Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders

[helvella]

The other day someone mention high doses of levothyroxine used for treatment resistant depression. Today, this paper appears.

Have to say, I can't help wondering if the lack of cardiovascular issues in any way implies that these people have anything unusual about their systems which makes them particularly tolerant, or even in positive need of high levels of thyroxine? Too many thoughts spinning round.

J Affect Disord. 2018 May 30;238:213-217. doi: 10.1016/j.jad.2018.05.034. [Epub ahead of print]

Long-term treatment with supraphysiologic doses of levothyroxine in treatment-refractory mood disorders - A prospective study of cardiovascular tolerability.

Pilhatsch M1, Berghöfer A2, Mayer-Pelinski R1, Berghöfer G3, Ricken R4, Möckel M5, Kühnle Y6, Sauer C1, Whybrow PC7, Bauer M8.

Author information

1 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

2 Institute for Social Medicine, Epidemiology and Health Economics, Charité - Universitätsmedizin Berlin, Berlin, Germany.

3 Herzmedizin Berlin, Berlin, Germany.

4 Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin Berlin, Berlin, Germany.

5 Division of Emergency Medicine, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Mitte, Berlin, Germany.

6 Medical Department, Division of Cardiology, Charité - Universitätsmedizin Berlin, Berlin, Germany.

7 Department of Psychiatry and Biobehavioral Sciences, Semel Institute for Neuroscience and Human Behavior University of California Los Angeles (UCLA), Los Angeles, CA, USA.

8 Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany. Electronic address: [e-mail].

Abstract

BACKGROUND:

To investigate long-term effects of adjunctive prophylactic treatment with supraphysiologic doses of levothyroxine (L-T4) on cardiovascular tolerability in 23 patients with treatment-refractory mood disorders.

METHODS:

Starting point for a comprehensive cardiovascular assessment in patients was the indication for long-term maintenance treatment with L-T4 (mean dose 463 mcg/day). Prospective longitudinal assessment of the cardiovascular risk profile included in addition to a physical examination and blood pressure measurement, several technical investigations: resting electrocardiogram, transthoracic echocardiogram, cardiac stress test, and holter electrocardiogram. Statistical analysis was performed by linear mixed effects models (LMM) for evaluation of longitudinal changes in various heart measures.

RESULTS:

During the mean observational period of 20.4 months none of the heart measures reached statistical significance in change over time. None of the assessed cardiac parameters of each single patient was in a range predictive for cardiac dysfunction.

LIMITATIONS:

Small sample size, no technical cardiac investigations prior to L-T4 initiation, no patient control group with mood disorders who did not receive L-T4.

CONCLUSIONS:

Results of this study indicated no increased risk for cardiovascular disorders during treatment with supraphysiologic L-T4 doses in patients with refractory mood disorders.

Copyright © 2018. Published by Elsevier B.V.

KEYWORDS:

Cardiovascular risk assessment; Levothyroxine; Thyroid; Treatment-refractory mood disorders

PMID: 29886201

DOI: 10.1016/j.jad.2018.05.034

ncbi.nlm.nih.gov/pubmed/298...

[helvella]

Suddenly remembered where, and found it. It was Muffy in this thread:

healthunlocked.com/thyroidu...

[Hennerton]

Yes, but what actually was the supraphysiologic dose? How can we judge if we do not know that. Have I missed something?

[helvella in reply to Hennerton]

They say: mean dose 463 mcg/day

Hopefully the full paper will become available in time but currently behind a paywall.

[Hidden in reply to helvella]

sounds high!

[jimh111]

I will try and get the full paper sometime. From what we see here I'm getting a bit annoyed with it so far! It's not clear whether supraphysiological doses of levothyroxine are any use for treatment of refractory mood disorders. High dose T3 certainly is in some cases but the problem with levothyroxine is that the body is very good at maintaining fairly normal T3 levels, especially in the brain. A study in rats showed that when given high dose L-T4 their brain T3 levels remain normal. The brain has a lot of type-2 and type-3 deiodinase activity which keeps its T3 levels steady. The heart is not so well protected.

It's wrong to describe it as a 'long term' study, cardiac damage from thyrotoxicity usually takes many years or decades to show up. Also, 23 patients is far too few to obtain statistical significance unless the effect is very dramatic.

Is supra-physiologic levothyroxine any use for refractory depression? Does it lead to cardiac risk? I don't believe this study contributes to these questions.

[helvella in reply to jimh111]

Fully agree it is a frustrating study. However, the paper does at least only claim to look at the cardiovascular side, and it also does identify shortcomings.

The response by jamesal0 - below - says what I feel many would have expected. Although only very mildly over-dosed, I absolutely hated being on 125 micrograms a day and dropped to 112.5. I am surprised that not one of even the small group withdrew or had issues that needed to be reported in the paper.

Hopefully, another paper will address whether it was seen to be effective in treating depression.

[Hidden]

What I am finding interesting is the whole reinvention of the wheel that is going on and I am a bit hopeful that it will continue. So it seems that some thyroid hormones might be helpful for deppression and that seems to be becomming more than accepted fact. There has also been this study that shows that people with CFS might need some thyroid hormones not due to a thyroid condition of course and neither is the depression. I think we could be seeing in the future discoverys that thyroid hormones help constipation and heart failure, migrianes and they might even help memory loss and prevent falls. We might well all be able to bi pass endos and go straight to CFS service or gastro doctor.Hypothyroidism might not be seen to exist in 20years time but all its symtoms willbe treated as separate conditions with hopfully a emphasis on symptom relief and blood results might not be a big consideration if the problems are not longer considered thyroid or systemic. It might be helpful if drug companys could also reinvent some thyroid hormones and new formula, patches or implants that they could make a killing from. Thye could calll them all different names and claim they target specific symptoms.

[helvella in reply to Hidden]

Pharmaceutical companies most certainly are looking at various analogs of thyroid hormones.

[Hidden in reply to helvella]

Iam rather proud of my ability to predict the future.Letshope they bring something out soon as for thefirst 7 or is it 10 years while it will be under patent the DRs will be giving outlike smarties andfor thefirst time in perhaps 60 to 70 years thyrloid patients will get enough hormone.

[Hidden in reply to Hidden]

"I am rather proud of my ability to predict the future"

Not another Mystic Meg I hope, lol

[jamesal0]

I'd be laying on the floor with heart palpitations, hands and feet on fire and crawling scalp if I took 463 mcg/day

[Daffers123 in reply to jamesal0]

Me too. I notice is I only take a little more than my current dose (75/88). I would be feeling very very unwell

[Starfish123]

I thought the reason Drs were so resistant to give NDT was due tests in the 1930’s were people were given the equivalent of 350mg a day and there were many deaths due to it within the subject group. Are they trying to ban levothyroxine by using the same type of test?

[Hidden in reply to Starfish123]

Thats sounds a bit like an drug company spread myth. I think one unexpected death would stop any trial and especially back then.

[jimh111]

It's fascinating that some patients feel more hypo when started on levothryxoine or have their levo dose increased. I'm currently looking into this and I believe TSH stimulates type-2 deiodinase (D2), especially in the brain. There is evidence that TSH promotes D2 activity but I do not feel there is enough evidence to claim this to be so with a high degree of certainty. Even though I'm convinced it does!

If TSH stimulates D2 and a patient has an unusually low TSH, e.g. due to central hypothyroidism or a down-regulated axis then there will be reduced D2 activity. In healthy people the brain relies mostly on T4 being converted to T3 by D2 activity in the brain. If TSH is lower than it should be the there will be insufficient T3 in the brain. If more L-T4 is taken TSH falls and brain D2 activity falls. An added complication is that reverse T3 also inhibits D2 activity. Thus, high doses of L-T4 are prevented from causing brain thyrotoxicosis. However, if the patient has an abnormally low TSH then these high doses of L-T4 are likely to make their brain deficient in T3 and they will 'feel' worse. (Other organs not so reliant on D2, such as the heart, will become thyrotoxic).

Patients in studies such as this one are usually selected on the basis of having an elevated TSH (usually above 10.0) and low fT4. Thus, these subjects are unlikely to have an abnormally low TSH. This might explain why these patients can tolerate these high doses of L-T4 whereas some of us feel worse on high doses of L-T4. It would also explain why some patients require L-T3, more T3 than the small amount secreted by the thyroid.

The above also illustrates why it is not a good idea to have blood taken early in the morning when TSH is elevated, a diagnosis of a down-regulated axis may be missed.

[Hidden in reply to jimh111]

Thank you. i was just thinking that if I took a huge dose of levo I would sleep for a week. It seemed when I as taking it that as you say the more I had the more hypo I became. MY TSh has never had the decency to raise much past 2. I suppose this may bedue to the fillers or something but the tinyest nibble of thyroid S knocks me out for 24 hours. I was told my nurse a pituaritary foundation that TSH tends to stick and not move at all if secondary hypo. Probably notas you say good to haveTSH taken early in the morning for good clinical assessment but for most of us there are no good clinical assessers so we have to play games.

[Hidden in reply to jimh111]

"The above also illustrates why it is not a good idea to have blood taken early in the morning when TSH is elevated, a diagnosis of a down-regulated axis may be missed."

Not sure what that means, could you explain a bit more Jimh111?

[jimh111 in reply to Hidden]

I've noticed that a lot of patients on thyroid forums who have difficult to treat hypothyroidism are suffering from quite bad hypothyroidism but have a TSH that is normal or only mildly elevated, often with an fT4 that is below the lower limit of its reference interval. When fT4 is e.g. around 10.0 TSH is usually quite high, say around 20 or 40. TSH rises quite quickly as fT4 starts to fall even within its reference interval.

So, if TSH is normal and fT3 and fT4 low in interval then something is wrong, the pituitary is not secreting enough TSH. By having the blood taken early am and artificially getting a TSH that is a little higher you are hiding the fact that the TSH is lower than it should be.

This may make it easier to get a diagnosis of primary hypothyroidism (failing thyroid gland) but it is the wrong diagnosis. In the long term it is better to get accurate readings and push for the correct diagnosis and treatment. The other complication is that TSH is changing rapidly early am and so it's very difficult to compare one result with another.

[Muffy]

Hi, I believe you are probably referring to my comment re high doses of thyroxine. This is the paper I was referring to.

Neuropsychopharmacology. 1998 Jun;18(6):444-55.

Treatment of refractory depression with high-dose thyroxine.

Bauer M1, Hellweg R, Gräf KJ, Baumgartner A.

Author information

Abstract

In an open clinical trial we investigated whether addition of supraphysiological doses of thyroxine (T4) to conventional antidepressant drugs has an antidepressant effect in therapy-resistant depressed patients. Seventeen severely ill, therapy-resistant, euthyroid patients with major depression (12 bipolar, five unipolar) were studied. The patients had been depressed for a mean of 11.5 +/- 13.8 months, despite treatment with antidepressants and, in most cases, augmentation with lithium, carbamazepine, and neuroleptics. Thyroxine was added to their antidepressant medication, and the doses were increased to a mean of 482 +/- 72 micrograms/day. The patients' scores on the Hamilton rating Scale for Depression (HRSD) declined from 26.6 +/- 4.7 prior to the addition of T4 to 11.6 +/- 6.8 at the end of week 8. Eight patients fulfilled the criteria for full remission (a 50% reduction in HRSD score and a final score of < or = 9) within 8 weeks and two others fully remitted within 12 weeks. Seven patients did not remit. The 10 remitted patients were maintained on high-dose T4 and followed up for a mean of 27.2 +/- 22.0 months. Seven of these 10 remitted patients had an excellent outcome, two had milder and shorter episodes during T4 augmentation treatment, and one failed to profit from T4 treatment during the follow-up period. Side effects were surprisingly mild, and no complications were observed at all. In conclusion, augmentation of conventional antidepressants with high-dose T4 proved to have excellent antidepressant effects in approximately 50% of severely therapy-resistant depressed patients.

PMID: 9571653 DOI: 10.1016/S0893-133X(97)00181-4

[Indexed for MEDLINE] Free full text

[jimh111 in reply to Muffy]

I found the full paper here nature.com/articles/1395162 and will have a read sometime. I have seen liothyronine (L-T3) used before but never levothyroxine for augmentation of antidepressants. If L-T4 works then it is the better option as it is safer but they would need to check whether equivalent doses are being used. For example in this study an average of 482 mcg of L-T4 was used which is equivalent to 161 mcg L-T3. From memory studies on L-T3 have used about 60 mcg so in this case although L-T4 is inherently safer they are using almost three times the equivalent dose. It would also be useful if they could compare how the patients feel on either option.