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The TRH test and urinary MHPG in unipolar depression
Journal of Affectioe Elsevier
Disorders, 5 (1983) 233-237
233
The TRH Test and Urinary MHPG in Unipolar Depression Harvey
A. Sternbach
‘, Larry Kirstein 3, A.L.C. Pottash 2, Mark Irl Extein ’ and Donald R. Sweeney ’
S. Gold
2,
I Research Fuciliiies, Farr Oaks Hospital, ’ Psychiatric Diagnostic Laborcrtories of America, Summit, NJ, and ’ Regent Hospital, New York, NY (U.S.A.) (Received 1 July, 1982) (Accepted 1I January, 1983)
Summary
Twenty-five men and 26 women with major unipolar depression were evaluated by the TRH test and urinary MHPG excretion. A significant positive correlation between TSH response to TRH and urinary MHPG was found in the men, though not in the women. These findings suggest that at least for depressed men, central norepinephrine deficiency may be the neurobiological substrate of blunted TSH responses to TRH.
Introduction
The thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) has been reported to be blunted in major unipolar depressives in spite of normal thyroid functioning as determined by basal levels of TSH, T4 and T3 (Loosen and Prange 1980; Extein et al. 198 1; Gold et al. 1981; Kirkegaard 198 1; I&stein et al. 1981; Sternbach et al. 1982). Urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) has been used to assess central noradrenergic state with low 24-h levels said to reflect norepinephrine (NE) deficiency (Maas 1975; Goodwin et al. 1978) and to predict therapeutic response to noradrenergic antidepressants (Fawcett and Maas 1972; Beckmann and Goodwin 1975; Goodwin et al. 1978). As the peptides TRH and TSH are regulated by biogenic amines (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) the assessment of the Address correspondence to Dr. Harvey A. Sternbach. Department of Psychiatry, Brentwood Neuropsychiatric Institute, 11301, Wilshire Blvd., Los Angeles, CA 90073, U.S.A.
0165-0327/83/$03.00
0 1983 Elsevier Science Publishers
B.V.
VA-UCLA-
234
relationship between TSH response to TRH and urinary MHPG in depressives could yield further insight into the possible role of norepinephrine in the etiology of the blunted TSH responses observed in depression. Davis et al. (1981) have recently reported that in a group of 20 male depressives (unipolar and bipolar) there was no significant correlation between TSH response to TRH and urinary MHPG, although patients with blunted TSH responses had statistically significant higher mean 24-h urinary MHPG levels than those with a normal TSH response. In this report, we describe data showing a significant positive correlation between urinary MHPG levels and TSH response to TRH in depressed men, though not in women. Subjects
and Methods
The patient sample consisted of 51 patients (26 women, 25 men) hospitalized for depression on the Neuropsychiatric Evaluation Units at either Fair Oaks or Regent Hospital. All patients met Research Diagnostic Criteria (Spitzer et al. 1975) for major unipolar depressive disorder with endogenous features. The patients ranged in age from 17 to 61 years; there was no significant difference between the mean (_t SD) age of the women, 38 ( f 10.0) years, compared with the men, 41 (+ 12.7) years (t = 0.8, df= 49). Patients were excluded from the study if they had thyroid, renal or hepatic diseases, alcoholism, drug abuse, or had taken medications known to affect either the TRH test (including lithium in the past 6 months) (Refetoff et al. 1979) or urinary MHPG (including any sympathomimetic medications). Serum thyroxine (T4), triiodothyronine (T3)-uptake, free thyroxin index and baseline TSH levels were within normal limits for all patients. The tests were administered to all patients as part of a two-center consecutive admission study of depressive illness, with urinary MHPG collection done prior to the TRH test. The patients were on a low monoamine diet for at least 3 days prior to collection of the two consecutive 24-h urine samples for MHPG. Urinary MHPG was collected, preserved and measured by methods described previously (Dekirmenjian and Maas 1970). Urine samples were excluded from analysis if the total creatinine excretion was less than 20 mg/kg for men and 15 mg/kg for women (Edwards et al. 1980). The mean value of the two 24-h samples was used as the final MHPG measure. An indwelling venous catheter was placed at 8.00 a.m. in patients who were at bedrest after an overnight fast. At 9.00 a.m., 500 pg of synthetic TRH was administered over 30 s through the catheter. Before and 15, 30, 60 and 90 min after TRH administration, small samples of blood were obtained for measurement of serum TSH in duplicate by radioimmunoassay (Hall et al. 1971). The maximum TSH response, or ATSH, was determined for each patient by subtracting the baseline TSH from the peak TSH level after TRH infusion (Extein et al. 1981; Kirstein et al. 1981). All patients with a ATSH < 7.0. pIU/ml were considered to have a blunted TSH response to TRH (Extein et al. 1981; Kirstein et al. 198 1). The t-test was used to assess significance of differences between the mean TSH and urinary MHPG levels of men and women, as well as mean urinary MHPG levels of patients with normal and blunted TSH responses to TRH. The Pearson product-
235
moment correlation coefficient urinary MHPG and age.
(r) was used to assess the correlations
between
TSH,
Results There was a statistically significant difference between the mean ATSH ( t SD) of the men, 6.57 (& 3.5) pIU/ml and women, 8.60 (+ 3.0) IU/ml (1 = 2.13, df= 49, P < 0.05, two-tailed). Seventeen (68%) of the men tested had a blunted TSH response to TRH, while 9 (35%) of the women had such a response. There was a statistically significant difference between the mean MHPG (&SD) of the men, 1494 (+ 777) pg/24 h, compared with that for the women, 1030 (+455) pg/24 h (t = 2.47, df= 49, P < 0.02 two-tailed). When we examined the relationship between ATSH and urinary MHPG, the men showed a significant positive correlation between TSH and MHPG (Pearson r = 0.49, P ,< 0.0 l), while the women did not (r = 0.14). There was a significant difference between the mean MHPG (f SD) for men with blunted TSH responses, 1232 (_+464) pg/24 h compared with men who had a normal TSH response to TRH, 2052 (+489) pg/24 h (t = 2.57, df= 23, P < 0.05, two-tailed); no such difference was found in the women, mean MHPG (I SD) for blunted TSH responders was 1.053 (k 260 pg/24 h compared with 988 (+ 348) pg/24 h for normal TSH responders (t = 0.32, df= 24). There was no significant correlation found for either sex between age and urinary MHPG (r = 0.16 for men, r = 0.24 for women), or between age and TSH (r = 0.35 for men, r = 0.28 for women).
Comment The results of this study indicate that for men there exists a correlation between TSH response to TRH (as measured by ATSH) and excretion of urinary MHPG, such that men with lower MHPG excretion are more likely to have a blunted TSH response. This would suggest that central NE deficiency may be the neurobiological substrate for the blunted TSH responses to TRH reported in depression (Loosen and Prange, 1980; Extein et al. 198 1; Gold et al. 1981; Kirkegaard 198 1; I&stein et al. 198 1; Sternbach et al. 1982). It is not clear, however, why women would not show a similar relationship between urinary MHPG and ATSH. Evaluation of neuroendocrine parameters in women is complex because of the need to consider such factors as whether the woman is pre- or post-menopausal and what phase of the menstrual cycle the woman was in at the time of TRH testing as it has been shown that the TSH response may by blunted during the luteal phase (Refetoff et al. 1979). As we did not control for this variable in the women we studied, we do not know whether the sex difference reported here is a result of such “menstrual” artifacts or is, in fact, real. We do not believe that age could account for this sex difference as there was no significant difference in age between the men and women studied. The significant
236
difference between the mean ATSH response seen in men and women is consistent with previous reports that euthroid women have higher TSH responses to TRH than euthroid men (Refetoff et al. 1979) i.e., a sex difference that is normally observed. The finding of only a trend toward negative correlation between ATSH and age was surprising in light of previous work (Snyder and Utiger 1972) showing that the ATSH decreases with increasing age. However, the mean (+ SEM) age of our population, 41 (+ 2.6) years, did not allow for a full examination of this issue in our study. Norepinephrine and other neurotransmitters have been shown to have direct effects on the regulation of TRH (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) and TSH responses in animals. It has been shown, for example, that increases in NE increase TRH, decreases in NE decrease TRH, and TRH increased NE release (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974). As depletion of NE can result in TRH reduction (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) and possible decreased TSH stores in the pituitary, lower central NE states, as reflected by low MHPG excretion in our male patients, may result in blunted TSH responses to TRH. Many studies have reported that a blunted TSH score helps differentiate unipolar depressives from bipolar, dysthymic and secondary depressives (Asnis et al. 1980; Gold et al. 1980; Extein et al. 1981). Studies of MHPG excretion on unipolar depression suggest biochemically heterogenous subgroups with low, normal or high MHPG values (Beckmann et al. 1975; Schildkraut et al. 1978; Hollister et al. 1980). This study reported a positive correlation between MHPG and ATSH score. Davis reported that primary depressives with a blunted TSH had higher urinary MHPG scores than depressives with a normal ATSH. Davis used 6.0 pIU/ml rather than 7.0 pIU/ml as a cut off defining a blunted ATSH. If we had employed 6.0 as a cut off for blunting, 5 of the 11 patients with MHPG scores of 1200 or less would be classified in the normal ATSH group, resulting in no significant difference between blunted and normal ATSH groups in mean urinary MHPG scores. Kirstein et al. (198 1) have previously shown that a ATSH of 7.0 is both a sensitive and yet specific cut off value for ATSH in unipolar male depression. One other difference between Davis’s study and this one related to the fact that, of his 20 patients receiving a TRH test and complying with 24-h urinary collections, as many as 10 may have been bipolar and not unipolar. This difference in diagnostic homogeneity also might have partially accounted for the conflicting result. The results of the present study suggest several new avenues for future investigation into the TSH response to TRH and urinary MHPG. First, future investigations would need to examine unipolar and bipolar depressed men and women separately to ascertain whether the sex differences reported here can be confirmed and whether differences exist among subtypes of depression. Such studies would need to carefully control for the menstrual status of the women for the reasons discussed earlier. Secondly, patient profiles could be drawn up based upon TSH response to TRH, urinary MHPG and cortisol response to dexamethasone. Such profiles may lead to a better understanding of the heterogeneity of depressive illness.
237
References Asnis, G., Nathan, R. and Halbreich. V., TRH tests in depression, Lancet. i (1980) 424. Beckmann, H. and Goodwin, F.K., Antidepressant response to tricyclics and urinary MHPG in unipolar patients, Arch. Gen. Psychiat., 32 (1975) 17-21. Davis, K.L., Hollister, L.E., Mathe, A.A., Davis, B.M., Rothpearl, A.B.. Faull, K.F.. Hsieh, J.Y.K., Barchas. J.D. and Berger, P., Neuroendocrine and neurochemical measurements in depression, Amer. J. Psychiat., 138(12) (1981) 1555-1562. Dekirmenjian, H. and Maas, J.W.. An improved procedure of 3-methoxy-4-hydroxyphenylethylene glycol determination by gas-liquid chromatography, Anal. Biochem., 35 (1970) 113- 122. Edwards, D.J., Spiker, D.G., Neil, J.F., Kupfer, D.J. and Rizk, M., MHPG excretion in depression, Psychiat. Res., 2 (1980) 295-305. Extein, I., Pottash, A.L.C. and Gold, MS., The thyrotropin-releasing hormone test in the diagnosis of unipolar depression, Psychiat. Res.. 5 (198 1) 3 1 l-3 16. Fawcett, J.. Maas, J.W. and Dekirmenjian, H.. Depression and MHPG excretion, Arch. Gen. Psychiat., 26 (1972) 246-25 1. Gold, MS., Pottash, A.L.C.. Ryan, N., Sweeney, D.R.. Davies, R.K. and Martin, D.M.. TRH induced TSH response in unipolar, bipolar, and secondary depression -~ Possible utility in clinical assessment and differential diagnosis, Psychoneuroendocrinology, 5 (1980) 147- 155. Gold, M.S., Pottash, A.L.C., Extein, I. and Sweeney, D.R.. Diagnosis of depression in the 1980’s. J. Amer. Med. Ass. 245(15) (1981) 156221564. Goodwin, F.K., Cowdry, R.N. and Webster, M.H., Predictors of drug response in the affective disorders - Toward an integrated approach. In: M.A. Lipton. A. DiMascio and K.F. Killam (Eds.), Psychopharmacology - A Generation of Progress, Raven Press, New York, NY, 1978, pp. 1277- 1288. Grimm, Y. and Reichlin, S., Thyrotropin-releasing hormone (TRH) - Neurotransmitter regulation of secretion by mouse hypothalamic tissue, in vitro, Endocrinol., 93 (1973) 626-63 1. Hall, R., Amos, J. and Ormston, B., Radioimmunoassay of human serum thyrotropin, Brit. Med. J., I (1971) 582. Hollister, L.E., Davis, K.L. and Berger, P.A., Subtypes of depression based on excretion of MHPG and response to nortriptyline, Arch. Gen. Psychiat., 37 (1980) 1107~1110. Jackson, I.M.D., Thyrotropin-releasing hormone, N. Engl. J. Med., 306(3) (1982) 145-155. Kellerer, H.H., Bartholini, G. and Pletscher, A., Enhancement of cerebral noradrenaline turnover by thyrotropin releasing hormone, Nature (Lond.), 248 (1974) 528-530. Kirkegaard, C., The thyrotropin response to thyrotropin-releasing hormone in endogenous depression, Psychoneuroendocrinol., 6(3) (1981) 189-212. Kirstein, L., Gold, M.S., Pottash, A.L.C. and Extein, I., Thyrotropin-releasing hormone test and male unipolar depression, BioI. Psychiat., 16(9) (1981) 8 19-823. Loosen, P.T. and Prange, Jr., A.J., Thyrotropin releasing hormone (TRH) A useful tool for psychoneuroendocrine evaluation, Psychoneuroendocrinol., 5 (1980) 63-80. Maas, J.W., Biogenic amines and depression, Arch. Gen. Psychiat.. 32 (1975)1357- 1361. Muscettola, G., Potter, W.Z., Gordon, E.K. and Goodwin, F.K., Methodological issues in the measurement of urinary MHPG, Psychiat. Res.. 4 (1981) 267-276. Refetoff, S., Frank, P.H., Roubebush, C.P. and DeGroot, L.J., Evaluation of pituitary function. In: L.J. DeGroot, G.F. Cahill, L. Martini, D.H. Nelson, W.D. Odell, J.T. Potts, Jr., E. Steinberger and A.I. Winegrad (Eds.), Endocrinology, Vol. 1, Grune and Stratton, New York, NY, 1979, p. 196. Reichlin, S., Martin, J.B. and Mitniek, M., The hypothalamus in pituitary thyroid regulation. In: E.B. Astwood (Ed.), Recent Progress in Hormone Research, Academic Press, New York, NY, 1972, pp. 229-286. Schildkraut, J.J., Orsulak, P.J., Schatzberg, A.F., Gudeman, J.E., Cole, J.O., Rohde, W.A. and LaBrie, R.A., Toward a biochemical classification of depressive disorders, Arch. Gen. Psychiat., 35 (1978) 1427- 1442. Spitzer, R.L., Endicott, J. and Robins, E., Research Diagnostic Criteria for a Selected Group of Functional Disorders, 2nd edition, New York State Psychiatric Institute, Division of Biometrics Research, New York, NY, 1975. Sternbach, H., Gerner, R.H. and Gwirtsman, H.E., The thyrotropin releasing hormone stimulation test A review, J. Clin. Psychiat., 43 (1982) 4-6.
Disorders, 5 (1983) 233-237
233
The TRH Test and Urinary MHPG in Unipolar Depression Harvey
A. Sternbach
‘, Larry Kirstein 3, A.L.C. Pottash 2, Mark Irl Extein ’ and Donald R. Sweeney ’
S. Gold
2,
I Research Fuciliiies, Farr Oaks Hospital, ’ Psychiatric Diagnostic Laborcrtories of America, Summit, NJ, and ’ Regent Hospital, New York, NY (U.S.A.) (Received 1 July, 1982) (Accepted 1I January, 1983)
Summary
Twenty-five men and 26 women with major unipolar depression were evaluated by the TRH test and urinary MHPG excretion. A significant positive correlation between TSH response to TRH and urinary MHPG was found in the men, though not in the women. These findings suggest that at least for depressed men, central norepinephrine deficiency may be the neurobiological substrate of blunted TSH responses to TRH.
Introduction
The thyroid-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) has been reported to be blunted in major unipolar depressives in spite of normal thyroid functioning as determined by basal levels of TSH, T4 and T3 (Loosen and Prange 1980; Extein et al. 198 1; Gold et al. 1981; Kirkegaard 198 1; I&stein et al. 1981; Sternbach et al. 1982). Urinary 3-methoxy-4-hydroxyphenyl glycol (MHPG) has been used to assess central noradrenergic state with low 24-h levels said to reflect norepinephrine (NE) deficiency (Maas 1975; Goodwin et al. 1978) and to predict therapeutic response to noradrenergic antidepressants (Fawcett and Maas 1972; Beckmann and Goodwin 1975; Goodwin et al. 1978). As the peptides TRH and TSH are regulated by biogenic amines (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) the assessment of the Address correspondence to Dr. Harvey A. Sternbach. Department of Psychiatry, Brentwood Neuropsychiatric Institute, 11301, Wilshire Blvd., Los Angeles, CA 90073, U.S.A.
0165-0327/83/$03.00
0 1983 Elsevier Science Publishers
B.V.
VA-UCLA-
234
relationship between TSH response to TRH and urinary MHPG in depressives could yield further insight into the possible role of norepinephrine in the etiology of the blunted TSH responses observed in depression. Davis et al. (1981) have recently reported that in a group of 20 male depressives (unipolar and bipolar) there was no significant correlation between TSH response to TRH and urinary MHPG, although patients with blunted TSH responses had statistically significant higher mean 24-h urinary MHPG levels than those with a normal TSH response. In this report, we describe data showing a significant positive correlation between urinary MHPG levels and TSH response to TRH in depressed men, though not in women. Subjects
and Methods
The patient sample consisted of 51 patients (26 women, 25 men) hospitalized for depression on the Neuropsychiatric Evaluation Units at either Fair Oaks or Regent Hospital. All patients met Research Diagnostic Criteria (Spitzer et al. 1975) for major unipolar depressive disorder with endogenous features. The patients ranged in age from 17 to 61 years; there was no significant difference between the mean (_t SD) age of the women, 38 ( f 10.0) years, compared with the men, 41 (+ 12.7) years (t = 0.8, df= 49). Patients were excluded from the study if they had thyroid, renal or hepatic diseases, alcoholism, drug abuse, or had taken medications known to affect either the TRH test (including lithium in the past 6 months) (Refetoff et al. 1979) or urinary MHPG (including any sympathomimetic medications). Serum thyroxine (T4), triiodothyronine (T3)-uptake, free thyroxin index and baseline TSH levels were within normal limits for all patients. The tests were administered to all patients as part of a two-center consecutive admission study of depressive illness, with urinary MHPG collection done prior to the TRH test. The patients were on a low monoamine diet for at least 3 days prior to collection of the two consecutive 24-h urine samples for MHPG. Urinary MHPG was collected, preserved and measured by methods described previously (Dekirmenjian and Maas 1970). Urine samples were excluded from analysis if the total creatinine excretion was less than 20 mg/kg for men and 15 mg/kg for women (Edwards et al. 1980). The mean value of the two 24-h samples was used as the final MHPG measure. An indwelling venous catheter was placed at 8.00 a.m. in patients who were at bedrest after an overnight fast. At 9.00 a.m., 500 pg of synthetic TRH was administered over 30 s through the catheter. Before and 15, 30, 60 and 90 min after TRH administration, small samples of blood were obtained for measurement of serum TSH in duplicate by radioimmunoassay (Hall et al. 1971). The maximum TSH response, or ATSH, was determined for each patient by subtracting the baseline TSH from the peak TSH level after TRH infusion (Extein et al. 1981; Kirstein et al. 1981). All patients with a ATSH < 7.0. pIU/ml were considered to have a blunted TSH response to TRH (Extein et al. 1981; Kirstein et al. 198 1). The t-test was used to assess significance of differences between the mean TSH and urinary MHPG levels of men and women, as well as mean urinary MHPG levels of patients with normal and blunted TSH responses to TRH. The Pearson product-
235
moment correlation coefficient urinary MHPG and age.
(r) was used to assess the correlations
between
TSH,
Results There was a statistically significant difference between the mean ATSH ( t SD) of the men, 6.57 (& 3.5) pIU/ml and women, 8.60 (+ 3.0) IU/ml (1 = 2.13, df= 49, P < 0.05, two-tailed). Seventeen (68%) of the men tested had a blunted TSH response to TRH, while 9 (35%) of the women had such a response. There was a statistically significant difference between the mean MHPG (&SD) of the men, 1494 (+ 777) pg/24 h, compared with that for the women, 1030 (+455) pg/24 h (t = 2.47, df= 49, P < 0.02 two-tailed). When we examined the relationship between ATSH and urinary MHPG, the men showed a significant positive correlation between TSH and MHPG (Pearson r = 0.49, P ,< 0.0 l), while the women did not (r = 0.14). There was a significant difference between the mean MHPG (f SD) for men with blunted TSH responses, 1232 (_+464) pg/24 h compared with men who had a normal TSH response to TRH, 2052 (+489) pg/24 h (t = 2.57, df= 23, P < 0.05, two-tailed); no such difference was found in the women, mean MHPG (I SD) for blunted TSH responders was 1.053 (k 260 pg/24 h compared with 988 (+ 348) pg/24 h for normal TSH responders (t = 0.32, df= 24). There was no significant correlation found for either sex between age and urinary MHPG (r = 0.16 for men, r = 0.24 for women), or between age and TSH (r = 0.35 for men, r = 0.28 for women).
Comment The results of this study indicate that for men there exists a correlation between TSH response to TRH (as measured by ATSH) and excretion of urinary MHPG, such that men with lower MHPG excretion are more likely to have a blunted TSH response. This would suggest that central NE deficiency may be the neurobiological substrate for the blunted TSH responses to TRH reported in depression (Loosen and Prange, 1980; Extein et al. 198 1; Gold et al. 1981; Kirkegaard 198 1; I&stein et al. 198 1; Sternbach et al. 1982). It is not clear, however, why women would not show a similar relationship between urinary MHPG and ATSH. Evaluation of neuroendocrine parameters in women is complex because of the need to consider such factors as whether the woman is pre- or post-menopausal and what phase of the menstrual cycle the woman was in at the time of TRH testing as it has been shown that the TSH response may by blunted during the luteal phase (Refetoff et al. 1979). As we did not control for this variable in the women we studied, we do not know whether the sex difference reported here is a result of such “menstrual” artifacts or is, in fact, real. We do not believe that age could account for this sex difference as there was no significant difference in age between the men and women studied. The significant
236
difference between the mean ATSH response seen in men and women is consistent with previous reports that euthroid women have higher TSH responses to TRH than euthroid men (Refetoff et al. 1979) i.e., a sex difference that is normally observed. The finding of only a trend toward negative correlation between ATSH and age was surprising in light of previous work (Snyder and Utiger 1972) showing that the ATSH decreases with increasing age. However, the mean (+ SEM) age of our population, 41 (+ 2.6) years, did not allow for a full examination of this issue in our study. Norepinephrine and other neurotransmitters have been shown to have direct effects on the regulation of TRH (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) and TSH responses in animals. It has been shown, for example, that increases in NE increase TRH, decreases in NE decrease TRH, and TRH increased NE release (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974). As depletion of NE can result in TRH reduction (Reichlin et al. 1972; Grimm and Reichlin 1973; Kellerer et al. 1974; Jackson 1982) and possible decreased TSH stores in the pituitary, lower central NE states, as reflected by low MHPG excretion in our male patients, may result in blunted TSH responses to TRH. Many studies have reported that a blunted TSH score helps differentiate unipolar depressives from bipolar, dysthymic and secondary depressives (Asnis et al. 1980; Gold et al. 1980; Extein et al. 1981). Studies of MHPG excretion on unipolar depression suggest biochemically heterogenous subgroups with low, normal or high MHPG values (Beckmann et al. 1975; Schildkraut et al. 1978; Hollister et al. 1980). This study reported a positive correlation between MHPG and ATSH score. Davis reported that primary depressives with a blunted TSH had higher urinary MHPG scores than depressives with a normal ATSH. Davis used 6.0 pIU/ml rather than 7.0 pIU/ml as a cut off defining a blunted ATSH. If we had employed 6.0 as a cut off for blunting, 5 of the 11 patients with MHPG scores of 1200 or less would be classified in the normal ATSH group, resulting in no significant difference between blunted and normal ATSH groups in mean urinary MHPG scores. Kirstein et al. (198 1) have previously shown that a ATSH of 7.0 is both a sensitive and yet specific cut off value for ATSH in unipolar male depression. One other difference between Davis’s study and this one related to the fact that, of his 20 patients receiving a TRH test and complying with 24-h urinary collections, as many as 10 may have been bipolar and not unipolar. This difference in diagnostic homogeneity also might have partially accounted for the conflicting result. The results of the present study suggest several new avenues for future investigation into the TSH response to TRH and urinary MHPG. First, future investigations would need to examine unipolar and bipolar depressed men and women separately to ascertain whether the sex differences reported here can be confirmed and whether differences exist among subtypes of depression. Such studies would need to carefully control for the menstrual status of the women for the reasons discussed earlier. Secondly, patient profiles could be drawn up based upon TSH response to TRH, urinary MHPG and cortisol response to dexamethasone. Such profiles may lead to a better understanding of the heterogeneity of depressive illness.
237
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