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

Coccaro, Emil F.; Lee, Royce J.; Kavoussi, Richard J.

doi:10.4088/jcp.08m04150

Cited by 145 publications

(68 citation statements)

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“…In addition, an fMRI study of emotional information processing in IED-IR subjects reported enhanced amygdala activation, compared with controls, specifically, in response to exposure to angry faces. Third, treatment with fluoxetine (Coccaro et al, 2009) These data extend those of other studies, as well, by using d-FEN as the 5-HT challenge probe. Most studies have involved d,l-FEN, which contains equal quantities of its d-and l-isomers.…”

Section: Discussionsupporting

confidence: 82%

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

Coccaro

Lee

Kavoussi

2009

Neuropsychopharmacol

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

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Section: Discussionsupporting

confidence: 82%

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

Coccaro

Lee

Kavoussi

2009

Neuropsychopharmacol

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“…To understand the potential efficiency of a drug, it is important to uncover its neural mechanism of action. Previous work has shown reasonable effectiveness of another SSRI, fluoxetine, in treating IED (Coccaro et al, 2009), and hence the current findings indicate a potential neural mechanism for SSRI functioning. The results suggest that escitalopram may affect the neural mechanisms of social-emotional and social-cognitive processes.…”

Section: Escitalopram Effects In Iedsupporting

confidence: 68%

“…Moreover, males with IED tend to increase intensity ratings of angry faces after tryptophan depletion that reduces 5-HT availability (Lee et al, 2012). 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.…”

Section: Introductionmentioning

confidence: 99%

Effects of Escitalopram Administration on Face Processing in Intermittent Explosive Disorder: An fMRI Study

Cremers

Lee

Keedy

et al. 2015

Neuropsychopharmacol

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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. A total of 17 subjects with current IED and 14 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-subject and Drug as within-subject factor was tested. Group × 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 with 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 these social-cognitive processes. Future research should further elucidate the long-term effects of SSRIs on various social-emotional tasks in IED.

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“…Serotonin has been implicated in a wide range of psychiatric disorders with antisocial and aggressive symptoms, including intermittent explosive disorder, antisocial personality disorder, and psychopathy (59)(60)(61), and these disorders are often treated with SSRIs such as citalopram (62). Our findings suggest that trait empathy measures could predict whether patients are likely to respond to SSRI treatment and imply that such treatments are less likely to succeed in psychopaths and patients with vmPFC damage, both of whom show a marked lack of empathy (63).…”

Section: Discussionmentioning

confidence: 99%

Serotonin selectively influences moral judgment and behavior through effects on harm aversion

Crockett

Clark

Hauser

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

412

300

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Aversive emotional reactions to real or imagined social harms infuse moral judgment and motivate prosocial behavior. Here, we show that the neurotransmitter serotonin directly alters both moral judgment and behavior through increasing subjects' aversion to personally harming others. We enhanced serotonin in healthy volunteers with citalopram (a selective serotonin reuptake inhibitor) and contrasted its effects with both a pharmacological control treatment and a placebo on tests of moral judgment and behavior. We measured the drugs' effects on moral judgment in a set of moral 'dilemmas' pitting utilitarian outcomes (e.g., saving five lives) against highly aversive harmful actions (e.g., killing an innocent person). Enhancing serotonin made subjects more likely to judge harmful actions as forbidden, but only in cases where harms were emotionally salient. This harm-avoidant bias after citalopram was also evident in behavior during the ultimatum game, in which subjects decide to accept or reject fair or unfair monetary offers from another player. Rejecting unfair offers enforces a fairness norm but also harms the other player financially. Enhancing serotonin made subjects less likely to reject unfair offers. Furthermore, the prosocial effects of citalopram varied as a function of trait empathy. Individuals high in trait empathy showed stronger effects of citalopram on moral judgment and behavior than individuals low in trait empathy. Together, these findings provide unique evidence that serotonin could promote prosocial behavior by enhancing harm aversion, a prosocial sentiment that directly affects both moral judgment and moral behavior. morality | punishment | ultimatum game | empathy | emotion

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

Abstract: 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.

Cited by 145 publications

References 0 publications

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

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

Effects of Escitalopram Administration on Face Processing in Intermittent Explosive Disorder: An fMRI Study

Serotonin selectively influences moral judgment and behavior through effects on harm aversion

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