Role of Pharmacogenetics/Pharmacogenomics in the Development of New Antidepressants

Abstract

The three chapters in this last section of the book are devoted to where the future of antidepressants may lie. Nalepa and Sulser discussed emerging new theories about the mechanisms that may underlie antidepressant efficacy. Such theories are guiding current drug development. Garlapati and colleagues discussed drugs currently in development for which information is in the public domain. This chapter is focused the furthest in the future and describes processes that will define new targets and mechanisms that might mediate antidepressant efficacy. These processes are the result of advances being made in molecular biology and neuroscience, which are leading to an improved understanding of the biological processes that subserve the regulation of higher brain function, including cognition, emotion, and sensory processing. Disturbances in these functions constitute psychiatric signs and symptoms. Given its focus on process, this chapter is as relevant to the development of drugs for psychotic, anxiety, and dementing illnesses as for affective illnesses, even though the focus of this book is antidepressants. This chapter describes how new findings from the human genome project will change the field of psychiatric drug discovery. The author first reviews the status of the human genome project and considers how findings from that project will (1) increase the number of potential targets for drug discovery, (2) help researchers understand the mechanisms that determine the drug concentration that is achieved on a given dose of a drug, and (3) help researchers determine the causes of variability in patients’ responses to a given dose of a drug. New findings concerning neuropeptides and other neurotransmitters that appear to be promising future targets for drug discovery are reviewed. The chapter describes the use of molecular biological approaches (e.g., transfecting sequences into cell lines or single cell organisms that do not normally contain them and studying their expression) to identify new receptors and neurotransmitters. The chapter also describes how the human genome is being searched for orphan receptors that can be used as “bait” to troll for and identify natural ligands (neurotransmitters), enabling researchers to discover biological processes that were either previously unknown or poorly understood and to map the distribution of neurotransmitters and receptors in the brain and identify their functions. Such knowledge will help pinpoint potential new targets (i.e., regulatory proteins) for drug discovery. The chapter concludes with a consideration of the challenges these new developments pose for researchers and clinicians. With the ever-expanding pool of potential targets for drug discovery, researchers need to conserve resources by carefully identifying targets that appear likely to have the greatest potential clinical utility. With the development of increasingly focused and targeted drugs that are likely to affect only the brain rather than peripheral systems, prescribers of antidepressants and other psychotropic drugs will need to be increasingly aware of the behavioral effects of the medications they prescribe as well as of the potential interactions that may occur with the increasing use of multiple, narrowly targeted medications.KeywordsHuman genome projectRational drug developmentDrug discoveryOrphan receptorsHigh-throughput screeningStructure-activity relationshipsMolecular targetingStages of drug developmentReverse pharmacologyBridging studies