"A research team led by San Diego scientists reports a milestone in psychiatry: They¡¯ve discovered how lithium relieves symptoms of bipolar disorder.
Lithium is a decades-old treatment for bipolar disorder, highly effective in those who respond. It comes with some side effects, and lithium has been superseded in large part by newer mood stabilizers.
But lithium¡¯s effectiveness in the one-third of bipolar patients who respond to the drug compares favorably with the newer medicines, its advocates say. Neglect of this inexpensive medication means bipolar patients who might be helped never get a chance to experience its benefit.
Understanding how lithium affects the brain to relieve bipolar disorder is key to developing even better drugs. And that¡¯s what scientists led by Evan Snyder, M.D. of the Sanford Burnham Prebys Medical Discovery Institute say they¡¯ve done.
The study was published in the Proceedings of the National Academy of Sciences. It is available at: j.mp/lithpath. Snyder was senior author. The first authors were Brian T. D. Tobe and Andrew M. Crain, also of SBP.
No one gene is responsible, Snyder said: Lithium-responsive bipolar disorder is a polygenic condition. That¡¯s why previous attempts to find a genetic cause have failed, Snyder said.
But by using the lithium response as a ¡°molecular can opener,¡± the scientists were able to pry the information out of the cells, Snyder said. And this method could potentially unravel the causes of other polygenic diseases, as long as there¡¯s a drug effective in that disease.
A further benefit of the study is that it might yield tests to more rapidly determine who will be helped by lithium, instead of the existing trial-and-error method, Snyder said.
he study used several different tools to discover what lithium does, Snyder said. These included studying patient-derived artificial embryonic stem cells called induced pluripotent stem cells, matured into neurons. They also looked at cadaver brains of bipolar patients. The tests included examination of cells from control bipolar patients who didn¡¯t respond to lithium.
Researchers then analyzed the resultant torrent of data to pick out the common threads among innumerable molecular pathways.
Fortunately, a manageable number of leads emerged, Snyder said. These all converged on one target, CRMP2, an intracellular protein that regulates neural networks.
Surprisingly, the gene that codes for the protein functioned normally in the patients. Errors crept in during ¡°post-translational¡± modification of CRMP2, Snyder said.
The can-opener approach holds promise for other polygenic diseases that resist traditional genomic analysis, Snyder said.
""In other words, just like a real can-opener, once you have entered the can, you can toss the can-opener and focus on what's in the can,¡± he said. ¡°That is the case here.¡±
""No one really knows the fundamental molecular mechanism that causes and/or underlies the pathophysiology of any psychiatric disease. Here we discovered a pathway which, since it seems to be improved by a drug must also, more importantly, be viewed as the 'cause' of the disease. And it is now that pathway that should be discovered.""
Snyder likened the process to the reverse of targeted drug discovery. In that process scientists first look for a molecular target, then develops a drug to reach that target.
""It's a bit like the world of medicine did with aspirin,"" Snyder said. ""We knew how aspirin worked long before we knew about prostaglandin pathways. But, once we discovered that pathway ¡ª because of aspirin ¡ª we unlocked the mysteries of inflammation. Same here.""
""I would even go so far as to say that bipolar patients that do not respond to lithium have an entirely different disease. For ease, we in medicine give them the same name because they look the same symptomatically ¡ª but they really are different and need different medications.""
""We used to do that with cerebral palsy ¡ª all kids with CP looked the same. But, once we started becoming more sophisticated, we split out those that had lysosomal enzyme deficiencies, or chromosomal abnormalities, etc. I think we will start being able to do the same with psychiatric disorders.""
Sold under various names, lithium carbonate has an extensive history as an effective treatment for bipolar disorder and other psychiatric conditions. And while it may be considered an old-fashioned drug, it¡¯s not difficult to find experts who say it¡¯s still an essential medication.
¡°Lithium is our gold standard treatment for bipolar disorder,¡± said Gerald A. Maguire, M.D., chair of the Department of Psychiatry and Neuroscience at the University of California, Riverside.
¡°There are many individuals who just respond to this treatment,¡± Maguire said. ¡°Also, many of our medications which are also FDA-approved for bipolar disorder have on their label that they work better when combined with lithium.¡±
Lithium is unsurpassed even decades of newer medications, wrote Edward Shorter, a social historian of medicine at the University of Toronto, in a 2009 article in the journal Bipolar Disorders.
¡°With the exception of ECT, lithium is the single most effective treatment in psychiatry,¡± Shorter wrote. ¡°Its side effects are easily manageable, and many patients stay on low-dose lithium for decades. Its benefits, in terms of the relief of mania and the prophylaxis of depression, are incalculable.¡±
Asked for comment on the new study, Shorter said it holds out the promise that lithium analogs could be developed that modulate the same molecular pathway, but have fewer side effects.
¡°Lithium is one of the most important drugs in psychiatry, in the treatment of depression, mania and bipolar disorder,¡± Shorter said. ¡°So this is potentially hugely important. One hopes that this will be followed up.¡±
A comparison of lithium against a newer drug, olanzapine (Zyprexa) found no evidence that olanzapine¡¯s higher cost was offset by reduced overall health care expenses, wrote Yuting Zhang of the Unversity of Pittsburgh in a 2008 article in The Journal of Mental Health Policy and Economics.
¡°I found that compared to similar lithium users, olanzapine users spent approximately $330 more on monthly average non-drug medical services during the first year after initiation of drug treatment,¡± Zhang wrote. ¡°The higher spending for olanzapine users was accounted for by both higher rates of re-hospitalization and more outpatient visits. In addition, olanzapine cost $153 per month while lithium cost $16 per month.¡±
¡°Including the direct cost of the drugs, compared to similar patients taking lithium, patients with bipolar disorder taking olanzapine spent $5,600 more annually on health care services.¡±
This doesn¡¯t rule out the possibility that olanzapine users experience a better quality of life that justifies the greater expense, Zhang wrote. But it does call into the assumption that higher-priced new drugs pay for themselves.
Of proteins and girders
Study leader Snyder of Sanford Burnham Prebys said the study began with an ¡°unbiased screen¡± to find possible leads.
""We started out with no preconceptions whatsoever,"" he said.
Researchers derived neurons from induced pluripotent stem cells taken both from patients who were lithium-responsive and controls who didn't respond to lithium. They then dosed the cells with lithium and performed proteomic screens on them, looking for differences in the proteins the cells produced. These produced leads.
""And you just pray there aren't going to be too many,"" Snyder said. ¡°We lucked out. In this group of experiments, there were about 15.""
""Then when we saw what those proteins were, and we did some bioinformatics just to see how they fit into each other,"" he said. ""What jumped out was this molecule called CRMP2, which sat right at the center of all the others .. and it fit right into axonal guidance, or connectivity.""
CRMP2 regulates the state of the cytoskeleton, the framework that gives cells shape.
""It's the kind of thing that, to people who go into neurobiology because they love the theory of mind and things like that, this is kind of boring,"" Snyder said. ""You're an architect, but somebody is talking to you about the girders. It's hard-core structure, the kind of thing that biochemists go nuts over, but maybe not neuroscientists who want to figure out why Beethoven would write a symphony.""
Funders of the study include the National Institutes of Health; the Viterbi Foundation Neuroscience Initiative; Stanley Medical Research Institute; the Tau Consortium; California Institute of Regenerative Medicine training grants; the California Bipolar Foundation; the International Bipolar Foundation; and Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems."