After 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.
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.
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 ).
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.