CHAPTER 8: Beyond SSRIs: Second-generation Reuptake Inhibitors for the Treatment of Depression

While the selective serotonin reuptake inhibitors (SSRIs) are an improvement over the earlier tricyclic antidepressants, they are limited in their effectiveness and have a unique side-effect profile. In this chapter is an assessment of the serotonin-mediated antidepressant strategies that have been identified from the primary and patent literature. The areas covered include combination serotonin reuptake inhibition and pre- or post-synaptic agonist and antagonist action. New approaches to targeting multiple biogenic amine transporters are discussed, as well as a summary of the stand-alone pre- and post-synaptic agonist and antagonist developments. The chapter focuses on the rationale for the antidepressant targets and the medicinal chemical strategies that have led to the newer molecular platforms.