31 - 29.31 Thyroid Hormones

29.31 Thyroid Hormones

McElroy SL, Guerdjikova A, Kotwal R, Weige JA, Nelson EB. Atomoxetine in the treatment of binge-eating disorder: A randomized placebo-controlled trial. J Clin Psychiatry. 2007;68(3):390. Minzenberg MJ, Carter CS. Modafinil: A review of neurochemical actions and effects on cognition. Neuropsychopharmacology. 2008;97(7):1477. Pivonello R, De Martino MC, Cappabianca P, De Leo M, Faggiano A, Lombardi G, Hofland LJ, Lamberts SWJ, Colao A. The medical treatment of Cushing’s disease: Effectiveness of chronic treatment with the dopamine agonist cabergoline in patients unsuccessfully treated by surgery. J Clin Endocrinology Metabolism. 2009;94(1):223. Pizzagalli DA, Evins AE, Schetter EC, Frank MJ, Pajtas PE, Santesso DL, Culhane M. Single dose of a dopamine agonist impairs reinforcement learning in humans: Behavioral evidence from a laboratory-based measure of reward responsiveness. Psychopharmacology. 2008;196(2):221. Quintana H, Cherlin EA, Duesenberg DA, Bangs ME, Ramsey JL. Transition from methylphenidate or amphetamine to atomoxetine in children and adolescents with attention-deficit/hyperactivity disorder: A preliminary tolerability and efficacy study. Clin Ther. 2007;29(6):1168. Rothenhausler HB, Ehrentraut S, von Degenfeld G, Weis M, Tichy M. Treatment of depression with methylphenidate in patients difficult to wean from mechanical ventilation in the intensive care unit. J Clin Psychiatry. 2007;61(10):750. Scott JC, Woods SP, Matt GE, Meyer RA, Heaton RK. Neurocognitive effects of methamphetamine: A critical review with meta-analysis. Neuropsychol Rev. 2007;17(3):275. Weisler RH. Review of long-acting stimulants in the treatment of attention deficit hyperactivity disorder. Exper Opin Pharmacother. 2007;8(6):745. Wernicke JF, Holdridge KC, Jin L, Edison T, Zhang S. Seizure risk in patients with attention-deficit-hyperactivity disorder treated with atomoxetine. Dev Med Child Neurol. 2007;49(7):498. 29.31 Thyroid Hormones Thyroid hormones—levothyroxine (Synthroid, Levothroid, Levoxine) and liothyronine (Cytomel)—are used in psychiatry either alone or as augmentation to treat persons with depression or rapid-cycling bipolar I disorder. They can convert an antidepressantnonresponsive person into an antidepressant-responsive person. Thyroid hormones are also used as replacement therapy for persons treated with lithium (Eskalith) who have developed a hypothyroid state. Successful use of thyroid hormone as an intervention for treatment-resistant patients was first reported in the early 1970s. Study results since then have been mixed; however, most show that patients taking triiodothyronine (T3) are twice as likely to respond to antidepressant treatment versus placebo. These studies have found that augmentation with T3 is effective with tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Nevertheless, many endocrinologists object to the use of thyroid hormones as antidepressant augmentation agents, citing such risks as osteoporosis and cardiac arrhythmias. PHARMACOLOGICAL ACTIONS Thyroid hormones are administered orally, and their absorption from the gastrointestinal tract is variable. Absorption is increased if the drug is administered on

an empty stomach. Thyroxine (T4) crosses the blood–brain barrier and diffuses into neurons, where it is converted into T3, which is the physiologically active form. The halflife of T4 is 6 to 7 days, and that of T3 is 1 to 2 days. The mechanism of action for thyroid hormone effects on antidepressant efficacy is unknown. Thyroid hormone binds to intracellular receptors that regulate the transcription of a wide range of genes, including several receptors for neurotransmitters. THERAPEUTIC INDICATIONS The major indication for thyroid hormones in psychiatry is as an adjuvant to antidepressants. There is no clear correlation between the laboratory measures of thyroid function and the response to thyroid hormone supplementation of antidepressants. If a patient has not responded to a 6-week course of antidepressants at appropriate dosages, adjuvant therapy with either lithium or a thyroid hormone is an alternative. Most clinicians use adjuvant lithium before trying a thyroid hormone. Several controlled trials have indicated that liothyronine use converts about 50 percent of antidepressant nonresponders to responders. The dosage of liothyronine is 25 or 50 μg a day added to the patient’s antidepressant regimen. Liothyronine has been used primarily as an adjuvant for tricyclic drugs; however, evidence suggests that liothyronine augments the effects of all of the antidepressant drugs. Thyroid hormones have not been shown to cause particular problems in pediatric or geriatric patients; however, the hormones should be used with caution in elderly persons, who may have occult heart disease. PRECAUTIONS AND ADVERSE REACTIONS At the dosages usually used for augmentation—25 to 50 μg a day—adverse effects occur infrequently. The most common adverse effects associated with thyroid hormones are transient headache, weight loss, palpitations, nervousness, diarrhea, abdominal cramps, sweating, tachycardia, increased blood pressure, tremors, and insomnia. Osteoporosis may also occur with long-term treatment, but this has not been found in studies involving liothyronine augmentation. Overdoses of thyroid hormones can lead to cardiac failure and death. Thyroid hormones should not be taken by persons with cardiac disease, angina, or hypertension. The hormones are contraindicated in thyrotoxicosis and uncorrected adrenal insufficiency and in persons with acute myocardial infarctions. Thyroid hormones can be administered safely to pregnant women, provided that laboratory thyroid indexes are monitored. Thyroid hormones are minimally excreted in breast milk and have not been shown to cause problems in nursing babies. DRUG INTERACTIONS

Thyroid hormones can potentiate the effects of warfarin (Coumadin) and other anticoagulants by increasing the catabolism of clotting factors. They may increase the insulin requirement for diabetic persons and the digitalis requirement for persons with cardiac disease. Thyroid hormones should not be coadministered with sympathomimetics, ketamine (Ketalar), or maprotiline (Ludiomil) because of the risk of cardiac decompensation. Administration of SSRIs, tricyclic and tetracyclic drugs, lithium, or carbamazepine (Tegretol) can mildly lower serum T4 and raise serum thyrotropin concentrations in euthyroid persons or persons taking thyroid replacements. This interaction warrants close serum monitoring and may require an increase in the dosage or initiation of thyroid hormone supplementation. LABORATORY INTERFERENCES Levothyroxine has not been reported to interfere with any laboratory test other than thyroid function indexes. Liothyronine, however, suppresses the release of endogenous T4, thereby lowering the result of any thyroid function test that depends on the measure of T4. THYROID FUNCTION TESTS Several thyroid function tests are available, including tests for T4 by competitive protein binding (T4 [D]) and by radioimmunoassay (T4 RIA) involving a specific antigen– antibody reaction. More than 90 percent of T4 is bound to serum protein and is responsible for thyroid-stimulating hormone (TSH) secretion and cellular metabolism. Other thyroid measures include the free T4 index (FT4I), T3 uptake, and total serum T3 measured by radioimmunoassay (T3 RIA). Those tests are used to rule out hypothyroidism, which can be associated with symptoms of depression. In some studies, up to 10% of patients complaining of depression and associated fatigue had incipient hypothyroid disease. Lithium can cause hypothyroidism and, more rarely, hyperthyroidism. Neonatal hypothyroidism results in intellectual disability and is preventable if the diagnosis is made at birth. Thyrotropin-releasing Hormone Stimulation Test The thyrotropin-releasing hormone (TRH) stimulation test is indicated for patients who have marginally abnormal thyroid test results with suspected subclinical hypothyroidism, which may account for clinical depression. It is also used in patients with possible lithium-induced hypothyroidism. The procedure entails an intravenous injection of 500 mg of protirelin (TRH), which produces a sharp increase in serum TSH levels are measured at 15, 30, 60, and 90 minutes. An increase in serum TSH of 5 to 25 mIU/mL above the baseline is normal. An increase of less than 7 mIU/mL is considered a blunted response, which may correlate with a diagnosis of depression. Eight percent of

all patients with depression have some thyroid illness. DOSAGE AND CLINICAL GUIDELINES Liothyronine is available in 5, 25, and 50 μg tablets. Levothyroxine is available in 12.5, 25, 50, 75, 88, 100, 112, 125, 150, 175, 200, and 300 μg tablets; it is also available in a 200 and 500 μg parenteral form. The dosage of liothyronine is 25 or 50 μg a day added to the person’s antidepressant regimen. Liothyronine has been used as an adjuvant for all of the available antidepressant drugs. An adequate trial of liothyronine supplementation should last 2 to 3 weeks. If liothyronine supplementation is successful, it should be continued for 2 months and then tapered off at a rate of 12.5 μg a day every 3 to 7 days. REFERENCES Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J. Does thyroid supplementation accelerate tricyclic antidepressant response? A review in meta-analysis of the literature. Am J Psychiatry. 2001;158:1617. Appelhof BC, Brouwer JP, van Dyck R, Fliers E, Hoogendijk WJ. Triiodothyronine addition to paroxetine in the treatment of major depressive disorder. J Clin Endocrinol Metab. 2004;89:6271. Aronson R, Offman HJ, Joffe RT, Naylor CD. Triiodothyronine augmentation and the treatment of refractory depression: A meta-analysis. Arch Gen Psychiatry. 1996;35:842. Bauer M, Baur H, Bergebifer A, Strohle A, Hellweg R. Effects of supraphysiological thyroxine administration in healthy controls in patients with depressive disorders. J Affect Dis. 2002;68:285. Baungartner A. Thyroxine and the treatment of affective disorders: An overview of the results of basic and clinical research. Int J Neuropsychopharmacol. 2000;3:149. Cooper-Kazaz A, Apter JT, Cohen R, Karapichev L, Mohammed-Moussa S. Combined treatment with sertraline and liothyronine in major depression: A randomized, double-blind, placebo-controlled trial. Arch Gen Psychiatry. 2007:64;679. Joffe RT. Thyroid hormones. In: Sadock BJ, Sadock VA, Ruiz P, eds. Kaplan & Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2009:3248. Joffe RT, Sokolov ST, Levitt AJ. Lithium and triiodothyronine augmentation of antidepressants. Can J Psychiatry. 2006;51:791. Johansson P, Almqvist EG, Johansson J-O, Mattsson N, Hansson O, Wallin A, Blennow K, Zetterberg H, Svensson J. Reduced cerebrospinal fluid level of thyroxine in patients with Alzheimer’s disease. Psychoneuroendocrinology. 2013;38(7):1058–1066. Koibuchi N. The role of thyroid hormone on functional organization in the cerebellum. Cerebellum. 2013;12(3):304–306. Lojko D, Rybakowski JK. L-Thyroxine augmentation of serotonergic antidepressants in female patients with refractory depression. J Affect Disord. 2007;103(1–3):252. Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR, Thase ME. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: A STAR*D report. Am J Psychiatry. 2006;163:1519. Posternak M, Novak S, Stern A, Hennessey J, Joffe A. A pilot effectiveness study: Placebo-controlled trial of adjunctive Ltriiodothyronine (T3) used to accelerate and potentiate the antidepressant response. Int J Neuropsychopharmacol. 2008;11(1):15. Sylven SM, Elenis E, Michelakos T, Larsson A, Olovsson M, Poromaa IS, Skalkidou A. Thyroid function tests at delivery and