The small, unrepresentative study group and the retrospective design permit no general conclusion about protective antidepressant drug effects on the hippocampus in major depression. There is also no preclinical basis for such speculation. The authors tried to claim such a basis by reference to a preclinical study of the agent tianeptine (2). They misled readers in stating, "Animal studies have shown antidepressants to protect against stress-induced decrease in neurogenesis with preservation of hippocampal volume during a social stress paradigm" (p. 1518). The cited study of social stress in tree shrews (2) examined no standard antidepressant agents. Tianeptine is not an accepted antidepressant agent. Placebo-controlled trials of its antidepressant efficacy are scarce (3), and its primary action is opposite to that of the antidepressant drugs that block monoamine membrane transporters. Functionally, tianeptine and fluoxetine have very different acute interactions with stress effects on hippocampal physiology (4) and opposite effects in behavioral pharmacology testing after long-term administration (5). In a chronic restraint stress model with rodents (6), fluoxetine does not possess the protective effect of tianeptine against dendritic atrophy in the hippocampus. In the tree shrew, social stress model, clomipramine has some protective activity similar to tianeptine (7), but it is a safe bet that none of the patients of Dr. Sheline and colleagues was treated with that drug. The authors lack a coherent preclinical case for their speculation, and what they proffer is misleading.