‘CNS Drug Discovery and Development: When Will We Rescue Tantalus?’ Neuropsychopharmacology Reviews Volume 2 on CNS Drug Discovery and Development: Challenges and Opportunities

T he muses sang about Tantalus, condemned to suffer forever in the underworld. He stood in water up to his neck, but could never quench his thirst, for whenever he bent to drink, the water receded. Above his head hung branches loaded with fruits, but whenever he tried to pick one, the branch bent out of his reach. FD’Aulaire’s Book of Greek Myths, p. 112 Disorders of the central nervous system (CNS) continue to be among mankind’s most devastating illnesses. Worldwide, they cause enormous suffering for those affected, impeding the ability of children to grow and learn, of adults to work and live productively, and of the elderly to age with dignity. Despite the enormous strides made over the last quarter century in understanding the possible causes of various CNS disorders, and the development of novel therapeutics to treat these disorders, those of us who work in this field have often felt like the mythical Tantalus. The past decade, in particular, has seen enormous excitement but equally enormous frustration. Like Tantalus who saw the water and fruit before him, so too do we clearly see our goals: understanding the etiology and mechanisms of CNS disorders and developing more effective therapeutics to treat them. And yet, our ability to put our knowledge into practice has remained elusively out of reach. We believe the time has come, however, to make a concerted effort to rescue Tantalus. The outstanding articles in this special issue make us realize we are getting closer to achieving our goals. What we need now is a concerted, cooperative effort between leaders in the fields of academia, government, and industry; with such an integrated effort, real, tangible progress can be made. CNS disorders have a relatively high prevalence and are characterized by many facets that make them particularly challenging to treat, including early onset (for example, autism in childhood or schizophrenia in young adulthood), a relapsing–remitting course (as with mood and anxiety disorders and OCD), and, often, disabling symptoms. CNS disorders, and the loose terms ‘neuropsychiatric’ and ‘neurodegenerative’ diseases, encompass a vast spectrum of devastating conditions that affect individuals at every stage of development, including Parkinson’s disease, Alzheimer’s disease, schizophrenia, mood disorders, addiction, and autism. These illnesses exert, in aggregate, a disproportionate burden on public health. To measure the burden of any given disease, the World Health Organization (WHO) developed the disability-adjusted life year (DALY) measure, which sums the years of life lost to premature mortality in a population, and the years lived with disability (YLD). Despite the significant link between psychiatric disorders and suicide, Figure 1 (below) reflects that worldwide, the major impact of these illnesses is the disability they create. In 2000, the WHO estimated that 12% of all DALYs and 31% of YLDs worldwide were because of neuropsychiatric disorders. In developing countries such as North America and Europe, which have fewer cases of infectious diseases or malnutrition than the developing world, neuropsychiatric disorders alone were responsible for a staggering 43% of all YLDs. Others have estimated that disabilities because of neurodegenerative and psychiatric diseases now represent the second most frequent cause of morbidity and premature mortality in the United States. The inordinately high personal, familial, societal, and financial burden of these disorders underscores the urgent need to develop novel drugs to treat them. For instance, Alzheimer’s disease affects approximately 4.5 million Americans, with costs estimated at roughly $100 billion annually. Notably, if current incidence rates hold, and no preventive treatments become available, it is estimated that by the year 2050 over 13 million Americans will be affected. Given the growing elderly population, and the slow pace of innovations in CNS therapeutics, identifying the specific disease mechanisms involved in Alzheimer’s disease is tremendously important, as is developing drugs capable of addressing both its causes and symptoms (see article by Roses). In some ways, however, our field has reached an impasse. That is, though we are acquiring more and more knowledge about the etiology and mechanisms of CNS disorders, and about putative therapeutics for these disorders, we have been unable to mount a concerted effort to put our knowledge into practice. In addition to the sheer complexity of the CNS, other obstacles include (for many of our disorders) lack of a defined pathology, no direct tissue accessibility, and the daunting fact that the complexity of Neuropsychopharmacology (2008), 1–4 & 2008 Nature Publishing Group All rights reserved 0893-133X/08 $30.00 ............................................................................................................................................................... www.neuropsychopharmacology.org 1 EDITORIAL