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Effects of age and diagnosis on thyrotropin response to thyrotropin-releasing hormone in psychiatric patients
Psychiatry Research, 17, 285-294
285
Elsevier
Effects of Age and Diagnosis on Thyrotropin Response to Thyrotropin-Releasing Hormone in Psychiatric Patients Andreas Received 198.5.
Baumgartner,
Lutz Hahnenkamp,
and Herald Meinhold
May 20, 1985; revised version received September
10, 1985; accepted
October
16,
Abstract. The thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) was studied in 64 age-matched healthy volunteers, 44 patients with endogenous depression, and 21 patients with schizophrenia. A significant negative correlation between ATSH and age was found both in healthy subjects and in depressed patients. We based our comparison on normal ranges for ATSH calculated from the ATSH values in the healthy subjects related to age. It was then seen that blunted TSH response to TRH does not occur significantly more often in depression (13.6%) than in healthy controls (4.7%). Blunted TRH test results were also found in a considerable number of severely ill schizophrenic patients (19%). Application of an improved radioimmunoassay revealed a highly significant correlation between TSH values at baseline and after stimulation, and showed decreased baseline TSH levels in subjects with blunted TRH test results. Key Words. Thyrotropin-releasing
hormone
test, depression,
schizophrenia,
age.
Blunted thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropinreleasing hormone (TRH) has frequently been reported in endogenous depression and in other psychiatric disorders (e.g., Prange et al., 1972; Kirkegaard et al., 1975; Hollister et al., 1976; Extein et al., 1981; Papakostas et al., 1981; Loosen and Prange, 1982; Targum et al., 1982; Winokur et al., 1983; Banki et al., 1984; Calloway et al., 1984; McGrath et al., 1984). However, no consensus has yet been reached on its etiology (Loosen and Prange, 1982; Calloway et al., 1984) or its clinical relevance as a possible “diagnostic marker” in psychiatric diseases. While some authors consider decreased TSH response to TRH (ATSH) to be highly specific for endogenous depression (e.g., Extein et al., 1980), others have observed this phenomenon in both manic and depressed patients (e.g., Kirkegaard et al., 1978) or suggested that the test results may be of help in distinguishing unipolar from bipolar depression (Gold et al.,
An earlier version of this report was presented at the 40th Annual Meeting of the Society of Biological Psychiatry, Dallas, TX, May 15-19, 1985. Andreas Baumgartner, M.D., is at the Psychiatrische Klinik und Poliklinik, Klinikum Charlottenburg der Freien Universiiat Berlin. Lutz Hahnenkamp was formerly Laboratory Assistant at the Psychiatrische Klinik und Poliklinik; his present address is at Oberstufenzentrum fur Chemie, Physik und Biologie, Fachbereich Biologic, Berlin, Harald Meinhold, Ph.D., is Associate Professor ofchemistry, Abteilungfur Nuklearmedizin, Klinikum Steglitz der Freien Universiht Berlin, Federal Republic of Germany. (Reprint requests to Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik. Eschenallee 3, 1000 Berlin 19, FRG.) 0165-1781/86/$03.50
@ 1986 Elsevier Science Publishers
B.V
286 1979, 198 1; Extein et al., 198 1) or primary unipolar from secondary depression (Asnis et al., 1980). TRH test results in schizophrenia are contradictory: While most studies have not revealed reduced ATSH values in schizophrenic patients (Loosen et al., 1977; Kirkegaard et al., 1978; Extein et al., 1982; Loosen and Prange, 1982; Targum, 1983; Banki et al., 1984), others have shown abnormal TRH test results in schizophrenia also (Langer et al., 1983). Thus, one purpose of our study was to investigate the incidence of blunted TSH response to TRH among both unipolar and bipolar depressed patients, and in schizophrenia. Furthermore. some evidence of an influence of age and gender on the TRH test has been found in endocrinological studies (Snyder and Utiger, 1972a, 1972b; Cuttelod et al., 1974; Wenzel et al., 1974; Olsenet al., 1978). The findings as regards a possible relationship between age and blunted TSH response in psychiatric patients are conflicting, and we are aware of only one study in which a decrease in the TSH response to TRH in the elderly has been described (Hollister et al., 1976). However, no other authors have reported this finding (Loosen and Prange, 1982). As it is precisely the depressive patients who usually exhibit wide interindividual age differences, a possible influence of age on the TRH test could be of some importance with respect to the incidence of blunted test results in this diagnostic group. We therefore also performed the TRH test in a sample of age- and sex-matched healthy volunteers to investigate possible effects of age or gender on the TSH response to TRH. Reports in the literature on the relationship between TSH values at baseline and after stimulation are conflicting (e.g., Targum et al., 1982; Loosen et al., 1983) and reliable baseline TSH levels are difficult to obtain for patients with blunted TRH test results, since the radioimmunoassay (RIA) methods so far commercially available show reduced sensitivity in the lower range of TSH measurements. For this reason, we used a special RIA technique with improved sensitivity in the lower range for our TSH measurements, to allow evaluation of the relationship between baseline and stimulated TSH values in subjects with both normal and blunted TRH test results. Methods All patients who were admitted to our six nonresearch wards between September 1983 and March 1984, and who met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for major depressive disorder (probable or definite), primary and endogenous subtype, were considered for inclusion in the study (n = 61). Seventeen of these patients were excluded for the following reasons: refused informed consent (n = 4) history of alcoholism/drug abuse (n q 4) Hamilton Rating Scale for Depression score < 18 (n = 3), concomitant medication such as thyroxine or hydrocortisone (n = 3) and concomitant somatic diseases (n = 3). Thirty-four patients had unipolar and 10 bipolar disorder. Thirty patients were female, 14 were male, and their mean (+ SD) age was 53.3 ? 15.3 years (range: 26-75). Twenty-one patients had not been taking any drugs before admission, and 23 patients had been on antidepressants, benzodiazepines, or neuroleptics. All drugs were withdrawn, and the TRH tests were conducted after a 3- to 5-day washout period following hospital admission. On the day of the TRH test, all patients were rated on the 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960). Their mean (* SD) score was 25.8 + 4.5 (range: 18-37). We also included 21 patients who met RDC for acute schizophrenia (probable or definite). We deliberately selected the most severely ill schizophrenic patients admitted to our hospital over half a year. Subtype diagnoses were paranoid (n = 17), catatonic (n q 3). and disorganized (n = I). Twelve patients were female, nine male, and their mean age (* SD) was 28.3 f 8.0 years
287
(range 18-54). In seven patients, the TRH test was performed after a 3- to 5-day washout period following hospital admission; in the other cases, immediate institution of neuroleptic treatment was considered necessary on hospitalization. Most of the patients (n q 10) were taking haloperidol, either orally or intravenously, with the dosage ranging from 5 to 30 mg/day. The remaining four patients were on perazine and flupentixol, respectively. All patients were rated on the Clinical Global Impression (CC1 II) (Guy and Bonato, 1970) severity scale on the day of the TRH test. Their mean (* SD) score was 6.8 * 0.7 (range 6-8), indicating that most of the patients were severely ill. All diagnoses and ratings were made by one psychiatrist (A.B.), who was unaware of the TRH test results. TRH tests were also performed on 64 healthy volunteers. Thirty-six of them were employees of the Psychiatric Clinic (age: 22-59 years), and 28 were retired volunteers who occasionally work for a drug research institute (age: 61-8 I years). Thirty-one volunteers were female, 33 were male, and their mean (* SD) age was 48.2 f 16.5 years (range: 22-8 1). None of our controls had a history of or showed signs of mental illness, and none of the patients or control subjects were suffering from any serious medical condition or were taking any medication that might interfere with TRH test results (Wenzel, 198 I). We also measured thyroxine (TJ, triiodothyronine (T3), FT,, FT,, and reverse T, in all patients and controls, and the patients were examined thoroughly for clinical signs of hyperthyroidism or hypothyroidism. No patient or control had a history of thyroid disorder, and no clinical signs were found at the physical examination or in the results of thyroid hormone concentration tests. However, we did find some abnormal patterns of thyroid hormone concentrations in both depressed and schizophrenic patients. These resembled a “euthyroid sick syndrome”and will be described in a later report. All TRH tests were carried out in the morning between 7:00 and 8:30 a.m. in the patients, and between 8:00 and 9:30 a.m. in the controls. Protirelin (Relefact) (400 pg) was injected intravenously over half a minute, and a blood sample was taken 30 minutes thereafter by a second venipuncture. We used 400 pg protirelin for the TRH test as this is considered to be the lowest dose that causes maximal stimulation of TSH (Snyder and Utiger, 1972~; Otsuki et al., 1973). We used only one blood sample to measure TSH 30 minutes after stimulation, as there is some evidence that in both depressed patients and healthy subjects multiple blood sampling after TRH injection does not afford important additional information about maximal ATSH as compared to only one sample drawn 30 minutes after TRH injection (Snyder and Utiger, 1972~; Otsuki et al., 1973; Wilkin et al., 1979; Loosen and Prange, 1982; Loosen et al., 1982). TSH was measured by using “TSH RIA Henning Supersensitiv” kits. With this method, which is described in detail elsewhere (Seidel et al., 1981), sensitivity is improved by using specially selected TSH-free human serum for preparation of standard samples and prolonging the incubation times. Eight standard sera with concentrations ranging from 0.19 to 25 mU/l were used for the standard curve. Standard or unknown serum (0.1 ml) was incubated with anti-TSH serum (0. I ml) for 48 hours (cold preincubation). After the addition of 0.1 ml i251-TSH, incubation was continued for a further 20-hour period. Separation of antibodybound from free radioactivity was performed by the double-antibody technique. Precipitating serum (0.1 ml) was added. After incubation for 30 minutes, the tubes were centrifuged and the precipitates counted. Incubation was carried out at room temperature. All samples were measured in triplicate in several assays. The lower limit of detection was 0.2 mu/I. Interassay coefficients of variation were 4.3% at a level of 1mU / 1,3.5% at a level of 6.3 mU / 1, and 6.4vo at a level of 20 mU / 1. Statistical evaluation was conducted by means of the t test (two-tailed) and by a three-way analysis of variance (ANOVA) with diagnosis, age, and gender as independent variables and ATSH as the dependent variable. In addition, we used the x* test for dichotomous variables. Fisher-Yates correction was not necessary for our sample (Camilli and Hopkins, 1979). Correlations between TRH test results and other variables, such as age or severity scores, were calculated by Pearson’s r correlation coefficient. The data are given as means with standard deviations (SD) where appropriate. In all calculations, p values of less than 0.05 were accepted as significant.
288 Results The mean increase in TSH after TRH (ATSH) in healthy controls was 8.4 f 4.4 (range O-25.8, Fig. 1). We calculated Pearson’s r coefficient between ATSH and age, and found a significant negative correlation between the two variables (r = -0.35, df= 62, p < 0.005) in healthy subjects. When we divided the control population into subgroups according to their ages, we found that there were no remarkable variations between the mean ATSHs of the subgroups under 60 years, but there was a decrease in the group of 60- to 70-year-old subjects and, especially, in the volunteers over 70 (Fig. 1). Fig. 1. Age-related
distribution
All healthy controls (n = 64)
of
ATSH values in healthy controls Healthy controls
< 40 years (n =21)
PO - 59 years In = 15)
------
. _---_-_
24 .25.9
A TSH
l
60 - 70 years (n = 10)
> 70
years (n = 18)
25.9
20
.
.
16
12
E-
... :: -
4-
OJ
. . .% . .
.
i . : . . . -----.
. .
. . .
-:_
;:j....
?A : .. .;.
-----
.. . ..
‘.’ v
i
-----_
. :.
: : .
. .. ..
_-----
. 0.
. . .
... : .
::
------
.
:.
-f .----.
l
a.4 k 4.4
9.7 + 3.2
10.7 f 6.6
6.6 + 1.9
5.7 t 3.1
The mean increase in ATSH in patients with endogenous depression was 7.8 f 0.4 (range: 0.3-26.5, Fig. 2) and we also found a significant negative correlation between age and ATSH in the depressed patients (r = -0.44, df = 42,~ < 0.005). We conducted a three-way ANOVA to evaluate the influence of age, diagnosis, and gender on ATSH. The effect of age was calculated by dividing the controls and the depressed patients into two groups of subjects, one under 60 years and one aged 60 or older. As none of our schizophrenic patients were older than 54, we did not include them in these calculations. Table 1 reveals a significant influence of age on ATSH in both healthy subjects and depressed patients, whose ATSH levels did not differ significantly. The influence of age on ATSH was not dependent on gender. It should be noted, however,
289
Fig. 2. Age-related distributions of ATSH depressive disorder and schizophrenia All patients with major depressive disorder (n=44) l
22
values
in oatients .
with
major
All patients with major depressivedisorder
< 40
years (l-l = 8)
26.5
l
40 - 59 years (n = 18)
60 - 70 years (n= 7)
Patients with schizophrenia al I < 60 years (n=21)
> 70 years (n= 11)
26.5 .-----_
-------
A TSH 18
:
:
. . . :
14
.
-y-
2
. . . .
A . :
t
*! :: .::. . . : 8 . .
6
:
. .
1.6 + 4.0
.
.
.
.
.
i
.
-
_:-
.. _ :: ‘= .
------
------
.
.. . . .
.
I . C. __-*%--
.
.
.
!.
10
-----_
------
.
.
i .
-----_ =’ . 11.6t6.4
7.9 * 3.9
6.5? 3.2
7.3 * 3.5
4.6 + 3.6
Table 1. Results of 3-way analysis of variance with agel, subgroup2, and gender as independent variables and ATSH as dependent variable Source of variation
Sum of squares
df
Mean squared
F
p
Main effects Gender
32.766
1
32.766
1.799
0.183
Subgroup
20.527
1
20.527
1.127
0.291
364.947
1
364.947
20.033
0.001
0.956
Aoe 2-Way interactions Gender-Subgroup
0.056
1
0.056
0.003
Gender-Age
24.295
1
24.295
1.334
0.251
Subgroup-Age
15.299
1
15.299
0.840
0.362
25.817
1
25.817
1.417
0.237
3-Way interactions Gender-Subarouo-Aae
1. All subjects 5 60 years were compared with all subjects > 60 years 2. Healthy subjects and depressed patients (see text).
that the depressed women under 50 years of age had higher ATSH values (mean 11.9 f 5.7) than male controls in the same age group (mean 6.8 f 1.6). We could not find significant correlations between ATSH and HRSD scores (r = -0.20, df = 42, NS), between ATSH and length of episode (r = -0.07, df =42, NS), or between ATSH and weight loss (in kg) during present episode (I = 0.08, df = 42, NS). The mean ATSH for the 21 patients with schizophrenia was 7.3 f 3.5 (Fig. 2) and did not differ from that of all healthy controls (t = 1.1, df = 83, NS). As none of our schizophrenic patients were over 54 years old, we also compared their mean ATSH with that of the healthy volunteers of under age 60 (10.1 + 4.6, Fig. 1) and found the difference between the two groups to be significant (t = 2.3, df q 55, p < 0.025). No significant correlations were found between ATSH and age (r q 0.23, df q 19, NS), ATSH and length of episode (r q -0.25, df q 19, NS), ATSH and weight loss (r = -0.16, df = 19, NS), or ATSH and CGI severity scores (r = 0.23, df = 19, NS). A significant correlation between ATSH and severity of illness; however, could hardly be expected, since almost all of our patients were severely ill. As our results show a clear tendency toward a decrease in ATSH in subjects over 60 years of age, and a still more pronounced decrease in ATSH in the volunteers over age 70, we set three age-related ranges of normal for ATSH. If the normal range was assumed to be the mean plus two standard deviations, this would result in a lower limit for ATSH at or near zero in the different age groups of the healthy subjects. We therefore log-transformed the data to achieve a better distribution of normality, and then designated normal ranges on the basis of the log-transformed mean plus two standard deviations. For the group of healthy subjects younger than 60 years, we found a range of normal for ATSH between 4.1 and 2 1.4; for the group between 60 and 70 years, we obtained a normal range of 3.4-14.6; and for all persons older than 70, the normal range was set at between 1.8 and 15.6. On application of these limits to our three populations, three healthy subjects (4.70/,), six depressed patients (13.6%), and four schizophrenic patients (19.0%) showed a blunted TSH response to TRH (Fig. 1 and Table 2). Thus, the rate of abnormal TRH test results did not differ significantly between the healthy subjects and the depressed patients, and between the depressed
Table S.‘Mean ATSH Lakes healthy
and rates of blunted
Subjects
n
Healthy
64
controls
Mean &SD ATSH
Bluntecf Normal
6.4k4.4
depressive
44
7.624.6
disorder Schizophrenia
in patients
and in
21
7.3k3.5
Non-age-related ranges of normal
Age-related ranges of normal for ATSH
3
( Major
response
controls
4.7%)
ATSH = 5 Blunted
Normal
ATSH = 7 Blunted
61
16
46
35
29
(95.3%)
(25.0%)
(75.0%)
(54.7%)
(45.3%)
6
38
14
30
22
(13.6%)1
(86.4%)
(31&‘/o)
(68.20/o)
(50.0%)
4 (19.0010)2
Normal
17 (81.0%)
4 (19.00/o)
1. x2 = 2.73, p > 0.05, NS. compared to the 9roup of healthy controls. 2. x2 = 4.3, p c 0.05, compared to the 9roup of healthy controls.
17 (81.0%)
9 (42.8%)
22 (50.01) 12 (57.2%)
291 and the schizophrenic patients (Table 2). A significant difference was only found between healthy subjects and schizophrenic patients (Table 2). Four of the six depressed patients with blunted TRH test results were over age 70. Two healthy controls and one depressed patient had increased ATSH values. Four of the six depressed patients with an abnormal TSH response to TRH had unipolar depression, and two bipolar. The mean ATSH of the patients with bipolar disorder was lower (6.3 ? 3.4) than that of the unipolar depressed patients (8.3 + 4.9), but the difference was not significant (t = 1.8, df = 46, NS). Finally, Table 2 shows that if we had applied a cutoff level of ATSH = 5 or ATSH = 7, as has been done by numerous workers who have not established their own age-related cutoff criteria, we would then have had 3 1.8% and 50.0% abnormally low TRH test results, respectively, in our depressed population. The mean baseline TSH level for all healthy volunteers was 1.7 * 1.3 mU/l compared to 1.5 f 1.4 mU/ 1for the depressed, and 1.9 f 1.4 mU/ 1for the schizophrenic patients. These differences were not significant (healthy vs. depressed subjects: t = 0.56, df 107, NS); and healthy volunteers vs. schizophrenic patients: t x0.26, df = 84, NS). There was a highly significant correlation between baseline and ATSH levels in healthy subjects (r 0.60, df = 62,~ < 10-s) in depressed patients (r= 0.46, df = 42,~ < lo-‘), and in schizophrenic patients (r 0.55, df = 19,~ < 0.01). The mean baseline TSH level for all healthy controls with a blunted TSH response (n= 3; 0.6 + 0.4 mu/l) was lower than that for all subjects with normal TRH test results (1.9 f 1.4 mu/l). Correspondingly, the mean baseline TSH level for the depressed patients with a blunted TSH response (n = 6; 0.6 f 0.2 mu/l) was lower than that for the depressed patients with normal TSH responses to TRH (1.9 + 1.5 mu/l). We also found a significant negative correlation between age and baseline TSH in healthy controls (r = -0.26, df = 62, p < 0.05),but not in depressed patients (r = -0.09, df = 42, NS). q
q
q
Discussion We found a significant negative correlation between age and TSH response to TRH in both healthy controls and patients with endogenous depression. To our knowledge, only a few authors have paid attention to the relationship between age and ATSH in psychiatric patients (e.g., Hollister et al., 1976; Linkowski et al., 1983; Calloway et al., 1984), some of whom were working with populations with an upper age limit of not more than 59 (Loosen et al., 1977) or 65 years (Takahashi et al., 1974). Only in the study by Hollister et al. (1976) was a tendency toward decreasing ATSH levels in older patients reported. However, several endocrinological studies suggest an effect of age on the TRH results, although the detailed findings are rather confusing: Snyder and Utiger (1972~) reported a significant decrease in ATSH in healthy male subjects over 40, but could not confirm this finding in normal women (Snyder and Utiger, 19726). Wenzel et al. (1974) found higher ATSH levels in women between 20 and 59 years old than in men of the same age, whereas no differences were found between younger and older men or between older men and older women. A decreased TSH response to TRH has also been reported in geriatric inpatients by Burrows et al. (1977) and in healthy subjects over 70 years old by Cuttelod et al. (1974) and Olsen et al. (1978).
292 The reason for the age dependence of TRH test results remains unclear. It has not been possible to demonstrate an effect of height or weight (Haigler et al., 197 1; Snyder and Utiger, 1972a), and the studies on thyroid hormones in old age have shown either diminished (Snyder and Utiger, 1972~; Nishikawa et al., 198 1) or normal (Olsen et al., 1978) levels of T, and no change in Tdvalues (Snyder and Utiger, 1972~; Olsen et al., 1978; Nishikawa et al., 1981). These findings do not suggest that disturbances in thyroid hormone levels account for the fall in the ATSH in older subjects. Therefore, a central dysregulation at the hypothalamic-pituitary level in older age must be considered as a possible cause of the effect of age on TRH test results. One clinical implication of our findings is that age-related limits of normal values for ATSH should be applied, as has already been suggested by Snyder and Utiger (1972~). As regards the dexamethasone suppression test, Meltzer and Fang (1983) emphasized that each laboratory should determine its own cutoff point, since the cortisol levels found differ widely from laboratory to laboratory, depending on the method or kit employed. The same applies to the measurement of TSH (Sternbach et al., 1983); thus we suggest that study groups should not simply adopt age-related ranges of normal for ATSH reported by other groups, but establish their own age-related normal ranges by investigating a population of age-matched healthy controls. In our study, we based our comparison on normal ranges for ATSH calculated from the ATSH values in healthy subjects related to age. It was then seen that blunted TSH responses to TRH do not occur significantly more often in depression than in the healthy controls. The wide variation in the rates of blunted TRH test results in depressed patients, which range from 0% (Coppen et al., 1980) to 64% (Extein et al., 1981), might thus be partly related to the fact that possible effects of age and laboratory differences were not taken into consideration. The use in this study of a RIA technique with improved sensitivity in the lower range of TSH showed a close correlation between TSH levels at baseline and after stimulation, suggesting that blunted TSH response to TRH is related to diminished TSH production in the pituitary gland. Explanations for abnormal TRH test results have been mainly speculative so far (e.g., Loosen and Prange, 1982; Calloway et al., 1984). Our finding that TSH responses can also be blunted in schizophrenic patients is further evidence that abnormal TRH test results are not related to any specific diagnosis, such as endogenous depression. Furthermore, we were unable to confirm differences between the TRH test results for unipolar and bipolar depressed patients. Thus, our results do not support the theory that the TRH test may be of value as an aid in differentiating between psychiatric diagnoses or subgroups. References Asnis, G.M., Nathan, R.S., Halbreich, U., Halpern, F.S., and Sachar, E.J. TRH test in depression. Lancer, I, 424 (1980). Banki, CM., Aratd, M., and Papp, Z. Thryoid stimulation test in healthy subjects and psychiatric patients. Acta Psychiatrica Scundinuvicu, 70, 295 (1984). Burrows, A.W., Cooper, E., Shakespear, R.A., Aickin, C.M., Fraser, S., Hesch, R.D., and Burke, C.W. Low serum L-T, levels in the elderly sick: Protein binding, thyroid and pituitary responsiveness, and reverse T, concentrations. Clinical Endocrinology, 7, 289 (1977).
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Meltzer, H.Y., and Fang, V.S. Cortisol determination and the dexamethasone suppression test. Archives of General Psychiatry, 40, 501 (1983). Nishikawa, M., Inada, M., Naito, K., Ishii, H., Tanaka, K., Mashio, Y., and Imura, H. Age-related changes of serum 3, 3’-diiodothyronine, 3’, 5’-diiodothyronine, and 3, 5diiodothyronine concentrations in man. Journal of Clinical Endocrinology and Metabolism, 52,517
(1981).
Olsen, T., Laurberg, P., and Weeke, J. Low serum triiodothyronine and high serum reverse triiodothyronine in old age: An effect of disease not age. Journalof Clinical Endocrinology and Metabolism, 47, 1111 (1978). Otsuki, M., Dakoda, M., and Baba, S. Influence of glucocorticoids on TRH-induced TSH response in man. Journal of Clinical Endocrinology and Metabolism, 36,95 (1973). Papakostas, Y., Fink, M., Lee, J., Irwin, P., and Johnson, L. Neuroendocrine measures in psychiatric patients: Course and outcome with ECT. Psychiatry Research, 4, 55 (1981). Prange, A.J., Jr., Lara, P.P., Wilson, I.C., Alltop, L.B., and Breese, G.R. Effects of thyrotropin-releasing hormone in depression. Lance& II, 999 (1972). Seidel, C., Heller, G., and Rohde, W. Methodische Vergleische zur radioimmunologischen Bestimmung basaler TSH-Spiegel im Serum. Endokrinologie, 78, 205 (198 1). Snyder, P.J., and Utiger, R.T. Response to thyrotropin-releasing hormone (TRH) in normal man. Journal of Clinical Endocrinology, 34, 380 (1972a). Snyder, P.J., and Utiger, R.D. Thyrotropin response to thyrotropin-releasing hormone in normal females over forty. Journal of Clinical Endocrinology and Metabolism, 34, 1096 (19726).
Spitzer, R.L., Endicott, J., and Robins, E. Research Diagnostic Criteria: Rationale and reliability. Archives of General Psychiatry, 35, 773 (1978). Sternbach, H.A., Gwirtsman, H.E., Gerner, R.H., Pekary, E., and Hershman, J. Methodological issues in the measurement of serum TSH-Implications for psychiatry. Psychoneuroendocrinology,
8,455
(1983).
Takahashi, S., Kondo, H., Joshimura, M., and Ochi, Y. Thyrotropin depressive illness: Relation to clinical subtypes and prolonged duration Folia Psychiatrica
et Neurologica
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28,355
responses to TRH in of depressive episode.
(1974).
Targum, S.D. The application of serial neuroendocrine challenge studies in the management of depressive disorder. Biological Psychiatry, 18, 3 (1983). Targum, S.D., Sullivan, A.C., and Byrnes, S.M. Compensatory pituitary thyroid mechanism in major depressive disorder. Psychiatry Research, 6, 85 (1982). Wenzel, K.W. Pharmacological interference with in vitro tests of thyroid function. Metabolism,
30, 717 (1981).
Wenzel, K.W., Meinhold, H., Herpich, M., Adlkofer, F., and Schleusener, H. TRHStimulationstest mit alters- und geschlechtsabhangigem TSH-Anstieg bei Normalpersonen. Klinische
Wochenschriften,
52, 722 (1974).
Wilkin, T.J., Baldet, L., Papachristou, C., and Jaffiol, C. The TRH-test. Which is the best index of TSH release? Annales d’Endocrinologie, 40, 495 (1979). Winokur, A., Amsterdam, J.D., Oler, J., Mendels, J., Snyder, P.J., Caroff, S.N., and Brunswick, D.J. Multiple hormonal responses to protirelin (TRH) in depressed patients. Archives
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40, 525 (1983).
285
Elsevier
Effects of Age and Diagnosis on Thyrotropin Response to Thyrotropin-Releasing Hormone in Psychiatric Patients Andreas Received 198.5.
Baumgartner,
Lutz Hahnenkamp,
and Herald Meinhold
May 20, 1985; revised version received September
10, 1985; accepted
October
16,
Abstract. The thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropin-releasing hormone (TRH) was studied in 64 age-matched healthy volunteers, 44 patients with endogenous depression, and 21 patients with schizophrenia. A significant negative correlation between ATSH and age was found both in healthy subjects and in depressed patients. We based our comparison on normal ranges for ATSH calculated from the ATSH values in the healthy subjects related to age. It was then seen that blunted TSH response to TRH does not occur significantly more often in depression (13.6%) than in healthy controls (4.7%). Blunted TRH test results were also found in a considerable number of severely ill schizophrenic patients (19%). Application of an improved radioimmunoassay revealed a highly significant correlation between TSH values at baseline and after stimulation, and showed decreased baseline TSH levels in subjects with blunted TRH test results. Key Words. Thyrotropin-releasing
hormone
test, depression,
schizophrenia,
age.
Blunted thyrotropin (thyroid-stimulating hormone; TSH) response to thyrotropinreleasing hormone (TRH) has frequently been reported in endogenous depression and in other psychiatric disorders (e.g., Prange et al., 1972; Kirkegaard et al., 1975; Hollister et al., 1976; Extein et al., 1981; Papakostas et al., 1981; Loosen and Prange, 1982; Targum et al., 1982; Winokur et al., 1983; Banki et al., 1984; Calloway et al., 1984; McGrath et al., 1984). However, no consensus has yet been reached on its etiology (Loosen and Prange, 1982; Calloway et al., 1984) or its clinical relevance as a possible “diagnostic marker” in psychiatric diseases. While some authors consider decreased TSH response to TRH (ATSH) to be highly specific for endogenous depression (e.g., Extein et al., 1980), others have observed this phenomenon in both manic and depressed patients (e.g., Kirkegaard et al., 1978) or suggested that the test results may be of help in distinguishing unipolar from bipolar depression (Gold et al.,
An earlier version of this report was presented at the 40th Annual Meeting of the Society of Biological Psychiatry, Dallas, TX, May 15-19, 1985. Andreas Baumgartner, M.D., is at the Psychiatrische Klinik und Poliklinik, Klinikum Charlottenburg der Freien Universiiat Berlin. Lutz Hahnenkamp was formerly Laboratory Assistant at the Psychiatrische Klinik und Poliklinik; his present address is at Oberstufenzentrum fur Chemie, Physik und Biologie, Fachbereich Biologic, Berlin, Harald Meinhold, Ph.D., is Associate Professor ofchemistry, Abteilungfur Nuklearmedizin, Klinikum Steglitz der Freien Universiht Berlin, Federal Republic of Germany. (Reprint requests to Dr. A. Baumgartner, Psychiatrische Klinik und Poliklinik. Eschenallee 3, 1000 Berlin 19, FRG.) 0165-1781/86/$03.50
@ 1986 Elsevier Science Publishers
B.V
286 1979, 198 1; Extein et al., 198 1) or primary unipolar from secondary depression (Asnis et al., 1980). TRH test results in schizophrenia are contradictory: While most studies have not revealed reduced ATSH values in schizophrenic patients (Loosen et al., 1977; Kirkegaard et al., 1978; Extein et al., 1982; Loosen and Prange, 1982; Targum, 1983; Banki et al., 1984), others have shown abnormal TRH test results in schizophrenia also (Langer et al., 1983). Thus, one purpose of our study was to investigate the incidence of blunted TSH response to TRH among both unipolar and bipolar depressed patients, and in schizophrenia. Furthermore. some evidence of an influence of age and gender on the TRH test has been found in endocrinological studies (Snyder and Utiger, 1972a, 1972b; Cuttelod et al., 1974; Wenzel et al., 1974; Olsenet al., 1978). The findings as regards a possible relationship between age and blunted TSH response in psychiatric patients are conflicting, and we are aware of only one study in which a decrease in the TSH response to TRH in the elderly has been described (Hollister et al., 1976). However, no other authors have reported this finding (Loosen and Prange, 1982). As it is precisely the depressive patients who usually exhibit wide interindividual age differences, a possible influence of age on the TRH test could be of some importance with respect to the incidence of blunted test results in this diagnostic group. We therefore also performed the TRH test in a sample of age- and sex-matched healthy volunteers to investigate possible effects of age or gender on the TSH response to TRH. Reports in the literature on the relationship between TSH values at baseline and after stimulation are conflicting (e.g., Targum et al., 1982; Loosen et al., 1983) and reliable baseline TSH levels are difficult to obtain for patients with blunted TRH test results, since the radioimmunoassay (RIA) methods so far commercially available show reduced sensitivity in the lower range of TSH measurements. For this reason, we used a special RIA technique with improved sensitivity in the lower range for our TSH measurements, to allow evaluation of the relationship between baseline and stimulated TSH values in subjects with both normal and blunted TRH test results. Methods All patients who were admitted to our six nonresearch wards between September 1983 and March 1984, and who met Research Diagnostic Criteria (RDC) (Spitzer et al., 1978) for major depressive disorder (probable or definite), primary and endogenous subtype, were considered for inclusion in the study (n = 61). Seventeen of these patients were excluded for the following reasons: refused informed consent (n = 4) history of alcoholism/drug abuse (n q 4) Hamilton Rating Scale for Depression score < 18 (n = 3), concomitant medication such as thyroxine or hydrocortisone (n = 3) and concomitant somatic diseases (n = 3). Thirty-four patients had unipolar and 10 bipolar disorder. Thirty patients were female, 14 were male, and their mean (+ SD) age was 53.3 ? 15.3 years (range: 26-75). Twenty-one patients had not been taking any drugs before admission, and 23 patients had been on antidepressants, benzodiazepines, or neuroleptics. All drugs were withdrawn, and the TRH tests were conducted after a 3- to 5-day washout period following hospital admission. On the day of the TRH test, all patients were rated on the 21-item Hamilton Rating Scale for Depression (HRSD) (Hamilton, 1960). Their mean (* SD) score was 25.8 + 4.5 (range: 18-37). We also included 21 patients who met RDC for acute schizophrenia (probable or definite). We deliberately selected the most severely ill schizophrenic patients admitted to our hospital over half a year. Subtype diagnoses were paranoid (n = 17), catatonic (n q 3). and disorganized (n = I). Twelve patients were female, nine male, and their mean age (* SD) was 28.3 f 8.0 years
287
(range 18-54). In seven patients, the TRH test was performed after a 3- to 5-day washout period following hospital admission; in the other cases, immediate institution of neuroleptic treatment was considered necessary on hospitalization. Most of the patients (n q 10) were taking haloperidol, either orally or intravenously, with the dosage ranging from 5 to 30 mg/day. The remaining four patients were on perazine and flupentixol, respectively. All patients were rated on the Clinical Global Impression (CC1 II) (Guy and Bonato, 1970) severity scale on the day of the TRH test. Their mean (* SD) score was 6.8 * 0.7 (range 6-8), indicating that most of the patients were severely ill. All diagnoses and ratings were made by one psychiatrist (A.B.), who was unaware of the TRH test results. TRH tests were also performed on 64 healthy volunteers. Thirty-six of them were employees of the Psychiatric Clinic (age: 22-59 years), and 28 were retired volunteers who occasionally work for a drug research institute (age: 61-8 I years). Thirty-one volunteers were female, 33 were male, and their mean (* SD) age was 48.2 f 16.5 years (range: 22-8 1). None of our controls had a history of or showed signs of mental illness, and none of the patients or control subjects were suffering from any serious medical condition or were taking any medication that might interfere with TRH test results (Wenzel, 198 I). We also measured thyroxine (TJ, triiodothyronine (T3), FT,, FT,, and reverse T, in all patients and controls, and the patients were examined thoroughly for clinical signs of hyperthyroidism or hypothyroidism. No patient or control had a history of thyroid disorder, and no clinical signs were found at the physical examination or in the results of thyroid hormone concentration tests. However, we did find some abnormal patterns of thyroid hormone concentrations in both depressed and schizophrenic patients. These resembled a “euthyroid sick syndrome”and will be described in a later report. All TRH tests were carried out in the morning between 7:00 and 8:30 a.m. in the patients, and between 8:00 and 9:30 a.m. in the controls. Protirelin (Relefact) (400 pg) was injected intravenously over half a minute, and a blood sample was taken 30 minutes thereafter by a second venipuncture. We used 400 pg protirelin for the TRH test as this is considered to be the lowest dose that causes maximal stimulation of TSH (Snyder and Utiger, 1972~; Otsuki et al., 1973). We used only one blood sample to measure TSH 30 minutes after stimulation, as there is some evidence that in both depressed patients and healthy subjects multiple blood sampling after TRH injection does not afford important additional information about maximal ATSH as compared to only one sample drawn 30 minutes after TRH injection (Snyder and Utiger, 1972~; Otsuki et al., 1973; Wilkin et al., 1979; Loosen and Prange, 1982; Loosen et al., 1982). TSH was measured by using “TSH RIA Henning Supersensitiv” kits. With this method, which is described in detail elsewhere (Seidel et al., 1981), sensitivity is improved by using specially selected TSH-free human serum for preparation of standard samples and prolonging the incubation times. Eight standard sera with concentrations ranging from 0.19 to 25 mU/l were used for the standard curve. Standard or unknown serum (0.1 ml) was incubated with anti-TSH serum (0. I ml) for 48 hours (cold preincubation). After the addition of 0.1 ml i251-TSH, incubation was continued for a further 20-hour period. Separation of antibodybound from free radioactivity was performed by the double-antibody technique. Precipitating serum (0.1 ml) was added. After incubation for 30 minutes, the tubes were centrifuged and the precipitates counted. Incubation was carried out at room temperature. All samples were measured in triplicate in several assays. The lower limit of detection was 0.2 mu/I. Interassay coefficients of variation were 4.3% at a level of 1mU / 1,3.5% at a level of 6.3 mU / 1, and 6.4vo at a level of 20 mU / 1. Statistical evaluation was conducted by means of the t test (two-tailed) and by a three-way analysis of variance (ANOVA) with diagnosis, age, and gender as independent variables and ATSH as the dependent variable. In addition, we used the x* test for dichotomous variables. Fisher-Yates correction was not necessary for our sample (Camilli and Hopkins, 1979). Correlations between TRH test results and other variables, such as age or severity scores, were calculated by Pearson’s r correlation coefficient. The data are given as means with standard deviations (SD) where appropriate. In all calculations, p values of less than 0.05 were accepted as significant.
288 Results The mean increase in TSH after TRH (ATSH) in healthy controls was 8.4 f 4.4 (range O-25.8, Fig. 1). We calculated Pearson’s r coefficient between ATSH and age, and found a significant negative correlation between the two variables (r = -0.35, df= 62, p < 0.005) in healthy subjects. When we divided the control population into subgroups according to their ages, we found that there were no remarkable variations between the mean ATSHs of the subgroups under 60 years, but there was a decrease in the group of 60- to 70-year-old subjects and, especially, in the volunteers over 70 (Fig. 1). Fig. 1. Age-related
distribution
All healthy controls (n = 64)
of
ATSH values in healthy controls Healthy controls
< 40 years (n =21)
PO - 59 years In = 15)
------
. _---_-_
24 .25.9
A TSH
l
60 - 70 years (n = 10)
> 70
years (n = 18)
25.9
20
.
.
16
12
E-
... :: -
4-
OJ
. . .% . .
.
i . : . . . -----.
. .
. . .
-:_
;:j....
?A : .. .;.
-----
.. . ..
‘.’ v
i
-----_
. :.
: : .
. .. ..
_-----
. 0.
. . .
... : .
::
------
.
:.
-f .----.
l
a.4 k 4.4
9.7 + 3.2
10.7 f 6.6
6.6 + 1.9
5.7 t 3.1
The mean increase in ATSH in patients with endogenous depression was 7.8 f 0.4 (range: 0.3-26.5, Fig. 2) and we also found a significant negative correlation between age and ATSH in the depressed patients (r = -0.44, df = 42,~ < 0.005). We conducted a three-way ANOVA to evaluate the influence of age, diagnosis, and gender on ATSH. The effect of age was calculated by dividing the controls and the depressed patients into two groups of subjects, one under 60 years and one aged 60 or older. As none of our schizophrenic patients were older than 54, we did not include them in these calculations. Table 1 reveals a significant influence of age on ATSH in both healthy subjects and depressed patients, whose ATSH levels did not differ significantly. The influence of age on ATSH was not dependent on gender. It should be noted, however,
289
Fig. 2. Age-related distributions of ATSH depressive disorder and schizophrenia All patients with major depressive disorder (n=44) l
22
values
in oatients .
with
major
All patients with major depressivedisorder
< 40
years (l-l = 8)
26.5
l
40 - 59 years (n = 18)
60 - 70 years (n= 7)
Patients with schizophrenia al I < 60 years (n=21)
> 70 years (n= 11)
26.5 .-----_
-------
A TSH 18
:
:
. . . :
14
.
-y-
2
. . . .
A . :
t
*! :: .::. . . : 8 . .
6
:
. .
1.6 + 4.0
.
.
.
.
.
i
.
-
_:-
.. _ :: ‘= .
------
------
.
.. . . .
.
I . C. __-*%--
.
.
.
!.
10
-----_
------
.
.
i .
-----_ =’ . 11.6t6.4
7.9 * 3.9
6.5? 3.2
7.3 * 3.5
4.6 + 3.6
Table 1. Results of 3-way analysis of variance with agel, subgroup2, and gender as independent variables and ATSH as dependent variable Source of variation
Sum of squares
df
Mean squared
F
p
Main effects Gender
32.766
1
32.766
1.799
0.183
Subgroup
20.527
1
20.527
1.127
0.291
364.947
1
364.947
20.033
0.001
0.956
Aoe 2-Way interactions Gender-Subgroup
0.056
1
0.056
0.003
Gender-Age
24.295
1
24.295
1.334
0.251
Subgroup-Age
15.299
1
15.299
0.840
0.362
25.817
1
25.817
1.417
0.237
3-Way interactions Gender-Subarouo-Aae
1. All subjects 5 60 years were compared with all subjects > 60 years 2. Healthy subjects and depressed patients (see text).
that the depressed women under 50 years of age had higher ATSH values (mean 11.9 f 5.7) than male controls in the same age group (mean 6.8 f 1.6). We could not find significant correlations between ATSH and HRSD scores (r = -0.20, df = 42, NS), between ATSH and length of episode (r = -0.07, df =42, NS), or between ATSH and weight loss (in kg) during present episode (I = 0.08, df = 42, NS). The mean ATSH for the 21 patients with schizophrenia was 7.3 f 3.5 (Fig. 2) and did not differ from that of all healthy controls (t = 1.1, df = 83, NS). As none of our schizophrenic patients were over 54 years old, we also compared their mean ATSH with that of the healthy volunteers of under age 60 (10.1 + 4.6, Fig. 1) and found the difference between the two groups to be significant (t = 2.3, df q 55, p < 0.025). No significant correlations were found between ATSH and age (r q 0.23, df q 19, NS), ATSH and length of episode (r q -0.25, df q 19, NS), ATSH and weight loss (r = -0.16, df = 19, NS), or ATSH and CGI severity scores (r = 0.23, df = 19, NS). A significant correlation between ATSH and severity of illness; however, could hardly be expected, since almost all of our patients were severely ill. As our results show a clear tendency toward a decrease in ATSH in subjects over 60 years of age, and a still more pronounced decrease in ATSH in the volunteers over age 70, we set three age-related ranges of normal for ATSH. If the normal range was assumed to be the mean plus two standard deviations, this would result in a lower limit for ATSH at or near zero in the different age groups of the healthy subjects. We therefore log-transformed the data to achieve a better distribution of normality, and then designated normal ranges on the basis of the log-transformed mean plus two standard deviations. For the group of healthy subjects younger than 60 years, we found a range of normal for ATSH between 4.1 and 2 1.4; for the group between 60 and 70 years, we obtained a normal range of 3.4-14.6; and for all persons older than 70, the normal range was set at between 1.8 and 15.6. On application of these limits to our three populations, three healthy subjects (4.70/,), six depressed patients (13.6%), and four schizophrenic patients (19.0%) showed a blunted TSH response to TRH (Fig. 1 and Table 2). Thus, the rate of abnormal TRH test results did not differ significantly between the healthy subjects and the depressed patients, and between the depressed
Table S.‘Mean ATSH Lakes healthy
and rates of blunted
Subjects
n
Healthy
64
controls
Mean &SD ATSH
Bluntecf Normal
6.4k4.4
depressive
44
7.624.6
disorder Schizophrenia
in patients
and in
21
7.3k3.5
Non-age-related ranges of normal
Age-related ranges of normal for ATSH
3
( Major
response
controls
4.7%)
ATSH = 5 Blunted
Normal
ATSH = 7 Blunted
61
16
46
35
29
(95.3%)
(25.0%)
(75.0%)
(54.7%)
(45.3%)
6
38
14
30
22
(13.6%)1
(86.4%)
(31&‘/o)
(68.20/o)
(50.0%)
4 (19.0010)2
Normal
17 (81.0%)
4 (19.00/o)
1. x2 = 2.73, p > 0.05, NS. compared to the 9roup of healthy controls. 2. x2 = 4.3, p c 0.05, compared to the 9roup of healthy controls.
17 (81.0%)
9 (42.8%)
22 (50.01) 12 (57.2%)
291 and the schizophrenic patients (Table 2). A significant difference was only found between healthy subjects and schizophrenic patients (Table 2). Four of the six depressed patients with blunted TRH test results were over age 70. Two healthy controls and one depressed patient had increased ATSH values. Four of the six depressed patients with an abnormal TSH response to TRH had unipolar depression, and two bipolar. The mean ATSH of the patients with bipolar disorder was lower (6.3 ? 3.4) than that of the unipolar depressed patients (8.3 + 4.9), but the difference was not significant (t = 1.8, df = 46, NS). Finally, Table 2 shows that if we had applied a cutoff level of ATSH = 5 or ATSH = 7, as has been done by numerous workers who have not established their own age-related cutoff criteria, we would then have had 3 1.8% and 50.0% abnormally low TRH test results, respectively, in our depressed population. The mean baseline TSH level for all healthy volunteers was 1.7 * 1.3 mU/l compared to 1.5 f 1.4 mU/ 1for the depressed, and 1.9 f 1.4 mU/ 1for the schizophrenic patients. These differences were not significant (healthy vs. depressed subjects: t = 0.56, df 107, NS); and healthy volunteers vs. schizophrenic patients: t x0.26, df = 84, NS). There was a highly significant correlation between baseline and ATSH levels in healthy subjects (r 0.60, df = 62,~ < 10-s) in depressed patients (r= 0.46, df = 42,~ < lo-‘), and in schizophrenic patients (r 0.55, df = 19,~ < 0.01). The mean baseline TSH level for all healthy controls with a blunted TSH response (n= 3; 0.6 + 0.4 mu/l) was lower than that for all subjects with normal TRH test results (1.9 f 1.4 mu/l). Correspondingly, the mean baseline TSH level for the depressed patients with a blunted TSH response (n = 6; 0.6 f 0.2 mu/l) was lower than that for the depressed patients with normal TSH responses to TRH (1.9 + 1.5 mu/l). We also found a significant negative correlation between age and baseline TSH in healthy controls (r = -0.26, df = 62, p < 0.05),but not in depressed patients (r = -0.09, df = 42, NS). q
q
q
Discussion We found a significant negative correlation between age and TSH response to TRH in both healthy controls and patients with endogenous depression. To our knowledge, only a few authors have paid attention to the relationship between age and ATSH in psychiatric patients (e.g., Hollister et al., 1976; Linkowski et al., 1983; Calloway et al., 1984), some of whom were working with populations with an upper age limit of not more than 59 (Loosen et al., 1977) or 65 years (Takahashi et al., 1974). Only in the study by Hollister et al. (1976) was a tendency toward decreasing ATSH levels in older patients reported. However, several endocrinological studies suggest an effect of age on the TRH results, although the detailed findings are rather confusing: Snyder and Utiger (1972~) reported a significant decrease in ATSH in healthy male subjects over 40, but could not confirm this finding in normal women (Snyder and Utiger, 19726). Wenzel et al. (1974) found higher ATSH levels in women between 20 and 59 years old than in men of the same age, whereas no differences were found between younger and older men or between older men and older women. A decreased TSH response to TRH has also been reported in geriatric inpatients by Burrows et al. (1977) and in healthy subjects over 70 years old by Cuttelod et al. (1974) and Olsen et al. (1978).
292 The reason for the age dependence of TRH test results remains unclear. It has not been possible to demonstrate an effect of height or weight (Haigler et al., 197 1; Snyder and Utiger, 1972a), and the studies on thyroid hormones in old age have shown either diminished (Snyder and Utiger, 1972~; Nishikawa et al., 198 1) or normal (Olsen et al., 1978) levels of T, and no change in Tdvalues (Snyder and Utiger, 1972~; Olsen et al., 1978; Nishikawa et al., 1981). These findings do not suggest that disturbances in thyroid hormone levels account for the fall in the ATSH in older subjects. Therefore, a central dysregulation at the hypothalamic-pituitary level in older age must be considered as a possible cause of the effect of age on TRH test results. One clinical implication of our findings is that age-related limits of normal values for ATSH should be applied, as has already been suggested by Snyder and Utiger (1972~). As regards the dexamethasone suppression test, Meltzer and Fang (1983) emphasized that each laboratory should determine its own cutoff point, since the cortisol levels found differ widely from laboratory to laboratory, depending on the method or kit employed. The same applies to the measurement of TSH (Sternbach et al., 1983); thus we suggest that study groups should not simply adopt age-related ranges of normal for ATSH reported by other groups, but establish their own age-related normal ranges by investigating a population of age-matched healthy controls. In our study, we based our comparison on normal ranges for ATSH calculated from the ATSH values in healthy subjects related to age. It was then seen that blunted TSH responses to TRH do not occur significantly more often in depression than in the healthy controls. The wide variation in the rates of blunted TRH test results in depressed patients, which range from 0% (Coppen et al., 1980) to 64% (Extein et al., 1981), might thus be partly related to the fact that possible effects of age and laboratory differences were not taken into consideration. The use in this study of a RIA technique with improved sensitivity in the lower range of TSH showed a close correlation between TSH levels at baseline and after stimulation, suggesting that blunted TSH response to TRH is related to diminished TSH production in the pituitary gland. Explanations for abnormal TRH test results have been mainly speculative so far (e.g., Loosen and Prange, 1982; Calloway et al., 1984). Our finding that TSH responses can also be blunted in schizophrenic patients is further evidence that abnormal TRH test results are not related to any specific diagnosis, such as endogenous depression. Furthermore, we were unable to confirm differences between the TRH test results for unipolar and bipolar depressed patients. Thus, our results do not support the theory that the TRH test may be of value as an aid in differentiating between psychiatric diagnoses or subgroups. References Asnis, G.M., Nathan, R.S., Halbreich, U., Halpern, F.S., and Sachar, E.J. TRH test in depression. Lancer, I, 424 (1980). Banki, CM., Aratd, M., and Papp, Z. Thryoid stimulation test in healthy subjects and psychiatric patients. Acta Psychiatrica Scundinuvicu, 70, 295 (1984). Burrows, A.W., Cooper, E., Shakespear, R.A., Aickin, C.M., Fraser, S., Hesch, R.D., and Burke, C.W. Low serum L-T, levels in the elderly sick: Protein binding, thyroid and pituitary responsiveness, and reverse T, concentrations. Clinical Endocrinology, 7, 289 (1977).
293 Calloway, S.P., Dolan, R.J., Fonagy, P., de Souza, V.F.A., and Wakeling, A. Endocrine changes and clinical profiles in depression: II. The thyrotropin-releasing hormone test. Psychological Medicine, 14, 759 (1984). Camilli, G., and Hopkins, K.D. Testing for association in 2 x 2 contingency tables with very small sample sizes. Psychological Bulletin, 85, 1011 (1979). Coppen, A., Rama Rao, V.A., Bishop, M., Abou-Saleh, M.T., and Wood, K. Neuroendocrine studies in affective disorders. Journal of Affective Disorders, 2,417 (1980). Cuttelod, S., Lemarchand-Beraud, T., Magnenat, P., Perret, C., Poli, S., and Vannotti, A. Effect of age and role of kidneys and liver on thyrotropin in man. Metabolism, 23, 101 (1974). Extein, I., Pottash, A.L.C., and Gold, M.S. TRH test in depression. Lancer. I, 923 (1980). Extein, I., Pottash, A.L.C., and Gold, M.S. Relationship of thyrotropin-releasing hormone test and dexamethasone suppression test abnormalities in unipolar depression. Psychiatr_v Research,
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