Effect of Levothyroxine Therapy on the Development of Depressive Symptoms in Older Adults With Subclinical Hypothyroidism: An Ancillary Study of a Randomized Clinical Trial | Depressive Disorders | JAMA Network Open | JAMA Network
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    Original Investigation
    Diabetes and Endocrinology
    February 10, 2021

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

    Author Affiliations
    • 1Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
    • 2Graduate School for Health Sciences, University of Bern, Bern, Switzerland
    • 3Department of General Internal Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
    • 4Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
    • 5Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
    • 6Service of Endocrinology, Diabetology, Nutrition, and Therapeutic Education, Geneva University Hospitals, Geneva, Switzerland
    • 7School of Public Health, University College Cork, Cork, Ireland
    • 8Institute of Cardiovascular Medicine, University of Glasgow, Glasgow, Scotland
    • 9University Hospital of Old Age Psychiatry, University of Bern, Bern, Switzerland
    • 10Departments of Medicine and Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California
    • 11Department of Medicine, Erasmus Medical Center, Rotterdam, the Netherland
    • 12Department of Public Health and Center for Healthy Aging, University of Copenhagen, Copenhagen, Denmark
    JAMA Netw Open. 2021;4(2):e2036645. doi:10.1001/jamanetworkopen.2020.36645
    Key Points

    Question  Does levothyroxine treatment have an effect on the development of depressive symptoms in older adults with subclinical hypothyroidism?

    Findings  In this ancillary study of a randomized, placebo-controlled clinical trial of 427 participants with subclinical hypothyroidism, there was no statistically significant difference in the adjusted between-group difference in the mean Geriatric Depression Score at 12 months between the levothyroxine and placebo groups.

    Meaning  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.


    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