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.

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

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.

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?

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

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

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.