The Treatment of Depression with T3

Psychiatry is one of the few specialties where we are "allowed" to use T3 (the active thyroid hormone, instead of the safer prohormone T4) for treatment of resistant depression.  (Please see yesterday's post for a thyroid primer).  The literature for its use is extensive but old.  Much of it was done before there were very reliable lab tests for thryoid function, so symptoms such as pulse, insomnia, anxiety, palpitations and reflexes were measured to judge whether someone was made "hyperthyroid" with the treatment or not.  I suppose that made them bolder, back in the day (also, there were very few options, medication-speaking, so all the people studying resistant depression did a little study on T3.  For the same reason there is a ton of data on lithium for bipolar disorder. It was the only game in town for decades.)

In any event, I thought I would take the opportunity to catch up on the latest and greatest in T3 supplementation and safety issues, particularly since the very large STAR-D trial used T3 and found it equally efficacious in resistant depression to lithium use, and better than many other pharmaceutical tinctures.  Fortunately there is an up to date review from the Green Journal, T3 Augmentation in Major Depressive Disorder:  Safety Considerations.  The article had a number of interesting points, particularly with regards to the standard endocrinology method of treating hypothyroidism with T4 monotherapy.  I'll get to that in a bit.

All right.  So the weakness of most of the studies is that they were short, typically 2-12 weeks.  Also, most of them were studies of augmentation or acceleration with the old-fashioned antidepressants, the tricyclics (or TCAs).  And when I think of the tricyclics, I think of a cruder but much more medication-stringent time.  TCAs have lots of side effects (weight gain, dry mouth, fast heartbeat) and are fatal in overdose.  However, they are effective for many,  and folks with very serious depression where they were nonfunctional and suicidal who responded to the medicine would take them because being without proved worse than the side effects of being on them.  The SSRIs, with fewer (but still not insignificant) side effects had not yet been invented, and mildly depressed women were still being given B12 shots by their primary care doctors, who also advised them to smoke to give them energy and motivation.  (Or gave them a tiny bit of dexedrine in the morning and some barbituates at night.)

So we are dealing with a subset of very depressed people who do not respond to the tricyclics.  They don't seem to be hypothyroid by physical symptoms or the lab tests of the time, but a certain percentage would respond to augmentation with active thyroid hormone.  In addition, "accelerating" the tricyclics (which, like most antidepressants, take several weeks to kick in) with a dose of T3 up front (isolated to 2-4 weeks, then discontinued) seemed to work too.  There are fewer studies of augmentation with SSRIs, but these are also short and the results are less definitive.

Why would T3 help? What does T3 do in the central nervous system? Well, a lot.  The thyroid has fingers in almost every physiological pie, after all.  And T3 not only may act as a direct neurotransmitter, but it also seems to increase the efficiency of serotonin signaling, much like a modern SSRI.  T3 also enhances neurogenesis in the central nervous system and could also enhance noradrenergic signaling.  The conversion from T4 to T3 occurs all over the body, but in the central nervous system it uses different active genes than in the periphery and occurs within the cells.  These differences could explain my own clinical observations--that T3 augmentation seems to work best in folks already diagnosed hypothyroid that are on T4 monotherapy.  And the literature (such as it is) seems to support my observation (1).

(I am ignoring selenium and iodine deficiency for the moment as does this literature.  Much of North America has fairly selenium-rich soil except some of the Eastern Coastal plain.  Given the wide geographic distribution of vegetables and other produce, frank selenium deficiency is rare.  Also, with the advent of iodized salt, frank iodine deficiency is also rare so that babies are very rarely born with congenital hypothyroidism.  These facts do not mean that our selenium and iodine levels are optimized, but, again, I would say a frank deficiency is rare).

So the good news is that T3 augmentation seems to help some and (relying on some limited longer-term data up to several years) it seems to be relatively safe (particularly in the short term), though post-menopausal women need to watch the possible side effect of osteoporosis, and there is a continued risk of heart arrhythmia.  So in heart-healthy and strong-boned folks with a serious bout of depression, a small dose of T3 is a good option, even if they are clinically and by laboratory measure euthyroid (normal thyroid) particularly if they are the type to have serious episodes and then bounce back, rather than the more chronically low-grade depressed people.

The goal for longer-term treatment is to use a dose that keeps TSH at the low end of normal (or even somewhat below normal if there are no hyperthyroid symptoms) and free T3 at the high end of normal (I can tell you that the recommended dose of 25-50mcg almost always seems to overshoot this goal, but it probably reflects the long history of shorter-term studies), while monitoring bone density and cardiac side effects frequently, particularly in post-menopausal women.   T3 augmentation does seem to work better in folks with higher TSH and lower free T3s at baseline, suggesting we are, indeed, treating a type of "subclinical hypothyroidism" with depression symptoms, maybe those who convert T4 to T3 just fine in the periphery but who are poor converters in the central nervous system.  Again, this would support my clinical observation of long term treatment.  Fairly useless in the euthyroid except for temporary severe exacerbations, but useful in the hypothyroid or subclinical hypothyroid.

And what about those endocrinologists who are so very down on combination therapy with T3 and T4 for hypothyroidism?  I've had some tell me point blank (over the phone) there is no literature support for treatment of hypothyroidism with anything but T4 monotherapy.  I've had to pull out the "psychiatric indication" card and then they will back off, mostly because most folks in medicine are a little scared of psychiatrists and psychiatric patients.  There's a little bit of literature of psychiatrists as the last shamans of Western medicine.  We don't typically wear the white coats.  We treat the unexplained.  We exist apart.  We may well be witch doctors.  In the US, insurance payments regard "mental health" and "medical" as separate entities.  But I'm wandering a bit.

Well, what about that literature for combination therapy (T3 and T4) vs monotherapy (T4 alone) for hypothyroidism?  Multiple studies and a meta-analysis have proven no benefit for combination therapy over T4 alone.  However, in several studies, patients had a preference for combination therapy that could not be explained by lab results or quality of life measurements.  In Denmark, one study using double-blind crossover methods treated patients with T3/T4 or T4 alone to equivalent TSH levels.  49% of the patients preferred combination therapy compared to 15% who preferred T4 monotherapy, and quality of life measures and depression and anxiety ratings were generally better on combination therapy than on T4 alone.  T4 monotherapy is safer, less likely to result in hyperthyroidism.  But to say there is no support for the alternative is incorrect.

From the evolutionary point of view in general a bit of seaweed and some selenium won't hurt.  In the case of Hashimoto's one must take care with iodine supplementation lest one worsen the condition (this seems less likely to happen if selenium is topped off).  Selenium excess is also a pretty bad idea.

But looking at the more modern basis of hypothyroid and depression treatment, the science behind T4 monotherapy is not yet ironclad.  T3 might yet come back from its banishment to psychiatry.