A Double-Blind, Randomized, Placebo-Controlled Trial of Fluoxetine in Patients With Intermittent Explosive Disorder

Clinical Neuroscience & Psychopharmacology Research Unit, Department of Psychiatry, University of Chicago, Chicago, IL 60637, USA.
The Journal of Clinical Psychiatry (Impact Factor: 5.14). 05/2009; 70(5):653-62. DOI: 10.4088/JCP.08m04150
Source: PubMed

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.

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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. "
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    • "In humans, low serotonergic functioning has been associated with antisociality, impulsivity, and hostile aggression towards the self and others [9]–[12]. Manipulation studies have shown that decreased serotonin levels can increase hostility and aggression, while increased serotonergic functioning can decrease hostility and aggression [13]–[21]. "
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