Human aggression is verbal and/or physical behavior directed at others (or objects) that results in injury to others (or objects). It is at the core of much human suffering and it is quite common. About four percent of the U.S. population have recurrent "anger attacks" and meet lifetime criteria for Intermittent Explosive Disorder (IED), a disorder of recurrent, problematic, impulsive aggression. In addition, another four percent of individuals have recurrent "anger attacks" that may not fully meet DSM-5 criteria for IED. Neurochemical brain studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters, particularly serotonin (5-HT). Evidence for a role for 5-HT in aggressive and suicidal behavior has been in the human literature since the late 1970s. Cerebrospinal fluid (CSF) levels of 5-HT metabolites (5-HIAA) have been reported as low in violent suicidal behavior and in those who have committed seriously aggressive acts such as homicide or attempted homicide. In addition, hormonal responses to 5-HT agonists are blunted in aggressive individuals and are inversely correlated with measures of aggression and suicidal behavior. Relevant to this proposal are data which report that the number of brain 5-HT-2a receptors are increased in those who had committed suicide by violent means and that brain and platelet 5-HT-2a receptors correlate in a positive direction with measures of aggression. In addition, similar findings have been reported regarding the PET neuroimaging of 5-HT-2a receptors in aggressive individuals. While stimulation of most 5-HT receptors increase behavioral inhibition, stimulation of 5-HT-2a receptors appear to do the opposite. If so, we hypothesize that blocking 5-HT-2a receptor activity with a 5-HT-2a receptor blocker will reduce aggressive responding in aggressive individuals. In this study, we propose to give a single dose of pimavanserin (and placebo on another day) and have aggressive individuals complete an analogue computer task of "aggressive responding". Because aggression is highly related to hostile social cognition, we will also have study participants complete a social cognition task to test the related hypothesis that pimavanserin can also reduce hostile social cognition. This project is designed to be an experimental medicine study to test the potential anti-aggressive efficacy of pimavanserin, a selective inverse agonist and antagonist of the serotonin 5-HT-2a receptor. As such, it is an early "proof of concept" study before, and without the expense of, conducting a clinical treatment trial.

Hypotheses of the study.

1. Pre-treatment with pimavanserin, but not placebo, will reduce aggressive responding in the Taylor Aggression Paradigm (TAP) in human subjects. Reduced aggressive responding in the TAP would be reflected by the subjects selecting fewer numbers of "high" and "very high" electric shock levels in response to provocation to pre-programmed shock levels in the context of the TAP.
2. Pre-treatment with Pimavanserin, but not placebo, will reduce hostile social cognition in aggressive individuals. Reduced hostile social cognition is reflected by an increase in the encoding of socially relevant information, a reduction in hostile attribution, and a reduction in negative emotional response while viewing brief (\~ 10 seconds) video clips of socially ambiguous interactions between two people. The task involved is the Video-Social-Emotional Information Processing (V-SEIP) Task.