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.