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.
Pramipexole
Pramipexole is a remarkably interesting medicine about which you are likely to hear a lot in the near future. It is an agonist, which means that it has a positive effect, on D2 dopamine receptors and also on a little-known group of dopamine receptors, known as the D3 group. If you want to get really clever the dopamine receptor D3 group is abbreviated to DRD3. Pramipexole has been in use for almost a decade in the treatment of Parkinson’s disease, and approximately 9.1 million prescriptions for pramipexole have been written in the U.S. since its launch in 1997. It is not without its problems. In Parkinson’s disease it may cause dizziness, involuntary movement, hallucinations, headache, difficulty falling asleep, sleepiness, and nausea. Some people have also had behavioral dyscontrol while taking it.
At a meeting in Athens in February of 2006, we saw confirmation of something that had been shown in previous research: pramipexole seems to be a very effective treatment for restless legs syndrome (RLS). A study published in the journal Neurology has given us a more detailed understanding of the risks and benefits of pramipexole.
The investigators report a 12-week, multicenter, double-blind, randomized, placebo-controlled study of fixed daily doses of pramipexole (0.25 mg, 0.50 mg, and 0.75 mg) involving 344 patients with moderate to severe RLS. Data from 339 patients were analyzed to evaluate the effect of pramipexole treatment on efficacy and safety. The mean age of patients was 51.4 years and the mean duration of RLS symptoms was 5.1 years. The results were very promising, even though half of the patients on placebo also showed an improvement. The most commonly reported side effect included nausea (19.0%), headache (17.8%), insomnia (10.5%) and somnolence (10.1%).
In Europe pramipexole it has been approved for use in this indication. It is marketed as Sifrol® / Mirapexin® In the United States we currently only have one approved medical treatment for RLS, and that is the GlaxoSmithKline medicine ropinirole (Requip), that works at the same D3 receptors in the brain and spinal cord. Ropinirole is effective in a proportion of people with RLS, but it has also been linked to sleepiness, drops in blood pressure and fainting, so those are included in its label.
RLS may be associated with some other illnesses so I was very interested to see two reports of the use of pramipexole in bipolar depression as well as a report of its possible use in REM Behavior Sleep Disorder.
One of the most exciting potential uses for pramipexole may be in some people with fibromyalgia. I’ve mentioned that fibromyalgia, bipolar disorder and some other psychiatric illnesses may be connected. The idea that we might be able to use just one medicine to support our Integrated Medicine approach is very attractive, and also helps point us toward a deeper understanding of what exactly goes wrong at the physical level in RLS, depression and fibromyalgia.
I’ll keep you posted.
Psychiatric Illnesses and Fibromyalgia
There’s an interesting and important article in last month’s issue of the Journal of Clinical Psychiatry, by a group of investigators from the University of Cincinnati.
They have shed important new light on fibromyalgia. We’ve recently learned how it is linked to disturbances of the serotonin transporter, as well as anti-inflammatory proteins, and that is may respond best to the kind of comprehensive multi-leveled approaches that we use in Integrated Medicine.
The new research compared people with fibromyalgia with people with rheumatoid arthritis, and it found that fibromyalgia, but not rheumatoid, may be associated with a range of psychiatric illnesses:
- Major depressive disorder
- Bipolar disorder
- Comorbid anxiety disorders including panic disorder, social phobia, posttraumatic stress disorder and obsessive-compulsive disorder
- Eating disorders and
- Substance abuse
What was particularly important in this study was that the psychiatric problems usually preceded the onset of fibromyalgia. So it wasn’t that people were developing psychological problems because they were in chronic pain.
It’s beginning to look as if fibromyalgia is part of a larger group of disorders that all share common etiologies or causes. Family studies have indicated that fibromyalgia and mood disorders share some of the same – perhaps genetic – determinants.
The study also confirms what we have said before: fibromyalgia is not only associated with some psychiatric problems, but also with other medical disorders, several of which may also co-exist with the same psychiatric problems. They include:
- Chronic fatigue syndrome
- Irritable bowel syndrome
- Interstitial cystitis
- Multiple chemical sensitivities and
- Migraine
Not only does this research highlight the need to check people with fibromyalgia to see if they might also be struggling with a psychiatric problem, but it is helping us home in on some of the mechanisms linking these apparently separate problems.
This particular study was done mainly in white women, and the investigators knew who had fibromyalgia, so there’s more work to be done.
But if you or a loved one is struggling with fibromyalgia, it is good news to know that we are making rapid progress in unraveling this horrible illness.
The Epigenetic Code
In Healing, Meaning and Purpose I reveal some of the extraordinary changes that are occurring in our understanding of genetics and inheritance. Even if you are currently learning genetics in college, it is quite likely that some of what your professors are teaching may already be out of date. I say that with the greatest possible respect: I find that in some of my fields of expertise, I am often having to update my teaching materials every week.
One of the remarkable discoveries that is generating huge amounts of new information is what we call epigenetics. This is the study of a form of inheritance that can occur without fundamental changes in gene sequences. This has to do with the idea that there is a second layer of programming on top of our DNA. A code that can change over our lifetimes in response to environmental change. Diet, hormones, chemicals in the environment, stress and even thought, emotion and behavior, can all change the ways in which our genes are expressed. Some of these epigenetic changes can be passed on to other generations. In other words, there can be an inheritance of acquired characteristics. Something that has been denied for over a century.
Let me give you a simple example. Studies of a particular species of mouse have shown that maternal diet has an effect on the coat color of the offspring. This was the result of what is known as methylation that altered gene expression. These changes in coat color were carried on to the next generation: the grandchildren of the mouse given the special diet. This created quite a stir, because it had been thought that epigenetic changes in cells are erased each time that a cell divides. Obviously that was not happening. We now have many examples of epigenetic changes being passed on to the next generation and the next. There are literally hundreds of scientific papers on the subject.
As I have written before in my last book and CDs, in articles and in reviews at Amazon and elsewhere, the traditional view of genetics has been one of genetic determinism. That we are all little robots whose entire lives are dedicated to nothing more than passing our DNA from one generation to the next. And the genes even dictated how we did that. I still know many gene jockeys who are convinced that the whole of human behavior will ultimately be explained by our genes, and that free will is therefore a myth.
I’m just as sure that they are wrong.
Let me give you an example. Identical twins have identical DNA, yet we have known for fifty years that one twin may get a genetic illness that the other does not. And the brains of identical twins, though they start out identical, quickly become quite different from each other because of the impact of the environment. Twin studies of mental illness have been going on at the Institute of Psychiatry in London since 1960. Every patient coming to the hospital is asked by the clerical staff if he or she is a twin. And there has been groundbreaking research on mentally ill twins at the National Institute of Mental Health for decades. And what have we learned? Though there may be a genetic component in schizophrenia, when we look at people with schizophrenia who have identical twins, only half of the twins have the illness, despite having the same DNA. The key difference is at the epigenetic level.
Marcus Pembrey from the Clinical and Molecular Genetics Unit at the Institute of Child Health, part of University College, London, has been at the forefront of the work on epigenetics. Marcus has had the opportunity to study the unusually detailed historical medical records of the isolated northern Swedish city of Overkalix. He and his colleagues found something astonishing. The grandsons of men who experienced famine during mid-childhood went through puberty earlier and had longer life spans, while the grandsons of men who were well fed in early childhood had an increased likelihood of diabetes. For females, the effect was similar but it was tied to the grandmother, rather than the grandfather. Presumably these responses are designed to adjust our early growth and reproduction to be ready for unpredictable changes adverse events in the environment. I would call this epigenetic resilience.
In a separate study done in Bristol in England, Marcus studied two generations of families, and found that fathers who had started smoking before age 11 had sons who were significantly heavier than average. There was no similar effect on daughters.
There is already some evidence that epigenetic factors may play a role in the development of bipolar disorder and schizophrenia. Many of us are becoming excited about the potential benefit that may flow from a better understanding of genetic and epigenetic mechanisms in major psychiatric disorders.
There is a new journal called, appropriately, Epigenetics that contains a treasure trove of important information. The editor is Moshe Szyf, form McGill University in Canada, and he recently pointed out that one single gene could have as many as 700 epigenetic programs associated with it.
His own research has linked epigenetic change to social interactions: the way in which we behave toward one another can lead to a change in how our genes operate.
Rats whose mothers groom and lick them when they are young grow up to be much calmer than rats whose mothers neglected them. There is, of course, nothing surprising about that. We all understand the importance of good child rearing. But what was surprising was the finding that epigenetic changes are the cause. By nurturing their young, the rat mothers activated a gene that suppressed the creation of cortisol, one of the stress hormones.
Pups who were neglected did not have that gene activated, so they produced more cortisol and were therefore more stressed out.
Knowing this, the researchers were able to increase the well-nurtured rats’ stress by injecting them with methionine, an amino acid commonly found in food supplements.
Here we have proof that the link between food and mood is not just due to transient chemical changes in the neurotransmitters of the brain, but that a chemical in our diet could cause fundamental changes in the way in which our genes work. In this case a rat’s emotions and state of mind. The implications for all of us are extraordinary.
Since 2003, a consortium of public and private firms in Europe has been working on the first Human Epigenome Project (HEP), and it hopes to have completed 10% of the map by the end of this year. As you can see, it is a lot more complicated than mapping the human genome, and epigenetic codes are constantly moving targets. The first reports from HEP have indicated that at least 20% of the genes studied so far can have their behavior modified by the environment. The food that we eat, the chemicals that we ingest and the attitude of our parents and peers can all change the way in which our genes function.
As Marcus Pembrey has said, “Child care has a whole new meaning.”
This is all crucially important, because one of our most important discoveries has been that human beings have been undergoing extremely rapid physical as well as psychological and social change, and that is one of the reasons why the Laws of Healing have been changing over the last century.
Irritable Bowel Syndrome, Mood Disorders, the Serotonin Transporter and Integrated Medicine
Whenever we run into two common conditions, it’s easy to imagine links where none really exists. Three years ago some colleagues from Oxford reported on a person with bipolar disorder and irritable bowel syndrome, and commented that the association was uncommon.
However there may after all be a genuine link between mood disorders and irritable bowel syndrome, that is a disturbance in the “third arm” of the autonomic nervous system. The first arm is the sympathetic nervous system, the second the parasympathetic and the third is the enteric or gut nervous system that is closely linked with key regions of the brain.
Not long ago there was an interesting report of a woman who had multiple problems including environmental allergies, atypical bipolar disorder, irritable bowel syndrome and Raynaud’s phenomenon. Such odd constellations of problems are quite familiar to anyone working in the major referral centers around the world, and some can be exceedingly hard to treat. Tough cases like this often stimulate further research. I once tried and failed to treat a woman with a chronic illness. When she came back a year later to see if I had any new ideas, I told her that I now had a shelf of books and over a thousand reprint of papers about her condition: I don’t like failing someone. And I’m not unique in that.
A new study from the Karolinska Institute in Stockholm, has found that chronic widespread pain, which, as I explained recently, is the cardinal symptom of fibromyalgia, is prevalent and co-occurs with other symptom-based conditions such as chronic fatigue syndrome, joint pain, headache, irritable bowel syndrome, and psychiatric disorders.
There is more and more evidence of a link between fibromyalgia, irritable bowel syndrome and depression. It is not just that people are sick and get depressed: as we shall see in a moment, the link is more subtle than that. Another illness seemingly linked to these three is interstitial cystitis.
Now some colleagues at the National Institutes of Health have been looking at a serotonin transporter (SERT) that regulates the entire serotoninergic system and its receptors. This transporter is found throughout the animal kingdom, telling us that it must be important.
In humans the gene is located on chromosome 17, and disturbances in it have been found in people with autism, ADHD, Tourette’s syndrome and bipolar disorder. Experiments using genetic engineering suggest that SERT may be a candidate gene for several human disorders, from obesity to irritable bowel syndrome. People who have disturbances in SERT tend not to respond so well to the serotonin reuptake inhibitors (SSRI’s) antidepressant medicines.
SERT is not the whole story. Some geneticists from Los Angeles have found evidence linking irritable bowel syndrome, depression, migraine and inheritance of mitochondrial DNA.
Many approaches have been tried to help people with these groups of problems. I always find it remarkable that psychological treatments can be so effective in conditions with a genetic component, for this once again proves that biology is not destiny.
The best approaches to conditions like irritable bowel syndrome and coexisting mood disorders is to use medications and psychological approaches. Many of us have also found that the addition of nutritional, environmental and subtle energetic approaches have been of great help, together with some work to uncover the meaning and transpersonal value of a chronic illness. That last piece is not the first priority, which is to help the person gain control of his or her life. But if we don’t do something to work with the meaning and purpose of an illness, it will usually come back in some form or other. This comprehensive approach differentiates Integrated Medicine from many other types of therapy.
Toxoplasmosis, Behavior and Mental Illness
This title may seem odd, but this item may actually turn out to have enormous implications for all of us.
A couple of years ago I read a fascinating book: Parasites and the Behavior of Animals, in which the author – Janice Moore from Colorado State University – cataloged some of the extraordinary ways in which parasites can impact the behaviors of a vast array of animals. As difficult as it is to interpret studies of parasites in humans, I kept coming back to some odd observations about an illness with which I’ve been involved for more than 30 years: schizophrenia. I kept wondering if some of the odd observations made over the years could be explained by the parasites?
What kind of odd observations?
- Reports of mental illness have been found throughout history, yet this strange illness that we now call schizophrenia seems to have been very rare until about 1750, when it increased dramatically throughout Western Europe. I have had the privilege of working at the Bethlem Royal Hospital from which got the word “bedlam.” I know of the incredible records kept there. Something began to change in some of the types of patients being admitted at that time. I have also had the opportunity to look at some of the records at the Philip’s Hospital in Southern Germany, which has been in existence since 1533. Again the records show the sudden appearance of many cases of something that had been quite rare until then. 1750 marked the early years of the industrial revolution in Europe and the mass migration of people from the countryside to the new and very crowded cities
- There has been recent evidence that being born and raised in a city increases your chance of developing schizophrenia.
- There is increasing evidence that acute episodes of psychosis, mania and depression are associated with increases in circulating inflammatory mediators. There is also intriguing new data that both psychosis and depression can be improved by giving people COX2 inhibitors.
- There has also been the strange observation that bipolar disorder may have been becoming more common in recent years, over and above our greater ability to recognize the illness.
Several years ago the well-known psychiatrist E. Fuller Torrey first suggested that a small protozoal parasite called Toxoplasma gondii might be responsible for all of these observations. Cats can carry it, which is why pregnant mothers are advised not to pet their cats during pregnancy.
The idea that such a complex disease as schizophrenia might sometimes be caused by a parasite caught the media’s attention, but in recent years the story – but not the ongoing research – died down a bit.
There was an excellent and provocative blog item by Carl Zimmer about this almost three weeks ago, but I wanted to check everything out before responding. He gave a brief review of a new paper published in the Proceedings of the Royal Society, by Kevin Lafferty from the University of California in Santa Barbara. Lafferty has attempted to correlate the varying rates of Toxoplasma in different countries with predominant personality traits and therefore – since our societies are aggregates of all our personalities, cultural characteristics.
That may all sound far-fetched, but I don’t think that it is. And I don’t think that the Proceedings would have taken a completely half-baked proposition.
I have also found a report published in the journal the Proceedings of the Biological Society. Four eminent authors, including Torrey, revisited the while issue of Toxoplasmosis and mental illness. When the parasite gets into the nervous system it can alter behavior: Rats are normally programmed to avoid cats, but once infected they are attracted to cats. Over the last few days I’ve been plowing the world literature, and I’ve learned some very interesting things that support the idea that Toxoplasma may be playing a role in several different types of psychiatric illness.
There is strong evidence that schizophrenia, bipolar disorder and major depressive disorder lie on a spectrum. The illnesses are not the same, but people often switch from one type of clinical presentation to another. The precise type if illness would be determined by the interaction of genes, physical and Intrapsychic environment. Nobody would be sufficiently naïve to try and reduce the whole of psychiatric illness to a single bug. Mental illness is a great deal more than just a physical problem, and apart from anything else, the rates of Toxoplasma infections show remarkable variations around the globe, while the rates of major mental illness are much the same everywhere.
So what have I learned?
- There are a remarkable numbers of studies showing that many people with schizophrenia have antibodies to Toxoplasma, including people having their first attack of the illness
- Blood donors infected with Toxoplasma have decreased levels of novelty-seeking
- In women who become infected, there are some marked changes in personality.
- Toxoplasma affects the dopamine systems of the brain that we know are intimately involved in mood, cognition, movement and motivation.
- Some drugs used to treat psychosis (haloperidol) and mood disorder (valproic acid) inhibit the replication of Toxoplasma gondii. The valproic acid already does it at concentrations lower than we normally aim for when treating humans.
- There is some intriguing work going on into the use of antibiotics to kill Toxoplasma and reverse its behavioral effects.
In the last few years, so many illnesses have turned out to have infectious origins, from peptic ulcers to arteriosclerosis and some cancers. Perhaps some mental illnesses will be next.
Last year Barry Marshall and Robin Warren were awarded the Nobel Prize in Physiology or Medicine for their pioneering work on Helicobacter. I have a strong sense that there are more prizes to come on the interaction between infectious agents, inflammation, genes, the psyche and the environment.
Perhaps the reason that some antipsychotics and mood stablizers can reverse some of the neurological damage associated with schizophrenia and bipolar disorder is becuase they are killing off the causative agents and allowing the brain to repair itself.
I shall keep you posted!
Gall Bladder Disease and Insulin Resistance
When I was a young student, everyone learned that gallstones were more common in people who were “Fat, female, fair and forty.” As you can see we lived in different times and nobody would say anything quite like that today. Not least because it’s now only partially correct. Gallstones are occurring at ever-earlier ages, because they are a recognized complication of obesity. And we all know that we are in the midst of a pandemic of overweight and obesity.
We have also been remarking on the number of people with bipolar disorder who have a history of gallstones.
For many years now, the explanation for the link has been to do with an increasing levels of cholesterol, which are a major precipitant of gallstones. There’s also evidence that high carbohydrate diets increase the risk of gallstones. Weight loss reduced the risk of developing them, though suddenly losing a lot of weight with an unbalanced diet may increase the risk of gallstones.
Now a paper from colleagues at three medical schools has just been published this month, and it helps clarify the connection. The conclusion of the scientists is important: insulin resistance itself seems to cause problems with the normal emptying of the gallbladder, and that would predispose people to the development of gallstones.
Insulin resistance is a feature of increasing weight. Several studies that have found increased rates of insulin resistance in people with bipolar disorder implying an increased risk of gallstones. Though gallbladder disease didn’t show up in a recent study from some friends in Toronto, I could not find any systematic studies of gallstones and bipolar disorder. And it is a study that needs to be done.
So there’s a tip for a researcher who can’t think of a project!
There's More to Weight Than Meets the Eye
There’s an interesting article about the associations between obesity and mental illness.
We’ve all become so used to people telling us about the physical consequences of carrying extra weight, so it is interesting to learn that obesity may also be associated with higher rates of mental illness.
We have here a typical chicken and egg problem.
Do people become depressed because they are overweight, or does depression and its treatments cause obesity?
The answer is probably "Yes." It is both.
Depression may cause insulin resistance and hypercortisolemia, which may result in weight gain. But insulin resistance alters the kinetics of some of the amino acids that are the building blocks of key neurotransmitters in the brain.
And this study re-emphasizes the importance of treating the physical, psychological, social, subtle and spiritual aspects of a problem simultaneously.
If we address only one of these dimensions, people will continue to suffer needlessly.
When our clinicians see overweight people with depression or bipolar disorder, they start by treating the mood disorder, but then immediately get to work on the weight problem. And all of it is part of the five vector, or five dimensional approach to treatment: physical, psychological, social, subtle and spiritual.
If we fail to respect and work with every aspect of a person, each problem will return to make us respond appropriately.
After all, illnesses are like any other problem: sent to educate us. Not just you, but also the person to whom you went for help.
