INT'L. J. PSYCHIATRY IN MEDICINE, Vol. 20(2) 193-208,1990

SUBCLINICAL HYPOTHYROIDISM: A REVIEW OF NEUROPSYCHIATRIC ASPECTS* JOHN J. HAGGERTY, JR., M.D. Department of Psychiatry UNC School of Medicine

ROBERT N. GOLDEN, M.D. Department of Psychiatry UNC School of Medicine

J. C. GARBUTT, M.D. Department of Psychiatry UNC School of Medicine and Clinical Research Unit Dorothea Dix Hospital

CORT PEDERSEN, M.D. Department of Psychiatry UNC School of Medicine

JEFFREY S. SIMON, M.D. Northbrook Hospital Brown Deer, Msconsin

DWIGHT L. EVANS, M.D. Departments of Psychiatry and Medicine UNC School of Medicine

CHARLES B. NEMEROFF, M.D., PH.D. Departments of Psychiatry and Pharmacology Duke University School of Medicine

ABSTRACT

The authors review current information about the prevalence, causes, course, and consequences of subclinical hypothyroidism. There is evidence that subclinical hypothyroidism may be associated with cognitive dysfunction, mood disturbance, and diminished response to standard psychiatric treatments. Recommendations are presented for the screening, evaluation and treatment of patients in whom subclinical hypothyroidism may be contributing to neuropsychiatric (lysfunction. (Int'l. J. Psychiatry in Medicine 20:193-208, 1990) Key Words: subclinical hypothyroidism, autoimmune thyroiditis, depression, bipolar disorder, organic brain dysfunction, thyroid hormone.

* Supported in part by NIMH Grants MH40524, MH42088, MH40159, MH39415, MH256-34622,33127-09, MH42625-01, and by the Foundation of Hope, Raleigh, North Carolina. Presented in part at the 42nd Annual Meeting of the Society of Biological Psychiatry, Chicago, Illinois, May 7-10,1987, and at the 140th Annual Meeting of the American Psychiatric Association, Chicago, Illinois, May 11-15,1987. 193 0 1990. Baywood Publishing Co.. Inc.

doi: 10.2190/ADLY-1UU0-1A8L-HPXY http://baywood.com

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CONCEPT Considerable evidence has accrued within the last several decades indicating that the boundary between normal thyroid function and thyroid failure is not distinct. Between “definitely” euthyroid and “definitely” hypothyroid is a spectrum of relative thyroid deficiency in which dynamic tests of the thyroid axis indicate diminished thyroid gland responsiveness even though basal thyroid hormone concentrations are within traditional limits of normality. Although our current technology does not allow strict delineation of when thyroid failure begins, we can now define relative degrees of thyroid abnormality within the aforementioned spectrum. A standard grading system has been developed which delineates three levels of hypothyroidism [ l , 21 (see Table 1). Patients with grade 1 (overt) hypothyroidism have the classic symptoms of primary hypothyroidism, and have abnormally low serum concentrations of triiodothyronine (T3) and/or thyroxine (T4). In grade 2 hypothyroidism, serum concentrations of T3 and T4 are within normal limits, but basal serum thyroid stimulating hormone (TSH) concentrations are elevated. It is unclear if there are any characteristic symptoms of grade 2 hypothyroidism. The grade 3 patient has normal basal plasma TSH and thyroid hormone concentrations, and an exaggerated TSH response to thyrotropin releasing hormone (TRH) challenge, but none of the classic symptoms of hypothyroidism. In regions with adequate dietary iodine, such as the United States, the majority of cases of hypothyroidism result from slowly progressive autoimmune thyroiditis (vide infra) [3]. Thus the presence of antimicrosomal or antithyroglobulin antibodies alone may define an even earlier form of thyroid failure. We have proposed calling this “grade 4” hypothyroidism. We will utilize the term subclinical hypothyroidism to refer to grades 2 , 3 , or 4 hypothyroidism in contradistinction to grade 1 hypothyroidism in which thyroid failure is overt. From the time that subclinical hypothyroidism was first defined by Wenzel et al. [ 11 and Evered et al. [2] ,it has generally been considered a “laboratory disease” with little clinical import because it lacks definable clinical symptoms. However, the criteria by which subclinical hypothyroidism has been judged asymptomatic have been primarily the somatic (non-CNS) symptoms of overt hypothyroidism. More recently the hypothesis has been advanced that even if it Table 1. Grades of Hypothyroidism

~~~

Grade 1 Grade 2 Grade 3 Grade 4

~

FTI

Basal TSH

.1

t t

TSH Response to TRH

Anti- Thyroid Antibodies

t t t

+ or + or + or -

~

N1 N1 N1

N1 N1

N1

+

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is “symptomless,” subclinical hypothyroidism may have long term consequences for non-endocrine organ systems [4], including the brain [5]. The TSH response to TRH may also be abnormally blunted rather than exaggerated. This finding, which is expected in hyperthyroid states, has also been reported in 20 to 30 percent of apparently euthyroid depressed patients [6], possibly due to stress related adaptations in TRH secretion or pituitary function. In psychiatric studies the blunted TSH response is most typically used as a research marker for studying neurohormonal adaptation rather than as clinical indicator of remediable thyroid gland dysfunction. Alternatively, it is possible that some patients who exhibit a blunted TSH response, particularly those with coexisting anxiety, have slightly increased thyroid function [7]. However, because generally accepted criteria for defining transitional hyperthyroid states have not yet been developed, “subclinical hyperthyroidism” currently remains a concept rather than a well characterized entity.

ET IOLOG I ES The etiologies for subclinical hypothyroidism are the same as for overt hypothyroidism: iodine deficiency, ablative treatment for hyperthyroidism or cancer, and autoimmune thyroiditis. Iodine deficiency still occurs commonly in non-industrialized societies as well as in isolated areas of developed countries [8].Goiter and cretinism are common in such areas. Although many individuals are able to compensate in part for the diminished availability of iodine, numerous studies document the frequent occurrence of elevated basal TSH concentrations accompanied by diminished but “normal” thyroid hormone concentrations in both goiterous and nongoiterous individuals from these regions [ 9 ] . A second important cause of subclinical hypothyroidism is ablative treatment for Graves’ disease or toxic nodular goiter. Following the restitution of a euthyroid state by either partial thyroidectomy or radioactive iodine treatment, thyroid function commonly continues to decline slowly, often over a period of years, resulting in eventual overt hypothyroidism. During this progression there may be a long period of time when the patient has subclinical hypothyroidism. The progression to overt hypothyroidism occurs in 30 to 60 percent of patients following partial thyroidectomy [ 10, 111, and in 15 to 20 percent of patients following radioactive iodine treatment [ 121. The autoimmune process in Graves’ disease involves both stimulating and destructive antithyroid antibodies. The slow decline of thyroid function may be due in part to the continued activity of the latter. Autoimmune thyroiditis is the largest single cause of subclinical hypothyroidism in developed nations [3]. The term “autoimmune thyroiditis” refers to a spectrum of disorders which are differentiated primarily by course, clinical characteristics, and specific type of antithyroid antibodies involved [13] .

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Included here are entities such as Graves’ disease, Hashimoto’s thyroiditis, atrophic thyroiditis, subacute thyroiditis, postpartum thyroiditis and others. All are capable of causing gradual destruction of the thyroid gland and hence may lead to subclinical and, eventually, overt hypothyroidism. The more acute forms of autoimmune thyroiditis such as Graves’ disease and Hashimoto’s thyroiditis can generally be recognized fairly early in the course of illness by characteristic clinical signs or symptoms such as hyperthyroidism or a tender, swollen thyroid gland. However, most cases of autoimmune induced thyroid failure are the result of chronic, insidious, and often silent thyroiditis generally referred to as symptomless autoimmune thyroiditis (SAT). This disorder is characterized by the presence of cytotoxic antithyroid antibodies, usually including antithyroglobulin or antimicrosomal antibodies, in low to moderate titers which persist over a period of years. Due to the slowly progressive course of SAT, afflicted individuals typically have subclinical grades of hypothyroidism for long periods of time before progressing to overt hypothyroidism which occurs at a rate of approximately 5 to 10 percent per year [3,14].

PREVALENCE AND POPULATIONS AT RISK The prevalence of subclinical hypothyroidism varies with age, sex, region and screening methodology [ 151. The exact prevalence of subclinical hypothyroidism, including all grades, has not yet been determined because it requires TRH infusion testing which is difficult to obtain on large community samples. Most prevalence estimates are therefore based on basal TSH measurements (grade 2 hypothyroidism) or by detection of antithyroid antibodies, which are associated with all grades of hypothyroidism and which are present in approximately 60 percent of individuals with grade 3 hypothyroidism [16]. The best study of the prevalence of subclinical hypothyroidism is probably that conducted in an English community by Tunbridge et al. [17]. They found that 2.8 percent of males and 7.5 percent of females had elevated basal plasma TSH concentrations. Antithyroid antibodies were found in 2.7 percent of males, 10.3 percent of females and in 6.8 percent in the population overall. Women over the age of forty-five had a prevalence of elevated basal TSH ranging from 10 to 17 percent depending on age, and up to 11 percent had positive antimicrosomal or antithyroglobulin antibody titers. It is important to note that the occurrence of antithyroid antibodies may vary considerably from region to region, with population rates ranging from a low of 2 percent in Africa [18] to 27 percent in Finland [19]. As opposed to goiter, the prevalence of autoimmune thyroiditis increases with high dietary iodine availability [ 151 . The exact mechanisms for this are uncertain, but may include B lymphocyte stimulation, increased antigen presentation, or a change in the antigenicity of thyroglobulin [15].

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The prevalence of subclinical hypothyroidism may possibly be higher in clinical populations. We have found a prevalence of antithyroid antibodies of 1 1 percent in a sample of family medicine outpatients (unpublished data). Within clinical populations several groups may be at particular risk. Because autoimmune diseases often occur together, patients with another identified autoimmune illness may have an increased risk for autoimmune thyroiditis and thereby subclinical hypothyroidism. For example, autoimmune thyroiditis occurs frequently in patients with diabetes mellitus [2G]. Women in the postpartum period are at risk for either transient or prolongeJ subclinical hypothyroidism due to postpartum autoimmune thyroiditis [21]. Finally, evidence of grade 2 hypothyroidism is found in at least 13 percent of elderly individuals [22] . Though some data suggest that subclinical hypothyroidism is more prevalent in psychiatric patients than in the general population, this is not definitively established because studies controlling for age and gender effects have not been conducted. Gold et al. [5] found that approximately 10 percent of psychiatric referrals with symptoms of depression or anergia had either grade 1, 2, or 3 hypothyroidism. Our group reported that 9 percent of psychiatric inpatients with affective disorders have elevated basal plasma TSH concentrations [23]. In a series of studies we have found a prevalence rate of positive antithyroid antibody titers ranging from 9 to 20 percent in affective disorder patients [23-251 and 9 percent in psychiatric patients with non-affective disorders [25]. Other investigators have reported a similar range of findings for affective disorder patients [16,26,27]. Our most recent studies indicate that the highest prevalence may occur in patients with mixed or depressed bipolar affective disorder regardless of lithium exposure [25]. We found antithyroid antibodies in 20 percent of patients with bipolar disorder, depressed type, and in 33 perceiit with bipolar disorder, mixed type. Antibodies occurred with equal frequency in lithium exposed and lithium non-exposed patients. A comparative study of antithyroid antibody prevalence controlling for age and sex is currently underway at our center. It should be noted that, if an association is borne out, it cannot be assumed that subclinical hypothyroidism causes psychiatric disorder. Stress, perhaps acting through known effects of cortisol on suppressor T Cell function, is thought to be an important activator of autoimmune disease [ 131 . It is thus also possible that psychiatric illness such as depression could predispose to the development of thyroid disorder. This is of particular interest in view of the stress-diatkds model of depression which continues to gain support. Subclinical hypothyroidism would be expected to increase not only TSH secretion, but TRH secretion as well. Recently Banki et al. reported increased cerebrospinal fluid concentrations of TRH in depressed patients [28] . The risk of subclinical hypothyroidism is increased by the use of certain medications. Lithium has been shown to interfere with thyroid hormone metabolism at several steps; it interferes with the actions of TSH on the thyroid

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gland, it decreases thyroid hormone release and it impairs thyroid hormone synthesis. The net effect is to cause a reduction in circulating thyroid hormone and a compensatory increase in TSH secretion. In most individuals the increase in TSH secretion is sufficient to maintain euthyroidism. However, anywhere from 4 to 10 percent of patients on lithium may develop overt hypothyroidism, while as many as 30 percent will show an elevated serum TSH [29,30]. Lithium also exacerbates pre-existing autoimmune thyroiditis as demonstrated by a rise in antithyroid antibodies titers [31]. The prevalence of antithyroid antibodies in lithium treated patients ranges from 14 to 43 percent [32-341. There is controversy as to whether this represents de-novo inducation of thyroiditis or exacerbation of preexisting illness [25,35]. Other substances that may induce thyroiditis and hypothyroidism, either subclinical or overt, include amiodarone, iodine or iodine containing drugs, and organic pollutants such as polychlorinated biphenyls (PCB), phenol, and others [ 151. Carbamazepine and other anticonvulsants are reported to decrease plasma thyroid hormone concentrations; however, this probably does not represent hypothyroidism because there is no compensatory increase in TSH secretion [36].

MEDICAL CONSEQUENCES There is some evidence that patients with subclinical hypothyroidism may be at increased risk for arteriosclerotic cardiovascular disease [371 . The mechanism for this is thought to be alterations in serum cholesterol, HDL concentrations, and LDL concentrations [38,391. Treatment-reversible changes in ventricular function have also been observed [40]. In the above instances the causative factor appears to be the decreased thyroid hormone concentration. Other cardiovascular problems have been observed that may be related to multisystem .autoimmunity for which the thyroid antibodies or thyroid dysfunction are only a signpost. The prevalence of mitral valve prolapse, for example, is significantly increased in patients with autoimmune thyroiditis 1411 .

PSYCHIATRIC CONSEQUENCES The organ system with the greatest vulnerability to mild thyroid hormone deprivation may be the CNS. In early hypothyroidism, circulating T4 concentrations drop while T3 concentrations are conserved [7]. The brain, which in contradistinction to other tissues preferentially utilizes circulating T4, may thus become hypothyroid before other organs [42]. This hypothesis is at least partially supported by a growing body of data indicating that subclinical hypothyroidism may affect cognition, mood, and mood cyclicity (vide infra). There is mounting evidence that subclinical hypothyroidism may be associated with cognitive dysfunction. Studies of neuropsychological functioning in goiterous regions of Latin America demonstrate diminished cognitive

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functioning even in individuals with normal thyroid hormone concentrations [43] . Performance on cognitive function tests globally improves in these regions following community wide iodine supplementation. Clinically significant organic brain dysfunction has been observed in psychiatric patients with grade 2 hypothyroidism [44]. In an ongoing study our group has observed impaired function on one or more subscales of the Wechsler Memory Scale in six of seven (85%) nonpsychiatric subjects with grade 2 , 3 or 4 hypothyroidism (unpublished data). In these subjects the maximum increase in TSH following TRH infusion (delta-max TSH) correlates with short and long-term Wechsler Memory Scores, and thyroid hormone treatment brings about parallel improvement in memory scores and TSH concentrations. In a recent investigation, Nystrom et al. followed memory function in twenty women with subclinical hypothyroidism during a cross-over thyroxine treatment study [45]. They found that 20 percent improved their memory scores after six months of thyroxine treatment. In a study of female depressed inpatients Reus et al. found that patients with antithyroid antibodies had lower scores on the Selective Reminding Task and a relatively exaggerated TSH response to TRH compared with euthyroid patients [26]. Finally Prange et al. at our Center found that subjects with low normal free thyroxine index (FT4 I) values had more post-ECT memory loss than did those with a high normal FT41 value [46]. Another possible psychiatric consequence of subclinical hypothyroidism is depression. Mood changes are common in hypothyroidism. It is not yet certain whether subclinical hypothyroidism in itself frequently causes major depression (see above). Nevertheless, it may at least have a detrimental effect on the course of major depression when the two disorders coexist. Targum et al. found a significantly increased rate of subclinical hypothyroidism in treatment refractory depressed patients who later responded to T3 augmentation [47]. Our group has observed that depressed patients with antithyroid antibodies are less likely than patients without antibodies to respond well to standard antidepressant treatment [46]. In a similar vein, Prange et al. found that euthyroid patients with a poor antidepressant response have a lower FT,I than do good responders [46]. Evidence has recently been presented indicating that some patients with major depression and subclinical hypothyroidism might respond to thyroid hormone alone [48]. Subclinical hypothyroidism may be particularly relevant in bipolar affective disorder. Cowdry et al. [49] and Sauer and Whybrow [50]have reported a very high prevalence of subclinical hypothyroidism in rapid cycling bipolar disorder. The findings in these studies cannot be disentangled from the thyroid effects of lithium treatment itself and have not been confirmed by Joffe et al. [5 I ] who attempted to account for this factor. At least three groups have reported that thyroid hormone treatment enhances the stabilization of rapidly cycling bipolar disorder either when used alone or in combination with standard mood stabilizers [50,52,53]. While our data indicate that vulnerability to subclinical

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hypothyroidism may predate lithium use in some bipolar patients, there is no doubt that lithium itself increases the likelihood of subclinical hypothyroidism through multiple mechanisms. Some of the cognitive dysfunction associated with lithium may be due to thyroid dysfunction, since cognitive test scores correlate with TSH concentration in lithium treated patients [54]. Finally, subclinical hypothyroidism has been implicated in several other psychiatric disorders. Lindeman et al. [55] have reported that thyroid disease is prevalent in the family members of anxiety disorders patients, but Stein and Uhde found no increase in antithyroid antibodies prevalence in this group [56]. Brayshaw [57] reported subclinical hypothyroidism in 75 percent of premenstrual syndrome patients (PMS) studied with TRH infusion and Roy-Byrne et al. [58] found an exaggerated TSH response to TRH infusion in 28 percent. However, data on the utility of thyroid hormone treatment in this disorder are conflicting [59].

EVALUATION An evaluation for subclinical hypothyroidism should be considered for patients with unexplained changes in mood, energy or cognition in combination with one or more risk factors such as family history of thyroid disorder, residence in a region of high goiter prevalence, history of other autoimmune diseases, a recent pregnancy, or advanced age. Psychiatrists should give special consideration to patients with refractory depression, rapidly cycling bipolar disorder, or any patient receiving or about to receive lithium. Fortunately, the initial screening tests for subclinical hypothyroidism are relatively inexpensive and easy to obtain, so the question becomes one of how far to proceed rather than whether to look for subclinical hypothyroidism at all. A screening evaluation consisting of total T4, T3U, TSH, and antithyroglobulin and antimicrosomal antibodies identifies most, but not all, subjects with subclinical hypothyroidism. An elevated basal TSH will identify subjects with grade 2 hypothyroidism. However, because TSH can be transiently elevated in basically euthyroid psychiatric [60] and medical patients [61] ,continued TSH elevation should be observed over at least two weeks before making this diagnosis on the basis of basal TSH alone. It is now evident that the new ultrasensitive immunoradiometric TSH assays (IRMA) are considerably better than the standard radioimmunoassays previously utilized. They have been claimed to be so sensitive that a single basal measurement can replace the TRH stimulation test in diagnosing subclinical hypothyroidism, though this may not be true in the psychiatric population. Antithyroid antibodies are not invariably detected with current methodology in all cases of subclinical hypothyroidism. In fact, titers tend to decrease as the illness progresses toward overt hypothyroidism [14]. They are however present in about 60 percent of patients with Grade 3 hypothyroidism [ 161 and thus

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remain a useful part of the screening evaluation. Histopathological studies indicate that even very low antibody titers are meaningful indicators of developing thyroiditis [62] . Thus, we define patients as antibody “positive” when either antithyroglobulin or antimicrosomal antibody is found in any detectable titer. The second step in the evaluation of subclinical hypothyroidism is the TRH infusion test. This procedure will rule out basal TSH false positives, will give a measure of the severity of thyroid axis dysfunction, and will identify those cases of Grade 3 hypothyroidism in which antibodies are not detectable. The details of this test are described in Appendix A. Contraindications are few, including seizure disorder [63] , uncontrolled hypertension [64] , and significant arrhythmia. A change in TSH concentration of 30 IU or greater, using radioimmunoassay techniques (RIA), is considered by most to be unequivocal evidence of at least grade 3 hypothyroidism. This cut-point may be inappropriate if TSH concentration is determined by one of the newer immunoradiometric techniques (IRMA). Recent data indicate that when this type of assay is used, it might be more appropriate to use as a cut-point a change in TSH concentration of 20 IU [ 6 5 ] . For the patient receiving lithium, evaluation for subclinical hypothyroidism may need to be repeated on an ongoing basis. However, not all patients need the same degree of surveillance. A prior finding of antithyroid antibodies or a prelithium history of thyroid disorder of any type indicates the need for at least yearly evaluation of anti-thyroid antibodies, basal TSH and serum thyroid hormone concentrations. On the other hand, the patient who is stable, relatively asymptomatic, and had negative antithyroid antibodies prior to initiation of lithium may not require regular retesting. Because of the potential for subclinical hypothyroidism to destabilize affective illness and to potentiate lithium’s effects on cognitive functioning, we recommend instituting thyroid hormone replacement as soon as basal TSH exceeds normal range. If there has also been a large increase in antithyroid antibody titers, signifying potential thyroid gland destruction rather than just inhibition, then discontinuation of lithium might be considered as well.

TREATMENT When to treat subclinical hypothyroidism remains controversial. While there is some evidence for long-term health consequences of subclinical hypothyroidism, we do not yet know enough about the relative risks versus benefits of long-term thyroid hormone administration in this disorder to justify routine treatment in all cases. Although relatively benign in most individuals, thyroid hormone treatment is not absolutely so. It may increase angina or arrhythmia in patients with preexisting cardiac disease. Side effects such as nervousness are observed even in low doses and may prove intolerable for some.

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More recently concern has arisen that chronic administration of thyroid hormone in supraphysiologic doses may be associated with accelerated osteoporosis in females [66]. The above cautions notwithstanding, there is good reason to consider a trial of thyroid hormone treatment for cases of grade 2 or 3 subclinical hypothyroidism that are accompanied either by mood or energy changes or by treatment resistant major affective disorder. There is presently less justification for thyroid hormone treatment for patients with antithyroid antibodies alone, although the possibility of occasional therapeutic benefit from early intervention cannot be ruled out. In general, T4 is recommended to treat thyroid disease [67] in contrast to T3 which has been used to potentiate tricyclic antidepressants in euthyroid patients (vide infra). T4, which is readily converted in the liver, kidney and brain to the more potent T3, has the advantage of a longer half-life and possibly better tolerability. The initial trial of thyroid hormone should be at least two months in duration, if possible, since CNS manifestations of thyroid deficiency are often slow to change. The authors initiate treatment with thyroxine, -025 mg/day, increasing to .05 mg as tolerated after one week. Patients can be kept at this dose or increased at one to two month intervals as necessary to normalize basal TSH or TSH response to TRH. Typical maintenance doses range from .05 to .15 mg/day. Thyroid and functional status should be carefully reassessed at least yearly to re-evaluate the appropriateness of the current dose of thyroid hormone. The one exception to this is rapidly cycling bipolar affective disorder in which hypermetabolic doses (enough to raise FT4 150% above upper limits of normal) may be required to achieve stabilization [50]. Indications of positive response to thyroid hormone treatment include improved energy and concentration and decreased frequency of major or minor mood swings. Small doses of T3 have been shown to potentiate tricyclic antidepressant response in some euthyroid depressed patients [68] . Thus T3, in doses of 25 to 50 micrograms, may be considered as an adjunctive treatment in cases of slow or limited tricyclic response even when subclinical hypothyroidism has been fully ruled out [69]. It is not known if this effect extends to T4. This response potentiation is not mediated by changes in serum antidepressant concentrations [70]. Candidate mechanisms include hormonally induced change in the conformation of noradrenergic receptors from alpha to beta specificity [7 11, reciprocal effects on brain T4 concentrations [72] ,and blockade of neuronal uptake of neurotransmitter [73]. APPENDIX A

The protocol described here differs from the full scale TRH infusion protocol standardly used in neuroendocrine research, in which TSH is sampled at 15 min. intervals for up to ninety minutes. While this abbreviated procedure does not

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provide all the information available from the full-scale protocol, the 30 min. delta-TSH agrees well with the delta max TSH and area under the curve calculated from measurements at multiple time points [ 741 . Thus it provides all the information necessary for the clinical evaluation of subclinical hypothyroidism, but with increased efficiency and reduced cost. The test should be conducted in the morning (8 AM-9 AM) following an overnight fast. An IV is inserted and, after a 30 minute rest, blood is withdrawn for measurement of basal TSH. TRH, at a dose of 500 micrograms, is then injected intravenously over a one-minute period. Blood pressure should be evaluated shortly thereafter and then at approximately 15 minute intervals. Thirty minutes after TRH injection a second blood sample for TSH is withdrawn. The IV is then removed, and the patient can resume normal activities. Interpretation of the TRH test generally is made by the calculation of the change in TSH from baseline t o 30 minutes (delta-max TSH). To obtain this, one simply subtracts basal TSH from the 30 minute value. In general, a deltamax TSH greater than 30 IU/ml by RIA assay or greater than 20 IU/ml by IRMA assay is considered t o represent an exaggerated response. The most common side-effects are transient nausea, warmth and urinary urgency that occur immediately after TRH injection. TRH has been reported to increase blood pressure two t o three minutes after injection, and thus patients with significantly elevated blood pressure should be studied cautiously, if at all. The TSH response to TRH is diminished by corticosteroids, decreased caloric intake and thyroid hormones, and is falsely raised by dopamine administration.

REFERENCES 1. K. W. Wenzel, H. Meinhold, M. Raffenberg, F. Adkofer, and H. Schleusener,

2. 3. 4.

5. 6.

7.

Classification of Hypothyroidism in Evaluating Patients after Radioiodine Therapy by Serum Cholesterol, T3 Uptake, Total T4, F-T4 Index, Total T3, Basal TSH, and TRH Test, European Journal of Clinical Investigation, 4 , p. 141, 1974. D. C. Evered, B. J. Ormston, and P. A. Smith, Grades of Hypothyroidism, British Medical Journal, 1 , p. 657, 1973. W. M. G. Tunbridge, M. Brewis, J. M. French, et al., Natural History of Autoimmune Thyroiditis, British Medical Journal, 282, p. 258, 198 1. P. B. S. Fowler, Premyxoedema: A Cause of Preventable Coronary Heart Disease, Proceedings of the Royal Society of Medicine, 70, p. 297, 1977. M. S. Gold, A. L. C. Pottash, and I. Extein, Hypothyroidism and Depression: Evidence from Complete Thyroid Function Evaluation, Journal of the American Medical Association, 245, pp. 1919-1922, 1981. P. Loosen and A. J. Prange, Jr., The Serum Thyrotropin Response to Thyrotropin-releasing Hormone in Psychiatric Patients: A Review, American Journal of Psychiatry, 139, pp. 405-416, 1982. G. M. Gillette, J. C. Garbutt, and D. E. Quade, TSH Response to TRH in Depression with and without Panic Attacks, American Journal of Psychiatry, 146, pp. 743-748, 1989.

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8. D. Koutras, Iodine: Distribution, Availability, and Effects of Deficiency on the Thyroid, in Proceedings of the VMeeting of the PAHOIWHO Technical Group on Endemic Goiter, Cretinism, and Iodine Deficiency, J. T. Dunn et al. (eds.), Pan American Health Organization, Washington, D.C., 1986. 9. M. E. Ermans, Endemic Goiter, in The Thyroid: A Fundamentaland Clinical Text, S. H. Ingbar and L. E. Braverman (eds.), Lippincott, Philadelphia, 1985. 10. D. Evered, E. T. Young, W. G. Tunbridge, et al., Thyroid Function after Subtotal Thyroidectomy for Hyperthyroidism, British Medical Journal, I , pp. 25-27, 1975. 11. A. J. Hedley, R. Hall, J. Amos, et al., Serum Thyrotropin Levels after Subtotal Thyroidectomy for Graves Disease, Lancet, 1, pp. 455-458, 1971. 12. R. N. Smith and G. M. Wilson, Clinical Trial of Different Doses of I3’I in Treatment of Thyrotoxicosis, British Medical Journal, 1 , pp. 129-132, 1967. 13. R. Volpe, Autoimmune Thyroid Disease, in Autoimmunity and Endocrine Disease, R. Volpe (ed.), Marcel Dekker, New York, 1985. 14. A. Gordin and B. A. Lamberg, Natural Course of Autoimmune Thyroiditis, Lancet, 1975. 15. M. Safran, P. Paul, E. Rotti, and L. E. Braverman, Environmental Factors Affecting Autoimmune Thyroid Disease, Endocrinology and Metabolism Clinics of North America, 16, pp. 327-342, 1987. 16. M. S. Gold, A. L. C. Pottash, and I. Extein, “Symptomless” Autoimmune Thyroiditis in Depression, Psychiatry Research, 6, pp. 26 1-269, 1982. 17. W. M. G. Tunbridge, D. C. Evered, R. Hall, et al., The Spectrum of Thyroid Disease in a Community: The Whickham Survey, Clinical Endocrinology, 7, pp. 481-492, 1977. 18. G. B. Salabe, H. Salabe-Lotz, I. Ilardi, C. Petracca, and K. Bile, Low Prevalence of Thyroid Antibodies in a Somalian Population, Clinical and Laboratory Immunology, 9 , pp. 55-57, 1982. 19. A. Gordin, J. Maatela, A. Mieltin, T. Helenius, and L. Lamberg, Serum Thyrotrophin and Circulating Thyroglobulin and Thyroid Microsomal Antibodies in a Finnish Population, Acta Endocrinologica, 90, pp. 33-42, 1979. 20. J. Nerup and A. Lernmark, Autoimmunity in Insulin-dependent Diabetes Mellitus, American Journal o f Medicine, 70, pp. 135-141, 1981. 21. H. H. Lervang, 0. Pryds, and H. P. Ostergaard, Thyroid Dysfunction after Delivery: Incidence and Clinical Course, Acta Medica Scandinavica, 222, pp. 369-374, 1987. 22. M. J. Rosenthal, W. C. Hunt, P. J. Carry, and J. S. Goodwin, Thyroid Failure in the Elderly: Microsomal Antibodies as Discriminant for Therapy, Journal of the American Medical Association, 258, pp. 209-213, 1987. 23. J. J. Haggerty, J. S. Simon, D. L. Evans, and C. B. Nemeroff, Elevated TSH Levels and Thyroid Antibodies in Psychiatric Inpatients: Relationship to Diagnosis and DST Response, American Journal of Psychiatry, 144, pp. 1491-1493, 1987.

SUBCLINICAL HYPOTHYROIDISM / 205

24. C. B. Nemeroff, J. S. Simon, J. Haggerty, Jr., and D. L. Evans, Antithyroid Antibodies in Depressed Patients, American Journal o f Psychiatry, 142, pp. 840-843, 1985. 25. J. J. Haggerty, D. L. Evans, R. N. Golden, C. Pedersen, J. Simon, and C. Nemeroff, The Presence of Antithyroid Antibodies in Affective and Nonaffective Psychiatric Disorders, Biological Psychiatry, 27, pp. 5 1-60, 1990. 26. V. I. Reus, J. Berlant, M. Galante, and N. Becker, Autoimmune Thyroiditis in Female Depressives, presented at the 41st Annual Meeting of the Society of Biological Psychiatry, Washington, D.C., May 9, 1986. 27. R. T. Joffe, Antithyroid Antibodies in Major Depression, Acta Psychiatrica Scandinavica, 76, pp. 598-599, 1987. 28. C. M. Banki, G. Bissette, M. Arato, and C. B. Nemeroff, Elevation of Immunoreactive CSF TRH in Depressed Patients, American Journal o f Psychiatry, 145, pp. 1526-1531, 1988. 29. C. H. Emerson, W. L. Dyson, and R. D. Utiger, Serum Thyrotropin and Thyroxine Concentrations in Patients Receiving Lithium Carbonate, Journal of Clinical Endocrinology and Metabolism, 3 6 , p. 338, 1913. 30. G. Lindstedt, L. Nilsson, J. Walinder, et al., On the Prevalence, Diagnosis and Management of Lithium Induced Hypothyroidism, British Journal of Psychiatry, 130, p. 452, 1977. 31. J. R. Calabrese, A. D. Gulledge, K. Hahn, et al., The Development of Thyroiditis in Patients Receiving Long-term Lithium Therapy, American JournalofPsychiatry, 142, p. 1318, 1985. 32. J. H. Lazarus, Endocrine and Metabolic Effects of Lithium, Plenum Press, New York, 1986. 33. D. H. Myers, B. H. Carter, B. H. Burns, et al., A Prospective Study on the Effects of Lithium on Thyroid Function and on the Prevalence of Antithyroid Antibodies, Psychological Medicine, 1 5 , p. 55, 1985. 34. P. Deniker, R. Eyquem, R. Bernheim, H. Loo, and P. Delarue, Thyroid Autoantibody Levels during Lithium Therapy, Neuropsycho biology, 4 , pp. 270-275, 1978. 35. R. A. Hassman and A. M. Mcgregor, Lithium and Autoimmune Thyroid Disease, in Lithium and the Endocrine System, F. N. Johnson (ed.), S. Karger, Basel, 1988. 36. P. P. Roy-Byrne, R. T. Joffe, T. W. Uhde, and R. M. Post, Carbamazepine and Thyroid Function in Affectively Ill Patients: Clinical and Theoretical Implications, Archives of General Psychiatry, 41, pp. 1150-1 153, 1984. 37. P. B. S. Fowler, Premyxoedema: A Cause of Preventable Coronary Heart Disease, Proceedings o f the Royal Society of Medicine, 70, p. 297, 1977. 38. P. B. S. Fowler, J. Swale, and H. Andrews, Hypercholesterolemia in Borderline Hypothyroidism Stage of Premyxoedema, Lancet, i , pp. 488-491, 1970. 39. B. U. Althaus, J. J. Staub, A. Ryff-De Leche, et al., LDL/HDL-Changes in Subclinical Hypothyroidism: Possible Risk Factors for Coronary Heart Disease, Clinical Endocrinology, 28, pp. 157-163, 1988.

206 I HAGGERTY E T A L .

40. D. S. Cooper, R. Halpern, L. C. Wood, et al., L-thyroxine Therapy in Subclinical Hypothyroidism: A Double-blind, Placebo-controlled Trial, Annals o f Internal Medicine, 101, pp. 18-24, 1984. 41. A. D. Marks, B. J. Channick, E. V. Adlin, R. K. Kesler, L. E. Braitman, and B. S. Denenberg, Chronic Thyroiditis and Mitral Valve Prolapse, Annals ofznternal Medicine, 102, pp. 469-483, 1985. 42. F. R. Crantz, J. E. Silva, and P. R. Larsen, An Analysis of the Sources and Quantity of 3,5,3’-triiodothyronine Specifically Bound to Nuclear Receptors in Rat Cerebral Cortex and Cerebellum, Endocrinology, I 10, p. 367, 1982. 43. R. Fierro-Benitez, R. Casar, J. B. Stanburly, et al., Long-term Effects of Correction of Iodine Deficiency on Psychomotor and Intellectual Development, Proceedings o f the V Meeting of the PAHOIWHO Technical Group on Endemic Goiter, Cretinism, and Iodine Deficiency, J. T. Dunn et al. (eds.), Pan American Health Organization, Washington, D.C., 1986. 44. J. J. Haggerty, D. L. Evans, and A. J. Prange, Jr., Organic Brain Syndrome Associated with Marginal Hypothyroidism, American Journal of Psychiatry, 143, pp. 785-786, 1986. 45. E. Nystrom, K. Caidahl, G. Fager, et al., A Double-blind Cross-over Twelve Month Study of L-thyroxine Treatment of Women with “Subclinical” Hypothyroidism, Clinical Endocrinology, 29, pp. 63-76, 1988. 46. A. J. Prange, J. J. Haggerty, J. Rice, and J. Browne, Marginal Hypothyroidism in Mental Illness: Preliminary Assessments of Prevalence and Significance, Proceedings of the XVZth CZNP Conference, Munich, 15-19 August, 1988, (in press). 47. S. D. Targum, R. D. Greenberg, R. L. Harmon, et al., Thyroid Hormone and the TRH Stimulation Test in Refractory Depression, Journal of Clinical Psychiatry, 45, p. 345, 1984. 48. P. J. Goodnick, I. L. Extein, and M. S. Gold, TRH Test in the Treatment of Depression, Proceedings of the 143rd Annual Meeting of the American Psychiatric Association, San Francisco, May 6-1 1, 1989, New Research Abstracts, p. 126. 49. R. W. Cowdry, T. A. Wehr, A. Zis, and F. Goodwin, Thyroid Abnormalities Associated with Rapidcycling Bipolar Illness, Archives o f General Psychiatry, 4 0 , pp. 414-420, 1983. 50. M. S. Bauer and P. C. Whybrow, The Thyroid Axis in Intractable Rapidcycling Bipolar Affective Disorder: Neuroendocrine Assessment and Treatment Response with High-dose Thyroxine, presented at the Annual Meeting of the American Psychiatric Association, Chicago, Illinois, 1987. 5 1. R. T. Joffe, S. Kutcher, and C. McDonald, Thyroid Function in Bipolar Affective Disorder, Psychiatric Research, 2 5 , pp. 117, 121, 1988. 52. H. C. Stancer and E. Persad, Treatment of Intractable Rapid-cycling Manicdepressive Disorder with Levothyroxine, Archives of General Psychiatry, 39, p. 31 1, 1982. 53. I. Extein, A. L. Pottash, and M. S. Gold, Does Subclinical Hypothyroidism Predispose to Tricyclic-Induced Rapid Mood Cycles? Journal of Clinical Psychiatry, 4 5 , pp. 290-291, 1982.

SUBCLINICAL HYPOTHYROIDISM / 207

54. J. H. Kocsis, E. D. Shaw, J. Hatterer, P. Stokes, and J. J. Mann, Cognitive and Motor Performance on Lithium, Proceedings of the 26th Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, p. 182, December 11-16, 1987. 55. C. G. Lindemann, C. M. Zitrin, and D. Klein, Thyroid Dysfunction in Phobic Patients, Psychosomatics, 2 5 , pp. 603-606, 1984. 56. M. B. Stein and T. W. Uhde, Thyroid Indices in Panic Disorder, American Journal of Psychiatry, 145, pp. 745-747, 1988. 57. N. D. Brayshaw, Treating Premenstrual Syndrome as Thyroid Disorder, Proceedings of the 140th Annual Meeting of the American Psychiatric Association, Washington, D.C., May 14, 1986. 58. P. P. Roy-Byrne, D. R. Rubinow, M. C. Hoban, G. N. Grover, and D. Blank, TSH and Prolactin Responses to TRH in Patients with Premenstrual Syndrome, American Journal of Psychiatry, 144, pp. 480-484, 1987. 59. U. Halbreich, S. Carson, N. Rojansky, J. Lane, and I. Alt, Twenty Percent of Women Who Report Premenstrual Dysphoric Change Might Have Subclinical Hypothyroidism, Proceedings of the 27th Annual Meeting of the American College of Neuropsychopharmacology , San Juan, Puerto Rico, p. 172, December 11-16, 1988. 60. K. L. Cohen and M. Swigar, Thyroid Function Screening in Psychiatric Patients, Journal of the American Medical Association, 242, p. 254, 1979. 61. E. T. Wong, S. G. Bradley, and A. L. Schultz, Elevation of Thyroidstimulating Hormone during Acute Nonthyroidal Illness, Archives of Internal Medicine, 141, pp. 873-875, 1981. 62. P. A. Bastenie, P. Neve, M. Bonnyns, L. Vanhaelst, and M. Chailly, Clinical and Pathological Significance of Asymptomatic Atrophic Thyroiditis, Lancet, i, pp. 915-919, 1967. 63. K. Maeda and K. Tanimoto, Epileptic Seizures Induced by Thyrotropin Releasing Hormone, Lancet, 1 , pp. 1058-1059, 1981. 64. G. D. Borowski, C. D. Garfuno, L. I. Rose, et al., Blood Pressure Response to TRH in Euthyroid Subjects, Journal of Clinical Endocrinology and Metabolism, 58, p. 197, 1984. 65. J. C. Garbutt, J. P. Mayo, G. A. Mason, and D. Quade, Impact of Improved TSH Assays on Definitions of Abnormal TSH Response to TRH, Biological Psychiatry, 2 5 , p. 208A, 1989. 66. T. L. Paul, J. Kerigan, A. M. Kelly, L. E. Braverman, and D. T. Baran, Longterm L-thyroxine Therapy is Associated with Decreased Hip Bone Density in Premenopausal Women, Journal of the American Medical Association, 259, pp. 3137-3141, 1988. 67. S. H. Ingbar, The Thyroid Gland, in Williams Textbook of Endocrinology, J. D. Wilson and D. W. Foster (eds.), W. B. Sanders Company, Philadelphia, 1985. 68. F. K. Goodwin, A. J. Prange, Jr., R. M. Post, et al., L-triiodothyronine Converts Tricyclic Antidepressant Non-responders to Responders, American Journal of Psychiatry, 139, p. 334, 1981. 69. G. Schwarez, A. Halaris, L. Baxter, et al., Normal Thyroid Function in Desipramine Nonresponders Converted to Responders by

208 I HAGGERTY E T A L .

70.

7 1. 72. 73. 74.

the Addition of L-triiodothyroxine, American Journal of Psychiatry, 141, p. 1614, 1984.39. J. C. Garbutt, B. Malekpour, M. R. Jonnalagadda, et al., Effects of Triiodothyronine on Drug Levels and Cardiac Function in Depressed Patients Treated with Imipramine, American Journal of Psychiatry, 136, pp. 980-982, 1979. P. Whybrow and A. J. Prange, Jr., A Hypothesis of Thyroid-catecholamine Interaction, Archives of General Psychiatry, 38, pp. 106-1 12, 1981. R. T. Joffee, P. P. Roy-Byme, T. W. Uhde, et al., Thyroid Function and Affective Illness: A Reappraisal, Biological Psychiatry, 19, pp. 1685-169 1, 1984. G. A. Mason, C. A. Walker, and A. J. Prange, Jr., Modulation of GamaAminobutyric Acid Uptake of Rat Brain Synaptosomes by Thyroid Hormones, Neuropsychopharmacology, 1, pp. 63-70, 1987. P. T. Loosen, G. A. Mason, and A. J. Prange, The TRH Test in Normal Subjects: Methodological Considerations, Psychoendocrinology, 2, pp. 147-153, 1982.

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