Many depressed and bipolar patients have undiagnosed thyroid dysfunction as the underlying cause or major contributor to their depression that is not detected by standard thyroid tests (23-38). The dysfunction present with these conditions includes down regulation of D1 (reduced T4 to T3 conversion) and reduced uptake of T4 into the cell, resulting in increased serum T4 levels with low intracellular T3 levels (24-26,30,31,35,39-45) and upregulated D3, resulting in elevated reverse T3 (23,24,30,31), which blocks thyroid effect (147,184-194) and is an indicator of reduced transport of T4 into the cell (183,193). Additionally, studies show that depressed patients have reduced T4 transport across the blood brain barrier due to a defective transport protein, transthyretin, resulting in significantly reduced thyroid levels in the brains of depressed patients despite “normal” serum levels and standard thyroid tests (23,39,40) as well as a reduced TSH response to TRH (28-31,43-50).
It is not surprising that T4 and T4/T3 combinations may have some benefit in depression; but due to the suppressed T4 to T3 conversion from suppressed D1(24-26,30) and reduced uptake of T4 into the cell and brain (25,31,39,40), timed-released T3 is significantly more beneficial than T4 or T4/T3 combination supplementation (25,41,202,225-227).
In the International Journal of Neruopsychopharmacology, Posternak M et al. published a double blind placebo control trial of 50 patients with normal thyroid function as defined by a normal TSH (1.5 +/- 0.8). The patients were randomized to receive 25 mcg of T3 or placebo in addition to antidepressant therapy (221). The study found almost a 2-fold increase in response rate with T3 and a 4.5 times greater likelihood of experiencing a positive response at any point over a six-week period with the addition of T3. Side effects were higher in placebo group on 10/11 criteria including a significant increase in nervousness with the placebo group.
Kelly T et al. investigated the effectiveness of T3 for the treatment of biopolar disorder in who patients had failed to adequately respond to an average of 14 medications used to treat their bipolar disorder. The average dose of T3 used was 90.4 mcg (range 13 mcg-188 mcg). The medication was found to be well tolerated and 84% experienced significant improvement and 33% had a full remission. Again, this is in patients who had not previously responded to numerous medications. One patient who was switched to T4 for cost reasons experienced a return of symptoms, which resolved with the reintroduction of T3. The authors concluded, “Augmentation with supraphysiologic doses of T3 should be considered in cases of treatment resistant bipolar depression… (227).” The authors thanked several doctors who encouraged them to go beyond the traditional 50 mcg of T3 because it has helped so many of their patients.
With over 4000 patients, The Star*D Report is the largest trial comparing antidepressant effectiveness for depression. It found that 66% of patients fail to respond to antidepressants or have side-effects severe enough to discontinue use. Of those who do respond, over half will relapse within one year (228). The trial found that T3 was effective even when other medications — such as citalopram (Celexa), bupropion (Wellbutrin), sertraline (Zolft), venlafaxine (Effexor), or cognitive therapy – were not. It was shown to be 50% more effective, even with the less than optimal dose of 50 mcg, under direct comparison with significantly less side effects than commonly used therapeutic approaches with standard antidepressants. The authors included a case study to exemplify the effectiveness of T3, especially when other medications are not:
- “Ms. “B,” a 44-year-old divorced white woman, became depressed after losing her job as a secretary in a law firm. She initially sought treatment from her primary care physician and then entered the STAR*D study. Ms. B met criteria for major depressive disorder and generalized anxiety disorder. Her baseline QIDS-SR score was 16. After 12 weeks on citalopram, her QIDS-SR score was 10 [minimal response]. She was then randomly assigned to augmentation with buspirone; she soon experienced gastrointestinal distress, and she stopped taking buspirone after 6 weeks. She elected to try one more augmentation agent and was randomly assigned to T3 augmentation. When she started T3 augmentation, her QIDS-SR score was 12. After 4 weeks, she felt that her mood and energy had lifted substantially. She felt better able to make decisions, organize, and prioritize and felt that she was able and ready to look for another job. “I felt as if my brain suddenly had oxygen,” she said, “and everything became clearer.” After 12 weeks, Ms. B felt back to normal, and her QIDS-SR score was 0 [complete resolution of symptoms] (228).”
With an understanding of thyroid physiology and associated dysfunction that is present in depressed patients, it is clear that timed-released T3 supplementation should be considered in all depressed and bipolar patients despite “normal” serum thyroid levels. Additionally, straight T4 should be considered inappropriate and suboptimal therapy for replacement in such patients.