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The Genetics-Driven Revival in Neuropsychiatric Drug Development

  • Michael J. Gandal
    Correspondence
    Address correspondence to Michael J. Gandal, M.D., Ph.D., 2309 Gonda Building, 695 Charles E. Young Drive South, Los Angeles, CA 90095-1761.
    Affiliations
    Program in Neurobehavioral Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

    Center for Autism Research and Treatment, and Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

    Semel Institute, and Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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  • Daniel H. Geschwind
    Affiliations
    Program in Neurobehavioral Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

    Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California

    Semel Institute, and Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
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      Drug development for central nervous system (CNS) disorders has dramatically slowed over the past decade, despite the growing burden attributable to neuropsychiatric disease worldwide (
      • Hyman S.E.
      Revolution stalled.
      ). The fundamental challenges in developing treatments to target brain-based illnesses include limited understanding of underlying disease pathogenesis and pathophysiology, lack of quantitative disease biomarkers, inherent challenges in developing predictive preclinical models, and the inaccessibility of the brain to direct investigation. Most currently approved classes of psychiatric medications were discovered by serendipity and continue to target the same molecular mechanisms as their prototypes, developed >50 years ago (
      • Hyman S.E.
      Revolution stalled.
      ). Candidate drugs entering clinical trials for CNS disorders have some of the lowest rates of ultimate regulatory approval, often as a result of lack of clinical efficacy. These candidates have historically been advanced based on performance in rodent models, which may be inherently limited in their ability to represent the complex human cognitive and behavioral processes that are affected by neuropsychiatric disease. Given this challenging atmosphere, a critical question is how the field can move forward to tackle such an enormous public health need. In this issue of Biological Psychiatry, Wendland and Ehlers (
      • Wendland J.R.
      • Ehlers M.D.
      Translating neurogenomics into new medicines.
      ) provide a sagacious framework championing the promise, while emphasizing the challenges, of using genetics to revitalize drug discovery programs in neuroscience. Melding this industry perspective with academic culture is likely necessary to create a common ground for accelerating discovery.
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      Linked Article

      • Translating Neurogenomics Into New Medicines
        Biological PsychiatryVol. 79Issue 8
        • Preview
          Brain disorders remain one of the defining challenges of modern medicine and among the most poorly served with new therapeutics. Advances in human neurogenetics have begun to shed light on the genomic architecture of complex diseases of mood, cognition, brain development, and neurodegeneration. From genome-wide association studies to rare variants, these findings hold promise for defining the pathogenesis of brain disorders that have resisted simple molecular description. However, the path from genetics to new medicines is far from clear and can take decades, even for the most well-understood genetic disorders.
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