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.
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?
Further studies to confirm and expand these findings, and to examine the clinical utility of the test.
Placebos can be powerful things, whether they come wrapped in a nicely colored box, or take the form of an enthusiastic clinician.
Dan Ariely, a behavioral economist at Duke University, and author of the excellent new book Predictably Irrational has written a letter in this week’s issue of the Journal of the American Medical Association in which he suggests that pill costing ten cents is not as effective at preventing pain as a $2.50 pill, even when they are identical placebos.
Ariely and a team of collaborators at the Massachusetts Institute of Technology recruited 82 people to participate in a study in which light electric shocks were administered to participants’ wrists to measure their subjective rating of pain. The 82 study subjects were tested before getting the placebo and after. Half the participants were given a brochure describing the pill as a newly approved painkiller that cost $2.50 per dose. The other half was given a brochure describing it as marked down to 10 cents, without saying why.
In the full-price group, 85 percent of subjects experienced a reduction in pain after taking the placebo.
In the low-price group, 61 percent said the pain was less.
Although simple and small, the experiment raises some large questions.
As Dr. Ariely says,
“Physicians want to think it’s the medicine and not their enthusiasm about a particular drug that makes a drug more therapeutically effective, but now we really have to worry about the nuances of interaction between patients and physicians.”
The results are consistent with previous data about how people perceive quality and how they anticipate therapeutic effects. What is interesting here is the combination of the price-sensitive consumer expectation with the placebo effect of being told that a pill works.
Would it help if prescription medications offer cues from packaging, rather than coming in indistinguishable brown bottles?
Is there a way of giving people cheaper or generic medications without them thinking they will not work?
As Dr Ariely says,
“At the very least, doctors should be able to use their enthusiasm for a medication as part of the therapy. They have a huge potential to use these quality cues to be more effective.”
Wise words!
“It requires a great deal of faith for a man to be cured by his own placebos.”
–John L. McClenahan (American Physician and Writer, 1935-)
“Your thoughts are like the seeds you plant in your garden. Your beliefs are like the soil in which you plant these seeds.”
–Louise Hay (American Spiritual Teacher, 1927-)
“Change your beliefs and you change your destiny.”
–Sterling Welling Sill (Elder of the Church of Jesus Christ of Latter Day Saints, 1903-1994)
Diabetes mellitus can be a devastating illness, especially when it comes on suddenly in a child or adolescent. In young people it is usually so-called Type 1, or insulin-dependent diabetes, an autoimmune disease in which the immune system attacks the insulin-producing beta cells in the pancreas. The disease can have a major impact on the whole family, and sometimes people forget the way in which it can affect siblings whose needs often need to be subordinated to the needs of the newly diagnosed young person.
And here is an important point: even when it appears suddenly, the disease process may have been going on for some time before the clinical symptoms appear. By the time that blood glucose levels begin to rise, it usually implies that the damage to the insulin-producing cells in the pancreas has reached a critical point, and the chance of recovery is low. Anything that we can do to prevent the disease from progressing to the point of producing symptoms would be immensely helpful, and that starts with early recognition before the pancreatic damage has reached critical.
Although we now understand a great deal about the interplay of genetic, environmental and immunological factors that may lead to the illness, this knowledge has so far not helped us very much. There has been a tremendous need to try and identify the early stages of the disease, but that goal has been elusive.
In healthy people monocytes remain quiescent unless they are activated by an infection or other stressor. Then the NF-kappa B pathway gets activated.
In people with Type 1 diabetes things work the other way round: monocyte NF-kappa B was already activated in the blood, and when exposed to infection the pathway shut down. This tells us that there is a problem of immune control that may cause diabetes to develop in children. It is this monocyte abnormality that will hopefully form the basis of a diagnostic test.
This work is assuming more urgency since there are several trials of diabetes vaccines underway, and if successful, it may become possible to identify and intervene in children at risk of Type 1 diabetes before it occurs.
In addition, understanding why the immune system loses control before the disease starts should open up a number of new options for prevention and treatment.
I have talked at some length about the possible link between toxoplasmosis and some forms of mental illness, but there is also another side to toxoplasmosis: the Toxoplasma gondii parasite infects nearly one-third of all humans: more than two billion people worldwide. In the United States alone, congenital toxoplasmosis occurs in an estimated 1 per 5,000 births a year and can cause severe vision loss, brain damage and even death. The human cost is incalculable, and in dollars and cents, it has been estimated that the annual cost of caring for these children may exceed $1 billion.
Toxoplasma gondii is carried by some cats and it is said that an infected cat can excrete up to 20 million oocysts over a period of two weeks, and every single oocyst is infectious. They are tenacious and can remain infectious in water for up to six months and in warm moist soil for a year of more.
Toxoplasma infects humans through three main routes:
Consumption of undercooked, infected meat
Ingestion of T. gondii oocysts in food, through accidental contamination from cat litter
Finally, a newly infected pregnant woman may pass the infection to her fetus, hence the warning that pregnant women should not clean the cat box
Not only is toxoplasmosis the most common parasitic infection in the world, but also it can cause particular problems in people with compromised immune systems, for instance people with cancer, autoimmune disease, AIDS or transplant recipients.
It is even possible for people with normal immune systems to suffer major organ damage from chronic infections. Eye disease leading to loss of sight can be caused both a primary infection and as a result of infection transmitted from mother to child. Damage to other organs has recently caused deaths among otherwise healthy young people during epidemics in Surinam and French Guiana.
The parasites that cause malaria are related to Toxoplasma gondii, and a new drug that will soon enter clinical trials for the treatment of malaria also appears to be 10 times more effective than the current gold-standard treatment of toxoplasmosis, a combination of the drugs pyrimethamine and sulfadiazine.
The drug works inhibiting the action of the from of the enzyme dihydrofolate reductase (DHFR) that is produced by the family of parasites that includes those that cause toxoplasmosis and malaria, and in cell culture studies, the drug appears actually to kill the parasite, rather than simply preventing its replication. This is very important: not only do most of the current medications have a good many side effects, they have little effect on Toxoplasma during certain phases of its life cycle. It can hunker down in the quiescent cystic phase and wait until the antibiotics are gone.
Rima McLeod, professor of ophthalmology and specialist in infectious diseases at the University of Chicago said,
“JPC-2056 has the potential to replace the standard treatment of pyrimethamine and sulfadiazine. Taken by mouth, is easily absorbed, bioavailable, and relatively nontoxic. In tissue culture and in mice, it was rapidly effective, markedly reducing numbers of parasites within just a few days.”
JPC-2056 is not a new drug. It was developed in the late 1980s by teams led by Wilbur Milhous and Dennis Kyle of the Walter Reed Army Institute for Research and David Jacobus of Jacobus Pharmaceutical Company. The original version was quite toxic, but the researchers found ways to reduce the toxicity and developed an oral version of the drug. Clinical trials using JPC-2056 to treat malaria are scheduled to begin later this year.
As you will see from my review, I just love the book, and it is amazing how Jeff’s work and mine fit together.
We are going to be having a panel discussion about the book on www.Business.VoiceAmerica.com on Thursday March 6th at 3PM Eastern, which is noon Pacific time. The discussion is also going to be archived for people in other time zones. I plan to put up a link as soon as it is available.
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