Aggression is a behavior with evolutionary origins, but is often both destructive and maladaptive in today’s society. Research over the past several decades has confirmed the involvement of neurotransmitter function in aggressive behavior. This research has centered around the “serotonin hypothesis.” As this literature continues to grow, guided by pre-clinical research and aided by the application of increasingly sophisticated neuroimaging methodology, a more complex picture has emerged. As current pharmacological and therapeutic interventions are effective but imperfect, it is hoped that new insights into the neurobiology of aggression will reveal novel avenues for treatment of this destructive and costly behavior.

The current article describes the creation and composition of the PennTwins Cohort and provides details on the demographic characteristics of the sample. The PennTwins Cohort was developed using a population-based method of ascertainment and currently has 9401 28- to 47-year-old twins, including 2225 confirmed twin pairs and 4951 twins whose co-twins have not yet registered. Zygosity data have been used to identify 919 monozygotic, 634 same-sex dizygotic, and 445 opposite-sex dizygotic pairs. GeoCode data on gender, age, and certain demographic characteristics were obtained for the addresses of all twins who were mailed invitations to be part of the cohort. Analysis of the available data show only very small differences between twins who are currently part of the PennTwins Cohort and potential twins who either did not respond to recruitment or who could not be located. Similarly, only very small demographic differences exist between twins from complete pairs and twins whose co-twins are not yet registered, and there are no differences across zygosity. Thus, despite a relatively low overall response rate (12% of all twins born in Pennsylvania from 1959–1978), there is no evidence that the sample differs in any meaningful respect from the larger population.

The aim of this paper is to clarify how neural mechanisms at the molecular level, specifically the serotonergic (5-HT) system and the hypothalamic–pituitary–adrenal axis system (HPA) in conjunction with early life stress may contribute to the emergence of aggression, self-directed and otherwise, in borderline personality disorder (BPD). Chronic dysregulation of these biological systems, which function to regulate stress and emotion, may potentiate the development of impulsive aggression in borderline personality conditions. Our central premise in this paper is that brain development, stress regulation, and early pathonomic experience are interactive and cumulative in their mutual influence on the development of impulsive aggression in BPD. We review the parameters of impulsive aggression in BPD, followed by a discussion of the neurobiological and neuroendocrine correlates of impulsive aggression with and without BPD. We then focus on the developmental continuities in BPD with attention to brain maturation of 5-HT and HPA axis function during the life span and the influence of early adverse experiences on these systems. Finally, we comment on the data of the relative stability of aggression in BPD, adolescence as a developmental stage of potential vulnerability, and the course of aggressive behavior during the life span.The authors thank Caroline Cozza, Michael McCloskey, and Kurt Knoblett for their comments during the preparation of this manuscript. This research was supported by research funding from the American Foundation of Suicide Prevention (J.K.G.), Grant MH066888-01 (R.L.), and the Borderline Personality Disorder Research Foundation (E.F.C.).

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.