Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial

Abstract

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: ClinicalTrials.gov Identifier: NCT01853579.

Figure 1.. Flowchart of Study Participants

In the Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism (TRUST) study sites in the Netherlands and Switzerland, depressive symptoms were measured using the Geriatric Depression Scale (GDS-15). TSH indicates thyroid stimulating hormone. ^aIn 87 participants from Ireland, depressive symptoms were measured using the Center for Epidemiologic Studies Depression 20-item scale (CESD-20); those participants were included in a secondary analysis on incidence of mild depression. In the UK, no depressive symptoms were measured.

Figure 2.. Subgroup Analyses: Difference in GDS-15 Score at 12 Months Between Levothyroxine and Placebo Groups

GDS-15 indicates Geriatric Depression Scale 15-item questionnaire (range, 0-15; higher scores indicate more severe depressive symptoms; minimal clinically important difference, 2 points). ^aPositive results indicate benefit of placebo. ^bAdjusted for age, sex, GDS-15 score at baseline, levothyroxine dose at baseline, and country.

Figure 3.. Update of Meta-analysis: Standardized Mean Differences Between Levothyroxine and Placebo Groups in Depressive Symptoms

Weights are derived from a random-effects meta-analysis of standardized mean differences. Standardized mean differences of −0.2, −0.5, and −0.8 correspond to small, moderate, and large clinical positive effects of levothyroxine, respectively. The size of the boxes indicates the study weight in the meta-analysis, the whiskers represent 95% CIs, the diamond shows the result of the meta-analysis, and the vertical dashed line represents the point estimate of the pooled standardized mean difference. HADS indicates Hospital Anxiety and Depression Scale; TRUST, Thyroid Hormone Replacement for Untreated Older Adults With Subclinical Hypothyroidism.