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Pswhia~ry Research, 2, 199-204 (I 980) Q Elsevier/ North-Holland Biomedical Press 199 The Thyroid-Stimulating Thyrotropin-Releasing Depression Hormone Response to Hormone in Mania and Bipolar Irl Extein, A.L.C. Pottash, Mark S. Gold, Jean Cadet, Donald R. Sweeney, Robert K. Davies, and David M. Martin Received December 3, 1979: occepred March 4. 1980. Abstract. The release of thyroid-stimulating hormone (TSH) from the pituitary after infusion of 500 pg of thyrotropin-releasing hormone (TRH) was decreased @ < 0.01) in manic patients and increased (I, < 0.01) in bipolar depressed patients compared to a control group of patients with personality disorders. These results suggest that the TRH test may be useful in the diagnosis of psychiatric disorders and in the prediction of response to pharmacotherapy. We discuss the role of central monoaminergic systems in changes in the TSH response to TRH. Key Words. Affective disorder, neuroendocrinology, thyrotropin-releasing hor- mone, thyroid-stimulating hormone, monoamines. Neuroendocrine testing has been one strategy for studying the biological substrate of affective illness (Ettigi and Brown, 1977). Abnormal neuroendocrine findings in patients with affective disorder may represent dysfunction that is primary to the mood disturbance. Neuroendocrine abnormalities may also serve as biological markers for changes in the central monoamine neurotransmitters norepinephrine, dopamine, and serotonin (5-hydroxytryptamine) which are implicated in the etiology and pharmaco- therapy of affective disorders. Because many hypothalamic releasing factors are under monoaminergic control, changes in the functional activity of one or more monoamine neurotransmitter systems may be expected to produce changes in a number of endo- crine systems. The results of neuroendocrine testing may have important implications for diagnosis and treatment, particularly with affective disorders. Elevated cortisol secretion (Sachar et al., 1973) and failure to suppress after a standard dexamethasone suppression test (Carroll, 1972) have been associated with major depressive disorder. The release of thyroid-stimulating hormone (TSH) from the pituitary after infusion of thyrotropin-releasing hormone (TRH) has been reported to be decreased in unipolar depression (Gold et al., 1977, 1979; Prange et al., 1972) and increased in bipolar Irl Extein, M.D., is Director of Research and Training, Fair Oaks Hospital, Summit, NJ, and Collaborative Scientist, Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD. A.L.C. Pottash, M.D., is Associate Medical Director, Fair Oaks Hospital, and Lecturer, Department of Psychia- try, Yale University School of Medicine, New Haven, CT. Mark S. Gold, M.D., is Director of Research, Psychiatric Diagnostic Laboratories of America, Summit, NJ, and Lecturer, Department of Psychiatry, Yale University School of Medicine. Jean Cadet, M.D., is Resident, Department of Psychiatry, Columbia University, New York. Donald R. Sweeney, M.D., is Clinical Director, and Robert K. Davies, M.D., is Medical Director, Fair Oaks Hospital. David M. Martin, B.A., is Associate Director, Psychiatric Diagnos- tic Laboratories of America. (Reprint requests to Dr. Extein at Fair Oaks Hospital, 19 Prospect St., Summit, NJ 07901.)

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Pswhia~ry Research, 2, 199-204 (I 980) Q Elsevier/ North-Holland Biomedical Press

199

The Thyroid-Stimulating Thyrotropin-Releasing Depression

Hormone Response to Hormone in Mania and Bipolar

Irl Extein, A.L.C. Pottash, Mark S. Gold, Jean Cadet, Donald R. Sweeney, Robert K. Davies, and David M. Martin

Received December 3, 1979: occepred March 4. 1980.

Abstract. The release of thyroid-stimulating hormone (TSH) from the pituitary

after infusion of 500 pg of thyrotropin-releasing hormone (TRH) was decreased @

< 0.01) in manic patients and increased (I, < 0.01) in bipolar depressed patients compared to a control group of patients with personality disorders. These results suggest that the TRH test may be useful in the diagnosis of psychiatric disorders and in the prediction of response to pharmacotherapy. We discuss the role of central monoaminergic systems in changes in the TSH response to TRH.

Key Words. Affective disorder, neuroendocrinology, thyrotropin-releasing hor- mone, thyroid-stimulating hormone, monoamines.

Neuroendocrine testing has been one strategy for studying the biological substrate of affective illness (Ettigi and Brown, 1977). Abnormal neuroendocrine findings in patients with affective disorder may represent dysfunction that is primary to the mood disturbance. Neuroendocrine abnormalities may also serve as biological markers for changes in the central monoamine neurotransmitters norepinephrine, dopamine, and serotonin (5-hydroxytryptamine) which are implicated in the etiology and pharmaco- therapy of affective disorders. Because many hypothalamic releasing factors are under monoaminergic control, changes in the functional activity of one or more monoamine neurotransmitter systems may be expected to produce changes in a number of endo- crine systems. The results of neuroendocrine testing may have important implications for diagnosis and treatment, particularly with affective disorders. Elevated cortisol secretion (Sachar et al., 1973) and failure to suppress after a standard dexamethasone suppression test (Carroll, 1972) have been associated with major depressive disorder. The release of thyroid-stimulating hormone (TSH) from the pituitary after infusion of thyrotropin-releasing hormone (TRH) has been reported to be decreased in unipolar depression (Gold et al., 1977, 1979; Prange et al., 1972) and increased in bipolar

Irl Extein, M.D., is Director of Research and Training, Fair Oaks Hospital, Summit, NJ, and Collaborative Scientist, Clinical Psychobiology Branch, National Institute of Mental Health, Bethesda, MD. A.L.C. Pottash, M.D., is Associate Medical Director, Fair Oaks Hospital, and Lecturer, Department of Psychia- try, Yale University School of Medicine, New Haven, CT. Mark S. Gold, M.D., is Director of Research, Psychiatric Diagnostic Laboratories of America, Summit, NJ, and Lecturer, Department of Psychiatry, Yale University School of Medicine. Jean Cadet, M.D., is Resident, Department of Psychiatry, Columbia University, New York. Donald R. Sweeney, M.D., is Clinical Director, and Robert K. Davies, M.D., is Medical Director, Fair Oaks Hospital. David M. Martin, B.A., is Associate Director, Psychiatric Diagnos- tic Laboratories of America. (Reprint requests to Dr. Extein at Fair Oaks Hospital, 19 Prospect St., Summit, NJ 07901.)

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depression (Gold et al., 1977, 1979). A nonsignificant trend for a decreased TSH response to TRH in mania has been reported as well (Gold et al., 1977 ;Kirkegaard et al., 1978). We report here that with bipolar affective disorder the magnitude of the TSH response to TRH seems to be a biological marker for the clinical poles of mania and depression. Manic patients showed a decreased TSH response to TRH, whereas bipolar depressed patients had an increased response.

Methods

Five consecutive patients who met Research Diagnostic Criteria (RDC; Spitzer et al.,

1975) for mania, five consecutive patients who met RDC criteria for major depressive disorder, bipolar type, and a control group of five consecutive patients with a primary diagnosis of personality disorder were included in the study. The bipolar depressed patients overlapped with those reported in a previous study (Gold et al., 1979). Age and sex distributions for each group of patients were similar. Patients with clinical evidence of thyroid disease were excluded from the study. T4, T3-uptake, and TSH levels were determined before the TRH infusion and were within normal limits for all patients. The patients were free of all medications except flurazepam for at least 1 week before the study. None of the patients had been on lithium for at least 6 months before the TRH infusion.

An indwelling venous catheter was placed in patients who were at bed rest at 8:30 a.m. after an overnight fast. At 9:00 a.m., 500 pg of synthetic TRH (Abbott) was administered through the catheter. Before and 15, 30, 60 and 90 minutes after TRH administration, small samples of blood were obtained for measurement of TSH and growth hormone in duplicate by radioimmunoassay (Gold et al., 1979). The maximum TSH response, or ATSH, was determined for each patient by subtracting the baseline

TSH level from the peak TSH level after TRH administration. Data are expressed as means It_ SD for five patients per group. Statistical difference between means was

determined by two-tailed f test.

Results

There were no significant differences in T4 or T3-uptake levels between groups. TSH concentration was found to increase significantly (p < 0.01) from baseline levels of 2.3 k 0.2 /11u/ ml to a peak of 6.8 + 3.1 pIu/ ml for the manic patients at 30 minutes after TRH infusion; from baseline levels of 3.0 + 0.7 pIu/ml to a peak at 30 minutes of 13.3 + 3.1 pIu/ml for the patients with personality disorders; and from baseline levels of 4.5 + 1.1 pIu/ml to a peak at 30 minutes of 21.3 * 5.1 p.Iu/ml for the bipolar depressed patients (see Fig. 1). There were no delayed peaks. TSH values peaked at 15 or 30 minutes for all patients. TSH concentrations of the manic and bipolar depressed patients at 30 minutes differed significantly from each other @ < 0.01) and were lower and higher, respectively, than the TSH concentration of patients with personality disorders at 30 minutes (JJ < 0.01). The mean maximal TSH response of 4.8 * 2.5 pIu/ml in the manic patients was significantly lower @ < 0.001) than the mean maximal TSH response of 16.0 & 4.5 pIu/ ml in the bipolar depressed patients (see Fig. 2). The mean maximal TSH responses of the manic and bipolar depressed patients

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Fig. 1. Serum TSH levels 15,30,60, and 90 minutes after i.v. infusion of 500 pg 01 : TRH in control, bipolar manic, and bipolar depressed patients

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f 13

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BIPOLAR MANIA

Y I I I 1

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15 30 60 90

TRH TIME (MINUTES)

Each value represents the mean f SEM for five patlents. * Denotes TSH values at 30 mmutes in manic and bipolar depressed patients, which were. respectively, lower and higher than in controls up < 0.01 1.

were, respectively, lower @ < 0.01) and higher (p < 0.01) than the mean maximal TSH response of 10.6 + 2.7 pIu/ml in the patients with personality disorders (see Fig. 2). Analysis of variance confirmed group differences )F= 13.2, df= 2, 12). The multiple range test showed significant differences @ < 0.01) between the bipolar depressed and each of the other two patient groups. The TSH responses of patients with personality disorders are in the same range as reported for normal subjects (Martin et al., 1977). Two bipolar depressed patients but none of the manic patients or patients with personality disorders had significant growth hormone increases after TRH infusion.

Discussion

The release of TSH from the anterior pituitary is mediated by the hypothalamic tripeptide TRH (Martin et al., 1977). The release of TRH is regulated by norepineph-

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Fig. 2. Maximum change in serum TSH level (peak TSH minus baseline), or ATSH, after infusion of 500 pg of TRH in control, bipolar depressed, and

bipolar manic patients

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CONTROL GROUP

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TRH TEST

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BIPOLAR DEPRESSION

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Each bar represents the mean t SEM for five patients. ’ Denotes I\TSH values of bipolar maw and bipolar depressed patlents, which are, respectively, lower and higher than control values up < 0.01 ). I\TSH values In bipolar manic and bipolar depressed patients are significantly different p c 0.001 I.

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rine, serotonin and dopamine (Kirkegaard et al., 1977; Martin et al., 1977; Reichlinet al., 1974). Norepinephrine and dopamine stimulate, and serotonin inhibits, TRH release. Thus, changes in the hypothalamic-pituitary-thyroid axis may be an index of changes in central monoaminergic transmission in affective illness. Our findings are consistent with the hypothesis that mania is characterized by increased central norad- renergic (or dopaminergic) transmission (Bunney and Davis, 1965). This increased transmission would lead to increased TRH release and subsequent homeostatic adjustment of the pituitary TRH receptors, which would become less sensitive, or “down regulate.” Our findings are also consistent with the hypothesis that bipolar depression is characterized by decreased noradrenergic transmission (Bunney and Davis, 1965) with decreased TRH release and subsequent increased sensitivity of pituitary TRH receptors. Hypothalamic hypothyroidism, characterized by supra- normal TSH response to TRH (Martin et al., 1977) may be a useful model for bipolar depression. The recent finding that TRH and serotonin are present in the same

neurons (Hokfelt, 1979) suggests that the observed changes in TSH response to TRH in bipolar illness may be related to changes in serotonin/TRH balance. Because there is some evidence that TRH itself has antidepressant effects (Prange et al., 1972) it is possible that alterations in TRH release are not just an index of changes in brain monoamines but are etiologically related to affective illness. The TSH response to TRH has been shown to be decreased in unipolar depression. Why unipolar depres- sion and mania manifest similar TRH test abnormalities is a question that requires further study.

The TRH test is a clinically practical neuroendocrine measure that may be useful in psychiatric diagnosis and treatment. The TSH response to TRH had been found to differ in unipolar, bipolar, and secondary depressions (Gold et al., 1977, 1979, in press; Kirkegaard et al., 1978; Prange et al., 1972) and the present results support reports of an increased TSH response to TRH in bipolar depressed patients. A potential use for TRH testing may be, for example, in predicting which patients with a first episode of depression may go on to develop bipolar illness (Gold et al., 1979, in press). The test may thus aid in selecting optimal medication, i.e., lithium vs. a tricyclic. The decreased TSH response to TRH in manic patients observed here suggests that the TRH test may be useful in differentiating mania from other euphoric, irritable, or excited states, including schizophrenic psychosis. It may also be helpful in the diagnosis of schizo- affective disorders and in predicting which schizophrenic patients might benefit from antidepressants or lithium. In identifying biologically distinct subgroups of patients with symptoms of depression or mania, the TRH test may have prognostic value (Kirkegaard et al., 1977) as a predictor of response to specific pharmacotherapy, and this possibility certainly merits further study.

References

Bunney, W.E., Jr., and Davis, J.M. Norepinephrine in depressive reactions. Archives of General Psychiatry, 13, 484 (1965).

Carroll, B.J. Control of plasma cortisol levels in depression: Studies with the dexamethasone suppression test. In: Davies, B., Carroll, B.J., and Mowbray, R.M., eds. Depressive Illness: Some Research Studies. Charles C Thomas, Publisher, Springfield, IL (1972).

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Ettigi, P.G., and Brown, G.M. Psychoneuroendocrinology of affective disorders: An overview. American Journal of Psychiatry, 131, 493 (1977).

Gold, M.S., Pottash, A.L.C., Davies, R.K., Ryan, N., Sweeney, D.R., and Martin, D.M. Distinguishing unipolar and bipolar depression by thyrotropin release test. Luncet, II, 411 (1979).

Gold, M.S., Pottash, A.L.C., Ryan, N., Sweeney, D.R., Davies, R.K., and Martin, D.M. TRH- induced response in unipolar, bipolar, and secondary depressions: Possible utility in clinical assessment and differential diagnosis. Psychoneuroendocrinology (in press).

Gold, P.W., Goodwin, F.K., Wehr, T., and Rebar, R. Pituitary thyrotropin response to thyro- tropin releasing hormone in affective illness: Relationship to spinal fluid amine metabolites. American Journal of Psychiatry, 134, 1028 (1977).

Hokfelt, T. Opening address. Conference on Regulation and Function of Neuro-peptides, Brescia, Italy, August 3 1 (I 979).

Kirkegaard, C., Bj@um, N., Cohn, D., Faber, J., Lauridsen, U.B., and Nerup, J. Studies on the influence of biogenic amines and psychoactive drugs on the prognostic value of the TRH stimulation test in endogenous depression. PsychoneuroendocrinoIogy, 2, 131 (1977).

Kirkegaard, C., Bjarum, N., Cohn, D., and Lauridsen, U.B. Thyrotropin-releasing hormone stimulation test in manic depressive illness. Archives of General Psychiatry, 35, 1017 (1978).

Martin, J.B., Reichlin, S., and Brown, G.M. Clinical Neuroendocrinology. F.A. Davis Com- pany, Philadelphia (1977).

Prange, A.J., Jr., Wilson, E.C., Lara, P.P., Alltop, L.B., and Breese, G.R. Effect of TRH in depression. Lancet, II, 999 (1972).

Reichlin, S., Jackson, I., and Seyler, L.E. Regulation of the secretion of TRH and LHRH. In: Seeman, P., and Brown, G.M., eds. Frontiers in Neurology and Neuroscience Research. University of Toronto Press, Toronto (1974).

Sachar, E.J., Hellman, L., Roffwarg, H.F., Halpern, F.S., Fukushima, D.K., and Gallagher, T.F. Disrupted 24-hour patterns of cortisol secretion in psychotic depression. Archives of General Psychiatry, 28, 19 (1973).

Spitzer, R.L., Endicott, J., and Robins, E. Research Diagnostic Criteria. Psychopharmacology Bulletin, 11, 22 (1975).