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Thyroid in Bipolar Depression

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Dr. Tammas Kelly shares tips on high dose thyroid in treatment-resistant bipolar depression.

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Published On: 04/25/2022

Duration: 14 minutes, 00 seconds

Related Article:Thyroid Augmentation in Bipolar Disorder,” The Carlat Psychiatry Report, April 2022

Chris Aiken, MD, Kellie Newsome, PMHNP, and Tammas Kelly, MD, have disclosed no relevant financial or other interests in any commercial companies pertaining to this educational activity.


In this third and final episode in our review of bipolar depression, Tam Kelly shares his experience with high dose thyroid.

Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. I’m Chris Aiken, the editor in chief of the Carlat Report. And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

KELLIE NEWSOME: This month, we’ve taken you on a tour of 22 therapies for bipolar depression, and today we cover #22: High dose thyroid.

CHRIS AIKEN: Thyroid augmentation is one of those treatments that clinicians often read about but rarely use, and part of the reason is that the nitty gritty details of dosing and managing this treatment are a bit more complex than they are for, say, venlafaxine. So in this month’s Carlat Report we interviewed Tam Kelly. Tam has treated over 2,000 people with high dose thyroid, most of whom had bipolar disorder, and he wrote a book about it – the Art and Science of Thyroid Supplementation in the Treatment of Bipolar Depression. But first, a preview of the CME quiz for this episode.

Which statement about high-dose thyroid in bipolar disorder is true?

A. Thyroid hormone treats bipolar depression, but only when added to an antidepressant

B. Thyroid hormone treats depression but can cause mania

C. Thyroid hormone treats bipolar depression but causes anxiety and irritability

D. Thyroid hormone treats depression and rapid cycling

CHRIS AIKEN: Thyroid hormone is better known as an augmentation strategy for antidepressants in unipolar depression. Meta-analyses rank it among the top therapies for treatment resistant depression, along with lithium and antipsychotic augmentation. But that’s not what this episode is about – this is about treatment resistant bipolar depression, and warning – the evidence supporting its use is not as strong as it is for unipolar – there are 2 or 3 controlled trials, depending on how you count them – but that pretty much puts it on par with the small crop of options in treatment resistant bipolar depression, which we walked you through in our last episode.

KELLIE NEWSOME: To recap, those were, in order of their clinical usefulness….

  1. Pramipexole, our top-line pick
  2. The modafinils: Provigil and Nuvigil, easy to use but not quite strong enough
  3. Ketamine ECT: Powerful but difficult to get
  4. Pioglitazone and celecoxib: novel meds with a mix of positive and negative studies

So where does thyroid fit on that list?

CHRIS AIKEN: I would place it near the top. But I’d emphasize that it is only for significant bipolar depression that is treatment resistant, but treatment resistance is defined as failure to recover after two medication trials.  

KELLIE NEWSOME: Dr. Kelly told us about 3 randomized controlled trials in treatment resistant cases – 2 in bipolar depression and 1 in rapid cycling bipolar disorder.

Dr. Kelly: There is a double-blind, placebo-controlled study showing that it works. There’s another double-blind, placebo-controlled study that failed because the males had such a high placebo response. But in females it worked. But overall it’s considered a failed study because of the high placebo response. 

There are numerous case series showing that it works – T3 and T4 that it’s helpful for bipolar in high doses, including mine with T3 with I think 129 or 139 patients on it for over five years. So yes it does continue to work though sometimes the dose needs to be increased.

CHRIS AIKEN: Some might think of thyroid as an upper, but I’ve argued on this podcast against thinking of medications as uppers and downers. It’s more complicated than that, and thyroid augmentation did not cause mania in these reports and in one of them it treated mixed symptoms. 

KELLIE NEWSOME: No one knows how thyroid augmentation works, but Dr. Kelly shared his best guess. 

Dr. Kelly: We know that bipolar’s have dysfunctional mitochondria, and it’s been well established that people with bipolar have low ATP levels inside their cells, and it takes ATP to get thyroid hormone across the cell membrane. Now that’s a very complex process of getting the thyroid across the cell membrane and it’s not completely understood. But it’s established that it does take ATP, so those three things are established. I think that creates a cellular hypothyroid state. 

The only place in the body that it doesn’t take energy to get thyroid hormone across the cell membrane is the pituitary. So the pituitary thinks there’s plenty of thyroid around while the rest of the cells are low. It’s a hypothesis, but it fits with the facts. And you know the higher doses just push enough inside the cells to make it up.

KELLIE NEWSOME: It’s almost analogous to insulin resistance in diabetes, where there is plenty of insulin in the body but the cells can’t make use of it. Dr. Kelly is hypothesizing that the brain cells in bipolar disorders – not the body but the brain – are unable to absorb thyroid so they need supraphysiologic doses to get what they are missing. But he also pointed out that it normalizes depressogenic changes on brain imaging.

Dr. Kelly: One of the important things to realize is about some of the support that thyroid works. There are two mirror imaging studies now that show that high doses of thyroid actually decrease some of the areas of the brain that are hyperactive that are associated with depression such as the dorsolateral prefrontal cortex; That’s the executive functioning area of the brain. It normalizes that. It helps that.

CHRIS AIKEN: That is interesting because normalizing the dorsolateral prefrontal cortex would – in theory – help mania as well as depression. But Dr. Kelly says the evidence stops there.

Dr. Kelly: Well, certainly I don’t think there are any studies on it. There are studies that it helps with rapid cycling.  I certainly see it help with rapid cycling in bipolar II’s and subthreshold bipolar’s. I don’t have experience enough for bipolar I to say, but the research and my clinical experience says it does help with rapid cycling which suggests that it would help with mania, but no research, no experience.

CHRIS AIKEN: So it’s a bit more complicated than uppers for depression and downers for mania, and there is a lot of overlap in the biology of these two mood episodes. Another stereotype is that thyroid augmentation causes anxiety, because anxiety is a symptom of thyrotoxicosis, but in one of those studies Dr. Kelly mentioned they did a secondary analysis looking at anxiety – and found that anxiety went down with high-dose thyroid in bipolar disorder.

Dr. Kelly: I do remember that study. It was not a good study, but I do agree that it can reduce bipolar anxiety.

KELLIE NEWSOME: Anxiety can be a side effect if you go too high in the dose, I mean, you can induce thyrotoxicosis with this treatment. But Kelly’s hypothesis is that high doses of thyroid are normalizing cellular function in the brain, and he told us about an unusual study that may not prove the point, but is at least consistent with it.

Dr. Kelly: In one of the more interesting papers out there from Germany, they gave, I think, 400 or 500 mg of T4 to refractory depression and refractory bipolar depressed patients and they all got better. But they also gave that to normal people to see what kind of effects that kind of dose would have on normal people. My question has always been how normal can you be to volunteer for something like that? But a third of the normal’s dropped out because they couldn’t hack the side effects and I believe most of the rest of the people left were having very difficult side effects. Thyrotoxic symptoms. Anxiety, sweating. I talked to the author and he said the people who volunteered for it were people in the lab, himself included. He said they were all “crawling-the-walls” with anxiety and sweating.

KELLIE NEWSOME: For the patients, high dose thyroid relieved their depression without any side effects, but for the normal subjects – the lab workers themselves – the treatment made them miserably anxious.

CHRIS AIKEN: And that gives you a hint of how Dr. Kelly doses thyroid medication in his practice. For more of that, check out our online article where he delves into all you need to know to get started with this therapy. The dosing, side effects, risks, and a pretty convincing answer about whether to use T3 or T4.

And now for the word of the day….Tovalt

15 years ago – exactly, to the day – on April 25, 2007 the FDA approved Tovalt, an orally disintegrating version of Zolpidem/Ambien. It was taken off the market not because of any problems, but because of poor sales, but you’ll occasionally see patients who used it and miss the slightly faster onset of action that orally disintegrating products have.

CHRIS AIKEN: Not to mention that Tovalt avoids the food interaction. Giving zolpidem with food delays the release by up to an hour, which can be dangerous for patients if they get out of bed before it kicks in. Food delays the release of other z hypnotics like zaleplon Sonata and eszopiclone Lunesta as well, but the effect is strongest with zolpidem.

KELLIE NEWSOME: But zolpidem is available as a sublingual form which probably has similar effects, but this is a confusing product because the sublingual goes by 2 names: Edluar and Intermezzo.  Basically Edluar is the full dose ambien sublingual meant to be taken before bed. Intermezzo – as in interrupted in the middle of the night- is a low-dose version that the FDA allows patients to take when they wake up in the middle of the night.

We learned about Tovalt from the new edition of the Medication Fact Book, one of the most popular books in the Carlat series which was just updated in its 6th edition by Talia Puzantian and Danny Carlat. The book has critical info on every psych med, including new releases like Caplyta and Libalvi, as well as treatment algorithms, natural therapies, and – my favorite part – a section on managing side effects where each side effect gets its own page. 

CHRIS AIKEN: My favorite part is the fun facts. Danny believes that medical education needs to be fun, or it can quickly turn boring. So he puts a fun fact about the history or cultural impact of the medication at the bottom of each page, as a kind of dopamine booster when you’ve made it through the technical parts. But I have to admit I cheated – when I got the book I read all the fun facts first. 

KELLIE NEWSOME: Here’s the fun fact for propranolol:

CHRIS AIKEN: You’re making me nervous.


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