Title: Effect of acutely altering serotonergic activity on the performance of tasks relevant to cortical- amygdaloid circuits in IED and control subjects.
Name: Royce Lee
Associate Professor of Psychiatry

University of Chicago

Year: 2002, 2003
Type: Research Grant
Summary: A large body of human and non-human animal work has linked central serotonergic dysfunction to impulsive, or reactive aggression. Increasing serotonin availability in the neural synapse by administering serotonin-reuptake inhibiting medication can reduce the frequency and severity of aggressive episodes in impulsive aggressive individuals, but treatment does not always lead to complete or meaningful remission of symptoms. This highlights the need for a deeper understanding of the mechanism linking central aberrant serotonergic function to the impulsive aggressive act. The prototypical trigger of an impulsive aggressive act is a perceived social provocation that evokes an emotional response, typically anger, disgust, or frustration. Given that serotonergic receptors are densely located in the prefrontal cortex and limbic areas of the brain, regions implicated in social and emotional behavior, it is biologically plausible that serotonergic deficits disrupt the processing of social cues and/or regulation of anger that act as triggers for aggression. The objective of this study was to test the hypothesis that impulsive aggressive individuals have heightened susceptibility to disturbed 5-HT availability on measures of emotional information processing relevant to social interaction. Acute tryptophan depletion results in a transient hyposerotonergic state, the effects of which have been verified by decreased peripheral and central measures of serotonin metabolism. This technique can thus be used to study the role of serotonin in mental/brain processes. There are reasons to believe that impulsive aggressive individuals are particularly susceptible to the effects of altered serotonin availability on processing of emotional information. The objective of this study was to test the causal role of serotonin function in abnormal processing of emotional faces impulsive aggression and aggressive behavior. The experiment tested the hypothesis that decreasing serotonergic function would result in altered processing of angry faces in impulsive aggressive subjects. Additionally, the effect of tryptophan depletion on self-aggressive behavior was tested using a novel self-aggression paradigm developed by Dr. Michael McCloskey and Dr. Mitch Berman.

All subjects in this study demonstrated the capacity to understand the risks and procedures of the study and provided written informed consent, using forms approved by The University of Chicago Institutional Review Board (IRB). All study procedures had ethnical approval by the IRB. 20 normal control (NC) subjects (10 men and 10 women) and 20 impulsive aggressive subjects diagnosed with Intermittent Explosive Disorder, or IED (10 men and 10 women), completed the study. As hypothesized, tryptophan depletion affected the processing of angry face stimuli in impulsive aggressive individuals by increasing the perceived intensity of expressed anger in the angry face stimuli, although the effect appeared to be predominantly in males. Tryptophan depletion also increased angry mood, with a larger effect in impulsive aggressive individuals. Finally, tryptophan depletion facilitated the selection of more intense shocks to the self in both controls and aggressive subjects. Heart rate was increased by tryptophan depletion in both normal controls and IED subjects, consistent with increased arousal and/or decreased parasympathetic tone as a result of hyposerotonergic states. In summary, the findings would suggested that impulsive aggressive males have an underlying vulnerability to the cognitive and emotional effects of disturbed serotonin function with respect to processing of emotional stimuli. In impulsive aggressive males, decreased serotonin availability results in increased anger and a perceptual bias towards threatening faces. However, not all of the effects of tryptophan depletion were specific to male, impulsive aggressive individuals. Heart rate was increased in normal controls as well impulsive aggressive subjects, and self-aggression increased in normal controls as well as impulsive aggressive subjects. Our findings are generally consistent with work showing that aggressive individuals are more sensitive to the effects of tryptophan depletion than non-aggressive individuals. At this point it is not known if aggressive individuals experience greater fluctuations in serotonin activity than non-aggressive individuals in response to conflict, or if they are in a hyposerotonergic state even at baseline. This is an important distinction, as a body of work suggests that serotonin may modulate dominance-related drives. Thus, a question for future work to address is whether aggressive individuals overreact to social provocation, or whether abnormal drive for dominance results in social conflict.

Bibliography: McCloskey MS, Ben-Zeev D, Lee R, Berman ME, Coccaro EF: Acute tryptophan depletion and self- injurious behavior in aggressive patients and healthy volunteers. Psychopharmacology (Berl) 2009; 203: 53  61