Trends in CNS Drug Discovery: Phoenix Rising

There is hardly a presentation or publication on the status and future of drug discovery that does not show a graph of the striking inverse relationship between the enormous drug discovery R&D investments and the staggering decline in new drug approvals (see Thong 2015 for a brief discussion of recent reviews on this subject). Especially R&D for diseases of the Central Nervous System (CNS) have seen failure after failure. As a consequence, almost all companies have downsized or abandoned their efforts in this field. Notwithstanding this dire state of affairs, I believe that Rahm Emanuel’s quote that “You never let a serious crisis go to waste” captures the essence of the present situation. Because “it offers an opportunity to do things that you thought you could not do before”. A quick look at the ‘Disruptive dozen’ technologies to diagnose and treat CNS diseases (World Medical Innovation Forum, 2015) seems to substantiate this statement. Some of the novel approaches such as the ‘electroceuticals’ seemed science fiction not that long ago!

Without doubt some of these technological advances helped to generate some much needed new excitement in - and hope for - our field. Although we do not want to get too excited and focused on technology alone. History has the tendency to repeat itself. This is not the first time that excitement has been generated by novel technologies (think the ‘-omics’, high through put screening etc.) that eventually did not deliver. Although we must not forget that they expanded the toolbox of drug discovery and therefore still add subtantial value. A key question is whether the current generation of novel technologies will again incrementally improve the way we are doing drug discovery. Or do they have this time the potential to fundamentally impact and change the future model for CNS drug discovery, and to decrease the high failure rates that we have had for so many years? In other words, are we at “the second half of the chess board” when developments accelerate at an unimaginable speed? (see Chapter 3 of Brynjolfsson and McAfee 2014 for a description of the chess board metaphor).

In this series of blogs, I will take a deep dive into the drug discovery literature to see if we are indeed at the second half of the chessboard. I will start with a look at recent progress with small molecule weight drugs as these are still the mainstay in CNS drug discovery. The next edition of this blog will accordingly focus on ‘the lower hanging fruit’, that is, novel insights from molecular pharmacology that allow to address known and well characterized targets - often neurotransmitter receptors in the brain - in more subtle ways. Often modulating, instead of blocking or boosting, receptor activity. The main attractiveness of such an ‘allosteric’ approach is that normalisation of protein activity in the disease state is thought to lead to a better therapeutic window between efficacy and side effects.


Thong (2015): Root Causes of the Pharmaceutical R&D Productivity Crisis (

World Medical Information Forum (2015): The disruptive dozen. (

Erik Brynjolfsson and Andrew McAfee (2014). The second machine age. Work, progress, and prosperity in a time of brilliant technologies. W.W Norton and Company, New York, London.


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