Royce Lee

A double-blind, randomized, placebo-controlled trial of fluoxetine in patients with intermittent explosive disorder.

BACKGROUND Intermittent explosive disorder (IED) is a disorder of impulsive aggression that affects as many as 7.3% of the U.S. population during some period of life. Since central serotonergic (5-HT) system dysfunction is related to impulsive aggressive behavior, pharmacologic enhancement of 5-HT activity should reduce impulsive aggressive behavior in individuals with IED. METHOD A double-blind, randomized, placebo-controlled trial of the selective 5-HT uptake inhibitor fluoxetine was conducted in 100 individuals with IED (research diagnostic criteria) and current histories of impulsive aggressive behavior. The primary efficacy measure was the aggression score from the Overt Aggression Scale-Modified (OAS-M) for Outpatient Use. Secondary efficacy measures included the irritability score from the OAS-M and the Clinical Global Impressions-Improvement scale (CGI-I) score. The study took place between July 1990 and July 1999. RESULTS Fluoxetine treatment resulted in a sustained reduction in OAS-M aggression, and OAS-M irritability scores, apparent as early as week 2 (p < .01 for aggression and p < .001 for irritability at endpoint). Fluoxetine was also superior to placebo in the proportion of responders on the CGI-I (p < .001). Closer examination of the data revealed that full or partial remission of impulsive aggressive behaviors, as reflected by the A criteria for IED, occurred in 46% of fluoxetine-treated subjects. Fluoxetine did not exert an antidepressant or antianxiety effect, and its effects on impulsive aggression were not influenced by presence of current symptoms of depression or anxiety. CONCLUSION Fluoxetine treatment has a clear antiaggressive effect in impulsive aggressive individuals with IED. However, while fluoxetines antiaggressive effects appear robust, they lead to full or partial remission of IED in less than 50% of subjects treated with fluoxetine.

Cerebrospinal fluid oxytocin, life history of aggression, and personality disorder

BACKGROUND Data from animal studies have identified oxytocin as an important modulator of social aggression. We have previously reported on a relationship between cerebrospinal fluid (CSF) levels of vasopressin and life history of aggressive behavior, a finding that is consistent with animal data. We hypothesized that CSF Oxytocin levels would be inversely related to dimensional measures of lifetime aggression. METHODS Lumbar CSF for morning basal levels of oxytocin was obtained from 58 consenting subjects with and without DSM-IV personality disorders. Aggression was assessed dimensionally using an interview instrument (Life History of Aggression (LHA)). The primary analysis was conducted using a linear regression model predicting variance in CSF Oxytocin concentration, including the predictors of LHA score, Sex, Height, and the presence or absence of personality disorder. RESULTS The model predicting variance in CSF Oxytocin concentration including LHA score was statistically significant, after removal of a single multivariate outlier. Inclusion of the outlier resulted in a most likely spurious interaction between Sex and LHA score. Presence or absence of personality disorder was not associated with variance in CSF Oxytocin levels. Exploratory analyses revealed a possible inverse relationship between CSF Oxytocin level and history of suicidal behavior. CONCLUSIONS As hypothesized, CSF Oxytocin levels were inversely correlated with life history of aggression. This represents the first such report of a relationship between oxytocin levels and aggression. The correlational, cross-sectional study design precludes causal inferences, but the data are consistent with the known effects of oxytocin on aggressive behavior in animals.

The neuropsychopharmacology of criminality and aggression.

Although the idea that aggression has biological components is not a new one, recent research in genetics, neuropsychopharmacology, and neuroimaging has helped clar ify the bi o log i cal con tri bu tions to ag gres sion. Studies to date have fo cused on serotonergic func tion and im pul sive ag gres sion. Re duced lev els of cerebrospinal fluid (CSF) 5-hydroxyindoleacetic acid (5-HIAA) are as so ci ated with im pul sive ag gres sion. Pharmacochallenge stud ies have foun d de creased serotonergic re sponsive ness as so ci ated with im pul sive ag gres sion. Neuroimaging stud ies sug gest a role for the prefrontal cor tex, along with other r egions of the brain, in the ex pres sion of ag gres sion. Se ro to nin is not the only as pect of brain func tion im pli cated in impulsive ag gres sion, and fur ther work is be ing done on other neurotransmitters and neuropeptides.

Developmental psychopathology and neurobiology of aggression.

The aim of this paper is to clarify how neural mechanisms at the molecular level, specifically the serotonergic (5-HT) system and the hypothalamic-pituitary-adrenal axis system (HPA) in conjunction with early life stress may contribute to the emergence of aggression, self-directed and otherwise, in borderline personality disorder (BPD). Chronic dysregulation of these biological systems, which function to regulate stress and emotion, may potentiate the development of impulsive aggression in borderline personality conditions. Our central premise in this paper is that brain development, stress regulation, and early pathonomic experience are interactive and cumulative in their mutual influence on the development of impulsive aggression in BPD. We review the parameters of impulsive aggression in BPD, followed by a discussion of the neurobiological and neuroendocrine correlates of impulsive aggression with and without BPD. We then focus on the developmental continuities in BPD with attention to brain maturation of 5-HT and HPA axis function during the life span and the influence of early adverse experiences on these systems. Finally, we comment on the data of the relative stability of aggression in BPD, adolescence as a developmental stage of potential vulnerability, and the course of aggressive behavior during the life span.

Aggression, Suicidality, and Intermittent Explosive Disorder: Serotonergic Correlates in Personality Disorder and Healthy Control Subjects

Central serotonergic (5-HT) activity has long been implicated in the regulation of impulsive aggressive behavior. This study was performed to use a highly selective agent for 5-HT (d-Fenfluramine, d-FEN) in a large group of human subjects to further explore this relationship dimensionally and categorically. One hundred and fifty healthy subjects (100 with personality disorder, PD and 50 healthy volunteer controls, HV) underwent d-FEN challenge studies. Residual peak delta prolactin (ΔPRL[d-FEN]-R; ie, after the removal of potentially confounding variables) was used as the primary 5-HT response variable. Composite measures of aggression and impulsivity were used as dimensional measures, and history of suicidal/self-injurious behavior as well as the presence of intermittent explosive disorder (IED) were used as categorical variables. ΔPRL[d-FEN]-R responses correlated inversely with composite aggression, but not composite impulsivity, in all subjects and in males and females examined separately. The correlation with composite aggression was strongest in male PD subjects. ΔPRL[d-FEN]-R values were reduced in PD subjects with a history of suicidal behavior but not, self-injurious behavior. ΔPRL[d-FEN]-R values were also reduced in patients meeting Research Criteria for IED. Physiologic responses to 5-HT stimulation are reduced as a function of aggression (but not generalized impulsivity) in human subjects. The same is true for personality disordered subjects with a history of suicidal, but not self-injurious, behavior and for subjects with a diagnosis of IED by research criteria. These data have particular relevance to the notion of impulsive aggression and the biological validity of IED.

Effects of MDMA and Intranasal Oxytocin on Social and Emotional Processing

MDMA (±3,4-methylenedioxymethamphetamine, ‘ecstasy’) is used recreationally, reportedly because it increases feelings of empathy, sociability, and interpersonal closeness. One line of evidence suggests that MDMA produces these effects by releasing oxytocin, a peptide involved in social bonding. In the current study, we investigated the acute effects of MDMA and oxytocin on social and emotional processing in healthy human volunteers. MDMA users (N=65) participated in a 4-session, within-between-subjects study in which they received oral MDMA (0.75, 1.5 mg/kg), intranasal oxytocin (20 or 40 IU), or placebo under double-blind conditions. The primary outcomes included measures of emotion recognition and sociability (desire to be with others). Cardiovascular and subjective effects were also assessed. As expected, MDMA dose-dependently increased heart rate and blood pressure and feelings of euphoria (eg, ‘High’ and ‘Like Drug’). On measures of social function, MDMA impaired recognition of angry and fearful facial expressions, and the larger dose (1.5 mg/kg) increased desire to be with others, compared with placebo. Oxytocin produced small but significant increases in feelings of sociability and enhanced recognition of sad facial expressions. Additionally, responses to oxytocin were related to responses to MDMA with subjects on two subjective measures of sociability. Thus, MDMA increased euphoria and feelings of sociability, perhaps by reducing sensitivity to subtle signs of negative emotions in others. The present findings provide only limited support for the idea that oxytocin produces the prosocial effects of MDMA.

Elevated plasma inflammatory markers in individuals with intermittent explosive disorder and correlation with aggression in humans.

IMPORTANCE Neurochemical studies in human aggression point to a modulatory role for a variety of central neurotransmitters. Some of these neurotransmitters play an inhibitory role, while others play a facilitatory role modulating aggression. Preclinical studies suggest a facilitatory role for inflammatory markers in aggression. Despite this, to our knowledge, no studies of aggression and inflammatory markers have been reported in psychiatric patients or in individuals with recurrent, problematic, impulsive aggressive behavior. OBJECTIVE To test the hypothesis that plasma inflammatory markers will correlate directly with aggression and will be elevated in individuals with recurrent, problematic, impulsive aggressive behavior. DESIGN, SETTING, AND PARTICIPANTS Case-control study in a clinical research program in impulsive aggressive behavior at an academic medical center. Participants were physically healthy individuals with intermittent explosive disorder (n = 69), nonaggressive individuals with Axis I and/or II disorders (n = 61), and nonaggressive individuals without history of an Axis I or II disorder (n = 67). MAIN OUTCOMES AND MEASURES Plasma levels of C-reactive protein and interleukin 6 were examined in the context of measures of aggression and impulsivity and as a function of intermittent explosive disorder. RESULTS Both plasma C-reactive protein and interleukin 6 levels were significantly higher in participants with intermittent explosive disorder compared with psychiatric or normal controls. In addition, both inflammatory markers were directly correlated with a composite measure of aggression and, more specifically, with measures reflecting history of actual aggressive behavior in all participants. CONCLUSIONS AND RELEVANCE These data suggest a direct relationship between plasma inflammatory processes and aggression in humans. This finding adds to the complex picture of the central neuromodulatory role of aggression in humans.

Cerebrospinal fluid 5-hydroxyindolacetic acid and homovanillic acid: reciprocal relationships with impulsive aggression in human subjects

While the relationship between cerebrospinal fluid 5-HIAA (CSF 5-HIAA) and aggression is typically reported as inverse, studies of some groups of aggressive individuals demonstrate a positive (or no) relationship, between these two variables. It is possible that simultaneous examination of both CSF 5-HIAA and CSF homovanillic acid (HVA), which co-vary in human subjects may clarify differences in reported findings in different groups of aggressive individuals. CSF 5-HIAA and CSF HVA concentrations were simultaneously examined in 60 healthy human subjects (40 with personality disorder and 20 healthy controls) and were correlated with measures of aggression and impulsivity. CSF 5-HIAA concentrations correlated positively, and CSF HVA concentrations correlated inversely, with a composite measure of impulsive aggression in all subjects as well as in the personality disordered subjects. The CSF 5-HIAA findings are consistent with those demonstrating reduced post-synaptic 5-HT receptor responsiveness to 5-HT agent challenge and suggest differences in the pathophysiology between different groups of subjects with aggressive behavior, particularly with regard to severity of aggressive behavior.

Relationship between psychopathy, aggression, anger, impulsivity, and intermittent explosive disorder

Intermittent explosive disorder (IED) in DSM-5 represents a disorder of recurrent, problematic, reactive (i.e., affective or impulsive), aggressive behavior that, over the lifetime, affects about 5-6% of individuals in the United States. While aggression is also observed in those with psychopathic personality, aggression in this context is frequently proactive rather than reactive, and neurobiological study suggests important differences between those with proactive aggression/psychopathy and those with reactive aggression. In this paper, we conducted two sets of analyses. First, a phenomenologic study to explore the frequency of psychopathic personality defined by the Psychopathology Checklist-Screening Version (PCL-SV) among IED and comparator participants and to explore differences in measures of aggression, anger, and impulsivity as a function of IED and psychopathic personality. Second, we re-analyzed data from five published studies to determine if psychopathic personality accounted for differences between IED and comparator participants. The first study found that only a modest proportion of IED participants display clinically substantial features of psychopathy and that measures of trait aggression and anger, rather than those of psychopathy, are the strongest correlates of IED. The second study found little evidence for any impact of psychopathy on reported findings in IED compared with various control participants.

Moderating effects of childhood maltreatment on associations between social information processing and adult aggression

BACKGROUND Associations between early life maltreatment, social information processing (SIP) and aggression in childhood and adolescence have been widely documented. Few studies have examined the importance of childhood maltreatment independent of SIP in the etiology of adult aggression. Furthermore, moderating effects of childhood maltreatment on the SIP-aggression links have not been explored. METHOD Hierarchical, multi-level models were fitted to data from n=2752 twins aged 20-55 years from the PennTwins Cohort. Adult aggression was assessed with the Life History of Aggression questionnaire. Childhood maltreatment was measured using the Childhood Trauma Questionnaire. Two aspects of SIP were examined: hostile attribution biases (HAB); negative emotional responses (NER). RESULTS Childhood maltreatment was positively correlated with adult aggression, independently of HAB and NER. In addition, childhood maltreatment moderated the relationships between both aspects of SIP and adult aggression. Specifically, the relationship between NER and aggression was stronger among individuals with higher levels of childhood maltreatment and NER was not associated with aggression for adults who experienced low levels of childhood maltreatment. Moderating effects of childhood maltreatment on the NER-aggression link were supported for total childhood maltreatment, emotional neglect and emotional abuse. In contrast, HAB was more strongly associated with adult aggression at lower levels of emotional abuse and physical neglect. CONCLUSIONS The current study provides insight into the mechanisms by which early life experiences influence adult aggression. Our findings suggest that childhood maltreatment may not only lead to increased levels of aggression in adulthood but may also modify the associations between SIP and adult aggression.