Saturday, December 27, 2008

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:


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.

Saturday, December 20, 2008

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.)

Sunday, December 7, 2008

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!

Friday, December 5, 2008

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.

Tuesday, November 25, 2008

Another excerpt from the upcoming new edition of my Med Guide

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.

Saturday, November 15, 2008

Trends in Psychiatry

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.

Herg√ľner 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.

Tuesday, September 9, 2008

AmEx project: Never mind!!!

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!

Friday, August 8, 2008

Please support FRAXA's nomination!

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!

Tuesday, August 5, 2008

Live too far away?

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 . 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.)

Monday, May 5, 2008


How can I make an appointment?

All appointments, initial or follow-up, must be made either in person or by emailing me at

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.

Sunday, April 20, 2008

Getting Started

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.)

Thursday, April 17, 2008

A New Kind of Practice

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.

Monday, April 14, 2008

I'm Baaaaack!!!!!!

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....