The drug known as venlafaxine was first synthesized in the early 1980s and was found to block the uptake of serotonin (5-HT) and, with lower potency, norepinephrine (NE), in rat brain synaptosomal preparations (Muth et al. 1986). Subsequently, it was shown to have in vivo activity in animal models of depression and to have little affinity for muscarinic or histaminergic postsynaptic receptors (Bolden-Watson and Richelson 1993; Muth et al. 1986). As such, venlafaxine was predicted to have a better tolerability profile than the tricyclic antidepressants (TCAs). Several early randomized, controlled trials (RCTs) confirmed that venlafaxine had antidepressant effects comparable to those of TCAs, with fewer side effects attributable to anticholinergic and antihistaminergic activity (see, for example, T. R. Einarson et al. 1999). The initial formulation of venlafaxine—now known as venlafaxine immediate-release (IR)—was approved by the U.S. Food and Drug Administration (FDA) for treatment of depression in 1994. An extended-release (XR) formulation was introduced a little more than 3 years later. Generic formulations of venlafaxine IR began to be introduced in 2007.