Of the many behavioral disturbances associated with severe mental and neurocognitive disorders, impulsive behaviors, including agitation and aggression, present unique challenges. Frontal inhibition, cognitive impairments, and executive dysfunction commonly combine to promote behavioral disturbances in severe mental and neurocognitive disorders, and the interplay between structures and circuits may explain a mechanism for the impulsive behaviors, agitation, and aggression. A circuit of periaqueductal gray matter, hippocampus, amygdala, and hypothalamus mediates threat response, a bottom-up impulse. Prefrontal cortex (PFC) serves a top-down role to inhibit those bottom-up impulses, and PFC dysfunction impairs a person’s ability to recognize social cues and increases the risk of impulsive aggressive responses by a person failing to make appropriate risk/reward assessments for inhibiting responses. Added sensory deficits in hearing, vision, or pain together with sensory processing and appraisal deficits in cognition combine to foster behavioral disturbances of agitation, aggression, and impulsive acts [1]. Of the PFC, specifically the ventromedial PFC and its connections to lower structures, such as the amygdala, serve this top-down inhibitory function [1, 2]. PFC-amygdala circuit connectivity is disrupted by dysfunction in associated serotonin and dopamine systems in several mental conditions. Enhancing serotonergic and dopaminergic signaling in and around this circuit provides a theoretical approach to pharmacologic agent selection for many of these behavioral disturbances. Severe mental and neurocognitive disorders, including traumatic brain injury (TBI), often show pathology in the brain regions associated with top-down and bottom-up structures, as described above [3].