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    Medical Discovery: Building to a Breakthrough

    Microscope with test tubes in the background

    Medical breakthroughs are the result of sustained, long-term research and collaborations among academia, industry, and federal partners. Scientific collaborations across institutions, research fields, and the world are key to developing the groundwork for achieving a breakthrough discovery.

    Getting breakthroughs from the bench to the bedside

    The types of research conducted by investigators at medical schools and teaching hospitals, and those within the federal government, help bring the next discovery from the lab to patients across the world.

    • Basic research provides the foundation of knowledge for the applied science that follows.

    • Translational research applies findings from one type of research and “translates” to the next stage, for example from basic to clinical. 

    • Clinical trials determine the safety and effectiveness of medications, devices, diagnostic products, and treatment regimens.

    Esketamine: Providing hope in mental health

    Roughly 4 million people in the United States have treatment-resistant depression. Now, esketamine — the discovery of which was possible with funding from the NIH and others for medical research in academic medicine — is giving those people hope for relief. Recently approved by the U.S. Food and Drug Administration (FDA), esketamine is the first new therapy in more than 30 years for the treatment of major depression.

    • 1920s (basic research)
      Discovery of the first chemical messenger produced by nerve cells, or neurotransmitter.1

    • Early 1960s (clinical trials)
      A research team at the University of Michigan first administers ketamine to humans, but how it interacts with the body to produce results is unknown.2

    • Pre-1980s (basic research)
      Neurobiology research, funded by federal partners, academic medical centers, and others, continues to identify neurotransmitters, including glutamate.

    • 1980s-1990s (translational research)
      The depletion of certain neurotransmitters fails to bring about depression symptoms in studies led by Yale investigators at West Haven VA Medical Center and Connecticut Mental Health Center. Researchers question the impact of these neurotransmitters and look at the possible role of glutamate in depression.3

    • 1990 (clinical trials)
      A team at the Yale School of Medicine and West Haven VA Medical Center study the effects of ketamine effects in healthy subjects to test novel treatment strategies for schizophrenia by examining the role of glutamate in symptoms associated with the disease.4

    • Mid-1990s (translational research)
      Building off earlier research into the role of the glutamate system in depression and schizophrenia, the Yale/VA team uses ketamine to examine how dysregulation of the system affects depression and finds a single dose rapidly alleviated depression in veterans at the West Haven VA Medical Center.5

    • 2006 (translational research)
      An NIH-led study shows that ketamine provides “robust and rapid antidepressant effect” to patients with depression.6

    • 2009 (translational research)
      An NIH-funded study led by researchers at the Icahn School of Medicine at Mount Sinai finds that within 24 hours of receiving ketamine, patients suffering from treatment-resistant depression show rapid improvement in suicidal thinking.7

    • 2010 (translational research)
      An NIH study replicates the results of the Icahn School of Medicine study.8

    • Early 2010s (translational research)
      Columbia University Irving Medical Center researchers examining physiological susceptibility to suicide, with funding from the NIH, discover that ketamine can ease suicidal thoughts more effectively than a control drug.9

    • 2018 (clinical trials)
      The results of a series of two multi-year Phase 3 trials led by a pharmaceutical company and involving a number of teaching hospitals show the safety and efficacy of a nasal spray form of a derivative of ketamine, esketamine.10,11

    • 2019 (clinical trials)
      The FDA approves a nasal spray form of esketamine that can only be administered under the supervision of a health care provider in a certified office or clinic.12

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    1 The Nobel Prize. Otto Loewi: Nobel Lecture. NobelPrize.org. Accessed Oct. 1, 2019. 

    2 Domino EF, Chodoff P, Corssen G. Pharmacologic effects of CI-581, a new dissociative anesthetic, in man. Clin Pharmacol Ther. 1965 May-Jun;6:279-91.

    3 Reviewed in: Berman RM, Krystal JH, Charney DS.  Mechanism of action of antidepressants:  monoamine hypotheses and beyond. In:  Biology of Schizophrenia and Affective Disease.  Watson SJ (ed), Washington D.C.:  American Psychiatric Press, 1996;295-368

    4 Krystal JH, Karper LP, Seibyl JP, et. al. Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch Gen Psychiatry. 1994 Mar;51(3):199-214.

    5 Berman R, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47(4): 351-354.

    6 Zarate CA, Singh J, Carlson P, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63(8):856-864.

    7 Price R, Nock M, Charney D, Matthew S. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. 2009;66(5):522-526.

    8 Zarate CA, Brutsche NE, Ibrahim L, et al. Replication of ketamine’s antidepressant efficacy in bipolar depression: a randomized controlled add-on trial. Biol Psychiatry. 2012;71(11):939-946.

    9 H, Choo T, et al. Ketamine for rapid reduction of suicidal thoughts in major depression: a midazolam-controlled randomized clinical trial. Am J Psychiatry. 2018;175(4):327-335

    10 Daly EJ, Trivedi MH, Janik A, et al. Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in patients with treatment-resistant depression: a randomized clinical trial. JAMA Psychiatry. 2019;76(9);893-903.

    12 FDA approves esketamine, the first major depression treatment to reach U.S. market in decades. STAT. March 5, 2019.