Fishing out the best therapeutics for neurological and psychiatric diseases is complex. Mehmet Fatih Yanik and colleagues show that the use of high throughput technologies opens fascinating possibilities of accelerating basic and translational research. In their paper published in Nature Communications, they combine neuromodulators with complementary effects on functional brain connectivity to identify highly effective candidates for polytherapies.
Treatment-resistant neurological and psychiatric disorders are a major public health problem impacting many millions of people worldwide. Existing therapeutics are ineffective in up to 40% of patients suffering from these disorders. Combining existing drugs (i.e. polytherapy) may provide benefit, but there are so many possible combinations that it is hard to investigate all of them.
The experimental setup used in the current study by Mostafa Ghannad-Rezaie, Peter Eimon, Yuelong Wu, and M. Fatih Yanik of the Institute for Neuroinformatics, UZH and ETH, and the Massachusetts Institute of Technology, allowed very fast and efficient testing of many compounds and their combinations. The high speed platform they developed is capable of imaging more than 15’000 neurons in 50 ms to map the brain-wide functional connectivity in large numbers of vertebrates under many conditions. The model system used for this study were zebrafish larvae with mutations of the human Dravet syndrome, a form of epilepsy and autism.
The researchers exposed the larvae to a set of 154 neuroactive compounds, including drugs prescribed for Dravet syndrome as well as a variety of other neuroactive drugs. First, they classified neuromodulators in clusters based on the functional brain connectivity changes they induced in the mutant zebrafish larvae. Then they combined compounds that fell into classes inducing complementary effects on functional brain connectivity and administered them together.
Using this approach, they were able to overcome the massive combinatorial challenge of polytherapy screening. In this study, combination of two compounds was sufficient to completely correct the brain activity patterns as well as behavior in an otherwise highly treatment resistant disorder: fluoxetine (an antidepressant) and mifepristone (an inhibitor of steroid receptors), both are not commonly used drugs for epilepsy treatment.
“Our results point to the need to look beyond monotherapy regimens and to utilize more sophisticated brain activity readouts that capture the full complexity of CNS disorders in future drug screens”, M. Fatih Yanik noted.
Ghannad-Rezaie M, Eimon PM, Wu Y, Yanik MF. Engineering brain activity patterns by neuromodulator polytherapy for treatment of disorders.
Nat Commun. 2019 Jun 13;10(1):2620. Pdf
Image: Brain connectivity measurement in a zebrafish larva. Provided by Prof. Yanik.
See also Prof. Yanik’s inaugural lecture video