472
BIOL PSYCHIA tE.Y !990;27:472--476
Increased Production of Thyroxine and Inappropriately Elevated Serum Thyretropin in Levels in Endogenous Depression C. Kirkegaard, A. Kctrner, and J. Faber
The increased serum thyroxine (T4) levels in endogenous depression (ED) might be due to an increased production or a reduced degradation of T4. We therefore performed turnover studies of radiolabeled T4 and 3,5,3'-triiodothyronine (?'3) in 6 patients with ED and 8 age-matched healthy controls. In ED, the median daily production of T4 was 130 nmol/day/70 kg, (range 100-186 nmol/day/70 kg) and elevated compared to control values which were 99 nmol/day/70 kg (range 85-142 nmol/day/70 kg) (p < 0.05), whereas that of T3 was similar in the two groups. Serum thyrotropin (TSH) levels (0.90 mUlliter, 0.18-2.15 mU/liter) were elevated in ED compared to a group of 7 L-T4-treated hypothyroid subjects with similar production and serum levels of T4 and I"3 (0.11 mUlliter, 0.07-1.10 mU/liter) (p < 0.02). The data show that increased serum T4 levels in ED are secordary to an increased thyroidal production of T4, which is at least partly due to inappropriately high serum TSH levels.
Introduction It is well ¢~ablished that patients with endogenous depression (ED) have slightly elevated serum thyroxine (T4) concentrations which normalize after recovery, whereas serum 3,5,3'-triiodothyronine (T3) levels are normal (Kirkegaard et al. 1975; Kirkegaard and Faber 1981; Roy-Byrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). We have recently demonstrated a similar pattern for the serum concentrations of free T4 and T3 (Kirkegaard and Faber 1986). In contrast, serum thyrotropin (TSH) levels (Unden et al. 1986; Mtiller and B6ning 1988) and the TSH response to thyrotropin-releasing hormone (TRH) are reduced in the depressed patients, and tend to normalize upon recovery (Kirkegaard 1981; Loosen and Prange 1982). Tile Leason for the increased serum total and free T4 levels in the depressed patients remains unclear, but it might be due either to increased thyroidal production and secretion of T4, or to a reduced degradation. Increased thyroidal production might be mediated by an increased activity of the hypothalamic-pituitary axis or by stimulation with some nonTSH substance, mimicking thyroidal autonomy. On the other hand, a reduced degradation of T4 might result in a decreased release of TSH. From Medical Department E (C.K, J.F.) and Department of Psychiatry D (A.K.), Frederiksberg Hospital, Copenhagen. Address reprint requests to Camten Kirkegaard M.D., Steno Memorial Hospital, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. Received January 26, 1989; revised May 26, 1989. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
Increased Thyroxine and Thyrotropin in Depression
BIOL PS~ CHIATRY 1990;27:472-476
473
The aim of the present study was to identify the mechanism responsible for the altered serum levels of T4 and TSH in ED. For that purpose we performed tracer turnover studies of T4 and T3 and measured serum TSH levels with a sensitive technique in patients with ED. The data were compared with those obtained in two groups of age-matched controls, one consisting of healthy subjects and another of L-T4-treated hypothyroid patients.
Methods Six patients (2 men and 4 women) with unipolar endogenous depression (ED) (ICD 8 diagnoses 296.0 and 296.2) were studied. Their ages ranged from 38 to 77 years (median age 63 years). The patients had been depressed for at least 3 weeks, and were hospitalized for 10-30 days, (median 14 days) before the kinetic studies. The severity of the depression was evaluated on the Hamilton Rating Scale (score 18-26, median 2 l). They had received no psychoactive medication for at least l week before the study, and none had received lithium. None of the patients had goiter or a history of thyroid disease. Eight unmedicated healthy controls (3 men and 5 women) without psychiatric or somatic diseases were studied. Their ages ranged from 25 to 85 years (median age 61 years). Another control group consisted of 7 women with severe pretreatment hypothyroidism on constant L-T4 therapy (with a ,~edian dose of 0.i3 rag/day, range 0.1-0.15 mg). Their ages ranged from 53 to 72 years (median age 58 years). Informed consent was obtained fcom each subject, and the study protocol was approved by the local ethics committee.
Tracer Kinetic Studies The turnover studies were performed using the single injection, noncompartmental approach (Oppenheimer et al. 1975a, 1975b). The practical application of this method has been previously described in detail (Faber et al. 1982). The metabolic clearance rate (MCR) was calculated from the disappearance curve of radioactive T4 and T3 (Oppenheimer et al. i975a, 1975b), and the production rate (PR) was obtained by multiplying the MCR and the serum T4 and T3 concentrations, respectively. The relative difference on duplicate estimations of both MCR and PR is approximately 10% (Faber et al. 1982). Serum T4 and T3 levels were measured by radioimmunoassay (K~lendorf et al. 1978). Normal range for serum T4 was 72-156 nmol/liter and for serum T3, 0.78-2.84 nmol/liter; n = 38. The free T4 and T3 index (FT41, FT3I) were calculated as the product of the T3 resin uptake and serum I'4 and T3 levels, respectively. Serum TSH concentrations were estimated in a pool of serum prepared from four or five samples obtained between ~) AM and 4 pM and was the mean of th~'ee estimations. An immunoradiometric assay (Sucrosep, Boots CelI-Tech, Slough, Berkshire, UK) was used for the estiraation. The lower detection limit was 0.05 mU/liter. The normal range for serum TSH was 0.165.9 mU/liter (n -- 98). The intra- and interassay coefficients of variations of the radioimmunoassays were below 5% and 10%, respectively. For statistical evaluation, Wilcoxon's test for unpaired data and Spearman's Rank sum correlation test were used.
Results The kinetic data in the patients with ED are given in Table 1. The main finding was a 30% increase in PR of T4 (p < 0.05) in patients with ED, whereas PR of T3 was normal. Serum TSH levels in the patients with ED were in median 0.90 mU/liter, range 0.18-
474
C.. Kirkegaard et al.
BIOL PSYCHIATRY 1990;27:472--476
Table 1. Turn-overParameters in Endogenous Depression (Median and Range) "1"4
Endogenous depression (n = 6) Healthy controls (n = 8) P
T3
s-cone. nmol/liter
MCR l/d × 70 kg
PR nmol/d × 70 kg
s-cone. nmoi/llie~
MCR l/d × 70 kg
PR nmoi/d × 70kg
109 (90-130)
I. 14 (0.89-1.77)
130 (100-186)
1.56 (1. i |-2~07)
23.4 (16.5-30.3)
33.1 (32.0-43.0)
104 (88-116) N.S.
!.01 (0.78-1.39) N.S.
99 (85-142) 0.05
1.84 (1.31-2.06) N.S.
18.6 (14.3-28.8) N.S.
34.6 (24.4-41.2) N.S.
2.15 mU/liter, not statistically different from control values which were 1.80 mU/liter, range 0.30-3.70 mU/liter. The severity of depression was evaluated by the Hamilton rating scale. No correlations with any of the turnover parameters were found. Increased thyroidal secretion of T4 might be mediated by TSH or some non-TSH factor such as thyroid-stimulating antibodies, increased serum levels of norepiaephrine, or vagal tone. In order to discriminate between these two possibilities, we compared the data from patients with ED with a group of patients with similar PR of T4 due to oral administration of L-T4, and thus not a TSH stimulation of the thyroid. Serum TSH levels were then compared in these two groups. No difference was found between the two groups with regard to PR of T4 [median range 130 (100-186) nmol/day × 70 kg in ED versus 132 (116-139) nmol/day × 70 kg in L-T4 treated hypothyroidism]; PR of T3 [median range 33 (32-45) nmol/day × 70 kg versus 38 (28-42) nmol/day × 70 kg]. Serum-free T4 index [median range 107 (82-125) arb.U, versus 121 (96-227) arb.U.] and serum-free T3 index [median range 1.41 (1.24-1.90) arb.U, versus 1.75 (1.43-2.21) arb.U.] were ~.imilar in the two groups. However, serum TSH levels were considerably higher among patients with ED than in the group of L-T4-substituted hypothyroid patients [0.90 (0.18-2.20) mU/liter versus 0. ll (0.07-1.10) mU/liter, p < 0.02]. Discussion The present study demonstrates that patients with ED have increased thyroidal production of T4 in the depressed phase. This finding explains the increased serum T4 and frec I'4 typically seen in patients with ED (Kirkegaard et al. 1975; Kirkegaard and Faber 1981, 1986; Roy-Byrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). Increased PR of T4 contrasts with the unaltered PR of T3 found in the same patients. Unaltered PR of T3, however, is in accordance with the usual finding of unaltered serum T3 and free T3 seen in FD (Kirkegaard et ale 1975; Kirkegaard and Faber 1981, 1986; RoyByrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). The discrepancy between increased PR T4 and unaltered PR T3 suggests that the extrathyroidal deiodination of T4 into T3 is reduced in ED. Reduced extrathyroidal T3 production is often seen in patients with nonthyroidal somatic disease and diminished caloric intake. However, in the patients studied, the depression was only of moderate severity as evaluated by the Hamilton rating score, and thus it is less likely that reduced caloric intake was a prominent symptom. Another explanation might be that the extra-
Increased Thyroxine and Thyrotropin in Depression
BIOL PSYCHIATRY 1990;27:472-476
475
thyroidal deiodination is reduced in order to protect the tissues against the increased supply of T4. Finally, the possibility exists that the primary event in ED is a decreased deiodination from '1"4to T3 in the brain, and that the increased PR of T4 is compensatory. Serum TSH was not reduced in patients with ED compared with normal subjects, suggesting an inappropriate TSH secretion. We therefore included a control group of hypothyroid subjects on constant L-T4 therapy who were selected because they had a PR of T4 within the range of the PR of T4 of the patients with ED. Despite similar PR of T4 as well as PR of T3, FT4I, and FT3I, patients with ED had considerably higher serum TSH levels than the L-T4-treated subjects, suggesting that the normal serum TSH values in ED represent an inappropriate elevation. Such inappropriately high serum TSH levels might be due either to an increased central stimulation by TRH or a decreased central inhibition of TSH release exerted by reduced activity of the inhibitors somatostatin or dopamine (Morley 1981). Also, a reduced intrapituitary deiodination of T4 into T3 might result ir~ increased secretion of TSH (Larsen 1982). In conclusion, the present study demonstrates that patients with active ED have increased thyroidpJ production of T4, which is at least in part secondary to stimulation by TSH. The study was supported by a grant from overlaegedr.med. Ejner Geert-J~rgensenog hustm Ellen GeertJ~rgensen's ~orskningslegat.
References Faber J, Lumholtz IB, Kirkegaard C, Siersbaek-Nielsen K, Friis T (1982): Isolation of radioactive iodothymnines for kinetic studies: A comparison of two methods. Acta Endocrino199:64-71. Kirkegaard C (1981): The thyrotropin response to thymtropin releasing hormone in endogenous depression. Psychoneuroendocrinolo&y 6:189-212. Kirkegaard C, Faber J (1981): Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression. Acta Endocrinol 96:199-207. Kirkegaard C, Faber J (1986): Influence of free thyroid hormone levels on the TSH response to TRH in endogenous depression. Psychoneuroendocrinology 11:491-497. Kirkegaard C, N~rlem N, Lauridsen UB, Bj~rum N, Christiansen C (1975): Protirelin stimulation test and thyroid function during treatment of depression. Arch Gen Psychiatry 32:115-118. K~lendorf K, M~ller BB, Rogowski P (1978): The influence of chronic renal failure on serum and urinary thywid hormone levels. Acta Er~locrinol 89:80-88. Larsen PR (1982): Thyroid-pituitary interaction. Feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 306:23-32. Loosen PT, Prangc AJ (1982): Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J Psychiatry 139:405--4t6. Morley JE (1981): Neuroendocrine control of thyrotropin secretion. Endocr Rev 2:396-436. Miiller B, B6ning J (1988): Changes in the pituitary-th~:roidaxis accompanying major affective disorders. A cta P sychiatr Scand 77:143-150. Oppenheimer JH, Schwartz HL, Surks MI (1975a): Determination of common parameters of iodothyronine metabolism and distribution in man by noncompartmental analysis. J Clin Endocrinol Metab 41:319-324. Oppenheimer JH, Schwartz HL, Surks MI (1975b): Erratum: Revised calculation of common p&"ameters of iodothyronine metabolism and distribution by noncompartmental analysis. J Cliu Endocrinol Metab 41:1172-1173.
476
BIOL PSYCHIATRY 1990;27:472-476
C. Kirkegaard et al.
Roy-Byrne PP, Joffe RT, Uhde TW, Post RM (1984): Catbamazepine and thyroid function in affectively ill patients. Arch Gen Psychiatry 41:1150-1153. Unden F, Ljungren J-G, Kjellman BF, Beck-Friis J, Wetterberg L (1986): Twenty-four-hour serum levels of 1"4 and T3 in relation to decreased TSH serum levels and decreased TSH response to TRH in affective disorders. Acta Psychiatr Scand 73:358-384.
BIOL PSYCHIA tE.Y !990;27:472--476
Increased Production of Thyroxine and Inappropriately Elevated Serum Thyretropin in Levels in Endogenous Depression C. Kirkegaard, A. Kctrner, and J. Faber
The increased serum thyroxine (T4) levels in endogenous depression (ED) might be due to an increased production or a reduced degradation of T4. We therefore performed turnover studies of radiolabeled T4 and 3,5,3'-triiodothyronine (?'3) in 6 patients with ED and 8 age-matched healthy controls. In ED, the median daily production of T4 was 130 nmol/day/70 kg, (range 100-186 nmol/day/70 kg) and elevated compared to control values which were 99 nmol/day/70 kg (range 85-142 nmol/day/70 kg) (p < 0.05), whereas that of T3 was similar in the two groups. Serum thyrotropin (TSH) levels (0.90 mUlliter, 0.18-2.15 mU/liter) were elevated in ED compared to a group of 7 L-T4-treated hypothyroid subjects with similar production and serum levels of T4 and I"3 (0.11 mUlliter, 0.07-1.10 mU/liter) (p < 0.02). The data show that increased serum T4 levels in ED are secordary to an increased thyroidal production of T4, which is at least partly due to inappropriately high serum TSH levels.
Introduction It is well ¢~ablished that patients with endogenous depression (ED) have slightly elevated serum thyroxine (T4) concentrations which normalize after recovery, whereas serum 3,5,3'-triiodothyronine (T3) levels are normal (Kirkegaard et al. 1975; Kirkegaard and Faber 1981; Roy-Byrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). We have recently demonstrated a similar pattern for the serum concentrations of free T4 and T3 (Kirkegaard and Faber 1986). In contrast, serum thyrotropin (TSH) levels (Unden et al. 1986; Mtiller and B6ning 1988) and the TSH response to thyrotropin-releasing hormone (TRH) are reduced in the depressed patients, and tend to normalize upon recovery (Kirkegaard 1981; Loosen and Prange 1982). Tile Leason for the increased serum total and free T4 levels in the depressed patients remains unclear, but it might be due either to increased thyroidal production and secretion of T4, or to a reduced degradation. Increased thyroidal production might be mediated by an increased activity of the hypothalamic-pituitary axis or by stimulation with some nonTSH substance, mimicking thyroidal autonomy. On the other hand, a reduced degradation of T4 might result in a decreased release of TSH. From Medical Department E (C.K, J.F.) and Department of Psychiatry D (A.K.), Frederiksberg Hospital, Copenhagen. Address reprint requests to Camten Kirkegaard M.D., Steno Memorial Hospital, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. Received January 26, 1989; revised May 26, 1989. © 1990 Society of Biological Psychiatry
0006-3223/90/$03.50
Increased Thyroxine and Thyrotropin in Depression
BIOL PS~ CHIATRY 1990;27:472-476
473
The aim of the present study was to identify the mechanism responsible for the altered serum levels of T4 and TSH in ED. For that purpose we performed tracer turnover studies of T4 and T3 and measured serum TSH levels with a sensitive technique in patients with ED. The data were compared with those obtained in two groups of age-matched controls, one consisting of healthy subjects and another of L-T4-treated hypothyroid patients.
Methods Six patients (2 men and 4 women) with unipolar endogenous depression (ED) (ICD 8 diagnoses 296.0 and 296.2) were studied. Their ages ranged from 38 to 77 years (median age 63 years). The patients had been depressed for at least 3 weeks, and were hospitalized for 10-30 days, (median 14 days) before the kinetic studies. The severity of the depression was evaluated on the Hamilton Rating Scale (score 18-26, median 2 l). They had received no psychoactive medication for at least l week before the study, and none had received lithium. None of the patients had goiter or a history of thyroid disease. Eight unmedicated healthy controls (3 men and 5 women) without psychiatric or somatic diseases were studied. Their ages ranged from 25 to 85 years (median age 61 years). Another control group consisted of 7 women with severe pretreatment hypothyroidism on constant L-T4 therapy (with a ,~edian dose of 0.i3 rag/day, range 0.1-0.15 mg). Their ages ranged from 53 to 72 years (median age 58 years). Informed consent was obtained fcom each subject, and the study protocol was approved by the local ethics committee.
Tracer Kinetic Studies The turnover studies were performed using the single injection, noncompartmental approach (Oppenheimer et al. 1975a, 1975b). The practical application of this method has been previously described in detail (Faber et al. 1982). The metabolic clearance rate (MCR) was calculated from the disappearance curve of radioactive T4 and T3 (Oppenheimer et al. i975a, 1975b), and the production rate (PR) was obtained by multiplying the MCR and the serum T4 and T3 concentrations, respectively. The relative difference on duplicate estimations of both MCR and PR is approximately 10% (Faber et al. 1982). Serum T4 and T3 levels were measured by radioimmunoassay (K~lendorf et al. 1978). Normal range for serum T4 was 72-156 nmol/liter and for serum T3, 0.78-2.84 nmol/liter; n = 38. The free T4 and T3 index (FT41, FT3I) were calculated as the product of the T3 resin uptake and serum I'4 and T3 levels, respectively. Serum TSH concentrations were estimated in a pool of serum prepared from four or five samples obtained between ~) AM and 4 pM and was the mean of th~'ee estimations. An immunoradiometric assay (Sucrosep, Boots CelI-Tech, Slough, Berkshire, UK) was used for the estiraation. The lower detection limit was 0.05 mU/liter. The normal range for serum TSH was 0.165.9 mU/liter (n -- 98). The intra- and interassay coefficients of variations of the radioimmunoassays were below 5% and 10%, respectively. For statistical evaluation, Wilcoxon's test for unpaired data and Spearman's Rank sum correlation test were used.
Results The kinetic data in the patients with ED are given in Table 1. The main finding was a 30% increase in PR of T4 (p < 0.05) in patients with ED, whereas PR of T3 was normal. Serum TSH levels in the patients with ED were in median 0.90 mU/liter, range 0.18-
474
C.. Kirkegaard et al.
BIOL PSYCHIATRY 1990;27:472--476
Table 1. Turn-overParameters in Endogenous Depression (Median and Range) "1"4
Endogenous depression (n = 6) Healthy controls (n = 8) P
T3
s-cone. nmol/liter
MCR l/d × 70 kg
PR nmol/d × 70 kg
s-cone. nmoi/llie~
MCR l/d × 70 kg
PR nmoi/d × 70kg
109 (90-130)
I. 14 (0.89-1.77)
130 (100-186)
1.56 (1. i |-2~07)
23.4 (16.5-30.3)
33.1 (32.0-43.0)
104 (88-116) N.S.
!.01 (0.78-1.39) N.S.
99 (85-142) 0.05
1.84 (1.31-2.06) N.S.
18.6 (14.3-28.8) N.S.
34.6 (24.4-41.2) N.S.
2.15 mU/liter, not statistically different from control values which were 1.80 mU/liter, range 0.30-3.70 mU/liter. The severity of depression was evaluated by the Hamilton rating scale. No correlations with any of the turnover parameters were found. Increased thyroidal secretion of T4 might be mediated by TSH or some non-TSH factor such as thyroid-stimulating antibodies, increased serum levels of norepiaephrine, or vagal tone. In order to discriminate between these two possibilities, we compared the data from patients with ED with a group of patients with similar PR of T4 due to oral administration of L-T4, and thus not a TSH stimulation of the thyroid. Serum TSH levels were then compared in these two groups. No difference was found between the two groups with regard to PR of T4 [median range 130 (100-186) nmol/day × 70 kg in ED versus 132 (116-139) nmol/day × 70 kg in L-T4 treated hypothyroidism]; PR of T3 [median range 33 (32-45) nmol/day × 70 kg versus 38 (28-42) nmol/day × 70 kg]. Serum-free T4 index [median range 107 (82-125) arb.U, versus 121 (96-227) arb.U.] and serum-free T3 index [median range 1.41 (1.24-1.90) arb.U, versus 1.75 (1.43-2.21) arb.U.] were ~.imilar in the two groups. However, serum TSH levels were considerably higher among patients with ED than in the group of L-T4-substituted hypothyroid patients [0.90 (0.18-2.20) mU/liter versus 0. ll (0.07-1.10) mU/liter, p < 0.02]. Discussion The present study demonstrates that patients with ED have increased thyroidal production of T4 in the depressed phase. This finding explains the increased serum T4 and frec I'4 typically seen in patients with ED (Kirkegaard et al. 1975; Kirkegaard and Faber 1981, 1986; Roy-Byrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). Increased PR of T4 contrasts with the unaltered PR of T3 found in the same patients. Unaltered PR of T3, however, is in accordance with the usual finding of unaltered serum T3 and free T3 seen in FD (Kirkegaard et ale 1975; Kirkegaard and Faber 1981, 1986; RoyByrne et al. 1984; Unden et al. 1986; Miiller and B6ning 1988). The discrepancy between increased PR T4 and unaltered PR T3 suggests that the extrathyroidal deiodination of T4 into T3 is reduced in ED. Reduced extrathyroidal T3 production is often seen in patients with nonthyroidal somatic disease and diminished caloric intake. However, in the patients studied, the depression was only of moderate severity as evaluated by the Hamilton rating score, and thus it is less likely that reduced caloric intake was a prominent symptom. Another explanation might be that the extra-
Increased Thyroxine and Thyrotropin in Depression
BIOL PSYCHIATRY 1990;27:472-476
475
thyroidal deiodination is reduced in order to protect the tissues against the increased supply of T4. Finally, the possibility exists that the primary event in ED is a decreased deiodination from '1"4to T3 in the brain, and that the increased PR of T4 is compensatory. Serum TSH was not reduced in patients with ED compared with normal subjects, suggesting an inappropriate TSH secretion. We therefore included a control group of hypothyroid subjects on constant L-T4 therapy who were selected because they had a PR of T4 within the range of the PR of T4 of the patients with ED. Despite similar PR of T4 as well as PR of T3, FT4I, and FT3I, patients with ED had considerably higher serum TSH levels than the L-T4-treated subjects, suggesting that the normal serum TSH values in ED represent an inappropriate elevation. Such inappropriately high serum TSH levels might be due either to an increased central stimulation by TRH or a decreased central inhibition of TSH release exerted by reduced activity of the inhibitors somatostatin or dopamine (Morley 1981). Also, a reduced intrapituitary deiodination of T4 into T3 might result ir~ increased secretion of TSH (Larsen 1982). In conclusion, the present study demonstrates that patients with active ED have increased thyroidpJ production of T4, which is at least in part secondary to stimulation by TSH. The study was supported by a grant from overlaegedr.med. Ejner Geert-J~rgensenog hustm Ellen GeertJ~rgensen's ~orskningslegat.
References Faber J, Lumholtz IB, Kirkegaard C, Siersbaek-Nielsen K, Friis T (1982): Isolation of radioactive iodothymnines for kinetic studies: A comparison of two methods. Acta Endocrino199:64-71. Kirkegaard C (1981): The thyrotropin response to thymtropin releasing hormone in endogenous depression. Psychoneuroendocrinolo&y 6:189-212. Kirkegaard C, Faber J (1981): Altered serum levels of thyroxine, triiodothyronines and diiodothyronines in endogenous depression. Acta Endocrinol 96:199-207. Kirkegaard C, Faber J (1986): Influence of free thyroid hormone levels on the TSH response to TRH in endogenous depression. Psychoneuroendocrinology 11:491-497. Kirkegaard C, N~rlem N, Lauridsen UB, Bj~rum N, Christiansen C (1975): Protirelin stimulation test and thyroid function during treatment of depression. Arch Gen Psychiatry 32:115-118. K~lendorf K, M~ller BB, Rogowski P (1978): The influence of chronic renal failure on serum and urinary thywid hormone levels. Acta Er~locrinol 89:80-88. Larsen PR (1982): Thyroid-pituitary interaction. Feedback regulation of thyrotropin secretion by thyroid hormones. N Engl J Med 306:23-32. Loosen PT, Prangc AJ (1982): Serum thyrotropin response to thyrotropin-releasing hormone in psychiatric patients: A review. Am J Psychiatry 139:405--4t6. Morley JE (1981): Neuroendocrine control of thyrotropin secretion. Endocr Rev 2:396-436. Miiller B, B6ning J (1988): Changes in the pituitary-th~:roidaxis accompanying major affective disorders. A cta P sychiatr Scand 77:143-150. Oppenheimer JH, Schwartz HL, Surks MI (1975a): Determination of common parameters of iodothyronine metabolism and distribution in man by noncompartmental analysis. J Clin Endocrinol Metab 41:319-324. Oppenheimer JH, Schwartz HL, Surks MI (1975b): Erratum: Revised calculation of common p&"ameters of iodothyronine metabolism and distribution by noncompartmental analysis. J Cliu Endocrinol Metab 41:1172-1173.
476
BIOL PSYCHIATRY 1990;27:472-476
C. Kirkegaard et al.
Roy-Byrne PP, Joffe RT, Uhde TW, Post RM (1984): Catbamazepine and thyroid function in affectively ill patients. Arch Gen Psychiatry 41:1150-1153. Unden F, Ljungren J-G, Kjellman BF, Beck-Friis J, Wetterberg L (1986): Twenty-four-hour serum levels of 1"4 and T3 in relation to decreased TSH serum levels and decreased TSH response to TRH in affective disorders. Acta Psychiatr Scand 73:358-384.
