Variable degrees of depression are known to be associated with hypothyroidism. Some patients recover from depression with the commencement of replacement thyroid hormones,[1-3] while others need antidepressants to recover from the associated depression.[4-7]
Concerning drug–drug interaction between replacement thyroid hormones and antidepressants, a meta-analysis reported preliminary evidence that selective serotonin reuptake inhibitors (SSRIs) slightly decrease thyroid hormones with unclear clinical significance. However, another report suggested that levothyroxine dose may need to be increased when concomitantly administered with SSRI, due to a possible suppressive effect on thyroid-stimulating hormone (TSH). In a different vein, Takahashi et al. demonstrated that the antithyroid effect of paroxetine was at the thyroid gland level probably interfering with thyroid hormone synthesis or secretion. Few other authors have also reported hypothyroidism following the use of other SSRIs such as escitalopram and sertraline.[11-13] More studies are needed to further understand the mechanism (s) of this interaction, whether it involves one or more of TSH suppression, impaired thyroid hormone synthesis or secretion, receptor, and/or postreceptor mechanisms.
Following extensive literature search, no report was found to have demonstrated the differential interaction of SSRIs and tricyclic antidepressants (TCAs) with levothyroxine. It was against this backdrop that we intend to report this case of suspected interaction of different classes of antidepressants with levothyroxine in a patient with primary hypothyroidism.
MATERIALS AND METHODS
Relevant data were retrieved from the patient’s notes. Extensive literature search of drug–drug interaction between replacement thyroid hormones and antidepressants was done using databases such as PubMed, PubMed Central, Google Scholar, and Embase.
A 25-year-old woman was recently diagnosed as having primary hypothyroidism with major depression. She was commenced on levothyroxine 50 mg daily on empty stomach with at least 1 h before meal, with some but not complete resolution of symptoms after 4 weeks. The dose of levothyroxine was then increased to 100 mg daily, but due to complaint of palpitation following ingestion of levothyroxine, it was taken as 50 mg twice daily. This led to the clinical and biochemical resolution of hypothyroidism at 2-month follow-up visit [Table 1]. However, the patient was still depressed necessitating the commencement of a SSRI: paroxetine 20 mg nocte. At 3-month follow-up visit, the symptoms of depression had remarkably subsided, but the symptoms of hypothyroidism began to re-appear confirmed by laboratory findings, cross-checked in a private laboratory [Table 1]. There was confirmed supervised and regular intake of levothyroxine, and the mother of the client was further instructed to supervise the administration. The patient was not on supplements containing biotin, calcium, iron, or magnesium, and levothyroxine was stored as per product insert at 20°C–25°C (68°F–77°F) and protected from light and moisture. Four weeks later, due to persistent worsening of hypothyroidism symptoms, thyroid hormone resistance was suspected, and the dose of levothyroxine was increased by 50 mg 4-weekly up to a dose of 300 mg daily in divided doses, leading to some clinical improvement at 8-month follow-up [Table 1].
At 9-month follow-up visit, the symptoms of hypothyroidism had begun to re-appear again confirmed by laboratory findings [Table 1], and cross-checked in a different laboratory, even with strict supervised compliance with both levothyroxine and paroxetine, leading to a clinical suspicion of drug–drug interaction between levothyroxine and paroxetine. Subsequently, paroxetine was replaced with amitriptyline 25 mg twice daily, titrated upward to 50 mg twice daily. At 10-month follow-up visit, the patient was clinically and biochemically euthyroid. Subsequently, she began to experience heat intolerance, palpitations, and excessive sweating. The dose of levothyroxine was gradually reduced over the next 4 months until she maintained clinical and biochemical euthyroid state at a dose of 100 mg daily [Table 1].
This is a case report of suspected differential drug–drug interaction of different classes of antidepressants with levothyroxine in a patient with primary hypothyroidism and a major depressive disorder. The patient became clinically and biochemically euthyroid at the 2nd month of treatment with levothyroxine, but there was no significant improvement in the associated depressive disorder. This lack of improvement in depression during hypothyroidism treatment with levothyroxine was also reported by some authors;[4-7] however, other reports demonstrated recovery of associated depression during hypothyroidism treatment.[1-3]
The patient was subsequently placed on paroxetine (SSRI) 20 mg nocte, with eventual improvement of depressive symptoms. However, the symptoms of hypothyroidism recurred despite confirmed supervised compliance with ingestion of levothyroxine in an empty stomach, at least 1 h before meals. The levothyroxine was kept at proper storage condition, and the patient did not ingest biotin-containing supplements, vitamins, iron, calcium, magnesium, or any other medication that can interact with levothyroxine. The continued escalation of levothyroxine dose up to 300 mg daily with only temporary improvement in symptoms of hypothyroidism became a recipe for the suspicion of interaction between levothyroxine and paroxetine. This suspicion was confirmed when paroxetine was replaced with amitriptyline, and the symptoms of hypothyroidism dramatically waned, and subsequently, even developed thyrotoxic symptoms and signs, leading to gradual reduction of levothyroxine dose back to 100 mg daily. This clinical scenario demonstrated, to a large extent, that paroxetine may have caused a clinically significant drug–drug interaction with levothyroxine, i.e., a significant reduction in its efficacy even after super-pharmacological doses were administered. From the serial thyroid function tests, the hypothyroidism following paroxetine administration was similar to that of primary hypothyroidism. This may mean that the mechanism of the drug–drug interaction may include inhibition of synthesis or secretion of thyroid hormones. This agrees with the report by Takahashi et al. where they also demonstrated reversible paroxetine-induced symptomatic hypothyroidism with a primary hypothyroidism-like picture. However, the exact mechanism for this interaction is a subject for future investigation.
At this juncture, it is pertinent to add that amitriptyline did not show clinically significant drug–drug interaction with levothyroxine, eventually maintaining recovery from the depressive disorder, coupled with a stable clinical and biochemical euthyroid state at a levothyroxine pharmacological dose of 100 mg daily. More studies will be needed to ascertain whether this differential drug–drug interaction pattern of paroxetine and amitriptyline is a class effect. Limitation of this report included the inability to perform therapeutic drug monitoring for levothyroxine, which can add more information as to the nature of the drug–drug interaction, and throw more light into the mechanism of the interaction, whether receptor and/or postreceptor mechanisms.
In patients having hypothyroidism with depressive disorder requiring antidepressant therapy, it may be better to administer TCAs than SSRIs, in order to avoid clinically significant drug–drug interaction with levothyroxine. However, more studies are needed to confirm this differential interaction, and decipher the mechanism(s) behind it.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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