Objective: To elucidate the neural mechanisms of depression. Background: Despite extensive study, the neurophysiology of the brain's state(s) corresponding to depression remains uncertain, Methods: HMPAO single photon emission computed tomographic (SPECT) scans were obtained from eight adults diagnosed with major depression resistant to medication (average age 51 years; 4 men) before and immediately after 10 days of 20 Hz repetitive transcranial magnetic stimulation (rTMS) (2000 stimuli/daily 30′ treatment). To maximize the likelihood that SPECT scans reflected the state of depression, rather than uncontrolled responses of patients to poorly constrained environments, HMPAO was administered while subjects performed a simple task involving continuous monitoring of the direction of a large arrow on a computer screen and continuously tapping with the left or right index finger according to the direction of the arrow. Mean baseline Beck Depression Inventory (BDI) score was 27.4 (SD = 8.3) and mean posttreatment BDI score was 17.5 (SD = 8.5). Results: Treatment responders (defined by reduction in BDI score of ≥ 30%) had significantly less pretreatment blood flow in the left amygdala compared with nonresponders. Responders demonstrated two patterns of change in regional blood flow with treatment: a reduction in orbitofrontal blood flow and/or a reduction in anterior cingulate blood flow. Nonresponders did not demonstrate any regional changes in blood flow with treatment. Conclusions: These results suggest that there may be either more than one state of depression, or that depression may be associated with more than one pattern of psychologic activity, which in turn defines the depressive experience for individual patients.