Levothyroxine Ineffective for Depressive Symptoms in Elderly Patients With Subclinical Underactive Thyroid

A recent rigorously conducted study found no benefits from therapy with the thyroid-hormone drug levothyroxine (EUTHYROX, LEVO-T, LEVOXYL, SYNTHROID, THYQUIDITY, THYRO-TABS, TIROSINT, TIROSINT-SOL, UNITHROID) in older adults with subclinical hypothyroidism (a mild form of underactive thyroid) who had depressive symptoms. This finding is crucial because depressive symptoms are a frequent reason for using levothyroxine therapy in this patient population.[1]

Importantly, levothyroxine is the most commonly prescribed drug in the U.S., with recent evidence indicating that as many as 61% of insured American adults newly diagnosed with subclinical hypothyroidism are initiated on the drug.[2]

The new study was published on Feb. 1, 2021, in the Journal of the American Medical Association (JAMA) Network Open.

About hypothyroidism

The thyroid gland makes hormones — most importantly, thyroxine — that are necessary for growth and development in children and for regulating energy levels and metabolism in people of all ages.[3] Free T4 is the active form of thyroxine used by the body. T4 production is induced by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland, a pea-sized structure in the brain.

Underactive thyroid (hypothyroidism), a common disorder that occurs when the thyroid gland does not make enough thyroid hormone to meet the body’s needs, is classified into two types. The first, overt hypothyroidism, is characterized by low blood levels of free T4 and high levels of TSH (the normal blood TSH level range is approximately 0.4 to 4.0 milli-international units/liter [mIU/L]). It usually is associated with nonspecific symptoms that decrease quality of life, such as cold sensitivity, dry skin, constipation, fatigue, muscle cramps, voice changes and weight gain. Other symptoms may include anxiety and depression, forgetfulness, slowed thinking and weak muscles.

The second type, subclinical hypothyroidism, is a mild form of underactive thyroid in which the levels of free T4 are within the normal range but TSH levels are elevated. Patients with subclinical hypothyroidism may not experience any of the symptoms associated with overt hypothyroidism. Therefore, the condition usually is diagnosed solely based on the results of thyroid function tests. Progression of subclinical hypothyroidism to overt hypothyroidism, if it occurs, is usually slow and variable.[4]

Clinical practice guidelines for overt hypothyroidism consistently recommend thyroid-hormone therapy — mainly with levothyroxine, which is taken orally once a day — to restore thyroid-hormone levels to normal.[5] This can help prevent complications such as heart disease and infertility, as well as poor brain development in children.

As discussed in the November 2019 issue of Worst Pills, Best Pills News, recent guidelines for subclinical hypothyroidism recommend against using thyroid-hormone therapy in most adults over age 30 with or without mild-to-moderate symptoms of subclinical hypothyroidism (one exception is adult patients with very high TSH levels [above 20 mIU/L]).[6] This is because recent evidence shows no clinical benefits for levothyroxine therapy in such patients in terms of improving quality of life or thyroid-related symptoms.[7] Furthermore, there is no strong evidence that treatment with levothyroxine is beneficial for reducing the risk of death or cardiovascular complications in subclinical hypothyroidism patients.[8]

The new study[9]

The JAMA Network Open study was part of a randomized, placebo-controlled clinical trial called TRUST that involved adults aged 65 or older with subclinical hypothyroidism who were not previously treated with levothyroxine. These subjects were recruited in the Netherlands and Switzerland from 2013 to 2016.

TRUST is the biggest trial so far to evaluate the effect of levothyroxine on depressive symptoms in subclinical hypothyroidism patients. It included 427 subjects with subclinical hypothyroidism who were identified from laboratory databases (mean age was 75 years). The study researchers defined subclinical hypothyroidism as having a persistently elevated TSH level (from 4.6 to 19.9 mIU/L) on two or more occasions that were at least three months apart but with normal free T4 levels.

Of these subjects, 211 were randomized to begin levothyroxine therapy for six to eight weeks at a dosage of 50 micrograms (mcg) daily (or 25 mcg for subjects with a body weight of less than 50 kilograms or coronary heart disease, such as previous heart attack or angina [chest pain or pressure that often spreads and is caused by inadequate blood flow to the heart through the coronary arteries]). Levothyroxine dosages were further adjusted in 25-mcg increments in these subjects based on TSH levels measured six to eight weeks after starting the drug and after each dose adjustment thereafter, as well as after 12 months of follow-up with the goal of reaching a TSH level that was within the normal range.

The remaining 216 subjects received a placebo and had mock dosage adjustments to resemble the frequency of dosage modifications of subjects in the levothyroxine group.

The study researchers compared depressive symptoms among subjects in the two groups at baseline and at follow-up using a validated depression self-rating scale.

They found that depressive symptoms among subjects in the levothyroxine group did not differ from those in the placebo group after 12 months of follow-up. There also were no statistically significant differences between subjects in the two groups in terms of newly developed mild depression.

These results remained consistent in several subgroup analyses based on age, sex or TSH levels. Additionally, subjects with higher depression scores at baseline did not improve with levothyroxine therapy compared with those who received the placebo.

The study researchers regarded the quality of the evidence from their trial as “high.” However, they acknowledged that their findings may not be generalizable to older adults with subclinical hypothyroidism who have severe depressive symptoms, a group that was not represented in their study.

What You Can Do

If your doctor has determined that you have subclinical hypothyroidism, discuss this article with him or her, particularly if you are an older adult considering thyroid hormone therapy.

Per the BMJ guidelines discussed in our November 2019 article, we generally do not recommend thyroid hormones for subclinical hypothyroidism in adults unless their TSH levels are persistently higher than 20 mIU/L, they are younger than 30, they have severe hypothyroidism symptoms, or they are trying to become pregnant or at risk of unplanned pregnancy.[10] Overall, all of these patients need to see a doctor on a regular basis to monitor the progression or resolution of their subclinical hypothyroidism.

If you and your doctor determine that you need thyroid-hormone therapy for any type of hypothyroidism, overt or subclinical, opt for levothyroxine — the standard drug for underactive thyroid.[11] Try to keep using the same levothyroxine formulation. Take the drug on an empty stomach — at least 30 minutes before breakfast — and do not take it within four hours of taking any antacids or supplements that contain calcium or iron.[12] Never stop taking the drug, skip a dose or take a higher dose without medical supervision. Taking too much levothyroxine can cause serious problems, such as atrial fibrillation (a common heart-rhythm disorder) or osteoporosis (bone thinning).[13]

Your doctor will order a blood test approximately six to eight weeks after you begin taking levothyroxine and adjust your dose if needed.[14] Each time you change your dose, you will have another blood test. Once you have reached a dose that works for you, your doctor will likely repeat the blood test in six months and then once a year.
 

References

[1] Wildisen L, Del Giovane C, Moutzouri E, et al. An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms. Sci Rep. 2020;10(1):19111.

[2] Brito JP, Ross JS, Kawkgi OM El, et al. Levothyroxine use in the United States, 2008-2018. JAMA Intern Med. 2021;181(10):1402-1405.

[3] National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease. Hypothyroidism. March 2013. http://www.niddk.nih.gov/-/media/Files/Endocrine-Diseases/Hypothyroidism_508.pdf. Accessed July 8, 2021.

[4] Subclinical hypothyroidism. No proof of benefit from treatment with thyroid hormone. Prescrire Int. 2020;29(216):160.

[5] Chiovato L, Magri F, Carlé A. Hypothyroidism in context: Where we’ve been and where we’re going. Adv Ther. 2019;36(Suppl 2):47-58.

[6] New guideline recommends against thyroid hormone treatment for most adults with mildly underactive thyroid. Worst Pills, Best Pills News. November 2019. https://www.worstpills.org/newsletters/view/1298. Accessed July 8, 2021.

[7] Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365(May 14):l2006.

[8] Subclinical hypothyroidism. No proof of benefit from treatment with thyroid hormone. Prescrire Int. 2020;29(216):160.

[9] Wildisen L, Feller M, Del Giovane C, et al. Effect of levothyroxine therapy on the development of depressive symptoms in older adults with subclinical hypothyroidism: An ancillary study of a randomized clinical trial. JAMA Netw Open. 2021;4(2):e2036645.

[10] Bekkering GE, Agoritsas T, Lytvyn L, et al. Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019;365(May 14):l2006.

[11] Oral treatments for hypothyroidism. Worst Pills, Best Pills News. November 2016. https://www.worstpills.org/newsletters/view/1067. Accessed July 8, 2021.

[12] AbbVie Inc. Label: levothyroxine (SYNTHROID). July 2020. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=1e11ad30-1041-4520-10b0-8f9d30d30fcc&type=display. Accessed July 8, 2021.

[13] Ibid.

[14] National Institute of Diabetes and Digestive and Kidney Disease. Hypothyroidism. March 2013. http://www.niddk.nih.gov/-/media/Files/Endocrine-Diseases/Hypothyroidism_508.pdf. Accessed July 8, 2021.