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Diagnosis of thyroid disorders is based onbiochemical and clinical data (Box 1, page 100),1

which might not be congruent. Clinical symp-toms of hypothyroidism, for example, are notori-ously variable. Severe biochemical hypothy-roidism may be associated with mild clinicalsymptoms, whereas mild biochemical hypothy-roidism may be associated with severe symptoms.2

Patients with thyroid disturbance and psychi-atric symptoms most often are diagnosed with adepressive-spectrum syndrome. Most common are:

• atypical depression (which may present asdysthymia)

• bipolar spectrum syndrome (includingmanic-depression, mixed mania, bipolardepression, rapid-cycling bipolar disorder,cyclothymia, and premenstrual syndromes)

• borderline personality disorder• or psychotic disorder (typically paranoid

psychosis).Psychiatric symptoms of hypothyroidism

(Table 1, page 105) are often prominent or evenprimary. Patients commonly show:

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p S Y C H I A T R YCurrent

Thomas D. Geracioti, Jr, MDResearch service

Cincinnati Veterans Affairs Medical CenterDepartment of psychiatry

University of Cincinnati College of Medicine

Is the thyroid causing your patient’s symptoms?

Identifying hypothyroidism’s psychiatric presentations

ypothyroidism—even when occult orsubclinical—can cause subtle or frank

changes in energy, mood, anxiety level, or cogni-tion. Some patients’ affective symptoms remit withthyroid hormone replacement or with antidepres-sants only after a euthyroid state is established.

To help you recognize hypothyroidism inpatients presenting with psychiatric illnesses andprovide effective treatment, this article describes:

• hypothyroidism’s signs and symptoms • primary and subclinical hypothyroidism,

thyroiditis, central hypothyroidism, and thy-roid hormone resistance

• laboratory screening for thyroid dysfunc-tion in patients with psychiatric symptoms.

OVERLAPPING CLINICAL SIGNSThyroid hormone is required for the metabolicactivity of every cell in the body. When patientsexperience symptoms related to abnormal func-tioning of the hypothalamic-pituitary-thyroidaxis (Figure), psychiatrists often are the first pro-fessionals they consult.

H

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Copyright® Dowden Health Media

For personal use only

For mass reproduction, content licensing and permissions contact Dowden Health Media.

99

The degree of impairment may depend on thepatient’s normal functional level. For example, awell-educated patient of mine with thyroiditis-related hypothyroidism reported word-finding

• impaired attention, concentration, learn-ing, and memory

• psychomotor slowing• and/or mental dullness.

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Thyroid hormone regulation: The hypothalamic-pituitary-thyroid axisFigure

Thyroid-stimulating hormone (TSH, thyrotropin) released into circulation by the pituitary stimulates thethyroid to synthesize and release thyroid hormone, including triiodothyronine (T3) and thyroxine (T4).TSH is regulated by hypothalamic elaboration of thyrotropin-releasing hormone (TRH), which stimulatesTSH release in a dose-dependent manner. Negative feedback from T3 and T4 downregulates TRH geneexpression and restrains the pituitary from responding to TSH. Most T3—the active hormone—isformed in circulation or in target tissues by deiodination of T4 by selenium-containing enzymes.

Illustration for CURRENT PSYCHIATRY by Rich Larocco

T3To all cells in body

Thyroid gland

T3T4

T4

TRH

TSH

© RICH LAROCCO

Pituitary

gland

Hypothalamus

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difficulties. Instead of asking her husband to takea bottle of wine from the rack, she asked him totake a bottle of wine from the “thing.”

Loss of vitality, fatigue, lethargy, hypersomnia(especially if sleep apnea is present), anddepressed mood also are com-monly seen.Depressive symptoms. Hypothyroid patients usuallymeet several criteria for amajor depressive episode—such as concentration difficul-ties, lassitude, low libido, andsometimes pessimism or sad-ness—and symptoms improveafter sustained thyroid hormone replacementtherapy.3 Women with mild hypothyroidism whoscreen negative for a psychiatric syndrome showstatistically significant mood improvement and

improved verbal fluency after 6 months oflevothyroxine replacement therapy.4

In some patients with no clear evidence of abiochemical or clinical thyroid disorder, moodsymptoms nevertheless respond to thyroid hor-mone augmentation of antidepressants.5

Anxiety symptoms. Occasionally thyroid dysfunc-tion is seen in patients with anxiety disorders,including panic disorder, agoraphobia, socialphobia, performance anxiety, post-traumaticstress disorder, and generalized anxiety disorder.6

It may seem counterintuitive, but hypothy-roidism is probably as common as hyperthyroid-ism in extremely anxious patients. Both hypo-and hyperthyroidism are seen much more oftenin patients with panic-level anxiety than in thegeneral population.

In a sample of 144 consecutive female psy-chiatric patients with a lifetime history of panicdisorder and/or agoraphobia:

• 27% had a history of thyroid disorder• 17% had hypothyroidism• 8% had hyperthyroidism.7

Hypothyroid symptoms. Associated symptoms ofhypothyroidism (Table 2, page 105) may includecold intolerance, lack of or reduced perspiration,dry skin, constipation, lethargy, psychomotor

slowness, and subjectiveparesthesias and muscle pains.

Edema is often present. The facetypically is swollen or “puffy” in the

morning, but by evening the lower legs(and not the face) are edematous.

Deep tendon reflexes usually relaxslowly after initial stimulation. Vascularresistance is increased, but hypertension isnot usual. Noradrenergic systems become

more active in a compensatory, counter-regulatory manner; however, brady-

cardia—when present—is sometimes profound.Weight gain can occur but often is conspicuouslyabsent.

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Hypothyroidism

Thyroid dysfunction: Psychiatricpatients show increased risk

Box 1

Psychiatric patients—particularly thosewith mood disorders—are more likely toexhibit biochemical evidence of frank or subclinical hypothyroidism, hyperthyroidism,and autoimmune thyroiditis than the generalpopulation. In a study of 17,533 Americans,1

approximately 12% had thyroid abnormalitiesand 80% of these were hypothyroid. An additional 17% of women and 9% of men tested positive for antithyroid antibodies.

Biochemical hypothyroidism was definedas TSH >4.5 mIU/L, with low total T4, and subclinical hypothyroidism as TSH >4.5 mIU/Lwith normal T4 levels. Population studies andother data have led some endocrinologists to regard serum TSH levels >2.5 mIU/L asabnormally high.

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Hypothyroidismmay be as commonas hyperthyroidismin extremelyanxious patients

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CAUSES OF THYROID DISORDERSPrimary hypothyroidism results from thyroid glandfailure. The many causes include iodine deficien-cy, but most cases of adult-onset or acquiredhypothyroidism are attributed to autoimmunethyroiditis (see page 110). In primary hypothy-

Severe hypothyroidism pre-sents with paradoxicaltremendous agitation, par-anoia, and aggressiveness.The skin is leathery, andfacies are characteristicallyrough. Myxedema is fairlycommon, even in high-functioning patients. Ihave seen only one case of so-called “myxedema mad-ness;” the female patient’shyperarousal, yelling, curs-ing, grossly poor cognitiveability, and loosely con-ceived paranoid delusionsare unforgettable.

Galactorrhea (related tohyperprolactinemia) can bea symptom of severehypothyroidism, presumablyfrom increased hypothala-mic thyrotropin-releasinghormone (TRH) drive.TRH is the main known secretagogue for pituitaryprolactin secretion. Infertility,oligomenorrhea, or amenor-rhea could be part of thehypothyroid clinical picture.Other symptoms. Macro-glossia and hypertrophy ofthe uvula are possible; in arecent report, dysarthriaresulting from these oralchanges was the only pre-senting symptom of a hypothyroid man.8 Dysar-thria promptly corrected after levothyroxinereplacement.

Hypothyroidism is a primary cause of centralsleep apnea caused by dysfunction of ventilatorycontrol and/or reduction in airway aperture.

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Hypothyroidism’s psychiatric signs and symptoms Table 1

Cognitive changes Impaired memory, psychomotor slowing,reduced attention span

Vegetative symptoms Hypersomnia, sleep apnea, fatigue,lethargy, apathy, anergia, low libido

Mood changes Depression, mood instability, mania, anxiety

Other Psychosis

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Hypothyroidism’s other signs and symptomsTable 2

Metabolic Low basal body temperature/cool skin, diminishedperspiration, weight gain or difficulty losing weight

Cardiovascular Bradycardia, dizziness

Dermatologic Dry, rough, or scaly skin; brittle nails; coarseor thinning hair (especially in women); pallor; dependent edema; myxedema/skin mucinosis (classically pretibial)

Digestive Nausea, constipation, enlarged tongue

Reproductive Oligomenorrhea, amenorrhea, infertility, miscarriage, delayed ejaculation

Musculoskeletal Muscle cramps, joint pain, paresthesias, numbness,and peripheral weakness, reduced exercise tolerance, delayednervous system ankle reflex

Sensory Upper eyelid drooping, dysarthria, hoarseness,diminished hearing, diminished taste (hypogustia)

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roidism, low serum T4 and/or T3 are seen in com-bination with elevated serum TSH. Circulatingfree T4 diminishes sooner than free T3 does as thebody attempts to preserve active hormone levels.In turn, total T4 and T3 diminishsooner than free hormone concen-trations. A compensatory increasein pituitary-elaborated TSH is seenas the brain and pituitary attempt tostimulate the thyroid to produceadequate thyroid hormone.In subclinical hypothyroidism, circu-lating free thyroid hormone con-centrations are within the normal laboratoryrange (typically in the lower range), but TSH iselevated. TSH concentrations >3.0 mIU/mLcall for repeat or follow-up biochemistry andclinical correlation.

The decision to treat subclinical hypothy-roidism with thyroid hormone replacement is lesscontroversial in psychiatry than in endocrinology.Psychiatric patients with subclinical hypothy-roidism—especially those with incompleteresponses to psychotropic therapy—should usual-ly be treated with thyroid hormone (Box 2).1

Free T3 levels in the lower 20% of the labora-tory’s normal range are cause for pause in apatient with a mood or psychotic disorder andany of hypothyroidism’s clinical stigmata, even ifthyroxine and TSH concentrations are normal. Thyroiditis is characterized by thyroid glandinflammation. The thyroid may be painful ornonpainful, enlarged, fleshy, goitrous, normal insize, or atrophic and fibrotic (especially late in thecourse).

Postulated precipitants include viruses andother infectious agents, vaccines, iodine excess,lithium therapy (Box 3),9 tobacco smoke, environ-mental chemicals or toxins, irradiation, and—arguably—cortically-mediated (psychological)stress in vulnerable individuals.

Clinically, thyroiditis syndromes often have along prodromal phase, wax and wane in severity,have an insidious and sometimes silent course,and can be serially associated with hyperthy-

roidism (especially earlyin the course), euthy-

roidism, or hypothyroidism(especially late in the course). Most

thyroiditis syndromes appear toresolve spontaneously, but many

become chronic or show evidence ofsubtle thyroid dysfunction years afterthe first occurrence or diagnosis.

Most presentations are nonspecific;symptoms may be limited to lethar-

gy, fatigue, and depression.Increased antithyroid antibody titers have beenlinked with psychotic and depressive syndromes inborderline personality disorder.10

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Hypothyroidism

When to try thyroid hormone therapyfor psychiatric symptoms

Box 2

Target psychiatric symptoms for prescribingreplacement thyroid hormone are depression;mood cycling or instability; low energy, fatigue,or lethargy; cognitive impairment (Table 1,page 105); and psychosis, if present. Becausethese symptoms are not specific to thyroid dysfunction, institute thyroid hormone onlywhen biochemical evidence of compromised or suboptimal thyroid function is also present.

Exceptions to this rule may includepatients with target psychiatric symptoms and:

• other hypothyroidism symptoms (Table 2, page 105 )

• circulating T3, free T3, or free T4 levelsnear the low margin of the normal rangeand/or TSH >3.5 to 4.0 mIU/mL.1

• a history of inadequate response topsychopharmacologic interventions

• symptoms of and a strong family historyof thyroid disease.

TSH concentrations>3.0 mIU/mL call forrepeat or follow-upbiochemistry andclinical correlation

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70% of affected children met diagnostic criteriafor attention-deficit/hyperactivity disorder.12

LABORATORY SCREENING TSH and thyroid hormones. The basic thyroidscreen is a combination of serum levels of TSH(“sensitive TSH”) and free thyroid hormones.

TSH has a circadian rhythm, with a noctur-nal surge amounting to a 50% to 200% increaseover daytime levels, beginning at around 6 to 8PM. Peak TSH pulsatile activity and levels areseen after sleep begins—usually after midnight—with trough levels and fewest TSH pulses in latemorning and early afternoon.13,14 This rhythmimplies that the most accurate TSH measure-ment may be obtained by drawing blood in the

In early thyroiditis, thyroxine and triiodothy-ronine secretion is often elevated, with low orsuppressed TSH. However, antithyroid antibodyproduction is associated with a significantlyincreased risk of eventual subclinical or frankhypothyroidism. Permanent hypothyroidism de-velops eventually in at least one-half of womenwith histories of postpartum thyroiditis.11

Central hypothyroidism stems from TSH deficien-cy. Both pituitary thyrotrophic failure and hypo-thalamic failure—secondary and tertiary hypo-thyroidism, respectively—are considered central(or “secondary”). Hypothyroidism of pituitaryand hypothalamic origins are lumped together as“central” because it is often very difficult to dif-ferentiate these pathologies. Thyroid hormone resistance, in which end-organ orcellular resistance to thyroid hormone signals isseen, is an increasingly recognized syndrome inclinical medicine. The typical case is an euthy-roid or hypothyroid individual with elevated T4and T3 and nonsuppressed or even frankly ele-vated TSH. Inappropriately elevated TSH com-bined with high thyroid hormone levels also canbe seen in TSH-secreting pituitary tumors, al-though the clinical picture in this case is one ofhyperthyroidism.

Thyroid hormone resistance ranges fromeuthyroid and clinically transparent to profound-ly hypothyroid, and different organs in the samepatient may show different sensitivities to thyroidhormone. Clinical features vary, depending onthe strength of thyroid hormone resistance.

Early emergence of resistance (as would beexpected in someone with an inherited thyroidhormone receptor abnormality) leads to develop-mental problems, including:

• short stature• mental or learning disabilities (including

attention deficits).In a study of 18 families with strong history

of generalized resistance to thyroid hormone,

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Long-term lithium therapylinked with hypothyroidism risk

Box 3

Patients taking lithium for mood stabilizationwill likely need supplemental thyroid hormoneeventually because lithium is thyrotoxic. Also,patients with bipolar mood symptoms oftenhave coexisting thyroid abnormalities, andgiving supraphysiologic thyroid hormonedosages sometimes converts those who do notrespond to mood stabilizers into responders.

Thyrotropin concentrations increasewithin 1 day after patients start taking lithiumcarbonate, but without commensurateincreases in T3 or T4. More often, T3 and T4concentrations decrease in the presence oflithium. Among 150 patients maintained onlithium for 10 years, hypothyroidism, autoimmune thyroiditis, or goiter developedat rates of 1.7%, 1.4%, and 2.1% per year,respectively. The study authors suggestedthat long-term lithium may increase the riskfor hypothyroidism in women and in patientswith thyroid autoimmunity.9

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morning before 9 AM. I have seen subclinicalhypothyroidism missed when clinicians relied onafternoon TSH levels.

In general medicine, TSH alone frequently isused as a routine screening tool. In psychiatricpractice, however, I recommend supplementingTSH with free T3 and free T4 because thyroidsystem dysfunction is frequent in psychiatric syn-dromes. If laboratory costs are a concern, free T4with TSH usually suffices for initial screening.

Although the unbound, free fractions of T3and T4 are of primary interest, total T4 and totalT3 are necessary to assess the thyroid gland’s syn-thetic capacity. When clinical evidence suggestsabnormal thyroid hormone function, orderrepeated or serial biochemical testing. Marginalbiochemical results also mandate repeat thyroidfunction studies, expanded to include:

• total thyroid hormone concentrations (ide-ally T4 and T3)

• antithyroid antibodies• serum cholesterol• prolactin.

Antithyroid antibodies. Obtain antithyroglobulinand antithyroid microsomal antibody titers if:

• thyroid hormone indices are abnormal ormarginal—in either direction

• or the patient now has, has had, or has afamily history of autoimmune-mediated

symptoms, such as lupus erythematosus orrheumatoid arthritis.

Negative or low antithyroid autoantibodytiters do not rule out thyroiditis as a cause ofhypothyroidism, as these titers are most likely to begenerated during periods of active inflammation.

Many autoantibodies react with thyroid-related elements. Most clinical laboratories canquantify antibodies directed against thyroid per-oxidase—also called antimicrosomal antibod-ies—and thyroglobulin. The presence of theseantibodies is associated with thyroid inflamma-tion and a risk of progression to thyroid failureand hypothyroidism.Other laboratory findings of hypothyroidisminclude hypercholesterolemia, mild hyperprolac-tinemia, and types of anemia (including iron-deficiency anemia with low ferritin levels).

References

1. Hollowell JG, Staehling NW, Flanders WD, et al. Serum TSH,T(4), and thyroid antibodies in the United States population (1988to 1994): National Health and Nutrition Examination Survey(NHANES III). J Clin Endocrinol Metab 2002;87:489-99.

2. Zulewski H, Muller B, Exer P, et al. Estimation of tissue hypothy-roidism by a new clinical score: evaluation of patients with variousgrades of hypothyroidism and controls. J Clin Endocrinol Metab1997;82:771-6.

3. Gunnarsson T, Sjoberg S, Eriksson M, Nordin C. Depressive symp-toms in hyothyroid disorder with some observations on biochemicalcorrelates. Neuropsychobiology 2001;43:70-4.

4. Bono G, Fancellu R, Blandini F, Santor G, Mauri M. Cognitiveand affective status in mild hypothyroidism and interactions withL-thyroxine treatment. Acta Neurol Scand 2004;110:59-66

5. Iosifescu DV. ‘Supercharge’ antidepressants by adding thyroidhormones: Why hormones help, and new data on SSRI augmentation. Current Psychiatry 2006;5(7):15-25.

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Hypothyroidism

Related resources

� American Thyroid Association. www.thyroid.org.

� Dunn JT. Guarding our nation’s thyroid health. J Clin EndocrinolMetab 2001;872:486-8.

� Pearce EN, Farwell AP, Braverman LE. Thyroiditis. N Engl J Med2003;348:2646-55.

� Sullivan GM, Mann JJ, Oquendo MA, et al. Low cerebrospinalfluid transthyretin levels in depression: correlations with suicidalideation and low serotonin function. Biol Psychiatry 2006;60(5):500-6.

Lin

e

Bottom

Antidepressants and mood stabilizershave limited efficacy in patients withabnormal thyroid function. Recognizingand correcting hypothyroidism, includingsubclinical presentations, can alleviatesymptoms similar to those of affectivedisorders, including atypical depression,bipolar syndromes, anxiety disorders,and others.

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6. Tancer ME, Stein MB, Gelernter CS, Uhde TW. The hypothalamic-pituitary-thyroid axis in social phobia. Am J Psychiatry 1990;147(7): 929-33

7. Orenstein H, Peskind A, Raskind MA. Thyroid disorders infemale psychiatric patients with panic disorder or agoraphobia.Am J Psychiatry 1988;145:1428-30.

8. Stollberger C, Finsterer J, Brand E, Tschabitscher D.Dysarthria as the leading symptom of hypothyroidism. Am J Otolaryngol 2001;22:70-2.

9. Bocchetta A, Mossa P, Velluzzi F, et al. Ten-year follow-up ofthyroid function in lithium patients. J Clin Psychopharmacol2001;21(6):594-8.

10. Geracioti TD, Kling MA, Post R, Gold PW. Antithyroid antibody-linked symptoms in borderline personality disorder.Endocrine 2003;21:153-8.

11. Premawardhana LD, Parkes AB, Ammari F, et al. Postpartumthyroiditis and long-term thyroid status: prognostic influenceof thyroid peroxidase antibodies and ultrasound echogenicity. J Clin Endocrinol Metab 2000;85:71-5.

12. Hauser P, Zametkin AJ, Martinez P, et al. Attention deficit-hyperactivity disorder in people with generalized resistance tothyroid hormone. N Engl J Med 1993;328:997-1001.

13. Ghizzoni L, Mastorakos G, Ziveri M, et al. Interactions of lep-tin and thyrotropin 24-hour secretory profiles in short normalchildren. J Clin Endocrinol Metab 2001;86(5):2065-72.

14. Mantzoros CS, Ozata M, Negrao AB, et al. Synchronicity of frequently sampled thyrotropin (TSH) and leptin concentra-tions in healthy adults and leptin-deficient subjects: evidencefor possible partial TSH regulation by leptin in humans. J Clin Endocrinol Metab 2001;86(7):3284-91.

15. Chopra IJ, Sabatino L. Nature and sources of circulating thy-roid hormones. In: Braverman LE, Utiger RD, eds. The thy-roid. A fundamental and clinical text. Philadelphia: Lippincott;2000:120-35.

cont inued f rom page 112

� ‘Supercharge’ antidepressantsby adding thyroid hormonesJULY 2006

Want to know more?See this related article

www.currentpsychiatry.com

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PROMISING NEW INVESTIGATOR AWARDS 2006-2007

The Neuroleptic Malignant SyndromeInformation Service (NMSIS) announces a competition to recognize promising newinvestigators, based on a scholarly paperaddressing “New insights on psychotropicdrug safety and side effects.”

Consistent with its mission to advance pharmacotherapy and patient safety, NMSISoffers these awards to promote educationand research by early career psychiatrists.Two prizes of $2,500 and $1,500 will beawarded toward travel costs to attend theAmerican Psychiatric Association annualmeeting in May 2007.

• Papers should address specific issues related to the award theme and be nolonger than 15 double-spaced, typed pages.

• Literature reviews, case reports, or originalstudies that are not in press or published areacceptable.

• Primary author must be a student, resident,fellow, or junior faculty member at or belowthe rank of assistant professor.

• Papers will be judged on originality, scholarship, relevance, and methodology.

Submit paper and the primary author’s curriculum vitae to Diane Van Slyke,11 East State St., Sherburne, NY 13460, fax 607-674-7910, or via e-mail todiane@mhaus.org. Deadline is Feb. 1, 2007.

Winners will be announced by March 1, 2007.

To learn more about NMSIS, visit www.nmsis.org.

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