A New Approach to the Diagnosis and Treatment of Depression
Although textbooks and pharmaceutical company literature often claim that the biological component of depression has been clearly defined, the fact is that we still have no certain knowledge about the molecular and biochemical disturbances in depressive disorders. Furthermore, our theories of how antidepressants are constantly being revised, and it is now thought likely that these drugs have several mechanisms of action.
There is an interesting study from the University of Illinois at Chicago College of Medicine and Maryland Psychiatric Research Center in Baltimore in today’s issue of the Journal of Neuroscience.
They have discovered that a change in the location of a protein in the brain could serve as a biomarker for depression. This is exceptionally important, since it may give us a simple and rapid laboratory test to identify patients with depression and, more importantly, to predict clinical response to specific antidepressants.
Over the last few years this same team of researchers, and others around the globe, have been examining a protein named Gs alpha that activates adenylyl cyclase. Adenylyl cyclase is a link in signal transduction that is in part responsible for the action of neurotransmitters including serotonin. Instead of just looking at the biochemical properties of the protein, they have also been looking at the way that it moves in the cell membrane, which in turn impacts the way in which neurotransmitters act on cells.
In both rats and cultured brain cells, Gs alpha changes its location in response to antidepressants, moving out of lipid “rafts” in the cell membrane, to areas of the membrane that allow more efficient communication among membrane components responsible for the action of neurotransmitters. Both antidepressant and antipsychotic drugs have been shown to concentrate in these lipid rafts.
In this new study, brain samples from depressed people who had committed suicide were compared with controls who had no history of psychiatric disorders. Although the total amount of Gs alpha was the same in the depressed and non-depressed, in people with depression, Gs alpha was stuck in these lipid “rafts.” Therefore the protein is unable to do its job of mediating the action of neurotransmitters. Antidepressants have the opposite effect, moving it to regions of the membrane where it can do its work. The localization of other G proteins was not different.
This is such a robust finding, that identifying the location of Gs alpha in the cell membrane may provide an objective diagnosis of depression and second, whether someone is responding to the chosen antidepressant therapy.
The senior author in this research is Mark Rasenick, who is distinguished university professor of physiology and biophysics and psychiatry at the University of Illinois. He described the lipid “rafts” and the importance of the findings like this:
“These “rafts” are thick, viscous, almost gluey areas, that either facilitate or impede communication between membrane molecules… When Gs alpha is caught in these lipid raft domains, its ability to couple with and activate adenylyl cyclase is markedly reduced. Antidepressants help to move the Gs alpha out of these rafts and facilitate the action of certain neurotransmitters.”
He goes on to say,
“This test could serve to predict the efficacy of antidepressant therapy quickly, within four to five days, sparing patients the agony of waiting a month or more to find out if they are on the correct therapeutic regimen.”
The findings may also help explain two old puzzles:
- Why do antidepressants take so long to work?
- Why do such chemically different compounds produce similar clinical effects?
We are going to need a load of further studies to confirm and expand these findings, and to examine the clinical utility of the test. But it’s a great start.
Here Comes the Sun: To Screen or Not To Screen?
I have been worried to see some people – all, I think, without scientific training – proclaiming that there is no need to protect ourselves against the sun because there is no evidence that sulight causes any health problems.
Ultraviolet radiation (UVR) from the sun has been part of the environment since the first cells began to form. When we discuss the effects of UVR on human health and the environment, the range of UV wavelengths is often subdivided into:
- UVA (400–315 nm), also called Long Wave or “blacklight”
- UVB (315–280 nm), also called Medium Wave
- UVC (< 280 nm) also called Short Wave or “germicidal”
The key questions are these:
Can sunlight cause health problems?
Do the benefits of sunlight outweigh their risks?”
UVB is required for the conversion of 7-deoxycholesterol to vitamin D, (the sunshine vitamin!) which is critically important in the maintenance of healthy bones, although there may also be another mechanism by which vitamin D is generated in the body. As we have seen research is making clear that vitamin D has other potential roles in the maintenance of human health. Low levels of vitamin D have been linked to:
- Rickets
- Osteomalacia
- Osteoporosis
- Maintaining the integrity of cell membranes
- Type 2 diabetes mellitus
- Schizophrenia
- Multiple sclerosis
- Pre-eclampsia (hypertension and accompanying problems during the late stages of pregnancy)
- Some types of cancer
- Fibromyalgia-like pains
- Immune deficiency: Africa Americans do not generate enough of a protein needed to ward off tuberculosis. Why? Because the protein needs vitamin D to be activated, and dark skin is inefficient at absorbing and converting UVR. It may also be that we see epidemics of colds and flu in the winter because that is when we have low levels of vitamin D, which allows the viruses to overwhelm our immune defenses.
This does not necessarily mean that taking extra vitamin D will ward off all of these problems.
In the days before the Industrial Revolution, unless we lived in the frozen North, we had no trouble in getting the amount of vitamin D that we needed. In most of the United States, during the summer months, 10-15 minutes outdoors at midday will generate around 10,000 international units (IU’s) of vitamin D in an average fair-skinned person. This is far in excess of the government’s dietary recommendations of 200 IU’s/day in people up to age 50, 400 IU’s up to age 70 and 600 IU’s in people over 70. Not surprisingly many experts – me included – believe and have provided evidence that these daily requirements are much too low. (Have a look at the comments here.)
Of course many of us do not spend much time outside and don’t take in as much in the way of vitamin D containing foods – such as milk and salmon – as we should. I’ve seen evidence to suggest that we in Atlanta are probably at the Northernmost point in the United States were we could hope to get enough sunshine and therefore vitamin D from modest winter exposure to the sun.
Recent data has suggested that if you spend no time at all in the sun, then you may need as much as 4,000 IU’s of vitamin D/day, though that figure has not yet been widely accepted.
Exposure to UVR, whether of solar or artificial origin, also carries potential risks to human health. UVR is a known carcinogen and excessive exposure, at least to the solar radiation in sunlight, increases the risk of cancer of the lip, basal cell, and squamous cell carcinoma of the skin and melanoma, particularly in fair-skinned populations. There is also evidence that solar UVR increases risk of several diseases of the eye, including cortical cataract, some conjunctival neoplasms, and perhaps also melanoma of the eye.
We have good data for the existence of a threshold amount of UV-B exposure that may lead to the formation of cataracts. The amount needed to cause cataracts depends in part on the amount of pigment in the eye, so albino rats get cataracts with much lower exposures to UV-B.
So what to do?
Sunlight has a definite benefit in preventing or treating many clinical problems and it is no surprise that after 3000 millennia we are adapted to make use of the sun’s largesse. What is less easy to understand is why an excess of sunlight can cause so many problems, unless it is our hairlessness and environmental change that has lead to a loss of the ozone layer.
Some years ago it was suggested that sunscreens may themselves cause skin cancer, but the data has shown that to be false. Indeed modern sunscreens almost certainly reduce melanoma risk.
So how do we balance the positive and negative effects of sunlight? A recent review precisely reflects my own thinking:
- We need some sunlight
- Depending on where you live, you need only a few minutes each day
- Sunscreens confer protection on the skin without blocking all the health benefits
- If you have a medical reason for avoiding sunlight, then your health care provider should measure your vitamin D status.
Rethinking Cancer
Over the last thirty years, there has been a gradual change in the way in which we conceptualize biological processes. Although the lion’s share of research is still dedicated to biochemical processes involving DNA, RNA and the cell membrane, other important concepts are being quite widely accepted. They include:
- Fetal imprinting
- Epigenetic control
- Self-organization
- Self-regulation
- Coherence over time
- Information exchange with the environment
- Symbiosis
- Morphogenesis
One way of thinking about this is to describe cells, organs and bodies as coherent information-rich processes. And when things go wrong, it is because these processes have gone awry. Information medicine is designed to bring the system back into coherence and harmony.
I have spoken before Integrated Medicine and in the next posting I am going to talk more about the difference between Integrated, integrative and integral medicine. But at this point suffice to say that Integrated Medicine is information medicine based on an understanding of these principles.
Several years ago I presented a paper at a closed meeting where I introduced the term “adult dysmorphogenesis,” to describe the way in which some disease processes – such as arteriosclerosis, arthritis and Alzheimer’s disease – could be better understood not as degenerative conditions, but as deranged information systems. These in turn disrupted the normal self-organizing principles of the body that lead it to constantly correct and repair itself. Part of my reasoning was that we were constantly seeing apparently irreversible conditions like broken down joints being repaired by information medicines like acupuncture and homeopathy.
With that background I was very interested to read an important paper in the journal Theoretical Biology and Medical Modelling.
The paper begins by highlighting three odd observations:
- Throughout the animal kingdom cancer hardly ever occurs in tissues that have a strong ability to regenerate
- In animals in which cancer occurs frequently, its incidence rises with age. If it occurs in a young animal it usually occurs in a tissue that has already been damaged
- In animals that have a strong ability to regenerate and repair organs, these mechanisms remain fairly efficient throughout life. In animals with weak regenerative and repair mechanisms, they tend to become less efficient with age.
The authors propose that when an organ is damaged it receives a signal to start undertaking repairs. The cancer cell is the one cell in an organ that is able to respond to the signal telling it to start to proliferate. It is the one cell that is trying to restore function. So simply removing a cancer might not work if the organ remains damaged: new tumor cells would simply keep emerging.
This paper is a good complement to another in the same journal. This one is a bit more mathematical, but also views cancer as a dynamic systems problem.
Ideas like this have come and gone before, but I have not seen them so well presented before, and they open up some new ways of thinking about a set of problems that is altogether too common.
Moving away from thinking that cancers are all simply the result of mutated or messed up DNA toward the idea that they may owe just as much to the environment in which they grow makes very good sense.
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.
Violence and Nutrition
There is a small but impressive body of evidence about the impact of nutrition on violence. It started with some simple observations concerning nutrient content and behavior in animals. In 1942 the wartime British government was persuaded to supplement the diet of all children with cod-liver oil and orange juice. It was speculated that among other ills, poor diets could lead to antisocial behavior. You humble reporter was still required to take this foul-tasting concoction when he was a child in England very many years after the War.
Over the years evidence has grown to support this link between nutrition and antisocial behavior and a longstanding debate developed about the possible role of nutrition and food additives on the ever-increasing rates of violence in society as a whole. Regular readers may remember the publication several months ago of a report entitled Feeding Minds that implicated nutritional changes in the burgeoning rates of mental illness in the United Kingdom.
Part of the problem with much of the work on nutrition and violence has been that there were vested interested involved. Some people have been trying to prove that all the world’s ills are the result of food additives and others have been trying just as hard to prove that their products are safe. The other problem has been the simplistic notion that it is possible to reduce human behavior to a single nutrient.
Humans are complex creatures. Coffee may make you irritable. If you happen to be a small coffee-drinking furry rodent, you may not be you may not have much choice in the matter. But one of the points about developing frontal lobes is that you should have the ability to override the coffee: you can choose whether or not you want to be irritable. A teenager may not be able to do that: he or she does not yet have fully formed frontal lobes. Alcohol can be such a big problem because not only does the alcohol stimulate some of the emotional regions of the brain but it also suppresses the frontal lobes. Whatever you may have done while under the influence probably seemed like a really good idea at the time!
There have now been a couple of very interesting studies that do suggest that nutritional supplementation may have a significant impact on violent behavior in prisoners.
The first modern experiment was reported in the British Journal of Psychiatry in 2002. 231 young adult prisoners were enrolled in a double blind, placebo-controlled, randomized trial of nutritional supplements comparing disciplinary offences before and during supplementation. The prisoners were given a capsule of “Forceval” as well as a combination of essential fatty acids (A daily dosage of four capsules providing 1260 mg linoleic acid, 160 mg gamma linolenic acid, 80 mg eicosapentaenoic acid and 44 mg docosahexaenoic acid). Those receiving the supplements committed an average of 26.3% fewer offences, which improved yet further with longer supplementation. The conclusion of the study was that, “Antisocial behavior in prisons, including violence, are reduced by vitamins, minerals and essential fatty acids with similar implications for those eating poor diets in the community.”
The British Guardian newspaper recently ran a well-balanced article about some of these research initiatives.
This research is being replicated at various sites because if it is true it has enormous implications for personal well-being and for the whole concept of legal responsibility.
Could it be that some of society’s ills are the result of a failed uncontrolled experiment in force-feeding the population?
Attention Deficit Disorder, Allergies and Membranes
There has been a long-running debate about the relationship – if any – between allergies and attention deficit disorder (ADD).
As long ago as 1991 a paper seemed to indicate that there were higher rates of hyperactivity in the parents of children with allergies as well as increased rates of allergies in children with ADD. Recently a study from New York seemed to show higher rates of allergic rhinitis in children with ADD. The problem with all this is that we are looking at two common problems and trying to sort out a genuine connection can be tricky.
I started thinking about this problem again, after a recent report that some children had symptoms of hyperactivity, inattention, attention-deficit/hyperactivity disorder, and excessive daytime sleepiness as a result of sleep-disordered breathing. But what was remarkable was the number who improved after they had their tonsils taken out. The tonsils are one of the first lines of defense in the immune system, which is why they so often become enlarged with infections, or for that matter in any kind of immunological reaction. Now I’m not much of one to take out tonsils unless there’s a really good reason, but it is certainly an important observation for anyone who has a child with behavioral or cognitive difficulties: he or she may not be sleeping properly.
I have seen quite a number of people who had physical and psychological problems, including headaches, depression and attentional problems, who turned out to have either allergies or environmental sensitivities, and when those were addressed, the symptoms resolved. I have also seen some people who followed the notoriously difficult Feingold diet with some success, even though the research doesn’t seem to be very supportive of elimination diets. And I’ve seen just as many people who got no relief at all from elimination diets.
I have just done a detailed literature review on the topics of allergy and attention, and I don’t think that we have enough evidence to suggest that everybody with attention deficit needs to see an allergist. But what this highlights is that not all people with attentional problems or hyperactivity have ADD. They may have attentional problems because of sleep disturbance, depression, anxiety, obsessive compulsive disorder and a range of other problems.
There is some exciting research indicating that one of the problems in many cases of ADD is a disturbance in the normal functioning of cell membranes. If that is correct, it may be that there are disturbances in the membranes of both neurons in the brain and membranes of cells in the immune system. That link is not entirely proven. But it has received further credence by the finding that some children and adults with ADD seem to show improvements of both attention and immune function when they take omega-3 fatty acids. I have recently been hearing some encouraging reports from people who have used the Omega-3 Formula made by Omegabrite (And no, I have no link with the company!)
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