TREATMENT FOR DEPRESSION
MORE ON MEDICATIONS THAT AFFECT THE NERVOUS SYSTEM

Following up on the previous posting, I would like to mention a fine article on antidepressants, “In Defense of Antidepressants”, that appeared in the New York Times last Sunday. Here is the link: http://www.nytimes.com/2011/07/10/opinion/sunday/10antidepressants.html
This is a good and thoughtful article and a needed antidote to the scare stories that have been written in the popular press. Depression is truly a disease rooted in the neurobiology of the brain. Though it is not totally understood, a lot is known about it. Modern treatment for depression is a great medical success story. The two best recent advances are 1) anti-depressants and 2) electro-convulsive therapy (ECT).

“Talking therapies” can also have an important role. But by “talking therapies” I mean mainly cognitive behavioral therapy and what is now often called “interpersonal therapy,” not the traditional psychoanalytic psychotherapy. Experts debate what these therapies entail. I would say that cognitive behavioral therapy is therapy based on learning theories. It takes the stance that a lot of mental illness is due to maladaptive learning, not just of facts but of patterns of behavioral as well as learned attitudes, feelings, and ways of reacting to life. The therapist attempts to re-educate the patient. Interpersonal therapy focuses on how a patient relates and interacts with others. But it also can include how the patient reacts to situations and events. In some ways it resembles the old-time psychoanalytic therapy but it is much shorter and it does not attempt to dredge up a lot of material from the so-called “unconscious.” It does not get really “deep” in that sense. Though it has never been really proven, I think that long term psychoanalytic therapy can offer a lot to the depressed patient. But it rarely offers a rapid return to better functioning. It can be very expensive. Insurance rarely covers many sessions and many psychoanalysts do not even take insurance. So if you want to see your Freudian oriented psychoanalyst three times a week you may be find yourself paying, say, $750 per week indefinitely. That would make me even more depressed. But if you could do it, in addition to the more modern briefer therapies, this could give you valuable insights and in a long term sense I think it includes both cognitive behavioral and interpersonal therapy. It would not surprise me if psychoanalytic therapy helped a person maintain a remission from depression even if it was not what was used to treat the acute depression. Due to the cost, perhaps the only way to obtain this is to see a psychiatrist who has a good psychoanalytic background. Such people will often integrate some psychoanalytic insights into a combined cognitive behavioral, interpersonal and pharmacological approach.

I just took a Harvard Medical School review course in depression treatment. The Harvard imprimatur does not mean that everything I learned is correct, but I think it was essentially correct and up to date. I cannot give you the course here, but let me summarize some points

1) Mild depression: Two options a) talking therapy alone for 2 to 6 weeks. If that does not help, add antidepressants

2) Moderately severe to severe: Medication required. Talking therapy as an adjunct may help but may not add much in the short term.

3) Severe depression that does not respond to medication and talking therapy for 4 weeks or more. ECT is strongly recommended if the patient is in good enough shape to take it.

There are all sorts of nuances and twists and turns in the actual treatments. The above is just a thumbnail sketch that in no way should guide your own treatment. But it serves to lay out the basic outline of a modern, well accepted standard of care. Those who trash the medication and ECT simply do not know what they are talking about.

Previously I recommended a few sources of information about medications. My top pick was, perhaps surprisingly, the Consumer Reports Health, http://www.consumerreports.org/health/home.htm. It costs about $20 per year. eMedicine is great bargain for textbook type information. It’s free. The Merck Manual is relatively inexpensive (about $60 on Amazon for the professional edition and less than $20 for the home health edition). Here’s another good one, The Medical Letter, http://secure.medicalletter.org/. This one’s a bit pricey: personal edition $98/year, medical health information provider edition $395/year, private practice edition $695/year. I’m believe that my medical library is subscribing to a group use of the private practice edition, though possibly it is the medical health information provider edition. I think that the personal edition is probably enough for most people. The other editions give you certain alerts and updates that are relevant to practice but I am quite sure that you get all the basic information for $98/year.

ONE PATIENT'S VIEW OF ALS
Amyotrophic lateral sclerosis (ALS, also called Lou Gerhig’s disease) is an extremely serious condition in which the motor neurons in the spinal cord, brain, and brainstem (which lies between the brain and spinal cord) die. Certain other neurons die as well but the main problem is caused by the gradual death of the motor neurons. This causes the patient to gradually get weaker and weaker. Eventually, he or she cannot move at all, swallow food, control the bowels or urinary flow, or breathe. Death usually occurs within four years of diagnosis. There is no effective treatment. Last Sunday the New York Times present an essay called “The Good Short Life” by a writer named Dudley Clendinen. You can read his gripping comments at http://www.nytimes.com/2011/07/10/opinion/sunday/10als.html?pagewanted=all. It appears that he has a suicide plan in place so that he will not have to linger on in a helpless condition. This is definitely not everybody’s choice. Many choose to go onto a respirator and fight it out for many years. There is, in my opinion, no absolute wrong or right in this. Here is a video he made earlier
http://www.baltimoresun.com/videobeta/?watchId=643baf6d-e2f4-4831-934e-7048532a7e38

PROTECTING YOURSELF AGAINST FALSE MEDICAL INFORMATION
I am a practicing physician, a medical research scientist, and a medical school teacher and many of my close relatives are physicians and medical scientists as well. But anyone who thinks it is easy for me and my family to make decisions about how various medical conditions should be approached and treated for ourselves and our loved ones would be mistaken. These are very tough issues. Many decisions are tough because there is a lack of settled opinion. Recently I read an online blog which pointed a finger at misleading advertisements by pharmaceutical companies (http://commonhealth.wbur.org/2011/07/online-ads-psych-meds/). I answered the blog in a comment which I am repeating here.

Misleading advertisements may play a role but I do not believe they are the only factors to be considered. I have found that the availability of medical information via the internet is a two edged sword. One can find information much faster than ever before. But even for a physician judging the quality, validity, and context of medical information is difficult. As with most other products, one must be skeptical of advertisements for medications. It is also important to be on the alert for information provided by those with hidden agendas regardless of whether they are commercial firms, government entities, or other interested parties. I do not think there is any perfect answer.

The column at http://commonhealth.wbur.org mentioned some reasonable point but I would urge readers to be skeptical about some of its recommendations as well.

1) The advice, from a Dr. Harold Bursztajn (whom I know and who is a very intelligent and thoughtful person) advises the reader to become aware of “what ‘adjunct’ means — Beware of recommendations that focus on FDA approval of a medication as an “adjunct” treatment without mentioning that this means that it’s not a first-line treatment for the condition in question.” I think it is misleading to tell people to “beware” of such recommendations. Though it is never wrong to know the precise “indication” for which a drug has been approved, this should not be interpreted as meaning that it is wrong to use the medication for other purposes. What is the best drug under a given circumstance is often debatable, but knowledge of indications for various drugs under various circumstances is an important part of the ever changing knowledge that physicians learn in medical school, residency and continuing education. In neurology, which I practice, it is often indicated, necessary, and demanded by the generally accepted standard of care to use the so-called “adjunct” medicines as first line and often “stand alone” medications. It is also often very valuable to use medications that have been approved for completely different purposes and were not even approved as an “adjunct” for that purpose (though it would be illegal for the company to advertise the drug for that purpose). The same is true for many other medical areas.

Depending on the spectrum of one’s patients, many good doctors prescribe “off label” at least 50% of the time. In the cases that I typically see, I prescribe “off label” about 25% of the time and I would be subjecting my patients to harm if I did otherwise. There are numerous reasons for this. The usual reason is that after a drug is approved for one usage, subsequent clinical research shows that it is as useful or even more useful for something else. But unless a drug company (or some other entity) is able to spend a large amount of money getting an additional approval, the formal FDA approvals for the other usages is never obtained. This is an accepted practice. Most medications with which I am familiar have many, many important uses aside from the FDA indications. Both neurology and psychiatry are fields in which “off label” uses, either using the “adjunct” drug as a first line treatment or using a medication for a completely different purpose than the one for which it was approved, is very common and, in my opinion, often very necessary.

2) The Commnhealth column says that patients should be aware that “indicated” does not mean “necessary.” It is true that “indicated” and “necessary” are not precise synonyms, but I doubt that making such a distinction is very helpful and it could be confusing. There are really many slightly different definitions of both of these words. “Necessary” is often used by insurance companies and other payers, especially when they reject payment (i.e. “the treatment was not necessary and, therefore, it is not covered”). Probably more important than the idea that indicated and necessary do not mean the same in thing is the caution that a treatment deemed “not necessary” or even “unnecessary” (by an insurance company, Medicare, an advice columnist or even your own doctor) does not always mean that the treatment is really not necessary to save your life or preserve your health. In my experience, I have seen a large number of patients who have been severely harmed by being told that a treatment was not necessary. But I cannot say, and I doubt that anyone can honestly be sure, whether more patients are harmed one way or the other. Some are harmed both ways, they fail to get treatments that would really do them a lot of good and they receive treatments that harm them. Blindly following FDA guideline (or blindly following any guidelines) tends to lead to such problems

3) Googling lawsuits and side effects of a drug was recommended. This could well give you some important information and I would never tell you not to do it. But doing so usually turns up isolated, random tidbits that are sort of like the “sound bites” in a political campaign. It is very hard to figure out the overall context. If you have a disease or other medical condition (e.g. traumatic brain injury) there are some other sources that I would recommend much more highly than googling for side effects of the drugs you were recommended. You really need to start with more comprehensive, connected accounts of the type that used to be found in (of all things) books (remember those?). Here are some modern alternatives.

a) This one may surprise you because it is so old fashioned. Subscribe to Consumer Reports. They actually have a separate online subscription for health articles (many of which are not included with the regular subscription). Despite my access to two medical school libraries, numerous personal medical journal subscriptions, and personal ownership of over $15 thousand dollars worth of medical textbooks (which at today’s prices is not all that many books), I actually subscribe both to the regular and health Consumer Reports and I often read their articles on medically related topics when something comes up in my own family. I’m not too proud to think that a “consumer” publication can teach me something. They have no advertising and though no one in the world is completely unbiased I think their articles are about as unbiased as you can get.

b) Online medical textbooks are available. The cheapest of these is EMedicine, which is now called Medscape Reference. You can still get to it via www.Emedicine.com. This IS supported mainly by advertising. But medical school libraries also pay to subscribe. It is peer reviewed. I have written and edited articles for it myself (and I have been paid three or four hundred dollars a year for the past few years doing so). I think its articles are of quite good quality, comparable to what one may find in a very expensive medical textbook. You probably can get to the advertising free version if you were to go to the closest medical school library and ask the librarian if you could look something up on one of the library’s computers (though I cannot guarantee that you would be given access). Public libraries may also have this version. But the text of the articles is exactly the same in both. So unless you are a super purist I do not see the advantage of the advertising-free paid version. Medical school and some public libraries also have many other medical texts. There is another online textbook called “Up to Date.” You can use the patient’s version free online. If you want the professional version it will cost you $44.95 per month. Physicians and other health professionals can subscribe for $495 a year (I bet they would let non-physicians get a year’s subscription as well but probably the idea is that an individual patient would need it only for a short time every now and then).

c) A handy and relatively inexpensive, yet comprehensive, medical textbook is the Merck Manual. There is both a patient’s version and a professional version. One need not be a physician to buy the professional version. They also have a website though I believe one must be a physician to get the online physician’s version. http://www.merckmanuals.com/professional/index.html

d) You might also want to look at my page on finding medical information at a different part of this website: http://www.neurospotlight.com/id22.html

My best general advice would be to start by reading whatever you can find about a given medication or category of medication in consumer reports. Then consider other sources such as EMedicine, the Merck manual, and websites of professional organizations and medical schools. If necessary, spend a few hundred dollars (if you can) and purchase a “real” medical textbook on the subject of interest. These days, many such books also include access to a more comprehensive website.

Following these suggestions will cost you anywhere from nothing (for EMedicine) to several hundred dollars if you end up buying some resources (Consumers Heatlh is about $20 per year). But though this may cost you a little, you will get a better understanding of the overall context of the treatments than you will obtain by wading through thousands of disconnected “sound byte” quality articles dredged up by Googling.

NYAM Author Night Series: Superheroes and Superegos Analyzing the Minds Behind the Masks
Location: The New York Academy of Medicine, 1216 Fifth Avenue at 103rd Street, New York, NY 10029
Speakers: Sharon Packer, MD


This comprehensive collection of essays written by a practicing psychiatrist shows that superheroes are more about superegos than about bodies and brawn, even though they contain subversive sexual subtexts that paved the path for major social shifts of the late 20th century.

Psychiatrist and social advocate Fredric Wertham lobbied against comics because of their sexual and sadistic subtext and their potential to reverse women’s roles and encourage same-sex behavior. However, Wertham’s McCarthy Era stance forgot that early superhero comics foretold Hitler’s threat—and offered solutions.
Superheroes have provided entertainment for generations, but there is much more to these fictional characters than what first meets the eye. Superheros and Superegos: Analyzing the Minds Behind the Masks begins its exploration in 1938 with the creation of Superman and continues to the present, with a nod to the forerunners of superhero stories in the Bible and Greek, Roman, Norse, and Hindu myth. The first book about superheroes written by a psychiatrist in over 50 years, it invokes biological psychiatry to discuss such concepts as "body dysmorphic disorder," as well as Jungian concepts of the shadow self that explain the appeal of the masked hero and the secret identity.
Readers will discover that the earliest superheroes represent fantasies about stopping Hitler, while more sophisticated and socially-oriented publishers used superheroes to encourage American participation in World War II. The book also explores themes such as how the feminist movement and the dramatic shift in women's roles and rights were predicted by Wonder Woman and Sheena nearly 30 years before the dawn of the feminist era.
Highlights
Looks at cultural psychology as much as individual psychology to analyze the political backdrop of superhero stories
Explores the importance of the secret self, the shadow self, and myths of metamorphosis, and shows how superheroes function as wounded warriors in contemporary society
Shows how the teenage creation of Superman of 1938 was prophetic and speculates whether the rise in superhero cinema in the 21st century may be equally prophetic of political catastrophes to come

--------------------------------------------------------------------------------

Schedule of Events:
Registration: 5:30 — 6:00 PM
Program: 6:00 — 7:00 PM
Registration Options:
This event is free but pre-registration is required
Copies will be available for purchase.
Sharon Packer, MD, is a practicing psychiatrist and assistant clinical professor of psychiatry and behavioral science at Albert Einstein College of Medicine of Yeshiva University, Bronx, NY. Her published works include Dreams in Myth, Medicine, and Movies and Movies and the Modern Psyche.

Registration Options:
General Admission / Free
Register
https://www.nyam.org/events/nyam_register.php?id=582

The tragedy in Alabama.
As a "Harvard trained" (partially, at least) neuroscientist, I feel a peculiar connectedness to the recent tragic triple murder in Huntsville Alabama which allegedly has been perpetrated by a "Harvard trained neuroscientist" as she is now commonly called in the media. There is even another connection. A friend of mine with whom I have co-authored one paper is also a co-author on several papers and abstracts with this person. In fact, her name seemed strangely familiar to me, though I am quite sure I have never met her. But I had read (or at least perused) the papers she co-authored with my friend and that is probably why I remembered her name.
Of course, I really do not feel that any of this gives me any special insight.

Who knows what to say about such horrible things? Should schools have courses in how to cope with career problems? Would that have helped? She did not get tenure. Some of you might say "big deal." To those of you who have ever been on an academic track, you know how tough that is. But it's not terrible enough for it to make any sense to kill someone. Most of us are going to have to get through many unfortunate events. We are going to lose contracts, grants, and---yes---jobs. We are going to submit papers and some of them are going to be rudely rejected with unflattering comments about our abilities. Loved ones will reject us and, yes, people we love are going to die and/or be killed. Is there a way to learn to cope with these things? Or do we say that most people can cope and the few who cannot are crazy? I don't know.

Speaking of coping, think of the families of those who were killed. Think of those who were injured. Think of the perpetrator’s own family. All this because someone did not get tenure? There is a huge disconnect here. What I am going to write next may sound ridiculously obvious and it is probably one of those things that will not do anyone any good. But just in case it might help someone, I am going to write it anyway.

Even if you lose that job, that grant, that contract, or whatever wonderful thing you want and deserve due to the total and complete unfairness of another person or persons, it is never going to be helpful to try to kill or injure that person. If you start thinking that it would be worthwhile to do so, go immediately to a competent mental health provider. If you ever think doing something like that is a good idea, something has gone wrong with your thinking and you need to get help right away. I know this sounds obvious, but perhaps we should have courses that just drum this into everybody's head to give them something to hold onto when their thinking goes astray. Maybe in such a case, it would not work. But, if anyone tells you that he or she is going to do such a thing, then get help for that person immediately. At least if you are sane you can hopefully recognize when someone else might be going astray. While I do not like the idea of "snitching" on people in general, if you think that someone is likely to hurt himself or others, you just have to do it.

Sorry for the moralizing, but this story really "hit a nerve."

Finally---Good News About Aging!

This whole dreary business of aging has been getting me down lately. Up to this point the only positive aspect seemed to be the comparison with the alternative. But now I have been cheered up a bit by a study described in Medicne World at http://medicineworld.org/stories/lead/1-2010/older-brains-make-good-use-of-useless-information.html This research shows that what might be thought of as a defect in older brains, the loss of the ability to filter out seemingly irrelevant information, appears to have an upside. The older learners bond items that younger brains do not and this may give them additional ability in making decisions. Perhaps this is one of the sources of wisdom, an attribute traditionally associated with age and experience. Of course, one might argue that this like what is sometimes said of flaws found in software, i.e. "it's not a bug, it's a feature." But, at least on the surface, these new findings seem to make sense.

Bring on the wisdom!

News from the AAN meeting:

For a large number of migraine sufferers (myself included) and neurologists (again, myself included) the development of the triptans for acute migraine was something of a miracle. But there are some migraines (and some migraineurs) that are not helped by these wonder drugs. That's why it is so encouraging that there are some fundamentally different medications coming down the pipeline.

Just to review, the triptans work by stimulating the 5-HT 1B/1D receptors. Sumatriptan (imitrex) was the first one developed. I use rizatriptan (Maxalt) for my own migraines. Others include zolmitriptan (Zomig) (I prescribe this a lot at my VA hospital because it is the only triptan pill on the formulary), frovatriptan (Frova), naratriptan (Amerge), almotriptan (Axert), and eletriptan (Relpax).

Here are some new treatment mechanisms that are getting close to the stage at which actual drugs may soon be approved (say in a year or two):

CGRP (calcitonin gene-related peptide) Antagonists. One of these, telcagepant, is actually in phase III trials right now. That means it is very close to the end of the testing process (again, a year or two).

Vanilloid receptor antagonists. Some of the vanilloid receptors are located on the same neurons as are the CGRP receptors. The vanilloid receptor antagonists seem to be less well studied and thus further from clinical readiness.

I do not have an in depth understanding of the mechanisms of either the CGRP or the Vanilloid receptors, but, apparently, blocking either the CGRP or the vanilloid receptors antagonizes the dilation of blood vessels located on the dura (a membrane surrounding the brain) by interfering with the action of capsacin (which is independently known to be a pain inducing substance). So this seems to make sense. The extra good part of both the CGRP and the Vanilloid story is that neither of these appear to induce vasoconstriction, which is sometimes a problem with the triptans (but it seems to me that blocking dilation of the dural blood vessels is somewhat akin to vasoconstriction, but I guess it is not direct vasoconstriction).

There is also a new type of serotonin agonist being studied. The new type activates the 1F receptors rather than the 1B and/or 1D receptors. The first prototype studied had too many side effects and was abandoned. But other such compounds are being developed.

Finally, some scientists are working on drugs that block nitric oxide synthase. But work on these is not as far along as work on the others. Frankly, I would think this could be dangerous because nitric oxide synthase is very beneficial. It is one of the good guys in helping to relieve cardiovascular and cerebrovascular constriction. I would be scared to block my nitric oxide synthase. But perhaps some smart person will find a safe way of doing it.

News from the AAN meeting: Headaches in Veterans returning from Iraq and Afghanistan

I treat a lot of Veterans at the VA, and I have been struck by the remarkable number of them who are returning from Iraq and Afghanistan with headaches. In most cases these are headaches that they never had before deployment. In the patients I commonly see, the cause seems to be exposure to a blast. The blast rarely involves being hit in the head with an object and it is unusual for the patient to have lost consciousness. Usually the source of the blast is an IED, an improvised explosive device, though it can be a bomb shot from a military weapon or some other type of explosion. I even thought of writing up some of the individual cases because some of them have very classic migraines that one rarely sees begin later in life. For example, I commonly see 50 year old patients who never had a problem with headaches. Then they were merely exposed to blast at quite a distance (sometimes more than the length of a football field), shaken a bit, but not knocked unconcious or otherwise visibly affected by the explosion. And then they they started having headaches which are often very similar to those of established migraineurs who have had migraines starting in childhood and extending throughout their whole adult lives. This impression of mine has now been strongly supported by a presention at the AAN. Brett J Theeler, M.D., of the Madigan Army Medical Center and his co-workers studied the case histories of 1000 returning soldiers. They found that 98% of soldiers who had suffered any type of blast injury, including the mild ones that I mentioned above. developed some type of headache problem. Many were migraines. Others seemed more like chronic tension headaches. There is a lot more to be learned about the problems associated with traumatic brain injury, even the type that initially appears to be extremely mild. From my perspective, however, there is a bit of good news. I have found that most of these headaches are quite treatable. I have gotten good results with standard headache medications in most of the patients. In some cases the underlying headache problem appears to be getting milder over time allowing me to taper down the levels of medication.

Just a quick post, almost a Tweet (but I'm not into "Twittering" at the moment) to mention that I am off to the American Academy of Neurology Meetings. They are in Seattle this year. Though I have been doing some research on Post Traumatic Stress Disorder (PTSD) and Traumatic Brain Injury (TBI) I did not write up an abstract this year. There is a good chance that I will have something instead for the Neuroscience meeting which is usually in November. If nothing else, I should come back with many things to add to "Updates in Neurology."

I am reactivating this blog to coincide with the rejuvenation of my "flagship" webpage, http://www.neurospotlight.com/. Though initially I had hoped to produce a constant flow of in depth analysis of neuroscience research, I did not have the time to make frequent detailed posts. In reactivating this blog, I am going to emphasize medical and scientific information gathering as well as whatever new and interesting things pique my interest in science, medicine, or even subjects further afield. Every now and then I will try to produce an in depth summary of current research as I did in my initial post in 2003. I think that was a pretty good post back then, though it is now quite out of date. I also will be adding some more links to other blogs. I just added four of them. They are the blogs of Joseph Kim MD MPH. They are

http://www.ultramobilehealth.com/
http://www.medicineandtechnology.com/
http://www.nonclinicaljobs.com/
http://www.medicalsmartphones.com/

The names are self explanatory, except perhaps for the third one, which is about non clinical jobs for physicians. The average person might say "How many physicians are interested in a job outside of clinical medicine?" The answer, apparently, is loads of them. Of course it depends on exactly what one considers nonclinical. Is teaching at a medical school nonclinical? Is public health nonclinical? Many doctors in those jobs would say "definitely not." But probably pure research, writing and journalism (even on medical related subjects), or development of software (even medical software) would be considered nonclinical. And, believe me, there are a lot of doctors going into those areas and many more considering it. In a future posting I may write a bit about what, I think, are the reasons.

New Sleep Gene Discovery Wakes Up Scientists: "Proteins that regulate sleep and biological timing in the body work much differently than previously thought, meaning drug makers must change their approach to making drugs for sleep disorders and depression and other timing-related illnesses"

What causes the damage in Huntington's Disease?

It's humbling that we now have so many disease genes cloned but still so little knowledge of how to use that genetic information to cure or understand many of these diseases. The gene for Huntington's Disease was cloned many years ago. But the gene sequence information has not lead to a cure. At last there is some inkling of how the gene may actually relate to the disease. A very nice paper by Ricki Lewis in The Scientist (1) summarizes some recent developments. My discussion below is largely derived from that paper.

Huntington’s disease (HD) was described over 100 years ago by Dr. George Huntington, an American physician who worked in Long Island New York (2). The dominant genetic pattern was also recognized at that time. Though a lot of excellent genetic pedigree analysis was done over the next 100 years, the “breakthrough” paper which will probably still be quoted in the next millenium was written by James Gusella and collaborators (3). They localized the gene defect to a genetic marker called G8 and found a gene called IT15 (“interesting transcript 15”) that was located within the G8 region. The gene product, a protein, was labelled “huntingtin.” In normal individuals huntingtin has a stretch of 34 glutamines. In people with HD this sequence of amino acids is elongated, it spans at least 40 glutamines (4). An increase in a sequence of glutamines is actually a commonly observed pattern in genetic disease, particularly neurological genetic disease. But how does having too many glutamines in the huntingtin protein lead to HD?

This question has vexed many neuroscientists years. An initial explanation was that the elongated stretch of glutamines produced excitotoxicity. Glutamic acid is an excitatory amino acid. It is vital in neurotransmission. But too much glutamic acid can overstimulate neurons and injure them. So possibly too many glutamines in a protein can make the protein neurotoxic. This is good idea, and it still may be significant, but no one has yet shown that the huntingtin protein actually interacts significantly with glutamate receptors.
More recent research appears to have found some possible mechanisms whereby the huntingtin mutation could cause significant neurological damage.

Mutant huntingtin may inhibit transcription in two possible ways.

1. In the normal process of transcription an important transcription factor is the cyclic AMP response element binding protein (CREB). The cyclic AMP response element is often abbreviated as CRE. There is another factor called CBP, the CREB binding protein, which apparently helps CREB performs its functions.

Huntingtin may interfere with CBP in two ways. CBP possess a stretch of 18 glutamines. According to Nucifora et al. it appears that the glutamines in the abnormally elongated huntingtin protein can bind the sequence of glutamines in CBP, inhibit CBP activity and thus inhibit transcription (5). In addition, CBP possess a site of enzyme activity. The activity is a type of “acetyltransferase” activity. It transfers an acetyl group (i.e. acetylates) some histone proteins. Proper acetylation of histones helps turn on transcription. A paper by Steffan et al. shows that mutant huntingtin can block the acetyltransferase activity of CBP. Not only that, but certain drugs---histone deacetylase inhibitors---can block the damage caused by the huntingtin (at least in a model system used the fly, Drosophila melanogaster) (6).
2. Disruption of protein degradation
Cells have certain ways of getting rid of damaged proteins. One way is by binding ubiquitin (a rather ubiquitous protein) to the damage protein. The ubiquinated proteins then go into a proteasome where they are processed and eliminated. Recent work by Bence, Sampat, and Kopito at Stanford suggests that the long tracts of glutamines in mutant huntingtin can gum up (so to speak) the proteasome system (7).

Suggestions for further reading. The first reference below, the review by Lewis, is probably the best source for anyone who wants to get a better understanding of the scientific research noted above. You can get her review on the internet at http://www.the-scientist.com/yr2003/may/hot_030519.html. You do have to register for The Scientist (which is free).
References:
1. Lewis, R. Huntington disease pathology unfolds. The Scientist. 17:32-33, 2003.
2. Huntington, G. W. On chorea. Medical Surgical Reporter. 26:317-21, 1872.
3. Gusella, J.F. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 306, 306: 234-8, 1983.
4. The Huntingtn’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is unstable in Huntington’s disease chromosomes. Cell, 72:971-83, 1993.
5. Nucifora, F. et al., Interference by huntingtin and atrophin-1 with CBP-mediated transcription leading to cellular toxicity. Science. 291:2423-8 2001.
6. Steffan J., et al., Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature. 413:739-43, 2001.
7. Bence N., et al., Impairment of the ubiquitin-proteasome system by protein aggregation. Science. 292:1552-5, 2001.