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Global perspectives on central nervous system drug innovation: achievements, barriers, and priorities for the next
Hiroyuki Uchida1, Gabriella Gobbi2, Joseph Zohar3
1Department of Neuropsychiatry, Keio University School of Medicine (International College of Neuropsychopharmacology, CINP), Tokyo, Japan.
Background:
Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.
Methods:
We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.
Results:
Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.
Conclusions:
To convert momentum into durable progress, we recommend: (1) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments, and non-for profit foundations; (2) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (3) data-driven development integrating RWE, AI/ML, and precision medicine; (4) the adoption of Neuroscience-based Nomenclature; and (5) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.
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