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.
References Ahkion, S., Chua, A., Kelly, A., Keeling, P.W.N., Barry, S. and Dinan, T.G. (1989) Abnormal forebrain noradrenergic alpha-2 receptor functioning in irritable bowel syndrome. Gastroenterology 5 (Suppl.), A3. American Psychiatric Association (1987) DSM-III-R: Diagnostic and Statistical Manual of Mental Disorders, 3rd edn. rev. American Psychiatric Association, Washington, DC. Banki, CM. and Arato, M. (1983) Amine metabolites and neuroendocrine responses related to depression and suicide. J. Affect. Disord. 5, 223-232. Barry, S. and Dinan, T.G. (1989) The effect of antidepressant treatment on alpha-2 adrenoceptor function in DSM-III major depression. Irish J. Psychol. Med. (in press). Berger, M., Doerr, P. and Lund, R. (1982) Neuroendocrinological and neurophysiological studies in major depressive disorders: are there biological markers for the endogenous subtype? Biol. Psychiatry 17, 1217-1242. Carroll, B.J., Feinberg, M. and Greden, J.F. (1981) A specific laboratory test for the diagnosis of melancholia. Standardisation, validation and clinical utility. Arch. Gen. Psychiatry 38, 15-22. Dinan, T.G. and Barry, S. (1989) Growth hormone responses to desipramine in endogenous and non-endogenous depression. Br. J. Psychiatry (in press). Ettigi, P.G. and Brown, G.M. (1977) Psychoneuroendocrinology of affective disorder: an overview. Am. J. Psychiatry 134.493-501. Extein, I., Pottash, A.L.C. and Gold, M.S. (1982) Neuroendocrine abnormalities in affective disorders. L’Encephale B, 203-211. Hamilton, M. (1976) Development of a rating scale for primary depressive illness. Br. J. Sot. Clin. Psychol. 6, 278-296. Katakami, H., Kato, Y., Matsushita, N. and Imura, H. (1984) Effects of neonatal treatment with monosodium glutamate on growth hormone release induced by clonidine and prostaglandin El in conscious male rats. Neuroendccrinology 38, 1-5. Katona, C.L.E., Theodorou, A.G., Davies, S.L. et al. (1986) Platelet binding and neuroendocrine responses in depression. In: J.F.W. Deakin (Ed.), The Biology of Depression. Gaskell, London. Leakmann, G., Schumacher, G., Benkert, 0. and Werder, K.V. (1977) Stimulation of growth hormone secretion of desipramine and chlorimipramine in man. J. Clin. Endocrinol. Metab. 44, 1010-1013.
234 Laakmann, G., Zygan, K., Schoen, H.-W. et al. (1986) Effects of receptor blockers on desipramine-induced pituitary hormone stimulation in humans. 1. Growth hormone. Psychoneuroendocrinology 11, 447-461. LaI, S., Tolis, G., Martin J.B. et al. (1975) Effects of clonidine on growth hormone, prolactin, luteinising follicle-stimulating hormone and thyroid stimulating hormone in the serum of normal men. J. Clin. Endocrinol. Metab. 41, 827-832. Loosen, P.T. and Prange, A.J. (1982) Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: a review. Am. J. Psychiatry 139, 405-416. Loosen, P.T., Prange, A.J. and Wilson, I.C. (1978) Influence of cortisol on TRH induced TSH response in depression. Am. J. Psychiatry 135, 244246. Matussek, N., Ackenhail, M., Hippius, H. et al. (1980) Effect of clonidine on growth hormone release in psychiatric patients and controls. Psychiatr. Res. 2, 25-36. Mitchell, P.B., Beam, J.A., Corn, T.H. and Checkley, S.A. (1988) Growth hormone responses to clonidine after recovery in patients with endogenous depression. Br. J. Psychiatry 152, 34-38. Pepper, G.M. and Krieger, D.T. (1984) Hypothalamic-pituitary-adrenal abnormalities in depression. In: R.M. Post and J.C. Ballenger (Eds.), Neurobiology of Depression. Williams and Wilkins, Baltimore, MD. Pekary, A.E., Hershinan, J.M. and Parlow. A.F. (1975) A sensitive and precise radioimmunoassay for human thyroid stimulating hormone. J. Clin. Endocrinol. Metab. 41, 678-684. Raite, S. (1983) The standards of human growth hormone assays. In: Z. Laron and 0. Butenandt (Eds.), Evaluation of Growth Hormone Secretion. Karger, Basel.
Reichlin, S. (1974) Neuroendocrinology. In: R.H. Williams (Ed.), Textbook of Endocrinology, 5th edn. Saunders, Philadelphia, PA. Reichlin, S. (1975) Regulation of the hypophysiotropic secretions of the brain. Arch. Intern. Med. 135, 1350-1361. Risch, SC., Kalin, N.H. and M urphy, D.L. (1981) Neurochemical mechanisms in the affective disorders and neuroendocrine correlates. J. Clin. Psychopharmacol. 1, 180-185. Sawchenko, P.E. (1982) Anatomic relationships between the paraventricular nucleus of the hypothalamus and visceral regulatory mechanisms: implications for the control of feeding behaviour. In: B.G. Hoebel and D. Novin (Eds.), The Neural Basis of Feeding and Reward. Haer Institute, Brunswick, ME. Schildkraut, J.J. (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509-522. Takahashi, S., Kondo, H. and Yoshimira, M. (1974) Thyrotropin responses to TRH in depressive illness: relation to clinical subtypes and prolonged duration of depressive illness. Folia Psychiatr. Neurol. 28, 355-365. Targum, S.D., Sullivan, A.C. and Bymes, SM. (1982) Neuroendocrine interrelationships in major depressive disorder. Am. J. Psychiatry 139, 282-286. Willner, P. (1985) Depression: A Psychobiological Synthesis. John Wiley and Sons, New York, NY. Winokur. A., Amsterdam, J. and Caroff, S. (1982) Variability of hormonal responses to a series of neuroendocrine challenges in depressed patients. Am. J. Psychiatry 139, 39-44. Yatham, L.N., Barry, S. and Dinan, T.G. (1989) Serotonin receptors, buspirone and the premenstrual syndrome. Lancet i. 1447-1448.
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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