GH response to intravenous clonidine challenge: absence of relationship with behavioral irritability, aggression, or impulsivity in human subjects.

Previous study suggests a role for post-synaptic alpha(2)-noradrenergic receptor sensitivity in irritability and/or aggression and impulsivity. In this study, we conducted intravenous challenges with the alpha(2)-noradrenergic agonist, clonidine, to assess the relationship between measures of impulsive aggression and post-synaptic alpha(2)-noradrenergic receptor sensitivity in human subjects. Subjects included 38 individuals with personality disorder and 28 healthy volunteer controls. Measures included the Irritability score and the Total Assault score from the Buss-Durkee Hostility Inventory (BDHI), Aggression score from Life History of Aggression (LHA) assessment, and Impulsivity scores from the Barratt Impulsivity Scale (BIS-11) and Eysenck Personality Questionnaire-II (EPQ-II). The Log of Peak DeltaGH[CLON] response was used as the index of post-synaptic alpha(2)-noradrenergic receptor sensitivity. No significant correlations were found between the Log of Peak DeltaGH[CLON] response and any measure used in this study. Unlike a previous investigation, this study provides little support for a role of post-synaptic alpha(2)-noradrenergic receptor sensitivity in aggression in healthy or personality disordered subjects.

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 (DeltaPRL[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. DeltaPRL[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. DeltaPRL[d-FEN]-R values were reduced in PD subjects with a history of suicidal behavior but not, self-injurious behavior. DeltaPRL[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.

Inverse relationship between numbers of 5-HT transporter binding sites and life history of aggression and intermittent explosive disorder.

The objective of this study was to determine if platelet 5-HT transporter (5-HTT) sites vary as a function of aggression, and/or impulsiveness, and differ as a function of Intermittent Explosive Disorder (IED). Accordingly, the number of platelet 5-HTT sites was assessed in 100 personality disordered (PD) individuals with varying degrees of aggressiveness. The number of platelet 5-HTT sites was assessed by examining the Bmax of H(3)-Paroxetine Binding to the blood platelet. Life history of aggression was assessed by Life History of Aggression. Impulsivity was assessed by the Barratt Impulsiveness Scale. Diagnoses of IED were made by both DSM-IV and Research Criteria. Examination of the data revealed that Bmax, but not Kd, values of Platelet H(3)-Paroxetine Binding correlated inversely with the LHA Aggression score (r=-.42 n=87, p<.001) but not with the BIS-11 Impulsivity score (r=.03, n=77, p=.777). PD subjects meeting Research Criteria for IED demonstrated a significant reduction in Bmax values for Platelet H(3)-Paroxetine Binding. These results were similar after accounting for the effect of lifetime history of depressive mood disorder on Bmax values for Platelet H(3)-Paroxetine Binding. These data indicate a significant inverse relationship between platelet 5-HTT and aggression, though not impulsivity, as a dimensional variable in personality disordered individuals. Results from the examination of IED as a categorical aggression variable suggest that Research, rather than DSM-IV, criteria better identify individuals with reduced numbers of platelet 5-HTT sites.

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 fluoxetine's antiaggressive effects appear robust, they lead to full or partial remission of IED in less than 50% of subjects treated with fluoxetine.

Placebo-controlled, randomized trial of fluoxetine in the treatment of aggression in male intimate partner abusers.

The objective was to determine the efficacy of treating aggressive behavior in men, with a history of intimate partner abuse, with fluoxetine. Twenty-six men with a history of intimate-partner-abusing behavior entered a randomized, placebo-controlled trial of fluoxetine (20-60 mg by mouth per day). The primary outcome measure was the Aggression score from the overt aggression scale-modified (OAS-M). Fluoxetine-treated patients (n=13) did not differ from placebo-treated patients (n=13) on any key demographic or behavioral variables. Although a significant 'pre-post' reduction in OAS-M Aggression score was noted in all patients, no drug-placebo differences for OAS-M Aggression scores were seen in any analysis. Despite the small sample, these results do not support the hypothesis that treatment with an SSRI is associated with a reduction in aggressive behavior among men with a history of intimate partner abuse.