Vol 4 n° 4 - Drug Development
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raditional measures of disease burden, such as prevalence and mortality, have vastly underestimated the personal, societal, and economic burdens of mental illnesses, which are more often disabling than lethal.The highly regarded World Health Organization (WHO)– World Bank study of the Global Burden of Disease1 defines the “disability-adjusted life year” (DALY) as healthy years of life lost to (i) premature death, or (ii) disability.As a cause of DALYs, depression ranks second only to heart disease in established market economies, and fourth overall.2 Realization of the need for treat- ments and, ultimately, for tested approaches to preven- tion has grown in response to the recognition of this high degree of burden. Approaches to drug discovery The textbook approach to drug discovery moves in logi- cal order from the bench to the bedside to the clinic to the community in sequentially ordered steps: molecular targets are defined through basic research; biochemical assays are used to screen for lead compounds; animal studies establish pharmacokinetic and pharmacodynamic parameters; and toxicology studies assess safety and risk. All these lead to human clinical trials in a multiphased developmental process that has been well documented. Though widely held as the ideal for basic, translational, and clinical research, the textbook approach has not char- acterized drug development in mental health. Rather, there have been three major discovery paradigms.3 Serendipity, the completely fortuitous discovery of ther- apeutic effects, is the typical pattern for drug discovery. In the early 1950s, for example, chlorpromazine was syn- thesized by Charpentier at Rhone-Poulenc.The surgeon Henri Laborit used the compound to induce a state of “artificial hibernation” and in 1952 forecast its potential for use in psychiatry. In that year, benefits were identi- C l i n i c a l   r e s e a r c h 3 2 5 Drug discovery and mental illness Barry D. Lebowitz, PhD; Herbert W. Harris, MD, PhD Keywords:  drug  development;  mental  illness;  clinical  trial;  mechanism-based paradigm Author  affiliations:  Barry  D.  Lebowitz,  PhD,  National  Institute  of  Mental Health, Bethesda, Md, USA; Herbert W. Harris, Senior Medical Director, Vela Pharmaceuticals, 3131 Princeton Pike, Building 4, Suite 216, Lawrenceville, NJ, USA Address for correspondence: Barry D. Lebowitz, PhD, National Institute of Mental   Health,   6001   Executive Boulevard,   Room   7160   MSC   9635, Bethesda, MD 20892-9635, USA
(e-mail: blebowit@mail.nih.gov) T Mental disorders are among the most disabling of all dis- eases. Effective well-documented medications have been available for many decades. Yet, limited understanding of the pathophysiology of mental disorders has impeded the development of novel treatments. Drug discovery must move toward a new mechanism-based paradigm using the tools of contemporary genetic and molecular medi- cine.  At  the  same  time,  this  new  paradigm  must  be matched by an equivalent effort to modernize established approaches to clinical trials methodology. Dialogues Clin Neurosci. 2002;4:325-328.