Depression is common in neurological conditions. Patients with epilepsy are significantly more likely to have depression than the general population. However, no published studies have examined the effects of antidepressants and psychotherapy on the brain in patients with epilepsy. A systematic review of 34 relevant neuroimaging articles was conducted on temporal lobe epilepsy (with and without depression), depression (with and without epilepsy), and cognitive behavioral therapy (CBT) and antidepressants through PET, functional MRI, SPECT or proton spectroscopic imaging. Results indicate hypoactivity in the frontal cortex and hippocampus, and hyperactivity in the left dorsomedial prefrontal cortex for depression (with and without epilepsy). Hypoactivity was consistently found in the frontal cortex and temporal region in temporal lobe epilepsy (with and without depression). Studies of nonepilepsy groups suggest that CBT impacts the frontal cortex, prefrontal cortex, temporal lobe, thalamus and hippocampus--all of these areas are dysfunctional in temporal lobe epilepsy with depression. The findings suggest that patients with epilepsy may benefit from CBT. More research is needed to establish CBT as evidence-based practice for epilepsy with depression.