Dr. Carroll suggests that atypical antipsychotic agents are not as effective as lithium augmentation. He cites a number needed to treat of four to five for lithium. As we noted, lithium augmentation has been studied in 10 placebo-controlled trials that have been previously reviewed (14). Nine of these studies were small, with less than a total of 36 patients. Perhaps the most important difference in the atypical antipsychotic trials is that only one of the lithium studies required that patients had to have failed at least 6 weeks of prior treatment (15). In that study, lithium was not more effective than placebo. In the largest, albeit uncontrolled, study of lithium augmentation (performed in the Sequenced Treatment Alternatives to Relieve Depression [STAR*D] study), lithium and thyroid hormone triiodothyronine (T3) augmentation were compared after two prior failed trials in 127 patients (16). While remission rates did not differ significantly in lithium- and T3-treated patients (15.9% versus 24.7%, respectively), significantly more patients taking lithium discontinued treatment because of intolerance (23.2% versus 9.6%, p=0.03). If the benefits are weighed against the risks, 11 of 69 patients receiving lithium remitted, while 16 were intolerant. This is not a favorable balance. In the pooled data from our meta-analysis, the remission rate for the atypical agents was 30.7%, and the discontinuation rate for adverse events was 9.1% (range: 4.4%–12.2%). Of course, these data are not from direct comparisons, and the patients in the atypical trials may have been less treatment resistant than those in the STAR*D study. Ultimately, only studies involving a direct comparison between atypical antipsychotic treatment and treatment with lithium can definitively inform clinicians and patients whether lithium augmentation is more effective, better tolerated, and safer than augmentation with an atypical antipsychotic.