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Intermittent explosive disorder is a much more common condition than previously recognized. The early age at onset, significant associations with comorbid mental disorders that have later ages at onset, and low proportion of cases in treatment all make IED a promising target for early detection, outreach, and treatment.

Fluoxetine treatment has an antiaggressive effect on impulsive aggressive individuals with DSM-III-R personality disorder.

SUMMARY Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behavior. The complex origins of impulsivity hinder identification of the genes influencing both it and diseases with which it is associated. We performed exon-centric sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B that is common (MAF >1%) but exclusive to Finns was identified. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon that was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviors in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioral phenotypes using founder populations, and suggests a role for HTR2B in impulsivity.

The role of central serotonergic (5-HT) system dysfunction in the regulation of aggression in both animals and man has been investigated for more than the past two decades. Evidence for reduced central 5-HT in the mediation of aggression comes from both behavioural and correlative studies. Functional reduction and augmentation of 5-HT activity is respectively associated with increased and decreased aggression in various animal models of aggression. While similar studies in man have not been performed, strong and consistent associations between indices reflecting reduced pre-synaptic 5-HT activity and aggression have been reported. Evidence of post-synaptic receptor upregulation in the brains of suicide victims has also been reported leaving the functional status 5-HT activity in such patients an open question. However, reduced neuroendocrine (i.e. prolactin) responses to fenfluramine, a 5-HT uptake inhibitor/releaser, which activates both pre- and post-synaptic sides of the 5-HT synapse, strongly suggest that overall central 5-HT activity is reduced in mood and/or personality disorder patients with history of suicidal and/or impulsive aggressive behaviour. Preliminary data with the 5-HT receptor agonist m-chlorophenylpiperazine further suggest that reduced activity of post-synaptic 5-HT receptors may be an important correlate of impulsive aggressive behaviour. Pharmacological agents with potent 5-HT pre- and/or post-synaptic augmenting effects should be tested clinically to determine their efficacy in the treatment of impulsive aggressive behaviour in psychiatric patients.

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