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CASE REPORT
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Which is better? Tricyclic antidepressant or selective serotonin reuptake inhibitor for depression in hypothyroidism: A case study


 Department of Internal Medicine, College of Health Sciences, University of Abuja, Abuja, Nigeria

Date of Submission19-May-2022
Date of Acceptance14-Aug-2022
Date of Web Publication17-Oct-2022

Correspondence Address:
Yakubu Lawal,
Department of Internal Medicine, College of Health Sciences, University of Abuja, Abuja
Nigeria
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/trp.trp_7_22

  Abstract 


Patients with hypothyroidism frequently have associated depressive disorder which may require antidepressant therapy. The clinical significance of drug–drug interaction between replacement thyroid hormones and antidepressants has remained controversial. Against this background, we present a case report of a suspected clinically significant drug–drug interaction between levothyroxine and an antidepressant in a patient with hypothyroidism and depressive disorder. A relevant patient's details were retrieved from the case 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 with primary hypothyroidism associated with a major depressive disorder. She was stabilized on levothyroxine 100 μg daily with clinical and biochemical euthyroidism 2 months later. Due to lack of significant improvement in her depressive state, she was commenced on paroxetine 20 mg nocte. Subsequently, the depressive symptoms remarkably subsided, but the symptoms of hypothyroidism recurred. Supervised and regular intake of levothyroxine was confirmed. The patient did not ingest supplements containing biotin, calcium, iron, magnesium, and she was not on other medications. Levothyroxine was stored as per product insert at 20°C–25°C (68°F–77°F), and it was protected from light and moisture. After ruling out these confounders, the dose of levothyroxine was gradually increased at 4-weekly interval to 300 μg daily until biochemical and clinical euthyroidism was achieved, though with suspicion of thyroid hormone resistance. On re-appearance of hypothyroidism symptoms even at such a high dose of levothyroxine, drug–drug interaction between levothyroxine and paroxetine was suspected, leading to the replacement of paroxetine with amitriptyline. Biochemical and clinical euthyroidism was subsequently achieved, and the patient even began to complain of thyrotoxic symptoms, until levothyroxine dose was gradually titrated downward to 100 μg daily to achieve and maintain clinical and biochemical euthyroidism. Levothyroxine may be better co-administered with tricyclic antidepressants than selective serotonin reuptake inhibitors (SSRIs) because of the suspected clinically significant drug–drug interaction demonstrated between levothyroxine and paroxetine (SSRI).

Keywords: Antidepressant, hypothyroidism, levothyroxine, selective serotonin reuptake inhibitors, tricyclic antidepressants



How to cite this URL:
Lawal Y. Which is better? Tricyclic antidepressant or selective serotonin reuptake inhibitor for depression in hypothyroidism: A case study. Thyroid Res Pract [Epub ahead of print] [cited 2022 Nov 30]. Available from: https://www.thetrp.net/preprintarticle.asp?id=358653




  Introduction Top


Variable degrees of depression are known to be associated with hypothyroidism. Some patients recover from depression with the commencement of replacement thyroid hormones,[1],[2],[3] while others need antidepressants to recover from the associated depression.[4],[5],[6],[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.[8] 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).[9] In a different vein, Takahashi et al.[10] 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],[12],[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 Top


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.

Case

A 25-year-old woman was recently diagnosed as having primary hypothyroidism with major depression. She was commenced on levothyroxine 50 μg 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 μg daily, but due to complaint of palpitation following ingestion of levothyroxine, it was taken as 50 μg 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 μg 4-weekly up to a dose of 300 μg daily in divided doses, leading to some clinical improvement at 8-month follow-up [Table 1].
Table 1: Serial thyroid hormone levels of the patient

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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 μg daily [Table 1].


  Discussion Top


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],[5],[6],[7] however, other reports demonstrated recovery of associated depression during hypothyroidism treatment.[1],[2],[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 μg 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 μg 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.[10] 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 μg 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.


  Conclusion Top


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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Wildisen L, Feller M, Del Giovane C, Moutzouri E, Du Puy RS, Mooijaart SP, et al. Effect of levothyroxine therapy on the development of depressive symptoms in older adults with subclinical hypothyroidism: An ancillary study of a randomized clinical trial. JAMA Netw Open 2021;4:e2036645.  Back to cited text no. 1
    
2.
Zhao T, Chen BM, Zhao XM, Shan ZY. Subclinical hypothyroidism and depression: A meta-analysis. Transl Psychiatry 2018;8:239.  Back to cited text no. 2
    
3.
Jurado-Flores M, Warda F, Mooradian A. Pathophysiology and clinical features of neuropsychiatric manifestations of thyroid disease. J Endocr Soc 2022;6:bvab194.  Back to cited text no. 3
    
4.
de Carvalho GA, Bahls SC, Boeving A, Graf H. Effects of selective serotonin reuptake inhibitors on thyroid function in depressed patients with primary hypothyroidism or normal thyroid function. Thyroid 2009;19:691-7.  Back to cited text no. 4
    
5.
Walshaw PD, Gyulai L, Bauer M, Bauer MS, Calimlim B, Sugar CA, et al. Adjunctive thyroid hormone treatment in rapid cycling bipolar disorder: A double-blind placebo-controlled trial of levothyroxine (L-T4) and triiodothyronine (T3). Bipolar Disord 2018;20:594-603.  Back to cited text no. 5
    
6.
Siegmann EM, Müller HH, Luecke C, Philipsen A, Kornhuber J, Grömer TW. Association of depression and anxiety disorders with autoimmune thyroiditis: A systematic review and meta-analysis. JAMA Psychiatry 2018;75:577-84.  Back to cited text no. 6
    
7.
Fukao A, Takamatsu J, Arishima T, Tanaka M, Kawai T, Okamoto Y, et al. Graves' disease and mental disorders. J Clin Transl Endocrinol 2019;19:100207.  Back to cited text no. 7
    
8.
Caye A, Pilz LK, Maia AL, Hidalgo MP, Furukawa TA, Kieling C. The impact of selective serotonin reuptake inhibitors on the thyroid function among patients with major depressive disorder: A systematic review and meta-analysis. Eur Neuropsychopharmacol 2020;33:139-45.  Back to cited text no. 8
    
9.
Benvenga S. L-T4 Therapy in the Presence of Pharmacological interferents. Front Endocrinol (Lausanne) 2020;11:607446.  Back to cited text no. 9
    
10.
Takahashi M, Sawayama E, Sawayama T, Miyaoka H. Reversible paroxetine-induced symptomatic hypothyroidism. Pharmacopsychiatry 2007;40:201-2.  Back to cited text no. 10
    
11.
Eker SS, Akkaya C, Ersoy C, Sarandol A, Kirli S. Reversible escitalopram-induced hypothyroidism. Gen Hosp Psychiatry 2010;32:7.e5-7.  Back to cited text no. 11
    
12.
Harel Z, Biro FM, Tedford WL. Effects of long term treatment with sertraline (Zoloft) simulating hypothyroidism in an adolescent. J Adolesc Health 1995;16:232-4.  Back to cited text no. 12
    
13.
Mazokopakis EE, Karefilakis CM, Starakis IK. Escitalopram-induced subclinical hypothyroidism. A case report. Hormones (Athens) 2012;11:101-3.  Back to cited text no. 13
    



 
 
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