Lithium augmentation is a commonly used strategy to manage treatment-resistant depression (Bauer and Dopfmer 1999; Nierenberg and Cole 1991). A meta-analysis of nine placebo-controlled studies of lithium augmentation found that the pooled odds ratio of response during lithium augmentation compared with the response during placebo treatment was 3.31 (95% confidence interval = 1.46–7.53) (Bauer and Dopfmer 1999). Few studies have been reported, however, that assess the effectiveness of lithium augmentation, especially with regard to augmenting the modern generation of antidepressants, and even fewer studies generate a cohort of treatment-resistant patients prospectively who are then randomized to receive lithium plus the antidepressant or alternative augmentations. In a controlled prospective trial, lithium augmentation was inferior to raising the dose of fluoxetine (Fava et al. 2002). Nierenberg et al. (2003) found that after a prospective trial of nortriptyline for patients who had up to five treatments that failed, lithium augmentation was no better than placebo.