Advertisement

pp 1-18 | Cite as

Drug Development in Psychiatry: The Long and Winding Road from Chance Discovery to Rational Development

  • Sheldon H. Preskorn
Chapter
Part of the Handbook of Experimental Pharmacology book series

Abstract

Based extensively on tables and figures, this chapter reviews drug development in psychiatry with an emphasis on antidepressants from 1950s to the present and then looks forward to the future. It begins with the chance discovery drugs and then moves to through their rational refinement using structure activity relationships to narrow the pharmacological actions of the drugs to those mediating their antidepressant effects and eliminating the effects on targets that mediate adverse effects. This approach yielded newer antidepressants which compared to older antidepressants are safer and better tolerated but nevertheless do still not treat the approximately 40% of patients with major depression (MD) which is unresponsive to biogenic amine mechanisms of action. This form of MD is commonly referred to as treatment resistant depression. Esketamine is an investigational antidepressant which has a novel mechanism of action: blockade of the glutamate NMDA receptor. Positive trials reported this year for esketamine make it likely this drug will be approved next year in the USA. These studies coupled with earlier studies with other NMDA drugs suggest approximately 60% of patient with TRD are rapidly and robustly responsive to this mechanism of action. Thus, there appears to be three forms of MD based on pharmacological responsiveness: (a) 60% responsive to biogenic amine mechanisms of action, (b) 24% (i.e., 40 × 60%) responsive to NMDA but not to biogenic amine mechanisms of action, and (c) 16% (i.e., 40 − 24%) not responsive to either of these mechanisms of action. Scientific investigation of these three groups may yield important information about the pathophysiology and/or pathoetiology of these different forms of MD. This information coupled with studies into the neurobiology (e.g., imaging studies, connectomes to name a few approaches being used) and genetics of MD should provide the fundamental knowledge which will permit a rational search for and discovery of newer antidepressant drugs and other somatic and psychotherapeutic approaches to the treatment of patients with different forms of MD based on pathophysiology and pathoetiology. Examples are given of how such discovery and development has occurred in other areas of medicine and even in central nervous system (CNS) space including six novel mechanisms of action CNS drugs which have been successfully developed and marketed over the last 25 years.

Keywords

Antidepressants Central nervous system biogenic amines Drug development Esketamine Major depression Mechanism(s) of action Psychiatric diagnosis Relative receptor binding Structure-activity relationships 

References

  1. Kraepelin E (1915) In: Barclay RM, Robertson GM (eds) Dementia praecox and paraphrenia. Krieger, Huntington NYGoogle Scholar
  2. Lavedan C, Forsberg M, Gentile AJ (2015) Tasimelteon: a selective and unique receptor binding profile. Neuropharmacology 91:142–147Google Scholar
  3. Preskorn SH (1990) The future and psychopharmacology: potentials and needs. Psychiatr Ann 20(11):625–633Google Scholar
  4. Preskorn SH (2010a) CNS drug development. Part I: the early period of CNS drugs. J Psychiatr Pract 16(5):334–339Google Scholar
  5. Preskorn SH (2010b) CNS drug development: part II: advances from the 1960s to the 1990s. J Psychiatr Pract 16(6):413–415Google Scholar
  6. Preskorn SH (2011) CNS drug development: part III: future directions. J Psychiatr Pract 17(1):49–52Google Scholar
  7. Preskorn SH (2014) CNS drug development: lessons from the development of ondansetron, aprepitant, ramelteon, varenicline, lorcaserin, and suvorexant. Part I. J Psychiatr Pract 20(6):460–465Google Scholar
  8. Preskorn SH (2015) CNS drug development: lessons learned part 2. Symptoms, not syndromes as targets consistent with the NIMH research domain approach. J Psychiatr Pract 21(1):60–66Google Scholar
  9. Preskorn S (2017a) Psychiatric and central nervous system drugs developed over the last decade: what are the implications for the field? J Psychiatr Pract 23(5):352–360Google Scholar
  10. Preskorn S (2017b) CNS drug development, lessons learned, part 4: the role of brain circuitry and genes – tasimelteon as an example. J Psychiatr Pract 23(6):425–430Google Scholar
  11. Preskorn S (2018) Drug-drug interactions with an emphasis on psychiatric medications. Professional Communications, Inc., West Islip, NYGoogle Scholar
  12. Preskorn SH, Baker B (2002) The overlap of DSM-IV syndromes: potential implications for the practice of polypsychopharmacology, psychiatric drug development and the human genome project. J Psychiatr Pract 8(3):170–177Google Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Sheldon H. Preskorn
    • 1
  1. 1.University of Kansas School of Medicine-WichitaWichitaUSA

Personalised recommendations