Pimavanserin and Aggression and Social Cognition.

The investigators are studying how certain drugs can reduce anger outbursts in people with anger problems. In this study the investigators seek to determine if a single 34 mg (two 17 mg tablets) oral dose of the 5-HT2a receptor blocker, pimavanserin, will reduce aggressive responding in individuals with impulsive aggression (Intermittent Explosive Disorder: IED) on a laboratory task that assesses aggression (Taylor Aggression Paradigm: TAP). We will also be examining how this drug impacts hostile social cognition e.g., hostile attribution). If pimvanserin reduces aggression in this study a next step would be a placebo-controlled treatment trial of pimavanserin in study participants with IED. Participation will first involve a remote (e.g., TEAMS) screening session. If potential study participants appear eligible they will come into the lab for an in-person session where participants will complete interviews and questionnaires and have a medical evaluation (including a physical exam, electrocardiogram, and screens for alcohol and drug use). During the next study session, participants will complete a diagnostic interview and a series of questionnaires, all of which can all take place on-line. During the next two sessions (which will be in-person) participants will undergo two (2) study sessions during which study participants will be given a study drug (orally). The drug given, pimavanserin, is currently available and is known to block serotonin receptors thought to be involved in regulating anger. After participants take the study drug, study participants will complete questionnaires and computer tasks for assessment of aggression and of hostile social cognition. Each of these two in-person study sessions will take at least eight (8) hours. A final on-line session will be done to make certain the investigators have all the data required by the study protocol.

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. 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. 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.

Aggression, Intermittent Explosive Disorder, Hostile Social Cognition, 5-HT-2a Receptor Antagonist, Pimavanserin

In the TAP, the subject competes against a fictitious opponent in a reaction time game during which the investigator manipulates provocation by having the "opponent" select increasing (mild) electric shock levels (i.e., a physically aggressive threat) which then elicits aggressive responding to the "confederate" when he/she loses a reaction-time task. Subjects can select shock from level 1 to level 9, and to select a "high" (10 level) or a "very high" (20 level) shock. The total number of "High" / "Very High" (10/20) shocks selected for the opponent is the outcome for heightened aggression in this study.

The V-SEIP contains eight video stories presenting possible (i.e., socially ambiguous) aggressive encounters between "Actor A" (who the subject is told to identify with) and "Actor B" who physically, or verbally, assaults the "primary individual". After viewing each video story (~ 10 seconds), the subject is asked to record all the elements of the video they recall; this is referred to as encoding (ENC). Then, the subject rates the likelihood that "Actor B" acted towards "Actor A" because he/she wanted to physically/emotionally hurt the other person (Hostile Attribution: HA). Finally, the subject is asked to rate the likelihood of how angry/upset they would be if this "event" happened to them (Negative Emotional Response: NER).

Inclusion Criteria: Participants will have a current (or past) DSM-5 diagnosis of Intermittent Explosive Disorder (IED). In addition, all participants must meet the following criteria: Participant is between 21 and 55 years of age and is able to give informed consent. Participant is physically healthy as confirmed by medical history, physical evaluation, ECG, and (in females) has a negative pregnancy test. Four weeks free of psychotropic medication. (Please note that only 10% of screened subjects take psychotropics of any kind because we recruit from the general community and such individuals are much less likely to be under psychiatric care at the time of recruitment; we do not take patients off their medication to enroll them in studies; such patients are referred for clinical treatment instead). Exclusion Criteria: All subjects with the following are excluded from study: Clinically significant medical condition. Prolonged QT-Interval ( > 0.45 / > 0.47 seconds for males/females). Life history of bipolar disorder / schizophrenia / organic mental syndrome or intellectual disability. Current major depressive disorder with a BDI score > 32. Current alcohol / drug use disorder of greater than mild severity. Current suicidal ideation. Allergy, or other contraindication, to pimavanserin. Current treatment with opiates or any agents that affect pain threshold. Unwilling/unable to sign informed consent document.

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