New Hypotheses to Guide Future Antidepressant Drug Development

Abstract

The emergence of molecular neurobiology is rapidly changing the traditional focus of antidepressant drug research with emphasis on effector sites beyond the receptors. This switch in emphasis is leading to new conceptual and methodological approaches to understanding the mode of action of antidepressants. Events beyond the receptors—intracellular signal transduction pathways and regulation of programs of gene expression—are promising new and exciting targets for antidepressants. A short historical review of the evolution of hypotheses (e.g., monoamine, b-adrenoceptor down-regulation, and the 5-HT/NE/ glucocorticoid link) concerning the mode of action of antidepressants is first presented. The chapter then presents an overview of new hypotheses concerning the mode of action of antidepressants and discusses the role of N-methyl-D-aspartate (NMDA) receptors in antidepressant action and the possible role of corticotropin releasing factor (CRF) antagonists and substance P receptor antagonists as antidepressants. Neurotransmitter-induced intracellular processes and the importance of crosstalk at the level of protein kinases are described. The chapter than discusses protein kinase C-related processes, G proteins, and transcription factors as potential targets for antidepressants and considers the convergence of neurotransmitter signals beyond the receptors at the level of protein kinase-mediated phosphorylation. To discover the next generation of antidepressants, two avenues of interrelated investigations seem promising: (1) a more rigorous elucidation of the molecular psychopathology of affective disorders and the development of animal models of depression with greater disease validity and (2) the development of new methodology to explore mechanisms beyond the receptors and second messengers in animal models of depression and in patients with affective disorders. Possible models of depression that may have increased disease validity are described. The chapter concludes with a discussion of how programs of gene expression are likely to affect antidepressant drug development. Differentially expressed genes and their protein products can be used as novel drug targets for the development of the next generation of antidepressants, which hopefully will meet the yet unmet criteria of greater efficacy, shorter onset of therapeutic action, and efficacy in therapy-resistant depression.