In this issue of the Journal, Wu and colleagues (3) report results of a large population-based analysis of stroke risk among antidepressant users in Taiwan. Previous studies have had conflicting results, though some have suggested a link between antidepressant use and stroke. For example, in the large Women's Health Initiative study of postmenopausal women, those receiving treatment with selective serotonin reuptake inhibitors (SSRIs) had a 45% relative increased risk of stroke compared with women not receiving antidepressant treatment (4). In addition, SSRI use was associated with a doubling of the risk of hemorrhagic and fatal stroke (4). One crucial methodologic issue facing observational studies of adverse effects in drug-exposed versus nonexposed subjects is the problem of confounding by indication. Antidepressant users likely differ from nonusers on a broad range of factors that can affect risk of cerebrovascular events, most notably the presence of depression, which itself has been implicated as a risk factor for cardio- and cerebrovascular disease. If we see an increased risk of stroke in comparing antidepressant users with nonusers, how do we know how much of the increase is attributable to the medication rather than the underlying depression, anxiety, or associated risk factors that distinguish users and nonusers? The answer is, we cannot be sure.