Proposals for future work on Bipolar Disorder

There are several different directions that Bipolar Disorder research is currently headed in, and it is likely that for the foreseeable future there will continue to be a convoluted assortment of studies on a wide variety of systems in attempts to elucidate the mechanisms behind this disease. However, in light of the research that was done to construct this review, there are three areas that, in the authors opinion, would benefit from further work.

Nestin+ neural progenitor cells Chen et al. 2014
Nestin+ neural progenitor cells
Chen et al. 2014

Firstly, continued development and use of new model systems for the study of disease pathology and disease mechanism. The work done by Chen, et al. in their 2014 paper was an excellent start to this. Now, if one could use the cell lines developed by the Chen, et al. group to follow the expression and interactions of individual proteins, specifically GSK-3, in cells from bipolar patients, it may be possible to gain a better understanding of the role this apparently very important protein plays in this disorder. Using the cell model developed by Chen et al. has some distinct advantages over animal models and the cancer cell based models that are usually used in this field because these new cell lines should have much more accurate expression profiles with regard to the human disease state, as oppossed to, say, an amphetamine induced mania model in mice would (for an example of such a model see Feier et al., 2013)

In addition to this, there is a surprisingly small number of crystal structures for GSK-3, and none of them have lithium or valproate bound to them. It would be especially useful to get a crystal or even an NMR solution structure of GSK-3alpha and beta bound with valproate in order to determine exactly how it is that valproate inhibits GSK-3, since it obviously doesn’t function the same way as lithium in this respect.

Valproic acid, marketed as Depakote, inhibits GSK-3 just like lithium, but due to obvious structural differences the mode of action needs to be different, and is not currently known
Valproic acid, marketed as Depakote, inhibits GSK-3 just like lithium, but due to obvious structural differences the mode of action needs to be different, and is not currently known
Credit: PubChem

Thirdly, once more structural work has been done on GSK-3 and other proteins of importance (likely to be determined with the neuron model system outline above), it would be a sensible next step to spend time optimizing drug formulations in order to get better therapeutic results. It is currently quite common for a drug not to work for a very large number of patients, but if the disease is better understood, then more precise drug formulation can take place based on known targets instead of the clinic observations and, in some cases, serendipity that allowed the medical field to arrive at the current suite of drugs used to treat Bipolar.

Taken as a set, these proposals could push the field forward significantly, and if successful they could allow for far more effective treatment of what is currently one of the most debilitating and difficult to treat mental disorders.