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Cited by 36Thyroid Disorders and TreatmentsThyroid and Parathyroid SurgeryHormonal and reproductive studies

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

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Wildisen, Lea, Feller, Martin, Del Giovane, Cinzia, Moutzouri, Elisavet, Du Puy, Robert S., Mooijaart, Simon P., Collet, Tinh-Hai, Poortvliet, Rosalinde K. E. +9 more·2021·JAMA Network Open
DOI 10.1001/jamanetworkopen.2020.36645PMC PMC7876592
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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.

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  • Later studies among adults aged 80 years and older with subclinical hypothyroidism confirmed that LT4 treatment, compared to placebo, was not significantly associated with improvement in hypothyroid symptoms, fatigue, or depressive symptoms.

    “Later studies among adults aged 80 years and older with subclinical hypothyroidism confirmed that LT4 treatment, compared to placebo, was not significantly associated with improvement in hypothyroid symptoms, fatigue, or depressive symptoms [53,54].”

    From T4+T3 Combination Therapy: An Unsolved Problem of Increasing Magnitude and Complexity (2021) · cites this paper as [54]

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Authors
Wildisen, L., Feller, M., Del Giovane, C., Moutzouri, E., Du Puy, R. S., Mooijaart, S. P., Collet, T.-H., Poortvliet, R. K. E., Kearney, P., Quinn, T. J., Klöppel, S., Bauer, D. C., Peeters, R. P., Westendorp, R., Aujesky, D., Gussekloo, J., & Rodondi, N.
Affiliations
  • University of Bern (CH)
  • Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland
  • Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
  • Leiden University Medical Center (NL)
  • University Hospital of Geneva (CH)
  • University College Cork (IE)
  • University of Glasgow (GB)
  • University of California, San Francisco (US)
  • Erasmus MC (NL)
  • University of Copenhagen (DK)
Corresponding author
Rodondi, Nicolas
ORCID
Venue
JAMA Network Open
Publisher
American Medical Association (AMA)
Published
2021-02-10
Volume
4
Issue
2
Pages
e2036645
ISSN
2574-3805 (ISSN-L)
DOI
10.1001/jamanetworkopen.2020.36645
PMC
PMC7876592
OpenAlex
W3128991335
Cited by
36
References
42
Citations by year
2026: 3 · 2025: 3 · 2024: 7 · 2023: 10 · 2022: 8 · 2021: 5
FWCI
5.59
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JAMA Network Open (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research at the University of Copenhagen (University of Copenhagen) (publishedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
  • Leiden Repository (Leiden University) (submittedVersion, cc-by)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by)
  • Bern Open Repository and Information System (University of Bern) (submittedVersion, cc-by)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
  • Lenus, The Irish Health Repository (Dr Steevens Hospital Library) (submittedVersion)
Funders
  • Velux Stiftung (PZ00P3-167826)
  • European Commission (278148)
  • Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (150025, 278148, 172676, 167826, 320030)
  • Schweizerische Herzstiftung (278148)
  • FP7 Health
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Health Sciences › Medicine › Surgery › Thyroid and Parathyroid Surgery
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
Keywords
levothyroxine, subclinical hypothyroidism, depressive symptoms, older adults, thyroid hormone replacement, thyroid-stimulating hormone, Geriatric Depression Scale, TRUST trial, meta-analysis update, antidepressant side effects, adverse events, quality of life, health-related quality of life
MeSH terms
Aged, Aged, 80 and over, Depression, Double-Blind Method, Female, Humans, Hypothyroidism, Male, Thyrotropin, Thyroxine, Treatment Outcome, Asymptomatic Diseases

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