The prefrontal cortex influence over subcortical and limbic regions governs antidepressant response by N=H/(M+R)

We review the evidence for relationships between metabolic activity of cortical, subcortical and limbic brain regions in depression and the efficacy of antidepressant agents. The influence of these regions can be described by an algebraic equation, N=H/(M+R), where N represents a homeostatic level of executive function, H represents prefrontal (Brodmann areas 9, 10, 11, 12; 46) and cingulate cortex activity (24, 25; 32), M represents subcortical (hippocampus, parahippocampal gyrus) influences, and R represents limbic (amygdala) influences. This hypothesis is based on depressed prefrontal cortex and enhanced amygdala and hippocampal metabolism in major depressive disorder, and the remission of these changes by most antidepressant interventions. The therapeutic efficacy of antidepressant strategies may depend less on their presumptive molecular mechanisms of action and more on their ability to restore the predominant metabolic and executive functions of the prefrontal cortex, and dampen excessive subcortical and limbic influences.