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Levothyroxine Therapy and Depression

Levothyroxine Therapy and Depression

Subclinical hypothyroidism is a condition defined as elevated thyroid-stimulating hormone (TSH) levels in combination with free thyroxine levels within the reference range. It is an early form of hypothyroidism, a condition in which the body doesn’t produce enough thyroid hormones. The term “subclinical” refers to the serum level of thyroid-stimulating hormone from the front of the pituitary which is above normal. Subclinical hypothyroidism is a common condition among the general population. It occurs mostly in women and older adults with a prevalence of up to 10% to 15%. Subclinical hypothyroidism is a commonly treated with oral levothyroxine therapy.

What causes subclinical hypothyroidism?  Our pituitary glands which are located at the base of our brain secretes multiple hormones including TSH (thyroid-stimulating hormone). This hormone triggers the thyroid to make hormones such as the T3 and T4. Subclinical hypothyroidism occurs when TSH levels are slightly elevated but T3 and T4 are normal. Subclinical hypothyroidism can be caused by the following:

  • a family history of autoimmune thyroid disease
  • injury to the thyroid
  • the use of radioactive iodine therapy
  • taking medications that contain lithium or iodine

Increasing evidence also suggests that patients with subclinical hypothyroidism should be routinely treated with levothyroxine. Current guidelines also recommend levothyroxine therapy for adults with TSH levels greater than 10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. In 2014, Levothyroxine has become the most prescribed drug in the US. It is also the second most prescribed in the UK in 2019. Regular testing or a lower TSH threshold could be one reason for the increase in levothyroxine prescription. 

Another common reason for starting levothyroxine therapy is depressive symptoms. A new meta-analysis of 4 trials on the effect of levothyroxine therapy in adult patients with subclinical hypothyroidism found no benefit for depressive symptoms. 

Study Objective

To understand the effect of levothyroxine on the development of depressive symptoms in older adults with subclinical hypothyroidism. This is currently the largest trial on this subject. The research aims to update the previous meta-analysis including the results from the current study.  

Study Design 

The Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial was a randomized, multicenter, double-blind placebo-controlled trial on the benefits of levothyroxine for patients 65 years or older with subclinical hypothyroidism.

This predefined ancillary used date from participants in the TRUST trial and a double-blind, random, placebo-controlled group from April 2013 to October 31, 2016. 


The trial included adults of the age 65 years or older and with subclinical hypothyroidism. All of the participants were identified from clinical and general practitioner laboratory databases and recruited from the community in Switzerland, the Netherlands, Ireland, and the UK. The study includes a total number of 473 participants from the subgroup of Netherlands and Switzerland.  This analysis was conducted from December 1, 2019, to September 1, 2020.


The study is part of a large international study on levothyroxine therapy in older adults with subclinical hypothyroidism (the TRUST trial). The study was conducted from April 2013 to October 31, 2016.  The study was predefined and registered in May 2013 separately from the primary TRUST trial. The participants were from 2 countries, Switzerland and Netherlands. Their depressive symptoms were measured at baseline and had a 12-month follow-up using the 15-item Geriatric Depression Scale. 

In a secondary analysis on the incidence of mild depression, individuals who participated from the TRUST site in Ireland were also included. In Ireland, depressive symptoms were calculated using the Center for Epidemiologic Studies Depression 20-item scale (CESD-20). The protocol of the TRUST trial was evaluated and approved by relevant ethics committees. Participants provided written consent to participate. This study followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline for clinical trials.

Depressive Symptoms

Depressive symptoms were evaluated using the 15-item Geriatric Depression Scale (GDS-15) at baseline and 12-month follow-up. The GDS-15 is the most recommended test for depression screening in older age, with validity to measure longitudinal changes. The GDS-15 score ranges from 0 to 15, with higher scores indicating a higher likelihood of depression. Score values from 0 to 2 indicate no depressive symptoms; 3-5, mild depressive symptoms; and 6 or greater, severe depressive symptoms.

Statistical Analysis

Statistical analysis was done from December 1, 2019, to September 1, 2020. For the primary outcome analysis, the researchers performed a modified intention-to-treat analysis using those participants having depressive symptoms outcome. Using the available data set, the researchers performed a power calculation with 427 participants with a standard deviation of 2 and a mean GDS-15 score in control of 1, which resulted in 100% power for detecting a mean difference of 2.0 points at a 1-sided α-level of .05. 

The researchers used a multivariable linear regression analysis to assess the mean difference and relative 95% CI in GDS-15 scores at the 12-month follow-up between the levothyroxine and placebo groups. They also adjusted the results for GDS-15 scores at baseline, age, sex, country, and starting dose of levothyroxine.


  • A total of 427 participants with subclinical hypothyroidism were included in this analysis. The mean (SD) TSH level was 6.57 mIU/L at baseline and decreased after 12 months to 3.83 (2.29) mIU/L in the levothyroxine group. In the placebo group, it decreased from 6.55 (2.04) mIU/L to 5.91 (2.66) mIU/L.
  • At baseline, the mean (SD) GDS-15 score was 1.26 (1.85) in the levothyroxine group and 0.96 (1.58) in the placebo group.
  • The mean (SD) GDS-15 score at 12 months was 1.39 (2.13) in the levothyroxine and 1.07 (1.67) in the placebo group with an adjusted between-group difference of 0.15 for levothyroxine vs placebo (95% CI, −0.15 to 0.46; P = .33). In a subgroup analysis including participants with a GDS-15 of at least 2, the adjusted between-group difference was 0.61 (95% CI, −0.32 to 1.53; P = .20).
  • Results did not differ according to age, sex, or TSH levels.
  • A previous meta-analysis (N = 278) on the association levothyroxine with depressive symptoms was updated to include these findings, resulting in an overall standardized mean difference of 0.09 (95% CI, −0.05 to 0.22).

Based on the findings, the researchers found that depressive symptoms didn’t change after levothyroxine therapy compared with placebo after 12 months. These results don’t provide evidence in favor of levothyroxine therapy in older persons with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

However, data were limited by small sample sizes. There are also potential biases such as the risk of bias assessment and publication bias. 


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