Correspondence

Elevated Serum Thyrotropin in Thyroxine-Treated Patients with Hypothyroidism Given Sertraline

N Engl J Med 1997; 337:1010-1011October 2, 1997

Article

To the Editor:

Patients with hypothyroidism and organic depression may need both levothyroxine and antidepressant drug therapy. In nine levothyroxine-treated patients with hypothyroidism (Patients 1 through 9) who were treated with sertraline (Zoloft, Pfizer), we found elevated serum thyrotropin concentrations, indicative of a decrease in the efficacy of levothyroxine (Table 1Table 1Effect of the Initiation of Sertraline Therapy on Serum Thyrotropin Concentrations and the Serum Free Thyroxine Index.). In addition, in two other levothyroxine-treated patients with thyroid cancer whose serum thyrotropin concentrations had been deliberately suppressed (Patients 10 and 11), the values rose into the normal range during sertraline therapy. The value for the serum free thyroxine index decreased in all patients in whom it was measured (Table 1). No patient had symptoms of hypothyroidism at this time. The patients ranged in age from 37 to 70 years (mean, 49), and all but one were women. The causes of hypothyroidism had included chronic autoimmune thyroiditis (in six patients), radioiodine therapy (three patients), and thyroidectomy (two patients). The duration of hypothyroidism ranged from 1 to 23 years (mean, 6).

Since this phenomenon had not been specifically sought, it was noticed only at the time of scheduled follow-up visits six weeks to six months after the start of sertraline therapy. All the patients had been taking the same dose of levothyroxine for at least six months, and all were thought to be taking it as recommended. The elevation in serum thyrotropin was confirmed one to three weeks later in six patients who were retested. The dose of levothyroxine was increased for all the patients. Two months after the increase, the serum thyrotropin concentration had returned to base line in seven patients, whereas in the remaining four a further dose increase was necessary.

The mechanism by which sertraline lowers serum thyroxine concentrations (and raises those of serum thyrotropin) is uncertain. We doubt that the absorption of levothyroxine is altered, because there was an appropriate increase in the serum thyroxine concentration,1 from 6.6 to 8.5 μg per deciliter (85 to 109 nmol per liter) in one patient three hours after an oral dose of 0.35 mg of levothyroxine. Serum concentrations of thyroxine-binding globulin, measured in six patients, did not change during sertraline therapy. Although some patients were taking medications that can alter the serum thyroxine concentration (ethinyl estradiol, conjugated estrogen, and phenytoin), these medications antedated the therapy with sertraline, and we doubt that they were responsible for the observed effects. One reported case in which sertraline caused a low serum total thyroxine concentration but normal concentrations of thyrotropin and free thyroxine in an adolescent patient2 indicates that sertraline may increase the clearance of thyroxine. We know of three other levothyroxine-treated patients whose serum thyrotropin concentrations remained stable after the initiation of sertraline therapy, but we have not yet determined the frequency with which patients treated with sertraline have altered requirements for thyroxine.

Karen C. McCowen, M.B., M.R.C.P.I.
Jeffrey R. Garber, M.D.
Harvard Pilgrim Health Care

Richard Spark, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215

2 References

1. 1

   Ain KB, Pucino F, Shiver TM, Banks SM. Thyroid hormone levels affected by time of blood sampling in thyroxine-treated patients. Thyroid 1993;3:81-85
   CrossRef | Web of Science | Medline

2. 2

   Harel Z, Biro FM, Tedford WL. Effect of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent. J Adolesc Health 1995;16:232-234
   CrossRef | Web of Science | Medline

Author/Editor Response

Spokespersons for Pfizer reply:

To the Editor: The letter from McCowen and colleagues describing small decreases in serum thyroxine concentrations and small increases in serum thyrotropin concentrations after the initiation of sertraline treatment in thyroxine-treated patients with hypothyroidism is consistent with previous reports of similar changes in patients treated with other antidepressant drugs. Post-treatment declines in serum thyroxine (sometimes with resultant increases in serum thyrotropin) have been described in euthyroid patients receiving other treatments for affective illness, including tricyclic antidepressant drugs, selective serotonin-reuptake inhibitors, lithium, and carbamazepine.1

We reviewed Pfizer's early-alert safety data base for sertraline through July 31, 1997, and identified 14 cases of hypothyroidism for which there was no other obvious cause and for which a possible relation to sertraline could not be excluded. Seven of the patients were taking thyroxine. In one case, the patient had a history of hypothyroidism during previous fluoxetine therapy; in another, hypothyroidism was diagnosed after the patient discontinued sertraline and initiated fluoxetine. Hypothyroidism is listed in the new product labeling for sertraline as an adverse event observed during post-marketing evaluation.2

In view of the literature indicating potential changes in thyroid function with many antidepressant drugs and the complex interrelation between the hypothalamic–pituitary–thyroid axis and affective illness, optimal management of patients with thyroid disease who are receiving any type of treatment for depression should include periodic reassessment of thyroid function.

Cathryn M. Clary, M.D.
Wilma M. Harrison, M.D.
Pfizer, New York, NY 10017

2 References

1. 1

   Shelton RC, Winn S, Ekhatore N, Loosen PT. The effects of antidepressants on the thyroid axis in depression. Biol Psychiatry 1993;33:120-126
   CrossRef | Web of Science | Medline

2. 2

   Sertraline. New York: Pfizer, 1997 (package insert).
   

Citing Articles (10)

Citing Articles

1. 1

   Gisah Amaral de Carvalho, Saint-Clair Bahls, Anke Boeving, Hans Graf. (2009) Effects of Selective Serotonin Reuptake Inhibitors on Thyroid Function in Depressed Patients with Primary Hypothyroidism or Normal Thyroid Function. Thyroid 19:7, 691-697
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   Annunziata Lapolla, M. G. Dalfrà, R. Spezia, R. Anichini, M. Bonomo, D. Bruttomesso, G. Di Cianni, I. Franzetti, A. Galluzzo, G. Mello, G. Menato, A. Napoli, G. Noacco, E. Parretti, C. Santini, E. Scaldaferri, L. Scaldaferri, M. Songini, L. Tonutti, E. Torlone, R. Gentilella, A. Rossi, D. Valle. (2008) Outcome of pregnancy in type 1 diabetic patients treated with insulin lispro or regular insulin: an Italian experience. Acta Diabetologica 45:1, 61-66
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3. 3

   2006. Thyroid hormones. , 3409-3416.
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   A. Lapolla, M. G. Dalfrà, D. Fedele. (2005) Insulin therapy in pregnancy complicated by diabetes: are insulin analogs a new tool?. Diabetes/Metabolism Research and Reviews 21:3, 241-252
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   David Simmons. (2002) The utility and efficacy of the new insulins in the management of diabetes and pregnancy. Current Diabetes Reports 2:4, 331-336
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   Nicole Ferko, Mitchell A. H. Levine. (2001) Evaluation of the Association Between St. John's Wort and Elevated Thyroid-Stimulating Hormone. Pharmacotherapy 21:12, 1574-1578
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7. 7

   Nalini Singh, Shawna L. Weisler, Jerome M. Hershman. (2001) The Acute Effect of Calcium Carbonate on the Intestinal Absorption of Levothyroxine. Thyroid 11:10, 967-971
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8. 8

   Glenda MacQueen, Leslie Born, Meir Steiner. (2001) The Selective Serotonin Reuptake Inhibitor Sertraline: Its Profile and Use in Psychiatric Disorders. CNS Drug Reviews 7:1, 1-24
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9. 9

   Alejandro R. Ayala, Mark D. Danese, Paul W. Ladenson. (2000) WHEN TO TREAT MILD HYPOTHYROIDISM. Endocrinology & Metabolism Clinics of North America 29:2, 399-415
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10. 10

    &NA;. (1997) Insulin lispro: use during pregnancy only 'if clearly needed'. Reactions Weekly &NA;:672, 2
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