Introduction
Thyroid function insufficiency can be classified as primary (due to thyroid hormone deficiency) and central (due to thyroid-stimulating hormone (TSH) deficiency or thyrotropin-releasing hormone (TRH) deficiency) 1. In general, central hypothyroidism is rare, with incidence estimated at 1:80,000 to 1:120,000 in the general population, and accounts for less than 1/100 cases of hypothyroidism1. Primary hypothyroidism is defined as TSH concentrations above the reference range and free thyroxine (free T4) concentrations below the reference range 1. In general, the relationship between serum TSH and free T4 is such that a small decrease in free T4 can result in a relatively large increase in serum TSH, which can subsequently lead to a TSH level that is above the reference range while the free T4 level is still within the reference range2. In cases of progression to primary hypothyroidism, TSH level typically continues to increase and free T4 level falls below the reference range1,2. Central hypothyroidism is characterized by a defect in thyroid hormone secretion due to insufficient stimulation by TSH1. Biochemically, central hypothyroidism is defined by low-to-normal TSH concentrations and a disproportionately low concentration of free T41. The laboratory criteria of hypothyroxinemia, defined as “normal TSH and Low free T4”, overlaps, to a great extent, with the laboratory criteria of central hypothyroidism 3-5.
Circulating thyroid hormones concentrations are regulated by the hypothalamic–pituitary–thyroid axis. TSH controls all aspects of thyroid hormone synthesis and release. Secretion of TSH is stimulated by TRH and inhibited by negative feedback through thyroid hormones6. It is known that central neurotransmitters system regulates/influences the hypothalamic–pituitary–thyroid axis3,5,7. Activation of the central dopaminergic and serotonergic system has been reported to inhibit hypothalamic–pituitary–thyroid axis, resulting in decrease in the release of TSH and thyroid hormones3,5,7.
Mirtazapine is a noradrenergic and specific serotonergic antidepressant. It is particularly effective in alleviating depressed mood and relieving anxiety and sleep-disturbance symptoms, with lower frequencies of drug-drug interaction. As a result, it is often used as an adjunctive antidepressant for moderate to severe major depressive disorder8,9. The current clinical literature regarding mirtazapine and thyroid function is scarce, with only one study by Gambi et al in 17 outpatients affected by major depressive disorder10. However, Gambi’s study did not examine whether patients developed hypothyroxinemia or central hypothyroidism. Most importantly, no comparison with no mirtazapine user was made in the Gambi’s study10.
Clinical presentation of thyroid function insufficiency varies greatly and generally without symptom specificity1. Combined with the fact that symptoms of thyroid function insufficiency and major depressive disorder overlap in many aspects such as fatigue, depression, and weakness 11, the evaluation of thyroid function in patients treated by antidepressants is predominantly biochemical1. However, because central hypothyroidism is rare, attention is typically paid only on patients with elevated TSH, and central hypothyroidism or hypothyroxinemia may be largely neglected3. Thyroid function insufficiency is associated with poor response to antidepressant therapies in patients with major depressive disorder12-14. Failure to recognize hypothyroxinemia or central hypothyroidism may result in neglected thyroid dysfunction in individuals treated by antidepressants, which may lead to poor response to treatment. Thyroxine has been used as a synergist for treatment-refractory major depression disorder15. Lower serum level of free thyroxine is also associated with more affective episodes and greater severity of depression in mood disorders16.
We have therefore conducted a retrospective cohort study to assess the association between mirtazapine use and hypothyroxinemia in patients affected by major depressive disorder. Because the evaluation of thyroid function was based on the reference ranges of TSH and thyroxine, we adopted the term “hypothyroxinemia” for the “normal TSH level and a disproportionately low level of free T4” in this study.