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

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.