Sunday, January 27, 2013

Is Schizophrenia an Autoimmune Disease?

Psychopathology and particularly psychosis has had a bit of a research dance with immunology over the past several years. For example, women with post-partum psychosis are more likely than controls to have anti-thyroid antibodies. And folks with schizophrenia and bipolar disorder are more likely to have strange anti-wheat protein antibodies than controls. In the recent, very large CATIE trial, 23.% of those with schizophrenia had IgA anti-AGA antibiodies (anti-gliadin) compared to 3.1% of a comparison group, and 5.4% had high levels of tTG antibodies compared to 0.8% of the comparison group.

Brahms Violin Concerto (very long, really famous bit begins at around minute 35)

No one is sure what these immune reactions mean. But it would be interesting to see how immune modulators might affect psychosis in a clinical trial. In evolutionary medicine, immune and inflammatory modulators could include a dietary intervention, probiotics, or even helminth therapies. To my knowledge, none of these have been applied to schizophrenia or post-partum psychosis in a clinical trial of any kind.

This week, a paper came out in the renamed Archives of General Psychiatry (Now JAMA Psychiatry) linking schizophrenia to a set of autoantibodies. The findings in this paper lend more credence to the idea that a subset of schizophrenia may be caused by an immune attack on the brain.  Blood from a group of unmedicated, hospitalized schizophrenics was compared to blood from people admitted with major depressive disorder, borderline personality disorder, and healthy controls.

9.9% of the actuely ill schizophrenics were found to have anti-NMDA receptor antibodies, compared with 2.8% of those with major depressive disorder, 0.4% of controls, and 0 of those with borderline personality disorder. The NMDA receptor (glutamate is the key neurotransmitter at this receptor) is known to be associated with psychotic symptoms. PCP and ketamine are NMDA receptor antagonists that rather famously cause agitation and psychosis.

Now there is already an illness of anti-NMDA receptors called "NMDA-R encephalitis." It affects  young women with a rare type of ovarian tumor called a teratoma, and presents with psychosis, agitation, memory problems, and seizures. It tends to progress to problems with the autonomic nervous system (which can control breathing, temperature and blood pressure regulation) and cause a catatonic state. It is treated, like many life-threatening autoimmune conditions, with high dose steroids and plasmaphoresis (or plasma exchange, which can clear the blood of the offending autoantibodies). The autoantibodies in the cases of NMDA-R encephalitis are to a different specific protein subunit of the receptor and tend to be in much higher concentrations than the folks with autoantibodies who had acute schizophrenia, so it is not exactly the same disease.  In this trial, however, two of the patients originally diagnosed with schizophrenia were re-diagnosed as NMDA-R encephalitis due to the type of antibodies they had. They also had some intriguing physical symptoms and CNS and blood  inflammatory markers that aren't typically found in schizophrenia.

But it is fascinating and needs to be studied in more populations at greater length. Is there a time coming when 10% of our first break psychosis patients might be getting plasma exchange and steroids? Would they be maintained on autoimmune dietary protocols (if effective for blood titres of antibodies) and relatively benign chronic immune modulators (again, just hypothesizing in an exciting sort of way) such as pig whipworm or killed M vaccae?

As always, more questions than answers, but getting one step closer to the bottom of the pathology of mental illness and brain diseases is always interesting, and always gives me hope. And what about the healthy control and the patients with major depressive disorder who had anti-NMDA-R antibodies? Are they more likely to have problems with psychosis or psychopathology? I suppose we will have to wait and see.

Friday, January 25, 2013

I know it has been a while.

The Kooks. Naive.

I've been really sick.  Flu I think! Though I've never had the flu before.  Fever and malaise and all that crap, for a week. Not like me at all. Caught it from my children, who caught it from my husband, who works at a hospital. Once the kids are sick and keep me up at night and cough in my face, I'm a sitting duck. I haven't been to the gym. I've been napping. Very strange. And so I did another abnormal move and put up a new post at Psychology Today without letting it burn out here at blogspot first.

Suicide and Vitamin D

I'm working on the book. Looking at new papers. Trying not to nap too much.  Looking to go beyond Crossfit for a new exciting training program (will definitely write up that one when it happens).

Forgive me human weakness.

Saturday, January 12, 2013

Cocoa and Cognitive Decline

One of the most heartbreaking fields of medicine is that of cognitive decline. I presented to  journal club of behavioral neurologists last fall and felt eviscerated… but I know why. There are all these families with loved ones struggling with dementa and hardly any evidenced-based treatments. It's an area rife for fraud and false hopes. Enter cocoa, among other miracle foods (like curcurmin).

New cool(ish) cocoa consumption paper

Crazy take on cocoa consumption and Nobel prizes

I'm not a huge fan of miracle foods. I do see how MCT oil/coconut oil could brush up a ketogenic prescription and help faltering brain energetics. But in general, I'm more a proponant ov avoiding crap processed foods for most meals and enjoying cheats immensely when they come along (like cake for your birthday).

Bruch: Violin Concerto (fast forward to 17:50 or thereabouts for the highlights…and your soul is dead if that last 5 minutes of the concerto doesn't move you)

So this paper is all about miracle foods in cocoa flavanols. FLAVANOLS. They decrease peroxidation and blood pressure and increase insulin sensitivty. In other words they are sexy.  Way sexy. Let's eat some blueberries and get a photo shoot sexy.

In this study, super high flavanol rich cocoa drinks were administered along with placebo to folks diagnosed with mild cognitive impairment, and the results showed the cocoa flavanoids decreased blood pressure, measures of insulin resistance and cognitive impairment. Working memory, long term memory, and executive functioning all seemed to improve.

From a clinical perspective, I have a hard time poo-pooing the findings. I see little downside from consuming flavanols in the mildly cognitively impaired population considering the likely long-term outcome. But we don't have enough data to make a truly informed choice, which should always make one hesitate.

And, lastly, the study was funded by Mars, Inc, who provided the cocoa drinks for the study…

Monday, January 7, 2013

The Primal Connection

A few weeks ago, Mark Sisson's company sent me his brand new book (the seventh in The Primal Blueprint series) which is going to be released tomorrow: The Primal Connection.**

I've always liked Mark's readable, organized writing. He has a knack for taking complicated and scientific subjects and distilling some common sense truth out of them. It doesn't mean I agree with him about all things, but I do always like his style and general message. Eat well, live well, play well, sleep well.

Dan Kroll: From Nowhere

The Primal Connection takes us beyond the food and exercise of The Primal Blueprint into further lifestyle tinkering along the same lines. It is a pop science book, meaning it isn't quite as hypothetical as it perhaps should be. For example, there is a popular theory espoused by The Primal Connection I've even explored on my blog, about a human population bottleneck somewhere around 50-75,000 years ago. The theory goes that as few as 1500-2000 individuals survived, and at that time a great leap forward in human technology and cave painting, etc. seemed to survive. Somehow humans developed some extra genius (was it shellfish and omega 3s Previc has postulated) during the bottleneck, and the smarter band survived. I've seen many writers (from Spencer Wells to Fred Previc) talk about this theory, but anthropologist John Hawks has posted some evidence refuting it, and some recent work published in Nature seems to suggest that the "great leap forward" happened more gradually some time in the last 100,000 years. Like many scientific ideas, the evidence is still being gathered.

Also, The Primal Connection continues to bash poor carbohydrates to some extent, and I rather wish he would just slap "processed" in front of carbohydrates, and I would feel secure in bashing them as a major component of a healthy human diet. It's just a small part of the book, however, in the beginning. It quickly moves on to other (still controversial) but very fun material, simple and meaningful hacks to making life better.

We begin with some psychology, but The Primal Connection really starts to build up speed when we move on to what is clearly some of Mark's favorite material, barefooting, posture, movement, and play. There are hacks for sleep positioning and even poop positioning.

Perhaps the most important part of the book is about disconnecting from modern distractions to connect more with nature, family, dirt (literally), and silence. Is our hyper multi-tasked digital overstimulated world detrimental to our primal brains? Probably. But Mark gives us tech-savvy, meaningful ways to reduce distraction, ditch the smartphone for select periods, and engage in serial, monotasked moments of play, creativity and flow, work, society, and solitude.

Eastern meditation tradition and books such as Calm Energy focus on engaging fully in the moment, living in the senses. Harnessing the serenity that comes from the present. A lot of what I do in my western medicine psychiatric clinic is talk basic relaxation and meditation with people. There's a lovely Buddhist saying I learned from Baron Baptiste: "The winds of grace are blowing all the time. All you have to do is raise your sails."

It's hard to help folks find that stillness, that serenity. That moment that can be easy to reach when you are standing with your feet in the sand, looking across the water at a Pacific Sunset. Perhaps not so easy when you have a huge pile of laundry and Dora is blaring on the TV. And it is hard to embrace the idea of going out barefoot to experience connectedness with the earth when there is 5 inches of snow on the ground. But primal connectedness can be found everywhere, any time, in its own way.

Just now I had to interrupt writing this post to put the 3 year old to bed. Little children can be challenging with the constant distractions. "Mama, mama, mama" is a constant refrain. Yet little ones also force you to "enjoy the moment" when they slow down your walk by needing to walk backwards, demonstrate a special spin move, or stopping to check every crack, ant hill, and puddle.  My youngest likes me to sit in the room with her when she is going to sleep, so I rock in the chair and close my eyes and listen to her lullaby songs, at least two or three. I listen to her breathing and the gentle music and try to keep the huge "things to be done list" and worries banished for that short time.

Even though those moments are filled with modern devices… ipods and stereo docks, rocking chairs, toddler beds… just existing with one's senses for a moment goes back to those days of hunting and gathering in the wilderness. Listening to the wind and calls of the birds and the rustling of leaves. Noting the colors of the grasses, seeing clues for direction, water, edible plants, signs of game. Sometimes my daughter wants to rock with me, I hold her hands in mine, keeping the soft little fingers warm. When she's nearly asleep, I carefully lift her into her bed. Those moments bring sanity from the distractions.

The Primal Connection is a roadmap to finding and maximizing those moments. From posture to earthing to swimming to sunshine to gardening, it is a way to move and exist in a more harmonious and natural way, one that will presumably complement our DNA and health. The science isn't all there yet, but the common sense is fully realized.

**Full disclosure, I am currently working with Mark's publishing company on a book about disordered eating.

Friday, January 4, 2013

Your Brain on Fructose

Right on the heels of the little case study I wrote about last time came a paper in JAMA that made a bit of a splash in the news: Effects of Fructose vs Glucose on Regional Cerebral Blood Flow in Brain Regions Involved With Appetite and Reward Pathways.

I know. Sounds like a nail-biter.

Stone Temple Pilots: Pretty Penny (from 1994! Ancient history. I like the fresh time signature used in the song.)

The paper is a Tale of Two Sugars, glucose and fructose. Fructose is somewhat sweeter than glucose, and it is metabolized differently (as those in the paleosphere are no doubt agonizingly aware). Fructose, for example, only causes slight bumps in insulin, which is known to work in the central nervous system to increase the satiety and decrease the reward value of food. Compared to glucose, fructose also doesn't increase a satiety hormone glucagon-like polypeptide 1, and fructose doesn't decrease levels of ghrelin, an appetite stimulating hormone.

Let's translate into something simple rather than paperspeak:

Glucose: Increases insulin, increases GLP-1, decreases ghrelin: all of which increase satiety and decrease reward seeking behavior.

Fructose: Barely increases insulin, doesn't increase GLP-1, and doesn't decrease ghrelin, so after ingestion you will presumably still be hungry and looking for the next bag of skittles.

In rats, if you inject fructose into the brain, it stimulates food-seeking behavior. If you inject glucose into the brain, rats decrease their food intake. Please do not inject fructose or glucose into your brain. And while that rat factoid is certainly interesting, I'm hoping that when you drink a vat of agave nectar*, much of the fructose doesn't get past the liver anyway, as it is pretty oxidizing and toxic in the bloodstream.

In human and rat brains, appetite is controlled in the hypothalamus. Sleep kinda lives there too. It's also part of the HPA axis that makes up our stress response. And the researchers hypothesized that if fructose stimulates appetite more than glucose, it will increase blood flow in the hypothalamus and other reward areas of the brain. They rustled up some humans and stuck them in a functional MRI to measure brain blood flow, and out came some data.

Here's another good STP song that you may not have heard, Atlanta (from No. 4)

20 normal weight, non-diabetic "healthy" volunteers were used, 10 men and 10 women, average age 31.The women were all scanned during the follicular phase of their menstrual cycle. Each volunteer was scanned and blood samples were taken after an overnight fast. Then they drank a glucose and (on a separate day) a fructose sweetened drink and were scanned again after 60 minutes. The order of drinks was blinded and randomized. The drinks are described as 75g** of sweetener, plus cherry flavored water. Participants were asked to rate fullness, and serum levels of glucose, appetite hormones, insulin, etc. were measured at 10 minute intervals after injestion through the scanning. Serum levels of fructose were also examined, to see how much got past the liver.

In a complimentary rodent experiment, they gave rats fructose IV and then measured the amounts of fructose that were in the brain to see if some made it through the blood brain barrier. Interesting.

The results! Well, hypothalamic blood flow tended to decrease after ingestion of glucose (within 15 minutes) ingestion wheras it did not with fructose. At all time points, blood flow in the hypothalamus was decreased after glucose compared to fructose drinks (presumably meaning that appetite was decreased after the glucose ingestion but not decreased with fructose ingestion). Glucose also decreased activity in the brain's striatum, which fructose did not. Predictably, both plasma glucose and insulin increased with glucose ingestion, whereas there was very little increase with fructose ingestion.

Plasma fructose in humans did increase after fructose ingestion compared to glucose (scary, and, duh), but levels of ghrelin and leptin were not different in the two groups. Another hormone, PYY, and then lactate was higher in the fructose drinkers. The glucose drinkers felt less hungry and more sated after drinking, whereas fructose drinkers still felt somewhat hungry and not quite as satisfied after the drink.

In the rodent study, fructose in the plasma did translate to an increase in fructose in the brain (compared to a saline IV), and they found that the RNA for fructose transporters (GLUT5) were expressed in the hypothalamus, liver, and kidney.

So, for a small study, rather interesting. Big difference in straight up fructose vs. glucose in how the brain and appetite centers react, and one would tend to think from the results that glucose decreases appetite and reduces food-seeking behaviors, whereas fructose doesn't really fill you up. Of course, no one drinks straight fructose unless you are glopping agave nectar into your tea, and it would have been interesting to see what the soda version of HFCS (from memory, I think it is 55% fructose, 42% glucose) did compared to straight-up glucose. And fizzy (hard to blind that one)! And cherry-flavored! Someone get me some healthy volunteers and an enormously expensive functional MRI machine!

*don't drink a vat of agave nectar
** the typical oral glucose tolerance test is 50g of dextrose in an orange-flavored concoction.