Thursday, May 5, 2011

Nature and Nurture - The Basis of Mental Illness

"So what's more important, doc? Genes or how you were raised?"

I'm asked that question or a variation thereof quite frequently. Some people wonder how much they can do to truly change, and others are concerned about the risk of mental illness their children might have. It's an important question, and while the simple answer is, "both are important," the complicated answer describes the very essence of the biology of psychopathology. And in that biology you also see the clues for cures.

So, yes, a molecular biology-heavy post. That calls for some music. Hmmm. The Airborne Toxic Event - Changing (right click to open in new tab).

Mental illness, as it turns out, has some of the highest genetic loading of any common illness*. Of course there are some rather famous single-gene disorders (like Huntington's or cystic fibrosis) whose risk seems to be almost entirely genetic, but right up there is schizophrenia, where 80% of the risk is genetic. That means if you have no relatives with schizophrenia, it is unlikely you will develop it. Genetic loading counts for a large portion of the risk for bipolar disorder and major depressive disorder as well.

Schizophrenia is the most studied of many of these disorders at a basic science level, I would say. And it is pretty clear that patients with schizophrenia and their close relatives have decreased prefrontal cortical efficiency. Since the prefrontal cortex is responsible for planning, elements of memory, controlling impulsivity, predicting outcomes, and many other important parts of thinking, having an inefficient cortex is very problematic, to say the least. Here's a slide showing the prefrontal network in schizophrenia:

You can click for a bigger version, of course, but the details aren't important for this blog post - the slide is really just a demonstration of the complexity and some of the neurons involved.

So, if schizophrenia is genetic, and we know the location in the brain where the first problems arise, can't we nail down the gene? In the last 5 years we've developed the capability to sequence genomes and check out genetic polymorphisms (differences in genes between one person and another) both rapidly and cheaply. This has enabled us to do a brute force hack of the genome, looking at the genes of many families and finding those genes that are common to families with schizophrenia and are absent in families without schizophrenia. I wrote about a similar study done for migraines a while back.

These types of genetic studies are fantastic - but you end up with tens of thousands of data points, so you can't possibly use the typical p value cut-off of 95% probability that the results are not due to chance (that's a decent enough definition for our purposes today - here's the real definition of p value). With that many data points and a p<0.05 cut-off, you are definitely going to end up with hundreds or even thousands of "statistically significant" correlations due to random chance. Therefore for studies like these, the cut-off is much, much smaller -- often <10 to the -8, for example.

Well, these studies have been done for schizophrenia, and two genes popped up, and they are not particularly exciting. Certain variants of the genes for NRGN and TGF4 were found to have an odds ratio of 1.21 and 1.33 for developing schizophrenia. That means if you have those genetic variants, instead of having a 0.5-1% of developing schizophrenia like the general population, you have a 0.6-1.2% chance of developing it (or thereabouts). So not a particularly risky genetic lot to draw!

What did we find out from these studies? Individual genes don't matter that much in the development of schizophrenia. But wait - didn't we just say that the risk for schizophrenia is 80% genetic? Well, let me throw out one more intimidating slide - a picture of the ErbB4 signaling pathway (this is just one bit of nerve signaling in certain areas, just one path by which signals get transmitted in a certain set of neurons - click for a better resolution, but again the big picture is far, far more important here than the details).

The Strokes - Under Cover of Darkness

The great thing about the brute force hack genetic studies is that if you have a computer, thousands of data points, and some grad students, you can just as easily look for correlations of not only 1, but 2 or 3 or 4 genetic polymorphisms. And when the schizophrenia researchers did that with the various genes associated with the ErbB4 signaling pathway, they hit the jackpot. All these genes interact with each other, like links in a chain. Break one link, and the brain can compensate. But break two links (so have two unfortunate genetic polymorphisms in this pathway), and your signaling becomes more inefficient. Your risk of schizophrenia goes up 8-fold. Break three links in the chain, and the risk for schizophrenia goes up 27-fold.

I'm using schizophrenia as an example - and many of the same genes and a severe inefficiency of the prefrontal cortical network are implicated in autism, by the way. Autism is likely to be, in a sense, a variant of schizophrenia that strikes much earlier in life. A similar story (but in different areas of the brain and with different specific signaling pathways) can be told for anxiety, depression, ADHD…

For heaven's sake I don't care how many rock songs you link, who cares and what does this have to do with nutrition and environment and blah blah blah…

All these pathways and all these signals have been running along using the nutrients and lifestyle we have evolved for thousands and thousands of generations. The signaling depends upon having magnesium, zinc, cholesterol, omega 3s and arachidonic acid, vitamin D, creatine, CoQ10, restorative sleep, appropriate lighting, proper energy efficiency and neuronal recovery and repair. Some of us are nearly bullet-proof. We have lickety-split efficient neural networks that seem to be able to run on garbage. Others of us have some sort of problem somewhere, and we need all our compensatory mechanisms working, and we need to give our neural networks all the raw materials in the right amounts.

My next post will focus more on depression, trauma, and the nitty-gritty of epigenetics. In the mean time let me reiterate:

What we do matters. What we eat matters. To be the optimal human being from the genetic hand we were given, we'd best live in a way that compliments our biochemical programming.

* Much of the information I'm presenting today is from lectures I attended last week by Carl Salzman, MD (of Harvard), Jeffrey Lieberman MD (of Columbia), and Daniel Weinberger MD (of NIMH and NIH) - all are world famous researchers in psychosis and psychiatry. I had the pleasure of attending many lectures by Dr. Salzman during my residency. These lectures were not sponsored in any fashion by the pharmaceutical industry.


  1. "What we do matters. What we eat matters." I think you are so right. My husband has one of those systems that can run on garbage, and while his energy levels may not be optimal, he's calm and doesn't get sick. Myself, son, parents and sibling are learning we have almost no margin of error when it comes to diet, we just fall apart (or become autistic). There is a saying that in autism you don't have to look too far in the woodpile to find an engineer. That applies very much to our family. I have to wonder if different personality types aren't somewhat due to biological factors. I also think gut flora plays a big role in this. Families share gut flora, or lack of, as well as genes. And many of these modern epidemics coincide with antibiotic use as well.

  2. Dr. Deans, this is fascinating. What a wondrous subject!

    Thank you very much for this post. If you don't mind a question or two.... :)

    Is there a way to know, without fancy testing, what our biochemical programming is? For example, I've discovered that a smidgen of Tyrosine powder in the morning makes me feel alert, poised, and pleasant. And it takes away the urge to drink pots of tea at industrial strength. Read, think, make self-experiments?

    Regarding what we do: does this mean frame of reference, lifestyle parameters, how we approach every possible conscious choice, etc.?

    The basic eating part, thank goodness, seems the easiest to have in hand. Dr. Harris' 12 Steps for me, with lots of fish and offal, and at Dr. Bernstein levels of carbs and eating schedule, with the law of small numbers keeping blood sugars nicely stable. Unless there is more....

    Thanks so very much for addressing how all the factors are connected to each other and the whole. I always smile a lot when I read your blog. It's great.

    Am looking forward to the depression, trauma and epigenetics grits.

    Thank you very much for offering such delights for us to read!

    With all best wishes. :)

  3. Nice post. I read it and all throughout one word kept recurring to me 'homeostasis'. A question: assuming that we can 'alter' our environment to a degree (and perhaps even influence our genes - methylation?) is there a possibility that our in-built homeostatic mechanism 'prevents' us from truly making a significant, long-lasting fundamental change to ourselves? (I am not looking for an answer by the way!)

  4. Mrs. Ed - it is remarkable how different people have different resiliencies. However - for the chronic stuff, you don't find out how resilient you are until it is too late...

    H - 23 and me has some testing, but frankly many of the genes are yet to be discovered. Here's my general rule - will testing change what you do, or would you be as healthy as possible regardless? If it won't change anything, what is the point of the test?

    How we think and cope is an important part of what we do, and makes a difference in how the brain works. I'll go into more of that in the depression/epigenetics/trauma post.

    Paul - I agree, however, epigenetic changes could also alter the homeostasis (more in the next post).

  5. Thanks Emily, fascinating as always, I have no formal training in this stuff and you always make it so understandable.

    Oh and at the exact point that the first song ended, you suggested the next one.. how did you know that? :)

  6. Now Emily your hitting the stride.......I can't wait to jump in soon with my contribution. Epigenetics is gonna make a lot things that don't make sense make a ton of sense. Dr K

  7. This seems to make a lot of sense to me, and it agrees with my intuitive understanding of mental illness, speaking as someone with mental problems. I have a family history of significant mental problems (my mother has had recurrent depressions, as did her father, and his family had some attic cases... my father has severe anxiety and alcoholism, my father's brother committed suicide presumably during depression, my father's mother had schizophrenia and died in a mental institution, my father's father had bouts of psychosis and depression and was on disability from it... crazy lot).

    I myself have mood disorder, I've had depression since I was a preteen, which became quite significant and imparing by the time I was 16. I was extremely nonfunctional as a teenager due to depression, and at my lowest point I did not function at all, complete self neglect, suicidal. Starting at 23 I began to have symptoms of mania, which seem triggered by sleep deprivation, seasons, as well as certain reproductive hormones (estrogen). Drugs can trigger it too.

    In spite of my mental problems I do not seem to have a severe disorder - I am not manic depressive. Intuitively I have always thought that I probably have maybe a few of the genes which make one vulnerable to manic depression, but I don't seem to manifest the whole syndrome, my brain always seems able to regulate itself and I never go too crazy for too long, and my depressions may be low but I come back from them and they only rarely, as in only a handful of times in my life affect my functioning to a significant degree.

    I've always felt, if only there were maybe a few additional adverse prenatal events, or a few more mental illness genes, I would probably be in a psychiatric ward. I am not totally sane and normal, that I know. Normal people don't spin out or fall down the way I do... but I am not "mentally ill" either because I am functional and self sufficient in spite of this instability. Never found myself in new york rambling about jesus.Never catatonically depressed.

    I do think, also, that environment interacts signfiicantly with the genetics, as you have stated. I was waaaaaaaaaaaay crazier and much, much, much more vulnerable to depression prior to attacking the problem with glucose controlling diet, inositol, acetly-l-carnitine, a barrel full of ALA DHA/EPA, and bright light therapy every day.

    My depression is barely a problem now. I do think what I am doing makes me more vulnerable to manic problems, and contrary to evidence ALA seems to promote manic events for me (flax is supposed to stabilize mood but I find it is more antidepressant). EPA/DHA however do not seem to affect me in that way. ALA is more effective for boosting my mood and I think the reason that is, is probably because omega 6 fatty acids are a depressant, and ALA is a competative precursor for LA (which is overrepresented in my high fat diet.) ALA intake is very important for people who eat a high fat, LA rich diet, because it mitigates the LA by competing for enzymes. EPA/DHA don't seem to do much for my mood acutely, ALA does, and I suspect it is because of the LA intake of my diet.

    Anyway, yea. I was waaaay crazier before doing this.

  8. My mother's only brother has schizophrenia. My mother is 71, I'm 30; she's tested positive for Celiac Disease, I've tested negative for Celiac Disease 3 times; she's had unipolar depression most of her life, I've had undiagnosed schizoaffective disorder since I was a child- it's either that, or a mood disorder with psychotic features- considering that I managed to eliminate the positive symptoms at age 22 after 2 years on a gluten free diet and have never taken psychiatric medication, to me, that's highly significant.

    I am incredibly curious regarding whether or not I contracted toxoplasmosis in the year before my symptoms began to be noticeable to my family and my classmates at school (depression, social anxiety, minor panic attacks that were triggered by auditory hallucinations, paranoia, abnormal social behavior, flat affect, brevity of speech, avoidant personality disorder / social withdrawal- I would literally hide from people). Eleven years ago, I also developed chronic symptoms of digestive disturbance which I only last year was able to recognize as acquired Fructose Malabsorption though I have yet to identify just what intestinal infection I likely got from some very sick cats could have set me down this path. The FM made my mental health issues even more difficult to deal with on a daily basis, after I'd made so much progress, because of the domino effect of malabsorption affecting my relationship with food, worsening my morale and my depression... although, in a way, the FM was a gift because without it I may never have removed gluten from my diet and would probably still be hearing voices as a result. I also would not have learned so many things about the human body / brain in connection with mental illness.

    We ate a lot of homemade, baked breads and desserts in my family out of tradition. My siblings and I experienced recurrent sinus infections, took various courses of antibiotics and some of us had minor surgery related to those sinus problems / infections. I'm pretty confident that my mother was malnourished during her pregnancy with me if not during all of her pregnancies, due to celiac disease. She has told me that during her pregnancy with me she was more depressed than she had ever been. I was her 9th and last pregnancy, youngest child; also, the lowest birth weight and the smallest of all of her kids still today at 5'5" and 115 pounds average. In comparison, she has been obese for several decades at 5'3" and 180+ pounds.

    Regarding your articles which have discussed inflammation and Kynurenine, etc, I wonder if you've read this, dated August 12, 2011:

    "Crossroads of Kynurenine Pathway Offers Leads for Schizophrenia and Neurodegenerative Disease Alike"