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 Feb 1;4(2):e2036645. doi: 10.1001/jamanetworkopen.2020.36645. (Original study)

Importance: Previous trials on the effect of levothyroxine on depressive symptom scores in patients with subclinical hypothyroidism were limited by small sample sizes (N = 57 to 94) and potential biases.

Objective: To assess the effect of levothyroxine on the development of depressive symptoms in older adults with subclinical hypothyroidism in the largest trial on this subject and to update a previous meta-analysis including the results from this study.

Design, Setting, and Participants: This predefined ancillary study analyzed data from participants in the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) trial, a double-blind, randomized, placebo-controlled, parallel-group clinical trial conducted from April 2013 to October 31, 2016. The TRUST trial included adults aged 65 years or older diagnosed with subclinical hypothyroidism, defined as the presence of persistently elevated thyroid-stimulating hormone (TSH) levels (4.6-19.9 mIU/L) with free thyroxine (T4) within the reference range. Participants were identified from clinical and general practitioner laboratory databases and recruited from the community in Switzerland, the Netherlands, Ireland, and the UK. This ancillary study included a subgroup of 472 participants from the Netherlands and Switzerland; after exclusions, a total of 427 participants (211 randomized to levothyroxine and 216 to placebo) were analyzed. This analysis was conducted from December 1, 2019, to September 1, 2020.

Interventions: Randomization to either levothyroxine or placebo.

Main Outcomes and Measures: Depressive symptom scores after 12 months measured with the Geriatric Depression Scale (GDS-15), with higher scores indicating more depressive symptoms (minimal clinically important difference = 2).

Results: A total of 427 participants with subclinical hypothyroidism (mean [SD] age, 74.52 [6.29] years; 239 women [56%]) were included in this analysis. The mean (SD) TSH level was 6.57 (2.22) 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 of 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).

Conclusions and Relevance: This ancillary study of a randomized clinical trial found that depressive symptoms did not differ after levothyroxine therapy compared with placebo after 12 months; thus, these results do not provide evidence in favor of levothyroxine therapy in older persons with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

Trial Registration: Identifier: NCT01853579.

Discipline Area Score
Physician 6 / 7
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Comments from MORE raters

Physician rater

This is not unexpected as previous studies on other aspects of subclinical hypothyroidism did not show any difference when comparing placebo with thyroxine replacement therapy. It is good, however, to have this information to present/discuss with patients.

Physician rater

This substudy of the TRUST study of levothyroxine (T4) in subclinical hypothyroidism confirms previous recommendations that preventing development of depression should not be an indication for prescribing T4 in subclinical hypothyroidism, even when the TSH is > 10. However, depressive symptoms in older adults are common (ca. 15%). It is noteworthy that although the mean GDS scores were low in both the T4 and control groups, the 95% CI included 9 and 12, respectively, which are consistent with mild depression. Additionally, in the subgroup analysis of Grade 2 subclinical hypothyroidism (TSH levels = 10), there was a statistically weak trend favoring T4. Based on the data presented, it is unknown whether participants with mild depression (GDS >5) and elevated TSH without other clinical symptoms of hypothyroidism significantly benefited from T4. It is likely that this subgroup was too small to be statistically meaningful. How duration of subclinical hypothyroidism affects depressive symptoms is also not known.
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