Lithium treatment of bipolar disordered subjects is associated with increases (toward normal) in the volume of the left ventral anterior cingulate cortex, a structure where the grey matter volume was previously shown to be abnormally reduced in bipolar disorder. Studies performed in experimental animals or humans have suggested that this brain structure plays a major role in inhibiting or regulating the autonomic and endocrine responses to threat or stress, and the emotional feelings that occur in response to internally generated sad or anxious thoughts and memories. The abnormal reduction in volume may indicate this region?s function is impaired in bipolar disorder, dysregulating emotional expression and experience. Lithium has been shown to increase the genetic expression of proteins that exert neuroprotective and neurotrophic effects, so correcting this brain abnormality may play an integral role in lithium?s mood stabilizing effect. Effects of the psychotropic medications pramipexole and (?) are currently being persued. In the past study year it was demonstrated that both the children of depressed parents, who are themselves putatively at high genetic risk for developing a mood disorder, also have a reduction in the ventral anterior cingulate volume. In addition, the "pregenual" and portion of the corpus callossum, which carries fibers from the ventral anterior cingulate, orbital cortex, and medial prefrontal cortex areas where we identified structural abnormalities in unipolar and/or bipolar depression, was also shown to be reduced in volume both in females with unipolar depression and in females with bipolar disorder. In addition, this abnormality was evident in their children and adolescent offspring who had not yet suffered from mood disorders themselves. These data collectively demonstrated that these abnormalities may be assocated with abnormalities of brain development that precede illness and may be associated with the vulnerability to developing depression. These results were reported at the Society for Neurosciences Annual Meeting and a manuscript describing these results is nearly completed.