Dr. Mike's Psychiatry Blog

Update on new treatments for fragile X---Part 4: MMP-9 inhibitors

2011-10-11T08:31:00.001-07:00

In 2007, Iryna and Doug Ethell of UC Riverside made the seminal finding of excessive activation of the enzyme Matrix Metalloproteinase-9 (MMP-9) in fragile X. They showed that excessive MMP-9 activity maintained dendritic spines in an immature state, and that this contributed to the behavioral abnormalities seen in the fmr1 KO mouse. Most importantly, they showed that the known inhibitor of MMP-9, the available antibiotic minocycline, could rescue all the abnormalities they found in the mouse model. This made minocycline an attractive off-the-shelf treatment for fragile X. Shortly thereafter, I started experimenting with the judicious off-label prescription of minocycline in a small number of carefully selected patients; the results were impressive, to say the least! Indeed, the effect of minocycline was too good, and too rapid to be solely the result of normalized developmental trajectory. Minocycline appears to have an early psychotropic effect which is independent of its fragile X-specific mechanism; this has been utilized in several studies of minocycline as a treatment for schizophrenia and obsessive-compulsive disorder (which leads to the intriguing possibility that minocycline could be an excellent treatment for autism spectrum disorders in general.) Keep in mind that, in the mice, treatment was a very long-term affair---the equivalent of years in human terms.

After conferring with Carlo Paribello, of the Fragile X Research Foundation of Canada, we quickly began organizing a clinical trial. This first trial was an open trial, designed to examine the pattern of responses in high and low dose minocycline treated subjects. The trial achieved excellent results, with substantial decreases in aberrant behaviors over 8 weeks of treatment. Long-term follow-up of these subjects was also done, and results of that phase of the trial are now being analyzed. Very few side effects were seen in either high or low dose groups, and the therapeutic effect seemed similar (though the number of subjects could not discriminate subtle differences.) This is not unexpected, since studies by surgeons have shown that typical antibiotic doses of minocycline (100 mg/d) inhibit MMP-9 levels by 50-75%. That is just about exactly what we want. One unexpected result from the study was that ¼ of all the subjects followed for a year had an increase in Anti-Nuclear Antibodies (ANA), a rather non-specific indicator of autoimmune reactions. None of these subjects had any actual symptoms, though serious autoimmune reactions to minocycline are seen (fortunately, only rarely.) We’re still not entirely sure what to make of this finding, as it’s not known just what percentage of people in the general population develop elevated ANA levels with chronic minocycline treatment. However, it could be a useful indication of impending autoimmune problems, and may be worth checking as a screening test. Interestingly, none of the patients that I treat directly have developed this kind of reaction to minocycline, though I have talked to a number of parents around the country who have encountered this problem.

A larger, placebo controlled trial is under way at the MIND Institute to follow up on these initial findings, and we look forward to these results. In the meantime, another bit of confirmatory evidence came from the lab of Kendal Broadie at Vanderbilt. His group has published results showing dramatic rescue of fragile X fruit fly abnormalities with minocycline---all the more impressive because the fly model is essentially a knockout of 3 genes (fmr1, fxr1, and fxr2.) This group also showed that genetic reduction of the fly equivalent of MMP-9 yielded similar results; this is significant, because minocycline does several different things, but MMP-9 inhibition does seem to be the active ingredient.

So, we have an excellent off-the-shelf treatment in the form of minocycline, a cheap generic medication with a long history and fairly benign safety profile. But some people, perhaps as many as ¼, have trouble taking it, and it’s not recommended for kids under 8 because of dental discoloration (which is not directly related to MMP-9 inhibition.) We at FRAXA are continuing to explore more specific alternatives to minocycline; there is interest in pharmaceutical companies in drugs which can inhibit MMP-9 specifically without some of the other effects of minocycline. However, this is a niche market, and only a few companies have active programs in this area, so it may be a while before we find anything better than minocycline in this area.

Update on new treatments for fragile X---Part 3: GSK3 inhibitors

2011-06-27T22:02:00.000-07:00

After mGluR5 antagonists, the drug class with the most extensive validation as a disease-modifying treatment for fragile X is one called GSK3 inhibitors. Glycogen Synthase Kinase 3 is a ubiquitous enzyme present in a number of signaling pathways throughout the body (a problem which we will re-visit later.) GSK3 beta is the specific version which is excessively active in fragile X (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707186/?tool=pubmed ), and studies in fragile X mouse, fly, zebrafish, and neural stem cells all show that reducing GSK3 activity, either genetically or with chemical inhibitors, can rescue a very wide range of fragile X phenotypes (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838793/?tool=pubmed ). FRAXA invested heavily in funding the study of GSK3-based treatment strategies following the original finding that MAP1b was one of the critical overexpressed proteins in fragile X (http://www.ncbi.nlm.nih.gov/pubmed/11733059). Since it is known that activation of MAP1b occurs via GSK3, it was recognized early on that inhibition of GSK3 could be therapeutic for fragile X. Subsequent evidence has shown this to be correct, and perhaps even an underestimate. GSK3 inhibitors appear to have as much therapeutic potential as mGluR5 antagonists, though they may not be quite as well tolerated.

While virtually every major pharmaceutical company in the world is working on improved GSK3 inhibitors for a number of different indications, there is an available drug which is an excellent GSK3 inhibitor. This drug is lithium. Ironically, even though lithium has a reputation for being rather toxic, it may turn out to be less toxic than any of the newer, “cleaner” GSK3 inhibitors in development. Indeed, most of these development programs are in trouble because of toxicity and off-target effects. It is because of the ubiquitousness of GSK3 that these side effects may be unavoidable (in fact, in this light, lithium looks pretty good!), but there are efforts to develop brain-specific GSK3 inhibitors which leave the rest of the body untouched.

Millions of people around the world have been treated safely and effectively with lithium for psychiatric disorders (especially Bipolar Disorder, a.k.a. Manic-Depressive Illness.) However, lithium has fallen out of favor with psychiatrists who now have many other options for treating psychiatric disorders, especially in the form of heavily promoted, brand name drugs like Zyprexa and Depakote. Lithium is a cheap generic, and no one is promoting it. It is also hard to prescribe, and no doctors other than psychiatrists have any experience using it. But lithium does appear to be therapeutic for fragile X, showing disease-modifying properties in animal models (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102293/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810609/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pubmed/21078304 and http://www.ncbi.nlm.nih.gov/pubmed/20705090, among others) and excellent results in a pilot clinical trial in fragile X patients ( http://www.ncbi.nlm.nih.gov/pubmed/18698192 ).

However, it is fair to say that lithium has not become a common treatment for fragile X, probably because it is widely perceived as a dangerous drug (whether this is correct or not, the perception certainly influences acceptance of the treatment by patients, families, and physicians.) Further trials are clearly warranted, however. A larger, controlled trial of lithium in fragile X subjects is a high priority for FRAXA. There is also the possibility of identifying available agents which can enhance the effectiveness of lithium (http://www.fraxa.org/researchTeam.aspx?id=659 ), and perhaps allow for lower dosing. This might eliminate the need for blood testing to determine lithium levels, one of the more unpleasant aspects of lithium treatment for patients and families. It is surprising to me that more psychiatrists are not prescribing lithium for their fragile X patients, especially in case where the psychiatric presentation alone (i.e. aggression or mood lability) might justify a trial of lithium. It may simply be that doctors today have so many choices, it’s easy to avoid lithium.

mGluR5 antagonists for fragile X

2011-06-20T14:55:00.000-07:00

The disease-modifying potential of this class of drugs, which block type 5 metabotropic glutamate receptors, has been incredibly well validated in animal models of fragile X. It’s actually so well validated that it’s unprecedented in the history of medicine. There really has never been another example of a small molecule fixing so many facets of a neuropsychiatric disease in multiple animal models. In part, this is because most neuropsychiatric diseases haven’t had very good animal models, at least until recently, but this just reinforces the point that fragile X is such an important model for the study of many other disorders---we have animal models that aren’t just models, they actually have fragile X. It seems like we’ve been talking about the promise of this treatment strategy forever, but it was only 2001 when the “mGluR Theory” of fragile X was conceived, and now we have 3 companies with active programs to develop their mGluR5 antagonists for fragile X (as well as the now-defunct Neuropharm, which may yet rise from the ashes.)

Novartis is the furthest along, and their compound AFQ056 just entered Phase IIb/III trials for adults and adolescents with fragile X at a large number of sites around the world (see clinicaltrials.gov for more details.) Trials in children are expected to follow soon. AFQ056 is a modern, advanced compound which appears quite safe, and also appears to be an effective treatment for complications of Parkinson’s disease (see http://www.ncbi.nlm.nih.gov/pubmed/21484867 ). It seems likely it will make it to the market for Parkinson’s, even if things don’t work out for fragile X, which is a reassuring backup plan. However, if the current round of clinical trials is successful, it could be marketed for fragile X as the first indication for any mGluR5 antagonist. The Phase II trial results with AFQ056 for fragile X have been published ( http://www.ncbi.nlm.nih.gov/pubmed/21209411 ) and much has been made of the different response to the drug in full mutation males with “full methylation” vs. full mutation males with “partial methylation” on a proprietary assay of methylation status used in this trial. However, it is important to remember that this was a relatively brief trial in a small number of subjects, so it is not surprising that the best effect was seen in the relatively pure sample of fully methylated (ie non-mosaic, for all practical purposes) subjects. Subjects in this trial received the full dose of AFQ056 for only one week; such brief treatment often results in a high placebo response rate, and that was clearly the case here. Clinical trials in psychiatry have shown over and over that the placebo effect generally wears off over 3-4 weeks, and the current phase of AFQ056 trials will dose subjects for much longer. I would expect that this longer treatment would result in statistically significant improvement in all fragile X subject groups, with decreased placebo effect. In addition, preclinical testing of mGluR5 antagonists in animal models predicts that fragile X patients would require much higher doses of these drugs for optimal effects, and that these doses would be well tolerated, so this trial may not have pushed to dose into the optimal range.

However, this raises an important issue with all the disease-modifying treatments for fragile X. How long does it take to see genuine developmental improvement, rather than simple symptomatic improvement? It stands to reason that longer trials are required to see genuine developmental effects, and that even longer trials are required to see disease modification in older subjects. As I noted in the previous post, having extensive preclinical validation gives us confidence that a particular therapeutic strategy will be disease modifying, even if this is not practical to demonstrate in a clinical trial. It may take years to see real developmental effects in 20 year olds, although clinical trials are rarely more than a few months long. Besides, drug companies aren’t required to show that they can cure fragile X, only make it measurably better. So, I’m expecting that this phase of the trials will show improvement in all subjects on AFQ056, with more severely affected subjects showing the best effect, as well as the least placebo response. But, these things are hard to predict---that’s why they do the trials!

Another Swiss pharmaceutical giant, Hoffmann-LaRoche (or just “Roche” to those of us in the know) also has an advanced mGluR5 antagonist, RO4917523, which has just completed a Phase II trial in fragile X adults. RO4917523 may actually be the most (chemically) sophisticated of all the drugs in development; it is ultra-long-acting and very potent. A tiny dose once a day is all that is required to block mGluR5 quite effectively. Results of this trial are a closely guarded secret, and no announcements have been made about future plans for RO4917523, so we are left in the dark concerning Roche’s intentions.
Seaside Therapeutics also has an mGluR5 antagonist, STX107, which was licensed from Merck. It has reportedly completed Phase I trials (normal volunteers), but has yet to be administered to any fragile X subjects. Phase II trials have yet to be announced. Seaside appears to be devoting much of its energy to the development of arbaclofen (R-baclofen, or STX209) for autism and fragile X; this will be discussed in another post.

As noted above, Neuropharm, a UK-based startup, is now out of business. The company’s fortunes rested on the near-certainty of approval of a proprietary formulation of fluoxetine (aka Prozac) for autism. However, their large, multicenter trial failed to show superiority to placebo, even though everyone still uses fluoxetine and other SSRIs for autism spectrum disorders, because they clearly do work. This serves as an important cautionary tale: trials can fail for any number of reasons! Anyway, their Phase I/II trial of fenobam was quite successful; it was only intended to show safety and tolerability, but also showed significant improvement in pre-pulse inhibition (PPI) in fragile X adults, with many anecdotal reports of behavioral improvement from a single dose. Fenobam, like Neuropharm may yet be resurrected---many companies around the world are looking at possible uses for this off-patent compound.

Many other companies have their own mGluR5 antagonists, typically developed at vast expense, and now looking for some purpose. It seems to be generally agreed that fragile X and Parkinson’s are good, proven indications for these drugs, so we anticipate that more companies will move into fragile X trials, especially if Novartis continues to have success with AFQ056.

Update on new treatments for fragile X

2011-06-18T20:13:00.000-07:00

In the coming weeks, I hope to provide up-to-the-minute updates (along with many frank opinions, since this is a blog!) about the status of all the various new treatments that have the possibility of disease modification in fragile X. I’ll do this in writing, since I do want to be fairly precise, and you may want to be able to copy these things; I’ll also reference much of what I say, except where the references are too numerous to list.

To do this, I’ll need to define a few terms, so let’s start there. First is the term “disease modification”, referenced above. We all are hoping for treatments which actually affect the course and the outcome of this single-gene disease we call fragile X. There are many available psychiatric drugs which can positively affect the behavioral manifestations of fragile X, and I’ve written plenty about them. But there is no indication that they change the long-term outcome in any significant way, as I noted in my last post. Obviously, the better kids do over the course of many years, the better their long-term prognosis, but the same can be said for any number of behavioral and educational interventions. There may very well be some kind of gray area here, but I think most of us can agree that we would like to see something much more specific, treatments which get to the very heart of the dysfunction in fragile X, and actually facilitate much more normal development. This is the mission of FRAXA, and it has become my life’s work, so I don’t consider these trivial distinctions. You’ll have to pardon me if I have some strong opinions in this area, and if I sometimes seem dismissive of ideas which are proposed that just don’t have the research backing to make them potentially “disease modifying” by accepted definitions.

So, how does one demonstrate that a particular treatment strategy might be disease modifying? Well, you could just give the treatment to patients and see what happens, based on some speculative theory of what’s wrong in the fragile X brain. This is the dominant model in autism studies today, and it carries over to some extent in fragile X. It is also quite common in psychiatry, and I’ve had the chance to observe the failure of this model on many occasions. For example, millions of children, adolescents, and adults take stimulant medications every day to enhance their attention (as well as decrease hyperactivity and other disruptive behaviors associated with ADHD.) Most parents hope, and assume, that this treatment will result in improved academic performance over the long term (we certainly see this in fragile X, too.) The drugs certainly work well in the short term, and efficacy is easy to demonstrate. However, most of the studies which have examined the long-term academic performance of kids with ADHD treated with stimulants show little, if any, advantage for the drugs. More recent studies have shown some benefits, but the results are debatable and more subtle than you might imagine (see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629512/?tool=pubmed for a more thorough review.) In the fragile X field, we just don’t have the time or money to try this willy-nilly approach, and the number of research subjects is too small to make it work.

A better way, I think, is to develop treatments based on the observed abnormalities in the animal models of fragile X (mainly fruit fly and mouse), then test potential treatments in those animal models. This initial observation would be considered basic science; the attempt to find ways to reverse a defect might be termed “translational research”, and the actual testing of a specific drug in the animal model would be called “pre-clinical validation”, leading to clinical trials in people with fragile X. The “FRAXA Method”, as I like to call it, is to fund this kind of progression from basic research, through translational research, followed by preclinical validation, leading to clinical trials of medications that have genuine potential to change the outcome of fragile X. We didn’t invent this method, and it really isn’t anything new at all---it’s what every pharmaceutical company does every day. But you’d think it was some sort of radical new approach, compared to the half-baked and poorly reasoned trials coming from many areas (not just the autism field, either; many clinical trials in psychiatry, or in the broader rare disease field are little more than wishful thinking, with no real scientific basis.)

In the next few installments, I’ll talk about the results of this approach, then move on to discuss some other developments in clinical trials for fragile X. Stay tuned!

Can "ordinary" meds have extraordinary effects?

2010-06-01T10:19:00.000-07:00

A viewer asks, if Zoloft can help with language in young fragile X kids with lots of anxiety, can it boost language development in kids without as much anxiety?

Also, what's a safe minimum age for these meds? How young is too young?

Clinical Trials: How do they work?

2010-05-28T18:23:00.000-07:00

A number of clinical trials are under way for fragile X! Here's the scoop on the system we have in the US and many other countries for developing new drugs.

Videoblogging fragile X: sympatholytics

2010-05-19T13:16:00.000-07:00

Here's the scoop on meds like beta blockers (propranolol, et al) and alpha agonists (clonidine, guanfacine) in young kids with fragile X.

Videoblogging fragile X: treatment cocktails

2010-05-17T11:49:00.000-07:00

Here's a response to one of the most common questions I get:

Blog for FRAXA

2010-03-29T16:54:00.000-07:00

People are always asking me how they can help FRAXA. Obviously, we'd all like to be able to raise tons of money for research, but if you're like me, you probably don't have a lot of extra cash, and you probably don't know anyone who does. But just about anyone with a little free time can blog, and you can use a free blog to help FRAXA. We'd like to set up a network of bloggers around the world to raise awareness of fragile X, and raise money for FRAXA---just email me ( fraxares@verizon.net ) and we can go over the details. It's fun, and if enough of us join together, it really can make a difference!

Science Q & A !!!

2009-09-08T07:37:00.000-07:00

Q: Something that has been on my mind for some time now and I hope that you will know where to look for an answer. Why do children with Fragile X exhibit a consistent phenotype, large ears, etc.? You will already have thought about this, I am sure. I just can't understand why a single protein deficiency would influence the general development of a human. Does it happen also with the mice? Does the fragile X mouse model exhibit similar phenotypic appearances? If not, then I would start to wonder if the model was accurate, wouldn't you?

A: Of course, we don't know all the details yet, but a few key answers to this question have come from the research. First of all, it is known (especially from drosophila work) that the normal role of FMRP, as an RNA-binding protein, is to help regulate directional growth in most (if not all) cells. This can be seen in fly oocytes, where normal anatomy is severely disrupted by mutations of dFMRP; fertility is also impaired, though this still does not result in sterility (which is very good luck for us, or we'd have no fly model of fragile X.) So, from this perspective we can see that this mutation would cause the greatest disruption in the most spatially differentiated cells: neurons. Other cells are affected, though, and that may explain some of the dysmorphic physical features.

The mice do have some physical phenotype, but I think it's just hard for us, as a different species, to recognize. Human facial recognition is very highly evolved; I doubt that the mice would be able to tell any difference in our faces! They certainly do have larger testes; no one has looked at their connective tissue, but I'm sure it's quite lax (just hard to examine or quantify this.)

Beyond direct effects on directional cell growth, there are the many known indirect effects, for example on hormone regulation. We know from Carolyn Beebe Smith's work at NIMH that protein synthesis is dysregulated in much of the fragile X brain, but the hottest of all the hot spots for excessive protein synthesis is the hypothalamus, with about 32% more activity in fraX vs. normal. That is a huge difference for a whole brain region! The hypothalamus is responsible for regulating a wide range of hormones in the body, and these, in turn, regulate cell growth in a number of ways. Because of the elaborate control mechanisms in the body, with multiple feedback loops, we don't see vast increases in one hormone or another at any one time in fragile X people, but we really haven't looked very hard, either. What is likely happening is that the fine regulation of hormonal response is lost. For example, Alan Reiss showed abnormal response of cortisol to social stress---but the cortisol levels weren't crazy-high, they were just a bit more prolonged than normal. Likewise, many of the facial features are reminiscent of acromegaly, though high levels of growth hormone have not been shown in humans or mice. It may be a more subtle defect than that. Interestingly, Abdeslem El-Idrissi at CUNY Staten Island has found low levels of somatostatin (in some ways, the opposite of growth hormone) in the knockout mouse; this could explain many features of fragile X, and is potentially treatable (somatostatin can be administered via injection, and synthetic analogs are being developed with oral bioavailability).

On a finer level, the excess in activated MMP-9 in fragile X, which was found in the mouse model by Iryna Ethell, could explain many of the CNS and non-CNS phenotypes seen in fragile X. This extracellular enzyme is part of a large and complex system which regulates the stiffness of the extracellular matrix---the foundation for all cell growth. We know that MMP-9 activity can be regulated through mGluR5 (at least in neurons) and that mGluR5 is present on many non-neuronal cell types. Of course, we can block MMP-9 activity directly with minocycline, but the evidence suggests that mGluR5 antagonists could also help with this problem, certainly in neurons, but probably in a great many other cell types as well. I certainly never expected that we would come up with treatments for the physical features of fragile X (and we weren't really looking for this) but it's quite promising. The experience with minocycline suggests that we can fix the lax connective tissue with this drug, and the research suggests that mGluR5 antagonists could work, too. Since most kids with fragile X (at least in the future) will be treated with these drugs well before the majority of physical development, this may modify the phenotype significantly. Time will tell if these findings hold up, or if the story is more complicated/less amenable to treatment.

Another Fragile X/Minocycline Blog

2009-08-25T09:11:00.000-07:00

Here's another mom blogging her daughter's minocycline trial;
no dramatic effects (yet), but it's nice to see a range of experiences.
Are there any blogs out there featuring fragile X boys and their experiences with minocycline?

Shameless Commerce

2009-07-20T20:35:00.000-07:00

The Medication Guide for Fragile X is now available as a download; faster and cheaper than the CD; exact same info from start to finish! This isn't an automated download service (we're definitely not that fancy!) so you'll get email instructions from me after ordering which will tell you how to download. It's not a huge file, but at over 15 MB, you'll definitely want broadband for this one. Ideal for all the folks in far-flung corners of the fragile X universe. I'll gladly refund your money if you're unable to accomplish the download, so don't be afraid of the technical stuff!

More Q & A with Dr. Mike

2009-07-08T08:41:00.000-07:00

Q: Our son is eight years old and has the full mutation Fragile-X gene, as well as autism (he is a mosaic). He is (essentially) non-verbal, with only one or two word sentences that are mostly not understandable and just express a need (food, water, etc.). Since his diagnosis in 2004 we have tried many different medications to address his main issues of anxiety, aggressive behavior (hitting people & things), impulse-control, perseveration, attention-deficit, & hyperactivity. We suspect his frustration from his lack of verbal abilities is causing a lot of his aggressiveness. He has been on Adderall for the ADHD symptoms and Zoloft for the anxiety for a few years. Then we read your medication book more carefully, and found out about your blog, and read your opinion about the stimulants' side effect of increased aggressiveness. At that time, about four months ago, we started reducing the Adderall and began the guanfacine (continued the Zoloft). He has now been off of the Adderall completely for about two months, and takes the guanfacine three times daily, which we gradually ramped up over time. About a month ago he started having some extreme meltdowns about twice per week that were uncontrollable, destructive, and lasting about 45 minutes each. We don't know what caused them, although we suspect one was due to getting scared from a cartoon. We literally had to hold him down to prevent him from hurting himself, others, or property. These episodes were frightening, especially since he's quickly getting bigger (after stopping the Adderall). That's when we started the Abilify to try to stabilize his moods. We started on 1mg at bedtime, but after a week we realized he was so tired all of the time, we backed off to .5mg. He was still very tired, so we also halved his guanfacine at bedtime, thinking the cumulative side effects of the Abilify and guanfacine were causing the sleepiness... Still sleepy. One problem is that when he's sleepy, that's a time when he starts hitting his four-year-old sister relentlessly. He is physically strong, quick, and agile, so we need to get a handle on this quick.

Here is my question: Your book says Stimulants and Abilify work well together, but what about guanfacine, Abilify, & Zoloft together? Could the side effect of drowsiness with the Abilify and Guanfacine be cumulative?

A: This sounds like a fairly common progression of events as hyperactivity gives way to aggression as a young boy with fragile X gets older. Stimulants can certainly aggravate this, and it's probably a good thing that the Adderall is gone. Abilify (aripiprazole) can duplicate some of the effects of stimulants and sympatholytic agents like guanfacine (Tenex), and it's no secret that I think Abilify is a great treatment for fragile X, though it's a powerful drug which probably shouldn't be anyone's first-line treatment. In this case, you are using it appropriately to treat severe agitation, and it should be helpful, though most likely at a higher dose (2-5 mg/d would be typical for an 8 year old boy.)

By itself, Abilify isn't especially sedating. However, drugs like guanfacine and clonidine block the body's ability to compensate (via the autonomic nervous system) for sedation caused by other drugs, thus intensifying the sedation. This effect can be more than additive---it can be synergistic in some cases. The good news is that you could probably lower the guanfacine as you increase the Abilify, and this would decrease the overall sedation; hopefully, the Abilify will take over the useful functions of the guanfacine (as well as provide a little stimulant-like boost in attention). You may want to reconsider the timing, too. You mention that you cut the guanfacine dose at bed time, but you need to remember that Abilify is ultra-long-acting (half life is 75 hours!) so it's in there all the time, regardless of when the pill is swallowed. Guanfacine is much shorter acting (half life around 12 hours) and causes most of its sedation in the first couple of hours after a dose. So, usually you'd keep a higher dose at bedtime (since you want him to sleep well) and reduce the daytime doses to minimize sedation. I should say that I am continually amazed at how sensitive people with fragile X are to drug withdrawal effects, and guanfacine causes significant withdrawal effects; I always recommend cutting doses very slowly, so think of this as a long-term proposition.

You didn't note the dose of Zoloft, but as I've mentioned many times, all the evidence is that higher doses of SSRIs are required for the best effect in treating fragile X and developmental disorders. This has been reinforced by a couple of high-profile failed trials of SSRIs in autism (most recently citalopram and fluoxetine) where the doses were, IMHO, way too low and the trial drug was no better than placebo. It's quite true that some kids simply can't tolerate high enough doses of SSRIs to get this benefit, but in your case, the guanfacine and Abilify should both offset the activation which is the main dose-limiting side effect. In other words, a higher dose of Zoloft will cause activation (basically, the opposite of sedation) which could be useful in this case, and the therapeutic effect of the SSRI will add to the overall efficacy of the regimen. Zoloft, guanfacine, and Abilify can all work quite well together; I've actually seen a number of kids who did very well on this exact combination. I generally think of meds like clonidine and guanfacine as being most useful earlier in life, when kids are most hyperactive; most will eventually decrease the use of these meds (and also stimulants) as they go through puberty and grow in size. Eventually, gravity takes over, and you simply can't be as hyperactive at full size. However, many people with fragile X benefit from the calming effects of clonidine or guanfacine as adults, and there's no problem continuing the treatment as long as it helps.

More Q & A

2009-06-26T15:54:00.000-07:00

Q: My son is 21 years old. He has been described as a higher functioning fragile x boy. Unfortunately, he has aggressive tendencies which have mysteriously gotten worse in the past month.

He is on citalopram, low dose Tenex, and a very tiny dose of BuSpar every day. We tried Abilify a couple of years ago, but stopped it. My recollection was that he began reporting hearing sirens and voices. Obviously not good. However, he has had some very violent episodes just lately - as many as six in the space of four days. We are back to trying Abilify because of this. (Two days into it, and no episode)

I'm wondering about the drug trials I heard were happening in Boston, or about any other thing you might suggest. I'm somewhat hopeful that the Abilify might work, but obviously want to look beyond that in case.

Our son has been working at a restaurant and at a nursery and is quite sociable when he is not having a bad day. He has had to spend the last three years being tutored at home, because the school decided they couldn't (or wouldn't) school him anymore because of his episodes. We were unable to find an out-of-district placement, and, being mistrustful of the school system, decided it was best for him to be tutored at home. The school has paid for this, but this program runs out this month.

It would be possible to find a work placement for him, except for this fear of aggressive episodes. I guess we're on the verge of desperation here.

A: Aggression in fragile X can be treated a few different ways, and you're actually already trying a couple of them. Ordinarily, we think of episodic aggression (sometimes classified as "Intermittent Explosive Disorder") in fragile X as a phenomenon which occurs as a result of severe and intolerable anxiety. For this reason, SSRIs (like citalopram) are often used. However, proper dosage is often the key to getting the best response; since you didn't specify the dose, let me say that ordinary doses like 20-30 mg/d may be somewhat helpful, but not give the best effect. Higher doses, more like those we might use for OCD, are often much more effective---40-60 mg/d would not be considered excessive, and you could even go higher, if needed, since it's so non-toxic.

BuSpar (buspirone) is also used to treat anxiety, and can be very effective in treating aggression, either alone or in combination with SSRIs. However, dosage matters here, too. A few people with severe episodic aggression will respond to amazingly low doses of buspirone (as little as 5 mg three times a day) but most require quite a bit more, up to 60 mg/d in divided doses. Aggression usually also involves some degree of physical hyperarousal, so Tenex is often used to damp down the autonomic nervous system in people with autism and fragile X. As you might guess, I'd suggest that a very low dose isn't enough to stop whatever is going on, so it could be worth trying more. Doses of about 2 mg three times a day would be considered average in a young adult male, so check your dosage and see how it compares.

Generally, I recommend optimizing the meds you're already on before adding new ones, but now that your son has gotten started on Abilify, I'll state that it is an excellent choice for severe behavioral problems in people with fragile X, although his prior poor response might have led me to try something a little different. Still, sometimes adverse effects are reported with a drug when they are really just coincidence; this is especially true with behavioral and psychiatric side effects. It sounds as though the Abilify trial is going well so far, though Abilify has a very long half life, so it accumulates in the system for about 10 days after starting it. In other words, the effective dose (in the bloodstream) will continue to go up, even if you give the same daily dose by mouth. If Abilify works for your son, it might be a good opportunity to clean up the rest of his med regimen but getting rid of the low doses of Tenex and BuSpar (gradually, of course, and over a long time---people with fragile X do seem unusually sensitive to drug discontinuation effects.)

The drug trials that are currently recruiting are mostly looking for subjects who are not on any meds already---this is to try to see the purest effect from the study drug. However, one drug which just finished a small but successful trial in fragile X subjects is widely available: lithium. Many people are scared off by potential toxic effects, but lithium has been taken safely by millions of people around the world, for a range of psychiatric disorders, and it can be remarkably effective. Even before we had specific evidence of efficacy in fragile X, lithium was recognized as an especially effective treatment for episodic aggression, so there is a clear rationale for using it here. Furthermore, there is substantial evidence from basic research and the previously noted clinical trial that lithium can have specific beneficial effects in fragile X, perhaps even improving development over time. The disadvantage is that only a psychiatrist would usually even consider prescribing lithium, since other medical professionals rarely have any experience with it; lithium use also requires regular blood tests, and this makes it unacceptable for many people.

In case you haven't seen it, check out my Xmas entry on minocycline. This may be of interest to you; while it's not something we think of as a psychiatric treatment effective in an emergency, minocycline is showing real promise as an off-label treatment for fragile X, and it often has rather rapid effects. My experience so far is that the best responses often occur in young adults already on atypical antipsychotics (like Abilify), so your son is in the right demographic.

Q & A with Dr. Mike

2009-06-17T17:55:00.000-07:00

(We) just took one of our adult sons with Fragile X (22 yrs old) to see an adult psychiatrist. We need help to moderate some of his obsessive traits. When he gets upset or is in anxious situations, he fixates on the name of a woman that he knows and repeatedly tells us to “call her up” or tells us that she phoned us when she didn’t, to the point where he has a blow up. Also in conversation, he’ll address people that he knows, like his grandparents, by the name of this woman. He rarely sees this woman. She’s the mother of a former classmate and one of the managers of our community Special Olympics team. This has been going on for a couple of years but seems to have gotten worse since he’s been out of high school for a year now.

So the question that I have for you concerns the drug Strattera that the psychiatrist recommends that we try on our son. Currently, my son only takes 2 mg of Tenex, 3 times daily and does not have any other health concerns (including heart or liver). When I read the information on any drug, you wonder why you would take it or give it to someone. Therefore, any opinion or additional information that you can give on this drug and it’s efficacy on a person with Fragile X Syndrome will be most helpful. Thanks in advance for anything you can tell us.

My immediate concern for our son is his obsessiveness. His talking about this other mom and reminding me often to make phone calls to people I might need to talk with is becoming more difficult to manage. I am wondering if the Strattera is a plan for attention issues not obsessions.

A: I think you're right to be concerned that Strattera is a treatment for attention deficit, not obsessional problems. In fact, Strattera may aggravate obsessional symptoms as well as anxiety, irritability, and aggression. The mainstay of treatment for these anxiety symptoms in all developmental disorders (and especially fragile X) is the SSRI class (ie Prozac, Zoloft, Paxil, Luvox, Celexa, and the various generic equivalents.) While there is some controversy about the effectiveness of SSRIs in children with "autism" (whatever that is!) as a result of 2 recent negative trials, it is quite clear that SSRIs are very effective in treating a wide range of symptoms in adults with developmental disorders, including and especially the kind of obsessional/repetitive/perseverative symptoms you describe. A number of well-done clinical trials have established efficacy in adults with MR/DD; it is my opinion that SSRIs work just as well in children, but studies are much harder to do in this population, and the results are confounded by the kinds of side effects that children often get. Most clinicians in the fragile X field have a very positive view of SSRIs, and feel that they are quite helpful with these symptoms. Strattera, on the other hand, has little information available via clinical trials in the developmental disorders population. In other words, there is no evidence that Strattera works for the kind of symptoms you describe; my clinical experience is that it doesn't, and it's certainly not the first thing I'd try (not even the fifth or sixth, actually.)

So Far, So Good....

2009-06-07T20:58:00.000-07:00

Seems like Abby is doing well on minocycline. Check it out at Julia's blog!

Adventures with minocycline...in real time

2009-05-28T05:44:00.000-07:00

I've added a link (on the left) to a really nice new blog by a fragile X parent who has just started her daughter on minocycline, and is blogging about the experience. I should say that I don't know these folks at all, other than getting permission to link. While they may well have gotten the idea to try minocycline from me and from this blog, I have no idea how it will all turn out---but check it out and follow the story.

Along the same lines, there is a recent paper from Japan suggesting that minocycline can act as a potent augmentation strategy for atypical antipsychotics (Risperdal, Abilify, etc.) in the treatment of schizophrenia:

Minocycline as adjunctive therapy for schizophrenia: an open-label study.

Clinical Neuropharmacology 2008 Sep-Oct;31(5):287-92.

Miyaoka T, Yasukawa R, Yasuda H, Hayashida M, Inagaki T, Horiguchi J.
Department of Psychiatry, Shimane University School of Medicine, Izumo, Japan. miyanyan@med.shimane-u.ac.jp

Minocycline is a caspase inhibitor, decreases inducible nitric oxide synthase, and has been shown to delay disease in a mouse model of neuropsychiatric disorders. Recently, we reported the antipsychotic effects of minocycline in patients with schizophrenia. In a pilot investigation, we administered minocycline (150 mg/d) for 4 weeks as an open-label adjunct to antipsychotic medication to 22 patients with schizophrenia. The Positive and Negative Syndrome Scale for schizophrenia showed statistically significant and robust clinical improvements with minocycline treatment, which were maintained at follow-up evaluation 4 weeks after the end of minocycline treatment. There were no adverse events. These results suggest that minocycline may be a safe and effective adjunct to antipsychotic medications, and that augmentation with minocycline may prove to be a viable strategy for "boosting" antipsychotic efficacy and for treating schizophrenia.

This raises the interesting possibility that minocycline may (among many things) enhance the effectiveness of atypical antipsychotics. So far, I have seen fragile X patients respond to minocycline montherapy, but many of the most impressive responses have been in people taking atypical antipsychotics as well. This is oddly similar to the results obtained with Ampakines in clinical trials with schizophrenic subjects, and possibly in fragile X subjects as well (as suggested in Liz Berry-Kravis' CX 516 trial.)

This may also be a good time to address a question which I get asked a lot: will older people with fragile X respond to treatment with minocycline? Obviously, we are early in the game, so it is hard to say anything definitive at this point. However, I have seen some of the best responses to minocycline in adult patients, and some of the youngest patients I've seen treated have shown no observable effect. This may be related to co-administration of atypical antipsychotics, or other meds, as noted above, which tends to be more common in older individuals. Or, it may simply be that in younger patients minocycline is correcting synaptic defects before they can cause obvious behavioral problems, whereas older people with fragile X have had a longer time to form abnormal connections and develop symptoms, so correction (however partial) results in more apparent improvement. Generally speaking, I've seen impressive responses in most young adults (let's say 15-25), with a somewhat more gradual and prolonged response in older people. Some of the fragile X kids in the 5-8 age range have had little apparent benefit, and their parents have elected to discontinue, especially with the perceived risk of dental staining. We'll see if this observation amounts to anything, but it does contradict the general assumption that most drugs with a specific mechanism of action should work best in the youngest patients. In a way, this would be a favorable effect; if therapeutic effects are generally most easily observed in young adults with fragile X, this will make future trials with a wide range of agents much easier to conduct.

It's About Time!!!

2009-03-20T05:15:00.000-07:00

The new edition of my book is finally available (see buy now button at left.) For the time being, it will only be available on CD (as one big pdf file,) but this does allow for a lower price and cheaper shipping. In a little while (a few months), I plan to make it available as a download, with no shipping charges at all. Depending on demand, a print version may be available at the end of the year, but shouldn't you just save a tree and get the e-version?

Any day now.....

2009-02-18T09:31:00.000-08:00

The new Med Guide is just about ready! I plan to release the first copies of the new edition on CD next week. While you're waiting, here's another sample:

nefazodone (Serzone)

indications: irritability, anxiety, aggression, obsessive-compulsive symptoms

pros: relatively little risk of activation, mildly sedating; generic available

cons: multiple dosing necessary; no liquid, chewable, or pediatric-size dose available; rare reports of liver toxicity

use: nefazodone is essentially a new, improved version of trazodone, to which it is closely related chemically; it is significantly better tolerated than trazodone because it causes less sedation and orthostatic hypotension. The mechanism of action of nefazodone is basically identical to that of trazodone: it inhibits re-uptake of serotonin and norepinephrine, while blocking a subclass of serotonin receptor (5HT2, the "bad" serotonin receptor). These differences mean that nefazodone is not as useful for sedation--for treatment of insomnia or acute treatment of agitation. However, nefazodone is more useful as an antidepressant, and as a treatment for anxiety disorders because therapeutic doses are far more easily tolerated.

Nefazodone offers a major advantage as a treatment for many of the typical symptoms of Fragile X: it is much less likely to cause the kind of excessive activation which is so often a problem in the treatment of children with other antidepressants. Its 5HT2 antagonist properties also likely yield enhanced antiaggressive effects compared to SSRIs, while its noradrenergic properties probably confer greater effectiveness in treating attention deficit. One minor disadvantage of this medication is that it must be given twice a day due to its short half-life. However, this can be an ideal choice for patients who have particular problems sleeping, since most of the total daily dose can be given at bedtime for a gently sedating effect.

common side effects

sedation: usually mild and transient; temporary dosage reduction often helpful

orthostatic hypotension: benign; can be minimized by initially dividing dose further, i.e. 25 mg four times a day rather than 50 mg twice a day

nausea: take with food; Pepto-Bismol is safe to use

uncommon side effects

priapism: not actually reported with this drug, but a theoretical concern since it is closely related to trazodone; discontinue medication immediately

headache: any OTC (over the counter) remedy is fine

dosage

children: start with 50 mg at bed time and increase as tolerated in 50 mg increments, using divided doses; usual effective dose is 100-200 mg/day; 300 mg/day is usually well tolerated in older kids

adults and teens: start with 50 mg two to three times a day, increasing as tolerated over the first week to 200-300 mg per day; maximum recommended dose is 500-600 mg per day

Update 2008: Nefazodone has gone through a number of ups and downs since its introduction. Initially, it gained great popularity as an alternative to SSRIs, but its market share was gradually diluted with later entries into the antidepressant field, like Celexa and Remeron. As its patent was nearing its end, reports surfaced of rare episodes of hepatotoxicity (liver damage) in some patients. These severe adverse effects were quite rare, and the FDA did not consider the risk sufficient to justify withdrawal from the market, but it did issue a “black box” warning, which spelled commercial death for Serzone. The original manufacturer stopped selling Serzone, but generic nefazodone is still available.

Nefazodone is actually a very safe drug, despite the dire warnings. The risk of hepatotoxicity is estimated at about 1 in 250,000 per year of treament (so, if you were on it for 10 years, you’d have a 1 in 25,000 risk of liver damage.) This is quite a bit less than similar risks from valproate or other common drugs, most of which don’t even carry this kind of warning. Nevertheless, this has scared virtually all pediatricians and child psychitrists away from this medication, and nefazodone has been used relatively little in pediatric populations. In the end, the popularity of the SSRIs swamped nefazodone.

This is a shame, in many ways. Nefazodone is significantly less likely than most other antidepressants to induce mania in people with Bipolar Disorder, and it is also much less likely to cause excessive activation in pediatric patients. It has a mild calming and sedating effect, which greatly aids sleep. It has few GI side effects, and is generally easy to take.

For fragile X patients (of any age), nefazodone has many advantages. Like the SSRIs, it blocks reuptake of serotonin, which gives it antidepressant, anxiolytic, and antiobsessional effects. It also blocks reuptake of norepinephrine, which further boosts mood and can help with attention. It blocks 5HT2 receptors, helping to stabilize mood and decrease aggression, and even conferring some antipsychotic effects. Finally, its antagonism of alpha 1 norepinephrine receptors may be especially helpful in facilitating sleep and decreasing hyperactivity in fragile X. While it’s far from a “clean drug” with just one mechanism of action, its multiple effects overlap very nicely with the symptoms seen in fragile X and other autism spectrum disorders. For these reasons, nefazodone is one of the most potentially useful drugs for the treatment of fragile X, even if it is one of the most under-utilized in actual practice.

Merry Christmas and Happy New Year! This is one of the more important excerpts from the upcoming new edition of my book...

2008-12-27T10:43:00.001-08:00

Newer Drugs Worth Noting:

Minocycline

Research sponsored by FRAXA Research Foundation has shown that the available antibiotic minocycline may be an especially effective treatment for the core deficits of fragile X. Preliminary results were presented at the recent conference, "The Shared Neurobiology of Fragile X Syndrome and Autism" at the University of Southern California, June 11-13, 2007. This work has just recent been published:

J Med Genet. 2008 Oct 3. [Epub ahead of print]

Minocycline Promotes Dendritic Spine Maturation and Improves Behavioral Performance in the Fragile X Mouse Model.

Bilousova T, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, Ethell IM. University of California Riverside, United States.

BACKGROUND: Fragile X syndrome (FXS) is the most common single-gene inherited form of mental retardation, with behaviors at the extreme of the autistic spectrum. Subjects with FXS and Fragile X mental retardation gene knock out (Fmr1 KO) mice, an animal model for FXS, have been shown to exhibit defects in dendritic spine maturation that may underlie cognitive and behavioral abnormalities in FXS. Minocycline is a tetracycline analog that has been used in clinical trials for stroke, Multiple Sclerosis and several neurodegenerative conditions. METHODS: We evaluated the effects of minocycline on dendritic spine development in the hippocampus of young Fmr1 KO mice, and in primary cultures of hippocampal neurons isolated from those mice. Cognitive effects of minocycline in young WT and Fmr1 KO mice were also evaluated using established behavioral tests for general cognition, activity and anxiety. RESULTS: Our studies demonstrate that minocycline promotes dendritic spine maturation both in cultures and in vivo. The beneficial effects of minocycline on dendritic spine morphology are also accompanied by changes in the behavioral performance of 3-week-old Fmr1 KO mice. Minocycline-treated Fmr1 KO mice show less anxiety in the elevated plus-maze and more strategic exploratory behavior in the Y-maze as compared to untreated Fmr1 KO mice. Our data suggest that these effects of minocycline may relate to its inhibitory action on MMP-9 expression and activity, which are higher in the hippocampus of Fmr1 KO mice. CONCLUSION: These findings establish minocycline as a promising therapeutic for the treatment of Fragile X mental retardation.

Essentially, fragile X is caused by the absence of a single protein, FMRP. FMRP normally regulates the production of a number of critical proteins in and around the dendrites of neurons in response to synaptic activity. It is a key mediator of synaptic plasticity, and dysregulation of synaptic plasticity is thought to be the basis of fragile X syndrome. In the absence of FMRP (as in fragile X syndrome,) there is excessive production of a discrete set of synaptic proteins, usually in response to activation of group I metabotropic glutamate receptors (mGluRs,) and our research has targeted these over-expressed proteins for potential therapeutic intervention. In particular, FRAXA-supported scientists have found that an extracellular enzyme called Matrix Metalloproteinase 9 (MMP-9) is significantly over-expressed in fragile X. MMP-9 is involved in tissue remodeling (including dendritic growth) and its over-expression in fragile X may also account for the universally observed soft tissue laxity. The neuronal abnormalities of fragile X (long, thin dendritic spines) can be duplicated by artificially over-expressing MMP-9. Likewise, stimulation of mGluRs increases MMP-9 and induces long, thin spines. Blockade of mGluRs in fragile X mice decreases MMP-9 and normalizes dendritic spines; we are currently working with several pharmaceutical companies to develop mGluR5 antagonists, but these are not yet available. However, it has been known for some time that minocycline potently inhibits MMP-9 at usual antibiotic doses, and crosses the blood brain barrier quite efficiently. In the fragile X mouse model, this same research project has shown that minocycline normalizes dendritic spines, reduces MMP-9 levels to normal, and (most significantly) treats behavioral abnormalities like anxiety and improves cognitive performance.

Coincidentally, a study of the treatment of regressive autism with minocycline was recently initiated at NIH, based on a completely different hypothesized mechanism of action---the theory that regressive autism is caused by an inflammatory and/or autoimmune process, and the known anti-inflammatory effects of minocycline. Anti-inflammatory and neuro-protective effects are also the basis for the use of minocycline in rheumatoid arthritis, MS, ALS, and several other neurodegenerative conditions. The dose ranges in studies addressing neurodegenerative conditions have usually been well above typical antibiotic doses, but the regressive autism study is utilizing a typical antibiotic dose, treating children as young as 3 years of age.

In yet another interesting coincidence, an Orphan Drug Designation was recently granted by the FDA for the development of minocycline as a treatment for pediatric obsessive-compulsive disorder; most fragile X patients display significant obsessive-compulsive symptoms. The animal studies described previously represent impressive proof of principle, and have prompted the organization of fragile X clinical trials. In the meantime, there has been some experience with open, off-label use of minocycline as an add-on treatment for fragile X, and it has been markedly positive to date in subjects ranging in age from 5 to 48.

Minocycline is ordinarily not recommended for patients under 8 years of age because of the risk of permanent tooth staining, though the autism trial mentioned above is treating patients as young as 3, and some studies suggest that the risk of enamel deposits is not as great as generally thought. The usual dose of minocycline is 50 mg PO qD or BID in younger patients, and 100 mg PO qD or BID in adults, and these are the doses used to date in fragile X subjects. Improved language utilization, decreased anxiety and repetitive/perseverative behaviors, decreased mood lability, and generally improved cognition have been reported in initial, uncontrolled use of minocycline. These effects are usually readily apparent within the first 2-3 weeks of treatment, though one would expect that longer-term treatment would be required to yield true developmental enhancement. Significant improvement in connective tissue abnormalities (such as flat feet and aortic root dilation) have been reporter with extended treatment.

It is worth noting that mice in the Ethell study were treated with minocycline for the first 4 weeks of their lives. This is the equivalent of human treatment for the first 2-3 years of life, and it is reasonable to assume that treatment later in life would require an even longer duration to achieve optimal results. Fortunately, minocycline has an excellent track record of safety in long-term use (typically for acne) in millions of teenagers worldwide. While rare (approx. 1:10,000) side effects such as severe autoimmune responses and elevated intracranial pressure have been reported, minocycline is clearly a much safer drug than any antipsychotic or any anticonvulsant on the market today. Clinicians rarely hesitate to employ those agents where appropriate, so we must now focus on clinical demonstration of efficacy in treating fragile X, and the first formal clinical trials are now under way.

This is intended to serve as an explanation of the rationale for prescribing minocycline as an off-label treatment for fragile X. It should not be considered full prescribing information or a formal recommendation, since pivotal proof of efficacy studies remain to be done. However, such studies are unlikely to be completed and published for at least 2-3 years; since minocycline is an available agent with a benign side-effect profile, it is likely that many fragile X families will entertain the possibility of a minocycline trial in the interim. Hopefully, this information is useful, along with the usual medical references, in weighing the risks and benefits of this developing treatment strategy in consultation with a trusted physician.

Newer Drugs Not Worth Noting, cont.

2008-12-20T10:07:00.000-08:00

Neurontin (gabapentin)

Neurontin is one of the least useful drugs in history, and the subject of one of the sorriest scandals in modern pharmaceutical history. A brief history, via Wikipedia:

Gabapentin is best known under the brand name Neurontin manufactured by Pfizer subsidiary Parke-Davis. A Pfizer subsidiary named Greenstone markets generic gabapentin. In December 2004, the FDA granted final approval to a generic equivalent to Neurontin made by Israeli firm Teva.

Neurontin is one of Pfizer’s best-selling drugs, and was one of the 50 most-prescribed drugs in the United States in 2003. However, in recent years, Pfizer has come under heavy criticism for its marketing of Neurontin, facing allegations that, behind the scenes, Parke-Davis marketed the drug for at least a dozen supposed uses for which the drug had not been FDA approved.

By some estimates, so-called off-label prescriptions account for roughly 90% of Neurontin sales. While off-label prescriptions are common for a number of drugs and are perfectly legal (if not always appropriate), marketing of off-label uses of a drug is strictly illegal. In 2004, Warner-Lambert agreed to plead guilty and pay $430 million in fines to settle civil and criminal charges regarding the illegal marketing of Neurontin for off-label purposes, and further legal action is pending. The courts of New York State, for example, have refused to certify a class of injured parties who took Neurontin for off-label use, finding that they had failed to state that they had any injury.

The University of California, San Francisco (UCSF) has archived and studied the documents made public by this case, which opens a unique window into pharmaceutical marketing and their illegal promotion. However, Pfizer maintains that the illegal activity originated in 1996, well before it acquired Parke-Davis (through its acquisition of Warner-Lambert) in 2000. Several lawsuits are underway after people prescribed gabapentin for off-label treatment of bipolar disorder attempted or committed suicide.

In fact, Neurontin was very heavily marketed (illegally) to psychiatrists (including this author) by its manufacturer as a new treatment for Bipolar Disorder, with no evidence to support its use. At one point, Neurontin was probably the single most commonly prescribed drug for Bipolar Disorder, and its use was widespread for many other off-label indications. Eventually, FDA pressure led the company to do some actual research, which showed that Neurontin was slightly less effective than placebo in treating Bipolar Disorder! So why did anyone ever prescribe this dud? Because it’s so well tolerated (again, from Wikipedia):

Gabapentin's most common side effects in adult patients include dizziness, drowsiness, and peripheral edema (swelling of extremities); these mainly occur at higher doses, in the elderly. Also, children 3–12 years of age were observed to be susceptible to mild-to-moderate mood swings, hostility, concentration problems, and hyperactivity. Although rare, there are several cases of hepatotoxicity reported in the literature.

Clinical experience in fragile X shows gabapentin to be rather ineffective in its primary indication (epilepsy) and entirely useless as a psychiatric treatment. Indeed, most fragile X patients treated with Neurontin exhibit markedly worse behavior. This typically manifests as behavioral disinhibition---decreased impulse control, defiant and unruly behavior, etc. Aggression, irritability, and mood lability (already a problem!) usually get much worse when Neurontin is introduced. Now, to be fair, gabapentin probably does have some role in the treatment of certain chronic pain conditions---it’s not complete garbage---but it is not a useful psychotropic, period.

As a litmus test for psychopharmacologists, you could not do better than simply asking how much Neurontin that doctor has used (this author has never written a single prescription or recommended it to any patient---ever.) Any psychiatrist who still uses this medication is not worth seeing; if any doctor recommends Neurontin to you or a family member for a psychiatric purpose, run away and don’t look back. (You may have noticed that I feel strongly about this; the misrepresentation of Neurontin by Big Pharma and the wholesale, unthinking acceptance of a worthless drug by the psychiatric profession represent embarrassing low points for both.)

What's All This Then?

2008-12-07T09:10:00.000-08:00

You may have noticed that I've begun posting some snippets from the new edition of my book, A Medication Guide for Fragile X. People have started asking when the new version is due. I'm planning to have it ready by mid to late January, 2009. It will be available exclusively right here on this web site. My plan is to sell it as an e-book only for at least the first year, since this is a much more effective, efficient, and eco-friendly way of disseminating the information.

Stay tuned for a special offer for all the early adopters out there!

Newer Drugs Not Worth Noting

2008-12-05T13:38:00.000-08:00

While new drugs are being introduced all the time, many are not especially useful in treating fragile X, or they have no particular advantage over existing drugs. Space doesn’t allow for discussion of every medication on the market, especially with the recent brand and formulation proliferation in the psychiatric marketplace. However, some drugs simply need to be avoided, and these do deserve a special mention.

Geodon (ziprasidone)

Geodon is an atypical antipsychotic which has never really caught on, mainly because every now and then it causes someone’s heart to stop suddenly (in technical terms, it causes Q-T prolongation, disrupting the electrical signals within the heart.) It is an effective drug, with antipsychotic and mood-stabilizing properties, though this (rare) side effect has kept it from widespread use, and it is hardly ever used in pediatric patients. On the plus side, it causes very little weight gain, though it probably has no advantage over Abilify in this regard. It can be difficult to dose in adults, with a highly non-linear dose-response relationship, and it is every bit as expensive as its atypical antipsychotic classmates. For these reasons, there has been little experience using this drug in the treatment of developmental disorders, and so this is not a drug to be recommended for use in fragile X.

Another excerpt from the upcoming new edition of my Med Guide

2008-11-25T10:18:00.000-08:00

Stimulants
The psychostimulants, as a class, have been around for a long time. These were some of the first drugs to be used in psychiatry, and so physicians feel fairly comfortable with these medications--some would say too comfortable. In children, stimulants are by far the most commonly prescribed psychoactive medications, primarily for the treatment of attention deficit/hyperactivity disorder (ADHD). Stimulants are also used, with questionable effectiveness, as appetite suppressants to promote weight loss. They can be valuable for people with narcolepsy, since their stimulating properties can help narcoleptics stay awake and function through the day. Some adults with ADHD also seem to benefit from stimulant medication.
Currently, there is a bit of controversy about the frequency with which stimulants are used; many people (this author included) feel that these medications are overprescribed and that ADHD is overdiagnosed. It is likely that the ability to attend, as a biological trait, exists on a continuum: some individuals are designed to focus narrowly on the task at hand, while others are always open to input from the environment, and are thus "easily distractable". It is also likely that many children and adults nowadays are labeled as having ADHD when they simply are normal individuals at one end of the spectrum. Viewed this way, medicating these individuals constitutes cosmetic psychopharmacology.
This argument certainly does not apply to Fragile X, however. Children with Fragile X have a well-defined, single-gene disorder which causes attentional deficits along with other characteristic symptoms. They (along with a fair number of children who really do have neurologically-based ADHD) have symptoms which offer a clear-cut rationale for the use of psychostimulants to enhance attention. The only reasonable question is whether these medications work for children with Fragile X.
To answer this question we must first consider how these drugs work. Although the mechanism of action is by no means fully understood, the conventional wisdom is that psychostimulants work by promoting release of certain neurotransmitters, especially dopamine (but also norepinephrine, as well as other things secreted along with them). The primary effect of psychostimulants, the enhancement of attention and concentration, is thought to result from the increased release of dopamine in the frontal areas of the brain. But, of course, the drug is present in other areas, too, and exerts effects there as well. The areas of the brain which regulate level of arousal, blood pressure, heart rate and other "autonomic" functions are also stimulated, while the area controlling appetite is inhibited. Under normal circumstances, most people are much more sensitive to the primary effect of facilitating dopaminergic transmission in the frontal lobes, and at most therapeutic doses will experience an enhancement of attention, concentration, and overall cognitive performance (which is why these medications were initially touted as "smart drugs").
As attention and concentration (referred to by some as "focus") increase with increasing doses of a stimulant, physical activity tends to decline, accounting for the paradoxical decrease in hyperactivity (which is ususally the objective of treatment). However, the primary and secondary effects of stimulants, enhancement of attention and reduction of hyperactivity, are known to occur at different dosages. Lower doses of a stimulant are likely to enhance attention optimally and improve cognitive performance, but may not control hyperactivity. Higher doses are likely to reduce hyperactivity, but may actually result in "overfocus", in which attention is focused so narrowly that actual cognitive performance declines. Still higher doses will cause psychiatric symptoms in virtually anyone, including irritability, aggression, anxiety, agitation, paranoia, or hallucinations. Fortunately, for most people the dose required to cause trouble is much higher than usual therapeutic doses. However, the situation is somewhat different for Fragile X individuals.
Fragile X predisposes one to anxiety, aggression, and agitation. On an intuitive level, it seems obvious that care should be taken with any substance which could aggravate these. On a biochemical level, psychostimulants are "sympathomimetic": they mimic the effects of adrenaline in the central nervous system, heightening arousal as well as increasing heart rate and blood pressure. Since Fragile X individuals often have problems with hyperarousal, stimulants may make matters worse in some cases. Many Fragile X individuals are able to achieve significant improvements in attention and cognitive performance with low doses of stimulants, though, and any potential adverse effects are readily reversible should they arise. Therefore, a trial of a stimulant is rational and safe for a Fragile X individual with particular attentional problems, but should be done with caution. Dosages should be relatively low, and it cannot be expected that significant reduction of hyperactivity will occur, at least compared to the sometimes dramatic response seen in "garden variety" ADHD. Careful monitoring for emergence or exacerbation of anxiety or aggression must occur throughout treatment. Many Fragile X parents are not informed of this risk, are unaware of the connection between stimulants and worsening of aggression or anxiety, and therefore continue administering the medication even when adverse psychiatric side-effects occur--despite the fact that these effects readily reverse upon discontinuation of the drug.
Psychostimulant medications can cause uncommon, but serious, medical problems. Most worrisome is the development of motor tics. This can start as a subtle, almost undetectable twitch, and progress to severe involuntary muscle movement. It usually stops soon after the stimulant is discontinued or the dosage decreased, but sometimes is frighteningly persistent. The key is to catch the tics early on; more persistent tics usually occur following longer treatment in which early signs were ignored. This side-effect is usually dose related, so reducing the dose can be helpful and allow for uninterupted treatment. Also, since most Fragile X children are treated with lower doses of stimulants, this may be less likely to occur in the first place (there are no reliable statistics on the frequency of this side-effect in Fragile X). Tics can also be treated with clonidine if they persist, or if the clinical judgment is made not to interrupt stimulant therapy.
Since they can be potent appetite suppressants, psychostimulants can cause some growth delays during long-term administration. Several studies have shown, however, that children will eventually catch up, even if the medication is continued. Often, "drug holidays" are taken during non-critical times (such as summer vacation) to expedite this process. In any case, growth charts should be carefully monitored for all children on stimulant medications, and significant growth delay is an appropriate reason for discontinuing the medication.
Specific side effects and their medical management are discussed in the individual reviews of medications.

Update 2008: The caveats concerning stimulants noted in this book have proven to be well founded, and just as frequently ignored as ever. Stimulants are nearly irresistable for all concerned, offering the promise of an instant fix for the disabling inattentiveness and the disruptive hyperactivity seen in nearly all children with fragile X. Teachers love stimulants because they help so many kids participate in class. Parents love them because they start working right away, and because they want their kids to get the most out of school. Pediatricians love them because they’re easy to prescribe and have a long safety record. The only problem is that they don’t work very well in kids with fragile X! At least half of all stimulant trials in fragile X kids end abruptly because of immediate psychiatric side effects---usually extreme irritability or increased aggression. Seizures and tics are also seen with alarming frequency in this population following the start of a new stimulant medication. However, these are all fairly obvious and easily recognized, and when the drug is discontinued the adverse effects dissipate rapidly. Perhaps more concerning are the psychiatric side effects which develop insidiously over much longer time frames; I have consulted on many cases in which a fragile X child has an excellent initial response to a stimulant with no apparent side effect, only to have multiples problem emerge months or years later. Most commonly, obsessive-compulsive symptoms worsen over time, as mood deteriorates and tantrums increase. Because stimulants cause significant physiological dependence, everything gets worse if any attempt is made to discontinue the drug, and this is often seen as evidence the stimulant is not to blame. In fact, this is only evidence that stimulants are potentially addictive, and demonstrates why they are highly controlled substances. The appropriate response is a gradual taper of the stimulant dose over the course of many months.
The entire field of Child Psychiatry appears to have come to the realization that excessive and indescriminate use of stimulants has led to an increase in childhood Bipolar Disorder, Anxiety Disorders, and psychoses. Indeed, the current fad is for overdiagnosis of Bipolar Disorder, after ignoring for decades that this condition can present in childhood. So, the most important lesson is to be vigilant over the long term; most medications which work right away have serious side effects which develop much later.

Trends in Psychiatry

2008-11-15T06:18:00.000-08:00

The medical field is just like any other kind of human endeavor: subject to fads and herd mentality. While we’d all like to think that doctors rely only on science and only care about the best available evidence, doctors are people, too. Like everyone else, doctors are heavily influenced by what other people think, and the opinions of their medical peers are very important in determining practice patterns. In addition, doctors must function in an environment where information is usually insufficient. We don’t know enough about how any part of the body works, yet all these parts can have problems, and doctors are expected to fix them when they do. Filling in these knowledge gaps is more art than science, and in this artistic facet of medicine, most doctors seek the consensus of their peers---medicine is a field for creative renegades only on TV.

So, each medical specialty has its own trends, which vary over time and by geographic region. This is by no means peculiar to psychiatry; all areas of medicine experience this same phenomenon, but here we are concerned with the effect of psychiatric fads on treatment of people with developmental disorders.

Major Tranquilizers: The Original Fad

The field of psychopharmacology didn’t really exist until the first antipsychotic drugs became available in the 1950’s. The first generation of antipsychotics, like Thorazine and Mellaril, revolutionized psychiatry by allowing direct biomedical treatment of psychosis. These “major tranquilizers” were powerful drugs with a wide range of effects (good and bad) which could actually treat schizophrenia and other major thought disorders for the first time. Unfortunately, the enthusiasm for these drugs was a bit overdone, and many people who were never psychotic were prescribed antipsychotics anyway. Why? As an old professor of mine used to say, “When all you have is a hammer, everything starts to look like a nail!” Nowhere did this megatrend of the 50’s cause more problems than in the medical management of developmental disorders. Enormous numbers of people with DD were prescribed major tranquilizers for a wide range of symptoms. In some cases, the drugs had genuine benefits, but in many others, the main effect was non-specific sedation. Decades later, the chickens finally came home to roost, as thousands of people with developmental disorders were diagnosed with irreversible, drug-induced movement disorders.

Nowadays, these older antipsychotics are rarely used, and seldom prescribed to children. However, we may be seeing a similar phenomenon in our time. The newest generation of antipsychotics, usually called “atypical antipsychotics”, are being prescribed in vast quantities to children and adults with developmental disorders. In part, this is because this class of drugs represents a significant advance compared to the older antipsychotics, though some critics argue that the differences in practice are not that great, and the real push is coming from pharmaceutical companies. Indeed, while the new drugs are more easily tolerated by patients, and they appear to be somewhat more effective in their primary indication, the treatment of schizophrenia, they are not the “silver bullet” many had hoped for. Risperdal (risperidone) became the first atypical antipsychotic actually marketed for the treatment of autism after a large and well-done study showed efficacy in treating the irritability and behavior problems associated with autism. The multicenter trial described below led to FDA approval of Risperdal for this indication, the first formal approval of any treatment for autism.

N Engl J Med. 2002 Aug 1;347(5):314-21.

Risperidone in children with autism and serious behavioral problems.

McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, Arnold LE, Lindsay R, Nash P, Hollway J, McDougle CJ, Posey D, Swiezy N, Kohn A, Scahill L, Martin A, Koenig K, Volkmar F, Carroll D, Lancor A, Tierney E, Ghuman J, Gonzalez NM, Grados M, Vitiello B, Ritz L, Davies M, Robinson J, McMahon D; Research Units on Pediatric Psychopharmacology Autism Network.
University of California, Los Angeles, USA.

BACKGROUND: Atypical antipsychotic agents, which block postsynaptic dopamine and serotonin receptors, have advantages over traditional antipsychotic medications in the treatment of adults with schizophrenia and may be beneficial in children with autistic disorder who have serious behavioral disturbances. However, data on the safety and efficacy of atypical antipsychotic agents in children are limited. METHODS: We conducted a multisite, randomized, double-blind trial of risperidone as compared with placebo for the treatment of autistic disorder accompanied by severe tantrums, aggression, or self-injurious behavior in children 5 to 17 years old. The primary outcome measures were the score on the Irritability subscale of the Aberrant Behavior Checklist and the rating on the Clinical Global Impressions - Improvement (CGI-I) scale at eight weeks. RESULTS: A total of 101 children (82 boys and 19 girls; mean [+/-SD] age, 8.8+/-2.7 years) were randomly assigned to receive risperidone (49 children) or placebo (52). Treatment with risperidone for eight weeks (dose range, 0.5 to 3.5 mg per day) resulted in a 56.9 percent reduction in the Irritability score, as compared with a 14.1 percent decrease in the placebo group (P<0.001). The rate of a positive response, defined as at least a 25 percent decrease in the Irritability score and a rating of much improved or very much improved on the CGI-I scale, was 69 percent in the risperidone group (34 of 49 children had a positive response) and 12 percent in the placebo group (6 of 52, P<0.001). Risperidone therapy was associated with an average weight gain of 2.7+/-2.9 kg, as compared with 0.8+/-2.2 kg with placebo (P<0.001). Increased appetite, fatigue, drowsiness, dizziness, and drooling were more common in the risperidone group than in the placebo group (P<0.05 for each comparison). In two thirds of the children with a positive response to risperidone at eight weeks (23 of 34), the benefit was maintained at six months. CONCLUSIONS: Risperidone was effective and well tolerated for the treatment of tantrums, aggression, or self-injurious behavior in children with autistic disorder. The short period of this trial limits inferences about adverse effects such as tardive dyskinesia.

This would seem to be good news, and in most ways it is. A commonly used treatment for autism spectrum disorders was shown to be efficacious in autistic children; this is good evidence that this drug and other atypical antipsychotics treat some of the most difficult symptoms of developmental disorders. However, all drugs have side effects, and antipsychotics have more than most. Some of these are well known and well described. For example, a number of movement disorders, some irreversible, can occur with these medications. Fortunately, newer drugs are less likely to cause these problems, especially at the lower doses usually prescribed in developmental disorders. However, they seem to have some special problems of their own, like pronounced weight gain in younger patients, and unusual side effects such as this:

J Child Adolesc Psychopharmacol.

Risperidone-induced enuresis in two children with autistic disorder.

Hergüner S, Mukaddes NM.
Department of Child and Adolescent Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

INTRODUCTION: Risperidone appears to be effective in treating behavioral problems in children with autistic disorder. Although increased appetite, weight gain, and sedation are among the most common side effects, risperidone-induced enuresis is rarely reported. METHOD: We will present two cases with risperidone-induced enuresis, and discuss our findings in the context of current literature. RESULTS: Two children aged 11 and 10 years, diagnosed with autism and mental retardation, have developed new-onset diurnal and nocturnal enuresis respectively on their first and second weeks of risperidone monotherapy (1.5 and 1 mg/day). They did not experience sedation, and their medical history and workup were unremarkable. As enuresis did not resolve spontaneously, we decided to substitute risperidone with olanzapine. Enuresis ceased rapidly after discontinuation of risperidone with no emergence when patients were treated with olanzapine 5 mg/day for a period of 6 months and 1 year, respectively. DISCUSSION: Although the pathophysiology of antipsychotic-induced enuresis remains unclear, a number of mechanisms including alpha(1)-adrenergic blockade, dopamine blockade, and antimuscarinic effects has been proposed. Olanzapine has lower alpha(1)-adrenergic and dopaminergic blockade properties, thus changing risperidone to olanzapine may be an alternative modality in risperidone-induced enuresis when antipsychotic treatment is crucial. Clinicians should be more vigilant about screening for this side effect, especially in younger population with developmental disabilities.

Urinary incontinence is not usually associated with treatment with older antipsychotics, yet the newer drugs can cause this with surprising frequency in younger patients with DD.
By itself, this isn’t a show-stopper, but this illustrates an important point. When a drug which is useful, but perhaps not the first choice in most cases, becomes the only drug actually officially approved for that indication, it suddenly becomes the first choice of many risk-averse doctors. Thus, Risperdal became the first choice for the treatment of all autism spectrum disorders, in the eyes of many physicians. That could be a big problem in the end, with atypical antipsychotics becoming more popular than their first-generation cousins ever were. While we’d like to think that these are simply better drugs, and their popularity is well-deserved, we may not know the whole story. People with MRDD suffer from a wide range of symptoms, and many are better treated with other classes of medications. Risperdal and other atypical antipsychotics may be the first choice for some of these symptoms, but they’re certainly not the first choice for most.

AmEx project: Never mind!!!

2008-09-09T07:01:00.000-07:00

Well, we finished #5 in voting, but for some reason, the advisors at the AmEx Members Project appear to have disregarded the nomination process entirely in their selection of their top 25---so we have not been invited to the second round. Thanks for your support.

UPDATE: following this execrable behavior by AmEx, we note that the company is is dire financial straits, and requesting bailout assistance from the government. Coincidence? We don't think so!

Please support FRAXA's nomination!

2008-08-08T13:29:00.000-07:00

FRAXA has been nominated for the AmEx Members Project---if we get enough votes, we could get a big cash prize to put toward fragile X research.

Vote now! Please---right now!

Live too far away?

2008-08-05T13:57:00.000-07:00

Since I've restarted my practice, many people have asked me how they can access my services if they can't come to Amesbury, Mass. Until now my answer has been consistent---I need to see the patient in person if I am to treat him. However, I'm now offering a new service---internet consultation. It may sound a bit unorthodox, radical, or downright crazy, but it's starting to make sense. Think of it this way: you live far away, so I'm not going to be your child's doctor, no matter what. It's bad medicine if we're too far apart, and you may have a very good doctor that you're already seeing. However, he/she may not have much experience treating fragile X. I have tons of experience treating fragile X, but only so many people live within range of my office.

Now, usually the biggest problem with treating patients from afar is ensuring proper diagnosis. A doctor may be very skilled at the best possible treatments, but if he's treating the wrong thing, it's not likely to help, and may do harm. In the case of fragile X, however, there is a difference: the diagnosis is quite precise, and the condition is remarkably consistent (despite the emphasis in the literature on the wide range of presentations.) Therefore, I believe it is appropriate and potentially helpful to offer consultations via internet/email for any individual with previously diagnosed fragile X. Because I can do this at my convenience, with no overhead, I can also do this at a substantially lower rate ($150/hr) than office consultations or long-term outpatient treatment.

A few disclaimers are in order. First of all, I will not be prescribing anything for anyone over the internet. You need to have a local doctor you trust who is willing to work with you and me, and who can make use of any recommendations that I make through our consultation. You should not expect that any other doctor will follow my recommendations slavishly---this is a good thing! There are many charlatans out there, and I could be one of them; I expect that I will need to communicate any recommendations in a sensible way that justifies that course of action. This service should not be used for any kind of medical or psychiatric crisis; clearly, you'll be looking for advice at a time when things aren't going well, but I won't be of any use to you in a truly dire situation. Few psychiatric treatments work quickly, and emergency measures cannot be implemented long-distance.

Finally, to clarify, I'm talking exclusively about psychopharmacology consultations for people with fragile X---just meds! To clarify even further, I'm expecting to be paid for this service (already gotten a few requests for free medical advice since I posted this!)

If you're interested or have questions, just email me at fraxa@comcast.net . I'm planning to have a PayPal button installed soon to buy time directly.

UPDATE: I've added PayPal buttons to the left to buy consulting time. For most simple questions about medications, or follow-ups from previous consultations, a half hour should suffice. For more complex problems, especially initial evaluations where you'd like me to review a significant volume of medical records, a full hour is suggested. Generally speaking, I'll generate longer write-ups from longer consultations (1-2 pages for an hour.)

FAQ

2008-05-05T13:28:00.000-07:00

How can I make an appointment?

All appointments, initial or follow-up, must be made either in person or by emailing me at fraxa@comcast.net

Where are you located?

My private practice office is in Amesbury, MA

What if I don't have email?

Obtaining treatment through this practice requires that you have an active email account at all times, and email is the preferred method for essentially all communication. There is no charge for reasonable email contact (ie once or twice during the interval between appointments.)

What if I can't wait, and I need to call?

You will be given emergency contact information at your initial appointment; however, all calls will be billed at the regular hourly rate. These fees must be paid in full prior to your next appointment. This includes calls to pharmacies for prescriptions, usually necessitated by missed appointments. Abuse of telephone contact is the major drain on a psychiatric practice, and is not reimbursable by any insurance plan; furthermore, it is very difficult to document telephone contacts adequately. Email solves some of these problems, and is therefore preferred.

What kind of insurance do you take?

None. This is a strictly cash only, fee for service practice. You may be able to get reimbursement from some insurance plans for this type of out-of-pocket expense, but I do not have billing facilities to process any paperwork.

How much do you charge?

My fees are $300 per hour, and no discounts are offered. Initial appointments for new patients are one hour (50 minutes of actual "face time") and follow-up appointments are 30 minutes (20 minutes of actual "face time"), which includes administrative time for writing notes.

How do I pay?

PayPal will be used for all payments. You needn't have a PayPal account to pay these, though it speeds things up a bit---I'll send you a bill prior to scheduling an appointment. Once you've paid through PayPal by credit card or bank transfer, you'll be given an appointment.

Getting Started

2008-04-20T07:38:00.000-07:00

I'm now accepting new patients for my outpatient psychopharmacology practice. The service I offer is primarily the prescription of psychoactive medications, though I do have extensive training in various forms of psychotherapy, and I am certainly willing to use those skills. Let me state from the beginning that though I plan to practice psychopharmacology primarily, this is not meant to imply that other treament modalities are not important. Rather, psychopharm is simply the hardest part to find, and on the market level, this is what most people are looking for (ie most already have a non-MD therapist of some kind, but need someone with training in my medical specialty to prescribe meds.)

The developmental disorders population is certainly the most underserved of all, with very few practitioners specializing in this kind of treatment. It is my fondest hope that I can build a practice primarily with patients with fragile X, autism spectrum disorders, and other developmental disorders; I've never specialized as a child psychiatrist, but I've always treated lots of kids in previous incarnations of my outpatient practice. Patients of all ages will be welcome in this practice, and I like to think that my experience in treating kids, adults, and geriatric patients will help me to provide better care across the entire age spectrum (something which is usually ignored, even in the few groups which do treat developmental disorders-DDs.) Traditionally, DDs are the subspecialty of some child psychiatrists, but few of them continue treating their patients into adulthood. In the past, this was usually because the kids ended up in institutions of one kind or another, so a state hospital psychiatrist would take over---with mixed results, as you might imagine.

Unfortunately, to build a practice like this on a part-time basis, it isn't feasible to work through insurance companies. Their policies are always restrictive, and the red tape is all-consuming; furthermore, since I aniticipate serving a clientele from a wide area, it will not be possible to accept all the different insurance plans. There are many other issues with insurance and managed care companies (ie they don't pay reasonable rates, then they don't even pay the bills they're supposed to pay) which led to my closing my previous outpatient practice. Therefore, I've made the decision to start out with a simple policy: this is old-school private practice---no insurance, cash only. Needless to say this isn't for everyone, but I will say that psychiatry is pretty cheap by today's medical standards, and the pychiatrist is the cheapest part of psychiatric treatment. Getting state-of-the-art psychopharm treatment costs a lot less than getting your car fixed or your house painted, and we don't think of using insurance for those things. And if you compare the hourly rates and total costs of psychiatric treatment with even the simplest legal services, we're a much better deal. But doctors don't go into medicine for the money (really!) so we always feel guilty about actually charging actual people actual money for our services. Well, I've gotten past that guilt, and it's the only way I can do this kind of practice. So, my apologies in advance, but no insurance, no discounts, cash only (actually, PayPal only, but more on that later.)

A New Kind of Practice

2008-04-17T08:33:00.000-07:00

For the last 15 years, my wife an I have been working hard to build a non-profit organization, FRAXA Research Foundation, with the goal of helping our son and all the other kids with fragile X. FRAXA has been a runaway success in all ways, and the research we've funded has resulted in a number of major improvements in treatment for fragile X. I'm quite certain that these treatments will each help significant segments of the autism population as well.

But, here's the frustrating part: even though we've identified a number of available drugs which can treat the core deficits and correct the synaptic defects in fragile X, and even though these drugs have now been tested in the fragile X animal models, many physicians are reluctant to prescribe them. They want to see results from human fragile X clinical trials---appropriate enough, and we're doing these, but the results will take many years to make it into journals. In the meantime, they're using other drugs which are at least as toxic, and may be aggravating the basic problems our kids are facing.

Take the case of lithium: it treats nearly all the facets of fragile X that we can identify in animal models. It's a widely prescribed medication, officially approved by the FDA for the treatment of Bipolar Disorder, and it has a long history of safe use in children. Yet few psychiatrists and no pediatricians will use lithium, and fragile X patients have a very difficult time getting a prescription for it, even with recent reports of success in initial trials.

An even more compelling case is the recent finding of dramatic therapeutic effects from minocycline, a synthetic tetracycline antibiotic. Minocycline appears to be a superb treatment for fragile X, based on preclinical efficacy in animal models. Our initial experience in humans (including my son) is even more promising. Best of all, it's an incredibly benign drug which has been shown safe in millions of patients over dozens of years (and it's cheap, too!) Yet, when fragile X parents go to their doctors armed with this info, their MDs respond that this is a dangerous drug that is too risky for them to prescribe. Huh??? There's a 1 in 10,000 chance of getting (easily reversible) lupus-like side effects or benign intracranial hypertension. 1 in 10,000! But this child has a 1 in 1 chance of having fragile X, and we know that minocycline has beneficial effects (more on that later, but it's unpublished, and I don't want to steal the researcher's thunder.) So, the clinical trials are beginning, but once again, it will be years before all doubts (reasonable and otherwise) can be addressed.

So the question is, how can we get these treatments out there as quickly as possible, within the bounds of good medical care? Inevitably, the answer involves my assuming a more direct role---I have to get back to treating more people myself. That's why I'm getting back into an outpatient practice, to bring some of these research discoveries into the clinic.

I'm Baaaaack!!!!!!

2008-04-14T17:09:00.000-07:00

Well, after a very long hiatus (nearly 10 years) I'm heading back to an outpatient practice. In the coming weeks, I'll be describing the scope of this practice and how I hope to run it, along with some musings about the work I've been doing all this time. It's important, because I think it will (or should) shape the way I do things. Details to follow....