Major depression is a highly prevalent, frequently debilitating illness that too often fails
to respond to currently available treatments such as antidepressant medication. Furthermore,
randomized controlled trials of antidepressants consistently demonstrate large placebo
effects. The investigators hypothesize that individual differences in the function of key
brain circuits underlie the observed variability in clinical responses to both placebo and
antidepressant medication. This study will test this hypothesis by recruiting
treatment-seeking volunteers with major depression, with or without comorbid nicotine
dependence. Volunteers will participate in positron emission tomography (PET) and functional
magnetic resonance imaging (fMRI) scans in the context of a treatment trial in which they
will receive both placebo and antidepressant medication. A major goal of the study is to
improve prediction of individual clinical responses in future treatment trials in which brain
imaging may be unavailable, and to study the mechanisms of antidepressant response in Major
Depression.