Thursday, September 8, 2011

Further Evidence that Mental Illness Exists

Long, long, long ago, I wrote several posts that were later updated for Psychology Today, mostly because it is the basis for my understanding of the pathology of depression with regards to that Big Bad of Diseases of Civilization, inflammation.  A nice tie-in to all those posts is here:

It is not, perhaps the friendliest of posts with all that biochemistry and all.  But rest assured it is of vital importance.  Especially this diagram (right click to open in new page and take a look).   And this post will not be particularly friendly either.  Mostly because I have caught up on a recent skirmish in the war between medicine and psychiatry, begun by the book reviews by the former editor and chief of The New England Journal of Medicine, Dr. Marcia Angell, and all the big names in psychiatry writers, specifically an article in Psychiatric Times by Ronald Pies, M.D. "Misunderstanding Psychiatry (and Philosophy) at the Highest Level."

In case you do not happen to be a clinical psychiatrist and do not care to dive into the debate, let me paraphrase (and allow me to take extreme liberty with my own interpretation of the stance of the two sides):  Dr. Angell:  "Psychiatrists are witch doctors."  Psychiatrists:  "You are ignorant and misinformed."

Music - Danse Diabolique (right click to open in new tab)

It is hard to be misunderstood.  Rest assured that I do not rely on incantations to treat my patients, but I do dislike equating psychiatry with the DSMIV.  The DSMIV, the cookbook describing all the diagnoses for research and insurance billing purposes, is not psychiatry.  A good psychiatrist listens and measures and watches for neurologic disorders, medical symptoms, experience, emotions, emotional expression, tremor, eye contact,  muscle tone, gait… most of these are not ever mentioned in the DSMIV.   I consider the DSMIV a necessary evil, for now.  A very clever former teacher of mine once said, "If all the copies of the DSMIV dropped to the bottom of the ocean, all the better for us, and all the worse for the fishes."  He asked that I not repeat that to anyone.  I won't attach his name, and details are changed to protect the innocent, as always...

So how do I cope with being a well-meaning witch doctor?  I write this blog.  I tear apart the pathologies of the DSMIV in the context of biology, biochemistry, nutrition, lifestyle and evolution.  For me, it is a more sensible and tenable approach than the random crapshoot of modern medicine epidemiology and the biased minefield that is psychopharmacology research.  And in my own little corner of the blogosphere, I feel all is safe and honest and going the right direction.  Most of the time.

Back to depression crashing the party.  I've talked quite a bit about serotonin, a term, I think, with which everyone is familiar.  Here is a nice article about serotonin in case you missed it. 

But serotonin is only a small piece of the whole story.  Our friendly neighborhood amino acid tryptophan can become all sorts of things - happy satiating serotonin, or enervating irritating kynurenic. Many, like the pioneering researcher Dr. Maes (who has hopped from Case Western Reserve (very respectable) to Antwerp (I'm sure, very respectable) to Thailand (well, let's reserve judgment until we know the whys and wherefores, though Thailand is a lovely place it is not a hotspot of respectable biomedical research!)) have been talking about inflammation and kynurenic for a decade or more.  And, finally, other researchers have been looking into it.  They call it kynurenine, but I'm not going to quibble.  

The new generation of researchers working out of the very respectable New York State Psychiatric Institute measured kynurenine levels in healthy controls, patients with major depressive disorders, and patients with major depressive disorders who have had suicide attempts in the past (all controls and only three of the depressed patients in this study were medication-free).  

And, low and behold, it was found that those with a previous suicide attempt were significantly more likely to have higher levels of serum kynurenine!  Let's back up - activation of the inflammatory cascade (theoretically via autoimmune or other mechanisms, like, say, to go out on a paleo limb, wheat or omega 6 fatty acids) increases the activity of an enzyme called IDO (indoleamine 2,3 dioxygenase) which will change the amino acid tryptophan into kynurenine rather than fat-n-happy serotonin. 

Serotonin levels actually have closer (negative) correlation with violence and suicide than depressed mood - and this study of kynurenine is no different - suicide attempters had the higher levels, and depressed patients without attempts had similar levels to healthy controls.  Interestingly, kynurenine levels did correlate with BMI and tryptophan levels, and more robustly in males than in females (males have a higher risk of suicide completion than females, though females have more suicide attempts).  

In previous studies, autopsies of suicide victims and  CNS samples of suicide survivors have shown increased levels of kynurenine in both.  

In mouse studies, increased kynurenine has been associated with activation of the neurotoxic (in excess) glutamate and even dopamine (which increases motivation and drive).  Stress seems to increase the activity of IDO (leading to increased conversion of tryptophan to kynurenine) and general suicide badness.  

In the end, I have to say that all that is psychologic is biologic.  And psychiatrists must keep an eye out for signs and symptoms, and while the DSMIV (and psychiatry skeptics) ignores signs, we do not.  Otherwise we remain guilty of the criticisms that the likes of Dr. Biffra will levy - which according to my comment (number 17) shows that he has very little understanding of the job of a psychiatrist. (Normally I like Dr. Biffra's ideas, but clearly he needs to consult with more expert psychiatrists if he is writing such posts!)

But ultimately I am not surprised.  Mental illness is not understood, and psychiatrists hold some of the keys to the temple.  Sometimes it is easier to eject what is misunderstood rather to absorb and understand it, regardless of biology or morality.

A little editorial addition on 9/9/11

I thought about not writing about the ongoing controversies in psychiatry as 1) it may not be of interest to many readers (though I do have several clinical psychiatrists who follow the blog, and hey, it's my blog and I will write about what interests me), and 2) it opens me up (fairly enough) to be a defender of modern clinical psychiatry, as I am critiquing the critic.  I'm not interested in the role of defender, as certainly some aspects of modern psychiatry (and indeed modern medicine) are indefensible, and the role is ably taken up by Drs Altschuler, Nierenberg, Friedman, and Pies (among others) who have written responses to Dr. Angell's reviews.

However, I do think that critiques of psychiatry are important and, again, not entirely unreasonable.  There is a risk with an atheoretical document like the DSMIV, with diagnosis based on a list of symptoms divorced from pathology (on purpose!)  and a profit-driven pharmaceutical research community to create more and more diagnoses and make pills to fit the diagnoses.  The ultimate argument of this critique is that a lot of mental illness is essentially made up.  My main objection to Dr. Angell's stance is to this sentence of hers (quoted from Dr. Pies' article linked above), where she starts by saying that psychiatry is different than other medical specialties:  "First, mental illness is diagnosed on the basis of symptoms (medically defined as subjective manifestations of disease, such as pain) and behaviors, not signs (defined as objective manifestations, such as swelling of a joint.)"

As I mentioned above, mental illness presents with many objective physical signs that have a known neuropathologic basis, and these signs are used all the time in clinical psychiatry.  That Dr. Angell would not know this fact betrays a rather shocking ignorance.  In addition, there are biomarkers for mental illness.  Zinc is one, kynurenine now likely another, various cytokines… in fact biomarker tests are now being marketed to psychiatrists for diagnosis of depression, but it is hard to convince a psychiatrist to jab someone with a needle and spend money on the test when you can merely ask the person about the symptoms of depression and find the same answer.  I suppose it might eventually be useful in cases where people are feigning depression for monetary gain (such as a faked disability case).

And I will suggest that just because there is an objective "sign" and "known pathology" doesn't make pharmacology less of a Faustian bargain in other more "objective" medical specialties.  Sure, for reflux you can send a scope down someone's esophagus and measure pH, and the medicine used to treat it will indeed change the pH via blocking the proton pump, but is it helping the overall pathology of acid reflux in the long run?  Statins will, indeed, lower cholesterol through a known mechanism, but despite the standard line that doctors have no idea that cholesterol is less important than the statin commercials will tell you, every well-trained and intellectually curious primary care doctor I speak with on a regular basis knows that statins work via their somewhat mysterious anti-inflammatory effect, not their cholesterol-lowering effect.   And what about sulfanylurea drugs used to boost insulin production in type II diabetes?  Sure, you improve the situation in the short term (and could possibly avert some long term hyperglycemia damage) - but you are making the patient more hyperinsulinemic in the process, and looking at longer term risks of worsening diabetes, and depending on the medication, there seems to be increased risks of pancreatic cancer and heart disease.

I would suggest that "knowing" the (almost invariably incomplete) pathology and having lab tests to check gives modern medical doctors a false sense of security in many cases.  I'm not saying we should throw the baby out with the bathwater, but we can't scapegoat psychiatry without holding other specialties of modern medicine accountable in our critique as well.  Pharmacology, whether it is with psych drugs, medical drugs, or pharmacologic use of supplements will always have unknown risks along with any benefits.

Add the risks of not using pharmacology (whether medical or psychiatric) - and you have a complicated picture of risks and outcome.  One that takes good training, a bit of humility, honesty, and time to figure out.  


  1. Outside of the 'witch doctor-ignorant' catfight I like this post. I like it because it contains yummy words like tryptophan and kynurenine. The whole tryptophan metabolic pathway is, to me, key to so many different physical and psychiatric presentations. Kynurenine and kynurenate (important pro-convulsant) are part of this, alongside others such as xanthurenic acid, quinolinic acid, melatonin and related compounds like bufotenin and those all important cofactors for the myriad of tryptophan metabolites (tetrahydrobiopterin, iron, etc). IDO and the various other strange, obscure indole derivatives are also a very under-researched branch of the tryptophan pathway in respect of many conditions with a psychiatric presentation.

  2. I tear apart the pathologies of the DSMIV in the context of biology, biochemistry, nutrition, lifestyle and evolution.

    Gee. What about volition and moral character or the lack of it? I guess they don't count.

    You're a reductionist. Plain and simple. I feel for your patients.

  3. Crikey, tearing apart the DSM makes room for 'mess' in the therapeutic encounter - everything becomes fodder for exploration! It's the polar opposite of reductionism.

    "You're a reductionist. Plain and simple." Is that irony or sarcasm? Either way, it's pretty funny.

  4. If "all that is paychologic ia biologic," what's your opinion of cognitive therapy?

  5. People who work well with cognitive therapy gain wonderfully from it.

  6. This offers a reasonable explanation why some people, like myself, may exhibit a paradoxical worsening of mood and a trend toward depression after chronic carbohydrate consumption... presuming, of course, there was some immunological change triggered by it that interferes with normal serotonin synthesis. Then we can see a situation where increased tryptophan availability (which is, presumably mediated by carbohydrate/insulin) would lead to a worsening mood, not an improving mood. However, the few times I had my CRP measured it was extremely low, status post weight loss and maintaining a very low carb diet, which suggests I am not/was not that inflammatory. Meh.

  7. Psychiatry is doing the best it can to help crazy and distressed people, but ultimately there is a problem with prescribing treatments based purely on symptoms without any pathophysiology or objective evidence.

    First, there is the bias of the diagnostician. I have seen three crazyesque doctors, with three diagnoses given to me.

    I don't think it is necessarily better that some doctors pay attention to the whole presentation of the patient (e.g. style of clothes, gait, eye contact). I think most psychiatrists do this already, and that's precisely the problem. You walk in the door, and based on how you look/present and what they think/feel, they "diagnose" you. Which is not very accurate, even if you are a good psychiatrist, there are limitations in how accurate you can be after seeing someone for a few minutes or just their external behaviors in your office. Think about it: this leads, very quickly, to taking powerful medication. You leave the office with a prescription. That's crazy.

    Speaking personally of the 3 diagnosticians I saw (2 research phd psychologists during one assessment, and 2 practicing psychiatrists for follow up)... of these 3 episodes, they all had a different take. In hindsight I can easily see how their own subjective biases, in turn, biased their diagnoses of me.

    The first (female) research docs thought I was serious bipolar crazy, and in hindsight this is because they work in research where so much emphasis is on bipolar. They did NOT think I had psychotic problem.

    The second (female) psychiatrist agreed I sounded bipolar but she also thought I may have a psychotic disorder or an organic problem... which in hindsight is because she worked in an inner city clinic where most of her clients are psychotic.

    The third (male) psychiatrist saw me and after, literally, 5 minutes with hardly any questions asked spontaneously told me my problem with depression is from being sensitive and contemplative and unable to handle negative thought processes, and he was even speaking to me in this gentle "you are a weak girl" tone.

    In hindsight, the labels they gave me had a lot more to do with their own experiences and perspective (gender, practicing capacity) than it did anything I was really experiencing.

    How many people, and doctors, were confidently diagnosing charlie sheen with a manic episode in march, based on a few television/radio interviews where he said stuff like "I'm on a drug called charlie sheen" and such? Everyone was waiting for the britney umbrella attack episode that would get him locked up, but it never came. He just went on tour and continued to behave in a logical grounded non-psychotic way suggesting he was never manic in the first place, just an obnoxious grandiose but ultimately sane jerk.

    Stuff like this happens more often than it doesn't happen, unfortunately.

    That's precisely because psychiatrist make diagnoses based on what they FEEL, which is based on how the patient presents to THEM, combined with their subjective emotional biases. There is no hard evidence, just intuition on behalf of the diagnostician. Diagnosticians do not even pay attention to the DSM, as you pointed out. If you say "winning" 5 times it means you are sane, 6 times is manic episode. Nowhere in the DSM is this written but this is how shrinks think. That's really not useful, IMO.

    Like I said, 3 different docs, 3 different diagnoses.... ultimately I realized they have no idea.

    I'm sure they help people sometimes, though, and I am not arguing against psychiatry, but there are major problems here, that is for sure.

  8. I think the converse is true too -- all that is biologic is psychologic. All those receptors in our guts, all those bacteria in our guts that aren't really "us" but are "us" which affect neurotransmitters and a whole mess of other things we don't yet understand, including immune system functioning and inflammation.

    The effect of mindfulness practice, for example, on inflammation. The indications that good talk therapy (of whatever flavor) releases endorphins and serotonin.

    It seems to me old school to try and separate mind and body any more, to assign one direction to the causality -- to say, that over there is a medical condition with mental health sequelae while this over here is a psychological disorder due to some "out of balance" neurotransmitters.

    When will we find a common language to talk about all of this, I wonder? Emily Dean comes closer than anyone I am reading to reaching for that common language. (speaking as a soon-to-be mental health practitioner with an auto-immune disease who follows a strict paleo diet and still grapples with the mental health dimensions of chronic inflammation).

    The person who has thyroid-related depression -- say we give them thyroid medication and their depression clears up. Is that the end of it? What wore out their thyroid? Stress? Adverse childhood events? Years of eating wheat with undiagnosed celiac disease? Why is one person more likely to succumb to stress-related inflammatory illnesses than another? Is it only genes? Does it have nothing to do with their support system? With their world view? With what other emotional and psychological resources they have at hand?

    I look forward to the day that the nutritionist (not the low-fat low-carb kind) and the meditation teacher and the psychiatrist and the talk therapist and the MDs and the yoga instructor and the TCM doctor all work under one roof to help patients whose problems never fit into tidy boxes (DSM or otherwise).

  9. The five minute psychiatry, sure!

  10. @ItsTheWooo2 I love your comment here.

    This interview with psych professor at Mount Holyoke offers a complementary view --

    I like the idea that we might treat suffering in all its various forms with whatever tools we have and that we continue to view the diagnostic categories with a lot of suspicion.

    I think categories can be important for research -- like for example, I think sloppy diagnostic categories when it comes to autism and CFS/FM have impeded greater understanding of these "conditions" over the last decade. Studies that lump people sloppily into loosely-defined syndromes end up not telling us a whole lot about what "interventions" might work or not.

    But then at the end of the day, we have individuals who walk into our offices, every one of them different. Does it matter so much that three different clinicians had three different diagnostic codes for your experience IF somewhere in there you find someone who helps you put together a plan to alleviate your suffering?

  11. Emily, I've been doing some thinking and research about the whole mind/body duality thing especially in regard to addiction and food reward. Anyway I came across an interesting quote from an AI researcher, something along the lines of emotional (chemical) thinking vs logical (electrical) thought. I realize that it is impossible to separate the two, but in your opinion is there some merit in this facile model?

    Put a different way, say the signal processing characteristics of neurons were figured out, more or less, allowing human brains to be emulated (more or less) using something similar to the doped silicon technology we currently use for computer logic gates. Would it be possible in this hypothetical scenario to build an emulated human brain that would be sort of be the logical or fixed emotional (since emotions are hardwired in) map of a human brain?

    If this sounds confusing it is because I'm not really sure what I'm trying to ask. I'm really just curious on your thoughts on the electrical vs chemical components of the mind vs brain.

  12. Until psychiatrists quit treating the symptoms and start treating the patient you might as well prescribe with a dart board. I've never had a psychiatrist ask me detailed questions about my chronic pain. They never ask me when and what I eat or what happens if I miss a meal (baaad). They don't ask my family about their observations.

    I get an interview, pills and the door. Very frustrating.

    Also previous suicide attempts is a crap metric. My brother never attempted suicide; he just hung himself. That's far more common than the cutters actually dying.

  13. In the following sentence, "Serotonin levels actually have closer (negative) correlation with violence and suicide than depressed mood - and this study of kynurenine is no different - suicide attempters had the higher levels, and depressed patients without attempts had similar levels to healthy controls." am I right that "higher levels" refers to kynurenine, not serotonin?

  14. Sean - I suppose I'm confused by your question. Ultimately communication occurs via electricity, he chemical neurotransmitters modulate the ease with which the membrane is ultimately depolarized or hyperpolarized - here is a description

  15. Pangolin - I'm so sorry to hear about your brother. Suicide is horrible (obviously) and often unpredictable and relatively rare, making it difficult to study without using large populations (which can be expensive and has limitations). However, it is well established in the literature that a previous suicide attempt is one of the strongest risk factors for eventual death by suicide. In addition, while certainly self-injurious folks who cut don't typically do it as a means to kill themselves, once you begin engaging in cutting, it also increases risk of death by suicide eventually.

    As to your experience with psychiatry, I am adding a long edit to my post today.

    Dim Tim - you are right, I was not particularly clear in that sentence. In this study, high kynurenine was a biomarker associated with previous suicide attempt, but not with current levels of depression (folks with major depressive disorder had similar levels of kynurenine than healthy controls). Typically, low CSF serotonin is more associated with suicide or violence than with depressive disorders.

  16. Sorry what is the evidence?


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