I've heard of both. I've also heard of a case where T3 supplementation triggered a panic attack, but I think the dosage was too high and that person was prone to panic. T3 is much more active than T4 -- and as I understand it, T4 is active only insofar as it is converted to T3 in your body (a reaction that depends in part on selenium). There is also evidence that T4 might convert to T3 fine in your body but poorly in your brain (see below). In my opinion, the psychiatrist's plan of T3 augmentation makes more sense given the evidence on the matter, though it brings a larger risk of hyperthyroidism -- and I totally understand why the endocrinologist suggested T4 instead, but I think it is largely an artifact of the way hypothyroidism is treated. 25 mcg of T3 is I think a bit high of a dose to start, I'd feel more comfortable with a starting dose of like 5 mcg and slowly go up as seems necessary.
What sort of depression symptoms are most prominent for you? Are your symptoms more like low energy, hypersomnia, low motivation, etc., or more anxious, insomnia, especially bad in the morning? And is your mood fairly reactive to good/bad events or is it pretty much just a solid depressed mood regardless of what happens?
Also, was your TSH high before the T3 was added or after? And when you say 'high,' do you mean higher than 4.0 mIU/L?
The most recent solid review article I could find was Rosenthal, L. J., Goldner, W. S., & O’Reardon, J. P. (2011). T3 Augmentation in Major Depressive Disorder: Safety Considerations.
American Journal of Psychiatry, 168(10), 1035–1040. doi:10.1176/appi.ajp.2011.10030402 It speaks to both the mechanisms and compares T3 to T4. Here are some relevant parts:
Mechanism discussion:
T3 acts in the cell nucleus, stimulating gene expression and energy metabolism in cells in every organ and potentially enhancing neurogenesis in the CNS (2). T3, both alone and in combination with fluoxetine, modulates gene transcription, with changes in mRNA coding for the 5-HT1A and 5-HT1B receptors (3). In the CNS, T4 conversion to T3 occurs intracellularly, which may be why T3 administration seems to have particular benefit in the treatment of affective disorders (4). The enzymes responsible for the conversion of T4 to T3 are also different in the CNS, perhaps explaining individual responses to T3 supplementation and the variability of symptoms in subclinical hypothyroidism. Cooper-Kazaz et al. (5) have demonstrated that genetic polymorphisms in the type 1 deiodinase (DIO1) gene, which assists in the conversion of T4 to T3, might help determine which patients will respond to T3 augmentation.
It is also possible that T3 acts directly as a neurotransmitter or that it directly influences neurotransmission through monoamines (3). Actions at noradrenergic, serotonergic, and beta-adrenergic neurons have all been demonstrated, largely through studies of hypo- and hyperthyroid states. Rodent studies have demonstrated serotonergic effects of T3 and T4, supporting the idea that serotonergic transmission is enhanced by normal thyroid functioning, potentially through desensitization of the 5-HT1A autoreceptor (6). T3 was initially thought to be active solely within the noradrenergic projection pathway, and it may serve as a co-transmitter with norepinephrine in the limbic system, but it has also been demonstrated in high concentrations in the serotonergic raphe nuclei and their projections (7).
I think it is fascinating that the conversion of T4-->T3 works differently in the CNS than everywhere else in the body... This suggests that the reason why T3 supplementation works in people with normal thyroid levels is that perhaps they have low T3 in the CNS but normal T3 elsewhere. If this is the case, T3 but not T4 supplementation would help.
Adjunctive w/ TCA:
The majority of the evidence base for use of T3 is for its coadministration with tricyclics. Two meta-analyses of T3 coadministration with tricyclics have been published, one reviewing acceleration trials (9) and the other augmentation trials (10). Acceleration is defined as the use of T3 at commencement of antidepressant treatment to enhance and hasten response. Augmentation is the administration of T3 in patients who are unresponsive or partially responsive to an adequate course of antidepressant treatment initiated previously.
Acceleration of antidepressant response with T3.
A meta-analysis by Altshuler et al. (9) of six double-blind, placebo-controlled studies (125 patients total) of T3 acceleration of tricyclics was positive. By definition, these were short-term studies of 2 to 3 weeks, and none discussed the option of continuing T3 once antidepressant response was achieved. In addition, many were conducted before the advent of more sensitive assays of thyroid functioning in the late 1980s. Three of these acceleration studies (11–13) obtained initial lab values of protein-bound iodine and looked at ankle jerk reflexes and serum T4 binding, but none performed follow-up testing. No differences in baseline thyroid tests were found between patients who responded to T3 and those who did not, but some authors speculated that there may have been subtle thyroid dysfunction in the responders that was undetectable by the assays. In addition, a significant gender effect was observed, with women responding more robustly than men. While women generally have been found to have higher rates of both comorbid depressive syndromes and thyroid disease, a consistent association has not been replicated.
Augmentation of antidepressant response with T3.
Aronson et al. (10) conducted a positive meta-analysis of T3 augmentation of tricyclics, finding eight controlled clinical studies with 292 patients. The studies were up to 12 weeks long, and several performed baseline and follow-up modern thyroid assays (4, 14–16). One positive study in 1977 conducted initial thyroid screening and additionally tested the CSF monoamine metabolites 5-hydroxyindoleacetic acid and homovanillic acid, hypothesizing that the mechanism of treatment with T3 was an increase of available monoamines (17). However, the study found no differences in CSF monoamine metabolites between the placebo and active T3 groups or between responders and nonresponders to T3.
Thase et al. (14) found no association between results of thyroid function tests or TRH stimulation testing at baseline and outcome in a subset of patients treated with T3. Joffe and Singer (4) evaluated T3 versus T4 in a randomized trial and found significant changes after 3 weeks in T3, T4, free T4, TSH, and T3 resin uptake in both groups, but these changes were not positive predictors of response; the main finding was that T3 was more effective than T4 as an augmenter. A 2-week augmentation study of lithium and T3 (15) found in 1993 that the two were equally effective and outperformed placebo, with baseline TSH documented as being within normal range.
Adjunctive with SSRIs:
T3 in Conjunction With SSRIs
Recently a number of studies have examined the augmentation of selective serotonin reuptake inhibitors (SSRIs) with thyroid hormone, but the data are more limited than with tricyclics. A review by Cooper-Kazaz and Lerer (18) found that not enough data were available yet for a meta-analysis but that a positive trend was revealed when the available double- and single-blind studies were analyzed. Papakostas et al. (19) reported a negative meta-analysis using strict inclusion criteria and finding only three adequate double-blind, randomized, placebo-controlled studies. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (20) evaluated SSRI augmentation using either lithium or T3 and found no statistical difference in efficacy between the treatments, but T3 had superior tolerability and adherence. All of these studies were short term, with the longest (STAR*D) lasting 12 weeks.
Two studies of T3 in combination with SSRIs included baseline and follow-up thyroid testing. In the first, Cooper-Kazaz et al. (21) compared sertraline (50–100 mg) combined with either T3 (25–35 μg) or placebo in an 8-week study and found that the sertraline-T3 combination produced superior response and remission rates. After 8 weeks of T3 supplementation, the mean TSH level fell significantly from 1.70 μIU/ml at baseline to 0.28 μIU/ml in responders, whereas nonresponders had mean pre- and posttreatment levels of 1.88 μIU/ml and 0.76 μIU/ml, respectively; responsiveness to treatment was significantly correlated (p=0.01) with the change in TSH level, suggesting that the therapeutic benefit could have been due to changes in the thyroid axis in this population. In a post hoc analysis, baseline T3 levels in patients who responded to T3 augmentation were significantly lower than in those who did not respond (107.60 ng/dl compared with 137.4 ng/dl, p=0.002). There was also a small but significant decline in TSH levels in the placebo group.
A combination study by Appelhof et al. (22) in which 124 patients were randomly assigned to receive paroxetine combined with 25 μg of T3, 50 μg of T3, or placebo showed a statistically significant dose-dependent increase of T3 levels along with lowered T4 (the final T4 levels after 8 weeks of treatment were 0.9 pmol/liter in the placebo group, 0.6 pmol/liter in the 25-μg T3 group, and 0.4 pmol/liter in the 50-μg T3 group). Significant changes in thyroid function on testing were associated with significant side effects in nine of 28 patients in the 50-μg group, including sweating, tremor, nervousness, and palpitations, but there were no significant differences between the 25-μg T3 and placebo groups. It is possible that noradrenergic effects of paroxetine due to norepinephrine transporter blockade exacerbated somatic symptoms that were consistent with a hyperthyroid state. Efficacy outcome was negative, with no differences between placebo and the two T3 groups.
While T3 compared well with lithium in STAR*D (20), and results with T3 as an augmentation or combination strategy are encouraging, more controlled trials are needed to fully determine the efficacy of T3 in combination with SSRIs.
Long-term Safety + reason the endocrinologist didn't like the idea:
There is good evidence to suggest that T3 administration is helpful in the treatment of depressive states, but only limited data are available on long-term safety. Few of the randomized controlled studies of T3 included both initial and follow-up thyroid function testing; those that did such testing showed expected changes in the thyroid axis and were largely reassuring on the issue of significant side effects. Many psychiatrists are nevertheless uncomfortable prescribing thyroid hormones to essentially euthyroid patients, and some of our colleagues in endocrinology may also find this practice controversial.
and
There is no consensus in endocrinology on use of thyroid hormone for the treatment of depression in euthyroid patients. When treating patients with hypothyroidism, endocrinology guidelines generally recommend using T4 monotherapy (25). Multiple studies, including a meta-analysis, have evaluated the difference between T4 monotherapy and T3/T4 combination therapy for the treatment of hypothyroidism. Overall no meaningful statistical differences have been found between the two regimens (26–31). Nevertheless, some studies have reported patient preference for combination therapy that was not explained by symptom outcomes, neurocognitive changes, or quality-of-life assessments (27). In one study (28), 44% of the patients reporting a preference for combination therapy had a suppressed TSH level, suggesting overreplacement of thyroid hormone. A study from Denmark (32) evaluated T4 monotherapy compared with combination T3/T4 therapy while maintaining equivalent TSH values. Quality-of-life scores and depression and anxiety rating scores were significantly better in seven of 11 categories with combined therapy compared with monotherapy, and 49% of patients preferred combination T4/T3 therapy, compared with 15% who preferred T4 monotherapy.
In euthyroid patients, high T3 dosages carry a higher risk of induction of hyperthyroidism. In this respect, preexisting hypertension, tachycardia, and hyperglycemia could all potentially be worsened by hyperthyroidism (33). Subclinical hyperthyroidism has also been associated with long-term side effects, including reduced bone mineral density and an increased risk of osteoporosis, especially in postmenopausal women (34, 35), and an increased risk of atrial arrhythmias (36). Thus, when thyroid hormones are used in treating depression, clinicians should closely monitor patients for biochemical or clinical evidence of hyperthyroidism.
There is also evidence that in patients being treated for hypothyroidism with T4 monotherapy, when they were switched to T4/T3 combined therapy they noticed that their mood was brightened, which I think is further evidence in support of T3 > T4.
From a different article -- Cooper-Kazaz, R., & Lerer, B. (2008). Efficacy and safety of triiodothyronine supplementation in patients with major depressive disorder treated with specific serotonin reuptake inhibitors. The International Journal of Neuropsychopharmacology, 11(5), 685.
Evidence in favor of T4 supplementation, particularly in bipolar disorder (though also concluding that T3 may be better):
T4 has been studied less extensively than T3 in the treatment of affective disorders. This may be due to the fact that T4 is converted to the more potent T3, which is the active hormone. Nevertheless, there is evidence for efficacy of T4, particularly in patients with bipolar disorder. The addition of supraphysiological doses of T4 to antidepressant-resistant unipolar and bipolar depression, improved the outcome in two open clinical studies (Bauer et al., 1998; Pfeiffer et al., 2004). Supraphysiological doses of T4 also improved bipolar disorder prophylaxis in a prospective open study (Bauer et al., 2002b). In a recent open study, moderate doses of T4 successfully augmented serotonergic antidepressants in female patients with refractory unipolar or bipolar depression (Lojko and Rybakowski, 2007). Several studies support specific
efficacy of T4 in the treatment of rapid-cycling bipolar disorder, reducing both amplitude and frequency of manic and depressive phases (Afflelou et al., 1997; Bauer and Whybrow, 1990; Whybrow, 1994). Finally, in one study comparing T4 and T3 potentiation of tricyclic antidepressants (TCAs), significantly more *patients responded to T3 compared to T4 (Joffe and Singer, 1990). In one study supraphysiological doses of T4 were associated with serious adverse effects (Pfeiffer et al., 2004).
Another study on this question -- Hage, M. P., & Azar, S. T. (2012). The Link between Thyroid Function and Depression. Journal of Thyroid Research, 2012, 1–8. doi:10.1155/2012/590648
Relevant quote:
Fewer studies assessed the efficacy of T4 in the treatment of affective disorders. Joffe and Singer found a significantly higher response to tricyclic antidepressants with T3 (53%) compared to T4 (19%) [71]. However, use of T4 in supraphysiological doses to treatment-resistant unipolar and bipolar depression was effective in approximately 50% of patients as reported by Baumgartner in a review of eight open clinical trials (N=78) [72]. Surprisingly, T4 in high doses was well tolerated even in patients treated for up to 51 months. However, in healthy subjects, supraphysiological T4 doses were less well tolerated due to higher increments in thyroid hormones after supplementation [73]. A possible explanation would be a greater inactivation of T4 to rT3 in depressed patients compared to healthy subjects [74].
Hope that helps! I assume from your post that you've tried lithium and lamotrigine? You should definitely try the MAO-Is before any of that more extreme stuff you mentioned, they can work wonders when nothing else works...
Now I'm going to go back through it all carefully...
