Discussion
In this retrospective cohort study, we demonstrated that the risk of
developing hypothyroxinemia in
patients who used mirtazapine was 64% higher than patients who did not
use, after adjusting for important confounders.
There are several strengths in this study. To the best of our knowledge,
this is the first study to report an association between mirtazapine and
increased risk of hypothyroxinemia. The large sample size of our study
helped to generate stable estimates. The use of electronic inpatients
records provided complete measurements of thyroid function: T4, free T4,
and TSH at baseline and during treatment. As a result, we could have
complete ascertainment of hypothyroxinemia. Furthermore, we excluded
patients who had thyroid dysfunction at baseline or who received mood
stabilizers (i.e. lithium, valproic acid, and oxcarbazepine) or
quetiapine during hospitalization and adjusted for a number of important
confounding factors including the baseline level of free T4 and TSH and
the use of other kinds of antidepressants during the treatment. Thus,
the impact of prior thyroid dysfunction or other psychiatric medications
on the observed association between mirtazapine use and hypothyroxinemia
would have been minimized.
Limitations of this study should be acknowledged. First, we had no
dynamic monitoring information of thyroid function. Although we have
collected data on serum thyroid hormone levels at baseline and during
hospitalization for antidepressants treatment, no additional follow up
tests were performed. As a result, we could not determine whether the
effect of mirtazapine on thyroid function persists after discharge from
hospital.
Second, the clinical symptoms/signs of thyroid dysfunction were not
available in this study. The laboratory criteria of hypothyroxinemia,
defined as “normal TSH and Low free T4”, overlaps, to a great extent,
with the laboratory criteria of central hypothyroidism3-5. Based on available
data, we could not definitely differentiate hypothyroxinemia from
central hypothyroidism. We adopted the term “hypothyroxinemia” for the
“lower free T4 (<12.00 pmol/L) and normal TSH level” in our study.
Case reports 17-21 and
clinical studies 22-26suggested that antidepressants other than mirtazapine may also be
associated with thyroid abnormalities. However, no conclusion could be
drawn from these studies due to small sample size23-26, cross-sectional
study design 22,
incomplete laboratory tests20,21,26.
and lack information whether hormone concentrations reached cut off
values23,24,26.
On the other hand, our study found that the incidence of
hypothyroxinemia in patients treated by SSRIs, SNRIs, or combined
treatment in non-mirtazapine group
was similar (data available upon request). Our findings, in principle,
were consistent with previous studies/reviews that SSRIs and SNRIs
reduced T4/FT4 levels but did not significantly affect TSH level27.
Compared with other treatments for major depressive disorder, the impact
of mirtazapine treatment on thyroid function has not been well
investigated. To date, only one study reported a significant decrease in
free T4 in 17 outpatients affected by major depressive disorder after
mirtazapine treatment for 6 months10. No change in TSH
was observed and no comparison with non-mirtazapine users was made in
that study 10. Although
that study did not report if free
T4 was dropped to the cutoff level defining hypothyroxinemia, the
significant decrease in free T4 after mirtazapine treatment10 provides some
support to our finding on mirtazapine and hypothyroxinemia association.
That previous study also reported a significant increase in FT3 after
mirtazapine treatment10, which was not
observed in our study. On the other hand, our study observed that the
degree of reduction in T4 and free T4 after mirtazapine treatment was
much higher than the reductions in T3 and FT3, which suggests that
peripheral conversion of T4 to T3 could be affected by mirtazapine
treatment, and this process may occur mostly in liver, heart, muscle and
gut, rather than in thyroid6. Increased peripheral
conversion of T4 to T3 may also be a consequence of a
compensatory response to lower function of
hypothalamic–pituitary–thyroid axis, due to changes in thyroid hormone
metabolism that serve to maintain normal circulating levels of T3 until
the late stages of dysfunction6.
More than 99% of circulating thyroid hormones is bound to serum
proteins. It is reported that commercially available testing kits might
show inaccurately low free thyroxine concentrations in patients treated
with drugs which have the capacity to displace thyroid hormone from
binding proteins, and it is suggested that serum dilution in assays
could reduce free thyroxine readout6. However, we observed
that the degree of reduction was very similar in both T4 and free T4.
For example, the reduction was 18.77% in T4 and 21.09% in free T4 in
the mirtazapine group. It is known that serum dilution in assays would
not affect T4 readout 6.
Therefore, in this case, the low serum free T4 levels observed in
patients treated with mirtazapine may not be due to artifactual
laboratory effects.
The key to maintain the level of serum free thyroxine is the negative
feedback regulation, an appropriate TSH synthesis and release in
response to serum thyroid hormone level changes6. Activation of the
central neurotransmitters system, such as dopaminergic and serotonergic
system, has been reported to inhibit hypothalamic–pituitary–thyroid
axis3,5,7.
The increased risk of hypothyroxinemia after mirtazapine treatment could
be explained by the central effect of mirtazapine on
hypothalamic/pituitary prevents the compensatory increase in TSH in
response to low T4, thereby ultimately presenting as higher incidence of
hypothyroxinemia in patients treated by mirtazapine. It has been
reported that antidepressants (other than mirtazapine), which improve
central dopaminergic and serotonergic system, seem to decrease T4/free
T4 levels but maintaining TSH level27. Our study found
that after adjusting for other antidepressant treatments, the
association between mirtazapine treatment and hypothyroxinemia remained
significant.
The finding of increased risk of developing hypothyroxinemia after
mirtazapine treatment may have significant clinical
implication.13 Symptoms
of thyroid dysfunction and major depressive disorder overlap in many
aspects such as depressive mood, fatigue and weakness11. Thus,
hypothyroxinemia could be easily ignored in major depressive disorder
treated with mirtazapine, if attention is paid only to those with
elevated TSH.
In addition, clinical studies indicate that thyroid hormone
supplementation can improve the response rate and can also convert
patients with refractory depression to responders15. The beneficial
effects of thyroid hormone supplementation has suggested that a central
hypothyroidism may exist in such patients15. Failure to
recognize hypothyroxinemia or central hypothyroidism may result in
ignored thyroid function insufficiency, which may lead to poor response
to treatment in individuals with major depression disorder. It may
therefore be important to identify thyroid function insufficiency during
antidepressants treatment for major depressive disorder, especially in
patients receiving mirtazapine as an adjunctive antidepressant.