When during my undergraduate years I learned that lithium carbonate treats depression and bipolar disorder, my first thought was “there’s something bizarre here”.
The most well-known observational studies suggested that even low levels of Li+ ions in drinking water reduce suicide incidence. However, there’s a lot of critics of these studies pointing out trivial ‘correlation = causation’ fallacy and poor study design for drawing serious conclusions.
New study demonstrates the effect of Li+ in induced stem cells. Well, the actual goal for the paper was to establish a relevant cellular model for bipolar disorder (BD). For that authors took fibroblasts from two sets of patients, Li-responsive (LR) and Li-non-responsive (LN) ones, as well as healthy controls. They differentiated the fibroblasts into dentate gyrus (DG) hyppocampal neurons and studied possible genetic sources of BD. The biggest change was detected in mitochondrial genes expression, which correlated with observed hyperactivity of BD iNeurons.
A real gem is the clinical relevance experiment. Authors tested the effect of LiCl on LR- and LN-derived BD iNeurons. As it turned out, Li+ indeed worked only in cells from LR patients but not in LN group. The effect was confirmed by electrophysiology and Ca2+ imaging. Further look into genetics showed change in expression of 560 genes in LR iNeurons, compared to 40 in LN. Of those 560, 84 were rescued BD genes, including those regulating mitochondria transport, protein kinase A (PKA)/protein kinase C (PKC) signaling and action potential.
Hopefully, further studies of the newly established iPSC model will provide new insights into genetics of BD and contribute to the development of more effective drugs. And these are badly needed, taking into account severe side effects of chronic lithium treatment. For sure, more rigorous genotyping of patients is needed but at least the model already substantially narrowed down the candidate genes.