A Comparison of Effects of Fluoxetine and Nortriptyline on the Symptoms of Major Depressive Disorder

To the Editors: An association of quetiapine treatment with thyroid dysfunction has been reported in clinical trials and in product labeling for the drug, which show small dose-related decreases in thyroid hormone levels, particularly total T4 and free T4, although only 0.4% seem to experience significant increases in thyroidstimulating hormone (TSH) levels. To our knowledge, there are only a few cases of quetiapine-induced hypothyroidism reported in the literature.5–8 Apparently, most of them are patients either with a history of compromised thyroid function5,7 or with normal TSH levels; furthermore, no antithyroid antibody titers were measured in these studies. Quetiapine fumarate is an atypical dibenzothiazepine agent whose antipsychotic properties are apparently mediated through combined action at dopamine (DA2) and serotonin (5-HT2) receptors; its efficacy is comparable to haloperidol, and it is well tolerated in the recommended doses. We report a case of a depressed patient on quetiapine who developed hypothyroidism that remitted after drug discontinuation. An autoimmune mechanism responsible for this reaction to quetiapine is being suggested. A 49-year-old woman diagnosed with a 20-year lasting dysthymia and 2 major depressive episodes 14 and 5 years ago was admitted to our hospital for treatment of persistent disabling dysthymic symptoms and impaired functioning. Over these years, the patient was administered a variety of antidepressant and anxiolytic agents with more or less success; during the last 4 years, she was abusing high doses of zolpidem (up to 150 mg/d) which had a mood-elevating effect and helped with her chronic sleep problems. In an effort to discontinue zolpidem and treat her low mood as well, 6 months before her admission, the patient was given venlafaxine (300 mg/d), paroxetine (30 mg/d), and quetiapine (800 mg/d) with no appreciable improvement of her condition. At the time of admission, although the patient’s past medical record was negative for a thyroid disease—the patient had been regularly screened for thyroid dysfunction because of a positive family history for hypothyroidism in 2 siblings and her persisting depressive symptoms—routine laboratory workup showed abnormal thyroid tests compatible with hypothyroidism (first assessment in Table 1). Besides, the clinical picture was suggestive of hypothyroidism; that is, there was modest weight gain, decline of appetite, hoarseness of voice, expressionless face, slowing of intellectual and motor activity, and constipation. Therefore, based on the few existing case reports implicating quetiapine in thyroid function alterations, the likelihood of a quetiapine-induced hypothyroidism was raised, and quetiapine was tapered off and discontinued over a week, while keeping the rest of medication unchanged. This resulted in the rapid normalization of thyroid (total T3, total T4, free T4, and TSH) laboratory values within the next 2 months (as shown in Table 1) and a concomitant steady mood improvement. The above association appears to be complex and remains to be clarified. Competitive metabolism of thyroid hormones and quetiapine by UDP-glucuronosyltransferase has been suggested as a plausible mechanism for the decrease of levels of thyroid hormones during quetiapine treatment. However, also a direct action of quetiapine on the hypothalamopituitary axis cannot be excluded, although TSH levels have been reported to remain unaffected, which is in disagreement with the case we present. Finally, it is noteworthy that the antithyroid peroxidase autoantibodies (anti-TPOs), considered as the most sensitive and specific marker of thyroid autoimmunity, were initially greater than normal limits but within the reference range after a couple of months after quetiapine discontinuation. This may be an indication either of an immune reaction due to quetiapine, similar to the one frequently reported in patients who develop subclinical or clinical hypothyroidism with associated circulating antiTPOs during lithium therapy,11–13 or an accidental finding corroborating the observation that mood and anxiety disorders frequently coexist with thyroid autoimmunity in the community. Further study of the quetiapine– thyroid axis interaction is obviously warranted. Meticulous long-term followup laboratory data are needed to draw definite conclusions on any potential relationship. However, monitoring of thyroid function at least in quetiapinetreated patients with a history of or a vulnerability to thyroid disease is strongly recommended.