Sunday, May 29, 2011

A Grand Unified Theory of Psychiatry?

It is no secret that on this blog, I am a reductionist.  All psychiatric illness (shoot, all of chronic Western disease) has the same pathology (inflammation) and starts with the same treatment (an anti-inflammatory lifestyle, including diet, healthy coping and stress amelioration, and good sleep).

At an individual level, of course, it is not so simple.  I can't be an effective doctor for you without knowing your experience, and spending enough time with you to figure out how you tick.  That way I can modulate my advice to meet you where you are.  And that in a nutshell is the failing of modern medicine.  It tries to replace a personal relationship with testing and algorithms in the name of science, efficiency, and expediency.  Problem is, for a doctor (especially a primary care doctor), such a practice is soul-killing (who wants to be responsible, in a litigious society especially, for the health of 5000 patients you barely know?).  For the nation, the algorithm is expensive, careless, and dangerous.  It works for the protoypical patient and in some obvious areas, such as safety checklists and counts in the operating room, but once anyone comes in with human quirks and complications, the data goes out the window.  Not to mention the ridiculous attention to relatively meaningless numbers (cholesterol panels, for example) in lieu of a rational human-friendly evolutionary model for health.

I live in Massachusetts, where managed care has a prominent role.  In psychiatry, several insurance companies have attempted to gather data based on various scales and standardize treatment to some extent.  I've participated (somewhat unwillingly - as it was clear from the outset the data gathering would simply use valuable time and resources better directed towards other things) in these endeavors, and also in research.  In the "real world" the use of scales to try to gather data for what works for the insurance company has proven each time to be a complicated disaster, and has been abandoned.  People in my waiting room aren't particularly interested in filling out the scales the insurance company wants them to, and thus the results are conflicting and meaningless.  In research or in the symptom scale measures I might choose for my patients based on our relationship and my knowledge of their history, there is a different sort of vibe.  It's a collaboration.  It's personalized medicine.  In research, the patients are pre-selected not to have certain comorbidities (so in general they are less complicated than the patients who show up at the actual doctor's office), and they are volunteers, even paid volunteers!

With enough data points and a big enough computer, I'm sure more rational models of algorithm care could be produced.  But for now, nothing replaces simply knowing your patient and spending time learning who they are.  Nothing replaces the art of medicine, particularly, I think, the art of personalized psychiatry.   And, perhaps counter-intuitively, we all suffer when medicine becomes increasingly compartmentalized and specialized.  All doctors should be generalists and have a robust clinical knowledge of all fields.  Recently, my consultations have been instrumental in diagnosing two cases of hyperparathyroidism - the only reason it came down to me is that I am the only one in a managed care model who has more than about 5 minutes at a time to spend with patients.  I'm expensive (being extensively, expertly trained over many, many years), but I like to think I'm worth it.  That said, your psychiatrist should not be diagnosing your hyperparathyroidism.  That's a travesty and a failure of modern medicine.

But - we stand to learn a great deal and develop confidence and wisdom if we dial down on the specific pathophysiology and genetics of psychiatric disorders.  And what we find, more and more (which is what one would suspect, from the Grand Unified Inflammation Theory), is that the pathologies and genetics overlap.  Another Nature paper came out recently, sent to me by Jamie Scott, that brings together the disparate diseases of schizophrenia and anxiety.  And that's kinda cool.  Let's break it down.

Convergent functional genomics of anxiety disorder: translational identification of genes, biomarkers, pathways, and mechanisms

A bit about anxiety.  It is the most prevalent psychiatric disorder, affecting 18.1% of Americans annually, but remarkably enough, less studied in a rigorous sense than the much more rare schizophrenia or autism spectrum disorders.  Some anxiety disorders seem to be based on an anxious temperament (generalized anxiety disorder, panic disorder) whereas others are based on obvious stressors (phobias, PTSD).  Others are mixed, like obsessive compulsive disorder.  Anxiety is typically along for the ride in depression (at least in the patients I see), and makes for a more complex patient more resistant to typical treatment.  In general, anxiety can be defined as a pathologic increased reactivity to the environment, driven by fear and uncertainty in light of perceived threats.

Anxiety disorders are the protoypical disorder of the modern world, where our hunter-gatherer brains are trying to manage remembering 50 passwords, the threat of H1N1 and terrorism, kidnapping and car accidents.

In the Nature paper, the authors used human and animal genetic data (emphasizing the gene expression studies rather than the specific gene studies) plus some controlled animal trials to dig up the most likely genes that might give you a predisposition to be more anxious than usual.  Not surprisingly, they found a lot of genes that were active in the hippocampus, related to stress hormone response and GABA transmission.  Other genes, such as polymorphisms in the dopamine system, are also obvious, and the "grand unified theory" supporting evidence is that many of these genes are also suspected to be awry in bipolar disorder, schizophrenia, and depressive disorders.  One suspect gene (QKI) has a central role in myelination, is a biomarker for anxiety, and there is evidence of changes in the expression in humans of QK1 in response to stress.

One of the top genetic pathways suspected in anxiety is also the pathway associated with signaling in Huntington's disease - a disease that is (speculatively) perhaps strongly associated with wheat consumption.  Gene expression, again, has been emphasized, which accounts for genetics, epigenetics, and environmental regulation.  "Genes that change together act together" - "the co-expression data sets… generted in various brain regions offer testable hypothesis for transcriptional co-regulation, and for epistatic interactions among the corresponding loci."

In English?  Our genes code our vulnerability to environmental insult.  Some of the same genes that make you vulnerable to schizophrenia also make you vulnerable to anxiety and depression.  The environmental insult is typically modulated through the stress response system, which is also modulated through diet and experience and movement and sleep.

Live and move and work and think like a human, and you will be more resilient.  Stray from our evolutionary programming, and you are going out on a limb.


  1. And now I really need to get to that Ancestral Health Symposium presentation...

  2. Man! I'm supposed to be studying and now you've got me trying to visualize a multi-axis spectrum representation of co-morbidity. Thanks!8-)

  3. And those of us who are your ancestors really appreciate your concern. Pay close attention! ;>)


  4. Very interesting!. Please if you can consider using bold in the main sentences, it helps to read long posts. Thanks

  5. Emily, I've been thinking about the same "grand unified theory" for weeks, and it's very reassuring that an actual psychiatrist thinks this is reasonable!

    One caveat I have with it is that it's a direct cause and effect model, which I think has inherent weaknesses; biological processes almost never really work like that. If you consider several papers showing that brain trauma can cause leaky gut in rats (, it seems reasonable to think that the inflammation/mental illnesses issue could be a feedback loop instead of a direct cause and effect since mental illness could cause inflammation and vice-versa.

    Something like this:
    Leaky Gut->Inflammation->Mental Illness->Worse Leaky Gut

    So I suspect the ultimate cause(s) are sometimes more than just diet, stress and sleep but improving those factors still seems like the most promising way to break the feedback loop, and restore normal physiology.

  6. Yes, I agree it is a cycle, and that sleep and the gut are essential to understanding everything.

  7. This is a Dr who works on the inflammatory theory of depression

  8. I've extensively referenced Maes in previous posts.

  9. You might want to add the amount of data on how gut microbes interacts with our genes. As an example, "one" bacteria might tune a hundred host genes. And we have billions of them in us. Add that we might have a lack of some of the nice one too..
    One part that might be of interest for the psychiatry is that we know some "neutral" bacterias react on the host signal noradrenaline as to act in a [for us] patologial way. So the traumatized person is perhaps both traumatized, and carry a huge amount of microbes in a patological state. That might develop into disease, maybe in ways that involves the brain.
    And then there´s of course the food..

    Modulation of mammalian cell processes by bacterial quorum sensing molecules.

    Stress at the intestinal surface: catecholamines and mucosa-bacteria interactions.

    Adrenaline modulates the global transcriptional profile of Salmonella revealing a role in the antimicrobial peptide and oxidative stress resistance responses.

    The two-component system QseEF and the membrane protein QseG link adrenergic and stress sensing to bacterial pathogenesis.

  10. How do urocortins fit in this model? They seem so promising, yet no one in the science blogosphere is writing about them.

  11. Perishedcore - I don't know but it does look exceedingly interesting (had a little chuckle because when I first read your comment, I thought you wrote "unicorns" rather than "urocortins")

  12. Blogg om - I've no doubt the gut component is huge. HUGE.

  13. Hmmm - unicorn. Now that's truly a magnificent nose to tail beast!

    I've been looking for blogging on urocortins in the science b'sphere, but so far, no luck. If you run across anything promising, please toss out a link.

    Thanks again for your posts. I end up spending a lot of time on the biochemistry websites reviewing and trying to comprehend the concepts.

    It seems that inflammation meets the criteria for adaptation: it has both compensatory acute and noncompensatory deranging chronic components. There may or may not be an individual sweet spot of max. adaptation with minimal neg. stress effect(leaning towards the notion that there is one), but there does seem to be a u curve for beneficial vs morbidity/mortality effect.

    From an ev standpoint - is it desirable to push the sweet spot (paleoish with some post ag foods, highly active, intermittent stressors, hormesis), to guard it(strict paleo, cross fit, paleo re-creation) or to ignore it (SAD, westernized sedentary, car culture)?

    Something else that I haven't read much about is the notion that hunter gatherer cultures were pretty closed with supposed uniform social and behavioral norms. That would provide, one would imagine, with both tangible and intangible forms of support to cope with illness, injury, childbirth, and acute stressors - drought, floods, weather-related natural stressors, pillaging, food competition, etc. In western societies, especially in the US, frontiersmanship is still the cultural ideal - every man for himself and by himself. That leaves many minorities with no overarching supportive culture, hence the derision and condemnation of vulnerable people (poor, sexual orientation, religious intolerance, marriage status, race, identifying with wealth, etc.). Exclusion and ostracism are routinely practiced, and the goal is to be "king of the hill" which results in a tendency towards "lord of the flies". In the US at least, there is a culture of human predation.

    I think that also is a toxic social culture and accounts for a lot of illness and premature deaths in everything from trauma to diabetes, morbid obesity to suicide.

  14. I think you are so right, I just wish the rest of medicine would catch up with you. When my mom went gluten-free (mostly, she'll still cheat, argh), not only did she loose her migraines but she noticed she lost alot of anxiety. Her stuttering got drastically better too. (I now wonder if stuttering is wheat related). She never talked about anxiety before so I wonder if she was so used to living that way that she didn't notice. She had been to many doctors for her migraines but no one could figure anything out. I have been so amazed at what diet can accomplish.

  15. Hi Emily,
    I've just read your post about ketonic diet and I totally agree that ketones are healthier for the brain. There is one thing that puzzles me if you have ideas bout:
    Usually fat soluble are the ones who passes the BBB. Yet, for in this case ketones (water solube) passes BBB yet fatty acids do not (I'm positive that some can since omega 3 has to pass).
    Wonder your thoughts about why this is the case and why the brain doesn't burn fatty acids.



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