This study investigates the functional neuroanatomy of unipolar major depression using positron emission tomography (PET) to measure regional cerebral blood flow (BF). A homogeneous subject group was selected based on criteria for familial pure depressive disease (FPDD), which is defined by family history and symptoms of depression. The study used a two-step approach to identify candidate regions of interest: first, by subtracting composite images from one-half of depressed and control subjects, and second, by testing these regions in a second set of subjects. The major cortical region identified was the left ventrolateral prefrontal cortex (VLPFC) and the medial prefrontal cortex, which showed increased BF in depressed subjects. Activity in the left amygdala was also significantly increased in the depressed group, suggesting a trait marker of FPDD. The study found that the abnormality in the left prefrontal cortex represents a state marker of FPDD, while the abnormality in the left amygdala may represent a trait marker. These findings suggest that a circuit involving the prefrontal cortex, amygdala, and related structures is involved in the functional neuroanatomy of depression. The study highlights the importance of using homogeneous subject groups and a two-step analysis to accurately identify and test regions of interest in functional imaging studies of depression.This study investigates the functional neuroanatomy of unipolar major depression using positron emission tomography (PET) to measure regional cerebral blood flow (BF). A homogeneous subject group was selected based on criteria for familial pure depressive disease (FPDD), which is defined by family history and symptoms of depression. The study used a two-step approach to identify candidate regions of interest: first, by subtracting composite images from one-half of depressed and control subjects, and second, by testing these regions in a second set of subjects. The major cortical region identified was the left ventrolateral prefrontal cortex (VLPFC) and the medial prefrontal cortex, which showed increased BF in depressed subjects. Activity in the left amygdala was also significantly increased in the depressed group, suggesting a trait marker of FPDD. The study found that the abnormality in the left prefrontal cortex represents a state marker of FPDD, while the abnormality in the left amygdala may represent a trait marker. These findings suggest that a circuit involving the prefrontal cortex, amygdala, and related structures is involved in the functional neuroanatomy of depression. The study highlights the importance of using homogeneous subject groups and a two-step analysis to accurately identify and test regions of interest in functional imaging studies of depression.