That Tapeworm Ate Your Depression

I'm a little embarrassed that Mark Sisson got to this one before I did.  But I'm sure he has several minions to scan the literature for him, whereas I have a few loyal friends and fellow bloggers.  Here it is, though, a new paper from the Archives of General Psychiatry, "Inflammation, Sanitation, and Consternation: Loss of Contact With Coevolved, Tolerogenic Microoganisms and the Pathophysiology and Treatment of Major Depression."

And I have to admit, after reading Mark's little blurb, I went to the paper expecting to be annoyed.  There are a lot of versions of the hygiene hypothesis (basically the idea that our environments are too clean) that make it sound as if your mom is a crazy germophobe and that's why you have asthma. Which doesn't make sense, because that remote control your kid is chewing on has about a billion microbes on it.  Also, you will often hear that "children just aren't exposed to childhood infections anymore" as we have vaccines and smaller family sizes and antibacterial soap.  But the typical childhood infections such as chicken pox, whooping cough, diphtheria, etc. are all as modern as eating grains, and were established in humans as we developed higher population densities and domesticated animals, so lack of exposure to those bugs wouldn't necessarily mess with our evolved immune system (also, there is some (association) evidence that exposure to common viruses increases inflammation and may increase our risk for depression).  That particular version of the hygiene hypothesis is dealt a death blow by the fact that inner city kids rife with childhood infections have the highest rates of asthma, much higher than isolated rural kids living out in the country with all the ragweed (1).

But I set aside my preconceptions and took a look at the paper, and thank goodness I did, because it is epic, amazing, and brilliant.  All psychiatrists, psychologists, and other doctors download it now if you have access and have a look.  It even includes the Dobzhansky quote "nothing in biology makes sense except in the light of evolution."

So here we go.  I've made a point before that depression is a result of inflammation.  Specifically, depression is associated with higher serum levels of IL-6, NFkappabeta, TNF alpha, and a host of other pro-inflammatory cytokines.  Medically healthy individuals with depression and a history of early life stress mount a larger inflammatory response to laboratory psychosocial stressors than do nondepressed controls.   The prevalence of major depressive disorders is increasing in all age cohorts, but especially in younger people, and countries transitioning to be part of the developed world experience increasing rates of depression along the way.  One would hypothesize, then, that something environmental in the modern world makes us vulnerable to depression (and other inflammatory diseases of civilization, such as MS, inflammatory bowel disease, type I diabetes, asthma, etc.).

"Overwhelming data demonstrate the prevalence of helper T cell type I...mediated autoimmune and inflammatory bowel and Th2 mediated allergic/asthmatic conditions have increased dramatically in the developed world during the 20th century, with increases in immune-mediated disease incidence in the developing world during the same period closely paralleling the adoption of first world lifestyles." 

Asthma, hay fever, type I diabetes, inflammatory bowel disease, and multiple sclerosis have all increased 2-3 fold in the developed world in the last 60 years.  Many of these conditions are highly comorbid with major depressive disorder.

I've focused on a pro-inflammatory diet as a hypothetical cause for increasing depression (along with obesity and the other diseases of civilization).  The vast majority of the depression literature, I would say, has focused on the pro-inflammatory aspects of a stressful modern life (which I contend isn't necessarily more stressful than life was 60 years ago, or 800 years ago, during the Bubonic Plague, for example).  This paper focuses on "the loss of a microbial modulated immunoregulation" of our Th1 and Th2 immune cells.

Quick review - childhood viral infections tend to mobilize type I T helper cells.   Since Th1 cells seem to balance and modulate the Th2 cells, one might expect that a lack of Th1 activation due to a sanitized environment would lead to naughty Th2 cells running rampant, causing asthma and allergy and the like.  That makes sense, except naughty Th1 cells seem to cause other autoimmune issues, like Crohn's disease, and the incidence of Crohn's disease has increased steadily along with asthma and allergy.   In fact, "most follow up studies have failed to show an association between childhood infection and increased autoimmune and/or atopic conditions in the modern world while continuing, in general, to find correlations between a first-world lifestyle and increases in these conditions."

But humans have been living with some microorganism and parasites for much longer than the childhood infectious diseases of the last 10,000 years of agriculture.  These ubiquitous organisms seemed to keep Th1 and Th2 cells busy without causing problems, in other words, the "old friends" germs "induced and maintained an adaptive level of immune suppression."  Or:

"the mammalian genome does not encode for all functions required for immunological development, but rather that mammals depend on critical interactions with their microbiome (the collective genomes of the microbiota) for health."

What are these organisms?  First off are the pseudocommensals, saprophytic mycobacteria that are found in mud and untreated water and on unwashed food.  They don't colonize the body, apparently, but were known to pass through it in large quantities historically:

A bunch of commensal species are known to inhabit our gut, among them Bacteroides, Lactobacilli, and Bifidobacteria.  And finally, the helminths (internal parasites, such as tapeworms) are the third member of the triad of "old friends."

There is a whole body of literature dedicated to animal studies showing how exposure to these "old friends" reduces autoimmine, inflammatory conditions, and even cancer.  A sugar molecule from Bacteroides species protected against colitis and distorted immune system development in germ-free mice.  Prebiotics known to increase Bifidobacteria in the rodent gut reduced serum concentrations of cytokines such as TNF alpha and IL-6.  "Metabolic products from gut microbiota reduce inflammation in animal models of a variety of human autoimmune and allergic disorders, as well as in [test tube] preparations of human [immune cells].  The health of the human gut microbiome has been shown to impact varied physiologic processes such as pain sensitivity, sleep, and metabolism (all of which are abnormal, by the way, in major depressive disorder.)  A parasitic worm, Schistosoma mansoni, can make a friendly phospholipid for us, phosphotidylserine.  Exposure to a pseudocommensal organism, M vaccae, reduced serum TNF alpha concentrations over a three month period compared to placebo (in humans and human monocyte cell lines).  Recall that TNF-alpha is increased in depression, and antidepressants reduce TNF-alpha - it does make one wonder if these "old friends" have antidepressant effects.

Without constant exposure to these immune modulating "old friends,"  it is plausible that modern humans are at risk for mounting inappropriate inflammatory responses, leading to many of those undesirable diseases of modern civilization, including depression.  I wonder if using inappropriate food, such as vast quantities of fructose, could destabilize the gut microbes and be part of the inflammatory process.  One could further postulate that exposing depressed individuals to "old friends" could act as a treatment.

Gut-depression links are already well known - psychological stress in humans is associated with reduced fecal Lactobacilli, and individuals with major depressive disorders had some fragments gut bacteria inappropriately floating around in their blood, suggesting the presence of leaky guts.  One small study showed that giving people a prebiotic that favors Bifidobacteria reduced anxiety in patients with irritable bowel (2), and another 2 month placebo-controlled study showed that lactobacillus treatment reduced anxiety (but not depression) in people with chronic fatigue (3).  Probiotic treatment did not reduce depressive symptoms in chronic fatigue patients in another small study, but it did improve some cognitive symptoms that are common in major depressive disorder (4).  M vaccae was administered to patients with renal cell cancer, reducing serum IL-2 and some depression symptoms (5), and in another larger study, killed M vaccae reduced depression and anxiety symptoms in lung cancer patients receiving chemotherapy (6). 

There is a long way to go before we start feeding people dirt and worms as an evidenced-based strategy for treating depression.  But...the ideas are intriguing, based in common sense, and scientifically sound.  People with the "short" genetic form of the serotonin receptor, for example, are known to be more vulnerable to major depressive disorder, and they are also more vulnerable to known forms of depression caused by inflammation, such as depression caused by interferon alpha treatment.  These findings link genetic vulnerability to environmental inflammatory factors to depressive symptoms.  Priming the body with known anti-inflammatory modulators should help depression.  Even if it might not seem that...tasty.

Obesity, Systemic Inflammation, and Bipolar Disorder

Mental illness is not invented, and psychiatry is not all in your head.  Today an exploration of the link between bipolar disorder and obesity.  And there is a link, despite the tremendous confounding fact that most of the medicines used to treat bipolar disorder definitely cause obesity, researchers separate out the medication component (and also look at reports from history, prior to medications even being available) to find a strong correlation.  But why, and how?

Cool song: Howler, Back of Your Neck. (right click to open in new tab)

Well, I don't have any definitive answers for you today as to the ultimate cause of bipolar disorder and why it is linked with obesity.  What we do have is a little recent observational study, Increased Levels of Adipokines in Bipolar Disorder that can serve as a handy review of some of our obesity hormones.  

Everyone, I'm assuming, has heard of insulin, and probably leptin.  Leptin is an adipokine, a chemical mediator produced by the fat tissue that can help tell the body how much fat is on board.  Most of you will know that leptin tends to be increased in obese folks, suggesting that obesity may be a function of leptin resistance.  There are other adipokines besides leptin, however, including resistin and and adiponectin.  Adiponectin is of particular interest, because it is known to be anti-inflammatory, the body makes quite a bit of it relative to other hormones, and its levels inversely correlate with obesity in adults.  Leptin is thought to be pro-inflammatory, and may be responsible for the activation of an inflammatory cytokine, TNF-alpha.  Adiponectin will help to decrease the production of TNF-alpha.  So, in general, an obese person will have lower than normal adiponectin and higher than normal leptin, with associated increases in inflammation.

In the study, 30 bipolar (type I) patients were compared with 30 matched (age, BMI, education level, and gender) controls.  All the bipolar patients were on medication (a huge weakness of the study).  Compared to the matched controls, the bipolar patients had higher levels of adiponectin, leptin, and one of the receptors for TNF-alpha.  The kind of medication (as the patients were on several different classes) and medical co-morbities did not correlate with the hormone levels.  Since, again, adiponectin is generally lower in obese individuals, it is interesting that the bipolar patients had higher levels than the controls of the same age, gender, and BMI.  

One previous study of obese bipolar patients showed the same increase in adiponectin.  A study of non-obese depressed bipolar patients had adiponectin levels lower than the controls.  Leptin has been more vigorously studied, and the levels are elevated in some and not in others. The only other study of previously manic but now normal mood patients had the same leptin levels (elevated).  

It's interesting, though we don't quite know what it means.  We get a hint of a large puzzle of a systemic illness, affecting mood, sleep, appetite, thought, immunity, and the adipose tissue.  The connecting process of inflammation is not controversial.  What causes the inflammation… that we don't yet know, and it is likely a confusing combination of factors.  There are a number of papers exploring, for example, peripheral biomarkers and different moods in bipolar disorder, helping us to figure out other pieces of the puzzle.  No one has all the answers. 

Stress and Your Gut (Or At Least A Mouse's Gut)

Several folks (Julianne and Chris Kresser come to mind) tweeted about this new paper last week, and it really is a doozy.  "Exposure to a social stressor alters the structure of the intestinal microbiota:  Implications for stressor-induced immunomodulation."  The associated editorial is worth a read as well, if you have access.  Also, the journal it comes from, "Brain, Behavior, and Immunity" is very cool.  The entire journal is devoted to subjects of interest to any psychiatrist who looks into the inflammation/brain connection.  And if inflammation itself is truly behind the pathophysiology of psychiatric disorders, then somewhere in the archives or future of this publication will be the holy grail linking inflammation via diet and lifestyle to actual brain pathology.

This paper is a nice start.  First some fun facts.  The external surfaces of the body (that includes the gut, by the way, as we are a funny tube within a tube) are populated with microbes.  So populated, in fact, that 90% of the cells that make up the roving bacteria party + human host are the commensal microbiome.  Yup.  90% of you (by cell number) is them.  Most of these colonizers and symbiotes live in the intestine, especially the large intestine.  In the Matrix world of commensal species, the large intestine is Zion.

Here's the crazy thing - we know very little about these species.  Mostly because the vast majority seem to be absolutely dependent upon us (as we turn out to be symbiotically dependent on them).  They can't be cultured without the host in a lab.  They need a living working gut, where they flourish, but are difficult to study.   That means we didn't have the capability even to catalog the species of gut bacteria until we could practically and relatively cheaply sequence DNA in large amounts, so not until the last 7 years or so.

The beasties live in a "largely stable climax community" in our guts as the result of natural selection for species best adapted to our habits and personal nooks and crannies.  Fortunately, the beastie community is pretty resilient, but factors such as a change in diet and antibiotics will obviously transiently affect the population.  In addition, exposure to stress also changes the population of beasties, the details of which were more clearly elucidated by the work in this paper.

The beasties do all sorts of nice things for us, really.  They make vitamin K, several B vitamins, and eat up carcinogens and other nasties.  Their health and composition are definitely related to the pathology of obesity and of diabetes (at least in mice).  And, not surprisingly, these bacteria impact the immune system.

Germ-free animals raised in sterile environments without commensal microbiota have a different sort of intestinal immune system, with a lower amount of intestinal antibodies and fewer immune cells.  Colonizing these sterile mice will result in normalization of the gut immune system.  Alterations in the intestinal microbiota has been linked to asthma in animals and humans, suggesting that the beasties modulate adaptive and innate immunity.

Y'all might remember that some of those cytokines and immune system chemicals that are produced in the process of inflammation are known to be elevated in the case of depressive disorders.  Chemicals with names like IL-6, TNF alpha, and interferon gamma.  IFNgamma is known to actually cause depression.  Who cares?  Well, translocation of gut bacteria through the gut lining into the comparatively sterile body interior results in a systemic increase in IL-6 and the other cytokines.  We talked about that a little bit in relation to depression and chronic fatigue in posts a few weeks ago.  Psychological stress in humans, such as caring for a sick relative or chronic work stress, also is associated with elevated cytokines IL-6 and TNF alpha.  So the question asked by these researchers (and subsequently answered) is - does psychologic stress change the microbiota population, and is that related to a cytokine change within the body?

The experiment itself was complex and consisted of several different arms, and many mice made the ultimate sacrifice (along with their gazillion commensal microbiota).  In short, some mice were mostly left alone, others were given antibiotics and stress, others just exposed to mean "aggressive mice," others were restrained, and others given antibiotics and restrained...

So what happened to the microbiota and the levels of cytokines in these various experiments?  Well, the mice exposed to stress had definite changes in internal beastie populations.  In general,  exposure to stress (the mean mouse, or restraint) led to "a reduction in microbial diversity and richness."   In addition, exposure to the stressor led to a significant increase in IL-6 levels.  Interestingly, the specific genus of the population of microbiota were significantly related to the generation of IL-6.  TNF-alpha and INFgamma were also increased in stressed mice, but not significantly.

In the antibiotic-treated mice (with a pummeled microbiota), the IL-6 did not increase in response to stress.  Antibiotics reduced the amount of bacteria about 100-fold, so while it didn't eliminate the commensal bacteria by any extent, it made a good dent in the population.

Taken together, these results tell us that stress affects our gut bacteria, which affect our immune system and cytokines.  We know those increases are related to changes in psychological states.

The editorial quote of note:

The strength of implementing a truly integrative systems approach when studying stress physiology has never been clearer than in the work by Michael Bailey and his colleagues in this issue of the journal.  These scientists investigated the impact of stressor exposure on multiple physiologic symptoms, including the intestinal microbiota and the immune system.  These data reveal dynamic interaction between these systems when orchestrating the innate immunological stress response. 

So yes, they control your brain.  To some extent.  Best keep the beasties happy.  Kefir and sauerkraut anyone?

Inflammation and Depression: Cause or Effect

Longest hiatus ever. We've been out of town, and then there is the business involved in preparing to go out of town and all the stuff piled up to do when you get back into town. I've been wanting to finish up the anxiety and depression chapter from The Hygiene Hypothesis and Darwinian Medicine (I started that chapter with "What is Evolutionary Psychiatry?" a month ago.  So here we are.

The Mighty Mighty Bosstones: The Impression That I Get 

Depression (and anxiety) are associated with multiple markers of inflammation in the body, though a source for inflammation is often not apparent. Mere exposure to psychological stress can cause elevations in pro-inflammatory cytokines, and the ability of stress to drive inflammation is increased in depressed individuals (as measured by levels of IL-6 and DNA binding of NF-kappaB. The most stressed students had larger increases in interferon gamma, IL-1receptor alpha, TNF, and IL-6 than students who were less stressed about an exam in one study. Since there is a truckload of evidence that stress is a major factor mediating depression, here is evidence that the stress causes the inflammation that causes the depression, not the other way around. And yet…

Just the administration of certain cytokines alone (as we've discussed at length before) can cause depression symptoms in humans and animals. Blocking the action of IL-1 in the central nervous system in animals will stop this effect. Humans with a depression syndrome caused by administration of proinflammatory cytokines will also respond to treatment with antidepressant medications. 

There are genetic studies of different families with depression vulnerabilities, and some of the genes implicated are in the inflammatory pathway (such as IL-1and TNF). In addition, folks with a certain type of serotonin (5HT) 1A receptor seem to be more vulnerable to the induction of depression by interferon alpha 2 beta. Interferon alpha will downregulate the production of the 5HT-1A receptor. Both anxiety and depression patients have been showed to have decreased 5HT-1A receptor, and certain folks with a subtype of the receptor are more vulnerable to anxiety and depression, and they also seem to be less responsive to certain antidepressant medications.

Inflammation also seems to impair the function of glucocorticoid receptors. That would explain why people with depression and anxiety seem to have high levels of cortisol, but decreased ability to respond to it in an effective way (so people feel fatigued and overwhelmed rather than energized and capable despite mountains of cortisol running through the body). The term "adrenal fatigue" which I often see in blogs and whatnot is misleading and "glucocorticoid resistance" is much more meaningul.

Anti-inflammatory agents have been shown to help with depression symptoms in certain cases. Usually the research uses fancy-schmancy anti-inflammatories (such as anti-TNF antibodies used in Crohn's disease and psoriasis), but celecoxib has also been shown to have some positive effects on major depressive disorder.

More standard antidepressant medications (of most of the major classes) have been shown to be anti-inflammatory in vivo and in vitro. For example, tricyclic antidepressants, norepinephrine reuptake inhibitors, and SSRIs have all been shownn to reduce the toxin-induced secretion of IFN gamma and IL-10 in a solution of red blood cells exposed to toxin.  In addition, in certain studies, people treated with antidepressants have decreased c-reactive protein levels after treatment, and decreased levels of release of TNF from whole blood samples. Electroshock treatment also decreases TNF in patients with major depression, as does vagus nerve electrode stimulation.

SSRIs in particular could have a direct action on a person's T cells. SSRIs work on the SERT (serotonin transporter). Certain immune cells have SERT and they use it to take up serotonin from mature T cells. The serotonin is eventually transferred to naive T-cells and seems to enhance their activation. This mechanism would explain how SSRIs at least could reduce pro-inflammatory cytokine expression (many of the pro-inflammatory cytokines are released from certain types of T cells). Since genetic polymorophisms in the promotor region of the SERT gene have also been shown to cause increased vulnerability to depression in those exposed to stress, this inflammatory mechanism may be the cause. We will have to look outside the brain to really understand all the systemic vulnerabilities and expressions of depression and anxiety. 

And finally we get to some mechanisms that I've actually discussed previously (the most common and widely accepted mechanisms of how depression goes hand in hand with inflammation, and how antidepressants seem to help when they do). Antidepressant drugs tend to reduce the activity of TDO which metabolizes tryptophan, the dietary precursor to serotonin. This action tends to oppose those of pro-inflammatory cytokines (such as IFN-gamma and IL-1) to increase the catabolism of tryptophan by IDO and of glucocorticoid hormones to increase catabolism of tryptophan by TDO. These medicines seem to increase plasma and brain tryptophan concentrations, and secondarily increased production of serotonin in the brain. Tryptophan and serotonin are also known immune regulators. So, once more, stress hormones and pro-inflammatory cytokines antagonize serotonin, tryptophan, and antidepressant drugs, and vice-versa.

Probiotics, which also seem to have anti-inflammatory effects, have had antidepressant and antianxiety actions in animal studies. The human studies are very few and far between (I reviewed them here and then a later mouse study here). The pseudocommensal M vaccae, which induces T regs and downregulates the chronic inflammatory state has also been shown to (unexpectedly) improve quality of life scores in people receiving it experimentally for asthma or psoriasis.  

There is a very new explosion of research concerning regulatory T cells and depression in animal models and even in human cell lines. The published studies seem to show that there is a type of autoimune dysregulation in depressive disorders and that the same old suspects of pro-inflammatory cytokines mediate the symptoms. Thinking about depression and anxiety as immune disorders helps us to frame a whole health approach for its treatment: anti-inflammatory diet, exercise (in personalized amount and difficulty) counseling, meditation, and appropriate use of different immune modulators (antidepressants are well studied, of course) as more studies come out showing efficacy and safety. 

Mental Health and Omega 3/6 Ratio, A New Review

Twitter is a black hole for time spitting out information like Hawking radiation. (I may have achieved the geekiest simile ever!)  I've been a bit busy, as the applications for preschool are pretty detailed, asking for medical records, descriptions of my culture, and different ways we help the little one settle down or take her nap (bribery and threats, mostly.  Oh, wait, the correct answer is "routine.") And sure, she's allergic to sunscreen.  Well, with all that going on the blogging and reading has gone by the wayside a little.  Also, most papers come out as a preview in the last week of the month, so there tends to be a rush of exciting new information all at once.  Then a dry spell.  If I'm fired up, I'll actually look into a topic in depth and do a nearly proper literature review.  But not having had the time to do that... there's always twitter (and Jamie Scott, who is sending me a slew of papers about mitochondria, histamine, and sleep because he is awesome that way.  I'm hoping to settle down and look at them sometime over the next couple of weeks).

Twitter!  The be-ripped Martin Berkhan tweeted up a paper earlier today that is a new review of Omega 3s and 6s.  The article, Evolutionary Aspects of Diet: The Omega-6/Omega-3 Ratio and the Brain, is a tidy look at omega-3 and omega -6 biochemistry detailing all the conversions and enzymes along the way for the biochem geeks.  In the end, it describes the more interesting stuff about the evidence that omega 3s, in fact, do have an important role in the brain, and that one would be a sad and foolish monkey indeed to consume the modern 25:1 6:3 ratio (just say no to corn and safflower and soybean oil...)  Another interesting fact - the review is written by Artemis P Simopoulos, who pretty much first popularized the Mediterranean diet with her book The Omega Diet: The Lifesaving Nutritional Program Based on the Diet of the Island of Crete.  Guess she knows what she's talking about with respect to the omegas.  

Let's dig in.  Hmmm... "psychologic stress in humans induces the production of pro-inflammatory cytokines such as IFN gamma, TNF alpha, IL-6, and IL-1."  Yup.  Too much omega-6 compared to omega 3 can lead to the overproduction of inflammatory cytokines, which for various reasons is Not Good.  Theoretically, changes in PUFA ratios can alter the function and structure of the serotonin receptors (for example, essential fatty acids in the plasma predict the CSF metabolites of serotonin and dopamine)(1).  Treatment with DHA and EPA can be useful in major depressive disorder and bipolar disorder.  Other researchers note that as the dietary ratio of omega-6/omega-3 increases, depression symptoms, TNF-alpha, IL-6, and the IL-6 soluble receptor increases.  Another group studied brains of people suffering from depression when they died vs. controls.  A decrease in AA/DHA ratios were negatively correlated with age in depressed people, but not in controls.  All these lines of evidence, including the randomized controlled trials of omega-3 supplementation, seem to support the idea that our brain needs omega-3s to work well and keep the mood stable.    

Now onto the studies of cognition and omega-3 PUFAs.  Turns out that when the neurons are stimulated with neurotransmitters, the PUFAs in the cell membrane can be released to become all sorts of different inflammatory and anti-inflammatory or signaling molecules.  The PUFAs also seem to influence cell migration and cell self-destruction (called apoptosis) - they even influence the length of telomeres, which are known to decrease with age, cancer, and cardiovascular disease.   A lot of neurochemistry has been elucidated in this area - the details are nicely summarized by Simopolous.  Suffice it to say that brain inflammation is part of the pathology of schizophrenia, dementia, and likely autism, and that omega 6/3 ratios could be important, and omega 3 supplementation (if done early on), can possibly be helpful.  There is some controversy as to the best ratio with which to supplement (2:1 EPA to DHA is recommended by Simopolous), and in these unknowns I prefer to fall back to the primary sources - fatty fish themselves.   

A study of prisoners showed many violent incarcerated young folks have deficiency ("0% intake") in omega 3 fatty acids from fish and selenium in the Table 5 of the paper, called "Diet of disaffection: nutrient intakes from a sample of disadvantaged young people."  Only 17% of them get adequate intake of magnesium too.  Interesting.

When one looks at studies of substance abusers, one also finds deficiencies of omega 3s.  Alcoholics, for example, are a known population rife with nutrient deficiencies (a med school professor used to call it the BBB diet - "beer, bread, and bologna.")  A group of researchers carried out a small double-blind randomized controlled trial of 3g EPA and DHA vs soybean oil control in substance abusers. After three months, the treatment arm had significantly reduced feelings of anger, anxiety, and cravings.  The increase in plasma EPA strongly correlated with the reduced anxiety, and the effects persisted for 3 months after the end of the treatment.

Putting it all together - the overall evidence suggests that if you want to be anxious, moody, depressed, violent, and craving addictive substances, by all means slurp down those omega 6 PUFAs. If you want more control over your brain and urges, maybe look into avoiding any extra 6 (the animal fats will have all that is necessary) and be sure to get the omega 3s you need via fish a few times a week or properly sourced beef or other grassfed ruminant meat.  This brain chemistry thing ain't so hard after all.

Depression 2 - Inflammation Boogaloo

It is well known that symptoms of clinical depression are likely mediated by inflammation in the brain. A number of lines of evidence support this idea, including that depressed people, old and young, have elevated levels of certain inflammatory proteins in the plasma and cerebrospinal fluid. Anti-inflammatory agents treat depression, and pharmacologic agents such as interferon-alpha, that cause depression, also lead to increases in the inflammatory proteins IL-6 and TNF-alpha. In addition, when someone who is depressed responds to antidepressant treatment, these same inflammation markers decrease (1). People with generalized inflammatory syndromes (such as acute viral illness, rheumatoid arthritis, insulin resistance, and cardiovascular disease) have higher rates of depression than the general population too. I also notice in my clinic that people who have had bone surgery tend to get depressed for a few weeks after the operation, more so than people who had other kinds of surgery. I always wonder if sawing through the bones releases an enormous wave of inflammatory cytokines.

There are several suspected mechanisms of how this inflammation leads to depression, many of them very cute. Here's one - the amino acid tryptophan is a precursor to Eli Lilly's second favorite neurotransmitter, serotonin*. Turns out that tryptophan is also the precursor to kynurenic. When the inflammatory cascade is activated, more tryptophan is made into kynurenic, which leaves less tryptophan around to make into Eli Lilly's second favorite neurotransmitter, serotonin. And everyone knows that without serotonin, we're unhappy (and angry). SSRIs work, in part, by undermining the effect of the inflammatory cytokines, pushing more tryptophan to be made into serotonin.

Here's another mechanism - inflammatory cytokines also interfere with the regulation of another neurotransmitter, glutamate. Glutamate is an excitatory neurotransmitter that, if left to go wild, can pound our NMDA receptors in the brain and wreak major havoc. No one wants overexcited NMDA receptors, and clinical depression is one among many nasty brain issues that can be caused by overexcitement. Astrocytes, little clean-up cells in the brain, are supposed to mop up excess glutamate to keep it from going nutso on the NMDA. Turns out inflammatory cytokines interfere with the clean-up process (2). The horse tranquilizer (and club drug) ketamine, when administered IV, can eliminate symptoms of severe depression pretty much immediately in some cases (do NOT try this at home) (3). Ketamine helps the astrocytes mop up glutamate, and it is assumed that this is how ketamine instantly cures depression. Unfortunately, the effects of ketamine don't last, otherwise it would be a nifty psychiatrist's tool, indeed.

Finally, inflammatory cytokines also push the brain from a general environment of happy "neuroplasticity" (mediated finally by our old friend, BDNF) towards an environment of neurotoxicity (sounds bad, and it is!).

In my post on vegetable oils, I made note of a popular theory that a relative imbalance between the consumption of anti-inflammatory omega 3 fatty acids (fish oil) and inflammatory omega 6 fatty acids (vegetable oil, such as corn oil) predisposes us to inflammation. The omega 6 fatty acids are the precursors for many of the nasty, depressing cytokines mentioned above (such as IL-6). Well, an absolute flurry of research has been done in this area in the last decade or so, because omega 3 fish oils would be a nifty, low side effect, cheap treatment for depression, if it worked. Some studies have been disappointing (4)(5). However, the largest study yet, hot off the presses, does show benefit (equal to a prescription antidepressant) for those who have depression, but not concurrent anxiety, at a daily dose of 150mg DHA and about 1000mg EPA. (DHA and EPA are fish oil omega 3 fatty acids).

Well, neat! But adding extra omega 3 is just one half of the omega 6/omega 3 balancing act. What if we decreased dietary omega 6 at the same time? Researchers looked at the blood levels and tissue levels of all the different kinds of fatty acid in this recent paper. Turns out that depressed people had higher amounts of omega-6 fatty acids, but the amounts of monounsaturated fats, saturated fats, and omega 3 fats were about the same between depressed and non-depressed individuals. (Other studies showed a decreased amount of omega 3 and an increased amount of omega 6 (6)).

As far as I know, there haven't been any major studies testing both a dietary decrease in omega 6 and supplementation with omega 3 for depression, but it would be an interesting intervention. Dr. Guyenet uses the work of Dr. Lands to make a case that reducing omega 6 PUFAs to less than 4% of calories would be a great way to reduce overall inflammation, and lots of Western disease. Hunter gatherers, such as the Kitavans, consume less than 1% of calories from omega 6 fatty acids. Right now, in the US, about 7% of our calories are omega 6 PUFAs.

In summary - inflammation is depressing! Fish oil may make it better, but avoiding corn/safflower/sunflower/soybean oil (theoretically) makes it all better still, and is the natural state for which we are evolved.

*Eli Lilly's favorite neurotransmitter is, of course, dopamine.

Stress Kills via Inflammation (Possibly)

What a week.  And more busy weeks to come.  I've been neglecting the blog and have only now moderated several days worth of comments, so they have been published now if you were waiting.  I'm starting to feel a bit Kurt Harrisy about comments over time, but for now I am leaving them open.  For the most part things aren't too rambunctious, but I am more easily annoyed these days.  Maybe wiser?  (Not likely).

I am getting more and more requests if I know any other evo med/nutritionally interested psychiatrists around.  Folks are asking from Atlanta to Vienna.  At the moment I know of four, including myself.  Three of us are in New England and one, Ann Childers MD, in Oregon.  My only advice is to keep checking Primal Docs and the Paleo Physician's Network.  The three other psychiatrists I know of seem to be excellent, well-trained, and careful folks, for what it is worth.  If other psychiatrists want to drop me comment (I can see it and not publish it if you ask), I'm more than happy to keep a list and to ask ahead of time if you want your name released to an interested party.  We are also working on a forum for doctors to share case studies, experience, and documentation, so let me know if that would interest any physicians out there (again, can leave a public comment, or leave a comment with a note not to publish if you want to remain incognito).

Love this song (all the songs I like when I first hear them end up being advertisements for Apple.  They should hire me to spot music for them, for sure…) Come Home by Chappo (right click to open in new tab).

Now, science.  Overshadowed by events and personalities sometimes.  I'm a psychiatrist.  I'm used to that sort of thing, but it doesn't mean it is particularly fun for me.  Perhaps it is less fun, as it feels more like work.  But the journals march on, and it is finally spring here.  Lifetime exposure to chronic psychological stress is associated with elevated inflammation in the Heart and Soul Study.

(It is so uncool to post links to Elsevier nowadays, but they have my favorite journal hostage so what can we do?  Ethics only take us so far, and then we have to write a Graham Greene novel, but we are still left with what to do.  This issue is the eternal crux of clinical medicine.  My patient does not walk out of the files of a clinical trial, where all sorts of comorbitities are excluded, but my patient still has clinical depression and still wants some reasonable advice…)

I like the Heart and Soul Study.  They are on my wavelength.  The methods are solid.  All the subjects have a history of some sort of cardiovascular disease, which is important (and they are mostly male, derived mostly from the VA, so keep that in mind).  And here they have looked into people's history of psychologic stress, measured their inflammatory cytokines, and hypothesize a connection.  The connection is confirmed by many other studies linking a history of trauma (all sorts) to elevations in cytokines.

The DL is that stress is linked to bad cytokines (IL-6, TNF alpha, C reactive protein, etc.) and that stress is linked to PTSD and Major Depressive Disorder and anxiety disorders which are also linked to the bad cytokines… as is cardiovascular disease, even in psychologically healthy individuals.  In addition, there are harmful behaviors which increase the inflammatory cytokines (substance abuse, smoking), and ameliorating behaviors that decrease them (exercise, meditation, sleep) less likely to be adhered to by those who have undergone inordinate psychological stress.

Where the rubber meets the road is that higher lifetime trauma was associated with higher levels of inflammatory cytokines at baseline and 5 years later.  When the researchers controlled for psychological symptoms of the trauma (for example, PTSD or a clinical depression), the relationship held, meaning those who had undergone trauma had elevations of inflammation even if their behavior and coping seemed more normal by psychiatric diagnostic standards.  In these folks with pre-existing cardiovascular disease, higher inflammation is associated with greater risk of death and complication.

Maybe I should leave off and move to Hawaii after all...

Depression: A Genetic Faustian Bargain with Infection?

In the past week or so there has been a deluge of papers relevant to the sphere of this blog.  And it is March, as in "beware the Ides of."  Any psychiatrist readers (northern hemisphere and likely accentuated at the higher latitudes) will know exactly what I mean.  As the sunlight returns the agitation and anxiety and insomnia are awakened.  The phone at clinic is ringing off the hook.  (Well, it is always ringing off the hook, but now more so than usual).  More importantly there is life, and family, and not nearly enough time in the day or week or universe.

Next week I'll be flying to Austin, so this song seems apropos: Los Lonely Boys--Heaven (right click to open in new tab).

In the mean time I can at least attend to a few of the papers and maybe crank out a new Psychology Today blog post or two…so I will start with a paper available full text online (from a Nature offshoot, Molecular Psychiatry) with the provocative theory of PATHOS-D.  It is really an amazing paper.  Go over and take a peek.  Absorb the diagrams.  It's a little dry, but way better than most of the nutrition literature.

Here is the theory.  Depression*, as we know, is associated with certain types of inflammation in the brain.  There are certain red immune system flags we see with the syndrome of depression quite frequently, most specifically increases in the cytokines TNF-alpha, IL-6, and C-reactive protein.    These chemicals found in the blood and spinal fluid tell us a brigade of our immune system is on high alert, kicking a** and taking names, so to speak.  Problem is, when there are no invading a**es left to kick (or the invaders are too clever and elude our defenses), our brains get the full onslaught and neurons die and then you can't concentrate, and you avoid social activities, and you cry a lot, and eventually your primary care doctor gives up on your therapist and celexa and sends you to see someone like me.

And we certainly know that genes in combination with stress will predispose us to depression.  But some folks are bulletproof.  They won't get depressed in the most dire of circumstances.  Other people seem to be far more vulnerable.  All it takes is a bit of a mismatch between temperament of parent and child and we have major psychopathology.  A predisposition to depression is hereditary, therefore it must be encoded in our genes.  But what genes?  The PATHOS-D authors would suggest that the genes that predispose us to depression also protect us from infection.

Infection?  All of us humans in the brave new modern world have endured 10,000 years of agriculture, which brought with it dense population and massive infectious disease. Tuberculosis, for example, is said to have killed most humans who have ever lived.  The same genes that might give us a genetic advantage against infectious pathogens may lead to vulnerability to depression.

Inflammation, like an army, is a double-edged sword.  People with trigger-happy immune systems are more likely to survive many infections (though a tricky beast like the 1919 flu killed the young adults with the most robust immune systems via massive pulmonary immune reactions and septic shock).  Since infections in the developing world tend to preferentially kill young children, there is strong selection pressure for genes that will save you when you are young, even if those genes have a cost later in life.  The selection pressure would have to be strong, as a clinical depression has obvious survival downsides, for both the person affected and his or her offspring.  Depression tends to be chronically recurring and also will strike folks in 20s and 30s, unlike, say, Alzheimer's or most cardiovascular disease, thus selection pressure against depression alleles would likely be significant…unless those same alleles protected against something even more deadly that often strikes even younger, like infectious disease.

Cool theory, but where is the evidence?

Well, just as in schizophrenia, geneticists have tried to brute force hack the human genome in order to find a "depression gene."  And just like in schizophrenia, they haven't had a lot of success.  The answer (again, similar to schizophrenia and probably a lot of other diseases that don't fall into a simple single-gene model) will likely lie in looking at a group of genes for particular functions (say, immune function, or brain communication) and finding many different problems in those pathways in those who are genetically predisposed to depression.   In all the genome searching, a couple of genes have come up consistently involved with depression in certain predisposed families.  Both of them happen to be involved with cytokine signaling/immune function.  That would be a heck of a coincidence.

One allele, -308A, has found to be associated with increased risk of depression along with decreased risk of tuberculosis infection, parvovirus B19, hepatitis B, and a lower risk of death when hospitalized while critically ill.

What about other genes that have been found to be associated with depression risk but weren't found on large population genome-wide association studies?  We've discussed many of these genes and pathways in the history of this blog. MTHFR 677T is a version of methylenetetrahydrofolate reductase with reduced activity.  That means the folate we eat in our diets will have a harder time being transformed into the folate that is active in the brain (methylfolate).  Since folate is necessary to make things such as neuroransmitters and DNA, a brain without folate is in a sad state.  Low MTHFR is associated with increases in homocysteine and overall inflammatory tone.  Since low folate is also associated with devastating birth defects, one would think there would be pretty strong selection pressure against this gene, but it is actually fairly common in the population.  Why?  Well, the inefficient version of MTHFR is found to be protective against cytomegalovirus infection, sexually transmitted disease, and hepatitis B.  In places where there is sufficient folate in the food, MTHFR inefficiencies may not be devastating and could mean protection against infections that cause other devastating birth defects and disease.  In sub-Saharan Africa there is low folate availability, and the MTHFR 677T allele is nearly absent there.

ApoE is another molecule we've discussed at some length.  It is a signaling molecule located on the surface of lipoproteins (which carry around fats and cholesterol and vitamins, like LDL).  ApoE4 is the original, ancestral allele, and those who carry it have a higher risk for both Alzheimer's disease and depression.  E4 is associated with increased inflammation in general.  E2 is a protective version and means decreased risk of major depressive disorder and Alzheimer's compared to E4.  The E4 allele may be protective against childhood diarrheal illnesses, while those with E2 seem to be more vulnerable to tuberculosis and malaria.

The most studied (and debated) alleles associated with depression are so-called short and long form of the 5HTTLPR.  This gene is a promotor region that tells the cell to make a serotonin transporter.  Those with the short allele (particularly with two short alleles) seem to have a much higher risk of developing major depression when exposed to early childhood trauma, whereas the long form of the gene is protective.  However, the short gene isn't all bad.  Those who have it seem to have a lower risk of dying from sudden infant death syndrome, and the gene is associated with higher circulating cytokines in response to stress, which could protect you if the stress is from being wounded or an infection.  In populations where the short gene is more common, there also tends to be more exposure to epidemic infections, suggesting selection pressure for the short gene.

Finally, there is some thought put into the clinical syndrome of depression and how it might protect you and your offspring if you do have an acute infection.  It is well known that inflammatory mediators (such as IL-6 or interferon) induce depression symptoms on their own.  If you have come down with an infectious disease, being depressed would keep you isolated and conserve energy, reduce appetite (maybe to induce ketosis to improve viral and bacterial immunity?)

I think the strength of an evolutionary/ancestral paradigm for studying disease helps to provide a sensible framework, like the PATHOS-D theory.  Clinically, it helps us to focus on the immune system and inflammation, and how that may have been altered by modern diet, stress, lack of parasites and pseudocommensals, changed sleep, infectious burden, and physical activity.   Forget the random crapshoot of mere brute force epidemiology.  There are too many confounders, and it will lead us in the wrong direction as often as not.  

*here we are using the clinical definition of depression.  Not just a sad mood for reason, such as grief.  Usually we are talking about a sad mood with inability to enjoy things we used to enjoy, poor concentration, poor or unrestorative sleep, appetite change (classically poor appetite), guilt, self-doubt, and even suicidal thoughts.  

Lithium and Inflammation

Lithium is an interesting sort of mineral salt. It sits on the periodic table right above sodium, and can fool our kidneys into thinking they are the same molecule. Scientists first figured out lithium could help stabilize mood in the late 1800s (when it was also used to treat gout). And, turns out, El Paso, Texas has high levels of lithium in the water, but low rates of violence and mental hospital admissions compared to other cities (1). Lithium was the original "up" ingredient in 7-UP soda (pretty sure lithium is not in there anymore!). The first research paper on lithium didn't appear until 1949, when Australian psychiatrist John Cade made his mark on psychiatric history. However, Greek physicians thousands of years earlier were treating mental disorders with mineral water now thought to be high in lithium.

Before John Cade, mania was treated with electroshock therapy or lobotomy, so lithium was a terrific option - in fact it was the first successful pharmaceutical treatment for mental illness (thorazine wasn't used for several more years). It has huge downsides - toxic to the thyroid and kidneys (and heart in high amounts), fatal in overdose, and a lot of the time it simply doesn't work. But when lithium does work, it is a wonderful thing. Suicidal depression and mood swings relieved within days. To this day, lithium is one of the few medications proven to decrease the risk of suicide (3).

Despite the fame and long term, widespread use, no one knew what the heck lithium actually did. In medical school, I was taught that it had some effect on the regulation of second messenger systems within the neurons (4). Meaning, like every other psychotropic medication, it buffs up the communication in the brain, presumably to help it work all the more smoothly. (We psychiatrists have almost no lab tests and no imaging studies to help us - we just have to sit with someone and figure out what might be going on. A handicap which lends itself to the search for holistic, evolutionary solutions - but everyone knows my bias!)

The good Dr. Hale sent me a link to this article in Psychiatric News, which sheds more light on lithium's possible mechanisms of action. The article references this paper in The Journal of Lipid Research, and the story herein involves more unfortunate rats.

We learn first of all that bipolar disorder is a major mental illness worldwide, and is characterized by mood shifts from severe depression to mania. Examination of the post-mortem frontal cortex of those with bipolar disorder shows an increase in neuroinflammatory markers (I'm sure you're not surprised), and an increase in the enzymes that regulate the expression of arachidonic acid. (Arachidonic acid is the highly-unstaturated fatty acid (HUFA) made from the omega 6 polyunsaturated fatty acids (omega 6 PUFAs), otherwise known as essential nutrients but Standard American Diet Villain Extraordinaire).

In this study, rats were given lithium-laced food or lithium-free food for 6 weeks, and then their little brains were examined to see what happened (sorry, they did not use non-invasive methods. The rats were anesthetized, however, before the final insult.)

To summarize the results - lithium decreases arachidonic acid in the brain and increases the concentration of an antiinflammatory metabolite of DHA (yes! Fish oil!). 17-OH DHA inhibits all sorts of other inflammatory proteins in the brain, like TNF-alpha. (For the biochemistry nuts - LiCl seems to intervene at the level of cPLA2 and sPLA2 and COX). Famous inflammatory modulator aspirin has been postulated to help lithium work better in bipolar disorder (5)

Interestingly enough, lithium has been shown to be the only effective drug (at least to slow the progression down) in another inflammatory, progressive, and invariably fatal neurotoxic disease, ALS (6), and is being studied in HIV dementia and Alzheimer's disease.

More Evidence for a Gut-Brain Connection

Someone (Stephen B) emailed me via Google +, which I didn't know was possible, mostly because I have yet to bother to figure out anything about Google +, mostly because my reading pile is dangerously high and Google+ wasn't very iPad friendly.   If I'm going to figure out any new complex system of communication with circles, it had better be with my feet warm and snuggly under the covers, thus iPad friendly.  Now you know my opinion, so go work on that, Google.

Neon Trees.  Everybody Talks (right click to open in new tab).

The abstract of the paper Stephan sent me seemed mighty intriguing indeed (pardon the font hiccup here but I am too lazy to type it out rather than cut-n-paste and Blogger is dreadful about editing such things.  My, I am certainly opinionated today!).  Ingestion of Lactobacillus strain regulates emotional behavior and central GABA receptor expression in a mouse via the vagus nerve

I know that title might not make everyone's heart go pitter patter immediately, but it is actually Evolutionary Psychiatry exciting. As I noted in a couple of previous blog posts, it is clear that (in mice, anyway) the wee beasties of the microflora in the gut (comprising about 90% of the cells in our bodies) have something to say about behavior and moods.  In addition, behavior and mood can affect the population of the gut flora.  But how the communication proceeds is a bit mysterious.  Hopefully this paper will shed some light.

First off, a little bit about GABA. It is the major inhibitory neurotransmitter in the central nervous system (glutamate being the major excitatory neurotransmitter). GABA is a nice glass of wine in front of the fire.   GABA is restful sleep.  GABA is tranquility and yoga.  Not surprisingly, GABA plays a major role in conditions such as anxiety disorders and irritable bowel syndrome.

Now let's introduce Lactobacillus rhamnosus.  These little bacteria can modulate the immune system via manipulation of TNF-alpha and IL-8, and can change T cell production.  In addition, in rodents, it reduces the autonomic nervous system response to intestinal distention and alters small intestinal motility.  That's a lot of long range action for a wee beastie.

So, for the study, the researchers gave some mice probiotics, and other mice got broth.  Then the mice were tortured in various ways to induce a stress response.  Some of the mice had surgery to sever the vagus nerve (which is the major communication highway between the gut and the brain).  And mice ultimately made the ultimate sacrifice to have GABA levels and mRNA levels measured in the brain.

The results:  mice who go the probiotics were, in general, more chilled out than the control mice.  The probiotic mice had lower levels of corticosteroid release in response to stress.  Steroids are something the body pumps out as an emergency reaction to stress, and while in the immediate timeframe they can save your life (grandma lifting the car off the toddler, for example), in the long run, chronically elevated stress hormones like steroids can lead to depression, anxiety, heart disease, you name it.

Mice who had their vagus nerves severed did not differ from the control mice so did not experience the anxiolytic effects of the Lactobacillus probiotic.  This would suggest the communication from the bacteria (via its own neurotransmitters? or via immune modulation in the gut) definitely goes through the vagus nerve on its way to the brain to control behavior.

In addition, when the brains of the little mice were tested, the amounts of mRNA of various types of GABA receptors (reflecting the amount of messages from the genes to create the GABA receptors) were higher in certain key brain areas of certain key subtypes of GABA receptor.

So what does it all mean? Actually, the authors of the study summarize nicely (the "HPA axis" is the connection between the brain and adrenal glands and how corticosteroids are released and regulated, and there is more font hiccuping. Sorry):

Furthermore, in this study we observed that L. rhamnosus administration reduces the stress-induced elevation in corticosterone, suggesting that the impact of the Lactobacillus on the CNS has an important effect at a physiological level. Alterations in the HPA axis have been linked to the development of mood disorders and have been shown to affect the composition of the microbiota in rodents… Moreover, it has been shown that alterations in HPA axis modulation can be reversed by treatment with Lactobacillus and Bifidobacterium. However, caution is needed when extrapolating from single timepoint neuroendocrine studies. Nonetheless, these data clearly indicate that in the bidirectional communication between the brain and the gut, the HPA axis is a key component that can be affected by changes in the enteric microbiota.

So, once again, a common ancestral practice to consume fermented foods rich in probiotics is quite interesting.  There is almost no evidence in humans as yet for psychiatric disorders (the only scientific evidence I'm aware of is discussed in my blog post here).  But all in all the data and research  looks to be very interesting, and perhaps promising.

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."

Glucose and the Hippocampus

At the beginning of September, there was a bit of a twitter about this new paper in Neurology.  In fact, some folks emailed me links and tweeted it to my attention.  And the paper turns out to be very interesting.  You can tell by the way it was written that the researchers were pretty stoked at the results, and that doesn't always sneak through in the dry modern medical literature.

(Funny little bit… almost every scientific paper has a sobering end paragraph about the limitations of the study at hand followed by several paragraphs about how lame the data is for one reason or another.  This paper says:  "This study has some limitations but also significant strengths."  For some reason I find that very amusing.  But then, I'm fairly easy to amuse.)

AWOLNATION: Kill Your Heroes

What I really like about the paper is the all-out, glorious way in which they attempt to link inflammation, hyperglycemia, coagulation, glucose, and body and brain pathology.  It's beautiful and bold and a bit more outside the box than I'm used to seeing in a neurology paper.  Let's dive in.

Of course we know that hyperglycemia and type II diabetes have been linked over and over again to cognitive decline, brain aging, and dementia.  Also, insulin resistance, obesity, and a higher caloric intake over time have also been linked to faster brain aging.  But what about high-ish levels of fasting blood glucose that are still in the normal range?  Well, even those have been linked to systemic inflammation, so these researchers thought they would run an observational study to see if you could see structural changes in the brain over time related to fasting glucose levels.

A random sample of 60-64 year old Australians were selected from compulsory voting rolls.  431 individuals underwent MRI scanning and fasting glucose testing at "wave 1" and also scanned four years later in "wave 2."  After all the exclusionary criteria were weeded through (including anxiety and depression, type II diabetes, incidentally found fasting glucose of higher than 6.1 mmol/L (110 mg/dl as I'm used to seeing it), stroke, neurologic disorders, etc.), 249 scans were used to make the current dataset.  A bunch of other measures were taken and included as well, such as blood pressure, medications, education, sex, smoking, BMI, and APOE phenotype.

Hippocampi from Wikimedia Commons

The scans were perused and the volume of the hippocapmus measured in 2001 and then in 2005.  Fasting plasma glucose in these individuals ranged from 3.2 mmol/L (58) to 6.0 (108).  And after calculations and whatnot were done, the fasting glucose level at wave 1 varied linearly with the amount of hippocampal atrophy 4 years later.

The researchers flipped all over themselves to find a way to screw up their findings.  They adjusted for the smaller intracranial volumes measured the second time.  They took out anyone with a fasting glucose > 5.6 (100) because that is the more stringent criteria recommended by the American Diabetes Association, wondering if the sample were skewed so that the highest normal fasting glucose folks had more atrophy. They excluded anyone with a greater than normal BMI. But no, the line remained pretty linear on analysis.  Then they added back in the type II diabetics and high fasting glucose folks and the line was still linear.  It seems pretty clear that the higher your fasting glucose, the smaller your hippocampus will be four years later, at least if you are a 60-64 year-old Australian from a certain geographic region.

(Turns out an "average" rate of hippocampal atrophy in a 60 year old is 2% per year, and this is the rate they found for the average fasting plasma glucose level in the sample (4.92 or 88.56). Nice synchronicity there.)

So they had fun with the experiment and even more fun with the data, but it is the discussion where the exitement nearly gets out of hand. It's Evolutionary Psychiatry-level pathological lumping.  I love it.

In animal models, rats with higher plasma glucose have greater brain damage when exposed to certain toxins.  (Specifically, reduction in hippocampal dendritic spine density.)  In humans, higher "normal"fasting glucose is associated with greater risk of developing type 2 diabetes and with poorer memory performance.  Higher glucose levels are associated with increased inflammatory cytokines such as TNF alpha, IL-6 and IL-10.  Inflammatory markers peaked higher and lasted longer in those with impaired glucose tolerance.  Chronic systemic inflammation is known to cause cerebral atrophy, and is the likely mechanism behind the correlation between increased glucose and neurodegeneration.

Another feature of type 2 diabetes is increased levels of certain clotting factors in the blood.  These increases lead to increased risk of vascular and heart disease in diabetics.  Prediabetics and folks with metabolic syndrome also have similar clotting factor abnormalities.  Inducing hyperglycemia in normal volunteers also induces platelet activation and other pro-clotting factors.  More clotting means more risk of microemboli, small strokes, and vascular and brain damage over time.  Since systemic inflammation and coagulopathies also seem to induce eachother, it could be these two together synergistically amplify  the risk of something like a chronically high glucose level.

Taking another step back, it is known that depression and anxiety are associated with an increased risk of diabetes.  High stress activation is mediated by increased HPA axis activation, which is not only associated with increased risk of diabetes but also increased risk of brain atrophy (particularly in the hippocampus and amygdala) and memory problems.   It could be the psychological stress leads to the HPA activation and increases glucose levels, leading to the brain atrophy.

Yes, stress can and will eventually kill you, once it stops making you stronger.

Life is funny that way.  And high fasting glucose levels are not a great idea.  Please don't get the idea that I'm endorsing a VLC diet at this point.  Remember, fasting glucose levels in the insulin-senstive individuals will tend to be as low or lower in those who regularly consume carbs than those who don't.  I think VLC diets have their place, but I'm unconvinced they are the perfect anti-aging tool for everyone.

Depression crashed your party

I've told you before I like Dr. Maes. Turns out he's been working the depression = inflammation angle for the past twenty years, isolating all the cellular mechanisms while we were all busy getting bored by drug reps peddling their newest serotonin reuptake inhibitors.

Maes is not only brilliant, but cranky. The main page of his website is devoted to accusing a Dr. Dantzer of stealing his ideas, and much of the introduction of this brand new paper harps on the fact that Dowlati's recent major meta-analysis of depression and inflammation left out much of Maes' work. Fortunately Maes' current paper cites 39 of his previous papers - so nothing will be left out here. I've got your back, cranky Belgian depression and inflammation researcher!

I'll begin by describing the immune system. It's complicated. Imagine an A-list party with all sorts of different security checks and bouncers. There are guys on the perimeter keeping the unwashed masses out, then there are guards on the inside keeping an eye on the elite, and maybe even spies working the crowd, searching for any crashers. The different security forces of our immune system have different names and duties, too. There are the B cells which work via little protein tags called antibodies (known as the "humoral immune system.") Then there are the natural killer cells, hungry macrophages, and other elite shock troops. Finally, you have the cell-mediated immunity, primarily the T cells, who run around messing with anyone who looks like he doesn't belong.

In several of the last blog posts, I mentioned high levels of IL-6 and TNFalpha as markers of depression. These inflammatory cytokines (among many more, such as IL-2, IL-12, interferon gamma, and biomarker neopterin) activate and prime the T cells, who then go out and do their killing. Therefore inflammation means, in a nutshell, that the body's security forces are out there, and the cell-mediated part of our inflammatory reaction is the major cause of the symptoms of depression.

Out-of-whack cell-mediated immunity has also been implicated in lupus, diabetes mellitus, schizophrenia, rheumatoid arthritis, several cancers, multiple sclerosis, and Grave's disease. But Maes has been able to link various participants in cell mediated immunity to many of the major symptoms of depression, including the "vegetative" symptoms (poor sleep, poor eating), the somatic symptoms (increased worry about illness and increased aches and pains), and the decreases of neurotransmitters serotonin and norepinephrine. He links it to the alterations in the HPA axis. Not to mention the actual inflammation in the hippocampus itself. To put it simply, Maes has described the complex biochemical mechanisms of depression using a single overriding, reasonable, and realistic theory of cell-mediated immunity. This is like learning the beautiful ins and outs of how too much fructose causes metabolic syndrome. In a word, awesome.

Maes and other researchers start by measuring a T-cell activating cytokine called sIL-2R. This little bugger is higher in the blood and CNS of people with cerebral lupus, depression, and mania. The worse the symptoms, the higher the levels, and the levels fall when the depression, lupus, and mania symptoms go into remission. Pretty telling. Other markers of cell-mediated immunity (soluble CD8 antigen and other T-cell surface markers, and levels of interferon gamma) follow a similar pattern.

One interesting tidbit - a lot of inflammatory disorders respond to steroids, which suppress the immune response. Asthma, multiple sclerosis, inflammatory bowel. Depression will often get worse with steroids, and Maes figures that's because depression is driven primarily by the T-cells, which are steroid-resistant compared to other parts of the immune response. In case you were wondering.

But let's get back to the actual mechanisms. I reviewed one in a previous post (a useful diagram is linked here). Inflammation causes our body to preferentially make tryptophan, the precursor to serotonin, into kynurenic and xanthurenic acid. Not only does this mean we have less happy, relaxing serotonin around, but kynuretic has the tendency to make us anxious and depressed all on its own. More specifically, T helper cells and indoleamine 2,3-dioxegenase (IDO), parts of our cell-mediated immune response, lower our serotonin levels and make us depressed. This mechanism is true of bipolar depression, major depression, adolescent depression, depression in heart failure patients... you name it, and IDO is smacking down our serotonin. Interferon alpha treatment for hepatitis C or multiple sclerosis will activate the very same mechanism to make us depressed. In animal models, specific cell-mediated immune activation causes lack of interest and changes and sleep and appetite consistent with the similar human symptoms of depression.

Antidepressants work by suppressing the cell-mediated immune response in specific ways. All major classes of antidepressants have been shown to have this effect in various models - tricyclics, SSRIs, SNRIs - they block the production of IL-6 and TNF alpha in immune cells, and also block a number of other acute inflammatory phase proteins, such as C-reactive protein and haptoglobin. Antidepressants are anti-inflammatory, and never-treated depressed individuals will have much higher markers of inflammation than those who are treated. While there are several studies of neuroimaging showing similar changes in metabolism of the brain with response to antidepressants or psychotherapy, I found only one that specifically measured psychotherapy and inflammation, from 2009 in depressed cancer patients. I was also able to find this study of yoga reducing C-reactive protein, IL-6 and other markers of inflammation. I think it makes sense to assume that any successful treatment of depression will be anti-inflammatory. Dance Dance Revolution did not reduce inflammatory markers in obese kids, however. Who knew?

Mood stabilizers, such a lithium and depakote, also affect the ratios of key inflammatory cytokines. Like the antidepressants, they suppress the cell-mediated immune response in specific ways that affect neurotoxicity and neuroplasticity.

I wish we had more evidence-based lifestyle and dietary trials for psychiatric disorders. Not just (probably biased) studies of medications and a few of psychotherapy, and not just a bunch of epidemiological studies. What if we knew for certain that dietary changes could could stop the inflammation in the first place? If I'm right about my paleolithic-style approach, then I could actually prescribe grass-fed steak (not currently FDA-approved) in addition to fish oil. Well, I'll keep looking!