Effect of Increased Levothyroxine Dose on Depressive Mood in Older Adults Undergoing Thyroid Hormone Replacement Therapy

Jae Hoon Moon; Ji Won Han; Tae Jung Oh; Sung Hee Choi; Soo Lim; Ki Woong Kim; Hak Chul Jang


Clin Endocrinol. 2020;93(2):196-203. 

In This Article

Abstract and Introduction


Objective: Depressive mood consequent to hypothyroidism can be reversed with levothyroxine (LT4) replacement therapy. However, it is unclear whether increasing LT4 dose confers additional mood benefits.

Design and Patients: A single-blinded before-and-after study of 24 patients with hypothyroidism who were aged 65 years or older and undergoing LT4 replacement therapy with stable doses.

Measurements: Geriatric Depression Scale (GDS-K) and Hyperthyroid Symptom Scale (HSS-K) were assessed at baseline, 3 months after increasing LT4 dose by an additional 12.5 μg/d, and finally 3 months after returning to the baseline dose.

Results: Serum thyroid-stimulating hormone (TSH) concentrations decreased at the higher LT4 dose (1.95 ± 2.16 vs 0.47 ± 1.09 mIU/L, P < .001) and recovered after returning to the baseline dose. Serum-free thyroxine levels and HSS-K scores were unchanged during the study period. GDS-K scores improved on the increased dose (9.5 ± 6.6 vs 7.5 ± 4.7, P = .029), and this improvement was maintained after returning to the baseline dose (9.5 ± 6.6 vs 7.4 ± 5.4, P = .010). Higher serum TSH was independently associated with both higher GDS-K and depression risk among those with depressive mood (GDS-K > 10) at baseline.

Conclusions: Depressive mood improves with increased LT4 dose, without significant hyperthyroid symptoms or signs, in older adults undergoing thyroid hormone replacement. These findings suggest the potential for varying the treatment target for hypothyroidism based on mood status and that low-dose LT4 treatment might be an ancillary treatment for depression.


With the globally increasing population of older adults, geriatric depression has become an important health problem. Depression is well known to increase socioeconomic costs, including suicidal thoughts, low work efficiency and increased medical costs.[1] In Korea, the socioeconomic costs of depression have increased steadily,[2] This is because Korea became a predominantly ageing society in 2017 and is experiencing the fastest ageing in the world.[3] About 10% of Korea's older adult population have major or minor depressive disorders,[4] 30% have clinically significant depression,[5] and 60% have a depressive symptom.[6] However, timely diagnosis of geriatric depression is difficult, and its adequate treatment is frequently insufficient.[7] Although medical therapy using antidepressants and psychotherapy are the mainstay depression treatments, adverse drug reactions, potential drug interactions and somatic comorbidities should be considered in older adults.[8] Therefore, multidimensional approaches and ancillary treatments are becoming important for managing geriatric depression.

The thyroid hormone, an important neuroregulator during central nervous system (CNS) development, also plays a crucial role in neurocognitive functioning.[9] Hypothyroidism, like depression, is widespread among older adults and its prevalence increases with age.[10] In addition, the association between hypothyroidism and depression is well known, and levothyroxine (LT4) replacement is effective for improving depressive symptoms in hypothyroid patients.[11,12] Therefore, screening for and treating hypothyroidism are recommended for patients with depression, especially older adults. When replacing LT4 in older hypothyroid patients, factors such as decreased absorption, concomitant use of medication, comorbidities and the adverse effects of excess thyroid hormone should be considered. Thus, stepwise dose adjustment and regular assessment of serum thyroid hormone levels are required to avoid iatrogenic thyrotoxicosis. However, the extent of LT4 treatment intensity to which depression improvement effect can be maximized, without adverse effects, is unknown.

This study investigated whether increasing the LT4 dose has additive mood benefits, without harmful effects, in older hypothyroid patients on a stable LT4 dose and euthyroid status.