tag:blogger.com,1999:blog-68189920367161063532024-03-13T12:30:45.579-07:00Dr. Mike's Psychiatry BlogMichael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comBlogger48125tag:blogger.com,1999:blog-6818992036716106353.post-55386609017701044052015-06-24T06:56:00.000-07:002015-06-24T06:59:25.625-07:00Metadoxine for fragile X---intermediate resultsAlcobra just announced results from their trial of a proprietary formulation of metadoxine in fragile X subjects, and there is a glimmer of hope in their announcement <a href="http://www.alcobra-pharma.com/releasedetail.cfm?ReleaseID=919218">(see here)</a>. While the drug did not show any beneficial effect on the primary outcome measure (essentially, an ADHD scale) it did result in some statistically significant improvement on 2 of 5 secondary measures. One of those showing improvement, the Vineland Adaptive Behavior Scale (VABS), is a well known and well validated outcome measure which has been used in other fragile X trials (though none of the other drugs resulted in improvement.) The other outcome measure showing improvement was the KiTAP, a computerized test of attention and distractibility. In both cases, the improvement was not only statistically significant, but also likely clinically meaningful; in other words, it was a relatively large effect.<br />
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The folks at Alcobra rightly note that this is the best showing to date for any drug in fragile X, and that both the KiTAP and VABS are appropriate and relevant outcome measures, and either could have been designated the primary outcome measure. The scale which was chosen as the primary endpoint, the ADHD RS-IV Inattentive subscale, was apparently chosen because the drug is thought to work mainly by enhancing attention, but the precise effect in fragile X could not have been anticipated.<br />
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It is possible that the VABS and KiTAP are just better or more useful scales for fragile X research, but it is also worth remembering that sometimes one or two secondary measures show apparent improvement which can’t be reproduced in subsequent trials. Alcobra has expressed interest in pursuing these findings, and they will presumably feature the VABS and KiTAP more prominently in the next round of metadoxine trials for fragile X. If they are able to reproduce these results, then this could be an important new treatment for fragile X.<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-59629896346495303032015-03-10T12:17:00.000-07:002015-03-10T12:17:32.547-07:00Re-examining the nature of fragile XIn the wake of negative results from several high-profile clinical trials in fragile X, we find ourselves questioning all of our previous assumptions about the nature of this disorder. After all, understanding the basic pathology of the disease is critical to development of new treatments---this is true across the board, in all branches of medicine. In the early days, shortly after the FMR1 gene was discovered and the normal protein product of the gene (FMRP) was identified, it was noted that FMRP was an RNA binding protein. So, whatever the normal function of the missing protein was, it seemed to have something to do with RNA metabolism. Since RNA is the template that is used to make new proteins, this meant that the fragile X protein was involved in regulating protein synthesis. A bit more work over the next few years led to the “mGluR Theory” of fragile X, the idea the FMRP normally regulates protein synthesis in dendrites in response to synaptic activity, and that in the absence of FMRP (in fragile X) there was abnormal protein synthesis, leading to excessive activity in some signaling pathways.<br />
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While this theory was extensively validated, pointing to the potential therapeutic value of mGluR5 antagonists as treatments for fragile X, there was always the possibility that this represented only a piece of the puzzle. After all, most biomedical research is done in fairly narrowly-focused model systems; the whole point of using models (animals, cells, etc.) is to simplify the incredibly and incomprehensibly complex human brain to the point where experimentation is feasible. Thousands of experiments by hundreds of scientists around the world confirmed that absence of FMRP led to consistent signaling abnormalities, and that these could be normalized by decreasing the function of metabotropic glutamate receptors, either genetically or pharmacologically. So, the mGluR Theory isn’t necessarily wrong, but clearly there’s more to the story.<br />
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Keep in mind that all of the above takes place in the postsynaptic compartment, otherwise known as the dendrite, or the dendritic spine to be more specific. However, it has been known all along that FMRP is normally present in the presynaptic compartment, otherwise known as the axon, as well as in surrounding glial cells like astrocytes (these are the non-neurons in the brain that perform many of the household chores.) So, the question has always been, what’s FMRP doing in all those other places? There’s no protein synthesis in axons, and there’s no synaptic activity in glia, so FMRP must be doing more than just regulating activity-dependent protein synthesis.<br />
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In the years since the original conception of the mGluR Theory, some valuable clues have come along. For example, FRAXA scientist Dr. Len Kaczmarek first found that FMRP interacts directly with certain ion channels to regulate neuronal excitability; specifically, he reported that one section of FMRP (not the RNA binding part) interacts with a large potassium channel called Slack to fine-tune the fidelity of auditory circuits. More recently, another FRAXA researcher, Dr. Vitaly Klyachko found that FMRP interacts directly with the presynaptic BK channel---literally the Big K (potassium) channel---to regulate neuronal excitability, and that absence of FMRP results directly in hyperexcitability of this system. In collaboration with Dr. Steve Warren, they examined samples from a patient with a rare mutation of FMR1. This patient has a point mutation in the gene, which results in a single amino acid change in the protein, which is produced in normal amounts. The patient has what is described as a “partial fragile X phenotype” of intellectual disability and seizure disorder, but without the physical features or typical behaviors of fragile X syndrome. Upon examining the protein produced from this mutation, Dr. Klyachko found that it had entirely normal RNA binding properties, resulting in normal activity-dependent protein synthesis and normal mGluR-LTD. The only problem caused by this single amino acid change was that this mutated FMRP couldn’t interact with BK channels, leading to increased excitability of the axon and greater neurotransmitter release. In other words, there is an entirely separate and very different presynaptic function for FMRP, not related to its RNA binding function in dendrites, and this represents another facet of fragile X, a distinct presynaptic phenotype unrelated to mGluR5.<br />
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It has long been known that FMRP is highly expressed in the non-neuronal cells of the brain (glia). Additionally, early experiments showed that normal neurons growing with fragile X glia demonstrated many of the same abnormalities we would expect to see in fragile X neurons. Conversely, growing fragile X neurons with normal glia reversed many of the usual structural abnormalities. Clearly, something is going on in fragile X glia, and that represents a potentially significant part of the disease mechanism. More recently, FRAXA researcher Dr. Yongjie Yang has shown that fragile X astrocytes (one main type of glial cell) have low levels of a key glutamate transporter, and this deficiency contributes to excessive glutamate levels in the synapse, resulting in hyperexcitability. This abnormality does not respond to mGluR5 antagonists; in fact, they may aggravate the problem. Thus, we have identified key glial phenotypes which appear to be independent of the other phenotypes described in neurons.<br />
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As we move forward, we may need to consider the contributions of these distinct presynaptic, postsynaptic, and glial phenotypes to the clinical presentation of fragile X. We may need to treat them separately for best overall effect, and the knowledge that different things are going on in different places in the brain may help us to develop combination drug strategies which can significantly alter the course of fragile X.<br />
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Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-60823655986665232962014-12-09T10:34:00.000-08:002014-12-09T10:40:08.580-08:00Pharmacogenomic Testing in PsychiatryA fellow clinician asked me what I thought about "pharmacogenomic testing" services which are now being offered, and heavily promoted. I guess people think of me as some kind of expert on genetics in psychiatry (hardly!), and I've previously mentioned that I don't think these tests are worthwhile.<br />
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Basically, this is genetic testing only for variations in metabolism of drugs; there are no genetic tests for any of the usual psychiatric disorders, and no tests of this kind are on these panels (I've looked at specific companies that offer this, but I won't name any names here---just commenting on the state of the technology.) Inaccurate diagnosis is one of the main reasons people don't respond well to treatment, and this testing doesn't provide any guidance there. So, this is the first issue.<br />
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There also aren't any validated tests for subgroups of depression or bipolar or schizophrenia that can tell you which patients are most likely to respond to which drug class (ie TCA vs SSRI vs SNRI.) That's #2 (that's probably coming next, though, and there is a lot of research going on to identify biomarkers for drug response within dx.)<br />
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#3 is that side effects and therapeutic effects (that's #4) don't always correspond to plasma levels, and so they certainly don't correspond very well to variations in metabolism. But if we just look at the levels achieved at a given dose (pharmacokinetics), then we can see that there are variations in absorption, distribution, and even elimination of the drug that have nothing to do with genetics (but are related to lifestyle, diet, weight, age, etc.) An obvious example: smokers metabolize benzodiazepines at twice the rate of non-smokers, on average. So, you might have a genotype which implies slow metabolism of benzos, but if you smoke, that gets you right back to average. These tests don't take that into account (some of them might ask if the patient smokes, but that's not a genotype). An even simpler example: you like to have a glass of grapefruit juice every morning; this makes you a very low 3A4 metabolizer, regardless of your genotype. So, it's much more important to ask people about their diet and lifestyle than it is to test their cytochrome genes. <br />
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There's also a parallel pharmacodynamic effect (that would be #5 and #6): two people with the exact same drug level can have radically different side effects and therapeutic results. This could be purely subjective (for example, one person simply has a low threshold for discomfort) but it also could be related to the actual physiological sensitivity of the target (usually a receptor and signaling pathway, in the case of psych meds.) There are many genetic variations in neurotransmitter receptors which are not fully understood (and not tested in these panels), and there are many more variations in signaling pathways which determine the sensitivity of target pathways, as well as those off-target pathways which cause side effects.<br />
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Surprisingly few drugs show tight correlations between plasma levels and therapeutic effects; obviously, you need a certain amount in your bloodstream to do anything, but in cases where there is a tight correlation, you can usually test for the level directly (as with TCAs.) For drugs like SSRIs, plasma levels aren't especially informative, and so they aren't routinely available.<br />
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However, in my mind, the main reason why these tests aren't especially useful (#7) is that you still need to use good clinical practice---you need to start the drug at a relatively low (subtherapeutic) dose in most cases, then increase gradually, monitoring for side effects. In the case of very long half-life drugs like Prozac or Abilify, you might start at a full dose, but you're essentially tapering up by letting the drug accumulate. You still need to inform the patient about likely side effects to watch out for, and you still need to assess whether an adequate response has been achieved, rather than placebo (another main reason for treatment failure.)<br />
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There's an argument to be made that this kind of testing can help to avoid those (rare) serious adverse effects which occur in unusually sensitive individuals who are very slow metabolizers, though I think any decent clinician should be able to catch these right away. One might also argue that this kind of testing can help identify patients who will definitely need higher doses for best effect (rapid metabolizers.) Here again, any competent clinician should know that the dose needs to be pushed because they aren't getting a real therapeutic effect, though admittedly very few clinicians seem to be capable of making the distinction between drug and placebo reliably. Still, you just can't assume that a patient who metabolizes a drug rapidly, and needs more of it for a true therapeutic effect, can actually tolerate the higher dose. That could be a major downside to having this kind of information, especially if less competent clinicians assume they need to simply start out at a high dose and push it up really quickly based on this kind of test.<br />
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In any case, it all comes down to cost. If this is cheap and easy, it could be useful in some cases, and post-marketing studies could make this kind of test even more useful. But, if it's expensive and time-consuming, I just don't think it's worth the trouble.<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-59470598553019120352014-11-25T21:30:00.002-08:002014-11-25T21:30:33.036-08:00Something to be thankful for---a major success for NeurenThis isn’t a fragile X trial, but the same Neuren compound that is in trials now for fragile X (NNZ-2566) has shown significant <a href="http://www.neurenpharma.com/IRM/Company/ShowPage.aspx/PDFs/1448-10000000/NeurensuccessfulinRettsyndromePhase2trial">positive effects in a Phase 2 trial for Rett syndrome</a>.<br />
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The results of the trial are interesting, in that improvement was seen a Rett syndrome-specific rating scale compared to placebo, and there was also improvement noted on the CGI-I (Clinical Global Impression of Improvement) and Caregiver Top 3 Concerns. However, there was no effect seen on ABC scores (Aberrant Behavior Checklist) compared to placebo. Many in the fragile X field have noted the inadequacies of the ABC; indeed, it was never designed or intended to be an outcome measure for clinical trials. In this case, a Rett-specific rating scale called the Motor-Behavior Assessment (MBA) showed a statistically significant and clinically meaningful treatment effect at the highest dose of the Neuren compound compared to placebo.<br />
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This is great news for those of us in the fragile X field for several reasons. First of all, it shows that this compound really does something---it seems to have useful properties in actual patients, and that’s not trivial. Second of all, this result demonstrates that disease-specific symptoms can improve significantly on the drug, and that improvement can be measured in a relatively short clinical trial. Additionally, it shows that a drug can have beneficial effects on core features of a genetically based developmental disorder, even if the more general rating scales (like the ABC) show no change. This is strongly reminiscent of the experience of many families and clinicians in recent fragile X clinical trials, where the drugs showed no advantage compared to placebo, but genuine improvement was noted in many subjects, with significant deterioration upon discontinuation of the drugs. Thus the calls for improved rating scales which can “capture” these core, disease-specific therapeutic effects. The Neuren fragile X trial is using some fragile X-specific outcome measures which will hopefully lead to similar positive results. The fact that this result is good news for Neuren also means that the company should remain financially viable for longer, so that they can continue the development of this compound for a number of indications---more “shots on goal”.<br />
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Of course, the usual caveats apply: this was a small study, and these results need to be replicated in a larger Phase 3 trial. Still, there’s a realistic possibility that we may see a similar result in fragile X!<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-12137328411268444472014-10-23T12:26:00.002-07:002014-10-25T20:54:00.605-07:00Here's a question we get all the time: I was wondering if the protein needed can be delivered another way, gene therapy, or via bacteria perhaps?Many people who are new to fragile X ask us about protein replacement strategies of one kind or another; it's an excellent question, and it's one we've been thinking about for a long time. After all, people with fragile X are only missing a single protein---isn't the simplest and most effective possible treament to just put that protein back in there? When FRAXA first started funding biomedical research, we were especially interested in exploring the possiblities of protein replacement therapy because this type of treatment was being commercialized by several biotech companies for several inborn errors of metabolism, like Gaucher's Disease.<br />
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However, we've subsequently found that there are several problems unique to fragile X that make a protein replacement approach very difficult, perhaps impossible. It all has to do with the nature of FMRP itself---this protein is a key regulator of dendritic protein synthesis whose own translation is very tightly regulated, bother spatially (where) and temporally (when). We have tried to add the protein into cells in a number of ways, and it is always quite toxic, because the protein needs to be at very specific places, only at very specific times---putting FMRP into cells in any way that does not involve natural regulatory mechanisms is not good for those cells, and it certainly doesn't fix fragile X.<br />
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One way to add some natural regulation to the process of restoring FMRP to cells is through gene therapy---add a copy of the gene, and let the cell make its own FMRP. This can actually be done in vitro, and even in the mouse model, and it works---sort of. The problem is that the version of the gene added to cells in this manner isn't exactly the same; it typically is packaged in some kind of viral "vector" and has some kind of viral promoter to get the gene going. This produces FMRP, but not the same way as it's naturally produced. However, this is a relatively minor problem. The major problem with gene therapy technology right now is that it still doesn't allow for delivery to the whole brain. The gene therapy experiments that have been done in fragile X have been done by injecting the vector directly into small areas of the (very small) mouse brain with a needle; this is completely impractical in humans.<br />
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We have been waiting for a technical advance that would allow delivery of gene therapy vectors (viral or synthetic) globally, because we know this is necessary for fragile X. The whole brain is affected, not just one small area (even conditions like Parkinson's Disease which involve relatively small areas of the brain still can't be treated by gene therapy.) Once the technology advances to the point that life-threatening conditions like Tay-Sachs can be treated by global CNS gene therapy, we should be able to adapt those techniques to gene therapy for fragile X. For now, we're still waiting.<br />
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Lastly, the idea of gene re-activation is especially attractive in fragile X. Most people with fragile X have a trinucleotide repeat expansion in the non-coding promoter region of the gene---this means that their mutation leaves them with their genetic code intact to potentially produce perfectly good FMRP. The only problem is that the gene is transcriptionally silenced. This means that it is densely methylated and wound around packing proteins called histones, which are de-acetylated to stabilize the DNA in a compacted form. There are other mechanisms of gene silencing and regulation of transcription that we are only now learning about, so turning a gene back on is far from simple. Turning only one gene on in any kind of targeted fashion is entirely impossible at this time---the technology simply doesn't exist, though lots of scientists are working on this.<br />
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We frequently get simplistic proposals to use chemical demethylating agents and histone deacetylase inhibitors as a way to get people with fragile X to start making FMRP again. This is another one of those things that looks easy if you're studying cells in a dish, but it's much, much harder to do in a whole brain. It's potentially very dangerous, because any chemical that can reactivate FMR1 will almost certainly reactivate many other genes. Furthermore, at this time there is no way to test any reactivation strategies, because we don't have any animal models with a transcriptionally silenced trinucleotide repeat expansion. Many attempts have been made to construct a "knock-in" (KI) mouse, but no matter how big the section of CGG repeats scientists introduce, the KI mice don't silence the gene the way people do. So, we have knockin mice that are excellent models of FXTAS, but they don't have fragile X. This is a problem we've been attacking by funding development of mice with human fragile X neural stem cells grafted into their brains, but it's been slow going. Until something like that is available, reactivation strategies are dead in the water.<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-2358217725225640252014-10-22T12:58:00.002-07:002014-10-25T20:53:09.430-07:00Can eating broccoli cure autism (or fragile X)?A fascinating new study is getting a lot of attention lately, so I decided to give it a closer read. A group of MGH, Harvard, and UMass autism researchers tested a broccoli sprout extract containing the antioxidant and apparent active ingredient sulforaphane in a double-blind, placebo controlled trial (read the full text <a href="http://www.pnas.org/content/early/2014/10/08/1416940111.full.pdf+html">here</a>).<br />
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The first caveat regarding this study is that the number of subjects is quite small; indeed, there were only 14 completers in the placebo group (using a 2:1 drug:placebo ratio), which could give rise to all kinds of misleading things. One thing I noticed was that there was no appreciable placebo response. An excessive placebo response can doom a trial, but when you see no placebo response at all, a red flag should go up in your mind. In small studies like this, the superiority of drug over placebo can result from an unusually small placebo response---a statistical fluke in the randomization process, really. If we then compare the placebo group showing no response to the drug group showing a typical placebo effect, but no actual treatment effect, it can appear that there is a big difference. This is essentially what happened in the first Novartis trial; the seven fully methylated subjects just happened to show no placebo response at all; in the larger study of the drug, this effect disappeared (in fact, the fully methylated group had an extra-large placebo effect.)<br />
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It was somewhat reassuring to see that ABC scores in the treatment group increased significantly 4 weeks after discontinuing, while still blind to treatment status, though there were numerous dropouts at this point, complicating interpretation. This kind of on/off effect is what you like to see, and is generally indicative of a true drug effect (of course it also means there is little carry-over effect, but most drugs do stop working when you stop taking them!) The effect of the broccoli sprout extract was significant, resulting in a 20+ point drop in ABC scores (note that the outcome measures were all the same as those used in recent fragile X trials.) However, the placebo response in the Novartis Phase IIb/III fragile X trials was actually quite similar in magnitude, so this could all be a statistical quirk.<br />
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Nonetheless, this is an intriguing result, especially since broccoli sprout extracts are widely available as nutritional supplements. But what about dosage? Can you actually get the same stuff used in this trial, and how much would you need? The study drug was a custom preparation which is not available anywhere, and the amount of sulforaphane given each day in the trial would be the equivalent of 20 or more capsules of the commercially available broccoli sprout extract, by my calculations. In addition, the potency of the extract was carefully monitored and maintained, implying that the compound is not entirely stable, and the pills you get at GNC might not even be as potent as they say (always an issue with unregulated nutritional supplements.) Still, 20 pills a day is possible as a treatment strategy. At this point, the evidence seems a bit weak, so I'd recommend waiting before trying this, but keep an eye on the broccoli story!Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-26221616892519394732014-09-24T15:42:00.001-07:002014-09-24T16:00:31.049-07:00More bad news...but then some good news for fragile X researchLet's get the bad news out of the way first---Roche <a href="http://www.fraxa.org/roche-reports-clinical-trial-negative-results/">announced</a> that the clinical trial of its lead mGluR5 antagonist for fragile X had failed to show any superiority on any of the outcome measures used (either primary or secondary.) They have also announced that they are cancelling their fragile X program. There aren't many details available at this point, though Roche has pledged to present and publish the data...eventually. I'm heading to the international mGluR conference in Sicily in a couple of days, and this is sure to be <b>the<i></i></b> hot topic; perhaps some new tidbits will be forthcoming. In any case, this was hardly a surprise. The Novartis results strongly suggested that the Roche compound would follow the same path; if anything, reports from the families participating in the Roche trial were even less promising than in the Novartis trial. If we are thinking that tolerance is a major problem, then the more potent and longer acting Roche drug may have even more problems with tolerance.<br />
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Now for some good news: the awards for the new fragile X research centers have been announced by the NIH. Three "Centers for Collaborative Research in Fragile X" will receive $35 million in funding over the next 5 years, and we couldn't be happier with the <a href="http://www.fraxa.org/nih-awards-35-million-to-fragile-x-research-teams/">choices</a>. These are all research groups that have been heavily supported by FRAXA over the years, and we think they will make a real difference, especially now that they have the resources to get things done!<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-75589466106984600342014-08-14T11:17:00.001-07:002014-08-21T15:51:15.796-07:00Question about fragile X therapeuticsAn astute reader asks: in light of recent experience, is the mGluR5 theory fatally flawed, and are there any other drugs which look promising?<br />
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In my opinion, the AFQ trials failed because of a dose range that was inadequate for fragile X, and because of the unexpected development of tolerance. Dosage problems are relatively easy to correct, but tolerance to the degree we observed may be a kind of fatal flaw, at least if we're talking about mGluR5 antagonists. The "mGluR Theory" is still probably correct; it's just that no one (least of all Novartis) expected tolerance to this drug---indeed, I'm not sure they would agree that's what happened. I think we saw a much better response than most people because our son was also on minocycline, effectively augmenting the response, and perhaps delaying the development of tolerance. This may be a clue to understanding the mechanism of tolerance, and how we can administer treatments for fragile X in the most effective way. We just finished the AFQ extension, and we're deep into the withdrawal now; withdrawal symptoms go hand in hand with tolerance, so this is to be expected, but it may also explain why some people in the trials did worse than placebo. A minor form of withdrawal is interdose rebound, and I suspect this was an issue for many people in the trial (though it's worth pointing out that few families thought their kids were actually worse on the drug; there were a few that got much worse, and I'll bet this is why.)<br />
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So, the mGluR Theory is still compelling, but we need to find another way to tone down the excessive mGluR signalling in fragile X. And we need to anticipate potential tolerance, and avoid drugs susceptible to tolerance. Incidentally, baclofen is well known to cause tolerance, so this may have been a problem in the arbaclofen trials, too. <br />
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Lithium modulates the activity of G-protein coupled receptor (GPCR, which includes mGluR) signalling, and has been extremely well validated in fragile X animal models. It has also been shown effective in preliminary clinical trials in fragile X subjects. Most importantly, given recent developments, lithium treatment does not result in any form of tolerance, at least not in the usual psychiatric indications. This is reassuring, and the use of this medication over the course of several decades in millions of patients, demonstrates that it is an effective therapeutic (whereas mGluR5 antagonist trials have failed in every case, for many different indications.)<br />
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There are 2 other possible explanations for the negative results from the Novartis trials. The one most often cited by virtually everyone in the field is the poor quality of the outcome measures available for fragile X clinical trials. These outcome measures, like the Aberrant Behavior Checklist and the Clinical Golbal Impression scales, are certainly crude instruments. There is little doubt that the "resolution" of these measurements is poor, and there is quite a bit of room for improvement in outcome measures for fragile X clinical trials. However, these trials simply did not show any hint of positive effect from the study drug (AFQ056); extensive analysis after the study ended ("post hoc analysis") showed absolutely no benefit from the drug compared to placebo.<br />
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There was one interesting result, though. Whereas many of the non-specific outcome measures (like CGI, VAS, and post-hoc narrative assessments from the clinicians) were essentially the same in placebo and all the drug dosage groups, the ABC scores got worse with higher drug dosage, and this effect was even statistically significant when the two trials (adult and adolescent) were combined. Now, this isn't a good result for the development of AFQ056, but it is interesting if we assume that the drug itself had no discernible effect (in other words, the result was a true negative.) We would expect that the drug group would have some side effects, that side effects would be greater at higher doses, and that in a special needs population side effects will usually express themselves as behavioral problems. So, if the drug doesn't work, you would expect the high dose drug groups would actually get a bit worse, and the ABC scores showed exactly that. Hmmm...maybe the ABC isn't quite as useless as everyone seems to think!<br />
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In any case, the outcome measures didn't doom this trial---the drug, as administered, simply didn't work (in most subjects.) The post hoc analysis didn't show even the tiniest suggestion of efficacy, and post hoc analyses always show something (this is another whole subject all by itself; using post hoc analyses can be an enormous tail-chasing exercise, with a host of new problems.) So, even when every detail could be examined outside the official trial protocol, a method virtually guaranteed to turn up something (at least a false positive!) turned up nothing at all. This gives us (well, me anyway!) great confidence that the drug didn't work the way was given. I doubt that the best outcome measures imaginable would have altered the results. Of course, we also need to re-visit the dosage issue. Most subjects in the trials were on doses that would be definitely sub-therapeutic; since dosing was fixed, and subjects were randomly assigned to dose groups, some people in the high dose group may have been on more than they needed. This isn't how psychopharmacology works in the real world; in clinical practice, we adjust the dose for optimal effects in each individual. However, in a clinical trial, this causes statistical headaches, so fixed dose groups are used.<br />
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So, the quest for improved outcome measures will continue.<br />
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The other possible explanation for the negative result (other than the obvious true negative condition) is that the effect is real but relatively subtle, possibly very gradual in onset, and not easily measured. In other words, it is below the level of resolution of any available outcome measure. But it is possible that AFQ monotherapy could have relatively little effect, while a rational drug combination could be quite effective. I have previously mentioned that we observed an excellent response to the study drug (though with significant subsequent development of tolerance.) Indeed, now that we have discontinued the AFQ, we know that the tolerance was only partial, because our son is clearly not doing well off the drug---probably some withdrawal symptoms mixed in with return of original fragile X behavioral symptoms. We are convinced that the drug has beneficial effects in fragile X, but our son is on other drugs, most notably minocycline. It seems quite possible that this makes a big difference, and that a combination of disease-modifying drugs may be needed to yield a therapeutic effect which is big enough to measure in this difficult environment. This is not unprecedented in medicine; for example, some antihypertensive drugs have relatively minor effects on blood pressure when given as monotherapy (and some show significant long-term tolerance), but are useful in combinations. All drugs push the system one way or another, but the system is designed to push back; more than one drug makes it harder for the system to compensate.<br />
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So, in the future, we'll be thinking about testing drug combinations in clinical trials. A more potent drug effect will also make it easier to validate new outcome measures, so this meshes well with the needs outlined above, and an integrated strategy is starting to take form!<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-75833805438769254952014-07-24T07:20:00.000-07:002014-07-24T07:22:02.813-07:00More on fragile X and MMP-9Just in case we're all getting despondent about the prospects for fragile X treatment, it's worth remembering that there are many potential disease-modifying strategies---it's not just mGluR5! Another major article from the Ethell lab at UC Riverside has shown the therapeutic potential of drugs that inhibit MMP-9. A nice lay description of the new paper is <a href="http://medicalxpress.com/news/2014-07-links-enzyme-autistic-behaviors.html">here</a> and the abstract of the article is <a href="http://www.jneurosci.org/content/34/30/9867.abstract">here</a>.<br />
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This latest work shows that human fragile X tissues have elevated levels of the extracellular enzyme MMP-9, as well as an increase in the active fraction of that protein (like most enzymes, MMP-9 can exist in an inactive form which can be switched on rapidly; this kind of regulation is important in most biological pathways.)<br />
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The Ethell lab also showed that genetic reduction of MMP-9 rescues most fragile X phenotypes in the mouse model. Previous work had shown that inhibition of MMP-9 with minocycline also had similar effects, but minocycline has many different actions. These experiments demonstrate conclusively that MMP-9 inhibition is the active ingredient. This is important, because pharma companies are working on drugs which inhibit MMP-9 without the antibiotic effects. They also showed that inhibition of this extracellular enzyme can normalize the activity of many of the intracellular signaling pathways (i.e. mTOR) that have been the focus of so much fragile X research. And, perhaps most interesting of all, they showed that genetic reduction of MMP-9 rescues the macro-orchidism phenotype in fragile X, something which has been relatively resistant to rescue with other therapeutic strategies. Since MMP-9 is a gelatinase, we have previously hypothesized that excessive MMP-9 activity in fragile X was responsible for the well-described lax connective tissue; confirmation that MMP-9 activity is indeed elevated in human fragile X tissue lends support for this idea, though this phenotype is difficult to measure in mice, so rescue effects were not assessed in this study.<br />
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All in all, this latest article adds to the growing body of evidence that MMP-9 dysregulation is a critical part of the pathology of fragile X, and MMP-9 should be considered a major treatment target for fragile X.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-66183634425753911842014-07-19T22:17:00.001-07:002014-07-19T22:17:26.087-07:00What to make of the clinical trial failures in fragile XTo summarize: the official results from both the adult and adolescent trials of AFQ056 for fragile X were decidedly negative. Not only was there no improvement on pre-designated outcome measures, but subjects did a bit worse on the drug than on placebo (and placebo effects were robust, but in line with other trials in developmental disorders.) However, it is important to note that trial subjects got better on the drug, just not as much better as on placebo. Extensive analysis of the trial results after the fact ("post-hoc analysis") revealed no obvious differences in clinical responses between the different drug dosage groups and placebo. Subjects with a fully methylated fragile X mutation didn't respond any better than those with a partially methylated mutation, more severely affected subjects didn't respond any better than less severely affected (or vice versa.) So, the drug simply didn't work in any way that anyone can see or measure objectively, though many families reported excellent results, and most of the subjects in the open label extension continued on the drug, apparently satisfied with the drug's effect.<br />
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Our personal experience, which may have been a bit aypical because of co-administration of minocycline, was much more positive than the official results. Even so, the great results we saw at the beginning of the trial, and then during the first few months of the open label extension, just didn't last. We think there is still some beneficial effect at this point, but we were certainly hoping for continuous improvement.<br />
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The most important point is that this isn't just a problem with outcome measures. It would be great if we could attribute this negative outcome entirely to inadequate outcome measures. It's still possible, though increasingly implausible, to claim that the drug is actually improving cognition and other important developmental outcomes which aren't captured by the outcome measures, while at the same time having little beneficial effect (and even some adverse effects) on behavior. However, that isn't what we saw at all. We saw clear improvements in mood and behavior (not to mention reflux), and our son's ABC scores plummeted (before creeping back up later.) We have not seen any major leaps forward in development, or dramatic improvements in cognitive function. Now, improved behavior and mood can make everything seem better, at least for a while, and this may be what some families were observing. When people feel better, they generally do more and expand their range of activities. But this effect won't alter developmental trajectories. In other words, it won't be truly disease-modifying unless there is a sustained effect on all major fragile X symptom domains.<br />
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Where does this leave us, then? Well, first of all, mGluR5 antagonists probably won't be a viable treatment for anything if tolerance develops to this extent, and we've seen tolerance develop to the anti-reflux effects as well as the CNS effects. It's no coincidence that so many of the mGluR5 programs around the world have failed and been discontinued. This implies that this target many not be viable for fragile X therapeutics, although it is possible that trials of higher doses of mGluR5 antagonists, perhaps in combination with other drugs, could still be effective. However, this greatly complicates the "re-purposing" strategy, since most drugs are developed with a particular dose range in mind, and most drug companies would need to go back and repeat this process specifically for fragile X. It is not likely that any company will be enthusiastic about incurring this expense in light of recent experience.<br />
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We have many more thoughts about where the fragile X research field needs to go, and we'll discuss those ideas in future posts.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-12902758167960157202014-06-30T07:06:00.002-07:002014-06-30T07:06:40.153-07:00Further thoughts on our AFQ experienceSo, the Novartis trials ended with a rather negative result. But we did see a lot of positives in our son along the way. Could it be that there was something about our case that made a response more likely? Well, I do think that the combination of minocycline and AFQ056 was probably much more effective than just AFQ alone. The preclinical evidence for minocycline as a disease-modifying agent in fragile X is very strong, and the clinical trials done to date, though probably not rigorous enough to be considered definitive proof of efficacy, have been positive (unlike some others!) It stands to reason that a combination of two drugs would work better, given that fragile X is a disorder that affects the brain globally. In other words, one drug might work well in one area of the brain, but not fix everything; another drug might work well in other areas or other pathways, so that the combo gives greater "coverage" and a better clinical response, especially with the rather crude outcome measures we're using. It would be interesting to see if trial subjects on minocycline had any better pattern of response, but I doubt there were enough subjects on the combination to analyze properly (especially since many of the subjects were outside the US, where minocycline use in fragile X is much less common.)<br />
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One question I've been asked a few times is, if there is tolerance developing to mGluR5 antagonists, why don't the rating scales from the trials show that? Why don't we see the scores go down, then back up? Of course, all of the above has an effect---most subjects aren't getting enough drug effect to notice in the first place. But this is also where the shortcomings of the outcome measures may come into play. The resolution of these rating scales, especially in the context of moderately large placebo responses, is simply nowhere near good enough to quantify tolerance (although, I should note that our scores did go way down, then back up a bit toward the end of the study; I believe our son's clinician ratings also showed this.) It's also quite possible that there are sub-groups of fragile X subjects who are particularly responsive to one drug or another. We've had friends who participated in both the arbaclofen trial and one of the mGluR5 trials, and some have had terrible experiences with one, but great effects from the other. Ideally, you'd like to be able to predict who would do better, either with a biomarker or via phenotypic features, but there's nothing available right now to do that. Indeed, we are caught in a bit of a Catch-22 scenario: we need to have a clinical trial success to demonstrate which outcome measures, biomarkers, and endophenotypes are most useful, but we need to have some of those things first to have successful clinical trials!<br />
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Perhaps one solution is to have pilot trials with combination treatments, as a way of getting more robust and reliable effects from the drugs. This would allow for better study of outcome measures and biomarkers, and it would allow us to figure out which ones are actually drug-responsive. It may be unrealistic to expect that any one drug can move the needle far enough to be measurable, but a two drug combo may have a better chance of success.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-63239156718111875352014-06-25T15:12:00.001-07:002014-06-25T16:07:06.520-07:00Novartis trial results are in, and they're not prettyThis year's Gordon Conference just finished,and Novartis presented their results for the first time (though advisors and advocates had been given a private peak months ago.) To say that the trial results for AFQ056 were disappointing would be the understatement of the century! While the company has already announced that the adult and adolescent trials failed to meet their pre-designated endpoints, the numbers looked really bad. This wasn't a case of the drug working, but placebo effects leading to an outcome that wasn't statistically significant; in this case, the effect of the drug was statistically significant, but in the wrong direction!<br />
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So, what went wrong? The evidence for using mGluR5 antagonists in fragile X was really strong going into these trials---in fact, about as good as it ever gets. The drug itself was an advanced compound that had been studied extensively. Of course, outcome measures have been a problem, and they're definitely not good enough. However, Novartis did an exhaustive analysis of all the data, plus they even went back and looked again at subjects who were reported by clinicians and caregivers as exceptionally good responders. None of this "post hoc" analysis revealed any positive effect of the drug compared to placebo---not even a glimmer of hope in adults or adolescents (and both trials came up with very similar results, providing some degree of cross-validation). The ABC and other outcome measures used might leave much to be desired, but they weren't the reason for these trial failures. Indeed, the trials were not "failures" in any sense, except that the results were decidedly negative. Novartis conducted an excellent pair of clinical trials which showed convincingly that AFQ056 doesn't work for fragile X, as least not as administered in these trials.<br />
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Perhaps the Roche compound will show much better efficacy; it is a different drug, and somewhat different methods are being used in the Roche trials. But our personal experience may offer some insights into what is going on, and this also leads me to be a bit pessimistic about the chances for mGluR5 antagonists in general.<br />
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Our 25 year-old son was one of the last adults enrolled in the AFQ trial; I should note that he was also on minocycline during this entire time, as he has been for many years. This is thought to have potentially disease-modifying properties for fragile X, and so this may have boosted the effect of the AFQ. His other meds are valproate, topiramate, and sertraline. He also has a lot of severe gastro-esophageal reflux, which means he spits up his food a lot if he eats too fast (it seems to be reflux, which is a physical effect based in the stomach and esophagus, rather than nausea, which is a centrally mediated process controlled by the brain.) In any case, when he started the blinded phase of the trial, we saw a rapid improvement in his mood, language, social function, and basically everything else. But we only saw one "bump" up during the dose titration, which led us to think he was on the lowest dose of the drug (this was later confirmed.)<br />
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Unexpectedly, his reflux went away entirely along with all this other improvement; I should also note that this was all after the 4 week placebo run-in (we'd been tipped off about that long ago!) But this is a guy who had never in his life gone for a whole week without barfing; this was a regular, daily event for us. Our son had not one single episode of reflux for more than one month after starting on that tiny dose of AFQ! Call it a side effect, or a bonus, but it was something very objective and hard to ascribe to placebo. Indeed, mGluR5 antagonists are known to increase tone in the lower esophageal sphincter, and have been studied as treatments for reflux. The first 6 weeks or so were great---we started doing all kinds of new things, like sailing and traveling, dining out and going to lots of new places. This, I thought, was what we had been waiting for! But then the effect started to wear off, little by little. The reflux came back, though only a bit here and there. <br />
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We figured this was no big deal, that in the extension phase we'd get to a higher dose and that would work much better. Which turned out to be true! When we started the open-label extension, our son got noticeably better with each dose increase, and tolerated the full 100 mg twice a day with no side effects to speak of, except the good one (no reflux at all!) This kept up for several months, and we were very happy. We assumed that things would just keep getting better and better as long as we kept up the AFQ. However, after a while (hard to say exactly when, because I think it was very gradual), many of the old behaviors started creeping back in, as did the reflux (in fact, they seemed bound together quite tightly.) As I write this, about 9 months after starting the full dose of AFQ, I'd estimate we've lost about 70-80% of the effect of the drug. We're probably not all the way back to baseline, but we're not finding that things are getting better and better all the time.<br />
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Now, even I realize that the placebo effect is very powerful, and that we are hardly objective observers in this case. I could easily be imagining improvements in mood or behavior, or we may have treated our son differently because of our expectations, leading to better behavior. But I can't explain the reflux as anything other than a real, physical effect. He ate the same food, the same way as ever. The mGluR5 antagonist simply helped him keep it down---it's known to do that. But even that effect wore off! Tolerance developed to that physical effect at approximately the same rate as the "central" effects that were the primary objective in this case.<br />
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So, in a nutshell, the problem we've seen, and the likely reason for the trials to fail, has been the development of extensive tolerance. This is quite unexpected, it's probably something intrinsic to mGluR5 in fragile X, and something I'll discuss more in upcoming posts.<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-49665384019050567142013-03-20T07:27:00.000-07:002013-03-20T07:27:22.576-07:00It’s not just mGluR5…there’s more than one way to fix fragile X<br />
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In case you somehow got the impression that FRAXA is only interested in mGluR5 research, or that we’ve quit funding basic research altogether, the most recent edition of the Proceedings of the National Academy of Sciences (PNAS) illustrates just why that’s not true. <br />
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Long after the seminal finding of increased mGluR-LTD in fragile X by Kim Huber and Mark Bear, FRAXA funded studies by Nobel-laureate Susumu Tonegawa investigating the role of the enzyme PAK in regulating the shape and function of dendritic spines. The results of this FRAXA-funded project demonstrated that genetic reduction of PAK could rescue most fragile X knockout “phenotypes” (the animal model equivalent of human symptoms.) This was essential proof of concept work which established PAK inhibitors as potential therapeutics for fragile X, and was the basis for a new company called Afraxis. The only problem was that no specific PAK inhibitors actually existed at that time, but Afraxis has been busy trying to find useful drugs that inhibit PAK (actually a family of enzymes, not one single enzyme.) The paper just published by Tonegawa and his collaborators from MIT, Afraxis, and universities in India and Korea, shows that a new compound which Afraxis calls FRAX486, inhibits all the PAKs in the brain at relatively low doses, and displays all the properties you’d expect of a useful drug. Most importantly, it appears to reverse most of the important animal model phenotypes with a single dose (though, presumably, daily dosing would work better as a human therapy.)<br />
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Read the whole thing: http://www.pnas.org/content/early/2013/03/14/1219383110.full.pdf+html?with-ds=yes<br />
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At this point, FRAXA has developed a large pipeline of drug candidates for the disease-modifying treatment of fragile X. We continue to fund basic research looking for more promising leads, but our main emphasis is on developing treatments based on the work we’ve already funded, which has given us plenty of candidates for therapeutics that can alter the course of fragile X. We’re excited about our partnerships with companies big and small, like Afraxis, because these partnerships are essential to bring new treatments to fragile X families in need.<br />
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-15905668290422458582012-12-02T22:07:00.002-08:002012-12-02T22:07:53.946-08:00An internet friend asked for my feedback on the following article:<br />
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<i>Primum Non Nocere: An Evolutionary Analysis of Whether Antidepressants Do More Harm than Good<br />
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Abstract<br />
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Antidepressant medications are the first-line treatment for people meeting current diagnostic criteria for major depressive disorder. Most antidepressants are designed to perturb the mechanisms that regulate the neurotransmitter serotonin – an evolutionarily ancient biochemical found in plants, animals, and fungi. Many adaptive processes evolved to be regulated by serotonin, including emotion, development, neuronal growth and death, platelet activation and the clotting process, attention, electrolyte balance, and reproduction. It is a principle of evolutionary medicine that the disruption of evolved adaptations will degrade biological functioning. Because serotonin regulates many adaptive processes, antidepressants could have many adverse health effects. For instance, while antidepressants are modestly effective in reducing depressive symptoms, they increase the brain’s susceptibility to future episodes after they have been discontinued. Contrary to a widely held belief in psychiatry, studies that purport to show that antidepressants promote neurogenesis are flawed because they all use a method that cannot, by itself, distinguish between neurogenesis and neuronal death. In fact, antidepressants cause neuronal damage and mature neurons to revert to an immature state, both of which may explain why antidepressants also cause neurons to undergo apoptosis (programmed death). Antidepressants can also cause developmental problems, they have adverse effects on sexual and romantic life, and they increase the risk of hyponatremia (low sodium in the blood plasma), bleeding, stroke, and death in the elderly. Our review supports the conclusion that antidepressants generally do more harm than good by disrupting a number of adaptive processes regulated by serotonin. However, there may be specific conditions for which their use is warranted (e.g., cancer, recovery from stroke). We conclude that altered informed consent practices and greater caution in the prescription of antidepressants are warranted.</i><br />
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Read the whole thing at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3334530/<br />
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It's always interesting to read and critique articles like this, because it gives me a chance to think about the Big Picture---in fact, I think I'll expand on this and make it into an extra-long blog post. I guess this article was thought-provoking; it certainly got my juices flowing, mainly because a lot of people ask me questions related to the points made in this article, and I think it’s important to answer these questions, because it’s easy to scare people away from the medical treatment they need. Some might say I'm biased, because I prescribe drugs; however, I've also done many thousands of hours of psychotherapy, too.<br />
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As an overview, this article is typical of its genre, and can be seen as part of the ongoing psychology/psychiatry turf war. It's not really just science, but also an opinion piece from people with an ax to grind, and probably some vested interest. The article is of poor quality, and the authors clearly do not understand many of the basic neuroscience topics they are purporting to review; many of the references are review articles, not original studies, and rely heavily on their own previous review articles and on those of co-authors who clearly run in the same circles. This is OK when you're in a small field, but this is not a small field. They are using a tiny fraction of the literature to support an opinion (that antidepressants do more harm than good) which is absolutely not supported by the weight of the available evidence. They also have an annoying habit of stating something non-controversial (i.e. serotonin is in platelets) and referencing that extensively, then asserting something outrageous without any reference at all---the journal reviewers shouldn’t let them get away with this, so this speaks to the quality of the journal.<br />
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It is always true in the life sciences that there is some contradictory evidence, no matter the subject. We don't know everything, and our concept of how the brain works will be evolving for a long time to come---certainly for the rest of our lives, and then some. We cannot be paralyzed by what we don't know when there is real human suffering. Depression, anxiety disorders, and other associated conditions which are commonly (and very effectively) treated with these medications exact an enormous human toll, and if we're going to wait until we understand everything about them before we start treating, we're going to be waiting for a very long time. We do the best we can with basic neuroscience research, translational research on disease mechanisms, preclinical research in animal models, and then carefully controlled clinical trials. The science is never settled, and our understanding is always subject to review (remember that when you hear other scientific issues discussed in the popular press.)<br />
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One of their main points is that there is a carefully regulated and highly evolved homeostasis in all these systems (i.e. serotonin), and that anything that perturbs it must necessarily cause dysfunction. You could say this about any medical treatment for any condition, so I guess all of modern medicine is suspect from this point of view (with the possible exception of antibiotics, but they'd probably argue that perturbing normal flora is dangerous, too.) The point they're obviously missing is that the system is already perturbed, and that's why we have a disease state. Some of the authors have previously written that depression (and by extension, just about any mental illness) is just a normal evolutionary response; that may or may not be true, but we haven't evolved much at all (genetically speaking) as a species in the last 10,000 years, while our lifestyle has changed radically. The same is true for the extensive discussion of withdrawal and discontinuation effects in the article; while it's certainly true that many patients relapse when antidepressants are discontinued, that’s also true for virtually all medical treatments of chronic (i.e. non-infectious) diseases. When patients stop taking antihypertensives, blood pressure rebounds---often higher than ever. If an epileptic patient stops taking seizure meds, more seizures are likely. If a diabetic stops taking insulin, they’re still diabetic, and their blood sugars go up. All of this is expected, yet the authors seem to proclaim that they have discredited antidepressants with this revelation.<br />
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The surprising thing is how few patients actually relapse---if it’s done right, most people are able to discontinue their antidepressants and have something like a lasting “cure”. Of course, the devil’s in the details, and it’s often not done right. It would be nice to have more research in this area, and much is underway; in the meantime, good clinicians have figured out the best methods for successful discontinuation. My clinical pearls: treat for at least a year at the optimal dose (longer if the depression is more chronic), then decrease the dose very gradually, and do it at a time of year that’s good for the individual patient (often, Spring is the best time of year.)<br />
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They really get bogged down when talking about neurogenesis; they mistakenly assert that neurogenesis is widely considered to be the mechanism of action of antidepressants; this is one theory, but not the consensus or established view by any means, so I'm not sure why they spend so much time and effort trying to poke holes in one theory of antidepressant mechanism of action. Anyone who’s ever spent any time thinking about this has come to the conclusion that the antidepressant response is essentially an alteration of gene expression (one manifestation of which might be increased neurogenesis, but it’s hard to imagine that’s the full extent of it.) All the different monoamine manipulations caused by available antidepressants are likely just means to an end, different ways of altering gene expression in the brain. It is no accident that hormonal alterations like increased cortisol or decreased thyroid hormone, which are thought to cause some cases of depression, are also known to cause widespread alterations in gene expression. There are probably many ways to get depressed or anxious, and the available treatments are just ways that we’ve found to (partially) reverse those processes.<br />
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The authors argue that the evidence for enhanced neurogenesis with SSRIs and other antidepressants is equivocal. Since there are hundreds, even thousands, of studies demonstrating this phenomenon in many different ways (not just the one they critique) and a relative handful that show a negative result, you could call that "equivocal", but I would call it a preponderance of evidence. Remember, there is always conflicting evidence in science! They speculate that if neurogenesis is increased with antidepressants, you should see more brain tumors. This is incredibly silly, and something they just made up (no reference at all, because it just isn’t true!) Neurogenesis does not lead to neoplasia (cancer) at all---those are two entirely distinct phenomena, and anyone with any medical training would know that. If neurogenesis is increased, you would expect to see more seizures with antidepressants---and you do! All known antidepressants result in a small but significant increase in seizures in trial populations; the risk isn’t great, but it’s there, and it’s probably a direct manifestation of increased neurogenesis. The interesting thing is that antidepressants vary widely in their seizure risk, but this does not correlate with antidepressant efficacy. SSRIs are low-risk, while other drugs like maprotiline (Ludiomil) and bupropion (Wellbutrin) are clearly much higher-risk. This suggests to me that neurogenesis is a sideshow, and not the primary antidepressant mechanism, but that’s just my opinion.<br />
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The article also spends a lot of time emphasizing the point that antidepressants just don’t work as well in clinical trials as most folks might imagine, and that there have been many trials (often unpublished) where the antidepressant fails to separate from placebo, or has a very small effect size. To some extent this is true, especially for those who don’t really understand drug trials, and just how difficult they are to conduct. What happens when a clinical trial isn’t properly designed and conducted? The result is that improvement on drug is not statistically superior to placebo; note that this does not mean that the trial drug doesn’t work. It could mean that, or it could mean that the trial simply wasn’t well done, for any number of reasons. However, it is exceedingly unlikely the drug would show superior efficacy compared to placebo by chance, or because of poor methodology. So, it’s a kind of one-way street: virtually all problems (other than outright fraud) lead to a result not significantly different from placebo. Positive trial results are important, and they are accorded great significance for just this reason---they are very hard to come by, because the system is heavily biased against a positive outcome in any double-blind trial. Of course, there are limits to this. If a drug goes through 20 trials, and only one shows significant efficacy compared to placebo, then it’s probably not a very effective drug. But if a drug is in 20 clinical trials, and only 12 are positive, that’s not bad (and fairly typical in psychiatry.) That is an effective drug, and the FDA understands that. It’s also important to understand that most subjects in clinical trials are chronic, difficult, treatment resistant patients; it is rare to find drug-naïve subjects in any psychiatric clinical trial. So, critics of antidepressants are always fond of citing big meta-analyses, where results are pooled from all the available studies, good and bad. This invariably diminishes the effect size and increases the placebo effect compared to the more successful, well-done studies. Psychiatric research is just like any other human endeavor, some of the people doing it are incompetent, and their efforts muddy the waters for everyone else.<br />
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In the real world, we tend to see much higher response rates among the general population. For example, in my practice of young and middle-age adults in a private outpatient setting, I generally found a response rate to SSRIs for depression and anxiety disorders of about 90% in patients on their first med trial---well in excess of the usual 70% response rate in most clinical trials. These were real, life-changing responses to treatment, with no “poop-out” after a while. Placebo responses never last, so I’m confident that most of these were real therapeutic effects. My success rate in discontinuing the antidepressants in this category of patients was about 60%, using my conservative methods; the unsuccessful 40% went back on the same medication, at the same dose, and virtually always did fine until the next time they wanted to attempt drug discontinuation.<br />
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This paper also includes a rather histrionic recitation of side effects of meds, focusing on SSRIs. Of course, all medications have side effects; it’s really surprising how many side effects are reported even in placebo-treated subjects. But most people on SSRIs don’t have major side effects, and many never notice anything at all; the body does adjust, so that the reported side effects usually dissipate as treatment goes on. Here again, this is not really different from what we see with any medical treatment. The authors go into gory detail about the risks of very rare side effects like hyponatremia (I’ve never seen a single case with any antidepressant---I have seen a bunch with the anticonvulsant Tegretol), and try to demonstrate that SSRIs cause cognitive impairment (there’s no evidence of it, and it has been tested directly.) Throughout, they make the most common mistake people make in this situation: they compare the rates of various problems in depressed people treated with antidepressants to the rates seen in normal untreated people. The problem is that depression causes many of these problems, like cognitive impairment, suicide, and excessive cardiac deaths. So, it’s hard to separate the symptoms of the disease from the side effects of the treatment.<br />
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I would also note that psychotherapy is not without side effects, especially since the authors seem to have the agenda of promoting psychotherapy. Now, I trained extensively in long-term, psychodynamic psychotherapy; I’ve done lots of it, and I’m very much in favor of it, as well as newer focused psychotherapy approaches. But I’ve also seen many patients (and some personal friends) devastated by poorly done or inappropriate psychotherapy. Drug side effects are usually easy to fix---just stop the drug. The kind of damage inflicted on these folks by incompetent psychotherapists can never be undone, not to mention the financial ruin and exploitation that went along with it. Most people assume psychotherapy has no side effects because they also assume it doesn’t do anything at all. Neither assumption is true.<br />
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As a final note, there have been several long-term studies of brain volume in people with depression (and similar studies in OCD). Having depression shrinks your brain on CT or MRI, and treatment with antidepressants (doesn’t seem to matter which ones, as long as they’re clinically effective) prevents this. This is a very powerful argument against most of the pseudo-biological speculation offered in this article, yet the authors gloss over these inconvenient facts entirely. Depression is very bad for your brain; antidepressants clearly help. Are they perfect? No, but their benefits clearly greatly outweigh their risks in the vast majority of people with serious Mood Disorders and Anxiety Disorders.<br />
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Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-52327430648921802112012-09-20T17:42:00.000-07:002012-09-20T17:50:28.745-07:002 New Arbaclofen Studies Getting Lots of Press!
<i>Two complementary studies were just published in Science Translational Medicine, and they’ve been getting a ton of attention in the media. Since lots of people are asking about these articles, and lots of reporters are calling to get my comments (and subsequently misquoting virtually everything I tell them,) I thought I’d give my official commentary here.</i>
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The first article (Henderson et al.) comes from researchers at Seaside Therapeutics, along with multiple academic collaborators around the world (including some of FRAXA’s favorite past grantees!) The authors present a series of experiments demonstrating preclinical validation of arbaclofen as a potentially disease modifying therapeutic in fragile X. This is significant, because arbaclofen entered clinical trials based on clinical observation of beneficial responses to (regular) baclofen in patients with fragile X, but without much preclinical testing in animal models of fragile X. Using a number of protocols previously established and accepted by fragile X researchers (and virtually all funded by FRAXA), this team showed that arbaclofen can rescue abnormal protein synthesis, AMPA receptor trafficking, audiogenic seizures, and dendritic spine abnormalities in the KO mouse. Thus, arbaclofen has passed a lot of the same tests that mGluR5 antagonists have passed to demonstrate potential for disease modification. While there is no single lab test which can show that a drug can cure fragile X, we think that the ability to correct a broad array of abnormalities, as shown in this study, strongly suggests that a drug strategy may be able to alter the course of fragile X (and therefore be “disease modifying”.) So, this looks really good for arbaclofen. As always, the usual caveats apply: mice aren’t humans, and the most critical aspect of translating this kind of preclinical finding into disease modifying clinical treatment is dosage. The authors of the study were careful to utilize realistic and practical doses of arbaclofen in their experiments, but it is always possible that the doses which can be tolerated by fragile X patients will not be adequate for truly disease-modifying effects (though perhaps still adequate for useful psychotropic effects.)
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The second paper (Berry-Kravis et al.) presented the data from Seaside Therapeutics’ Phase II trial of arbaclofen in 63 subjects with fragile X; this seems to be the article that is getting most of the attention from the science press. It is essential to understand that Phase II clinical trials are primarily designed to demonstrate the safety and tolerability of the test drug in the target population (i.e. fragile X.) Efficacy is a secondary consideration, but criteria are specified in advance which can provide an initial demonstration of efficacy, and a Phase II trial can be quite useful for defining qualitative aspects of the drug response. In this article, it was clear that arbaclofen was quite safe and well tolerated; indeed, the low rate of side effects compared to placebo might suggest that the dose range chosen for the study was a bit too low. While this trial failed to demonstrate any advantage (statistically, or even numerically) of arbaclofen over placebo in the chosen primary outcome measure (the Irritability subscale of the Aberrant Behavior Checklist, or ABC-I) there was a definite sense from parents and the clinicians conducting the study that those on the active drug did better than those on placebo (“blinded treatment preference”.) In other words, the clinicians and the people closest to the trial subjects could tell who was on the active drug, with a moderate degree of certainty, and those subjects seemed to do better. Unfortunately, this is not the kind of outcome measure that the FDA would allow for approval of a new drug, but it is an indication that arbaclofen is doing something useful.
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As outlined in the article, things got much more interesting when the data were examined after the fact (“post hoc analysis”.) While the Irritability subscale of the larger ABC (the designated primary outcome measure) did not change with arbaclofen treatment, the Lethargy and Social Withdrawal (L/SW) subscale did improve slightly. Moreover, a recent re-factoring of the ABC to make it more “fragile X friendly” showed that the L/SW scale could be replaced with a slightly modified Social Avoidance subscale which was more relevant to fragile X. If the trial results were analyzed in light of this fragile X-specific re-factoring of the ABC, and if only the subjects with elevated Social Avoidance scores were included in the analysis (roughly half of the study population,) then arbaclofen appeared to lower Social Avoidance scores significantly. Additionally, subjects entering the study with elevated Social Avoidance subscale scores showed statistically significant improvement on the Clinical Global Impression Improvement scale (CGI-I), a standard assessment which is considered an acceptable outcome measure by the FDA. Unfortunately, post hoc analysis is not acceptable for FDA approval. But this kind of analysis can inform subsequent studies, and Seaside is now conducting Phase III trials of arbaclofen, using the outcome measures found in this study to be most reliable in demonstrating the therapeutic effects of arbaclofen. So, in the end, perhaps the greatest value of this clinical trial is that it will make future trials of arbaclofen (and perhaps other fragile X treatments) better, and more likely to succeed.
Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-83659467147747500152012-09-07T08:25:00.000-07:002012-09-07T08:28:48.300-07:00What works, and what doesn’t At the start, it’s always hard to know what methods will work best for something as complex as the development of disease-modifying treatments for fragile X. But, we’ve always tried to let the science lead us down the right path. At this point, the results are unequivocal, and they have shaped how we are looking for the Next Great Thing in fragile X treatments.
As a bit of background, it’s worth noting that there are two basic ways of approaching treatment research for any disease: rational drug discovery vs. high-throughput screening.
Rational drug discovery means exploring the basic mechanism of disease and identifying specific “treatment targets” that might be expected to correct the underlying problem. Usually, the target is an enzyme (a protein which facilitates biochemical reactions in the cell) or a receptor (a protein, usually on the cell surface, which detects small amounts of a chemical messenger, such as a neurotransmitter, and reacts in various ways.) Once a potential therapeutic target is identified, small molecules (i.e. drugs) which affect the target in the desired way can be tested in animal models. It’s usually best to look for targets which need to be inhibited for a therapeutic effect, since it’s usually easier to find enzyme inhibitors or receptor antagonists (there are lots of ways to interrupt biological functions with small molecules, but fewer ways to enhance them.)
High-throughput screening (HTS) means finding a simple assay, usually based on single cells or even ground up cells, but placing thousands of them in small wells in test plates, then randomly adding thousands (sometimes hundreds of thousands!) of different drugs and looking for a response (via automated equipment), without worrying about the specific mechanism of action. The hope is that many pleasant surprises could emerge from this method, that existing drugs could show unexpected therapeutic effects. The system needs to be set up properly, with some thought given to the “readout” being examined (what specific reaction you’re looking for in those miniature test tubes, like activation of one specific gene), and it is understood that many false positives (as well as false negatives) will be generated, so any “hits” from the system need to be validated later in other model systems. This is one of the standard methods that drug companies have used to look for new treatments, and it is being used increasingly in academic labs as well. A related technique, high-content screening (HCS), uses more sophisticated robotics and computers to look at more complex readouts, like dendrite shape (for an example relevant to fragile X.)
Over the years, we’ve funded a lot of both kinds of research. Certainly, basic research into the mechanisms of disease is necessary early on for both approaches, and we started out by focusing on that. At a certain point, however, we were able to sponsor HTS projects, as well as projects looking at preclinical (animal model) efficacy of potential therapeutic compounds identified by the rational approach. Looking back on the results from the past 15 years, it is clear that the rational drug discovery approach has been far more productive, and that HTS has been a big disappointment. It turns out that the fragile X experience has mirrored the general experience with HTS in pharma and academia, where the overall results have simply not justified the investment. In our case, the rational approach has produced many notable successes like lithium (and other GSK3 inhibitors), ampakines, mGluR5 antagonists, minocycline, GABA (A&B) agonists, MEK and ERK inhibitors, BK channel openers, and many others---some you’ve heard a lot about, others which we’ll be talking about much more in the near future. There is now a large pipeline of new disease-modifying treatments in development for fragile X, and all of them have come from the rational drug discovery approach. Many of these therapeutic strategies have important cross-application in the treatment of other disorder (especially autism, but the list of potential applications in other brain disorders is quite long, indeed.)
Why no success with HTS? Well, it is becoming apparent (at least in retrospect) that the biggest problem results from the nature of fragile X itself. For example, when scientists have tried to find a simple cell-based readout, they find that fragile X cells (stem cells, in this case) display increase proliferation. Run that through a high-throughput screen, and you get lots of “hits” which rescue this particular phenotype. The problem is that they’re all cancer drugs which are far too toxic to use in fragile X. As it turns out, the same signaling pathways which are over-active in fragile X neurons are really just re-configured versions of the signaling pathways which regulate cell growth and division in other cells. Part of the differentiation process, which makes one cell a liver cell and another, a neuron, is just a minor tweaking of these same pathways to accomplish radically different things in various parts of the body. All cells have similar building blocks, and drugs can’t always distinguish between them. So, it is very important to choose the readout of the HTS system very carefully, and with some consideration of this basic nature of fragile X pathology. We are hopeful that high-content screening may allow us to find novel agents which can rescue very specific defects found in fragile X (like abnormally developed dendrites,) but this is still an emerging technology.
Again, we must go where the science leads us, and learn from these valuable experiences. While fragile X is turning out to be a different sort of problem from what we might have originally expected, we are learning ways to fix the abnormalities caused by this disorder, and better ways to look for new treatments. In the end, fragile X research and rational drug discovery will ultimately teach us a great deal about how the brain works, and about what’s wrong in a host of other disorders like autism, Alzheimer’s Disease, and schizophrenia. Even though we’ve always known this fragile X research was important work, because we care so deeply about our children’s futures, it may turn out to be even more important than we could have imagined.
(double-posted here and at the official FRAXA Blog---check it out at fraxa.org/blog )Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-57666766113568718042011-10-11T08:31:00.001-07:002011-10-11T08:31:39.313-07:00Update on new treatments for fragile X---Part 4: MMP-9 inhibitorsIn 2007, Iryna and Doug Ethell of UC Riverside made the seminal finding of excessive activation of the enzyme Matrix Metalloproteinase-9 (MMP-9) in fragile X. They showed that excessive MMP-9 activity maintained dendritic spines in an immature state, and that this contributed to the behavioral abnormalities seen in the fmr1 KO mouse. Most importantly, they showed that the known inhibitor of MMP-9, the available antibiotic minocycline, could rescue all the abnormalities they found in the mouse model. This made minocycline an attractive off-the-shelf treatment for fragile X. Shortly thereafter, I started experimenting with the judicious off-label prescription of minocycline in a small number of carefully selected patients; the results were impressive, to say the least! Indeed, the effect of minocycline was too good, and too rapid to be solely the result of normalized developmental trajectory. Minocycline appears to have an early psychotropic effect which is independent of its fragile X-specific mechanism; this has been utilized in several studies of minocycline as a treatment for schizophrenia and obsessive-compulsive disorder (which leads to the intriguing possibility that minocycline could be an excellent treatment for autism spectrum disorders in general.) Keep in mind that, in the mice, treatment was a very long-term affair---the equivalent of years in human terms.<br /><br />After conferring with Carlo Paribello, of the Fragile X Research Foundation of Canada, we quickly began organizing a clinical trial. This first trial was an open trial, designed to examine the pattern of responses in high and low dose minocycline treated subjects. The trial achieved excellent results, with substantial decreases in aberrant behaviors over 8 weeks of treatment. Long-term follow-up of these subjects was also done, and results of that phase of the trial are now being analyzed. Very few side effects were seen in either high or low dose groups, and the therapeutic effect seemed similar (though the number of subjects could not discriminate subtle differences.) This is not unexpected, since studies by surgeons have shown that typical antibiotic doses of minocycline (100 mg/d) inhibit MMP-9 levels by 50-75%. That is just about exactly what we want. One unexpected result from the study was that ¼ of all the subjects followed for a year had an increase in Anti-Nuclear Antibodies (ANA), a rather non-specific indicator of autoimmune reactions. None of these subjects had any actual symptoms, though serious autoimmune reactions to minocycline are seen (fortunately, only rarely.) We’re still not entirely sure what to make of this finding, as it’s not known just what percentage of people in the general population develop elevated ANA levels with chronic minocycline treatment. However, it could be a useful indication of impending autoimmune problems, and may be worth checking as a screening test. Interestingly, none of the patients that I treat directly have developed this kind of reaction to minocycline, though I have talked to a number of parents around the country who have encountered this problem.<br /><br />A larger, placebo controlled trial is under way at the MIND Institute to follow up on these initial findings, and we look forward to these results. In the meantime, another bit of confirmatory evidence came from the lab of Kendal Broadie at Vanderbilt. His group has published results showing dramatic rescue of fragile X fruit fly abnormalities with minocycline---all the more impressive because the fly model is essentially a knockout of 3 genes (fmr1, fxr1, and fxr2.) This group also showed that genetic reduction of the fly equivalent of MMP-9 yielded similar results; this is significant, because minocycline does several different things, but MMP-9 inhibition does seem to be the active ingredient.<br /><br />So, we have an excellent off-the-shelf treatment in the form of minocycline, a cheap generic medication with a long history and fairly benign safety profile. But some people, perhaps as many as ¼, have trouble taking it, and it’s not recommended for kids under 8 because of dental discoloration (which is not directly related to MMP-9 inhibition.) We at FRAXA are continuing to explore more specific alternatives to minocycline; there is interest in pharmaceutical companies in drugs which can inhibit MMP-9 specifically without some of the other effects of minocycline. However, this is a niche market, and only a few companies have active programs in this area, so it may be a while before we find anything better than minocycline in this area.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-62439935230798681582011-06-27T22:02:00.000-07:002011-06-27T22:04:26.743-07:00Update on new treatments for fragile X---Part 3: GSK3 inhibitorsAfter mGluR5 antagonists, the drug class with the most extensive validation as a disease-modifying treatment for fragile X is one called GSK3 inhibitors. Glycogen Synthase Kinase 3 is a ubiquitous enzyme present in a number of signaling pathways throughout the body (a problem which we will re-visit later.) GSK3 beta is the specific version which is excessively active in fragile X (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2707186/?tool=pubmed ), and studies in fragile X mouse, fly, zebrafish, and neural stem cells all show that reducing GSK3 activity, either genetically or with chemical inhibitors, can rescue a very wide range of fragile X phenotypes (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2838793/?tool=pubmed ). FRAXA invested heavily in funding the study of GSK3-based treatment strategies following the original finding that MAP1b was one of the critical overexpressed proteins in fragile X (http://www.ncbi.nlm.nih.gov/pubmed/11733059). Since it is known that activation of MAP1b occurs via GSK3, it was recognized early on that inhibition of GSK3 could be therapeutic for fragile X. Subsequent evidence has shown this to be correct, and perhaps even an underestimate. GSK3 inhibitors appear to have as much therapeutic potential as mGluR5 antagonists, though they may not be quite as well tolerated.<br /><br />While virtually every major pharmaceutical company in the world is working on improved GSK3 inhibitors for a number of different indications, there is an available drug which is an excellent GSK3 inhibitor. This drug is lithium. Ironically, even though lithium has a reputation for being rather toxic, it may turn out to be less toxic than any of the newer, “cleaner” GSK3 inhibitors in development. Indeed, most of these development programs are in trouble because of toxicity and off-target effects. It is because of the ubiquitousness of GSK3 that these side effects may be unavoidable (in fact, in this light, lithium looks pretty good!), but there are efforts to develop brain-specific GSK3 inhibitors which leave the rest of the body untouched.<br /><br />Millions of people around the world have been treated safely and effectively with lithium for psychiatric disorders (especially Bipolar Disorder, a.k.a. Manic-Depressive Illness.) However, lithium has fallen out of favor with psychiatrists who now have many other options for treating psychiatric disorders, especially in the form of heavily promoted, brand name drugs like Zyprexa and Depakote. Lithium is a cheap generic, and no one is promoting it. It is also hard to prescribe, and no doctors other than psychiatrists have any experience using it. But lithium does appear to be therapeutic for fragile X, showing disease-modifying properties in animal models (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102293/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810609/?tool=pubmed and http://www.ncbi.nlm.nih.gov/pubmed/21078304 and http://www.ncbi.nlm.nih.gov/pubmed/20705090, among others) and excellent results in a pilot clinical trial in fragile X patients ( http://www.ncbi.nlm.nih.gov/pubmed/18698192 ).<br /><br />However, it is fair to say that lithium has not become a common treatment for fragile X, probably because it is widely perceived as a dangerous drug (whether this is correct or not, the perception certainly influences acceptance of the treatment by patients, families, and physicians.) Further trials are clearly warranted, however. A larger, controlled trial of lithium in fragile X subjects is a high priority for FRAXA. There is also the possibility of identifying available agents which can enhance the effectiveness of lithium (http://www.fraxa.org/researchTeam.aspx?id=659 ), and perhaps allow for lower dosing. This might eliminate the need for blood testing to determine lithium levels, one of the more unpleasant aspects of lithium treatment for patients and families. It is surprising to me that more psychiatrists are not prescribing lithium for their fragile X patients, especially in case where the psychiatric presentation alone (i.e. aggression or mood lability) might justify a trial of lithium. It may simply be that doctors today have so many choices, it’s easy to avoid lithium.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-22512538472080571582011-06-20T14:55:00.000-07:002011-06-20T15:07:01.909-07:00mGluR5 antagonists for fragile XThe disease-modifying potential of this class of drugs, which block type 5 metabotropic glutamate receptors, has been incredibly well validated in animal models of fragile X. It’s actually so well validated that it’s unprecedented in the history of medicine. There really has never been another example of a small molecule fixing so many facets of a neuropsychiatric disease in multiple animal models. In part, this is because most neuropsychiatric diseases haven’t had very good animal models, at least until recently, but this just reinforces the point that fragile X is such an important model for the study of many other disorders---we have animal models that aren’t just models, they actually have fragile X. It seems like we’ve been talking about the promise of this treatment strategy forever, but it was only 2001 when the “mGluR Theory” of fragile X was conceived, and now we have 3 companies with active programs to develop their mGluR5 antagonists for fragile X (as well as the now-defunct Neuropharm, which may yet rise from the ashes.)<br /><br />Novartis is the furthest along, and their compound AFQ056 just entered Phase IIb/III trials for adults and adolescents with fragile X at a large number of sites around the world (see clinicaltrials.gov for more details.) Trials in children are expected to follow soon. AFQ056 is a modern, advanced compound which appears quite safe, and also appears to be an effective treatment for complications of Parkinson’s disease (see <a href="http://www.ncbi.nlm.nih.gov/pubmed/21484867">http://www.ncbi.nlm.nih.gov/pubmed/21484867</a> ). It seems likely it will make it to the market for Parkinson’s, even if things don’t work out for fragile X, which is a reassuring backup plan. However, if the current round of clinical trials is successful, it could be marketed for fragile X as the first indication for any mGluR5 antagonist. The Phase II trial results with AFQ056 for fragile X have been published ( http://www.ncbi.nlm.nih.gov/pubmed/21209411 ) and much has been made of the different response to the drug in full mutation males with “full methylation” vs. full mutation males with “partial methylation” on a proprietary assay of methylation status used in this trial. However, it is important to remember that this was a relatively brief trial in a small number of subjects, so it is not surprising that the best effect was seen in the relatively pure sample of fully methylated (ie non-mosaic, for all practical purposes) subjects. Subjects in this trial received the full dose of AFQ056 for only one week; such brief treatment often results in a high placebo response rate, and that was clearly the case here. Clinical trials in psychiatry have shown over and over that the placebo effect generally wears off over 3-4 weeks, and the current phase of AFQ056 trials will dose subjects for much longer. I would expect that this longer treatment would result in statistically significant improvement in all fragile X subject groups, with decreased placebo effect. In addition, preclinical testing of mGluR5 antagonists in animal models predicts that fragile X patients would require much higher doses of these drugs for optimal effects, and that these doses would be well tolerated, so this trial may not have pushed to dose into the optimal range.<br /><br />However, this raises an important issue with all the disease-modifying treatments for fragile X. How long does it take to see genuine developmental improvement, rather than simple symptomatic improvement? It stands to reason that longer trials are required to see genuine developmental effects, and that even longer trials are required to see disease modification in older subjects. As I noted in the previous post, having extensive preclinical validation gives us confidence that a particular therapeutic strategy will be disease modifying, even if this is not practical to demonstrate in a clinical trial. It may take years to see real developmental effects in 20 year olds, although clinical trials are rarely more than a few months long. Besides, drug companies aren’t required to show that they can cure fragile X, only make it measurably better. So, I’m expecting that this phase of the trials will show improvement in all subjects on AFQ056, with more severely affected subjects showing the best effect, as well as the least placebo response. But, these things are hard to predict---that’s why they do the trials!<br /><br />Another Swiss pharmaceutical giant, Hoffmann-LaRoche (or just “Roche” to those of us in the know) also has an advanced mGluR5 antagonist, RO4917523, which has just completed a Phase II trial in fragile X adults. RO4917523 may actually be the most (chemically) sophisticated of all the drugs in development; it is ultra-long-acting and very potent. A tiny dose once a day is all that is required to block mGluR5 quite effectively. Results of this trial are a closely guarded secret, and no announcements have been made about future plans for RO4917523, so we are left in the dark concerning Roche’s intentions.<br />Seaside Therapeutics also has an mGluR5 antagonist, STX107, which was licensed from Merck. It has reportedly completed Phase I trials (normal volunteers), but has yet to be administered to any fragile X subjects. Phase II trials have yet to be announced. Seaside appears to be devoting much of its energy to the development of arbaclofen (R-baclofen, or STX209) for autism and fragile X; this will be discussed in another post.<br /><br />As noted above, Neuropharm, a UK-based startup, is now out of business. The company’s fortunes rested on the near-certainty of approval of a proprietary formulation of fluoxetine (aka Prozac) for autism. However, their large, multicenter trial failed to show superiority to placebo, even though everyone still uses fluoxetine and other SSRIs for autism spectrum disorders, because they clearly do work. This serves as an important cautionary tale: trials can fail for any number of reasons! Anyway, their Phase I/II trial of fenobam was quite successful; it was only intended to show safety and tolerability, but also showed significant improvement in pre-pulse inhibition (PPI) in fragile X adults, with many anecdotal reports of behavioral improvement from a single dose. Fenobam, like Neuropharm may yet be resurrected---many companies around the world are looking at possible uses for this off-patent compound.<br /><br />Many other companies have their own mGluR5 antagonists, typically developed at vast expense, and now looking for some purpose. It seems to be generally agreed that fragile X and Parkinson’s are good, proven indications for these drugs, so we anticipate that more companies will move into fragile X trials, especially if Novartis continues to have success with AFQ056.Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-66921942477141311642011-06-18T20:13:00.000-07:002011-06-18T21:42:45.497-07:00Update on new treatments for fragile XIn the coming weeks, I hope to provide up-to-the-minute updates (along with many frank opinions, since this is a blog!) about the status of all the various new treatments that have the possibility of disease modification in fragile X. I’ll do this in writing, since I do want to be fairly precise, and you may want to be able to copy these things; I’ll also reference much of what I say, except where the references are too numerous to list.<br /><br />To do this, I’ll need to define a few terms, so let’s start there. First is the term “disease modification”, referenced above. We all are hoping for treatments which actually affect the course and the outcome of this single-gene disease we call fragile X. There are many available psychiatric drugs which can positively affect the behavioral manifestations of fragile X, and I’ve written plenty about them. But there is no indication that they change the long-term outcome in any significant way, as I noted in my last post. Obviously, the better kids do over the course of many years, the better their long-term prognosis, but the same can be said for any number of behavioral and educational interventions. There may very well be some kind of gray area here, but I think most of us can agree that we would like to see something much more specific, treatments which get to the very heart of the dysfunction in fragile X, and actually facilitate much more normal development. This is the mission of FRAXA, and it has become my life’s work, so I don’t consider these trivial distinctions. You’ll have to pardon me if I have some strong opinions in this area, and if I sometimes seem dismissive of ideas which are proposed that just don’t have the research backing to make them potentially “disease modifying” by accepted definitions.<br /><br />So, how does one demonstrate that a particular treatment strategy might be disease modifying? Well, you could just give the treatment to patients and see what happens, based on some speculative theory of what’s wrong in the fragile X brain. This is the dominant model in autism studies today, and it carries over to some extent in fragile X. It is also quite common in psychiatry, and I’ve had the chance to observe the failure of this model on many occasions. For example, millions of children, adolescents, and adults take stimulant medications every day to enhance their attention (as well as decrease hyperactivity and other disruptive behaviors associated with ADHD.) Most parents hope, and assume, that this treatment will result in improved academic performance over the long term (we certainly see this in fragile X, too.) The drugs certainly work well in the short term, and efficacy is easy to demonstrate. However, most of the studies which have examined the long-term academic performance of kids with ADHD treated with stimulants show little, if any, advantage for the drugs. More recent studies have shown some benefits, but the results are debatable and more subtle than you might imagine (see <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629512/?tool=pubmed">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2629512/?tool=pubmed</a> for a more thorough review.) In the fragile X field, we just don’t have the time or money to try this willy-nilly approach, and the number of research subjects is too small to make it work.<br /><br />A better way, I think, is to develop treatments based on the observed abnormalities in the animal models of fragile X (mainly fruit fly and mouse), then test potential treatments in those animal models. This initial observation would be considered basic science; the attempt to find ways to reverse a defect might be termed “translational research”, and the actual testing of a specific drug in the animal model would be called “pre-clinical validation”, leading to clinical trials in people with fragile X. The “FRAXA Method”, as I like to call it, is to fund this kind of progression from basic research, through translational research, followed by preclinical validation, leading to clinical trials of medications that have genuine potential to change the outcome of fragile X. We didn’t invent this method, and it really isn’t anything new at all---it’s what every pharmaceutical company does every day. But you’d think it was some sort of radical new approach, compared to the half-baked and poorly reasoned trials coming from many areas (not just the autism field, either; many clinical trials in psychiatry, or in the broader rare disease field are little more than wishful thinking, with no real scientific basis.)<br /><br />In the next few installments, I’ll talk about the results of this approach, then move on to discuss some other developments in clinical trials for fragile X. Stay tuned!Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-9390481173941711002010-06-01T10:19:00.000-07:002010-06-01T10:23:21.321-07:00Can "ordinary" meds have extraordinary effects?A viewer asks, if Zoloft can help with language in young fragile X kids with lots of anxiety, can it boost language development in kids without as much anxiety?<br /><br /><object width="640" height="505"><param name="movie" value="http://www.youtube.com/v/PG0ExSjac-M&hl=en_US&fs=1&rel=0"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/PG0ExSjac-M&hl=en_US&fs=1&rel=0" type="application/x-shockwave-flash" allowscriptaccess="always" allowfullscreen="true" width="640" height="505"></embed></object><br /><br />Also, what's a safe minimum age for these meds? How young is too young?<br /><br /><object width="640" height="505"><param name="movie" value="http://www.youtube.com/v/94GTKgpFS28&hl=en_US&fs=1&rel=0"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/94GTKgpFS28&hl=en_US&fs=1&rel=0" type="application/x-shockwave-flash" allowscriptaccess="always" allowfullscreen="true" width="640" height="505"></embed></object>Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-23775011805586200932010-05-28T18:23:00.000-07:002010-05-28T18:29:27.967-07:00Clinical Trials: How do they work?A number of clinical trials are under way for fragile X! Here's the scoop on the system we have in the US and many other countries for developing new drugs.<br /><br /><object width="640" height="505"><param name="movie" value="http://www.youtube.com/v/nho0tGyjR08&hl=en_US&fs=1&rel=0"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/nho0tGyjR08&hl=en_US&fs=1&rel=0" type="application/x-shockwave-flash" allowscriptaccess="always" allowfullscreen="true" width="640" height="505"></embed></object>Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-10960530594211679002010-05-19T13:16:00.000-07:002010-05-19T13:21:02.812-07:00Videoblogging fragile X: sympatholyticsHere's the scoop on meds like beta blockers (propranolol, et al) and alpha agonists (clonidine, guanfacine) in young kids with fragile X.<br /><br /><object width="500" height="405"><param name="movie" value="http://www.youtube.com/v/0XD1gbKVph4&hl=en_US&fs=1&rel=0&border=1"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/0XD1gbKVph4&hl=en_US&fs=1&rel=0&border=1" type="application/x-shockwave-flash" allowscriptaccess="always" allowfullscreen="true" width="500" height="405"></embed></object>Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-52882888678198111692010-05-17T11:49:00.000-07:002010-05-17T11:50:58.557-07:00Videoblogging fragile X: treatment cocktailsHere's a response to one of the most common questions I get:<br /><br /><object width="500" height="405"><param name="movie" value="http://www.youtube.com/v/5CsiSvKiuiM&hl=en_US&fs=1&rel=0&border=1"></param><param name="allowFullScreen" value="true"></param><param name="allowscriptaccess" value="always"></param><embed src="http://www.youtube.com/v/5CsiSvKiuiM&hl=en_US&fs=1&rel=0&border=1" type="application/x-shockwave-flash" allowscriptaccess="always" allowfullscreen="true" width="500" height="405"></embed></object>Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.comtag:blogger.com,1999:blog-6818992036716106353.post-53492948809189183902010-03-29T16:54:00.000-07:002010-03-29T17:01:39.288-07:00Blog for FRAXAPeople are always asking me how they can help FRAXA. Obviously, we'd all like to be able to raise tons of money for research, but if you're like me, you probably don't have a lot of extra cash, and you probably don't know anyone who does. But just about anyone with a little free time can blog, and you can use a free blog to help FRAXA. We'd like to set up a network of bloggers around the world to raise awareness of fragile X, and raise money for FRAXA---just email me ( fraxares@verizon.net ) and we can go over the details. It's fun, and if enough of us join together, it really can make a difference!Michael Tranfaglia MDhttp://www.blogger.com/profile/10179105469688480017noreply@blogger.com