Selectivity of Antidepressants: From the Monoamine Hypothesis of Depression to the SSRI Revolution and Beyond

In 2003, available pharmacotherapy for mood disorders was based almost entirely on observationsfrom the 1950s and 1960s that agents that enhance monoamine transmitter function are effective antidepressants.Preclinical studies show that chronic administration of all effective antidepressants increasesthe efficiency of post-synaptic 5-HT transmission. Many antidepressants also modify noradrenergicfunction in the central nervous system. For the majority of antidepressants, these long-termchanges in serotonergic and/or noradrenergic function result from direct antagonism of serotonin and/or norepinephrine transporters (also termed “uptake sites”). Pharmacotherapy that is highly selectivefor one transporter over another has been demonstrated to be effective and tolerable, whereas agentsthat act on multiple transporters may not necessarily achieve better efficacy and may be associatedwith additional adverse events. Nevertheless, the rationale is in place to suggest that antidepressantsthat block both the serotonin and norepinephrine transporters might provide better efficacy, which canonly be determined by empirical testing.