Hypothyroidism—or is it depression?

MARK S. GOLD, M.D. H. ROWLAND PEARSALL, M.D.

Hypothyroidismor is it depression? ABSTRACT: Growing recognition of the importance of the thyroid in affective disorders has been accompanied by development of more sensitive thyroid tests. The article briefly reviews the basics of thyroid regulation, describes current laboratory tests, reports a 10% incidence of undiagnosed hypothyroidism in studies of almost 400 depressed or lethargic patients, and recommends an approach to the thyroid work-up for the psychiatrist. Hypothyroidism is routinely considered in the differential diagnosis of depressive and anergic states, and is screened for with determinations of serum thyroxine (T 4), triiodothyronine (T3), and basal thyroid-stimulating hormone (TSH).' This approach may not enable the clinician to identify the majority of patients who have thyroid disease as the primary diagnosis or who have thyroid failure as a major precipitant to their depression. During the past decade our understanding of clinical hypothyroidism has broadened and with the aid of improved laboratory tests the diagno-

sis can now be made much earlier, long before classic myxedematous symptoms ever become manifest. 2.3 Even when overt or classic hypothyroidism is present, it is usually diagnosed well before the patient is referred to a psychiatrist. Early thyroid failure with its predilection for behavioral presentation is much more likely to manifest as depression or lack of energy to a psychiatrist. Because of the advances in psychiatric nosology and thyroid testing, study of depressed patients for evidence of hypothyroidism has intensified. Increased basic research has re-

Dr. Gold is director ofresearch at Fair Oaks Hospital and at Psychiatric Diagnostic Laboratories ofAmerica, Summit, NJ. Dr. Pearsall is co-director, outpatient services, PsychiatriC Associates of New Jersey. Reprint requests to Dr. Gold at the hospital, 19 Prospect St., Summit, NJ 07901. 646

kindled theoretical interest in the importance of thyroid hormones in mood regulation, mood swings, and affective illness. Numerous studies 4 . 14 demonstrate strong correlations between primary affective disorders and several neuroendocrine abnormalities, particularly following provocative stimuli such as dexamethasone and TSH response to thyrotropin-releasing hormone (TRH). TRH itself can alter mood 4 . 15 and reverse central depressant syndromes. It is widely distributed throughout the brain and by implication is of critical importance far beyond the hypothalamic pituitary axis.'6-18 T 4, T 3, and TRH also have "arousal" effects that may reflect neuromodulatory influences on catecholamine and indoleamine pathways in the brain.16.19.2o Clinical studies,2o.21 which in many cases preceded basic understanding of thyroid interaction with biogenic amines, have demonstrated antidepressant effects for thyroid hormone and imipramine given together in the treatment of depression. There is a report 20.21 of improved mood in rePSYCHOSOMATICS

sponse to TSH given alone to a group of depressed women. These and other data 10.11.22-24 along with the improved understanding of diagnostic techniques for early hypothyroidism prompted our recent studies 2s .26 of the continuum of overt to subclinical hypothyroidism. In these studies the incidence of hypothyroidism in patients with a chief complaint of depression or lack ofenergy who have the criteria for major depressive disorder (DSM III) or major depression, unipolar subtype (RDC), appears to be much greater than previously believed. In view of the increased importance of thyroid dysregulation in affective disorders, this paper reviews major features in the regulation of thyroid hormones, laboratory assessment of thyroid function, our recent data on the relationship of hypothyroidism and depression, and recommendations on the work-up of hypothyroidism. Thyroid regulation and measurement The thyroid is part of the neuroendocrine system known as the hypothalamic-pituitary-thyroid (HPT) axis. This axis translates input from the CNS into influences on hypothalamic-pituitary hormonal output, which in turn controls thyroid hormone secretion. The HPT axis and various directions of action of thyroid hormones are illustrated in Figure I. The hypothalamus secretes TRH into the portal hypophyseal circulation and thereby into the pituitary gland. 22 Release of TRH is influenced by input from the limbic and other areas in the CNS and probably from circulating levels of TRH and thyroid hormones. 23 •24 While TRH has extra-HPT functions and effects, it also acts at speJULY 1983' VOL 24· NO 7

Feedback modulation of TSH secretion

Pituitary

To receptors in peripheral tissues

5·HT - 5-hydroxytryptamine NE - norepinephrine DA - dOpamine.

FIGURE I-The hypothalamici'ituitary-lhyroid (HPT) axis and directions ofaction ofthyrOid hormones. 647

Hypothyroidism

citic receptors in the pituitary gland to release thyroid-stimulating hormone (TSH) into the circulation. The TSH in tum acts on the thyroid gland to promote release of the two active forms (T4and T3) of circulating thyroid hormone into the peripheral circulation. Serum T 4 and T3levels serve as a feedback mechanism to the pituitary gland to modulate TSH secretion, possibly through changes in TRH receptor sensitivity. In the presence of decreased thyroid hormones, as in the hypothyroid patient, a given amount of TRH stimulates supersensitive TSH receptors causing a proportionately larger release of TSH. These changes are homeostatic attempts to compensate and to promote increased release of thyroid hormones from the gland. The thyroid gland secretes T 4 primarily but not exclusively, and about one third of this T 4 undergoes conversion to T 3 by deiodination in peripheral tissues, such as the liver and kidney. T) is now thought to provide most of the actual thyroid activity in peripheral tissues. Although T4 is secreted at eight to ten times the rate of T 3, the latter is three to four times more potent.23 Both T 4and T 3are bound to serum proteins such as thyroxine-binding globulin (TBG) and thyroxine-binding prealbumin (TBPA). Only a relatively small fraction of the total pool of T 3and T4 is actually free in the circulation and available to bind at receptor sites. Approximately 40% of the T 4 is converted by deiodination of the inner ring into reverse T 3, an apparently inactive form, which only now is being studied in psychiatric and thyroid illnesses. Whether excessive conversion to reverse T 3can produce a functionally hypothyroid state in the presence of a blunted

TRH test (aTSH <7JLIU/mL) is unknown. Adequate dietary intake of organic iodine (I) and iodide (1-) is important in thyroid metabolism for production of T 4and T 3.

Thyroid tests Laboratory assessment of thyroid function has improved considerably in terms of what can be measured and the accuracy of the measurement. Although the most common screening test is to measure the levels of the circulating thyroid hormones, thyroid function can be evaluated at several points in the HPT axis. The most usefullaboratory tests of hypothyroidism are total T4, T3, T3RU, TSH, and TRH stimulation. Total bound T4 in the serum is measured by competitive proteinbinding assay or radioimmunoassay (RIA). The T4 level measured by these methods is increased by increases in TBG capacity, such as during pregnancy, with oral contraceptives, in infectious hepatitis, or with certain antipsychotic medications (eg, perphenazine). T4 is decreased when TBG capacity is decreased, as in patients with protein-losing nephrotic syndrome. The actual amount of circulating free T 4 can be measured directly using dialysis techniques. Bound T3 is also measured by RIA and the free T 3can be determined as well. It is important to know the method of analysis reported by the laboratory in order to properly correlate the test results with the patient's clinical state. Another useful measurement is not of T 4and T 3themselves, but of T3 resin uptake (T3RU). This is a determination not of T3concentration directly but of the number of available binding sites for the hormones on serum proteins such as

TBG. This test allows for some correction of the TBG effects mentioned above. To determine T3RU, a fixed amount of patient serum is mixed with T 3 labeled with radioactive iodine (T3*) and with a resin to absorb excess T 3* not bound to serum TBG. The relative amount of excess T 3* absorbed onto the resin is measured. The result is that in illnesses with excess thyroid hormone (hyperthyroidism) or a deficiency of TBG, most of the TBG binding sites are already filled with T 4, and there is a relative excess of T 3*, which is absorbed by the resin. The opposite is true in hypothyroidism or situations with an increase in TBG. Here there are relatively more open binding sites on the TBG and more T 3* is bound so that less is left to be absorbed by the resin. The free thyroxine index (FTI) is the calculated product of total thyroxine and T3RU. It tends to correct for TBG variation and correlates well with the actual concentration of free thyroxine as determined by dialysis techniques. At the pituitary gland, TSH levels can be measured to assess function and responsiveness to feedback inhibition. Normally as thyroid hormone levels fall, TSH slowly increases as necessary, in an attempt to boost thyroid gland output to maintain the euthyroid state. Repeated compensatory pituitary changes in the face of frank thyroid failure eventually lead to the typical pattern in overt hypothyroidism of decreased T4 and markedly elevated TSH levels. Thyroid failure is immediately compensated for by increasing TRH receptor sensitivity, resulting in increased TSH release. When the pituitary can no longer maintain normal T 4 and T 3 levels through superstimulation of remaining functional thyroid gland PSYCHOSOMATICS

by augmenting TSH, the patient becomes overtly hypothyroid. Occasionally a pituitary tumor that is nOI responsivc to serum thyroid hormone levels may produce excessive TSH. In this case the Ihyroid gland responds by increased output of thyroxine and the pattern is of elevated T 4, elevated TSH. and hyperthyroidism.

The TRH stimulation test IU7.JI is a provocative test of thyroid function at the pituitary and indirectly of thyroid gland function itself. This test involves giving a small amounl ofTRH and measuring the TSH, and. depending on the c1ini· cal issues. the prolactin or growthhormone response of the pituitary. In normal control subjects the TSH level increases within 60 minutes by seven to 151'IU/mL over the base· line values. This peak minus the baseline TSH is the ilTSH. In hy. pothyroid patients the latter is markedly increased and values of greater than 30 I'IU/mL are common. This occurs because the pituitary is already producing extra TSH reserve 10 enable the individualto compensate for the decrease

in thyroid hormones, and because, although resting TSH levels may be normal. the pituitary gland is exceplionally responsive to TRH slimulation at any lime of reduced circulating T4 and TJ. 32 .J6 Screening for thyroid autoanti· bodies is useful in assessing the status of Ihe Ihyroid gland. although this test is not a direct measure of thyroid function. The immune system is capable of making antibodies to. and destroying, Ihe thyroid gland. Serum can be tested for Ihe presence of such antibodies. Two common antigens are thyroid microsomes and Ihyroglobulin, both present in the thyroid gland. The presence of antibodies to eilher of these antigens is abnormal, and can be directly tested for by ana· Iyzing the serum for anli-M or anti-T antibodie,s wilh available immunologic techniques."·" In symptomatic patients high anti· body titers are considered evidence of an autoimmune disease process involving the thyroid. Hypothyroidism and depression It has long been recognized'·"·J9·'"

...,....

Ihal depressive symploms such as weakness, lack of "nergy, constipa. lion, and appetite and weight change are often present in patients with overt hypothyroidism. The clinical signs and symptoms of thy. roid failure and the DSM·I1I cri· teria for major depression share many common features.2· 40·• 1 Psychiatric investigators have studied hypothyroidism in psychiatric pa· tients and have advocated routine testing for many years to rule out thyroid dysfunction. However, until recently only those patients with numerous clinical symptoms and marked changes in T. and/or TSH were likely to be detected. These patients with clinical and chemical evidence of myxedema are readily diagnosed nowadays and rarely present to psychiatrists. Over the past decade it has been increasingly recognized that there is a spectrum of thyroid dysfunc. tion, and this has led to the devel· opment of systems for grading hypothyroidism. 2J Grading has been aided by the more widespread availability of TRH testing, which allows laboralory detection of hy-

.-

.

T.bIe 1-GI'IIdes of HypoIhJroldl....

.

•

, ph

Overt

lSI",. I. _ . .

DecrllSld T.

Classic features such as lack of energy, weight gain, cold intolerance, constipation, and hoanIenes8

Increased lSH Incl888ld TSH

0,..2

Mild

A few minor or early I:\lnical symptoms such as fatigue, dry sldn, and conslIpal\Oll

NormalT. Borderline TSH Incl888ld TSH

0,..3

Subclinical

Few if any clinical signs, some symptoms 01 depresslon

Normal T. NormallSH IncI888Id lSH

i JULY 1983' VOL 24' NO 7

or else lack of energy

,

(

Hypothyroidism

pothyroidism at a much earlier stage (Table I outlines the grades of hypothyroidism). Identification of depressed patients with early thyroid dysfunction stimulated our interest in the actual incidence of this disorder in psychiatric patients with symptoms ofdepression. Initial efforts focused on assessing the incidence of hypothyroidism in patients depressed enough to require inpatient admission. 2s Among 250 such consecutive inpatients, we found that 20 patients (8%) showed some hypothyroidism on comprehensive clinical evaluation and thyroid testing, including the TRH test. Two of the 20 patients had Grade I overt hypothyroidism with positive clinical findings and the typical laboratory pattern. Eight had evidence of mild hypothyroidism with a few clinical symptoms such as dry skin, weight gain, and fatigue, along with normal T4levels, mildly elevated TSH, and increased aTSH. Ten had no clinical symptoms of hypothyroidism other than complaints oflack of energy or depressed mood with normal T4 and TSH, but a TSH values greater than 30 ItIU/mL. These findings suggested that hypothyroidism can be detected at a much higher rate among depressed patients than had previously been thought. Does this reflect increased sensitivity of the TRH test in diagnosing hypothyroidism, or does this inpatient population reflect a skewed and selected sample of atypical or especially ill tertiary-referral hospital patients? To examine this question, we recently collected similar data 42 for 44 consecutive psychiatric outpatients, with a Research Diagnostic Criteria (ROC) diagnosis of major unipolar depression. Three of these patients had a aTSH

greater than 30 ItIU/mL and an additional three were between 20 and 30 ItIU/mL. None of these patients had Grade 1 hypothyroidism. Although the sample is small, this result suggests that the increased incidence of hypothyroidism is not limited just to inpatients. Furthermore, it indicates that a formal ROC or DSM-III diagnosis does not in any way rule out a primary thyroid disorder. If only "routine" thyroid testing had been done in either the inpatient or outpatient populations, only 10% of the hypothyroid patients would have been detected. The etiology of hypothyroidism is diverse. Autoimmune mechanisms are frequently implicated and can be screened for with relative ease. 40•43 .44 To further investigate possible mechanisms of hypothyroidism in our patients, we recently studied 100 patients admitted for inpatient evaluation and treatment of depression or lack of energy.4S Fifteen of these patients showed evidence of hypothyroidism (zero, Grade 1; five, Grade 2; and ten, Grade 3). Additional testing for the presence of antibodies to either thyroglobulin or thyroid microsomes revealed that nine of these 15 patients had positive titers

of antimicrosomal antibodies. The presence of antibodies suggests an autoimmune etiology for the thyroid dysfunction. In patients without other evidence of thyroid disease, the name "symptomless autoimmune thyroiditis" (SAT) has been proposed for persons with augmented TSH response to TRH and circulating thyroid antibodies. 46 .49 We have found that SAT is characterized by normal T4 and T3, elevated aTSH, clinical symptoms of depression or else lack of energy, and the presence of antithyroid antibodies. Finally, screening for thyroid antibodies in the above outpatient population showed positive antimicrosomal titer in five of the six patients with aTSH greater than 20 ItIU/mL. Two of these patients also manifested positive antithyroglobulin titer. Table 2 summarizes data for all our study patients to date. It shows that 10% of the inpatients and outpatients with depression or lack of energy have some hypothyroidism. Having found this, are there implications of treatment? At present, the data for answering this question are limited. Overt hypothyroidism must be treated with thyroid hormone replacement regardless of

Table 2-Number of Depressed or lethargic Inpatients and Outpatients with Chemical Evidence of Hypothyroidism GnKIe of hypothyroidism

1-overt

2-Mlld

3-Subcllnlcal

Total.1I gr8del

Inpatients (N - 350)

2

13

20

35

44)

1

2

3

15 (4")

23 (6")

6 41 (10")

Outpatients (N

=

Total (N - 394)

3(1")

PSYCHOSOMATICS

what other psychiatric treatment is used. These patients do not respond to traditional treatments for depression, although many have received antidepressants and electroconvulsive treatment. Patients with mild hypothyroidism are also poor antidepressant responders and good candidates for thyroid hormone replacement even though serum thyroid hormone levels are normal. Thyroid replacement for persons with subclinical hypothyroidism is an open question at present; however, WenzeP advocates medium-dose levothyroxine treatment. The available data suggest that these Grade 3 patients are at increased risk eventually to develop overt hypothyroidism and myocardial infarction. Grade 3 patients appear to be presenting to psychiatrists with disturbances of mood and energy in disproportionate numbers. 25 .45 They are candidates for a trial of thyroid hormone if other treatment approaches are unsuccessful, and they must be closely watched for development of more overt hypothyroidism over time. Thyroid work-up Evaluation of the thyroid gland in the depressed or lethargic patient requires that the psychiatrist focus attention on three aspects of evaluation-clinical history, physical examination, and laboratory testing. Overreliance on or neglect of any major area increases the risk of missing hypothyroidism. The clinical history may be filled with classic symptoms of decreased thyroid dysfunction, as shown in Figure 2, or it may consist of nothing more than vague complaints of decreased energy or depressed mood. The nature of the clinical symptoms depends in part on the JULY 1983' VOL 24· NO 7

severity or grade of the hypothyroidism. It is helpful to use a standardized method to review with patients possible symptoms of thyroid disease. The Thyroid Dysfunction Checklist (Table 3) enables the clinician to screen for the presence or absence of typical symptoms and signs of both hypothyroidism and hyperthyroidism. The presence of more than four or five positive items suggests possible thyroid

dysfunction and a need for vigorous laboratory testing. Some signs of thyroid dysfunction may be screened for in a brief physical examination (exophthalmos, sweating, nervousness, hair loss, and hoarseness). The patient's clothing may suggest recent weight loss or gain, and possible heat or cold intolerance. The feel of the skin permits assessment of whether it is excessively dry or moist. With

(continued)

o

Percent

25

75

50

tOO

•

I

"I

.,.\,

Weakness

I

Dry skin

lethargy

;

Slow speech

Edema of eyelids

.;

::, ,',

"

".

J"

Sensation of cold Decr~ sweating

;

I

Cold skin

Thick tongue

»,

.,

Edema of face coa~r\ess of hair

I

Skin pallor

Memory IlllPBi"":'80t Constipation

.-

W~htgain

..

Loss of hair

lip pallor Dyspnea

PeriphElrale<:fema

I

Hoarseness 0-

AA()I'e~j$; ,

·1

Nervousness

MeflOl'r~

",

I

Palpitation

Deif.-s '.. Precordial pain

J

I

FIGURE 2-C1assic symptoms ofovert hypothyroidism: Frequency ofoccurrence in percent. 651

Hypothyroidism

palpation of the thyroid gland itself one can determine whether the gland is enlarged. if so in what ways. and whether it is tender. Auscultation of the thyroid for evidence of bruit is easily done when blood pressure is checked and is most often positive in the presence of goiter. Finally. a brief neurologic examination is done to look for evidence of lid lag. fine tremor (hyperthyroidism). and delayed reflexes (hypothyroidism). In patients with evidence of overt. Grade I hypothyroidism. the T4 and TSH will both be abnormal and will confirm the clinical diagnosis. Patients with possible Grades 2 or 3 hypothyroidism should have the TRH stimulation test to establish the diagnosis. All patients with a .lTSH of 20 J.LIU/mL or more should be tested for thyroid antibodies. Table 4 outlines a specific protocol for administering the TRH test and monitoring the subsequent change in TSH from the baseline values.

Table 3-Thyroid Dysfunction Checklist POSI Ive family history Weight loss Increased appetite Weight gain Cold intolerance Heat Intolerance Depressed mood Lethargy lack of energy Nervousness Sweating Conslpalon Hoarseness

through surgery or radioactive iodine treatment. may explain only a small number of cases. Studies are needed to investigate influences of age and geography on early hypothyroidism. The mean age of our patients was 35 years and there was some increase in .lTSH with age. It is worth studying ado-

Hair loss Exophthalmos Coronary artery disease Recent myocardial infarction Arrhythmias Pulse at 90 or more per minute Hypertension Dry skin Thyroid brUit Goiter Fine tremor Lid lag

lescent and geriatric populations to assess early hypothyroidism and the usefulness of TRH testing in these age groups. A multicenter study to confirm that our findings are not an isolated geographic effect is also needed. Appropriate treatment strategies for these patients should be stud-

Table 4-TRH Test Protocol

Future directions Many questions are unanswered about the spectrum of thyroid failure and its relationship to depression. Studies are needed to more clearly delineate the psychiatric symptoms that accompany the different grades of hypothyroidism. This might enable us to better identify patients with potential thyroid dysfunction. Our data 4< suggest that roughly half of the identified hypothyroid patients have positive thyroid antibodies. The primary etiology for our findings is evidently autoimmune in nature. 4" The etiology in the other half needs to be clarified. Environmental factors. dietary iodide deficiency. and overcorrection of previous hyperthyroidism. either

I

1. Patients take nothing by mouth after midnight and are at rest In bed by

8:30

AM.

2 Indwelling venous catheter IS placed and a normal saline drip started to keep the line open. 3 At 8.59 AM blood is taken through a three-way stopcock for determination of T3RU, T3RIA, T4, and TSH levels (reverse T3 is optional). 4.

At 9 AM 500 p.g of TRH (protirelin) IS slowly given I.V. over a 30-second period. Side effects from the Infusion may include a transient sensation of warmth. deSire to urinate, nausea. metallic taste, headache, dry mouth, chest tightness, or a pleasant genital sensation. These effects are generally short-lived and mild.

5 Blood samples are taken through the stopcock before the TRH IS administered and at 15, 30, 60. and 90 minutes after the infUSion to measure changes In TSH (determination of prolactin and/or growth hormone oplional).

PSYCHOSOMATICS

ied. Who should have thyroid hormone replacement and who is likely to respond to antidepressants and thyroid hormone in combination are unanswered questions. This work may also have implications for patients treated with lithium carbonate. Lithium, like radioactive iodine, produces a decrease in circulating thyroid hormones and at times this can lead to clinical hypothyroidism. 50.54 This effect seems to occur through several mechanisms,55-58 including inhibition of T4 and T 3 release from the thyroid, and the decrease in thyroid hormone is initially compensated for by increased TRH receptor sensitivity followed by increased TSH output from the pituitary, as in other forms of hypothyroidism. Thus, patients with hypothyroidism secondary to lithium therapy might be expected to show a gradation of symptoms, and perhaps these patients should be considered for thyroid replacement hormones when Grade 2 or 3 changes occur. TRH testing as part of the pre-lith-

ium work-up and repeat testing during therapy will be helpful in clarifying this point. It is interesting to speculate about whether the interactions between (I) lithium and thyroid hormone, and (2) thyroid hormone and adrenergic receptors might have implications for understanding affective disorders and for explaining part of the therapeutic effect of lithium in mania. Thyroid hormones and the catecholamines share the precursor tyrosine. Some researchers 59 hypothesize that this shared structure may manifest itself by interaction between thyroid and catecholamine receptors. Specifically, thyroid hormones increase fJadrenergic receptor activity and this may facilitate the action of catecholamines like norepinephrine (NE) at eNS receptor sites. Hypothyroid states may act to reduce the sensitivity of these catecholamine receptors, therefore decreasing effective availability of neurotransmitters, and producing or contributing to a depressed mood.

At the other extreme, it is hypothesized that manic states reflect excess NE or dopamine (DA) neurotransmitter activity.60·61 Recent work 62 •64 on TSH testing in mania is consistent with this and shows that manic patients have a decreased or blunted ~TSH on TRH testing. TRH release may be facilitated by NE and DA and inhibited by serotonin. 65 .66 If there is increased NE activity in mania, we might expect facilitated TRH release and subsequent reduced sensitivity of TRH receptors on the pituitary gland. The response to the TSH test should then be diminished, which is what is observed. Screening of hypothyroidism can be done relatively easily and, for the psychiatrist who deals with depressed patients every day, the yield will be significant. Antidepressant efficacy can be improved by reducing the heterogeneity of depressed patients and by consequently treating more depressed and fewer hypothyroid patients with antidepressants. 0

choses. New York, Raven Press, 1975, pp 347-358. Carroll BJ, Curtis GC, Mendels J: Neuroendocrine regulation in depression. Arch Gen Psychiatry 33:1039-1044.1976. Extein I, Pottash ALC, Gold MS. et al: The thyroid-stimulating hormone response to thyrotropin-releasing hormone in mania and bipolar depression. Psychiatry Res 2: 199204,1980. Prange AJ, Lipton MS, Nemeroff CB, et al: The role of hormones in depression. Life Sci 20:1305-1318,1977. Extein I, Pottash ALC. Gold MS: Relationship of thyrotropin-releasing hormone test and dexamethasone suppression test abnormalities in unipolar depression. Psychiatry Res 4:49-53. t981. Loosen PT, Prange AJ: Serum thyrotropin response to TRH in psychiatric patients: A review. Am J Psychiatry 139:405-419. 1982. Gold PW. Goodwin FK, Wehr T. et al: Pituitary thyrotropin response to thyrotropin-releasing hormone in affective illness: Relationship to spinal fluid amine metabolites. Am J Psychiatry 134:1028-1031,1977. Targun SO. Sullivan AC. Byrnes SM: Compensatory pituitary-thyroid mechanism in major depressive disorder. Psychiatry Res

6:85-96,1982. 15. Gold MS, Pottash ALC, Ryan N, et al: TRH-induced TSH response in unipolar. bipolar. and secondary depressions: Possible utility in clinical assessment and differential diagnosis. Psychoneuroendocrinology 5: 147 -155. 1980. 16. Morley JE: Extrahypothalamic thyrotropinreleasing hormone-its distribution and its functions. Life Sci 25: 1539-1550. 1979. 17. Jackson IMD, Reichlin S: Brain TRH is independent of the hypothalamus. Nature 267:853-854,1977 18. Braitman OJ. Auker CR. Carpenter DO: Thyrotropin-releasing hormone has multiple actions in cortex. Brain Res 195:244-248. 1980 19. Brown GM, Psychiatroc and neurological aspects of endocrine disease, in Krieger DT, Hughes JC (eds): Neuroendocrinology, Sunderland, Mass, Sinauer Associates, 1980. pp 185-194. 20. Prange AJ, Wilson IC, Rabon AM, et al: Enhancement of Imipramine antidepressant activity by thyroid hormone. Am J Psychiatry 126:457-469, 1969. 21. Prange AJ, Wilson IC, Knox A. et al: Enhancement of imipramine by thyroid-stimulating hormone: Clinical and theoretical impli-

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38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

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