The use of thyroid hormone has a long history in psychiatry. It is one of the oldest treatments we have dating back to the 1930’s when desiccated sheep thyroid was used to treat “disorders of periodic catatonia”. Today, the use of thyroid hormone (TH) for treatment-resistant depression is promoted by some of the most respected clinical guidelines for mood disorders in Canada and the United States. The efficacy and safety of TH in depressed patients is supported by numerous studies including the well-known STAR*D study (Nierenberg et al., 2006).

One theory as to why TH is helpful for depression is that it may be correcting an underlying problem with the trafficking of TH in the brains of depressed patients. Depressed patients with normal circulating levels of TH may have a diminished ability to transport TH into the cell. The transport of TH into cells is an energy intensive process, requiring a lot of cellular energy in the form of ATP (Hennemann et al., 2001). Depressed patients are more likely to have mitochondrial dysfunction for a variety of reasons and may not produce enough ATP to meet the brain’s extremely high energy demands (Manji et al., 2012), including the energy demanding process of transporting thyroid hormone into brain cells.

The pituitary gland tightly regulates how much thyroid hormone is produced by the thyroid gland. The pituitary has its own set of thyroid hormone transport systems that is not energy intensive and does not require ATP. For this reason, the pituitary is not vulnerable to the same type of cellular level hypothyroidism that other tissues may experience when there is mitochondrial dysfunction. This may explain why circulating thyroid hormone levels can appear normal in a person who is clinically exhibiting symptoms of hypothyroidism that originates from a defect at the cellular level.

The brain has its own system for transporting thyroid hormones that is distinct from other tissues in the periphery. Transthyretin is a thyroid hormone binding protein that is found in abundance in the cerebral spinal fluid that bathes the brain. Transthyretin binds to thyroid hormone (T4) and delivers it across the blood brain barrier. Human subjects with refractory depression have significantly lower concentrations of transthyretin in their cerebral spinal fluid when compared to healthy control subjects (Sullivan et al., 1999). This is one possible way there can be a thyroid hormone deficit in the central nervous system of depressed patients despite apparently normal thyroid hormone levels in the periphery.

TH raises serotonin in the cortical areas of the brain and increases serotonin receptor sensitivity. TH increases noradrenergic signaling throughout the body, affecting energy and metabolism. When it works for treatment-resistant depression, TH can dramatically improve energy, depressed mood, cognition, and anxiety. It may reduce appetite in the beginning and cause a little bit of weight loss, but later it tends to increase appetite without causing weight gain.

Supraphysiological doses of TH was shown to be generally well tolerated and highly effective in patients with treatment-resistant depression (T. F. Kelly & Lieberman, 2009; T. Kelly & Lieberman, 2009). Depressed patients appear to tolerate high doses of TH much better than healthy control subjects (Bauer et al., 2002). High dose TH in healthy subjects caused significant side effects such as sweating, tremor, and elevated heart rate, which was severe enough to cause 38% of healthy subjects to drop out of the study early. In contrast, 0% of the depressed subjects dropped out due to side effects. This higher tolerance for supraphysiological doses of TH suggests a greater requirement for TH in individuals with treatment-resistant depression that cannot be ascertained by looking at thyroid function lab tests alone.

Depression is a complex system wide problem. Occasionally, some patients don’t respond even after numerous medications and lifestyle changes. When depression is resistant to standard treatments, hypothyroidism at the cellular level could very well be the missing link.

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References

Bauer, M., Baur, H., Berghöfer, A., Ströhle, A., Hellweg, R., Müller-Oerlinghausen, B., & Baumgartner, A. (2002). Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders. Journal of Affective Disorders, 68(2–3), 285–294. https://doi.org/10.1016/S0165-0327(00)00363-3

Hennemann, G., Docter, R., Friesema, E. C. H., de Jong, M., Krenning, E. P., & Visser, T. J. (2001). Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability. Endocrine Reviews, 22(4), 451–476. https://doi.org/10.1210/edrv.22.4.0435

Kelly, T. F., & Lieberman, D. Z. (2009). Long term augmentation with T3 in refractory major depression. Journal of Affective Disorders, 115(1–2), 230–233. https://doi.org/10.1016/j.jad.2008.09.022

Kelly, T., & Lieberman, D. Z. (2009). The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS. Journal of Affective Disorders, 116(3), 222–226. https://doi.org/10.1016/j.jad.2008.12.010

Manji, H., Kato, T., Di Prospero, N. A., Ness, S., Beal, M. F., Krams, M., & Chen, G. (2012). Impaired mitochondrial function in psychiatric disorders. Nature Reviews Neuroscience, 13(5), 293–307. https://doi.org/10.1038/nrn3229

Nierenberg, A. A., Fava, M., Trivedi, M. H., Wisniewski, S. R., Thase, M. E., McGrath, P. J., Alpert, J. E., Warden, D., Luther, J. F., Niederehe, G., Lebowitz, B., Shores-Wilson, K., Rush, A. J., & STAR*D Study Team. (2006). A Comparison of Lithium and T 3 Augmentation Following Two Failed Medication Treatments for Depression: A STAR*D Report. American Journal of Psychiatry, 163(9), 1519–1530. https://doi.org/10.1176/ajp.2006.163.9.1519

Sullivan, G. M., Hatterer, J. A., Herbert, J., Chen, X., Roose, S. P., Attia, E., Mann, J. J., Marangell, L. B., Goetz, R. R., & Gorman, J. M. (1999). Low levels of transthyretin in the CSF of depressed patients. The American Journal of Psychiatry, 156(5), 710–715. https://doi.org/10.1176/ajp.156.5.710

Medical Disclaimer: The information mentioned in this article is not intended to diagnose, treat, cure, or prevent any disease. The information provided is for educational purposes only and is not intended to replace the relationships with your medical provider(s). Before initiating any treatment, please first consult with your licensed medical provider.