Monday, August 30, 2010

Your Brain on Ketones












Saturday, August 28, 2010

Family Tree








(Daniel Boone image courtesy Wikipedia)

Friday, August 27, 2010

Ketogenic Diets and Bipolar Disorder 2

Yesterday I made a brief introduction to the topic of ketogenic diets and bipolar disorder.  Today I want to discuss some of the issues raised in that post a little more thoroughly.

First let's talk a bit about how nerves work.  It's pretty cool, really, but involves a little biochem and physics, so bear with me.  Now a picture, courtesy the US government and wikipedia:

Nerve impulses and signals travel along the nerve fibers via electricity.  How that happens is that the extracellular levels of ions and the intracellular levels of ions are maintained at a very different level.  Inside neurons, the sodium concentration is about 10mM, but outside, it is 130mM or more - rather like there are a bunch of balls stored in a container on top of a hill.  Open a little door on the side of the container, and the balls come pouring out and down the hill.  Potassium is the opposite - levels are very high inside the cells, and quite low outside (1).

Neurons have plasma membranes like other cells in our bodies.  Those membranes are somewhat like a tarp that has been oiled on both sides.  Charged ions such as sodium and potassium can't get through unless they go through special ion pumps that are located in the cell membranes.  The sodium pump, in fact, may use up to 50% of the energy in our brains (2)! 



It's Friday.  I know.  But it's important to understand the above to some extent to understand why a ketogenic diet might change the ionic environment in our brains.

Before we get to a ketogenic diet, let's look at lithium, carbamazepine, and valproic acid (depakote), all medications that have anti-seizure and mood stabilizing properties.  Lithium is especially interesting, because, if you recall, it looks a lot like sodium, so much so that our kidneys can become confused.  Seems our brains can too.    In rats treated with lithium, the lithium displaces the intracellular sodium in the neurons, and overall sodium is decreased.  The changed sodium gradient may be central to the mood-stabilizing effects of lithium.  (You doctors out there will be squinting at me right now - hey, lithium isn't an anti-seizure med!  Well, actually, it used to be used as one.  Most psychiatrists will know that we can get away with somewhat lower doses of many medicines for mood control than neurologists need for seizures - an exception to this is depakote - sometimes.  Lithium can be horribly toxic at levels high enough needed to control seizures, so it is never used for seizures now.  But it does have anti-seizure potential.)  Carbamazepine is a little mysterious, but one of its effects is to definitely inhibit the voltage-sensitive sodium channels.  (Lamotrigine, another anti-seizure and mood stabilizing drug, does something very similar).  Valproic acid (depakote) has a whole load of actions, and can increase GABA, making it a pretty good anti-anxiety med.  Another thing it does is to decrease the rapid-fire ability of the spazziest neurons, probably by inhibiting the sodium channels.



Sounds good!  Well, some intrepid doctors in Israel had a bipolar patient who didn't respond that well to medication, and after discussion with the patient and family, it was decided to try a ketogenic diet (5).  The patient fasted for 48 hours and began what is described as a "classic" ketogenic diet for two weeks.  Oddly, she didn't have any urinary ketones.  After two weeks, the doctors added MCT oil (coconut maybe?  It doesn't specify), which low-carbers will also know can induce a more reliable ketogenic state.  The patient was pretty gung-ho on the diet, and the doctors made note that her compliance was good for the month the diet was tried.  She showed no clinical improvement, no loss of weight, no urinary ketosis, and no changes in liver function.  Seems odd that she wouldn't get ketosis while fasting or on a strict ketogenic diet, but perhaps that's why it didn't work.  I'll discuss a second case below.

On the internet, one can find a number of anecdotes about people improving bipolar symptoms with ketogenic or low carb diets.  But, as I mentioned yesterday, there are absolutely no systematic scientific studies.  The last thing you would want to do is, all on your own, ditch your meds and try a home-made ketogenic diet without anyone's help.  Ketogenic diets can have pretty bad side effects - constipation, menstrual irregularities, elevated serum cholesterol (if you care) and triglycerides (not good), hemolytic anemia, elevated liver enzymes, kidney stones, and gall stones.  Up to 15% of kids on a ketogenic diet will get changes in the heart conduction which puts them at higher risk for death (again, this was thought to be mediated via selenium deficiency).  Valproic acid + ketogenic diet seemed to worsen the side effects (6).  Now some of these ketogenic diet studies were done at the height of the low-fat era, and likely designed by some pretty lipophobic nutritionists.  And, like Atkins, many of the original ketogenic diets will have no regard for the omega6:omega3 ratio.  Here's a case where Atkins made manic psychosis a lot worse - I wonder about that, as arachadonic acid (omega 6 metabolite) administration has also been shown to worsen psychosis.  In that case, the patient was on valproic acid also, and that may have been part of the problem.  A natural sort of ketogenic diet (think Inuit) would probably have a lot fewer of these complications and side effects.


Thursday, August 26, 2010

Ketogenic Diets and Bipolar Disorder 1

Bipolar disorder is a challenging illness, with various clinical presentations. In "type one" people struggle with alternating symptoms of mania and depression. In "type two," depression is the primary state, with the occasional rare bit of hypomania. By mania, I mean increased energy, increased sexuality, religion, insomnia, and spending money. It feels great right up until reality comes knocking on the door. Medication has been proven to be helpful in decreasing the number of manic and depressive episodes. Typically, the medications are anti- seizure medicines also, such as depakote, lamotrigine, and carbamazepine.

Most low-carb followers will know that ketogenic (extremely low carb) diets have been used to treat epilepsy for a hundred years. Would the same diets be useful in bipolar disorder (1)?

Now is the time to add a special disclaimer. No ketogenic diet has ever been systematically studied with respect to bipolar disorder. If you have bipolar disorder, please discuss any thoughts you might have from reading this article with your personal physician. The one case study I could find in the literature showed *no* benefit from a ketogenic diet. (4:1:1 fat:protein: carb) Bipolar disorder is an illness I wouldn't want to face alone.

In the literature for epilepsy, patients were encouraged to fast for 12-36 hours to promote ketosis, and then to follow a dietary plan with less than 20 g carbohydrate daily (or even lower, in most research ketogenic diets). In doing so their brains would be flooded with ketones, and most importantly, promote extracellular acidosis. There are several seizure medicines (such as gabapentin) that are no good for bipolar disorder. When scientists look closely, they find that only the seizure medicines that promote a reduced extracellular sodium concentration are helpful in bipolar disorder. Ketosis does exactly that.

It all looks great on paper, but as I mentioned earlier, when well- intentioned doctors tried to use a ketogenic diet to treat resistant bipolar symptoms, they came up with a big zero (2). And while ketogenic diets are definitely safe short term, when ever we begin to talk about treating epilepsy or bipolar disorder, we are talking about long-term strict compliance. No cookies. No bread. One would need to work with a knowledgeable nutritionist, and there are reports of patients on ketogenic diets for epilepsy dying of selenium deficiency (3). (my paleo perspective - you are eschewing your vegetables, eat your organ meats!).

In the next post I will review the case studies above more closely, and delve more deeply into the biochemistry of sodium ions and the NMDA receptor. I know you can hardly wait!  (It's here - be sure to check out Ketogenic Diets and Bipolar Disorder 2)

Tuesday, August 24, 2010

Yoga (ba) GABA

One of my standard recommendations for people who have anxiety is to practice yoga. There are controlled clinical trials demonstrating its efficacy (1)(2), and who hasn't felt that amazing sense of serenity and well-being after a particularly good yoga class? Part of treating anxiety is to bring people down from the state of constant alertness, to help someone be comfortable in his or her own skin for once. Yoga, through the process of holding (sometimes) uncomfortable positions and breathing through the stress, is a direct physical practice for allowing yourself to get through a psychological stress. Eastern ways of viewing stress, as a wave to allow to crash over you rather than as something you can fight, can be helpful in teaching people how to cope.



Activate the GABA receptors in the brain with ambien, Xanax, a glass of wine, and you get relaxed and sleepy. When these substances are constantly in the brain and then rapidly withdrawn, you suddenly have overexcited GABA receptors and you can get unfortunate side effects such as insomnia, anxiety, and seizures.



Recently, the same group at BU did a second, somewhat larger study (4) comparing walkers and yoga practitioners. (I won't have access to the full text of this study for 3 months unless I go to the actual medical library.  Uncool, Journal of Alternative and Complementary Medicine!) Again, healthy people were studied, not anyone with psychiatric illness. This time, 19 yoga practitioners and 15 walkers did yoga or walked for an hour three times a week for twelve weeks. The yoga practitioners reported improved mood and anxiety compared to the controls, and MRIs showed increased GABA in the thalamus of the yoga practitioners compared to the walkers.



Sunday, August 22, 2010















Friday, August 20, 2010

Chronic Stress is Chronic Illness - Wherefore Art Thy Regulatory Mechanisms?

So here's how mammals roll.  We perceive a threat, and then our brains jump into action.  First step - the brain's fear center, the amygdala, and the brainstem stimulate the paraventricular nucleus (PVN) to secrete corticotropin-releasing hormone (CRH).  CRH moseys on down to the pituitary gland, where CRH stimulates the production and release of adrenocorticotropic horomone (ACTH).  ACTH is released into the bloodstream on the fast track to the adrenal glands, where it tells the adrenal glands to pump out the steroid hormones.  Woo hoo!

But we can't jack ourselves up forever.  All bodily systems have innate negative feedback loops.  We eat a huge meal, and leptin regulates our appetite at the next meal to keep us at our body set point, as long as we don't fall too far from the evolutionary paradigm when it comes to what we eat, or we don't have certain kinds of medication or a metabolic disorder screwing up the system.

In the brain, the hippocampus (there's that part of the brain again!) and the left prefrontal cortex can send inhibitory signals to the PVN, telling it to lay off producing the CRH.  No CRH, no ACTH.  No ACTH, no adrenal gland production of steroids.  That would presumably shut down the acute stress response.  What is the signal to tell the hippocampus and the prefrontal cortex to shut off the steroid hormone tap?  Cortisol!  That's the negative feedback - get too much cortisol, we shut off production.  Pretty nifty. 

But here's the problem.  As we found out yesterday, prolonged cortisol exposure damages the hippocampus.  We just aren't designed to cope with prolonged stress forever.  And when we damage to hippocampus, we damage our negative feedback loop (1)(2).  The shut-off valve is broken, so we continue to release cortisol.

We all have different baseline stress levels.  Research suggests that up to 62% of our stress hormone activity levels are inherited.  Also, chronic dysregulation of the HPA axis and stress hormones in childhood will affect how the brain develops, causing increased vulnerability to further stress throughout life (3). 

(A sobering aside here - when I was in medical school in the late 90s, the first teenagers were showing up in the diabetes clinic with type II diabetes - insulin resistance and metabolic syndrome may have begun years earlier.  Before that, type II diabetes was called "adult-onset diabetes." Hyperglycemia damages the brain and raises cortisol levels.  We can't escape the conclusion that this may well be chemically similar to exposing a child's developing brain to repeated emotional trauma.  There's a bit of literature on type I diabetes and an increased incidence of psychological problems - but usually it is explained as an adolescent trying to exert independence with a risky illness and risky medicine (insulin).  I found this abstract on type II diabetes but I don't have access to the paper.)

Can diet change cortisol?  Is a crappy diet a source of chronic stress?  Well, cortisol can change diet in a group of socially housed female rhesus monkeys.  The stressed (subordinate) monkeys chose to eat more calories than the dominant monkeys (4).  Leptin administration seems to decrease subordinate monkey cortisol levels, but made no difference in the dominant ones (5). Dominant females also develop less atherosclerosis than subordinate monkeys (6).  (Note to self- foster good karma so that you do not have to come back as a subordinate female rhesus monkey).   

In human women, calorie restriction and dieting caused an increase in cortisol levels (7).  But longer studies of men showed that losing fat can actually lower cortisol levels (this would make sense, if losing fat decreases insulin resistance and hyperglycemia). Here's an interesting study comparing hormones and metabolism in 16 women with PCOS (polycystic ovarian disease which is often accompanied by insulin resistance).  They ate a high fat "western" meal or an isocaloric low fat, high fiber meal, and then the researchers measured blood glucose, insulin, testosterone, and cortisol for the next 6 hours.  The low fat meal resulted in glucose levels significantly higher and insulin levels twice as high as the high fat meal for several hours after the meal (Oops! Why do we recommend low fat high fiber diets for insulin resistance again?)  But both meals reduced cortisol equally.

But the heart of metabolic dysfunction is in the immune system.  Inflammation.  We know that chronic stress and acute stress can cause immune reactions and inflammation in addition to the whole stress  hormonal cascade (in fact it is thought to be caused by the hormonal cascade) (8).  We also know that high protein meals and tryptophan increase the stress hormone response.  Would an inflammatory protein (like casein) cause a cortisol response?  In this study, yes and no.  The more allergenic casein caused less of a stress hormone response than the supposedly less allergenic casein hydrolysate.  When the same proteins were administered to the same men through their noses (don't snort casein at home, kids!), there was no difference in hormonal response, suggesting that the signal to activate the stress hormones occurs in the gut, not the blood.  These were normal weight, healthy men, too, with no history of mental disorders and not on any medication.  Would there be a difference in someone who is chronically stressed?

The diet and inflammation area is in the midst of a flurry of research right now.  Hooray!  I'll keep an eye out for more info.  Right now we can say that a diet predisposing one to metabolic syndrome (via hyperglycemia) will definitely increase stress hormones, and the whole metabolic picture includes hippocampal damage and increasing risk of depression and anxiety.  We also know that chronic stress will likely predispose you to metabolic syndrome.  Does chronic exposure to an allergenic protein like wheat or a high level of inflammatory linoleic (omega 6) fatty acid directly cause chronic increased stress hormone response (and therefore metabolic syndrome and depression and anxiety via the robustly evidenced stress hormone route?).  I'll look further.

Thursday, August 19, 2010

Stress is Metabolic Syndrome

In a previous post I described a little bit about the HPA axis. That's hypothalamic-pituitary-adrenal axis, or master glands of stress and how they rule the body and the world. In today's post I want to explore a little more about how stress affects our metabolism and our minds.

Just to review, we have a stress response system in case something dangerous happens. And it works great for that kind of situation - send out a wave of stress hormone, a grandmother can lift the car off the trapped toddler. We can run faster, have better stamina, bleed less. What actually happens is that glucocorticoids (cortisol) and epinephrine (adrenaline) are released from the adrenal glands, and these hormones have a wide variety of effects on the body - increasing our cardiovascular capacity, decreasing our immune function, and increasing our ability to mobilize energy. Our own personal temporary superhero juice.

Acute stress has effects in the brain, too (1). Glucocorticoids bind to receptors in particular regions of the brain that encode memory (the hippocampus and the amygdala), so that years later, we can often remember stressful events as if they happened yesterday. This mechanism is part of the basis of flashbacks for people with PTSD.

And then there's chronic stress. Exposure to adrenaline and cortisol on a chronic basis can have disastrous effects on the body and brain. It is thought to contribute to the pathology of cardiovascular disease, high blood pressure, the spreading of cancer, immune system problems, and type I and type II diabetes. Chronic stress is of course also thought to cause, in part, many anxiety disorders and depressive disorders.

Cushing's syndrome is a disease caused by excess cortisol. Imaging studies have shown that people with Cushing's syndrome have a shrunken hippocampus. People with PTSD, and depression also tend to have a shrunken hippocampus. As I've described before, the hippocampus is the epicenter of how depression is toxic to the brain.

It's hard to study neurochemical goings-on in the the brains of living people, as we have the tedious tendency to be using our brains (though sometimes it is not obvious). For that reason, animal models are often used for experiments to really find out what is going on in a depressed or anxious brain. And the typical way to induce depression in a rat, for example, is to expose it to stress. And sure enough, the rat will begin to have changes in weight, disrupted sleep cycles, altered HPA axis function, and neurological changes in the hippocampus and the amygdala. Lithium and some antidepressants seem to protect the brains from the stress in animal models, reducing the amount of neurological changes in the brains. Chronic stress also causes an increase in glutamate in rat brains, which is one of the mechanisms we explored in Depression 2 - Inflammation Boogaloo. Humans will have elevated glutamate in their spinal fluid if they have anxiety.

All right. Blah blah blah. Stress makes you depressed. News flash! But here's where it gets interesting. Because, turns out, people with diabetes have many of the same neurological and morphological changes in the brain as depressed and anxious people do. Hyperglycemia accelerates brain aging and causes irreversible neuron loss in the hippocampus.

Cortisol seems to cause insulin resistance not only in the muscles and liver (which most paleo-minded folks will be aware of), but also in the hippocampus. Diabetics with poor glucose control have elevated cortisol, too. It's all a disastrous circle of sugary hormonal bodily terror. In an insulin-sensitive person, increases in insulin levels cause our cells to whip out the GLUT4 transporter, so that glucose is sucked from the blood into the muscle and fat. Cortisol seems to wreck the function of the GLUT4 transporters to some extent, leaving increasing levels of glucose floating around in the blood. Once you have hyperglycemia, you begin to favor oxidation over antioxidation. In the brain, glutathione (supreme antioxidant) levels are decreased in the hippocampus, leading to the rule of toxic glutamate. The NMDA receptor seems to increase. Not favorable to a healthy state of mind. All these changes decrease synaptic plasticity and repair. Exercise, estrogen, and antidepressants seem to be protective against this effect.

Now let's talk about the insulin receptor itself. The cerebellum, hypothalamus, and hippocampus all have insulin receptors, and insulin itself seems to be involved in mood states and cognition. If someone is insulin-resistant, adding insulin will help a person think more clearly. Insulin sensitivity seems to be associated with appropriate movement of glucose transporters GLUT4 and GLUT8 in the hippocampus to the cell membrane and the endoplasmic reticulum. Jamie Scott had a recent post on the cognitive effects of insulin resistance and diabetes.

Okay. Well, none of these findings are a huge surprise. We knew stress was bad. We knew insulin resistance was bad. Experimental animal models show that pharmacological interventions can reverse or slow down some of the damage. But hey, wouldn't it be better to avoid the chronic stress and insulin resistance in the first place? Better for the brain, better for the body.

Modern life requires work before play. Productivity before relaxation. Ability to afford the time to exercise before one actually gets the time to exercise. Hey, that's life, but take it to the automaton extreme (and add processed food and partially hydrogenated fat), and it rots our brains and ruins our bodies. But we will spend and spend until we have no more credit left. We need to change some of the incentives out there. Chronic, expensive disease is on the back burner, and it will bankrupt us.

Tuesday, August 17, 2010

Love and Opium

First a few interesting tidbits from the news. The stories reference presentations of data at a conference, so I don't have more specific information. But what there is has some interest from an inflammation/chronic disease perspective:

Childhood stress leads to adult ill health, studies say (BBC)

"A series of studies suggest that childhood stress caused by poverty or abuse can lead to heart disease, inflammation, and speed up cell ageing...In one study, researchers from the University of Pittsburgh looked at the relationship between living in poverty and early signs of heart disease in 200 healthy teenagers. They found that those from the worst-off families had stiffer arteries and higher blood pressure.

Another study presented at the conference showed that childhood events such as the death of a parent or abuse can make people more vulnerable to the effects of stress in later life and even shorten lifespan. Researchers at Ohio State University looked at a group of older adults - some of whom were carers for people with dementia. They measured several markers of inflammation in the blood which can be signs of stress, as well as the length of telomeres - protective caps on the ends of chromosomes which have been linked to age-related diseases.
The 132 participants also answered a questionnaire on depression and past child abuse and neglect. A third study reported some sort of physical, emotional or sexual abuse during childhood. Those who did face adversity as children had shorter telomeres and increased levels of inflammation even after controlling for age, care-giving status, gender, body mass index, exercise and sleep."

I'd like to know how they studied the inflammation, but these studies have another piece of information to add to the big puzzle - psychological stress leading to inflammation leading to chronic disease being a likely scenario.

One more interesting news item from the New York Times - a bunch of neuroscientists go camping to study the effects of turning off all the digital stimuli on the brain. Can neuroscientists just relax in the wild? Either they can't, or they wanted to figure out how to write off the camping trip on their taxes...

But now on to opium! In psychiatry we have a a whole recipe book of diagnoses called the DSM IV-TR. The original DSM was derived from an army handbook used by psychiatrists in WWII, some derived from handbooks developed by the Germans from their observations in the late 19th century, and a lot of the rest derived from psychoanalytic thinking. In the DSM I (1952), there were two kinds of illnesses, for the most part, psychosis and neurosis. Psychotic illnesses were defined by a break from reality (as in paranoid or religious delusions in schizophrenia or manic psychosis), and neurotic illnesses were considered to be reactions to psychological stressors and events.

There is also currently a category of illness that has to do with coping skills and temperament called the "personality disorders." It's not a particularly good term and I wish they had thought of another - "I'm sorry, the diagnosis is that your personality is disordered" is not a particularly useful approach to helping people.

For the longest time, it was thought that psychotic illnesses were more genetic/organic, and neurotic illnesses (such as depressive illness, or post-traumatic stress disorder) were reactions to stress and more amenable to treatment by psychotherapy. A type of personality disorder called "borderline personality disorder" was an exception to the neurotic rule - those afflicted tended to unravel and even appear to be psychotic while receiving the old-fashioned on the couch free association type of therapy called psychoanalysis. That's where the name "borderline" came from in the first place - it was thought to be on the "borderline" between psychosis and neurosis.

What is borderline personality disorder? It describes a type of temperament and coping, usually in women but found in men also, where someone is highly sensitive, prone to dramatic relationships, depression, anxiety, addiction, eating disorders, and self-injurious behavior such as cutting. It is very common, with nearly 6% of the population affected. Unlike depression which tends to come and go over the years, personality disorder symptoms are more stable and chronic, though for most people, borderline symptoms do tend to get better over the decades as we live and learn. It most often develops in someone who was abused as a child, but people can have it without ever being abused. Usually it happens in those cases when there is a mismatch of temperament between parent and child. More modern types of therapy can be helpful for the symptoms, but you can only imagine what it must have been like to have borderline personality disorder and to feel unsure and anxious, free associating on the couch while your therapist said very little back in the psychoanalytic days. That kind of therapy would be like re-experiencing the neglect and abuse of childhood in its own way, and that is why psychoanalysis made borderline personality disorder worse. Ultimately, borderline and some of the other personality disorders can get better as people learn to feel worthy and loved.

But, like everything else, we've discovered that even the personality disorders have biological underpinnings. I'm not sure why people continue to be surprised by these findings - it all happens in our bodies, and is thus mediated by biochemistry. In the case of borderline personality disorder, a paper and editorial in this month's American Journal of Psychiatry explore a link between borderline symptoms and opiate receptors.

We all have opiate receptors. They are activated by our natural endorphins, and can help with pain relief and relaxation. Opiate receptors are also activated by opiates, derived from the opium poppy - morphine, oxycodone, heroin, vicodin, percocet, etc. etc. etc. There are opiate activators found in certain varieties of food, most notably wheat (the exorphins) and milk (beta casein A1). We can increase our own endorphin activity through several behaviors - exercise, binging, binging and purging, and self-injury. (While self-injury is a risk factor for eventual suicide, in general people do not engage in cutting as a suicide attempt, but rather the painful act relieves anxiety and focuses psychic pain on a physical level). The placebo effect is also thought to be mediated through activation of the endorphin system (1).

In the paper, scientists measured how an opiate binder called [11C]carfentanil showed up in the brain of living borderline patients with a history of self-injury and in normal controls. They found pretty significant differences within the two groups, suggesting that the patients with borderline personality disorder who self-injure have differences in their opiate systems. Other studies have shown that people who engage in self-injurious behavior such as cutting have lower levels of endoprhins in the blood at baseline and differences in their endorphin genes compared to non-injurers.

Our endorphins regulate many of our social interactions, and almost anything we do to self-soothe, from childhood on, will activate our endorphin system. A certain subset of people, self-injurers in particular, will have less ability to self-soothe that seems to be genetically mediated, so they may go to more desperate measures (binging, addiction, self-injury) in an attempt to feel better. The same endorphin system deficit can explain some of the social problems that people with borderline personality disorder experience.

There are many levels of speculation to engage in at this point. The deficits run in families, and anyone can see how anxious, addiction-prone families can lead to less than optimal conditions for a growing child trying to find his or her way. Epigenetics may well play a role. Add chronic stress and inflammation, poor health, and SAD - there's a whole recipe for generation after generation of biologically mediated mental distress. Fortunately, as we develop more understanding of the underpinnings of these conditions, we can start helping people with specific and sensible treatments.

Sunday, August 15, 2010

More about sunlight, food, and serotonin












Yup, complicated.


Saturday, August 14, 2010

Theory of Mind and Evolutionary Psychiatry

We are human because we are social.  There is some debate as to why we became quite so social, but the predominant theory is that when we left the forests for the savanna, a larger group offered better protection from predators.  Living in large groups (on Facebook and elsewhere we tend to have 150 people we keep fairly decent track of) required many changes in our brains that no primate had needed before.  We were required to understand from another person's point of view, not just empathy, which is understanding how another feels and is common to all primates and many animals, but actually be able to picture ourselves in someone else's dirty bare feet and figure out what he or she would do, and why.  Understanding the intentions and dispositions of others and reflecting upon our own mental state is vital for survival in a large group.  We developed moral codes, social rules, and language.  Language is most interesting because quite a bit of our speech is not plain, but metaphor, requiring years of learning to understand the context and the culture.

The size of the neocortex relative to body size in primates is directly related to the usual size of the family group or tribe of that kind of primate.  We have the biggest neocortex, and the biggest tribes.  The only exception to this rule is gorillas, who live in relatively small groups, but have rather large brains.   The size of the neocortex is also directly proportional to the lifespan of primates - we have the longest.  The size of the social group of primates is also directly correlated with the length of time we are considered "juvenile," and in humans, that extended period of youth means that we are also selected for longevity, with a post-reproductive lifespan of several decades (1).

Deception requires understanding the "theory of mind" in another.  Self-deception may be the most advanced trait of all (right up until it becomes a little too much self-deception) - as someone who has no understanding of their own unacceptable wishes will appear to be more trustworthy and sincere.  

Evolutionary Psychiatry was born because I want to figure out how to heal.  I know how to make symptoms better.  I spent eight years in medical school and residency learning how to make symptoms better.  But the population is getting sicker and sicker, and the only reasonable theoretical paradigm I could find to explain the core dietary and psychological problems was an evolutionary one.  I have no interest in self-deception, however temporarily adaptive it may be.

There is an excellent evidence-based textbook for Diet and Western Disease (Food and Western Disease: Health and nutrition from an evolutionary perspective), but Dr. Lindeberg makes no reference to psychiatric issues in his book that I recall.  Most evolutionary psychiatry texts (such as Textbook of Evolutionary Psychiatry: The origins of psychopathology) have quite a bit of biology, but are, frankly, more psychologically oriented. 

One cannot ignore psychology.  It can outflank biology sometimes, it takes years to master, decades to perfect, and I use it every single day at work.  But biology usually has the upper hand.  And what are we doing, anyway, merely sending people off to get coping skills when their neurons are starving for cholesterol or omega 3 fatty acids or zinc or magnesium or serotonin or dopamine?  The growing biological evidence is that much of mental illness is autoimmune in nature.  I noted in a previous post that therapy is anti-inflammatory, but we have so much knowledge and so many tools.  No one gets to my office without going through a great deal of suffering - would you ever seek out the help of a psychiatrist if you didn't absolutely have to?  Everyone deserves a full-spectrum approach.

I looked at a number of popular press "food and mood" type books out there.  Check out the top ten on Amazon, and I assure you, I have read them all.  While many have some interesting information, they all have serious limitations and are, for the most part, scarcely evidenced-based.  The best two are Primal Body-Primal Mind: Empower Your Total Health The Way Evolution Intended (...And Didn't)and Depression-Free, Naturally: 7 Weeks to Eliminating Anxiety, Despair, Fatigue, and Anger from Your Life, but both leave you with the feeling you need 20-40 supplement pills a day just to make it through, and the latter has a whole section on the ridiculous "blood-typing" diet that has been thoroughly debunked, seriously straining the credibility of the entire book.  That's not good enough for me, or for my patients.  My goal is to present credible, practical, evidenced-based information day after day.

Our ancestors ate food, not supplements.  On a public health level, I'm trying to get away from supplements as much as I am trying to decrease the need for prescription medications.  I blog about interesting medicines and supplements because it teaches me the biochemistry and the connection to dietary vitamin deficiency or inflammation.  On a personal level, supplements and medications may be efficacious.  But understanding supplements is not my mission. 

Five years ago I could not have done this.  I have a toe in academia, but scarcely a toe.  I have a busy practice, the responsibilities of a business, two very young children and a husband and no ability to visit the physical medical library more than a few times a year.  I have no research assistants other than you, the blogging community.  And yet there is no moral excuse for not writing this blog.  I need to know how to heal, and I've trained for too long and know too much to be satisfied with merely mitigating the symptoms.  A wonderful therapist is an invaluable person, but his or her special gift is to allow and to facilitate others to figure out their own path - "don't just do something, sit there."  I have only a limited capacity to do therapy, as I am always trying to "do."  Perhaps it is youth, hubris, or naivete, but I would really like to heal. 

We are human because we are social.  Online access and a wonderful, worldwide educated community actually interested in this ridiculous little niche of evolutionary psychiatry has made this blog far better than it would have been with my own resources and knowledge.

Please, keep commenting.  Please challenge and question.  Being social makes us human.  Knowledge and education may save our humanity.

And for my weekly conceit - Delibes, the Flower Duet from Lakme....

Friday, August 13, 2010

The Evolution of Serotonin

Jamie Scott's Midwinter Blues post was the fourth of four (unplanned) complementary fructose/fructan posts on Primal Muse and Evolutionary Psychiatry. Here's the whole "series" in case you missed out:

1)FODMAPS (on Primal Muse)
2)IBS, Fructose, Depression, Zinc, and Women (on Evolutionary Psychiatry)
3)Dietary Strategies for Fructose Malabsorption (on Evolutionary Psychiatry)
4)Midwinter Blues (on Primal Muse)

Anyway, I found Jamie's last post both extremely interesting and incredibly expensive.  He linked this article about sunlight and serotonin, which turned out not to be a paper, but rather the first chapter of the Handbook of the Behavioral Neurobiology of Serotonin. I know most of you might find a new pair of vibrams or Hermes perfume or The Primal Blueprint Cookbook: Primal, Low Carb, Paleo, Grain-Free, Dairy-Free and Gluten-Free an irresistible purchase. I have a weakness for impenetrable neurological biochemistry tomes. Unfortunately my institutional access did not grant me the rights to the chapter (which could be purchased for $31), but I wasn't going to pay $31 for a single chapter when I could spend, say, 5X as much on the whole book. (Hopefully Mr. Dr. Deans is not reading this post...)  The good news is I get points on my credit card, so eventually I'll have enough to get a second iRobot 560 Roomba Vacuuming Robot, Black and Silver. Or maybe even a iRobot 330 Scooba Floor-Washing Robot.  Until then, I have my Handbook about Serotonin and we'll start with chapter one: Evolution of Serotonin, Sunlight to Suicide.

Biochemistry is all about energy and chemical reactions. And on planet Earth, most of the business of life occurs with chemical reactions driven by sunlight. The very first photosynthetic reactions occured with a molecule known as an "indole" - a benzene ring with a pyrrole ring attached.

It's not obvious, but that molecule has lots of electrons whizzing around, and the carbon atom at position "3" above is extremely reactive and will lose electrons very easily.   Add light to specific types of  indoles, and energy will be created as molecular hydrogen is released.  It is postulated that this reaction first occurred on Earth 3 billion years ago.  This is the beginning of light-based life.

Tryptophan, the dietary amino acid (and the rarest amino acid in the diet, according to Primal Body-Primal Mind: Empower Your Total Health The Way Evolution Intended (...And Didn't)) precursor to serotonin, is an indole.  It happens to be the most fluorescent amino acid under blacklight.  Tryptophan absorbs light energy, and is a vital amino acid for photosynthesis in sea bacteria, algae, and plants.  The process of photosynthesis creates oxygen from water, using the energy from the electrons whizzing around on tryptophan, among other things.  This creation of oxygen by photosynthesis changed our planet's atmosphere and made our lives possible.

Plants evolved a specific energy factory within their cells called a chloroplast, whose function is to capture light for energy, and to create tryptophan.   Chloroplasts are where chlorophyll lives.  Tryptophan is also made in all primitive unicellular organisms and plant systems.  Animals (like humans) do not make tryptophan and must obtain it through diet.  The best source for humans is from the meat of other animals, though tryptophan remains tough to get into the brain, as it is the least abundant amino acid in muscle tissue, and it has to compete with all the other more abundant aromatic amino acids (tyrosine, phenylalanine, leucine, isoleucine, valine, and methionine) for the aromatic amino acid transporter.  Everyone is waiting in the lobby for the elevator, and only a few can ride to the top at a time. 

Serotonin is made from tryptophan only in mast cells and neurons.  However, cells in every single organ have special uptake proteins to capture circulating serotonin from the blood. 

Other derivative molecules of tryptophan include melatonin (important in the sleep-wake cycle), psilocybin (the active molecule in psychogenic mushrooms), ergotamine, yohimbine (a traditional aphrodisiac), and LSD.  Most of these compounds are active in the human brain because they can stimulate the serotonin receptor.  A tryptophan-based compound called auxin affects cell growth in plants, enabling shoots and leaves to extend out towards the light.

In order to make serotonin, tryptophan has to go through a couple of enzymatic reactions.  First, tryptophan hyrodxylase makes tryptophan into 5-HTP.  Then tetrahydrobiopterin and aromatic amino acid decarboxylase (plus vitamin B6 and zinc) make 5-HT (serotonin).   Serotonin is degraded by MAO.

Tryptophan hydroxylase may be the oldest enzyme to attach oxygen to other molecules.  Since oxygen is generally quite reactive and toxic biochemically, this was an early way to safely get rid of excess oxygen created by photosythesis in primitive organisms.  The light receptors in the human (and other animal) retina are very similar to serotonin receptors and were first thought to evolve a billion years ago.  Serotonin is the oldest neurotransmitter, and the original antioxidant.  There are 20 different serotonin receptors in the human brain, and serotonin receptors are found in all animals, even sea urchins. 

In other animals, serotonin is involved in swimming, stinging, feeding modulation, maturation, and social interaction.  In general, it is thought of as a growth factor for animal brains.  In humans, deficiency of serotonin is implicated in autism, Down's syndrome, anorexia, anxiety, depression, aggression, alcoholism, and seasonal affective disorder.  Light therapy and serotonin-increasing medications are both effective treatments for depression that occurs with low levels of sunlight.   Light exposure increases serotonin in humans, and serotonin levels are lowest in midwinter, and higher on bright days no matter what time of year.  10,000 lux light therapy decreases suicidal ideation.

Tryptophan is an important amino acid, most readily available from animal sources (vegetable sources such as pumpkin seeds contain phytic acid which may inhibit its absorption), and its many important  derivative molecules work best with plenty of sunlight.  Think of it as your own little bit of photosynthesis.  Sometimes we're not as different from cyanobacteria as we'd like to think...

Thursday, August 12, 2010

Western Diet and ADHD






Now some discussion.




Tuesday, August 10, 2010

Circles of SAM-E

Figuring out biochemistry is rather like watching a group of kids playing on the playground. Lots of kids bounce off each other, swing from jungle gyms for no apparent reason, and toss balls around. In the end, energy was consumed and fun was had.

One of the ball-carriers in our livers and brain is the vitamin co-factor SAM-E (pronounced "Sammy"). Otherwise known as S-Adenosyl methionine, SAM-E has a cute little sulfur moiety on it (the "S") that can carry around biochemical balls known as methyl groups (-CH3). You're probably really excited to learn that carrying around methyl groups is an extremely important job, and SAM-E is the go-to running back, the Earl Campbell or the pre-marijuana Ricky Williams of the vitamin crew.

SAM-E is important in depression because, along with folate, B6, and B12, it helps create three of the major neurotransmitters from their dietary amino acids - dopamine, norepinephrine, and serotonin. We can make SAM-E, but without enough essential vitamins (including B6 and B12) and the amino acid methionine, we can't make enough of it or recycle it. And studies have shown that people with depression tend to have lower serum levels of SAM-E.

A new study and editorial about SAM-E came out in this month's Green Journal (the American Journal of Psychiatry - which I'm embarrassed to say I can never remember the proper name of because we always call it the Green Journal). The research team is from the Mass General - George Papakostas, David Mischoulon, Jonathan Alpert, and Maurizio Fava. Full disclosure, back (a while ago!) when I was a chief resident, I had the opportunity to sit in on their weekly research meetings. They were doing some initial planning about SAM-E, but at the time they were mostly focused on the STAR-D trial. They were always pleasant, professional, and would toss brilliant ideas back and forth - it was quite invigorating just to be in the room, though we were all stuffed into a small space for the amount of people, with research assistants sitting on tables on the perimeter, and several of the key players (Alpert or Mischoulon) doing the same, if they arrived late!

Anyway, this current study, "SAMe Augmentation of Serotonin Reuptake Inhibitors for Antidepressant Nonresponders With Major Depressive Disorder. A Double-Blind, Randomized Clinical Trial" is pretty similar to drug industry trials of pharmaceuticals, though it was funded by an NIH grant, and the SAM-E and matching placebo were freely provided by Pharmavite (who makes SAM-E, I assume). They used healthy depressed adults with no history of bipolar disorder, no risk of getting pregnant during the trial, no psychosis, and no substance abuse who were already taking antidepressants. This is an augmentation trial - as we know from every antidepressant study in history and STAR-D (Sequential Treatment of Resistant Depression), antidepressants (no matter what variety) help about 30% of people feel pretty normal, 30% of people feel a bit better, and 40% of people feel the same or worse. SAM-E has a bunch of trials (between the IV and oral trials, I think I count 20!) showing it has similar efficacy to antidepressants, mostly tricyclics. Because SAM-E has a different mechanism than the standard antidepressants, it's important to see how the two might work together. Alone, they are all pretty "meh" unless you are in the lucky 30%. Together, you might start to approximate the body and brain environment that we would have with the types of stress, exercise, and nutrition for which we were evolved, without the excess inflammation and autoimmune reactions that cause depression in the first place... sigh. (I think these trials are interesting because they tell us a bit about the biochemistry of depression. And medicines can help! I've seen it many times. But if we don't find and address the possible dietary and environmental and psychological causes, adding medication can be a bit like pissing into the wind, if you pardon the expression. Just like with diabetes.)

In this preliminary study of 73 already-depressed on antidepressants individuals, the SAM-E augmented the effect pretty well, and without side effects, for the most part (most common ones are upset stomach and diarrhea, like any vitamin). SAM-E (dosed at 800mg twice daily by the end of the study) dropped the Hamilton D depression score by 10 points from baseline, while the placebo-treated group dropped only 6 points. I know that doesn't sound too exciting - but there are only a few FDA-approved medications for the treatment of resistant depression, and they can have some pretty horrible side effects, and they didn't work as well as SAM-E did in this particular study. There are reasons that it is not quite fair to compare the studies of other medicines to this SAM-E study, and they are all duly discussed in the editorial (which appears to be free online and linked above!).

Sweet! Take a vitamin (basically) and boost your antidepressant! SAM-E has also had some studies showing that it can protect the liver and reduce joint pain in arthritis. Win-win! What are the down sides?

Well, like any antidepressant worth its salt, SAM-E can cause mania and anxiety. In fact, I would feel remiss in recommending that anyone start it without at least talking about it with their doctor or therapist, and having a family member watch for signs of mania. Theoretically, if you take SAM-E and you don't take enough of the co-factors, you can end up with a lot of homocysteine lying around. Homocysteine is a marker for heart disease, but that doesn't stop some articles I read from suggesting that SAM-E could increase your risk of heart disease by increasing homocysteine if you don't take a multivitamin with it. (SIGH. Correlation does not equal... ah, never mind). I would be more concerned that it wouldn't work as well without the necessary vitamin cofactors - so take a multi with it! Also, it's expensive. The 800 mg twice a day dose would cost $111 dollars a month at this national chain (though some people might be able to get away with lower doses). For that, you could get a prescription antidepressant and a couple of visits to a therapist covered by insurance. Also, like any over the counter supplement, "buyer beware." Some of them are sold by milligram weight rather than by milligram dose - you wouldn't want to spend big bucks for half the amount you thought you were getting! In 2000, early tests of SAM-E products by an independent laboratory showed that half of the products had less SAM-E than claimed. By 2007, it seems the companies cleaned up their act, and testing of 11 brands showed they were what they claimed to be.

And, of course, no one knows the long term side effects of piling on SAM-E.

Better that we avoid all this in the first place by having an all-star vitamin football team from your terrific, organic and local grown, grassfed and pastured all natural foods diet and a clean, anti-inflammatory playing field from childhood. But sometimes the works are already a bit gunked up. We have some professional cleaning solutions, though those have some down sides, it may not be as much of a down side as leaving the works gunked up.