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.