The Psychopharmacology of Aggressive Behavior: A Translational Approach Part 1: Neurobiology Stefano Comai, PhD, Michael Tau, BSc, and Gabriella Gobbi, MD, PhD Abstract: Patients with mental disorders are at an elevated risk for de- veloping aggressive behavior. In the last 19 years, the psychopharmaco- logical treatment of aggression has changed dramatically because of the introduction of atypical antipsychotics into the market and the increased use of anticonvulsants and lithium in the treatment of aggressive patients. Using a translational medicine approach, this review (part 1 of 2) examines the neurobiology of aggression, discussing the major neuro- transmitter systems implicated in its pathogenesis, namely, serotonin, glutamate, norepinephrine, dopamine, and F-aminobutyric acid, and also their respective receptors. The preclinical and clinical pharmacological studies concerning the role of these neurotransmitters have been reviewed, as well as research using transgenic animal models. The complex inter- action among these neurotransmitters occurs at the level of brain areas and neural circuits such as the orbitoprefrontal cortex, anterior cortex, amygdala, hippocampus, periaqueductal gray, and septal nuclei, where the receptors of these neurotransmitters are expressed. The neurobio- logical mechanism of aggression is important to understand the rationale for using atypical antipsychotics, anticonvulsants, and lithium in treating aggressive behavior. Further research is necessary to establish how these neurotransmitter systems interact with brain circuits to control aggressive behavior at the intracellular level. Key Words: aggression, serotonin, glutamate, norepinephrine, dopamine, GABA, knockout mice, psychopharmacology, translational medicine (J Clin Psychopharmacol 2012;32: 83Y94) P atients with mental disorders present an elevated rate of ag- gressive behaviors. Patients with psychosis, for example, are 5 times more likely than the general population to commit vio- lent acts, defined as ‘‘physical attacks on other persons, or on one’s self (self-mutilation), with deliberate destructive intent sufficiently severe to justify a legal measure.’’ 1 Impulsivity refers to acting without control or premeditation; it is a factor strictly linked to aggression, and when present, it increases the risk of aggressive behavior. Agitation is ‘‘an inappropriate verbal, vocal, or motor activity that is not explained by ap- parent needs or confusion per se.’’ It includes behaviors such as aimless wandering, pacing, cursing, screaming, biting, and fighting, and it may evolve through a verbally or physically aggressive behavior. 2 Aggression is a complex phenomenon associated with ge- netic, neurobiological, and psychosocial factors. Impairments of many neurotransmitter systems, including serotonin (5-HT), dopamine (DA), and norepinephrine (NE), are implicated in the biology of aggression. Dysregulation of several receptor sub- units and other neuronal elements has recently been reported, in- cluding the 5-HT 1B , F-aminobutyric acid A (GABA-A), GABA- B , and glutamate (N-methyl D-aspartate [NMDA]) receptors; the 5- HT transporter; the enzymes monoamine oxidase A (MAO-A) and nitric oxide synthase; and neuroactive steroids. 3Y10 The purpose of this article was to review recent advancements in the treatment of aggression by integrating pharmacological findings from clinical research with neurobiological knowledge gained from basic science research. This translational approach is nec- essary, as the results of clinical trials alone are limited in utility by the complexity of aggressive behavior. For example, ex- tremely aggressive patients often cannot be included in research for safety reasons, and research in aggressive populations, such as prison inmates, is frequently difficult to conduct because of legal and ethical challenges. 11 For these reasons, a translational approach, spanning basic and clinical science, may offer a superior tool and scientific framework for examining the treatment of aggression. This ap- proach is currently the standard in pharmacological research and is a priority for federal and foundational funding. 12 Although clinical research is critical for establishing evidence-based guidelines for treatment, there are indeed several aspects of ag- gression that illustrate the importance of integrating basic and clinical research. First, aggression is a heterogeneous behavior, and clinical research alone is often insensitive to its various facets. For example, aggression is related to impulsivity, vio- lence, irritability, and hostility, and medicines may target one or more of these phenomena. Insight gleaned from basic research can help disentangle these various constructs. Second, aggres- sive behavior exhibits high comorbidity with a range of psy- chiatric conditions, including schizophrenia, bipolar disorder, dementia, personality disorders (in particular, borderline and antisocial personality disorders), posttraumatic stress disorders, traumatic brain injury, addiction, and pervasive developmental disorders. The neurobiological mechanisms accounting for aggression in these distinct disorders might vary, and basic research might be able to better focus on those elements spe- cific to aggressive behavior in each condition. Lastly, the eti- ology of aggression is multifaceted and is influenced by several neurobiological factors, including genes and the environment, and clinical research trials are limited in taking into account these subtle distinctions. For all these reasons, a translational knowledge is necessary to integrate these multidimensional facets of aggression and thereby help clinicians and researchers to understand the rationale of pharmacological treatments. In this review, the aggressive behavior was considered as a unique entity, because at present there does not exist a con- sensus in both animal and human classifications of aggression REVIEW ARTICLE Journal of Clinical Psychopharmacology & Volume 32, Number 1, February 2012 www.psychopharmacology.com 83 From the Neurobiological Psychiatry Unit, Department of Psychiatry, McGill University and McGill Health Center, Montreal, Quebec, Canada. Received October 25, 2010; accepted after revision August 4, 2011. Reprints: Gabriella Gobbi, MD, PhD, Neurobiological Psychiatry Unit, McGill University, 1033, Av. des Pins Ouest, Montreal, QC, Canada H3A 1A1 (e-mail: gabriella.gobbi@mcgill.ca). The authors did not receive any grants or honoraria from pharmaceutical companies for this review. Part 2 will be published in the April issue of the Journal. Copyright * 2012 by Lippincott Williams & Wilkins ISSN: 0271-0749 DOI: 10.1097/JCP.0b013e31823f8770 Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.