Monoamine and neuropeptide-related function: prospects for novel therapeutics of depression

Treatment of depression has been dominated by monoamine hypotheses for nearly half a century. Although the ultimate downstream targets of manipulation of biogenic amine transport and metabolism are signal transduction cascades, neurotrophic factors and ultimately genomic fine-tuning, much of drug development has remained focused on strategies to facilitate a rapid initial augmentation of synaptic neurotransmitter levels. Both monoaminergic agents that are highly specific in their target receptor stimulation and agents that modify multiple monoamine systems will move through the stages of drug development in coming years. Furthermore, recent landmark successes and initial pilot data indicates that small molecule peptide receptor antagonists for substance P, corticotrophin releasing factor and eventually others will be of increasing importance, since they may more subtlety modulate neurotransmission and only act on already deranged neural circuits. Eventually treatment strategies may begin to target intracellular kinase and phosphatase activity and other signal systems responsible for transporter and receptor trafficking patterns, as well as via more direct pathways toward mobilization of neurotrophic factor activity. In the near future however, refinement of monoamine strategies to treat depression will continue to guide thinking and development of novel drugs for depression. This review focuses primarily on developments relevant for the evolution of monaminergic and neuropeptide-based drugs for depression.