A Double-Blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Patients With Intermittent Explosive Disorder
ABSTRACT 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.
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.
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.
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.
- SourceAvailable from: Daniel R Rosell
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- "Furthermore, S allele carriers for the 5-HTT promoter region polymorphism (5-HTTPLR) tend to be more aggressive (Aluja et al., 2009; Payer et al., 2012) and have lower 5-HTT availability in 5-HTT rich brain regions (Willeit and Praschak-Rieder, 2010). Serotonin-specific reuptake inhibitors (SSRIs) are effective for reduction of impulsive aggression (Coccaro et al., 2009), and this effect depends on genotype of the 5-HTT (L/L homozygotes respond better than S allele carriers) (Silva et al., 2010), highlighting the importance of individual differences. Despite burgeoning evidence on the importance of the 5-HTT in impulsive aggression, few studies have investigated its in vivo distribution in the brains of patients with IED-IR. "
ABSTRACT: Serotonin (5-HT) has consistently been implicated in the pathophysiology of impulsive aggression. In the current study, we tested the hypothesis that 5-HT transporter (5-HTT) binding is reduced in the anterior cingulate cortex (ACC) in impulsive aggressive patients. Additionally, we characterized pathological personality dimensions, with a specific focus on callousness (i.e. emotional indifference, a facet of psychopathy). Callousness is putatively positively correlated with presynaptic 5-HT, and thus could potentially confound the hypothesized negative relation between 5-HTT levels and trait aggression. We determined 5-HTT binding with positron emission tomography and [(11)C]DASB in 29 patients with intermittent explosive disorder (IED-IR) and 30 controls. We assessed group differences in 5-HTT binding in the pregenual ACC, amygdala and subcortical regions and examined correlations between 5-HTT binding and clinical measures. There were no significant differences in 5-HTT binding between IED-IR patients and controls. Trait callousness exhibited a significant, positive correlation with ACC 5-HTT availability. Among IED-IR patients, a trend-level negative partial correlation was observed between trait aggression and ACC 5-HTT availability, while covarying for callousness and age. Exploratory analyses revealed a significant negative correlation between state aggression levels and 5-HTT availability in subcortical regions, namely striatum and thalamus. We did not confirm our hypothesis of lower ACC 5-HTT availability in impulsive aggressive patients, however, the positive correlation between callousness and ACC 5-HTT availability likely played a confounding role. Subtypes of aggression (e.g., reactive vs. proactive aggression), which are differentially associated with pathological personality dimensions such as callousness, may contribute to variability between 5-HT functioning and aggression.Journal of Psychiatric Research 08/2014; 58. DOI:10.1016/j.jpsychires.2014.07.025 · 4.09 Impact Factor
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- "Both disorders start in adolescence or early adulthood and subsequently follow episodic and/or chronic courses  . Similar comorbidity patterns, abnormalities of central serotonin and noradrenaline neurotransmission , and positive response to mood stabilizers         and antidepressant drugs          are the other common features. Another finding supporting a possible ICD-BD relationship is the increased prevalence of mood disorders in patients with ICDs and the increased prevalence of ICDs in patients with BD . "
ABSTRACT: Impulsivity is associated with mood instability, behavioral problems, and action without planning in patients with bipolar disorder. Increased impulsivity levels are reported at all types of mood episodes. This association suggests a high comorbidity between impulse control disorders (ICDs) and bipolar disorder. The aim of this study is to compare the prevalence of ICDs and associated clinical and sociodemographic variables in euthymic bipolar I patients. A total of 124 consecutive bipolar I patients who were recruited from regular attendees from the outpatient clinic of our Bipolar Disorder Unit were included in the study. All patients were symptomatically in remission. Diagnosis of bipolar disorder was confirmed using the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Impulse control disorders were investigated using the modified version of the Minnesota Impulsive Disorders Interview. Impulsivity was measured with the Barratt Impulsiveness Scale Version 11. Furthermore, all patients completed the Zuckerman Sensation-Seeking Scale Form V. The prevalence rate of all comorbid ICDs in our sample was 27.4% (n = 34). The most common ICD subtype was pathologic skin picking, followed by compulsive buying, intermittent explosive disorder, and trichotillomania. There were no instances of pyromania or compulsive sexual behavior. There was no statistically significant difference between the sociodemographic characteristics of bipolar patients with and without ICDs with regard to age, sex, education level, or marital status. Comorbidity of alcohol/substance abuse and number of suicide attempts were higher in the ICD(+) group than the ICD(-) group. Length of time between mood episodes was higher in the ICD(-) group than the ICD(+) group. There was a statistically significant difference between the total number of mood episodes between the 2 groups, but the number of depressive episodes was higher in the ICD(+) patients as compared with the ICD(-) patients. There was no statistically significant difference between the age of first episode, seasonality, presence of psychotic features, and chronicity of illness. A statistically significant difference was observed between the ICD(+) and ICD(-) groups in terms of total impulsivity, attention, nonplanning, and motor impulsivity scores as determined by the Barratt Impulsiveness Scale Version 11. The present study revealed that there is a high comorbidity rate between bipolar disorder and ICDs based on Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision, criteria. Alcohol/substance use disorders, a high number of previous suicide attempts, and depressive episodes should alert the physician to the presence of comorbid ICDs among bipolar patients that could affect the course and treatment of the disorder.Comprehensive psychiatry 07/2011; 52(4):378-85. DOI:10.1016/j.comppsych.2010.08.004 · 2.26 Impact Factor
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- "In humans, low serotonergic functioning has been associated with antisociality, impulsivity, and hostile aggression towards the self and others –. Manipulation studies have shown that decreased serotonin levels can increase hostility and aggression, while increased serotonergic functioning can decrease hostility and aggression –. "
ABSTRACT: Animal and human adult studies reveal a contribution of serotonin to behavior regulation. Whether these findings apply to children is unclear. The present study investigated serotonergic functioning in boys with a history of behavior regulation difficulties through a double-blind, acute tryptophan supplementation procedure. Participants were 23 boys (age 10 years) with a history of elevated physical aggression, recruited from a community sample. Eleven were given a chocolate milkshake supplemented with 500 mg tryptophan, and 12 received a chocolate milkshake without tryptophan. Boys engaged in a competitive reaction time game against a fictitious opponent, which assessed response to provocation, impulsivity, perspective taking, and sharing. Impulsivity was further assessed through a Go/No-Go paradigm. A computerized emotion recognition task and a staged instrumental help incident were also administered. Boys, regardless of group, responded similarly to high provocation by the fictitious opponent. However, boys in the tryptophan group adjusted their level of responding optimally as a function of the level of provocation, whereas boys in the control group significantly decreased their level of responding towards the end of the competition. Boys in the tryptophan group tended to show greater perspective taking, tended to better distinguish facial expressions of fear and happiness, and tended to provide greater instrumental help to the experimenter. The present study provides initial evidence for the feasibility of acute tryptophan supplementation in children and some effect of tryptophan supplementation on children's behaviors. Further studies are warranted to explore the potential impact of increased serotonergic functioning on boys' dominant and affiliative behaviors.PLoS ONE 06/2011; 6(6):e20304. DOI:10.1371/journal.pone.0020304 · 3.23 Impact Factor