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Hi! Jim Phelps here for the Psychopharmacology Institute. For this Quick Take, welcome to the strange and controversial world of subclinical hypothyroidism. First, the controversy of definition. Subclinical hypothyroidism is routinely described as a TSH that’s above normal with free T4 remaining in the normal range. In case you’ve been confused by this, as I was, “subclinical” in this context does not refer to symptoms, just lab results. We’ll encounter another more aggressive definition of clinically relevant but normal TSH shortly here.
Why should you as a practicing psychiatric specialist care about subclinical hypothyroidism? Because a TSH in the upper quartile of normal, meaning over 2.5 but still in the normal range according to the laboratory indices, has been associated with a higher frequency of depressive episodes, more severe symptoms, and poorer response to treatment in people with major depression.
Those who have values of over 2.5 but not over the upper limit of normal represent a larger percentage of people than you might think because the population distribution of TSH values is not a bell-shaped curve. It’s skewed. There’s a big hump around 1.5 and then a long tail extending way out toward 4. A 2018 review by Bruce Cohen and colleagues in the American Journal of Psychiatry suggests that anything over 2.5 is not normal from a mood point of view. And is subclinical hypothyroidism common? What percentage of your patients have it?
If you work with children and adolescents, here’s some insight from a new study from Germany that examined the prevalence of various levels of thyroid abnormalities in 360 depressed adolescents compared to a national reference cohort. They found that 10% of the depressed kids had subclinical hypothyroidism vs 2% of the reference cohort. Remember that this version of subclinical hypothyroidism is a TSH over the upper limit of the laboratory range of normal, with free T4 still in the normal range. For comparison, a 1996 study of adults with depression showed that 20% had subclinical hypothyroidism, but that was in a treatment-resistant population. So, it’s common.
Now, is subclinical hypothyroidism a cause of depression? Or is it a consequence? The authors of this German study stressed that this really isn’t known at this point. Nevertheless, thyroid hormone clearly has efficacy in the treatment of depression, which suggests that maybe there is a causal relationship here—meaning that thyroid function has something to do with causing depression, not just coming along as a consequence.
Nevertheless, here are some important specifics. First, the literature strongly supports thyroid hormone as an adjunct treatment, meaning an add-on to an antidepressant that’s not working well enough. But the support is not so strong. Indeed, it’s rather weak for a thyroid hormone as a treatment unto itself. That has interesting implications regarding the causality puzzle, right? In any case, adjunctive thyroid hormone can help even when thyroid measures are in the normal range. For example, when T3 was compared to lithium as an adjunct treatment in the STARD study, T3 was given without reference to baseline thyroid indices. Now, parenthetically, I really wonder if in the STARD, the responders to T3 might have been more likely to have a TSH over 2.5 compared to the nonresponders. In other words, they were in that group that Cohen and colleagues think as not normal, but their TSH is still in the “normal range.”
Let’s get back to the next point regarding thyroid hormone as a treatment for depression, and that’s the T4 or T3 question. If you’re going to use thyroid hormone as an adjunct, which form should you use? Endocrinologists lean toward T4, but in the literature on thyroid hormone as an adjunct treatment for depression, it’s mostly T3. The Cohen review doesn’t favor either. Instead, they emphasized that TSH should be driven below 2, that’s uIU/mL, unless side effects like agitation intervene. According to them, “in our own practices, unless response is seen at lower dosages, we often attempt to achieve enough thyroid hormone supplementation to drive the TSH to 1.0 or just below.” Got it? A TSH of 1.0 or just below in order to say “been there, done that.”
Perhaps the most important in this entire consideration of thyroid hormone is the metamessage: Thyroid hormone is part of the toolkit for psychiatrists. Monitoring TSH is part of our responsibility. We should not leave this to primary care, and we should be prepared to discuss this whole territory with endocrinologists. If you find that daunting, read the review by Bruce Cohen and colleagues in the American Journal of Psychiatry. It will empower you.
Abstract
Increased Prevalence of Subclinical Hypothyroidism and Thyroid Autoimmunity in Depressed Adolescents: Results From a Clinical Cross-Sectional Study in Comparison to the General Pediatric Population
Raphael Hirtz , Manuel Föcker, Lars Libuda, Jochen Antel, Dana Öztürk, Cordula Kiewert, Martin Munteanu, Triinu Peters, Dagmar Führer, Denise Zwanziger, Michael Thamm, Johannes Hebebrand, Corinna Grasemann
Objective: The study was undertaken to determine the prevalence of subclinical and overt thyroid dysfunction as well as thyroid autoimmunity in depressed adolescents in comparison to the general pediatric population. Additionally, the relationship between parameters of thyroid function and Beck Depression Inventory-II (BDI-II) scores was examined.
Methods: Parameters of thyroid function (thyrotropin, free thyroxine, thyroid peroxidase antibodies) and prevalence of thyroid dysfunction and autoimmunity were determined in 360 adolescents (11-19 years) with at least mild depression (BDI-II score > 13) between June 2016 and December 2019 and in a representative reference cohort without evidence of impaired mental health from a nationwide survey (German Health Interview and Examination Survey for Children and Adolescents [KiGGS], 2003-2006).
Results: There was a higher prevalence of thyroid peroxidase antibody positivity in depressed adolescents (mean ± SD BDI-II, 30.0 ± 10.4) compared to KiGGS participants (depressed adolescents: 5.8%, 95% CI [3.7-8.6]; odds ratio [OR] 1.9, P = .009, d = 0.36; KiGGS participants: 3.1%, 95% CI [2.5-3.9]). The prevalence of subclinical hypothyroidism was likewise higher in depressed adolescents (9.1%, 95% CI [6.3-12.4] vs KiGGS participants: 2.1%, 95% CI [1.6-2.7]; OR 4.7, P < .001, d = 0.85), but no other types of thyroid dysfunction had a higher prevalence. There was no significant relationship between parameters of thyroid function and BDI-II scores, as examined by multiple regression considering relevant covariates. The positive results were verified in a subsample of patients with a confirmed diagnosis of depression (N = 284).
Conclusions: The prevalence of subclinical hypothyroidism and of thyroid autoimmunity in depressed adolescents is increased. The etiology of these observations is not well understood, and further studies to examine the underlying relationship are required. Moreover, thyroid autoimmunity may constitute an additional risk factor for depression on its own.
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Reference
Hirtz, R., Föcker, M., Libuda, L., Antel, J., Öztürk, D., Kiewert, C., Munteanu, M., Peters, T., Führer, D., Zwanziger, D., Thamm, M., Hebebrand, J., & Grasemann, C. (2021). Increased Prevalence of Subclinical Hypothyroidism and Thyroid Autoimmunity in Depressed Adolescents: Results From a Clinical Cross-Sectional Study in Comparison to the General Pediatric Population. The Journal of Clinical Psychiatry, 82(2), 20m13511.
Related References
Cohen, B. M., Sommer, B. R., & Vuckovic, A. (2018). Antidepressant-resistant depression in patients with comorbid subclinical hypothyroidism or high-normal TSH levels. American Journal of Psychiatry, 175(7), 598-604.
