suggest that this response

depends

on the stimulation of the (Ye adrenoceptors of the arcuate nucleus of the hypothalamus (Katakami et al., 1984). An acute oral challenge of the tricyclic antidepressant desipramine, which acts as a NA reuptake inhibitor, also stimulates (Y? receptors (Laakmann et al., 1986) and causes a release of GH in normal healthy controls. This response is blunted in depression (Laakmann et al., 1977; Dinan and Barry, 1989) and especially so in poststroke depression (Barry and Dinan, submitted).

oral contraceptives were excluded (we have previously found marked fluctuations in neuroendocrine responses at different points in the menstrual cycle; Yatham et al., 1989). All patients were physically healthy, euthyroid and had no previous history of thyroid disease or lithium usage. Patients aged over 45 had a baseline ECG. Severity of depression was assessed by the Hamilton Depression Rating Scale (HDRS; Hamilton, 1967) and only those with a severity than 17 were considered suitable

score of greater for inclusion.

On day 1, the TRH test was carried out. Patients presented fasting at 8.30 a.m. An indwelling cannula was inserted in a forearm vein. A baseline blood sample was taken for thyroxine and TSH estimation. Ten minutes later a further baseline sample was taken followed by an injection of 200 pg TRH (Roche) over a 2-min interval. Further blood samples were drawn at 20 and 60 min. Patients remained on bed rest for the duration of the test. Serum TSH was estimated by radioimmunoassay (Pekary et al., 1975). Basal TSH estimation was given as the average of the two initial blood

231

samples. ATSH was calculated as peak serum TSH concentration minus basal serum TSH concentration. A blunted TSH response was defined as ATSH of less than 5 mu/l. Loosen and Prange (1982) indicate that this offers the best discrimination between depressives and healthy controls. Previous studies in this department of 30 healthy controls support this observation (unpublished). On the same day at 10 p.m. the DST was carried out. The patient was given 1 mg synthetic dexamethasone orally. At 4 p.m. the following day, a venous blood sample was drawn for cortisol estimation. A cortisol level of greater than 137 nM/l (5 pg/dl) was considered to be abnormal (Carroll et al., 1981). On day 3 the GH challenge took place. An indwelling cannula was inserted into a forearm vein at 8.30 a.m., following an overnight fast. The patient was allowed to relax for 20 min before blood was taken for growth hormone estimation. Two baseline 8-ml samples were collected with a 15-min interval in lithium-heparin tubes. Subjects remained resting for the duration of the test and were prevented from sleeping. An oral dose of desipramine (1 ml/kg body weight) was given. Blood for further growth hormone estimation was collected at 90, 120 and 180 min following oral desipramine. Growth hormone was assayed by a double-antibody radioimmunoassay (Diagnostic Products Corporation Method; Raite, 1983). Subjects with baseline growth hormone levels greater than 3 mU/l were excluded. Responses were regarded as blunted if growth hormone levels failed to rise at least 5 mU/l above baseline values. Results Twenty-four patients (80%) showed some abnormality on at least one of the parameters studied. Sixteen patients (53%) had a blunted GH response to the desipramine challenge. Fourteen patients (47%) were DST non-suppressors. Eight patients (26%) had a blunted TSH response to the TRH challenge (Table 1). Nine patients (30%) were both DST non-suppressors and had a blunted GH response. We could find no statistical association between DST non-suppression and blunted GH responses (x2 = 0.62, df = 1, NS). Four patients (13%) had simul-

TABLE

1

PATIENT AND

CHARACTERISTICS

INCLUDING

DST,

TSH

GH RESPONSES

Sex

As

HDRS

F

58

43

ATSH 8.5 (+)

0.0 ( - )

78.3 ( + )

F

28

25

2.8 ( - )

5.2 (+)

48.2 ( + )

F

39

36

3.7 (-)

0.0 ( - )

33.4 (+)

F

19

29

9.8 (+)

9.4 (+)

63.3 ( + )

F

35

32

4.6 ( - )

16.5 (+)

413.7 ( - )

F

20

33

9.0 (+)

15.5 (+)

F

65

31

3.4 (-)

0.0 ( - )

359.9 ( - )

F

75

22

5.3 (+)

0.0 ( - )

150.3 ( - )

F

60

23

16.4 ( + )

0.0 ( - )

76.0 ( + )

F

33

24

14.1 ( + )

13.4 ( + )

108.0 ( + )

F

38

29

6.2 ( + )

0.0 ( - )

333.2 ( - )

F

55

32

7.2 ( + )

9.7 ( + )

307.4 ( - )

F

30

19

11.2 (+)

0.0 ( - )

F

26

22

22.1 ( + )

6.5 ( + )

352.7 (-) 257.7 ( - )

AGH

DST

132.0 (+)

39.3 ( + )

F

26

31

7.9 ( + )

0.0 (-)

F

61

38

7.8 ( + )

51.3 (+)

F

52

30

3.6 (-)

33.0 ( + )

F

13

34

14.8 (+)

0.0 ( - )

150.0 (-)

F

43

30

3.9 (-)

3.5 (-)

435.3 ( - )

F

29

36

10.3 ( + )

3.3 (-)

45.3 (+)

M

41

22

10.2 ( + )

0.0 (-)

30.0 ( + )

M

36

30

6.4 (+)

46.6 ( + )

M

30

36

6.0 ( + )

21.5 (+)

M

29

25

12.1 (+)

M

30

27

4.8 (-)

M

25

31

7.5 (+)

3.2 ( - )

358.0 ( - )

M

60

34

17.7 (+)

2.2 ( - )

213.3 (-)

16.9 (+) 4.8 ( - )

317.0 (-) 38.7 (+)

35.8 ( + ) 402.2 ( - ) 36.5 ( + ) 191.0(-)

M

41

19

5.0 (+)

10.9 ( + )

M

50

30

9.3 (+)

0.0 (-)

53.5 (+)

M

44

19

4.8 ( - )

12.7 ( + )

52.3 (+)

( +).

normal response

to challenge;

(-

), abnormal

49.9 ( + )

response

to

challenge.

taneously blunted GH and TSH responses. No statistically significant relationship was found between GH and TSH blunting (x2 = 0.48, df = 1, NS). Four patients (13%) were DST non-suppressors and also had blunted TSH responses. These phenomena appeared to occur independently (x2 = 0.48, df= 1, NS). We examined each of the biological parameters in turn to determine if a statistical relationship could be found between abnormality on any of these factors and severity of depression on the HDRS. We correlated GH and TSH response (as measured both by area under the curve and maximum response relative to baseline) with the HDRS for each patient. No significant correlations were found (r (GH) = 0.17,

232 TABLE

2

ENDOCRINE

RESPONSES

IN RELATION

TO AGE

AND

SEX ATSH

AGH

cut-off

DST

Nor-

Blunt-

Nor-

Blunt-

Nor-

Blunt-

ma1

ed

ma1

ed

mal

ed

< 35 10

2

I

5

7

5

5

5

5

5

7

3

7

1

2

6

2

6

22

8

14

16

16

14

35-54 (n=lO) 55 + (n=E) Total n = 30

x2 = 5.2

x* =1.19

x2 = 0.8

df = 2. NS

df = 2, NS

df = 2. NS

Male 8

2

5

5

6

4

14

6

9

11

10

10

22

8

14

16

16

14

Female (n=20) Total n = 30

between

(Dinan

found the test useful with endogenous and depression ity scale). marginally

depressives

and Barry,

1989).

and

healthy

We have

in distinguishing non-endogenous

not

patients forms of

(as judged by the Newcastle endogenicIn the present study it is found to be more sensitive than the DST in detect-

ing major depression. not, however, correlate

Response on the test does with severity of depression

as assessed by the HDRS. The test may have some predictive ability. Those patients who when unmedicated show blunting tend to have a better response

to treatment

with

either

electroconvul-

sive therapy or tricyclic antidepressants (Barry and Dinan, 1989). We have suggested that NA (Ye

(2) sex (n=lO)

point

controls

(1) 4~ (n==12)

tion, which is complicated by interindividual absorption differences. Our previous work indicates that a response of 5 mU/l offers an effective

x2 = 0.02 (with Yak’s

d/=1,

NS

x= = 0.66

x2 = 0.26

correction)

d/ = 1, NS

df = 1, NS

NS; Y (TSH) = 0.13, NS). Neither did severity of depression correlate with the post-dexamethasone cortisol level (r = 0.29, NS). In analysing our data we also divided our subjects by sex, and also into three broad age groupings. However, we did not find that any of the abnormalities could be attributed factors (Table 2).

to age or gender

Discussion Our results clearly demonstrate biological abnormality in patients

a high level of who fulfill the

DSM-III criteria for major depressive disorder. Only one in five patients had normal responses in all three tests. There is some overlap between the abnormal results but why patients show abnormality on a specific test is not clear. The desipramine/GH stimulation test is relatively novel. It is less subjectively unpleasant than the clonidine/GH stimulation test but has the disadvantage of using the oral route of administra-

receptor downregulation is a homoeostatic mechanism which comes into play in depression but is not involved cess. Mitchell functioning

in the core pathophysiological

pro-

et al. (1988) assessing (Ye adrenoceptor using the clonidine/GH stimulation

test suggest that it is a trait marker which does not normalise with effective treatment. Blunted responses in the present study are not associated with any specific clinical features of depressive illness. Recently we have reported an association between such blunting and the presence of gastrointestinal (GI) symptoms (Ahkion et al., 1989). The GI symptoms on the HDRS may not be sensitive enough to detect a relationship. Eight patients had a blunted TSH response and this level ports Five with show

of blunting is consistent with previous re(for review see Loosen and Prange, 1982). of the eight had responses which normalised treatment while the other three continued to blunting even when normothymic. These

three were characterised by the fact that they each had a strong family history of affective disorders and numerous admissions for treatment of depression. They were undoubtedly the most chronic of the 30 patients assessed. Takahashi et al. (1974) have also found a link between TSH blunting and chronicity of depression. Numerous putative transmitters control the release of central TRH including the monoamines NA, DA and 5HT. Both NA and DA appear to stimulate TRH cells

233

(Reichlin, 1974) and 5HT appears predominantly to inhibit them (Reichlin, 1974). Abnormalities of 5HT metabolism in depression may account for increased output of TRH leading eventually to downregulation of the TRH receptor and thus the blunted response. If NA dysfunction was responsible for the blunting one might expect a greater overlap in abnormal responses between the (Ye and TRH stimulation tests. Only four patients had this combined abnormality. Our finding of 47% DST non-suppression is consistent with the large volume of literature in this area. Subsensitivity of (Y* adrenoceptors could result in increased adrenocorticotrophic hormone (ACTH) output leading to ACTH receptor downregulation and resultant DST non-suppression. Previous reports have found a link between DST non-suppression and GH blunting (Berger et al., 1982; Katona et al., 1986; Dinan and Barry, 1989). In the present series of patients no significant association was established between the results of the two tests. There is, however, a trend for an increase in both GH blunting and DST non-suppression with increasing patient age but this does not reach statistical significance. The three tests were conducted over a 3-day period and this raises the possibility of one test influencing another. This may be the case but the fact that the results are in general in keeping with published reports of each test in isolation would suggest it is not. Clearly there is ethical difficulty in unduly delaying treatment in severely depressed patients. Our problems were compounded in younger female patients in that we delayed endocrine testing until a set point in their menstrual cycle. This has not in general been the practice in research to date but our published data (Yatham et al., 1989) and unpublished data suggest that monoamine receptor sensitivity markedly fluctuates throughout the menstrual cycle. In the case of (Ye receptors in healthy controls we find maximal responses in mid-cycle which significantly diminish premenstrually. The 2-week wash-out of psychotropic medication is probably inadequate, but 21 of the 30 patients in this study were medication-free for more than 6 months. There were no significant response differences between patients who were entirely medication-free and those subjected to a 2-week wash-out.

The use of multiple endocrine tests in the same patients during both depressive episodes and periods of remission opens the possibility of delineating biological subgroups and determining the relative predictive value of the various tests. The present study describes such an approach in a relatively large sample of depressed patients.

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