I've made a couple of recent posts about hypothyroidism:

http://lesswrong.com/lw/nbm/thyroid_hormones_chronic_fatigue_and_fibromyalgia/
http://lesswrong.com/lw/n8u/a_medical_mystery_thyroid_hormones_chronic/

It appears that many of those who read them were unable to extract the core argument, and few people seem to have found them interesting.


They seem extremely important to me. Somewhere between a possible palliative for some cases of Chronic Fatigue Syndrome, and a panacea for most of the remaining unexplained diseases of the world.


So here I've made the core argument as plain as I can. But obviously it misses out many details. Please read the original posts to see what I'm really saying. They were written as I thought, and the idea has crystallised somewhat in the process of arguing about it with friends and contributors to Less Wrong. In particular I am indebted to the late Broda Barnes for the connection with diabetes, which I found in his book 'Hypothyroidism: The Unsuspected Illness', and which makes the whole thing look rather more plausible.

CORE ARGUMENT


(1.1) Hypothyroidism is a disease with very variable symptoms, which can present in many different ways.

It is an endocrine hormone disease, which causes the metabolism to run slow. A sort of general systems failure. Which parts fail first seems random.

It is extraordinarily difficult to diagnose by clinical symptoms.


(1.2) Chronic Fatigue Syndrome and Fibromyalgia look very like possible presentations of Hypothyroidism


(1.3) The most commonly used blood test (TSH) for Hypothyroidism is negative in CFS/FMS


=>


EITHER


(2.1) CFS/FMS/Hypothyroidism are extremely similar diseases which are nevertheless differently caused.


OR


(2.2) The blood test is failing to detect many cases of Hypothyroidism.

It seems that one is either forced to accept (2.1), or to believe that blood hormone levels can be normal in the presence of Hypothyroidism.


There is precedent for this:


Diabetes, another endocrine disorder (this time the hormone is insulin), comes in two forms:


type I : the hormone producing gland is damaged, the blood hormone levels go wrong.         (Classical Diabetes)

type II: the blood hormone levels are normal, but for some reason the hormone does not act. (Insulin Resistance)


I therefore hypothesize:


(3) That there is at least one mechanism interfering with the action of the thyroid hormones on the cells.


and


(4) The same, or similar mechanisms can interfere with the actions of other hormones.


A priori, I'd give these hypotheses a starting chance of 1%. They do not seem unreasonable. In fact they are obvious.

The strongest evidence against them is that they are so very obvious, and yet not believed by those whose job it is to decide.

CURRENT STATUS  (Estimated probability)


(1.1) Uncontroversial, believed by everyone involved (~100%)


(1.2) Similarly uncontroversial (~100%)


(1.3) By definition. With abnormal TSH, you'd have hypothyroidism (~100%)


(2.1) Universal belief of conventional medicine and medical science, some alternative medicine disagrees (~90%)


(2.2) The idea that the TSH test is inaccurate is widely believed in alternative medicine, and by thyroid patient groups, but largely rejected by conventional medicine (~10%)


(3) There is some evidence from alternative medicine that this might be true (~10%)


(4) My own idea. A wild stab in the dark. But if it happens twice, you bet it happens thrice [1] (~0.000001%)

Some Details


(1.1) Clinical diagnosis of Hypothyroidism is very out of fashion, considered hopelessly unreliable, doctors are actually trained to ignore the symptoms. There is a famous medical sin of 'Overdiagnosing Hypothyroidism', and doctors who fall into sin are regularly struck off.


(1.2) I don't think you'll find anyone who knows about both diseases to dispute this.


(1.3) True by definition. CFS/FMS symptoms plus abnormal TSH would be Hypothyroidism proper, almost no-one would disagree.


(2.1) This is the belief of conventional medicine. But the cause of CFS/FMS is unknown.

Generally the symptoms are blamed on 'stress', but 'stress' seems to be 'that which causes disease'. This 'explanation' seems to be doing little explanatory work. In fact it looks like magical thinking to me.

Medical Scientists know much more about all this than I do, and they believe it.

On the other hand, scientific ideas without verified causal chains often turn out to be wrong.


(2.2) (The important bit: If the TSH test is not solid, there are a number of interesting consequences.)


I've been looking for a few months through the endocrinological literature for evidence that the sensitivity of the TSH test was properly checked before its introduction or since, and I can't find any. It seems to have been an unjustified assumption. At the very least, my medical literature search skillz are not up to it. I appeal for help to those with better skillz.


It is beyond doubt that atrophy or removal of the thyroid gland causes the TSH value to go extremely high, and such cases are uncontroversial.


The actual interpretation of the TSH test is curiously wooly.

It has proved very difficult to pin down the 'normal range' for TSH, and they have been arguing about it for nearly forty years, over which the 'normal range' has been repeatedly narrowed

The AACB report of 2012 concluded that the normal range was so narrow that huge numbers of people with no symptoms would be outside it, and this range is not widely accepted for obvious reasons


There are many other possible blood hormone tests for hypothyroidism. All are considered to be less accurate or less sensitive than the TSH test. It does seem to be the best available blood test. It does not correlate particularly well with clinical symptoms.


(3) Broda Barnes, a conventional endocrinologist working before the introduction of reliable blood tests, was convinced that the most accurate test was the peripheral basal body temperature on waking.

He considered measuring the basal metabolic rate, and rejected it for good reasons. He considered that desiccated thyroid was a good treatment for the disease, and thought the disease very common. He estimated its prevalence at 40% in the American population. His work is nowadays considered obsolete, and ignored. But he seems to have been a careful, thoughtful scientist, and the best arguments against his conclusions are placebo-effect and confirmation bias. He treated thousands of patients, his treatments were not controversial at the time, and he reported great success. He wrote a popular book 'Hypothyroidism: The Unsuspected Illness', and his conclusions have fathered a large and popular alternative medicine tradition.


John Lowe, a chiropractor who claimed that fibromyalgia could be cured with desiccated thyroid, found that many (25%) of his patients did not respond to the treatment. He hypothesised peripheral resistance, thought it genetic, and used very high doses of the thyroid hormone T3 on many of his patients, which should have killed them. I have read many of his writings, they seem thoughtful and sane. I am not aware of any case in which John Lowe is thought to have done harm. There must be some, even if he was right. But if he was wrong he should have killed many of his patients, including himself. He was either a liar, or a serial murderer, or he was right. He was likely seeing an extremely biased sample of patients, those who could not be helped by conventional approaches.


(4) I just made it up by analogy.

There is the curious concept of 'adrenal fatigue', widespread in alternative medicine but dismissed as fantasy outside it, where the adrenal glands (more endocrine things) are supposed to be 'tired out' by 'excessive stress'. That could conceivably be explained by peripheral resistance to adrenal hormones.

CONSEQUENCES


If (3) is true but (4) is not:


There are a number of mysterious 'somatoform' disorders, collectively known as the central sensitivity syndromes, with many symptoms in common, which could be explained as type 2 hypothyroidism. Obvious cases are Chronic Fatigue Syndrome, Fibromyalgia Syndrome, Major Depressive Disorder and Irritable Bowel Syndrome, but there are many others. Taken together they would explain Broda Barnes' estimate of 40% of Americans.


If (4) is true:


Then we can probably explain most of the remaining unexplained human diseases as endocrine resistance disorders.

HOW CAN THIS BE TRUE, BUT HAVE BEEN MISSED?


This is the million-dollar question!


My favourite explanation is that in order to overwhelm 'peripheral resistance to thyroid hormones', one needs to give the patient both T4 and T3 in exactly the right proportions and dose.


Supplementation with T4 alone will not increase the levels of T3 in the system, since the conversion is under the body's normal control, and the body defends T3 levels.


But T3 is the 'active hormone'. Without significantly increasing the circulating levels of T3, the resistance cannot be overwhelmed.


On the other hand, any significant overdosing of T3 will massively overstimulate the body, causing the extremely unpleasant symptoms of hyperthyroidism.


This seems to me to be sufficient explanation for why various trials of T4 supplementation on the central sensitivity disorders have all failed. In almost all cases, the patients will either have seen no improvement, or have experienced the symptoms of over-treatment. Only in very few cases will any improvement have occurred, and standard trials are not designed to detect such effects.


It is actually just luck that the T4/T3 proportion in desiccated thyroid is about right for some people.


Alternatively, there may just be some component in desiccated thyroid whose action we don't understand.

PERSONAL EXPERIENCE


I displayed symptoms of mild-to-moderate Chronic Fatigue Syndrome, and my wonderful NHS GP checked everything it could possibly be. All my blood tests normal, TSH=2.51. I was heading for a diagnosis of CFS.


After four months I mysteriously partially recovered after trying the iron/vitamin B supplement Floradix, even though I wasn't anaemic.


I started researching on the basis that things that go away on their own tend to come back on their own.


I noticed that I had recorded, in records kept at the time of the illness, thirty out of a list of forty possible symptoms of Hypothyroidism, drew the obvious conclusions as so many others have, and purchased a supply of desiccated thyroid in case it came back.


It did come back, and after one month, I began to self-treat with desiccated thyroid, very carefully titrating small doses against symptoms, and quickly noted immediate huge improvement in all symptoms. In fact I'd say they were gone.


My basal temperature rose over a few weeks from 36.1 to ~36.6 (average, rise slow over several weeks, noise ~ +-0.3 day to day).


One week, holding the dose steady in anticipation of more blood tests, I overdid it by the truly minute amount of 3mg/day of desiccated thyroid, which caused all of the symptoms of the manic phase of bipolar disorder (whose down phase is indistinguishable from CFS, and whose up phase looks terribly like the onset of hyperthyroidism), The manic symptoms disappeared within twelve hours of ceasing thyroid supplementation, to be replaced by overwhelming tiredness.


I resumed thyroid supplementation at a slightly lower dose, and feel as well as I have done for ten years. It's now been ten weeks and I am becoming reasonably confident that it is having some effect.

POSSIBLE CAUSATION


Such catastrophic failures of the body's central control system CANNOT be evolutionarily stable unless they are extremely rare or have compensating advantages.


I am thus drawn to the idea of either:


(a) recent environmental change (which seems to be the alternative medicine explanation)


(b) immune defence (which would explain why e.g. CFS often presents as extended version of the normal post-viral fatigue)

If the alternative is being eaten alive, it seems all too plausible that an immune mechanism might be to 'wall off' cells in some way until the emergency is past, even if catastrophic damage is a side effect.

STRONG PREDICTIONS

Low Body Temperature


It is a very strong prediction of this theory that low basal metabolic rates, and thus low basal peripheral temperatures will be found in many sufferers of Chronic Fatigue Syndrome and Fibromyalgia.

If this is not true, then the idea is refuted unambiguously.

Thyroid Hormone Supplementation as Palliative

It is a less strong prediction, but still fairly strong, that supplementation of the hormones T4 and T3 in carefully titrated doses and proportions will relieve some of the symptoms of CFS/FMS.


Note that T4 supplementation alone is unlikely to work. And that unless the doses and proportions are carefully adjusted to relieve symptoms, the treatment is likely to either not work, or be worse than the disease!


SOME SELECTED POSSIBLE IMPLICATIONS / PREDICTIONS

I've been very reluctant to draw my wilder speculative conclusions in public, since they have the potential to do great harm whether or not the idea is true, but here are some of the less frightening ones that I feel safe stating:


I state them only to encourage people to believe that this problem is worth thinking about.


Endocrinology appears not to be too interested, and my crank emails to endocrinologists have gone unanswered.


One of the reasons that I feel safe stating these four in public is that Broda Barnes thought them obvious and published popular books about them, so they are unlikely to come as a surprise to anyone outside endocrinology:


Dieting/Exercise/Weight Loss


Dieting and Exercise don't work long term as treatments for weight loss. The function of the thyroid system is to adapt metabolism to available resources. Starvation will cause mild transient hypothyroidism as the body attempts to survive the famine it infers. This may be the explanation for Anorexia Nervosa.


Diabetes


Diagnosis of diabetes was once a death sentence. With the discovery of insulin, allowing diabetics to control their blood sugar levels, it became survivable.

However it still has terrible complications, a lot of which look like the complications of hypothyroidism.


If a hormone-resistance mechanism interferes with both insulin and thyroid hormones, the reason for this is obvious. Diabetics with well-controlled blood sugar are dying in their millions from a treatable condition.


Heart Disease


One of the very old tests for hypothyroidism was blood cholesterol. It was thought to be a reliable indicator of hypothyroidism if present, but it was not always present.


A known symptom of hypothyroidism is atherosclerosis and weakness of the heart.


I would imagine that hypothyroidism initially presents as low blood pressure, due to the weakness of the heart. As the arteries clog, the weakened heart is forced to work harder and harder. Blood pressure goes higher and higher, and eventually the heart collapses under the strain.


Blood pressure reducing medications may actually be doing harm. A promising treatment might be to correct the underlying hypothyroidism.


Smoking


Cigarettes are full of poisons, and smoking is correlated with very many diseases.


It could be that smoking causes amongst its effects peripheral resistance, which causes clinical hypothyroidism, which then causes everything it usually causes. And that would be my bet!


It could be that hypothyroidism causes a very great number of bad things, including depression, which then causes smoking.


Smoking may not actually be that dangerous, and it might be possible to mitigate its bad effects.

[1] Madonna, "Pretender", Like A Virgin, Power Station Studios, New York, New York (1984)

I'm going to stop there. There are quite a lot of similar conclusions to be drawn. Read Barnes.


I also have some novel ones of my own which I am not telling anyone about just yet.


What the hell do I, or any of the quacks who have been screaming about this for forty years, have to say in order that someone with real expertise in this area takes this idea seriously enough to have a go at refuting it?

EDIT: This keeps confusing people (including me): Low Basal Metabolic Rates. The amount of oxygen you use once you have been asleep for a while. That's what the thyroid apparently controls in adult animals. Daytime won't do, that's probably under the control of something else. And peripheral temperatures. Not core. We're interested in the amount of heat flowing out of the body. Which is not quite the same thing as temperature....

EDIT : WHY THIS IS WORTH A CLOSE LOOK, EVEN THOUGH IT IS LIKELY WRONG!

Thanks to HungryHobo for making me make this point explicitly:

This is a very simple and obvious explanation of an awful lot of otherwise confusing data, anecdotes, quackery, expert opinion and medical research.

And it is obviously false! Of course medicine has tried using thyroid supplementation to fix 'tired all the time'. It doesn't work!

But there really is an awful lot unexplained about all this T4/T3 business, and why different people think it works differently. I refer you to the internet for all the unexplained things.

In just the endocrinological literature there is a long fight going on about T4/T3 ratios in thyroid supplementation, and about the question of whether or not to treat 'subclinical hypothyroidism'. Some people show symptoms with very low TSH values. Some people have extremely high TSH values and show no symptoms at all.

I've been trying various ways of explaining it all for nearly four months now. And I've found lots of magical thinking in conventional medicine, and lots of waving away of the reports of honest-sounding empiricists, who have made no obvious errors of reasoning, most of whom are taking terrible risks with their own careers in order to, as they see it, help their patients.

I've read lots of people saying 'we tried this, and it works', and no people saying 'we tried this, and it makes no difference'. The explanation favoured by conventional medicine strongly predicts 'we tried this, and it makes no difference'. But they've never tried it! It's really confusing. A lot of people are very confused.

I think that simple explanations are extra-worth looking at because they are simple.

Of course that doesn't mean they're right. Consequence and experiment are the only judge of that.

I do not think I am right! There is no way I can have got the whole picture. I can't explain, for instance 'euthyroid sick syndrome'. But I don't predict that it doesn't exist either.

But you should look very carefully at the simple beautiful ideas that seem to explain everything, but that look untrue.

Firstly because Solomonoff induction looks like a good way to think about the world. Or call it Occam's Razor if you prefer. It is straightforward Bayesianism, as David Mackay points out in Information Theory, Inference, and Learning Algorithms.

Secondly because all the good ideas have turned out to be simple, and could have been spotted, (and often were) by the Ancient Greeks, and could have been demonstrated by them, if only they'd really thought about it.

Thirdly because experiments not done with the hypothesis in mind have likely neglected important aspects of the problem. (In this case T3 homeostasis and possible peripheral resistance and the difference between basal metabolic rate and waking rate, and the difference between core and peripheral temperature and the possibility of a common DIO2 mutation causing people's systems to react differently to T4 monotherapy).

So that even if there are things you can't explain (I can't explain hot daytime fibro-turks...), you should keep plugging away, to see if you can explain them, if you think hard enough.

Good ideas should be given extra-benefit of the doubt. Not ignored because they prove (slightly) too much!

I reckon that we should be able to refute or strongly support the general idea from reports in the published literature. Here is some stuff that I have found recently. There is a comment that looks like this. Add anything you find to it, and I'll move it up here.

ADD EVIDENCE FOR OR AGAINST HERE

Found this for "Wilson's syndrome", but can only see the abstract:

http://www.ncbi.nlm.nih.gov/pubmed/16883675

It looks like it might be supportive, but it also looks crap. No mention of blinding, randomising, or placebo in the abstract.

Can anyone see the actual paper and link to it here? And can anyone work out whether these guys are allies of Wilson, or trying to break him? Because that matters.

This, on the other hand:

http://www.ncbi.nlm.nih.gov/pubmed/9513740

Looks solid, and looks like refutation. They claim normal average core temperatures in CFS. I have quibbles, of course:

I'd expect the core temperature to be well defended. So I'm not worried by that per se, but they do talk about relation to oral temperature, and they do talk about metabolic rate, so they've obviously thought about it, and I can't quite work out what they did there.

Also, the reason that they're measuring this is because their CFS patients have all been complaining about low oral temperatures and the fact that even when they've got a fever, they're not hot. So errr?? Do all the CFS patients believe this theory and are (un)consciously faking? I mean, I can believe that, but is it true that all CFS patients think this theory is true? Who is telling CFS patients to take their temperatures and why?

On the other hand, their actual graphs do look funny. There's a strange shape to the CBT vs time graph in CFS, but n=7, I think, so maybe that's just noise.

These guys:

http://www.sciencedirect.com/science/article/pii/S0024320515301223

Are actually claiming HIGHER peripheral temperatures in Fibromyalgia. But I think they're measuring during the day. I've no idea how to explain that, or what it might mean.

Barnes claimed: Measure axillary temperature on waking. Should be 98.6+/-0.2F (so 37C+/-0.1), lower is bad. Treat with lots of thyroid (1/2-2 grains).

I claim (from just me, and I am perfectly capable of fooling myself): measure oral temperature on waking. Was low (~36.1), has gone higher (36.6-7-8-9) under influence of small amounts of thyroid (1/3 grain). Feel fine now.

Can anyone find: Large numbers of CFS/FMS patients have normal metabolic rate while sleeping or just after waking, no exercise allowed, or normal axillary or oral temperature on waking, again no exercise allowed?

Because that's what I'm looking for at the moment, and it is refutation. I will have to pull off some clever moves indeed to get round that.

Oh, yes, and there's a paper by Lowe himself, finding exactly what I expect him to find:

http://www.ncbi.nlm.nih.gov/pubmed/16810133

Can anyone dig up quibbles with this that can make me discount it?

Oh Jesus:

Clinical Response to Thyroxine Sodium in Clinically Hypothyroid but Biochemically Euthyroid Patients G. R. B. SKINNER MD DSc FRCPath FRCOG, D. HOLMES, A. AHMAD PhD, J. A. DAVIES BSc and J. BENITEZ MSc Vaccine Research Trust, 22 Alcester Road, Moseley, Birmingham B13 8BE, UK

This I can't explain at all! He treated CFS people with tiny amounts of T4, and worked up the dose until they were all better. Worked a treat, apparently. Can anyone break it?

It simultaneously breaks me and proves that CFS is a thyroid problem. I think. Help! Again, no placebos, but a large clinical trial that seems to have worked, by a careful man.

I wouldn't dream of suggesting that anyone steal this using sci-hub.io by typing the title into the search box and then solving the easy CAPTCHA which is in English even though the instructions are all in Russian. You should write to the authors and request a copy instead.

Four 2003 Studies of
Thyroid Hormone Replacement Therapies:
Logical Analysis and Ethical Implications
Dr. John C. Lowe

Lowe again, my rationalist hero, publishing in his own journal, referencing his own papers and books. This time I think he's made maths mistakes. But that's my department, so I'm going to go away and think about it. I mention the paper here to avoid the obvious mistake of deciding whether to mention it after I've had a proper look.

Effective Treatment of Chronic Fatigue Syndrome and Fibromyalgia—A Randomized, Double-Blind, Placebo-Controlled, Intent-To-Treat Study

Jacob E. Teitelbaum*, Barbara Bird, Robert M. Greenfield, Alan Weiss, Larry Muenz & Laurie Gould

DOI:10.1300/J092v08n02_02

ABSTRACT

OK, how do we discount this one? I haven't even read it yet. Can anyone see it?

Thyroid Insufficiency. Is Thyroxine the Only Valuable Drug?

DOI:10.1080/13590840120083376

W. V. Baisier, J. Hertoghe & W. Eeckhaut

ABSTRACT

Bored now. Anyone find me anything that says this doesn't work?

I've even heard rumours that Lowe himself did PCRTs of his treatments. And probably published them in some chiropractic house mag. I can't even find those.

A rich seam of thyroid vs depression papers, all found through: http://psycheducation.org/

Since he's got a cause, I expect to find them all in favour. I'm going to list them here before reading them in order to avoid the obvious mistake of cherry picking from the cherry basket, and then add comments once I've read them / their abstracts.

Further evidence pointing in the opposite direction is very welcome!

I also tried:
https://www.ncbi.nlm.nih.gov/pubmed/?term=thyroxine+major+depression

and some of those are also here. I can't remember which ones I found through psycheducation and which ones through pubmed.
Bloody browser tabs, sorry, I should have been more careful.

J Affect Disord. 2014 Sep;166:353-8. doi: 10.1016/j.jad.2014.04.022. Epub 2014 May 2.
A favorable risk-benefit analysis of high dose thyroid for treatment of bipolar disorders with regard to osteoporosis.
Kelly T1.

J Clin Endocrinol Metab. 2010 Aug;95(8):3623-32. doi: 10.1210/jc.2009-2571. Epub 2010 May 25.
A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study.
Parle J1, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, Heath C, Sheppard M, Franklyn J, Hobbs FD.

Conclusions:

This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.

J Affect Disord. 2002 Apr;68(2-3):285-94.
Effects of supraphysiological thyroxine administration in healthy controls and patients with depressive disorders.
Bauer M1, Baur H, Berghöfer A, Ströhle A, Hellweg R, Müller-Oerlinghausen B, Baumgartner A.

J Affect Disord. 2009 Aug;116(3):222-6. doi: 10.1016/j.jad.2008.12.010. Epub 2009 Feb 11.
The use of triiodothyronine as an augmentation agent in treatment-resistant bipolar II and bipolar disorder NOS.
Kelly T1, Lieberman DZ.

Am J Psychiatry. 2006 Sep;163(9):1519-30; quiz 1665.
A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report.
Nierenberg AA1, Fava M, Trivedi MH, Wisniewski SR, Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF, Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ.

Nord J Psychiatry. 2015 Jan;69(1):73-8. doi: 10.3109/08039488.2014.929741. Epub 2014 Jul 1.
Well-being and depression in individuals with subclinical hypothyroidism and thyroid autoimmunity - a general population study.
Fjaellegaard K1, Kvetny J, Allerup PN, Bech P, Ellervik C.

Mol Biol Rep. 2014;41(4):2419-25. doi: 10.1007/s11033-014-3097-6. Epub 2014 Jan 18.
Thyroid hormones association with depression severity and clinical outcome in patients with major depressive disorder.
Berent D1, Zboralski K, Orzechowska A, Gałecki P.

Mol Psychiatry. 2016 Feb;21(2):229-36. doi: 10.1038/mp.2014.186. Epub 2015 Jan 20.
Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.
Bauer M1,2, Berman S2, Stamm T3, Plotkin M4, Adli M3, Pilhatsch M1, London ED2, Hellemann GS5, Whybrow PC2, Schlagenhauf F3.
    Abstract

Mol Psychiatry. 2005 May;10(5):456-69.
Supraphysiological doses of levothyroxine alter regional cerebral metabolism and improve mood in bipolar depression.
Bauer M1, London ED, Rasgon N, Berman SM, Frye MA, Altshuler LL, Mandelkern MA, Bramen J, Voytek B, Woods R, Mazziotta JC, Whybrow PC.

Minerva Endocrinol. 2013 Dec;38(4):365-77.
Hypothyroidism and depression: salient aspects of pathogenesis and management.
Duntas LH1, Maillis A.

J Psychiatr Res. 2012 Nov;46(11):1406-13. doi: 10.1016/j.jpsychires.2012.08.009. Epub 2012 Sep 7.
The combination of triiodothyronine (T3) and sertraline is not superior to sertraline monotherapy in the treatment of major depressive disorder.
Garlow SJ1, Dunlop BW, Ninan PT, Nemeroff CB.

Mol Psychiatry. 2016 Feb;21(2):229-36. doi: 10.1038/mp.2014.186. Epub 2015 Jan 20.
Levothyroxine effects on depressive symptoms and limbic glucose metabolism in bipolar disorder: a randomized, placebo-controlled positron emission tomography study.
Bauer M1,2, Berman S2, Stamm T3, Plotkin M4, Adli M3, Pilhatsch M1, London ED2, Hellemann GS5, Whybrow PC2, Schlagenhauf F3.