Levothyroxine Not Effective for Depressive Symptoms, Ancillary Study Finds

February 12, 2021
Patrick Campbell

An analysis of data from the TRUST trial supports guideline recommendations against levothyroxine for reducing depressive symptoms in older adults with subclinical hypothyroidism.

An ancillary study of a large phase 3 trial examining use of levothyroxine in adults with subclinical hypothyroidism is offering clinicians greater insight into the effects of levothyroxine treatment on the development of depression symptoms.

Results of the study, which assessed data from the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial, demonstrated no evidence to suggest levothyroxine therapy was associated with a reduction in risk of developing depressive symptoms in older adults with subclinical hypothyroidism.

“This ancillary study of a randomized clinical trial found no effect of levothyroxine therapy on the development of depressive symptoms in older patients, even among those with a TSH level higher than 10 mIU/L, although this group was relatively small. Findings from this study do reinforce the current recommendation that levothyroxine therapy should not be prescribed to reduce the risk of depressive symptoms in adults with subclinical hypothyroidism, with high quality of evidence,” wrote investigators.

With guidelines recommending against levothyroxine for depressive symptoms conflicted by the results of recent meta-analysis, a team of investigators based in Sweden sought to draw a more clear determination of the effects of levothyroxine on depressive symptoms in older adults. To do so, the team designed their ancillary study as an evaluation of data from the TRUST trial, which is the largest trial examining levothyroxine in older adults with subclinical hypothyroidism.

A double-blind, randomized placebo-controlled, parallel-group clinician trial conducted between April 2013 and October 2016, TRUST enrolled 737 adult patients 65 years of age or older with persistent subclinical hypothyroidism. Patients included in the study from the Netherlands and Switzerland underwent assessments of depressive symptoms at baseline and 12-month follow-up.

Of note, subclinical hypothyroidism was defined as the presence of thyroid-stimulating hormone (TSH) levels (4.6-19.9 mIU/L) with free thyroxine (T4) within the reference range. Additionally, assessments of depressive symptoms were performed using the Geriatric Depression Scale (GDS-15).

In total, 427 patients were identified for inclusion in the ancillary study—216 randomized to placebo and 211 randomized to levothyroxine. The overall study cohort had a mean age of 74.52 (SD, 6.29) years and 56% were women. At baseline, the levothyroxine arm had a mean TSH level of 6.57 (SD, 2.22) mIU/L and this decreased to 3.83 (SD, 2.29) mIU/L at 12 months. In the placebo arm, the mean TSH level at baseline was 6.55 (SD, 2.04) mIU/L and this decreased to 5.91 (SD, 2.66) mIU/L at 12 months.

The GDS-15 scores at baseline and 12 months were 1.26 (SD, 1.85) and 1.39 (SD, 2.13), respectively, in the levothyroxine group. In the placebo group, the GDS-15 scores were 0.96 (SD, 1.58) and 1.07 (1.67) at baseline and 12 months, respectively. Analysis indicated an adjusted between-group difference of 0.15 for levothyroxine vs placebo (95% CI, 00.15 to 0.46; P=.33).

Additionally, a subgroup analysis of patients with a GDS-15 score of at least 2 yielded an adjusted between-group difference of 0.61 (95% CI, -0.32 to 1.53; P=.20). Investigators pointed out these results did not differ according to age, sex, or TSH levels.

This study, “Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism,” was published in JAMA.