Science Q & A !!!

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

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

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

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

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

Q:

(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....

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

Adventures with minocycline...in real time

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!!!

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.....

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.