Bupropion was discovered more than 40 years ago when investigators were searching for an antidepressant with a novel mechanism of action and safer side-effect profile. Synthesized in 1966, this unique compound, different from tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs), was found to have antidepressant activity in animal models that are predictive of antidepressant activity in humans (Soroko and Maxwell 1983). Bupropion was discovered to have minimal sympathomimetic and anticholinergic side effects and a safer pharmacological and biochemical profile in comparison with other antidepressants. Although both bupropion and selective serotonin reuptake inhibitors (SSRIs) were developed with similar goals in mind, their mechanisms of action are unique (Hudziak and Rettew 2004; Soroko and Maxwell 1983). Bupropion is classified as an aminoketone antidepressant (Mehta 1983). Its mechanism of action is thought to be via dual inhibition of norepinephrine and dopamine reuptake (NDRI) without clinically significant serotonin reuptake inhibition (Horst and Preskorn 1998; Stahl et al. 2004). Both bupropion and SSRIs appear to be equally efficacious in the treatment of major depression (Feighner et al. 1991). The sustained-release (bupropion SR) formulation, approved in 1996, has also proved to be significantly better than placebo in preventing depression relapse (Weihs et al. 2002). Bupropion's tolerability is superior to that of SSRIs, with minimal effects on weight, less sedation, minimal withdrawal symptoms upon discontinuation, and fewer or no sexual side effects (Thase et al. 2005).