Richard G. Petty, MD

Psychiatry Below the Neck

There is more and more evidence that schizophrenia and bipolar disorder and perhaps also major depressive disorder, are illnesses affecting the whole body and not just the brain and mind.

It has been known for over a century that some physical problems, including type 2 diabetes mellitus, obesity, cardiovascular diseases and some forms of cancer appear to be more common in people with major mental illnesses. All of this was known long before the current concerns about obesity, diabetes and some antipsychotic medicines. It is also clear that the physical problems cannot just be explained away by social deprivation and poor lifestyle choices.

The new understanding of mental illness as a systemic problem, opens up some extraordinary opportunities for treatment and perhaps even for prevention. In some new research due to be published next month, investigators have identified some abnormal proteins in the liver and on red blood cells that are similar to some abnormal proteins already identified in the brain.

These proteins are primarily involved in energy metabolism in cells and in protection against oxidative stress. The implication from this is that schizophrenia and many of the associated health problems may be a consequence of impaired energy metabolism together with damage by free radicals.

You will see why this is so exciting: it looks as if we have an entirely new way of approaching, treating and perhaps preventing the most serious of mental illnesses.

A New Understanding of Mood Medicines and Cells

We are in the midst of a revolution in our understanding of how many medicines work. Most students are still taught that the key to their actions is simply a matter of binding to a receptor, and then some magic occurs in the cell. But over the last few years there has been a sea change in how we see the actions of many medicines. In many ways the focus on receptor pharmacology is so 1990s.

Several years ago our group and others began to speculate that one of the ways of modulating the interaction of insulin with cells was to modify the characteristics of the cell membrane in which the insulin receptors sit. If we could change the fluidity of the cell membrane, then we could change the sensitivity of the insulin receptor. We also went a bit further and wondered whether high cholesterol levels might be associated with coronary artery disease because it changed the way in which growth factors interacted with cells in the vessel walls.

One of the reasons that fish oils may yet turn out to be helpful in some mood disorders is because they may change the behavior of cell membranes and therefore the behavior of receptors.

I have admired the work that has bee done by Husseini Manji and his group that is now at the National Institute of Mental Health in Bethesda, Maryland. Their interest is in bipolar disorder and there is a very nice update on the group’s work in the journal Biological Psychiatry.

The group is unraveling the ways in which effective medicines work at the cellular level and what actually goes wrong in bipolar disorder. We know that people with severe mood disorders may experience regional impairments of what we call structural plasticity and cellular resilience. This means that the cells find it more difficult to learn and respond to environmental changes. We think that this is why some people with severe mood problems fail to benefit from many medicines and also have so many long-term cognitive problems. So the search is on for strategies that may enhance and maintain the normal connections between neurons. The good news is that there are several new strategies on the horizon.

This notion of impairment in the normal plasticity and resilience of the brain is also why psychosocial approaches are an essential component of successful treatment. When they are coupled to the right medicine as well as the strategies that we employ in Integrated Medicine, the effects can often be very gratifying.

The Heart Master Cells

There are two extremely important papers (1, 2,) in this month’s issue of the journal Cell.

The heart is composed of three major types of cell: Cardiac muscle cells that make up the heart itself and whose contractions pump blood; smooth muscle that cells that are found in the walls of the heart’s own blood vessels and finally endothelial cells that line the heart’s blood vessels. There are many other special types on neural and endocrine cells in the heart, but these three form the basis of the circulatory pump that keeps you alive.

In one of the papers, scientists identified a cell that has the capacity to produce all three major tissues in the heart, the other group found a cell that produces two of the three cell types. One appears to generate structures on the left-hand side of the heart, and the other on the right-hand side. The findings challenge the old idea that the heart’s different cell types are so different that they must have come from separate sources.

What this means is that some unknown mechanism can make a single stem cell “decide” to become one of the three cell types.

Until very recently it was assumed that there was no way that a damaged heart or brain could regenerate itself. We now have proof positive that this dogma is wrong and it raises some extraordinary possibilities for repairing the heart.

These new papers follow others that have worked out the mechanism by which a little creature common in the tropics – the zebrafish – is able to mend his heart if it gets broken, and some research published in the journal Nature that showed that a molecule called thymosin beta-4 can make progenitor cells in the outer layer of the heart migrate deeper into the heart and carry out repairs.

My old friend Professor Jeremy Pearson – with whom I shared a lab and an office for seven years – is now the Associate Medical Director of the British Heart Foundation, and he had this to say about the second of those papers:

“By identifying for the first time a molecule that can cause cells in the adult heart to form new blood vessels, Dr Riley’s group have taken a large step towards practical therapy to encourage damaged hearts to repair themselves, a goal that researchers are urgently aiming for.”

And Professor Colin Blakemore, the chief executive of the British Medical Research Council, said:

”Finding out how this protein helps to heal the heart offers enormous potential in fighting heart disease, which kills more than 105,000 people in the UK every year.”

Jeremy Pearson was very helpful when I first started fleshing out and presemting the ideas about the reversibility of problems like arteriosclerosis, ischaemic heart disease, stroke and Alzheimer’s in the late 1980s. He was initially very skeptical, but did what a good scientist should. He didn’t shut down the discussion but kept it going with challenging questions.

The important point from all this research is not just that it supports many of the basic concepts of Integrated Medicine, but it also reminds us that when someone says that a disease is untreatable or irreversible, they may well be wrong.

Tips for Trips

I’ve not written any new items for a couple of days while I was in England and out of range of anything resembling a decent Internet connection.

But a grand total of seventeen hours on planes made me think that it’s high time to tell you about some of my tips and techniques for dealing with the rigors of flying.

I’ve got so many of them that my tips will stretch over more than one article.

By now most people will have heard about the importance of:

  1. Maintaining hydration: the low pressure and dry atmosphere on planes can quickly dehydrate us. I try to drink at least 20 fluid ounces every two hours that I’m in the air.
  2. Avoid drinking alcohol and coffee.
  3. Keep mobile. When it is safe to do so: walk up and down the aisle. Stretch your legs and arms and gently rotate your neck while sitting in you seat.

The most worrying things about flying is the risk of developing a Deep Vein Thrombosis (DVT). This is an important topic: one in 2,000 long-distance passengers will suffer a blood clot, which can be fatal if the clot detaches and reaches the lungs: this is known as pulmonary embolism. DVTs are more likely to occur if there is a change in the rate of blood flow, the character of the blood of the normal functioning of the walls of the large veins. There are a number of well-recognized risk factors for the development of DVTs:

  1. Obesity
  2. Immobility
  3. Oral contraceptives
  4. Some cancers
  5. Cigarette smoking

There is a great long list of potential causes, but our focus today is on factors that can increase your risk of developing a DVT if you fly.

DVTs have been recognized to occur not just in passengers on planes, but also in people at extremely high altitude.

For many years it has been assumed that the low pressure and the immobility together increase the risk of DVT. But new research from the Universities of Leicester and Aberdeen was published in the Journal of the American Medical Association in May.

In a study of 73 people, the researchers found that sitting for long periods was the main cause, and warned people about all forms of travel.

During the study, the volunteers spent eight hours sitting in chambers with reduced air pressure and oxygen. They were allowed to move around for a couple of minutes each hour. They were then also tested in a chamber without changes in the atmosphere. The idea was to simulate the conditions on a plane. Blood samples were taken before and after each “flight” to check for factors involved in blood clotting.

For all these factors, no significant differences were seen between blood samples taken from volunteers on a simulated flight or exposed to normal air pressure. So it is not the low air pressure and oxygen saturation that is to blame: it is the lack of movement.

It is also unlikely that the advice to take an aspirin before a flight is going to be much help.

During my travels I have seen people selling extracts of horse chestnut (Aesculus hippocastanum) to prevent DVTs. There is actually some research that horse chestnut can help with chronic venous insufficiency. But there is no credible evidence that taking a couple of horse chestnut capsules will prevent a DVT, or the less severe problem of ankle swelling. And horse chestnut is well known to have a number of side effects, so there doesn’t seem to be much point in taking it to prevent ankle swelling and DVTs when flying.

The smart move (ha!) is to do regular exercise during flight, and to avoid dehydration.

I’ll tell you some of my tips for turning flights into highly productive work time and how to avoid jet lag in other posts.

Another Reason to Eat Your Greens

“Health requires healthy food.”
–Roger Williams (Indian-born American Chemist who did pioneering work on the Vitamin B Complex, 1893-1988)

Earlier this year several news outlets including Time picked up a story that has been causing a great deal of discussion in medical circles.

Most of us have been extolling the virtues of fruits and vegetables for decades, but it’s always nice to have an extra piece of evidence to support what we’ve been saying. The question has been how to go from large-scale epidemiological studies proving the benefits of vegetables to the inner workings of a person’s arteries.

Investigators from Wake Forest University School of Medicine in Winston-Salem, North Carolina published an important study in the Journal of Nutrition. What they did was to study genetically altered mice, who had been bred to have a very high risk of developing rapid arteriosclerosis: the formation of fatty plaques in the arterial wall that can eventually block blood flow and lead to heart attacks and stroke.

Half the mice were fed a vegetable-free diet and half the mice were fed a diet that included broccoli, green beans, corn, peas and carrots.

After 16 weeks, the researchers measured the cholesterol content in the blood vessels and estimated that plaques in the arteries of the mice were 38% smaller. Cholesterol, and particularly the “bad” cholesterols VLDL and ILDL fell markedly in the mice on the healthy diet, but these improvements were not on their own enough to explain the improvement in the blood vessels: the anti-atherogenic effects of the vegetable diet remained largely unexplained by the variation in plasma lipoproteins or body weight.

There was a 37% reduction in serum amyloid – a marker of inflammation in mice – suggesting that consuming vegetables may inhibit inflammatory activity. This is line with data from other studies indicating that fruit and vegetables should be key components of an inflammation-lowering program. This is very important: in the last twenty years it has become very clear that arteriosclerosis is intimately associated with inflammation in the arterial wall.

Many inflammatory conditions including rheumatic fever, rheumatoid arthritis, systemic lupus erythematosus and psoriasis, are all associated with an increased risk of developing arteriosclerosis.

Interestingly some years ago Dean Ornish presented evidence indicating that diet and exercise could reverse arteriosclerosis. I’ve always found Dean’s work interesting, well done and persuasive. It surprises me to see how many people remain unconvinced. This new research provides indirect support for his work.

The average person only eats three portions of fruit and vegetables a day: we should all be eating at least five, and they should be of as many different colors and types as possible: there is excellent evidence that combinations of fruits and vegetables are much better for your health than just eating one or two types.

As an aside, I must admit that I’m no fan of animal experiments: I don’t and won’t do them. And every time that I hear about them, I think that we need to say a sincere thank you to the animal kingdom for their sacrifice in helping us.

“God, in His infinite wisdom, neglected nothing and if we would eat our food without trying to improve, change or refine it, thereby destroying its life-giving elements, it would meet all requirements of the body.”
–Jethro Kloss (American Nutritionist and Writer 1863-1943)

“In fresh fruit and vegetables and nuts are all the vitamins and minerals and high grade proteins the human body needs to bring it to a state of physical perfection and to MAINTAIN it in that state indefinitely.”
–Herbert Shelton (English Evolutionary Philosopher, 1820-1903)

“Nothing will benefit human health and increase the chances for survival of life on earth as much as the evolution to a vegetarian diet.”
–Albert Einstein (German-born American Physicist and, in 1921, Winner of the Nobel Prize in Physics, 1879-1955)

Laughter is The Best Medicine

“Time spent laughing is time spent with the gods.”
–Japanese Proverb

In the book and movie Anatomy of an Illness, Norman Cousins reported how he overcame a sever arthritic condition with a combination of huge doses of vitamin C, together with a positive mental attitude and hours of laughing at Marx Brothers movies. He wrote that, "I made the joyous discovery that ten minutes of genuine belly laughter had an anesthetic effect and would give me at least two hours of pain-free sleep. When the pain-killing effect of the laughter wore off, we would switch on the motion picture projector again and not infrequently, it would lead to another pain-free interval."

I’ve had a longstanding interest in the vascular endothelium, the single layer of cells that line blood vessels. Some very small blood vessels consist only of endothelial cells. These cells form the interface between the blood and the tissues, and they are involved in many disease processes. They are involved in diabetic vascular disease, arteriosclerosis, inflammation, many infections, and they play a role in the spread of tumors. There is some new evidence that laughter is good for you in more ways than one.

Investigators from University of Maryland School of Medicine found that watching a funny movie had a healthy effect on blood vessel function, allowing them to expand and contract more effectively in response to changes in blood flow. But watching a mentally stressful movie, like a war drama, may have the opposite effect, causing the vascular endothelial cells to narrow and restrict blood flow. On average, artery diameter increased by 22% during laughter and decreased by 35% during mental stress.

This work follows on from earlier research that showed an inverse association between sense of humor and coronary heart disease: people who laughed a lot seemed less likely to suffer form heart disease.

There is a very nice review article available online that confirms what is intuitively obvious humor and laughter may have a positive influence on health and on the outcome of many diseases.

There may be something to the old saying, "You don’t stop laughing because you grow old; You grow old because you stop laughing.”

Thrifty Genes, Thrifty Bodies and the Barker Hypothesis

“They have sown the wind, and they shall reap the whirlwind.”
–The Bible (Hosea, 8:7)

In 1962, a geneticist named James Neel first proposed a “thrifty gene” theory to explain why 60% of adult Pima Indians living in the United States have diabetes, and 95% are overweight. Neel’s theory was that populations like the Pimas, that have for millennia relied on farming, hunting and fishing for food, would experience alternating periods of feast and famine. Neel hypothesized that in order to adapt to these extreme changes in caloric needs, people developed a “thrifty gene” that allowed them to store fat during times of plenty so that they would not starve during times of famine.

A similar theory was advanced to explain the high rates of diabetes in people from the Indian subcontinent, once they are exposed to plentiful supplies of food. These was traced by the great Diaspora from central Asia at the end of the last age, when the ancestors of modern Indians and Pakistanis made the great trek through modern Afghanistan into the Indus valley. A journey that had been impossible at the height of the Ice Age and which was still difficult. The idea was that people who could quickly lay down a lot of intra-abdominal fat would have a huge survival advantage.

This is an attractive hypothesis, but here have always been some problems with it:

  1. The gene or genes would have to be able to work with the environment: the Pimas of Mexico and people living in rural India do not have the high rates of diabetes and obesity
  2. Despite looking for over 40 years, no such gene has yet been found
  3. If the thrifty gene is so advantageous, why doesn’t everyone have it?
  4. Until recently, famines were rare and usually occurred every 100-150 years. As John Speakman has pointed out that would mean that most human populations have experienced at most 100 famine events in the course of their evolutionary history
  5. Famines do increase mortality but only in about 10% of the population
  6. In famines most people die of disease rather than starvation, and the worst affected are the young. Having a “thrifty gene” would not help them survive starvation OR disease
  7. Simple genetic models would suggest that famines would not provide enough selective advantage and there has not been enough time for a “thrifty gene” to have penetrated the population

There could yet be some complex genetic model involving “reserve” genes that appear when needed, or some epigenetic inheritance, but we have no evidence for that either.

A second concept is gaining a lot of traction. It is what is known as the “Thrifty phenotype,” and is part of a larger theory called the “Barker Hypothesis.” I’m going to stick my neck out, and predict that David Barker may receive the Nobel Prize in medicine for his discoveries. They are that important.

Essentially the Barker Hypothesis suggests that in addition to genetic, epigenetic and environmental factors in disease, there is another, and that is the intrauterine environment. The idea is that if a mother is malnourished, she can modify the development of her unborn child. From an evolutionary perspective, her body is preparing the unborn child to survive in an environment where food is in chronic short supply, resulting in the “Thrifty phenotype:” smaller body size, lower metabolic rate and a propensity to be less active.

The problem is this. If you are born with the thrifty phenotype and actually grow up in an affluent environment, you are more likely to develop obesity, diabetes and vascular disease later in life. If true – and virtually all the evidence suggest that it is – then it has serious implications for countries that are transitioning from sparse to better nutrition, and may have contributed to some of our current health problems. Many of us were born to mothers who had poor nutrition, either because of the Great Depression, the Second World War, poverty, or just plain poor information about good nutrition during pregnancy. And now we are reaping the whirlwind.

The hypothesis has become sophisticated. If you are born small or premature, then your liver and kidneys may not have completed their final growth spurt, which might predispose you to metabolic problems and hypertension.

The story of how this all came to light would be worthy of Sherlock Holmes himself.

English counties used to have people who were responsible for providing midwifery services. In the county of Buckinghamshire a single midwife collected data for almost thirty years. Information about the mother, the length and weight of the baby and the weight of the placenta. Information that would be impossible to collect these days. Some civil libertarian somewhere would probably dream up some way of hiding this enormously important information.

David Barker discovered these extraordinarily good records, and then set about finding the adults that these babies had become. And what he found has changed medicine: babies who had small placentas – a good measure of being small or premature – were more likely to develop obesity, diabetes or hypertension as adults. Then he and others turned their attention to other early physical characteristics and found correlations with health later in life. The highest risk of coronary heart disease was seen amongst people who were born small and became heavier during childhood.

The practical implications?

Find out your own birth weight and anything else that you can about your early development.

If you were a very large baby (bigger than nine and a half pounds), it implies that your mother may perhaps have had a metabolic problem. If you were small (less than five and a half pounds), then you should get the regular health checks that we recommend for anyone in a “high risk” group.

Measuring Insulin Resistance

After doing so much research, lecturing and writing about insulin resistance, I have constant requests for more information on how to measure it in clinical practice. This is not an academic exercise: it is estimated that a person on the road to developing type 2 diabetes may have been insulin resistant for as long as twelve years before the disease is diagnosed.

In high-risk populations, there is a lot of value in regularly checking plasma glucose, but the problem is that once glucose begins to rise, it implies that the pancreas can no longer keep up with the demand for insulin and that we may be passing the point of no return.

These are the most common questions that I get::

  1. Should you be having your insulin level measured?
  2. Should you have your insulin resistance measured?
  3. What’s normal?

First, measuring insulin levels themselves is not of much value: they bounce around a good deal in the course of a day, and many things can alter your circulating insulin levels.

Second, accurate measurement of insulin resistance is an expensive and cumbersome procedure involving intravenous sampling of blood and in some cases also giving intravenous insulin.

Third, there is no such thing as “normal.” Results derived from any kind of test are a “reference range.” This means that they show how a result related to a large group of apparently healthy people. This is an important concept. I often have students say, “What’s normal?” There is no such thing. Blood tests help and guide us but can only be understood in the context of the whole person.

We never treat a laboratory value: we treat people. You may be interested to have a look at an earlier article about this important issue.

But all is not lost: we do have a blood test that can be used to guide us. We don’t have evidence to suggest that we should be using it to screen the whole population for insulin resistance. Instead it is a test to help guide us in high-risk populations. The test is called the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR).

The original paper was published by a group of experts form the university of Oxford in 1985. The drawback of the HOMA-IR is that it is a mathematical model, and it’s only as good as the accuracy of an individual laboratory’s insulin assay.

Since then, the HOMA-IR has been used in epidemiological studies such as the famous Framingham study and there has been a lot of work on trying to correlate the HOMA-IR with other measures of insulin resistance. There are now over one thousand papers that reference it, and we have had a great deal of experience in using it in our studies of insulin resistance in people with mental illness.

Apart from research, we only use the HOMA-IR as a guide in high-risk individuals. A simultaneous fasting glucose and insulin are taken.

Insulin resistance (HOMA IR) =
Fasting insulin (µU/ml) X Fasting glucose (mmol/l) divided by 22.5.

Most studies now suggest that the cut-off for insulin resistance should be 1.7; although some have been slightly more forgiving, and suggested that up to 2.5 may be acceptable. But remember that the HOMA-IR is only giving us an estimate to help with the overall evaluation of a high-risk individual, and we do not treat a laboratory value.

If the value is above 2.5 many experts would suggest intervention if there are also features of the insulin resistance syndrome. The key interventions are diet and exercise, both of which have been proven to reduce insulin resistance. A very interesting approach adopted in two European studies has been to treat high risk people with a medication called metformin, and were able to show that within a year several cardiovascular risk factors improved.


One of the principles of integrated medicine is that anything that’s good for you should have more than one benefit. So omega-3 fatty acids may help with cardiovascular health, mood, memory, attention deficit disorder, as well as the health of skin and bones.

Another one is the blueberry. I’ve been sufficiently impressed by the data on the health benefits of blueberries to have been a regular grower and consumer for years. They contain a number of potentially healthful compounds including polyphenols and anthocyanins, which can help modulate and balance the free radical systems of the body. Remember what I said recently about the value of keeping some free radicals in the body? The last thing that we want to do is to be rid of all of them!

There is reasonably good evidence that regularly eating blueberries can support cardiovascular health and there have been suggestions that they may reduce the risk and aggression of cancers of the prostate and colon.

There is also some evidence in animals that some of the components of blueberries may reduce inflammation and the effects of strokes – interruptions to the blood flow in the brain.

As a consumer, I’ve been carefully watching the growing evidence indicating that blueberries – or some of their constituents may have effects on animal cognition, brain aging and the normal neuroprotective mechanisms in the hippocampal region of the brain.

We do not yet have proof that these same effects occur in humans, and there are always three questions when we look at nutritional data:

  1. Can we extrapolate from the animal to humans? Mice are not men
  2. Are the amounts of blueberries or blueberry extracts even close to what humans could consume without spending all day eating, or getting a terribly upset intestine? There have been countless reports of the benefits of supplements that had to be taken in the most enormous doses to do any good. I’ve mentioned before the problem of L-arginine, which is sold as a “Natural Viagra.” Except that you need to take around nine grams for it to do much good, and most supplements contain less than a tenth of that. Regular readers will also remember my report concerning an article on coffee and sex. It was said that coffee would raise a woman’s libido. And indeed it does, if she drinks at least ten large cups of coffee at once. And coffee is a marvelous diuretic.
  3. When extracts are used, are we sure that we are getting the correct ingredient of the fruit? Many beneficial fruits contain just the right combination of nutrients to help us, so each can be taken in a small dosage or concentration. As with so much in integrated medicine, combinations are key. Take out one extract of a fruit, and you may lose the clinical effect that you wanted.

All that being said, the evidence is becoming progressively more interesting, and there is enough suggestive evidence for me to keep packing away the blueberries.

And just to show that I leave no stone unturned when checking the literature on your behalf, I rejoiced to learn that supplementing the diet of Arctic char with various supplements – including blueberries – improved the quality of his, ahem, semen. I do not know how this information will help any of us yet. Neither do I really know why a fish would want to eat blueberries or any of the other supplements that they were tried on. Though I’m sure that people have often asked similar off the wall questions about some of my research….

Sexual Health

One of the principles of integrated medicine is that anything that is really good for you should impact more than one system of the body. So for example omega-3 fatty acids will, in moderation, help your cardiovascular system, brain, mood and skin.

There is a good example of this in a study published this month in the Journal of Urology. The research was orchestrated by the Harvard University School of Public Health in Boston, and involved 22,086 American men followed over fourteen years. The findings confirm the importance of lifestyle choices to the risk of developing erectile impotence. Some of the same things that are bad for the heart also dramatically increase the risk of developing impotence. Men who were obese at the beginning of the study were 90 percent more likely to develop erectile dysfunction (ED) than were normal-weight men. Similarly, smokers had a 50 percent greater risk than non-smokers of developing ED. On the positive side, regular exercise appeared to protect against erectile problems. Men who reported the highest exercise levels at entry into the study’ were 30 percent less likely than their inactive peers to develop ED over the next 14 years.

The reason for these associations is primarily to do with blood flow. Anything that impedes blood flow increases the risk of ED, and anything that improves it will likely have a beneficial effect. We already know that people with diabetes mellitus and hypertension are far more likely to develop ED.

The message is very straightforward. If we ever needed any more evidence that smoking and obesity are bad for you, this is it. Stopping smoking, losing weight and taking regular exercise will all reduce your risk of developing ED. And if stopping smoking is a problem, not only do we have new medicines coming along, but I’ve also had some good results with homeopathy and the tapping therapies.

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