A new approach for treatment of subthreshold bipolar disorders: Targeted high dose levothyroxine+repetitive TMS for mitochondrial treatment

[helvella]

A very interesting paper.

Difficult to grab any individual bits for discussion or introduction. The whole paper isn't very long.

Even if bipolar disorders are not themselves of much direct interest, it might be worth a quick read because it discusses the control group as well and their ability to tolerate these high doses (300 micrograms a day - and much higher).

Note that the mention of valproate avoidance has now (since publication of this paper) extended to include males - and is very important.

The authors are all based in the UK.

A new approach for the treatment of subthreshold bipolar disorders: Targeted high dose levothyroxine and repetitive transcranial magnetic stimulation for mitochondrial treatment

Andy Zamar 1 Abbi Lulsegged 2 Christos Kouimtsidis1,3*

1 Consultant Psychiatrist, The London Psychiatry Centre, London, United Kingdom

2 Consultant Endocrinologist Health 121 Ltd., London, United Kingdom

3 Honorary Senior Lecturer Imperial College London, London, United Kingdom

Bipolar spectrum disorder includes Bipolar I, Bipolar II and subthreshold bipolar disorders (BD). The condition is highly prevalent, disabling and associated with high mortality. Failure of diagnosis is high. Subthreshold presentations present as 4 or more changes in polarity, are generally less responsive to standard treatment and as a result, drug combinations are often needed. High Dose Levothyroxine (HDT) has been reported to be safe and effective with this condition. Treatment response has been associated with mutations in thyroid activating enzymes and intra cerebral transporter protein carrier. Repetitive Transcranial Magnetic Stimulation (rTMS) has been shown to be effective in bipolar depression and has been proved to have neuroplastic effect. Present authors had reported clinical evidence of safe and effective use of a combination treatment protocol. Potential mechanisms of action of the combined treatment protocol and the role of mitochondria function are discussed.

Open access here:

frontiersin.org/articles/10...

[RedApple]

A very interesting paper about jaw dropping doses of levothyroxine without any any signs of thyrotoxicosis !

'Several studies indicated the good tolerability of treatment in BSD (40), as far as comorbid anxiety symptoms (38), lack of any signs of thyrotoxicosis (34, 35, 38–40) even in doses of 600 mcg and 150–1,000 mcg (37, 41). Osteoporosis remains a concern for long-term HDT use despite reassuring data on the contrary (37) with only sporadic cases reported of women with mood disorders having reduced bone mineral density (BMD) on HDT '

[SlowDragon Administrator]

Lots of research papers on how bipolar and thyroid and autoimmune thyroid antibodies

bmcpsychiatry.biomedcentral...

psycom.net/bipolar-disorder...

[RedApple in reply to SlowDragon]

Yes indeed. But this paper is specifically about very high dose levo and its affect (or not) in BP patients.

[BB001]

'Treatment response has been associated with mutations in thyroid activating enzymes'

Makes me wonder whether these patients fT3 is low and they just haven't been diagnosed as hypothyroid because of the reliance on TSH and FT4 blood tests and exclusion of symptoms.

[helvella in reply to BB001]

I don't think that would explain how they were able to tolerate 500 micrograms of levothyroxine a day. Most of us, if we took that, we likely feel horribly over-dosed. Regardless where we started - extremely hypo, slightly hypo, just about right, ...

[BB001 in reply to helvella]

I never had symptoms of hyperthyroidism / over- medication when I was on levothyroxine only, even when I was dosed so that my fT4 was 38-43 in a range 11-26, over a two year period from 2004-2006. I always had hypothyroid symptoms: fatigue, brain fog, joint pains, freezing cold etc which is why my GP kept increasing my levothyroxine dose. It would be interesting to see if they followed them long term, as in 2007 I was diagnosed with macular degeneration despite having no genetic history or any of the other main risk factors e.g. smoking and I suspect high doses of levothyroxine whilst having extremely poor converson of T4 to T3. I don't have Dio2 genetic mutations but I do have Dio1.

[Litatamon in reply to BB001]

But apparently signs of too high of a dose can be quite similar to not enough hormones.My levothyroxine prescription is for 300 mcg (I take 275mcg, it is to 💯 make sure I receive my dose in 50s & have room to increase) so I too would love to have more studies.

[BB001 in reply to Litatamon]

In my case I needed a high dose of levothyroxine to get my T3 high enough because I'm a really poor converter of T4 to T3, it still didn't manage to get my T3 up enough which is why I still had symptoms

Edit. As you can see, when my fT4 was 43, my fT3 was above range, but not by much, and certainly not what you would expect from a fT4 that was nearly double its range.

The below results are from my patient record from a long time ago. My GP realised these results were off and kept referring me to different endocrinologists, but none gave me any different treatment options to levothyroxine.

free T4 level 28.1 pmol/L [9 - 24] = 127.33% , free triiodothyronine level) 4.6 pmol/L [2.8 - 7.1] = 41.86%

Free T4 level 43 pmol/L [9 - 24] = 226.67%. Free triiodothyronine (fT3) level 7.9 pmol/L [2.8 - 7.1] = 118.60%

I'm best when my fT3 is 5.2 to 5.4 in a range of 2.5-6.0 i.e around 77-83% of range.

[Litatamon in reply to BB001]

Do you take T3 now?

[BB001 in reply to Litatamon]

Yes I'm prescribed T3 on NHS. I'm allergic to levothyroxine, it makes me itch.

Please see the edit to my comment you replied to.

[Omze in reply to BB001]

My case is exactly like urs , my conversion starts at t4 21> , currently I m taking 300 mcg t4 , and t4 is at 27 , t3 at 4.6 , I feel the best when it's near 5.0 worst if I push it more as higher t4 than this will cause severe anxiety and tachy.Need to discuss more with U, so u r off t4 and now on t3 , dose?

[BB001 in reply to Omze]

I'm now prescribed 70mcg T3. I have though substituted 75mg Thyro-Gold for 5mcg T3. My eqivalent T3 dose this winter has varied between 65-70mcg. It varies with the weather. When it's colder I need more T3 by upto 5mcg.Currently I'm actually taking 62.5mcg T3 + 75mg Thyro-Gold. Tomorrow's NHS blood test will tell whether this is sufficient or too much. Resting heart rate of 66 suggests it's about right, but I like the objective measure of a blood test to validate it. If my resting heart rate is 70+ I'm over-medicated.

It's difficult to put your results into context without units and ranges.

Personally I think my high dose levothyroxine had long term consequences, that manifest 3 years later).

My body has been under immune stress as a result of inadequate T3 levels for many years, leading to numerous allergies and intolerances.

[BB001 in reply to Omze]

A quick rule of thumb guide for working out conversion rates is ft3 ÷ ft4 when on no medication or levothyroxine only (I.e. no medication that contains T3). For you this is 4.6 ÷ 27 = 0.17, which puts you in the reason of a 'Poor Converter' according to Midgley et al in this research 'variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiency '. This poor conversion rate and my experience suggests you need a significant amount of your T4 replacing with T3. If you do so, remember T4 has a long half life, so you would need to reduce your T4 and add T3 in slowly in 5mcg increments.

[BB001 in reply to helvella]

I've just looked up my results from years ago when fT4 was 43.Free T4 level 43 pmol/L [9 - 24] = 226.67%.

Free triiodothyronine (fT3) level 7.9 pmol/L [2.8 - 7.1] = 118.60%

I seem to be one of the people that copes with 300mcg levothyroxine without obvious symptoms of overdosing (though long term i think this caused me problems).

From an earlier test results notebook, I've got a note that says 300mcg dose, pulse rate 50, unfortunately i haven't got blood tests to go with it.

Could it be due to Thyroid Receptor antibodies?

[Omze in reply to BB001]

Yes , ur thyroid receptors are not that receptive , u need to break the feed back cycle of t3/t4 to feel better and I think t3 is better for U , but t4 at 300 mcg after 3 months will give u a t3 of near 5.0 after adding thyroid sensitizer

[Omze in reply to BB001]

Ok thankyou for the reply , I just wana ask u , what if u continued ur t4 300 mcg wothout t3 addition, what do u mean by this dose long term effect?

[BB001 in reply to Omze]

what if u continued ur t4 300 mcg wothout t3 addition,

I spent many years on T4. A fair proportion of them dosed so my fT4 was high in range or above range. The switch to T3 has only been in the last 3 years.

what do u mean by this dose long term effect?

Three years after having high FT4 levels of 43pmol/L, and presumanly low FT3, I developed macular degeneration despite having none of the risk factors for it and no genetic history for it. I can think of nothing else remarkable in my medical history that would have triggered it. It might be that it was the 300mcg dosing a decade before, that triggered the changes that led to macular degeneration and the macular degeneration only became apparent later. To pick up something like this, a trial would need to last for decades.

[Omze in reply to BB001]

Thankyou for ur reply,I have following questions:

When ur t3 was >7.0 on thyroxine , u could have decreased the dose of thyroxine to get near 5.2 , the level at which u felt better , why to add t3

Do u have TED (thyroid eye disease) or glaucoma symptoms , or any kind of eye proptosis or increased lacrimation or any eye symptoms before getting diagnosed MD

[arTistapple]

I can’t pretend to understand this completely. However I am blown away with the explanation of thyroid hormones, their effect, generally and particularly, with reference to the genetics/enzymes on conversion and effect on peripheral tissue and mitochondria. They use knowledge with an ease and familiarity we rarely see from our endocrinology ‘masters’. A proper building on previous research. An ability to move on!

Where is this knowledge and ‘acceptance’ in endocrinology itself? Why is endocrinology so unable to use similar, to further the treatment of thyroid issues? It’s like there is a definite block on this knowledge and it’s application in thyroid treatment. With this level of information in existence why is thyroid treatment so poor for the so-called 20% of us who can’t thrive on the treatment and guidelines in place (or at least from the translation in our medics heads). There has been little or no change in treatment for hypothyroidism since, Davidson’s Principles and Practice of Medicine - fifteenth edition 1987. That’s 37 years.

At this rate we should shortly be able to be treated for hypothyroidism by psychiatrists (or indeed cardio’s or rheumatologists etc etc) and endocrinology can dispose of us nuisances altogether.

In saying that, I would not like to be sent home with a prescription for 300mcgs of levo to be taken daily. I did not pick up that these people were getting in-house treatment. It’s a pretty serious affliction to be sent home as a research subject with that big a dose, unaccompanied. My NHS endo experiment with 150 mcg (about 18 months ago) went so wrong, I am still having trouble getting over it.

[helvella in reply to arTistapple]

One aspect which is so important is that it seems to have shown one group has a very different response to high dose levothyroxine than everyone else.

The group is probably small enough that they are effectively invisible in population-level statistics. Then practitioners use inferences from population-level statistics to guide treatment in everyone.

[arTistapple in reply to helvella]

Excellent point! It still does not explain the utter sluggishness with which the research into hypothyroidism meets ‘practice’ and the unfortunate 20%. Somehow it’s perfectly acceptable to overlook us.

[helvella in reply to arTistapple]

One of the most famous things medical students are taught is that if they hear hoof-beats then think horses, not zebras.

Statistically, that is probably valid in a single patient presentation. Look at the most likely thing first. They might treat 80% of such patients such that the issue is satisfactorily resolved.

But, when a zebra has been wrongly treated as a horse twenty times, and is still unwell, even simple statistics start to make it likely they are actually a zebra rather than a horse.

(Please don't try to take this too literally. It falls apart entirely if you do that. Just take the flavour, smile (hopefully), and move on.)

[Litatamon in reply to arTistapple]

Just curious, was the 150 mcg a big jump at the time?

[arTistapple in reply to Litatamon]

I was on 100mcg. I knew no better really. So it was a 50% raise and took my T4 up to 126%!! I was pretty ill. I had just found the Forum and was watching and reading etc. This was our most esteemed endocrinologist’s advice to my GP. A very experienced GP but he had nothing to say. No advice etc etc. I was so confused after that horrible experience AND I was in a hurry after many years with a lack of diagnosis. I do wonder about allowing my T4 to go up a little but there actually seems to be little to be gained when it apparently looks like it’s a straightforward case of lousy conversion.

[Litatamon in reply to arTistapple]

Thank you. So sorry you went through that. I was curious, as I had a horrid experience when my former endocrinologist put me from 112 to 200 in one go & I too had no idea and was just starting out here. She at least admitted it was against protocol but she did not like how abysmal my labs were at the time.

My body went cuckoo. And of course she did not care as that brought me close to normal range. Not there but closer, so she felt successful while I was in agony.

And now I am around 275 mcg, with none of those issues at 200mcg.

[arTistapple in reply to Litatamon]

Yikes! Well great you have it worked out now! I feel I have got a lot to learn but I find reading a problem at the moment but most importantly sorting out my executive functioning is possibly my worst problem. I spend an inordinate problem with anything requiring ‘order’ of any kind.

[BB001 in reply to Litatamon]

Have you checked your FT4 and FT3 levels at that dose of 275mcg levothyroxine? I'm wondering whether you actually need some of the T4 replaced by T3.

[arTistapple]

I can and thank you. Just feeling extra bitter this morning.

[buddy99 in reply to arTistapple]

Feeling extra bitter so badly on some days that I start considering seeing a shrink. It's difficult not to be bitter when a good portion of your life has been completely ruined, when your experience and knowledge counts for nothing and does not lead to results (other than negative reactions and traumatic events) at all. Helplessness and anger equals bitterness. It is a reality for many with chronic disease. This research, for example, will not convince current practitioners of anything. Their ways are set in concrete. That's what can make anybody bitter....having the knowledge and running into these concrete blocks (repeatedly) without getting better results. A zebra in a herd of horses must also be a horse, right?

[arTistapple in reply to buddy99]

Buddy99 thanks for replying and helping today. I have had a mainly good run for what feels like a few weeks (possibly days) and today I just ‘ran out’. I read your bio before replying. I think maybe to some extent from others, maybe my rundown to finally being diagnosed was at a shallower, longer angle than many. However when I feel like this …. I am a bit embarrassed to admit ‘bitter’ but I really like your explanation, of it. It gives it some better rounded explained meaning.

My heart goes out to Susieibbo301 and her precious daughter.

[buddy99 in reply to arTistapple]

Yes, if anybody has reason to be bitter, Susieibbo301, would be a good candidate. This is horrific! So, so much avoidable pain. 😥

Also, I bit this back before, but while doctors are watching the horses and missing the zebras, patients are looking for the donkeys among the asses.

[arTistapple in reply to buddy99]

Love that. Brought a huge smile to my face at the idiocy we must deal with constantly. Notwithstanding Susieibbo301 situation who is clearly dealing with her situation with an enormous level of dignity. Admire her greatly. Thanks again buddy99.

[BB001 in reply to buddy99]

I totally understand how you feel. It took me a very long time to be heard, even when the information and evidence I was presenting to different endocrinologists was indisputable. The only thing I can suggest is to keep trying. I found the thyroidpatients.ca website useful in my quest to achieve appropriate thyroid medication, which in my case is T3 as I'm allergic to porcine NDT and Bovine NDT didn't have a high enough T3 to T4 rato.

Thyroidpatients.ca provides research based articles.

[buddy99 in reply to BB001]

Thank you. I have the hardest time reading the articles on thyroidpatient.ca. I find most research papers easier to read than her publications. Maybe her writing style and my brain do not connect. Just can't wrap my head around it.

[BB001 in reply to buddy99]

Try paulrobinsonthyroid.com his blogs are easier to read.

[Susieibbo301]

This is very interesting. My daughter had bipolar disorder - didn’t connect to thyroid issues but then they wouldn’t look for it. Darling girl took her own life in desperation as on ghastly psychiatric drugs for 8 years. I have a strong genetic link to hypothyroidism from both sides of my family. My endo in London (private and too expensive for me now) knew of this connection with bipolar a few years ago.

It may be very helpful for people with that terrible condition.

[helvella in reply to Susieibbo301]

Susieibbo301,

Thank you for taking the time to reply - especially with such a relevant and awful comment.

As I posted, I was desperately hoping that the information would eventually reach the right people.

[Susieibbo301 in reply to helvella]

thank you Helvella. Let’s hope that this can help some people. Susie

[DizzyD in reply to helvella]

This post caught my attention because it mentioned bipolar (have not read paper yet). Back in 2011 i was diagnosed with bipolar and medicated for it with a variety of anti psychotic pills....told I could not be prescribed lithium because I dont have a thyroid. Honestly, I suspected my levo dose was too high but shrink refused to focus on my thyroid status. Prior to diagnosis, my thyroid levels were never checked. As soon as i was discharged from psych unit I stopped taking the meds and from that day onwards i have not had any manic episodes. I did some research after i was discharged, because i believed my dose of levo was too high (confirmed via a private thyroid blood test) which could be the cause of the initial hyper, manic, sleep deprived symptoms etc. Research papers i found confirmed my suspicions...! People can display psychotic tendencies on high dose of levo. Question is can people with genuine bipolar disorder benefit from very high doses of Levo?

Off to read paper now to find answer to my question.

thanks helvella

[Susieibbo301]

I have just seen Dr Abbi Lulsegged’s name on the top of the paper.

[bluejourney]

Thank you helvella for posting this - a very interesting read, especially as, (with my FT3 only 27% through the reference range) I am still struggling to get a T3 prescription from one of the authors!!!

[ratoncita]

very good book by Mary Shoman “Living Well With Hypothyroidism” or listen to her podcasts. Very informative!

[BB001]

Some links to find out more about MAST cell issues and to get support:

mastcellaction.org/

Facebook group

MAST CELL ACTION - MCAS UK Support Community. Charity Number 1164917.

Body with arrows pointing to body parts and the related MCAS symptoms

[BB001]

And the list of good suits sorbitol is on good in...Bananas

Does bread contain sorbitol?

Ready-made baked goods: e. g. also bread, as sorbitol is often used as a humectant. Sorbitol is often called “E 420” here in the list of ingredients. Bread sold over the counter at the bakery doesn't have to list sorbitol as an ingredient! You have to ask [this was from the Google highlight from this source: 'Sorbitol intolerance – Symptoms, causes, help on frusano.com '