What Is the Nature of Serotonergic Abnormalities in Human Aggression?

Abstract

T he archival report by Rylands et al. (1) in this issue of Biological Psychiatry represents exciting new work in the biology of human aggression. Although a role for central serotonin (5-HT) in human aggression has been studied for more than 30 years, the very specific aspects of how the 5-HT system may be altered in aggressive individuals are only now being examined because of newer technologies and the willingness to look beyond basic biologic principles. Rylands et al. (1) performed ligand-binding positron emission tomography studies, targeting the 5-HT transporter (SERT) and the 5-HT-2a receptor, in 14 subjects characterized as being impulsive aggressive and 13 subjects characterized as compared being not impulsive aggressive. In brief, the investigators reported that SERT availability is significantly increased in brain stem areas and reduced, although nonsignificantly, in cortical brain areas. More importantly, although the investigators reported a direct association between SERT availability and several measures of impulsivity and aggression in their subjects, they reported that the strongest association was with measures of adversity and stressful life events in childhood. They suggest, furthermore, that this latter finding points to an exciting, potential, etiologic link to altered 5-HT function and impulsive aggression in humans. In this commentary, I will discuss several aspects of this report in terms of methodology and in terms of how it relates to the field as it has developed since the late 1970s. The idea that brain 5-HT has any relationship with aggression was first proposed in the 1970s when demonstrated that altering brain levels of 5-HT uncovered an inverse relationship with aggression in animal models. In other words, when 5-HT was experimentally reduced, aggressive responding in the model animal increased, and when 5-HT was experimentally enhanced, aggressive responding decreased. The first evidence of this in human subjects was published in 1979 when Brown et al. (2) reported an inverse correlation between lifetime levels of actual aggressive behavior and lumbar cerebrospinal fluid (CSF) levels of the major 5-HT metabolite, 5-hydroxyindolacetic acid (CSF 5HIAA) in personality-disordered subjects. This was followed by the work of Linnoila et al. (3), who reported that reduced CSF 5HIAA levels in humans were linked to aggressive behavior that was specifically impulsive in nature. At the same time, Stanley et al. reported that victims of violent suicide, compared with those who also died violently but by accident, had lower numbers of SERT (4), and higher numbers of 5-HT-2, receptors in frontal cortex (5). Together this suggested that presynaptic 5HT activity was low and that postsynaptic receptors had