Friday, February 10, 2012

Thyroid and Psychiatric Illness

The thyroid is one of those glands that is hooked into everything.  Mood, cognition, metabolism, bones, heart, cholesterol… all can be affected by perturbations among the thyroid hormones.

Chris Kresser has done a great series of articles and it's worth a look if you are unfamiliar with the thyroid or if you want a comprehensive refresher.  In fact he did such a good job it seems hardly worth reinventing the wheel, so I thought I would start with psychiatric disease and then address any questions and chase the rabbit holes that will inevitably open up.

My information today comes from a review done for the American Journal of Psychiatry this month and pointed out to me by my fantastic colleague Dr. Hale:  Abnormal Thyroid Function Tests in Psychiatric Patients:  A Red Herring?  This review is conventional to the extreme, but I find it is often very useful to start with conventional reasoning and pick apart where there may be issues or something missing.

I will begin with the briefest of primers so that we are more or less on the same page:

The Killers, All These Things That I've Done (right click to open in new tab)

All right.  As with everything endocrine, there is a feedback loop, but for our purposes we will start with the hypothalamus, which makes a chemical called thyrotropin releasing hormone (TRH).  This chemical toodles on down to the anterior pituitary, which produces thyroid stimulating hormone (TSH).  TSH then directs the thyroid gland itself to release thyroid hormone.  The two major ones are T3 (triiodothyronine) and T4 (thyroxine).  High levels of T3 and T4 should feedback to the pituitary and cause it to decrease the amount of TSH secreted, thus nicely regulating itself.  The other important thing to know is that iodine is essential for the creation of the thyroid hormones, and that T4 is actually a prohormone (and is the major hormone secreted by the thyroid) while T3 is the active hormone.  Selenium is required to turn T4 into T3.

Courtesy Wikipedia Commons
Lots of things can go wrong within this complex system.  For example, a nodule in the thyroid can start producing thyroid hormone like gangbusters and won't respond to feedback inhibition.  This is hyperthyroidism, with classic lab results of high T3, high T4, and typically undetectable TSH.  Symptoms are a racy metabolism, so weight loss, rapid heartbeat, somewhat elevated body temperature, insomnia, anxiety, etc.

In the opposite case, the thyroid can stop responding to the pituitary TSH stimulation and stop producing thyroid hormone.  This is known as hypothyroidism, and will result in low T3 and T4 with a very high TSH.  Symptoms can include weight gain, fatigue, depression, cold intolerance, hair loss, and slow heart rate among others.

These two primary thyroid disorders can cause a host of psychiatric symptoms, including depression, mania, dementia, and even psychosis.   If someone comes to my office with weight gain, cold intolerance, fatigue, and depression, I'd better well check the thyroid and grab a pulse rate while I'm at it.  I'd look pretty silly treating hypothyroidism with therapy or antidepressants.

Besides these basic thyroid problems, thyroid hormones can be off kilter in a variety of other ways.  Chris Kresser's series goes into great detail, but with rare exceptions, these abnormalities are not due to thyroid problems in the actual gland.  Alterations in thyroid function can occur in response to all sorts of systemic illnesses, stress states, and medications, and perturbations in the thyroid function tests not thought to be due to actual hypo or hyperthyroidism is called "nonthyroidal illness." In general, any pattern of tests that don't quite fit the classic  hypo/hyperthyroid patterns will indicate a nonthyroidal illness.

Sepsis, heart attack, major surgery, autoimmune disease… all of these can lead to a characteristic pattern of thyroid tests including low T3, normal to low T4, and high reverse T3.  TSH is often normal, but can be low and later become elevated during recovery.  These abnormalities are extremely common and are seen in about 75% of hospitalized medical patients.  The kicker is these abnormalities seem to be a physiologic response to the illness and they resolve without any intervention in a few months.  The reason these changes happen is (as always) complicated, but inflammatory cytokines such IL-6, IL-1, and TNF alpha are likely involved, altering feedback regulation along the hypothalamic-pituitary-thyroid axis.

Starvation, fasting, or a very low carb diet can tend to lead to low TSH, normal or slightly elevated free T4, and low T3.  There is nothing wrong with the thyroid and this is not "hypothyroidism" per se, but a normal physiologic response to perceived starvation, and it should resolve without other intervention once someone stops fasting or increases carbohydrate intake.  Sepsis (severe infection) will often present with low TSH, normal free T4, and low free T3, a similar pattern.  Again, once the infection is cleared, the abnormalities will resolve on their own.  This "low T3" syndrome is a bad predictor in the case of cardiovascular disease (1), but that doesn't mean that treating with T3 would be smart.  There is some reason to suspect that "low T3" may be a maladaptive response and T3 after a heart attack may be a good idea after all (2), but I think the proof will be in future research (3).

As we noted before, primary thyroid problems can cause psychiatric symptoms.  However, the reverse is also true, and up to 33% of psychiatric inpatients will have abnormal thyroid tests.  As in the case of the medical "nonthyroidal illness," these abnormalities will tend to be characteristic of the disorder and will also resolve on their own within a few months.  In acute psychosis, for example, TSH is usually normal while total T4 is often elevated.  In mania, total T4 and free T4 will be elevated.  In depression, TSH may be a little low or high, with a high free T4 and low or high total T3.

In general, it is recommended that nonthyroidal illness is NOT treated with thyroid hormone.  In nonthyroidal illness, the low T3 or other abnormality may be part of the adaptive inflammatory response (I've linked some thoughts about possible exceptions above).  This reasoning is why conventional medicine suggests testing TSH alone, and checking other hormone levels only if the TSH is out of whack.  Without multiple findings indicative of thyroid problems (a typical hyper or hypothyroid) symptom complex, it is unlikely to be a primary thyroid issue, except in the elderly, who can sometimes show few symptoms.    Other folks with a history or family history of autoimmune disease, treatment with lithium, radiation exposure, goiter, etc. are obviously at higher risk for primary thyroid disease and one should have higher suspicion.

"Subclinical hypothyroidism" is a bit of a gray area between true thyroid illness and the nonthyroidal problems.  TSH will be high, while free T4 will be low or normal. Usually multiple hypothyroid symptoms will indicate a thyroid problem, while no symptoms will indicate nonthyroidal illness and will resolve on its own, which should show up in serial lab tests over months.

From my perspective as a physician, I tend to rely on the TSH and not aggressively pursue mildly abnormal T4s or T3s, particularly if there are no other symptoms.  However, I think low grade iodine and selenium deficiencies are rarely thought of by a conventional physician and may lead to thyroid symptoms and subclinical or confusing lab results. ("Are you eating too much millet? Is not a typical question in the standard medical interview). In addition, there is some controversy as to the appropriate range of TSH considered normal.  In the past it was around 0.8 or 1.0-6.  Now many labs have narrowed the threshold by reducing the upper limit to 3.5 or 4.  However, in most true hyperthyroidism (99%) there will not be much of a question -- TSH will be undetectable.  In true hypothyroidism, it is not unusual to see levels higher than 20.

TSH levels >2.5 are associated with a greater risk of cardiovascular disease.  But is that due to other factors, such as systemic inflammation?  Does it make sense to use thyroid hormone to treat a mere number?  How is that different from treating a cholesterol number with a medicine for the specific purpose of getting the number into a "better" range?  I think we are still coming to a consensus as to the right thing to do in the case of "subclinical hypothyroidism."

As we discussed in the comments of a previous post, psychiatry is pretty much the only specialty where we have a large amount of data and clinical reason for using T3 hormone to treat depression symptoms.  Most primary care doctors and endocrinologists will use T4 exclusively.  In general, T4 the prohormone is safer, and the body should be able to make about as much T3 as it needs (provided selenium levels and vitamin levels are okay).  Conversely, being too aggressive with T3 can lead to death.

However, as I noted, I've found T3 to be generally ineffective or uncomfortable for most, and the only folks who seem to respond well already have diagnosed hypothyroidism and are on synthetic T4.  I've also found that the recommended psychiatry doses (25 to 50 mcg T3) are way too high, and lead to mild hyperthyroidism symptoms within several months.  I've had better luck with lower doses of T3 (around 5 mcg) combined with lowering the dose of T4.  My anecdotes are hardly data, but I think I might have caught some poor converters from T4 to T3, or maybe they are selenium deficient.  In conventional endocrinology these folks don't really exist, but I'm usually able to get away with treatment if I document "for psychiatric indication."


  1. Thanks for the post!
    Typo? "Hypothyroidism... symptoms can include weight *loss*... If someone came into my office... with weight gain... I'd look pretty silly..."

  2. I find certain things about blood tests and subsequent actions on their basis to be confusing. For instance, if someone presents on the low end of a free t3 blood test (i think they range from 70 to like 200..), and they have all the symptoms of hypothyroidism (lethargy, depression.etc), what should a psychiatrist do...prescribe some amphetamine salts to get rid of the symptoms, or try with a low dose of t3 as you noted at the end?
    I understand at several points throughout the article you also mention that unbalanced blood markers should resolve on their own without intervention. But if the patient is still experiencing symptoms that make life rather difficult, shouldn't [low dose] t3 therapy be given a chance?

  3. Question, would you at all suspect hypothyroidism if a person were fasting (eating very little) fairly long term, and exhibiting signs of psychosis, and these both came on (apparently) rather suddenly?

  4. Hi! could you comment sometime on the new paper that came out about rapid amyloid plaque clearing in mice w alzheimers? ("ApoE-Directed Therapeutics Rapidly Clear β-Amyloid and Reverse Deficits in AD Mouse Models")... I was wondering if there were any nutritional implications. Thanks : )

  5. Psychic24 - the real issue (and one I will go into in the next post) is what do you do long term? I'm going to do a whole review on T3 in depression next.

    Robert - sometimes psychosis can lead to fasting, not the other way around. Anyone with new onset psychosis should get a full medical work-up including tox screens, thyroid testing, MRI, other basic labs, rule out of Wilson's disease, etc. If there is a history of gastric bypass other nutritional labs should be tested (thiamine in particular). If the person is elderly it is almost always medical (dementia, brain tumor, delirium, etc.), though there is a second spike of new onset bipolar disorder for women around menopause.

  6. That's interesting bc when I went too low Carb my ft3 went even further down and my tsh crept higher than it's ever been..4. 5. I am now eating more carbo hydrates and taking selenium

    1. I don't necessarily associate starvation with low-carb, assuming one is eating sufficient fats and proteins to fuel the brain, etc. I am curious, metabolically speaking, what the carbohydrate link is to the thyroid. Dr. Deans - could yo go into more detail please?

  7. Interesting - thanks Emily,
    I have subclinical hyporthyroid, and have been a little concerned about the heart disease issue.
    My TSH is down to 4, T3 and T4 in normal range but low. No clinical symptoms. Just hoping the heart disease thing is an association, and possibly continuing with a strict gluten free paleo diet, and selected supplements will keep me heart disease free despite the Hashimotos.
    I guess I'll have an answer in 20 years or so!

  8. Very interesting! I have been trying to troubleshoot and optimize my and my partner's thyroid hormones.

    Seems like most regular old internists do not look at anything other than a TSH that shows up bold and out of range.

  9. My Wife's TSH is Higher 12 - 14 however T3 and T4 are within range and am on Eltroxin 100mg since thyroidectomy in 1993.
    Is it a matter of concern.

  10. As a now thyroidless Hashi's/thyroid cancer patient, I find this info very interesting! Thanks for posting! Psychic24, today's thyroid patients test TSH, Free T4 and Free T3 levels. This is all, any other tests are considered outdated such as the Total T3 test you are referring to, which sadly, is still be performed by various physicians. Also, testing for Hashimotos antibodies is a good idea as well. And yes, T3 is hard to handle for most at doses like 25 or 50 mcg - even with no thyroid and a TSH of 50, I could not tolerate 25 mcg Cytomel. I was violently ill until it cleared my system.

  11. Confused. THS is within normal range for the UK at 5, FT3 AND FT4 both in the normal range. Antibodies elevated. The TSH would be considered borderline high in other countries. What does this mean in terms of the slightly high antibodies of 74 with a ref range of <50 ??? Symptoms are weight gain, swollen puffy eyelids, specially in the morning, weight gain, and EXCESSIVE hunger pangs, arrythmias. No CNS, depression. Low on iodine (allergic to seaweeds and Lugol) I don't over eat. Very low carb diet. I am on selenium, chromium, multivits, multi minerals, Vit E, Q10, Flax seed oil, and zinc.

  12. A little off topic, but I have a burning question. Would you happen to know what an expecting mother in Dallas, Texas in 1956 would have been given for "hypothyroidism" and just how it was diagnosed, since TSH and other tests would probably not have been in use at the time? She said she felt "terrible/horrible" before the meds/difficult pregnancy, then she felt better after taking whatever it was, but did not need to take it after delivery. (uh oh). Iodine not in pill form at that time, so she should have been able to remember whatever it was she took. Synthroid not in big use. Or was she just given DES for a "high risk" pregnancy, which was pretty much the standard of care at that time. Any insights much appreciated. I have only been able to get one other professional to speculate about what was being given at that time for hypothyroidism, but he is a scientist, and not an MD. No other MDs I have asked seem to know what the standard of care would have been at that time. Thank you.

  13. What did the scientist suggest it was?
    I read that Russians doctors use to tell their
    hypo patients to eat black radishes daily. The raphins
    (can't quite remember) would stimulate hormones release. I since read of one person who did this, successfully.

  14. What are your thoughts on hypohyroidism and adrenal fatigue? Is one has very low cortisol, or struggles with it- would this cause low thyroid issues?

  15. i had severe eye burning on synthroid and bouts of depression. now on dessicated t3 and t4, feeling much better so far.

  16. I have stumped doctors with subclinical hyperthyroidism. One test, (quite a while ago) my TSH was .198 and I was told this was "very low". My T3 and T4 were in the lower limits of normal. A nodule was also found at one point. An herbal nutritionist explained that I could very well be hypothyroid, that it was probably resistivity to thyroid hormones. She said the body produces more hormones, so still may have under activity of hormones at the cellular level and are producing enough (she may have said too much) thyroid hormone, which cells can't utilize. She said it may look like hyperthyroidism because cells are resistant to hormone and may actually be hyper thyroid.
    I have been on the GAPS protocol for two years and have not gone back to have my levels checked. I know that I can feel like a mental patient at times and wonder if the excess emotions are caused by my thyroid issues. If you have any thoughts, I would be so grateful!

    1. Hi Pamela,
      Based on my naturopath's diagnosis and the research I've done, you definitely fit the diagnosis of NonThyroidal Illness Syndrome, or Low T3 Syndrome. Chris Kresser has a great series of articles on this condition. Basically, my understanding is that underlying infections, inflammation, and illness (assuming you're not starving) are what cause this condition. In my case, it was a ketogenic diet causing chronic high cortisol levels leading to gut disbiosis (candida overgrowth) and elevated systemic inflammation. No bueno. I'm finally seeing some improvement after a few months (no medication but increased carbs and anti-inflammatory diet/lifestyle). I wish you the best!

  17. I developed NTIS after doing a 2 month stint on a ketogenic diet last Spring. I thought I'd researched the protocols thoroughly and was shocked to learn that the elevated cortisol that results from ketosis could lead to a cascade of serious and long-lasting health problems (In addition to the NTIS, my thyroid antibodies are now elevated, neurotransmitters have tanked, and my ASI shows cortisol disregulation.) As a devoted member of the Paleo community, I'm glad to see this issue being discussed as so many tout low carb as the solution to all health woes. Fyi, I saw you speak at Paleo(f)x this year and was uber impressed! Thanks for your hard work.


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