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: 5.5). 05/2009; 70(5):653-62. DOI: 10.4088/JCP.08m04150
Source: PubMed


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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    • "Conversely, fluoxetine (a selective serotonin reuptake inhibitor (SSRI) that increases 5-HT availability) was shown to reduce impulsive aggressive behavior in patients with personality disorders and comorbid IED (Coccaro et al, 2009). Two studies in other aggressive populations (Silva et al, 2010; George et al, 2011) replicated this finding. "
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    ABSTRACT: The neurobiological underpinnings of Intermittent Explosive Disorder (IED) are traditionally linked to deficiencies in the serotonergic system. In this study, we investigated the effects of escitalopram, a Selective Serotonin Reuptake Inhibitor (SSRI), on brain activation during face processing. We expected that escitalopram would reduce amygdala activity in IED, and in addition, we explored the effect in other social-emotional related brain regions. Seventeen subjects with current Intermittent Explosive Disorder and fourteen healthy controls participated in a randomized, double-blind, placebo-controlled, counterbalanced fMRI face processing study. The analysis focused on the faces compared to a fixation baseline contrast, and a factorial model with Group as between and Drug as within subject factor was tested. Group x Drug interaction effects were found in the amygdala (small volume corrected) and the left temporal parietal junction (TPJ; whole-brain corrected). Escitalopram increased amygdala activation in controls, but surprisingly not in IED. However, the TPJ showed increased activity in IED on escitalopram compared to placebo. The TPJ is associated with social-cognitive processes, such as perspective taking and empathy. The TPJ findings suggest that SSRI administration may reduce aggressive tendencies towards other people by enhancing social-cognitive processing of empathy and perspective taking of others during emotional face processing. Future research should further elucidate the long-term effects of SSRIs on various social-emotional tasks in IED.Neuropsychopharmacology accepted article preview online, 24 June 2015. doi:10.1038/npp.2015.187.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 06/2015; DOI:10.1038/npp.2015.187 · 7.05 Impact Factor
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    • "However, only, experimental studies examining aggressive responding in the laboratory, with and without pretreatment with antiinflammatory agents, can shed light on whether IL-1β or other inflammatory cytokines are related to aggressive behavior in any meaningful causal fashion. Given that a disorder of aggression, intermittent explosive disorder displays, a 2% to 3% 1-year prevalence rate in the US (Kessler et al., 2006), and that currently available psychotropic treatments bring <50% of those treated into remission (Coccaro et a., 2009), additional strategies for the examination and intervention of aggression in human subjects is needed. "
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    ABSTRACT: Background. Neurochemical studies have pointed to a modulatory role in human aggression for a variety of central neurotransmitters and neuromodulators such as cytokines. While animal studies of cytokines suggest an aggression facilitating role for central cytokines, especially for IL-1β and other cytokines, no cerebrospinal fluid (CSF) studies of cytokines have yet been reported in regard to human aggression. Methods. Basal lumbar CSF samples were obtained from 38 physically healthy subjects with DSM-5 Personality Disorder (PD) and assayed for CSF Interleukin-6 (log IL-6) and CSF soluble IL-1 Receptor II (sIL-1RII) protein in the context of their relationship with measures of aggression. Results. CSF sIL-1RII (r = .35, r(2) = .12, p = .03), but not log IL-6 (r = -.05, r(2) = .00, p = .76), levels were positively correlated with a composite measure of aggression. Adding relevant covariates, including CSF levels of serotonin and dopamine metabolites, to the statistical model doubled the strength of this relationship (partial r = .54, r(2) = .29, p = .002). No relationship was seen with history of suicidal behavior or with any measure of impulsivity, negative affectivity, or of general dimensions of personality. Conclusion. These data suggest a positive relationship between at least one inflammatory cytokine in the central nervous system and aggression in human subjects. This finding adds to the complex picture of the central neurochemistry of impulsive aggression in human subjects. © The Author 2014. Published by Oxford University Press on behalf of CINP.
    The International Journal of Neuropsychopharmacology 02/2015; 18(7). DOI:10.1093/ijnp/pyv001 · 4.01 Impact Factor
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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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    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 · 3.96 Impact Factor
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