The thyroid axis and depression.

Abstract

Hypothyroidism may give rise to frank depression that usually responds to thyroxine therapy. Depressed subjects with subclinical hypothyroidism and/or autoimmune thyroiditis should probably also be treated similarly. Most patients with depression, although generally viewed as chemically euthyroid, have alterations in their thyroid function including slight elevation of the serum thyroxine (T4), blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) stimulation, and loss of the nocturnal TSH rise. These changes are generally reversed following alleviation of the depression. The role of adjuvant triiodothyronine (T3) treatment in resistant depression has not been established, but the data suggest that it will be beneficial in about 25% of cases. However, controlled trials to establish this approach are needed. The underlying mechanism leading to the beneficial response from T3 is unknown, but may reflect brain hypothyroidism in the context of systemic euthyroidism. The hypothalamus in culture, which is analogous to a deafferentated hypothalamus in vivo, shows a paradoxic increase in TRH production after glucocorticoid stimulation. It is known that in human depression there is a functional disconnection of the hypothalamus with impairment of the inhibitory glucocorticoid feedback pathway from the hippocampus to the hypothalamus that results in the typical elevated cortisol levels and impaired dexamethasone suppression. It is postulated that a similar situation prevails with regards to the thyroid axis and that the increased T4 in depression, as well as the blunted TSH response to exogenous TRH, reflects glucocorticoid activation of the TRH neuron leading to increased TRH secretion with resultant down regulation of the TRH receptor on the thyrotrope. Normalization of thyroid function after treatment may result in part from an inhibitory response of the TRH neuron to antidepressant medication, although other effects may also be responsible.