Fluoxetine response in impulsive–aggressive behavior and serotonin transporter polymorphism in personality disorder

Silva, Hernán; Iturra, Patricia; Solari, Aldo; Villarroel, Juana; Jerez, Sonia; Jiménez, Marco Raúl Mejía; Galleguillos, Felipe; Bustamante, M. Leonor

doi:10.1097/ypg.0b013e328335125d

Cited by 52 publications

(34 citation statements)

References 60 publications

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“…The allele S was shown to be related to the higher propensity to violence, and the presence of the genotype SS explains 5% of the interindividual variance in aggressive behavior in humans. Despite some inconsistency in the results, the allele S showed significant association with increased aggression and impulsivity in various cohorts including children (Davidge et al 2004;Beitchman et al 2006), adolescents (Gerra et al 2005), adopted children (Cadoret et al 2003), adolescent and young girls (Sysoeva et al 2009), cocaine-dependent individuals (Patkar et al 2002), patients with personality disorders (Retz et al 2004;Silva et al 2010) and others. For the allele S, odds ratio values typically range between 2 and 3 (Table 1) suggesting a strong contribution of this 5-HTT variant to impulsivity/aggression-related traits.…”

Section: Serotonin Transportermentioning

confidence: 99%

Genetic determinants of aggression and impulsivity in humans

Павлов¹,

2011

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Human aggression/impulsivity-related traits have a complex background that is greatly influenced by genetic and non-genetic factors. The relationship between aggression and anxiety is regulated by highly conserved brain regions including amygdala, which controls neural circuits triggering defensive, aggressive, or avoidant behavioral models. The dysfunction of neural circuits responsible for emotional control was shown to represent an etiological factor of violent behavior. In addition to the amygdala, these circuits also involve the anterior cingulated cortex and regions of the prefrontal cortex. Excessive reactivity in the amygdala coupled with inadequate prefrontal regulation serves to increase the likelihood of aggressive behavior. Developmental alterations in prefrontal-subcortical circuitry as well as neuromodulatory and hormonal abnormality appear to play a role. Imbalance in testosterone/serotonin and testosterone/cortisol ratios (e.g., increased testosterone levels and reduced cortisol levels) increases the propensity toward aggression because of reduced activation of the neural circuitry of impulse control and self-regulation. Serotonin facilitates prefrontal inhibition, and thus insufficient serotonergic activity can enhance aggression. Genetic predisposition to aggression appears to be deeply affected by the polymorphic genetic variants of the serotoninergic system that influences serotonin levels in the central and peripheral nervous system, biological effects of this hormone, and rate of serotonin production, synaptic release and degradation. Among these variants, functional polymorphisms in the monoamine oxidase A (MAOA) and serotonin transporter (5-HTT) may be of particular importance due to the relationship between these polymorphic variants and anatomical changes in the limbic system of aggressive people. Furthermore, functional variants of MAOA and 5-HTT are capable of mediating the influence of environmental factors on aggression-related traits. In this review, we consider genetic determinants of human aggression, with special emphasis on genes involved in serotonin and dopamine metabolism and function.

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Section: Serotonin Transportermentioning

confidence: 99%

Genetic determinants of aggression and impulsivity in humans

Павлов¹,

2011

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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. However, despite the evidence for the central role of 5-HT, it is unknown how SSRI administration affects the neural mechanism of IED.…”

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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“…Rhesus display polymorphisms of the MAOA (Newman et al 2005) and 5HTLLPR (Lesch et al 1997) genes similar to those in humans. Both MAOA (Yu et al 2005), and 5HTLLPR (Kim et al 2006; Silva et al 2010) polymorphisms demonstrate associations with therapeutic response to fluoxetine in humans, but associations with PK have not been studied.…”

Section: Introductionmentioning

confidence: 99%

Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model

Golub

Hogrefe

2014

Psychopharmacology

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Rationale-The selective serotonin reuptake inhibitor (SSRI) fluoxetine is the only psychopharmacological agent approved for use in children. While short-term studies of side effects have been performed, long-term consequences for brain development are not known. Such studies can be performed in appropriate animal models if doses modeling therapeutic use in children are known.Objectives-To identify a daily dose of fluoxetine in juvenile monkeys which would result in serum fluoxetine and norfluoxetine concentrations in the therapeutic range for children.Methods-Juvenile (2.5 year old rhesus monkeys, n=6) received single administration of doses of 1, 2 and 4 mg/kg-d fluoxetine on a background of chronic dosing at an intermediate level to provide steady state conditions to model therapeutic administration. Using nonlinear modeling, standard pharmacokinetic parameters were derived. Cerebrospinal fluid monoamine neurotransmitters were assayed to confirm the pharmacological effects.Results-Dose-dependent AUC and Cmax values were seen while Tmax and absorption/ elimination half-lives were minimally influenced by dose. A dosage of 2 mg/kg-d given over a 14 week period led to steady state serum concentrations of active agent (fluoxetine + norfluoxetine) similar to those recorded from drug monitoring studies in children. Cisternal cerebrospinal fluid concentrations of serotonin increased significantly over the 14 week period, while concentrations of the serotonin metabolite (5-HIAA) were lower but not significantly different.Conclusions-2 mg/kg/d fluoxetine in juvenile rhesus monkeys provides an internal dose similar to therapeutic use in children and will help establish a valuable animal model for understanding fluoxetine therapeutic and potential adverse effects in children.

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Fluoxetine response in impulsive–aggressive behavior and serotonin transporter polymorphism in personality disorder

Cited by 52 publications

References 60 publications

Genetic determinants of aggression and impulsivity in humans

Genetic determinants of aggression and impulsivity in humans

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

Fluoxetine: juvenile pharmacokinetics in a nonhuman primate model

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