Serendipity drives discovery in psychiatry, engineering gets it across the line, says Steve Paul

From muscarinic breakthroughs to next-gen psychedelics, what’s changing — and what isn’t — in the search for psychiatry medicines: The BioCentury Show

With disease biology still murky and trials notoriously noisy, psychiatry R&D is advancing fastest where teams can solve engineering problems. Delivery, selectivity and tolerability fixes are turning long-standing hypotheses into usable medicines, says veteran CNS drug developer Steven Paul.

Psychiatry programs have some of the lowest success rates in the industry. While human genetics has become the bedrock of target validation in other disease areas, the highly polygenic nature and heterogeneity of psychiatric conditions has resisted clean biological narratives. Few drug developers have had a closer view of the field’s false starts — and occasional breakthroughs — than Paul, who has moved from NIH science to pharma R&D leadership and now to venture-backed company building.

Paul serves as board chair at Seaport Therapeutics Inc., which he co-founded in 2024 with former leaders of PureTech Health plc (LSE:PRTC; NASDAQ:PRTC) — the company-creation group that also launched Karuna Therapeutics Inc., another Paul-led venture.  Bristol Myers Squibb Co. (NYSE:BMY) agreed to acquire Karuna for $14 billion in December 2023.

Human genetics may not be a clear guide, Paul said, but human biology still can be, if developers can engineer around the constraints that have obscured efficacy signals in the clinic, from peripheral side effects to inadequate exposure. Paul was frank that serendipity still plays a disproportionate role in psychiatry. The differentiator, he said, is whether teams can engineer and execute their way from an unexpected signal to a usable medicine.

Paul laid out the thesis in a conversation with The BioCentury Show, walking through the development logic behind Karuna’s muscarinic approach in schizophrenia, and the delivery and trial-design choices Seaport is using to revisit neuroactive steroid biology in depression.

He also weighed in on psychedelics. He’s optimistic one of today’s late-stage candidates will win approval, but the bigger inflection may come later, from compounds that preserve 5-HT2A–driven antidepressant effects while avoiding the hallucinogenic “trip” that complicates blinding in trials and limits commercial scalability.