REVIEW ARTICLE
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
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
Journal of Clinical Psychopharmacology & Volume 32, Number 1, February 2012
Copyright © 2011 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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-HT1B, 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
www.psychopharmacology.com 83
Comai et al Journal of Clinical Psychopharmacology
and violent behavior.13 Even though some authors tried to es-
tablish a correlation between the different neurotransmitters
and subtypes of aggressive behavior,14 more work is needed
to understand the role of each receptor in animal and human
behavior.
The World Health Organization in 200215 defines violence
as the intentional use of physical force or power, threatened or
actual, against oneself, another person, or against a group or
community, that either results in or has a high likelihood of
resulting in injury, death, psychological harm, maldevelopment,
or deprivation. Moreover, it divides violence into 3 broad cate-
gories: self-directed, interpersonal, and collective. Lesch and
Merschdorf 4 distinguished among several subtypes of aggres-
sion depending on the presence of causes or motivation, nature
of trigger, characteristics of mediators, form of manifestation,
direction, and function. Gollan et al16 classified aggressions into
3 categories, namely, medically related aggression, premeditated,
and impulsive. It has also been proposed that distinct pattern of
aggressive behavior could subserve different biological mech-
anisms, for example, the impulsive but not the premeditated
aggression is likely associated to a reduced serotonergic activity
(see Serotonin: Human Literature).17
Animal research has been extensive and critical for devel-
oping investigations in translational research.18 One general
classification adopted in both animal and human studies is the
distinction into offensive and defensive models.19 In animals, a
classification into predatory, intermale, territorial, maternal ir-
ritable, fear-induced, and instrumental aggression has been
proposed, whereas in humans, there is the dichotomic distinction
between overt versus covert, reactive versus proactive, affective
versus predatory, and hostile versus instrumental.18,20 However,
more translational research is required to find a consensus be-
tween animal and human aggressive behavior. For a recent de-
tailed discussion on definitions of aggression that is out of
the scope of this review, we suggest to the reader a recent review
by Takahashi et al.3
Despite these previously mentioned limitations, preclinical
models of aggression are an excellent tool for understanding this
heterogeneous behavior in both animals and humans,21 in fact
most of the studies performed in animals have been replicated in
humans and represented the biological basis of the psycho-
pharmacology of aggressive human behavior. The scope of this
review is to link this preclinical knowledge to the fundamental
framework of human therapeutics.
Thus, in this part 1 of 2 review, we decided to focus on the
role of 5-HT, DA, GABA, glutamate, and NE in the etiopatho-
genesis of aggressive behavior, because they have been largely
studied in animals, and they represent the pharmacological tar-
gets of the medications available at the moment for the treatment
of such disorder (see part 2).
SEROTONIN AND AGGRESSION
Serotonin is the most studied neurotransmitter in ag-
gression. According to a PubMed search using the MeSH terms
‘‘5-HT’’ and ‘‘aggression,’’ the earliest study in which a link
between aggression and 5-HT was hypothesized was issued by
Bourgault et al22 in 1963. Following that report, many animal
and human studies were performed, and in the last 20 years,
there has been an average of 100 new studies published each
5 years, of which 30 are reviews.
Evidence from animal research using pharmacological,
neurobiological, and genetic designs suggests that a dysfunc-
tional serotonergic system might play a role in heightened ag-
gression. In general, low levels of 5-HT appear to be associated
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& Volume 32, Number 1, February 2012
with aggressive behavior, although the relationship might be
more complex than previously believed. Indeed, normal ag-
gressive behavior aimed at social dominance was shown to be
positively correlated with serotonergic function.23 More recent
research suggests that 5-HT’s effects may be limited to certain
types of aggression, such as impulsive aggression, or perhaps
instead to factors such as impulse control and emotion regula-
tion.24 Furthermore, evidence suggests a distinct role of 5-HT in
controlling functional aggressive behavior and violence,25 thus
challenging the view that 5-HT inhibits aggression.
Serotonin: Animal Research
First studies carried out by Italian and French researchers
and reporting manipulations of the serotonergic system corre-
lated with modifications of aggressive behavior date back to the
1960s.26Y28
In a pioneering experiment, Koe and Weissman29 showed
that rats injected with p-chlorophenylalanine, which depletes
brain 5-HT by selectively and irreversibly inhibiting tryptophan
5-hydroxylase enzyme, expressed mildly enhanced aggressive-
ness and irritability in response to handling. Other researchers
showed that p-chlorophenylalanine potentiates mouse-killing
behavior in rats but antagonizes other types of aggressiveness,
indicating that different types of aggression rely on different
neurobiological mechanisms.30 Later, it was demonstrated that
isolation-induced aggression was attenuated in rats treated with
5-hydroxy-DL-tryptophan and the peripheral decarboxylase in-
hibitor seryltrihydroxybenzine.31 Parallel to these behavioral
findings, the authors observed an increase in brain 5-HT levels;
meanwhile, rats injected with p-chloro-N-methylamphetamine,
which depletes 5-HT, exhibited an increased fighting frequency
accompanied by a whole-brain decrease in 5-HT levels.31
Endogenous levels of neurochemicals also seem to be re-
lated to aggressive behavior. In rats, 5-HT concentrations in
the prefrontal cortex (PFC) decrease to 80% of baseline levels
during aggressive confrontations, as measured using micro-
dialysis.32 These findings extend to primate models. In one
study, a significant negative correlation was found between ce-
rebrospinal fluid (CSF) levels of 5-HIAA and high rankings of
aggression in free-range rhesus monkeys.33 These results were
later replicated in female rhesus monkeys.34 Other findings from
the same authors have demonstrated that low 5-HIAA levels are
also associated with increased risk taking and weakened impulse
control.35Y37 These characteristics may represent the more prox-
imal effect of lowered 5-HIAA levels, with heightened aggres-
sion occurring as a result.24 In male vervet monkeys, Raleigh
et al38 found that enhancement of central serotonergic activity
using tryptophan or fluoxetine is related to the acquisition of
high dominance status. Experimenters have also used genetic
knockout mice to assess the effects of modulations to the sero-
tonergic system, including mice lacking the genes encoding for
5-HT receptors, the 5-HT transporter (5-HTT), and the MAO-A
enzyme (Table 1).
There are certain pitfalls inherent in interpreting the results
of experiments using knockout procedures. First, gene deletion
may incur long-term developmental sequelae distinct from the
acute effects of monoamine depletion; second, because receptor
knockout mice (eg, 5-HT1A knockout) lack both autoreceptors
and heteroreceptors, these experiments are sensitive neither
to the effects of different receptors, nor to their effects in dif-
ferent regions of the brain.42 Regardless, evidence from genetic
knockout experiments drawing a connection between 5-HT
dysfunction and aggressive behavior is useful when supported
with other forms of evidence, such as polymorphism research
in human populations.
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Journal of Clinical Psychopharmacology & Volume 32, Number 1, February 2012 Psychopharmacology of Aggression

TABLE 1. Animal Studies on Aggression Using Genetic Manipulated Mice

Neurotransmitter Study Target Behavioral Test Outcome

39
Serotonin Saudou et al 5-HT1B KO mice Resident-intruder , Latency and j number and intensity
of attacks to the intruder in 5-HT1B
KO mice vs WT
Cases et al40 MAO-A KO mice Resident-intruder , Latency to attack the intruder in adult
KO mice vs WT; j 5-HT levels in
the brain of KO mice vs WT
Brunner and Hen41 5-HT1B KO mice Resident-intruder and , Latency and j number and intensity
maternal aggression of attacks in 5-HT1B KO mice vs WT
in both behavioral paradigms
Zhuang et al42 5-HT1A and 5-HT1B Resident-intruder and j Aggression in 5-HT1B KO mice;
KO mice maternal aggression , aggression in 5-HT1A KO mice
Holmes et al43 5-HT transporter Resident-intruder j Latency and , frequency of attacks
(5-HTT) KO mice to the intruder in KO mice vs WT.
Same latency and , frequency of
attacks in heterozygous 5-HTT
mice vs WT.
Beaulieu et al44 Knockin mice expressing Dyadic , Brain 5-HT production (-80%) and
a mutant with Tph2 form numbers of attacks
Osipova et al45 Mice with Tph2 C1473G Spontaneous , Tph2 activity and aggression intensity
polymorphism aggression in 1473G homozygous mice
Alenina et al46 Tph2 KO mice Home cage j Aggression (injuries) for both males
observation and females Tph2KO vs WT mice
K. P. Lesh Tph2 KO mice Resident-intruder , Latency and j number of attacks
(2011) (personal
communication)
Dopamine Cases et al40 MAO-A KO mice (See 5-HT)
Gogos et al47 COMT KO mice Homogeneous set , Latency and j number of aggressive
bouts in heterozygous COMT-deficient
vs WT mice. No differences
homozygous COMT null mutant
vs WT mice.
Rodriguiz et al48 DAT KO mice Resident-intruder j Reactivity and aggression in DAT KO
and dyadic vs WT mice
GABA Stork et al49 GAD65 KO mice Resident-intruder No change in latency and grooming and
, total number of attacks in both
heterozygous and homozygous
GAD65 vs WT mice
Gammie et al50 Gene expression study Maternal aggression j GABA A receptor subunit >1
in mice selected for expression in hypothalamus and
high maternal preoptic regions of lactating selected
aggression vs nonselected control mice
Liu et al51 GAT1 KO mice Resident-intruder in , Latency and number of attacks
the home cage and in homozygous GAT1 vs WT mice
neutral arena
Glutamate Brodkin et al52 Genome-wide scan to Resident-intruder Gria3 gene (encodes for a subunit
identify aggression or dangler of the ionotropic glutamate receptor
QTLs in aggressive AMPA3) accounts for the strain
mice strains differences in aggression
Duncan et al53 NR1 (NMDA R1 subunit) Resident-intruder Absence of species-typical fighting
hypomorphic mice
Vekovischeva et al54 GluR-A subunit-containing Resident-intruder , Aggression in GluR-A
AMPA receptors paradigms subunit-containing AMPA
KO mice receptors KO vs WT mice
Norepinephrine Sallinen et al55 >2C Receptor KO, and Resident-intruder , Latency to attack in >2C receptor KO
mice with tissue-specific vs WT mice; j latency to attack in
overexpression of >2C mice with overexpression of >2C
receptor receptor; no effects on duration of
attacks
Haller et al56 Norepinephrine transporter Resident-intruder j Aggressiveness in NET-KO vs
(NET) KO mice WT mice only in the 1st encounter
of repeated defeat exposure
Marino et al57 DA A-hydroxylase Resident-intruder , Or nearly lack of aggressive behavior
KO mice in DA A-hydroxylase KO vs WT mice

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Comai et al Journal of Clinical Psychopharmacology
Interestingly, the 5-HT1A partial agonist buspirone,25,58 the
5-HT1A agonist 8-OHDPAT, ipsapirone, alnespirone, and the
mixed 5-HT1A/5-HT1B eltoprazine shown in animal models
have potent antiaggressive affects.25 More recently, the mixed
partial agonist S-15535 has demonstrated more potent anti-
aggressive effects than 5-HT1A agonists.25 The partial agonist
is a drug that acts as an antagonist in presence of a big amount
of the endogenous agonist (ie, 5-HT at the level of dorsal raphe,
the major source of 5-HT in the brain) and as an agonist
in presence of a low level of endogenous agonist (ie, postsyn-
aptic level). For this reason, one may hypothesize that a partial
agonist could act as an antagonist at the level of 5-HT1A auto-
receptor (increasing the firing activity) and as an agonist at the
postsynaptic level, thus recovering a normal 5-HT function.
Notably, quetiapine, an atypical antipsychotic that possesses
antiaggressive properties, acts as a 5-HT1A partial agonist at the
presynaptic and postsynaptic level (see part 2, Figure 1).
Serotonin: Human Literature
In humans, empirical evidence suggests that 5-HT dys-
function is typically connected with impulsive, rather than pre-
meditated aggression.
Cerebrospinal Fluid 5-HIAA Levels and Aggression
Serotonergic abnormalities have been associated with
impulsive aggression in various populations, including psy-
chiatric patients, criminal offenders, and healthy subjects. This
serotonergic dysfunction is frequently reported as an attenu-
ated concentration of 5-HIAA in the CSF. In a landmark study,
Brown et al,59 replicated later in 1982,60 reported that there
was a negative correlation between history of aggression and
CSF 5-HIAA levels in a sample of military men with person-
ality disorders and ‘‘difficulties adjusting to military life.’’
Another study reported that depressed patients who had low
levels of 5-HIAA in the CSF were more likely to attempt suicide
and to use violent means to do so than those who had high
levels of 5-HIAA.61 It has been hypothesized that the link
between aggression and low 5-HIAA is specific to impulsive
behavior. In a sample of 36 murderers and attempted murderers,
it was determined that impulsive violent offenders had lower
CSF 5-HIAA than those who premeditated their crimes.62
Another study reported that low CSF 5-HIAA is predominantly
associated with high impulsivity.63 Similar correlations were
also reported in children and adolescents with disruptive be-
havior disorders, even though for some measures of aggression
the negative correlation with CSF 5-HIAA levels was not
significant.64
Despite positive findings, the body of research connecting
low 5-HIAA levels with heightened aggression has been criti-
cized on the grounds of its use of small sample sizes and its in-
ability to control for various confounding factors, such as gender
or concurrent psychopathology. As well, many studies have
failed to find an association between the two variables (for
a review, see Roggenbach et al65). Studies using more metic-
ulous methodologies will help better elucidate the relationship
between aggression and CSF 5-HIAA levels.
Neuroendocrine Challenge Studies
Aggression researchers have often used participants’ neu-
roendocrine response to 5-HT agonist administration as a mea-
sure of 5-HT function. In one experiment, a blunted prolactin
response to a challenge with fenfluramine, a 5-HT releaser and
uptake inhibitor, was associated with suicide attempts in male
patients with major affective disorder and personality disorder
and impulsive aggression scores in the personality-disordered
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& Volume 32, Number 1, February 2012
group.17 In another study in subjects with personality disorders,
prolactin responses to D-fenfluramine were inversely correlated
with participant aggressiveness, as measured by the Point Sub-
traction Aggression Paradigm, a laboratory measure of aggres-
sion, as well as a measure of aggressive ideation.66 Because
an attenuated prolactin response is characteristic of presynaptic
and/or postsynaptic 5-HT dysfunction, the results of these two
studies support the hypothesis that serotonergic dysfunction
might be related to aggressive behavior in people affected with
personality disorders. In another study, it was reported that ele-
vated self-rated aggressivity was correlated with a blunted neu-
roendocrine response to ipsapirone, a partial agonist specific
to 5-HT1A receptors.67 Furthermore, self-rated aggression and
impulsivity are inversely correlated with neuroendocrine re-
sponse to fenfluramine challenge in healthy controls.68
Additional research in this area suggests that early ex-
periences may represent a possible mechanism for the genesis
of 5-HTYrelated impulsive aggressivity. Rinne et al69 reported
that female patients with borderline personality disorder (BPD)
exhibited an attenuated prolactin response to a meta-chlor-
ophenylpiperazine challenge, as compared with healthy con-
trols. Notably, within the BPD group, the prolactin response
was inversely correlated with the frequency of childhood
physical and sexual abuse. Furthermore, the severely abused
subgroup alone accounted for the statistically significant dif-
ference in prolactin response between the BPD group and
control group, suggesting that the alteration of serotonergic
function may not be related specifically to the BPD diagnosis,
but instead to childhood trauma. In summary, this finding
suggests that childhood abuse might lead to an adult seroto-
nergic dysfunction, which could represent a possible mecha-
nism for the appearance of pathological aggressiveness in
adulthood.
Pharmacological Manipulations
In the last 15 years, considerable evidence has emerged
suggesting that drugs modulating the 5-HT system attenuate
aggressive behavior. In particular, experimental evidence sug-
gests that modulating the serotonergic system by administering
selective serotonin reuptake inhibitors such as paroxetine and
fluoxetine, which increase postsynaptic availability of 5-HT
by blocking reuptake, can attenuate aggression. This result has
been supported by randomized, double-blind, placebo-controlled
experiments studying aggressive patients’ performance on an
in-laboratory measure of aggression,70 as well as personality-
disordered subjects’ scores on interview assessment mea-
sures.71 Remarkably, atypical antipsychotics, many of which
act as antagonists on 5-HT2A receptors, have antiaggressive
effects. These data suggest that the 5-HT2A receptor plays a
major role in the neurobiology of aggression, as confirmed by
preclinical studies in animal models.72 In addition, using posi-
tron emission tomography and the selective 5-HT2A receptor
antagonist radioligand [11C]MDL100907, orbitofrontal 5-HT2A
receptor availability has been demonstrated to be greater in
patients with current physical aggression compared with patients
without current physical aggression and healthy control sub-
jects,73 confirming that this receptor is implicated in impulsive
aggression.74 Data on the efficacy of atypical antipsychotics
possessing a 5-HT2A antagonism are reviewed in part 2.
DOPAMINE AND AGGRESSION
A PubMed search using the MeSH terms ‘‘dopamine’’ and
‘‘aggression’’ reveals that the first indexed article regarding
this issue was published by Karczmar and Scudder75 in 1967.
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Journal of Clinical Psychopharmacology & Volume 32, Number 1, February 2012
Interestingly, of the 303 articles and 37 reviews currently
indexed, practically half were published before 1980.
However, the exact nature of DA’s relationship to aggres-
sion is unclear, and evidence for DA playing a specific role in
aggressive behavior is limited.76 Several studies in the field of
DA are associated with research in addiction. It is indeed well
known that several drugs abused by humans, such as morphine,
cocaine, amphetamine, and alcohol, increase DA release in the
shell, but not in the core, of the nucleus accumbens (NAc).77,78
Because these drugs also increase patients’ risk of committing
violent acts, it has been hypothesized that there is a link between
violence and DA release, at least in acute intoxication.79 In
support of this hypothesis, D2/D1 antagonists such as halo-
peridol are clinically used in the treatment of aggression.
However, additional preclinical and clinical research is required
to establish a link between dopaminergic drugs of abuse and
violence, and more clinical trials are needed to support the use of
dopaminergic antagonists to prevent and treat the violence linked
to drugs of abuse. It has also been hypothesized that DA is nec-
essary for aggressive behavior to occur, reflecting the motivational
aspect of violence (for a review, see de Almeida et al6 and Nelson
and Chiavegatto80). Remarkably, DA levels in rats’ NAc are
significantly increased up to 60 minutes after a confrontation in
the resident-intruder test, with peak levels of 140% occur-
ring approximately 20 to 30 minutes after the confrontation.32
Dopamine: Animal Research
Activation of dopaminergic system has been shown to play
a critical role in the modulation of aggressive behavior. Spe-
cifically, DA is localized in brain regions involved in the control
of aggressive behavior. In Syrian hamsters in which offensive
aggression was facilitated because of anabolic androgenic ste-
roid treatment throughout adolescence, aggression was highly
correlated with changes in hypothalamic DA levels,81 and D2
receptors were the DA receptor subtype mediating the behav-
ioral changes.82 Increases in tyrosine hydroxylase and DA
transporter mRNA levels have been found in ventral tegmental
area of winner male mice compared with losers and controls
when they experienced repeated agonistic confrontations.83 In
an experiment aimed at studying differences in the mesocor-
ticolimbic DA system between A/J and BALB/cJ mice, 2 strain
that show different aggressiveness, with the first being docile and
the second aggressive, a significant variation in DA utilization and
in the expression of D1 and D2 receptors between the 2 strains
was found.84
At mesolimbic level, electrophysiological in vivo record-
ings in freely moving rats demonstrated that an increase in do-
paminergic activity takes place during a highly aversive condition
such as defeat stress.85 Other experiments have examined the
relationship between endogenous DA levels and aggression.
Mice that engaged in isolation-induced fighting behavior be-
fore killing exhibit increased Vmax and Km values for DA uptake
in their mesocortical nerve endings, as compared with mice that
did not fight.86 Furthermore, longer fighting times resulted in
‘‘dose-dependent’’ increases in Vmax and Km. In another study,
it was demonstrated that previously defeated ‘‘intruder’’ rats
exhibited increased DA in the NAC and PFC, but not the lateral
striatum, when intruding on rats who had previously defeated
them.87 A rise in DA levels was also reported in nucleus accum-
bens during and after a single aggressive episode88 and when
aggression was enhanced by alcohol administration.89
These increases might reflect the motivational elements of
aggression, as these DA increases are similar to those seen with
other motivated and cue-triggered behaviors.6
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Psychopharmacology of Aggression
Pharmacological manipulations appear to exert a nonspe-
cific effect on aggression, and experiments have produced mixed
results. For example, amphetamine, which enhances dopaminer-
gic activity, can increase, decrease, or fail to change aggressive
behavior depending on various conditions such as dose, context,
and type of aggression.90 Research using specific pharmaco-
logical targets has also produced equivocal results. Aggression
can be attenuated by administration of D1 partial agonist SKF
38393,91 D1 antagonist SCH 23390,92 D2 agonist quinpirole,91
and D2 antagonist raclopride.93 Other experiments have suggested
that D1 antagonist SCH 23390 and D2 antagonist emonapride do
not modulate aggression.94 Differences in methodology and the
types of aggression measured may help explain these equivo-
cal findings; for example, different drug doses can lead to dis-
tinct effects on inhibitory D2 autoreceptors and postsynaptic
D1 and D2 heteroreceptors.
Genetic studies targeting enzymes involved in the metab-
olism of DA (MAO and catechol-O-methyltransferase [COMT])
or the DA transporter suggest also a pivotal role of such neu-
rotransmitter in the control of aggressive behavior (Table 1).
Surprisingly, although knockout mice for DA receptors (ie, D1
and D2 knockout) have been extensively used in mood disorders’
research, they have never been characterized for aggressive
behavior.
Dopamine: Human Literature
Cerebrospinal fluid levels of homovanillic acid, a DA me-
tabolite, are lower in impulsively aggressive violent offenders
with antisocial personality disorder than in nonimpulsively aggres-
sive offenders with paranoid or passive-aggressive personality
disorder.62 However, further evidence supporting the relation-
ship between impulsive aggression and endogenous DA levels
in humans is limited.
Dopamine antagonists, particularly typical antipsychotics
such as haloperidol, have been used effectively for decades to
treat aggression in psychotic patients.6,95Y97 Recently, however,
atypical antipsychotics, which act preferentially on other neu-
rotransmitter systems rather than the dopaminergic system, have
shown improved efficacy over typical antipsychotics (for a re-
view, see part 2).
GABA AND AGGRESSION
The first evidence of a relationship between the GABAergic
system and aggressive behavior was reported by Brody et al,98 in
1969, several years after the first studies on aggression, 5-HT,
and DA. The involvement of GABA in aggression has received
far less attention from experimenters than have other neuro-
transmitters. Indeed, a PubMed search using the MeSH terms
‘‘GABA’’ and ‘‘aggression’’ revealed only 40 indexed articles in
the last 10 years.
The role of GABA receptors in aggression may appear
counterintuitive and paradoxical. Indeed, in clinical practice,
benzodiazepines, which are positive allosteric modulators of
GABAA receptors, are clinically used to ‘‘calm’’ people with
impulsivity and violent behavior, but in other cases, they can also
exert proaggressive effects.
In acute and emergency situations, because of their anti-
anxiety and soporific-hypnotic properties, benzodiazepines can
be used as antiaggressive agents. The sedative and antiag-
gressive properties of benzodiazepine seem to be linked to their
agonistic effect on the GABA-A/>1 subunit.99 Benzodiazepines
alter aggressive behavior in a biphasic manner, with low doses
increasing attacks and threats and high doses decreasing these
behaviors.99 The low doses seem to be reversed by the GABA
antagonist flumazenil100 (for a review, see Miczek et al.76).
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Comai et al Journal of Clinical Psychopharmacology
Interestingly, a similar effect was observed also in humans.101
Moreover, in long-term treatment, they induce a syndrome of
dependence and withdrawal characterized by enhanced agita-
tion and aggressive behavior.79
For these reasons, the modulation of GABA neurotransmis-
sion via a different mechanism than that of benzodiazepines
may represent a better tool for the treatment of aggression.
Pharmacotherapies using anticonvulsants, which indirectly acti-
vate GABAergic transmission through GABA synthetic enzymes,
are commonly used to treat aggressive patients. Examples in-
clude valproate, phenytoin, and carbamazepine (see part 2).
These drugs may attenuate impulsive aggressive acts specifi-
cally. In 1 study, for example, phenytoin significantly reduced
the number and severity of aggressive acts in a group of im-
pulsively aggressive prison inmates, but not in a group of non-
impulsively aggressive inmates.102 In another study using a
double-blind, placebo-controlled design, the frequency of impul-
sive-aggressive outbursts was decreased during phenytoin treat-
ment as compared with baseline levels and placebo.103 Similarly,
treatment with tiagabine, a GABA reuptake inhibitor, signifi-
cantly reduced aggression in a sample of 10 male parolees, as
measured by the Point Subtraction Aggression Paradigm.104
GABA: Animal Research
Microinjection of GABA into the hypothalamus of cats
did block the attack and fight behavior produced by electrical
stimulation or injection of L-glutamate into the same nucleus.98
Later, it was demonstrated that injection of GABA or a structural
analog in the olfactive bulb of ‘‘killer’’ rats inhibits the mouse-
killing behavior of the rat.105 Results from postmortem studies
comparing brain GABA levels between aggressive and nonag-
gressive mice have provided equivocal results. Five-month-old
aggressive C57 mice exhibit lower GABA levels and turnover
rates in the amygdala, striatum, and substantia nigra than did
3-month-old, nonaggressive C57 mice and nonaggressive DBA
mice.106 Conversely, compared with a nonaggressive group,
aggressive female hamsters exhibit significantly higher levels
of GABA binding in their limbic, striatal, and diencephalic
structures, although not in the cortex or pons/medulla.107 These
disparate findings may be partly due to species differences.
A large body of research suggests that benzodiazepines,
which enhance GABA activity by positively modulating the
GABAA receptor subtype,6 exert bitonic effects on aggressive be-
havior.76,108 As previously mentioned, they tend to increase ag-
gression at low doses and decrease aggression at high doses.109
The mechanism accounting for this bitonic effect is unclear.
Complicating matters further, the distinct effects of different
doses of benzodiazepines might also interact with the individ-
ual’s psychological and social history.110
Recently, the important role of GABAB receptors in con-
trolling escalated aggression has also been demonstrated.
Takahashi et al8 showed in male mice that GABAB receptors
modulate serotonergic neural activity in the dorsal raphe nucleus
and, in particular, that the presynaptic GABAB receptors on
nonY5-HT neurons are responsible for the escalation of ag-
gressive behavior.
Interestingly, there is also evidence that GABA activation can
increase aggression, which runs contrary to most experimenters’
hypotheses. In rats, intracerebroventricular injections of 4,5,6,7-
tetrahydroisoxazolo[5,4-c]pyridine-3-ol, a GABA agonist, facili-
tate aggression toward mice, whereas administration of the GABA
antagonist bicuculline attenuates aggressive behavior.111 Genetic
studies targeting GABA receptors or enzymes involved in GABA
metabolism (Table 1) confirm the hypothesis that the development
88 www.psychopharmacology.com
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& Volume 32, Number 1, February 2012
of novel antiaggressive drugs acting on the GABA system should
target the GABA synthesis enzymes, as opposed to directly
modulating the GABAA receptor complex.
GABA: Human Research
Research in humans has supported the hypothesis that ag-
gression is related to low levels of GABA, although some con-
flicting evidence has emerged. In 1 study assessing 33 patients
with a family history of primary unipolar depressive disorder,
plasma GABA levels were inversely correlated with self-reported
aggression, whereas no such correlation was found in patients
without a family history of depression.112 However, it is impor-
tant to consider that it is unclear how exactly plasma levels and
brain levels of neurotransmitters relate. In another study, it was
reported that 9 adolescent inpatients with a history of at least
3 suicide attempts exhibited a decreased density of platelet
peripheral-type benzodiazepine receptors, as compared with a
control group composed of age-matched psychiatric inpatients
without past suicide attempts.113 The suicidal group also had sig-
nificantly higher aggression scores.
On the other hand, a direct correlation between levels of
GABA in the CSF and measures of impulsivity has also been
reported in personality-disordered patients and healthy controls,114
paralleling the results of previous studies that have demonstrated
increases in aggression following benzodiazepine administration.
In another study, patients with personality disorders who had
attempted suicide exhibited elevated GABA CSF levels, but no
significant relationship was observed between CSF GABA levels
and aggression, measured either dimensionally or categorically.114
GLUTAMATE, NMDA RECEPTORS,
AND AGGRESSION
Of the various glutamate receptors, NMDA receptors ap-
pear to be the most promising targets for pharmacological in-
tervention in treating aggression, although emerging evidence
suggests that other receptors, including both ionotropic and
metabotropic receptors, may play a role in aggression. However,
results from experiments are mixed, and the literature is signif-
icantly less robust than is the case with other neurotransmitters.
Indeed, a PubMed search using ‘‘glutamic acid’’ and ‘‘aggres-
sion’’ as MeSH terms produces only 33 indexed articles, of
which only 11 were published in the last 10 years. The low
number of research reports suggests that this field of research
remains quite unexplored.
Glutamate: Animal Research
In an early experiment, when glutamate was microinfused
into the hypothalamus of cats, it elicited attack and fight be-
havior in the same manner that did electrical stimulation.98
Many experiments have investigated the behavioral effects
of NMDA antagonists, including phencyclidine (PCP) and
dizocilpine (MK-801). However, results from these studies have
proven somewhat equivocal.115,116
In rapid eye movement sleepYdeprived rats, the relationship
between PCP dose and level of aggression follows an inverted
UYshaped curve.117 Another study in mice suggests that PCP
administration facilitates fighting under certain rearing and
housing conditions.118 However, other research challenges the
hypothesis that NMDA receptors exert a selective role on ag-
gression. It has been reported that several NMDA channel
blockers and antagonists (PCP, MK-801, memantine, DCPPene)
inhibit displays of aggression, but only at doses that also produce
ataxia, suggesting that NMDA channel blockade does not se-
lectively affect aggression.116
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Journal of Clinical Psychopharmacology & Volume 32, Number 1, February 2012
Still, support for a glutamatergic role in aggression continues
to surface. GPI-5232, an inhibitor of the enzyme N-acetylated-
>Ylinked acidic dipeptidase, which is responsible for converting
N-acetylaspartylglutamate to N-acetylaspartate and glutamate,
dose-dependently lowers aggressiveness in highly aggressive,
individually housed mice.119 However, these results are not
specific to NMDA receptors, and there is also evidence that other
glutamate receptors are involved in aggression. For example,
JNJ16259685, a selective antagonist of mGlu1 receptors, extin-
guishes or attenuates aggression at several doses.120 Thus, the
role of non-NMDA, glutamatergic receptors represents a possi-
ble target for future research.
Moreover, the relationship between glutamate and aggres-
sion has also been examined with relation to rodent genetic
manipulation (Table 1), confirming that also non-NMDA
receptors are involved in controlling aggressive behavior.
Glutamate: Human Research
Human research investigating the relationship between
glutamate and aggression is sparse, although a meta-analysis
pooling the results of three 6-month randomized studies reported
that treatment with memantine, a low-potency noncompetitive
NMDA antagonist, resulted in significantly more participants
experiencing improvement in the agitation/aggression symptom
cluster than treatment with placebo.121 Recently, it has also been
demonstrated that antiaggressive drugs such as valproate and
topiramate act on NMDA and AMPA receptors (see part 2).
NOREPINEPHRINE AND AGGRESSION
The study by Bourgault et al22 was also the first to suggest
that NE is involved in aggression. Since then, research using a
variety of designs has supported the hypothesis that the norad-
renergic system is involved in aggression. Similar to DA, a
PubMed search using the MeSH terms ‘‘norepinephrine’’ and
‘‘aggression’’ shows that almost half of the indexed articles on
this topic were published before 1980 (172 articles over a total
of 355), and only 39 reports from the last 10 years are indexed,
of which 2 are reviews.
In a recent review, Miczek and Fish115 suggest that the
noradrenergic system may play a ‘‘permissive’’ role in aggressive
behavior, helping to determine whether an individual elects to
fight or flee in response to a challenge. Accordingly, studies in
animals and humans have investigated whether differences and
changes in NE are related to levels of aggression.
Norepinephrine: Animal Research
In an early experiment, male rats were subjected to daily
2-hour periods of immobilization stress for 4 weeks, following
which they showed long-lasting increases in shock-induced
fighting and hypothalamic activity of tyrosine hydroxylase,
which was believed to reflect enhanced synthesis of catecho-
lamines such as DA, NE, and epinephrine.122 Based on these
findings, the authors proposed a hypothetical mechanism for the
etiology of aggressive behavior, in which early-life stress, such as
abuse, results in dysfunctionally increased catecholamine syn-
thesis, in turn producing pathological aggressiveness.
Research using neurotransmitter-specific functional lesions
has also investigated the role of NE in aggression. In one experi-
ment, highly aggressive male mice were intraventricularly treated
with 6-hydroxy-DA to destroy noradrenergic terminals in
the brain, following which there was a significant inverse corre-
lation between NE depletion and fighting.123 Similarly, rats given
an intraventricular injection of 6-hydroxydopa, which reduces
brain NE, but not DA, are more aggressive than controls.124
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Psychopharmacology of Aggression
Pharmacological interventions targeting the noradrenergic
system have also been shown to modify aggressive behavior. For
example, maprotiline, an NE reuptake inhibitor, stimulates ag-
gression during dyadic social interactions in male mice.125
The effects of noradrenergic manipulations on aggression
may be partly due to actions on >2-receptors. For example, de-
sipramine, an NE reuptake blocker, increases isolation-induced
aggression in mice in a dose-dependent manner.126 The >2-
receptor blocker yohimbine, but not the >1-receptor blocker
prazosin, dose dependently counters this desipramine-induced
enhancement in aggression. Treatment with clonidine, an >2-
receptor agonist, also blocks the desipramine-induced enhance-
ment of isolation-induced aggression. The effect of clonidine is
linked to its agonistic properties at the >2-adrenergic autoreceptor;
indeed, activation of the adrenergic autoreceptor decreases the
firing activity and release of NE at the postsynaptic level. In
another study, the >2-receptor antagonist yohimbine was shown
to inhibit isolation-induced attack, but not defensive behaviors,
in mice.127 In addition, >2C-knockout mice attack faster than
wild-type mice, whereas tissue-specific overexpression of >2C-
receptors results in an increased latency to attack55 (Table 1).
Considering these results, the >2-receptor system may represent
a target for future pharmacological treatments for aggression.
Genetic studies in mice targeting NE transporter and DA
A-hydroxylase enzyme further demonstrate that modulation of
NE system may be helpful in treating aggression (Table 1).
Norepinephrine: Human Research
Research in humans has primarily focused on the A-re-
ceptor system. Treatment with A-blockers, including proprano-
lol, appears to attenuate levels of aggressive behavior. In a review
of the case reports of 7 patients experiencing belligerence fol-
lowing acute brain insult, various doses of propranolol, which
blocks postsynaptic A-adrenergic receptors, effectively con-
trolled belligerence in all cases.128 Similar studies using chart
reviews have reported that A-blockers attenuate aggression in
hostile schizophrenic patients129 and patients experiencing ag-
gressive behavior following CNS lesions.130 Pindolol, which
blocks A-receptors as well as 5-HT1A receptors, has also been
shown to decrease aggressive incidents when augmenting antipsy-
chotic treatment in schizophrenic inpatients, using a randomized,
placebo-controlled, double-blind crossover design.131 However,
another study demonstrated that propranolol reduced aggression
in only a minority of chronically aggressive inpatients, sug-
gesting that the effects of A-blockers may interact with other
factors.132 In line with animal research, the >2-receptor agonist
clonidine has been extensively used in the treatment of agitated
and aggressive patients (for a review, see Fava133).
RECEPTORS AND AGGRESSION:
WHERE DO THEY PLAY?
Pharmacological experiments carried out in animals and
humans have not always explored the site of action of anti-
aggressive putative drugs. Consequently, several questions arise
concerning the sites of action of the different drugs. Drugs for
aggression can indeed act at the presynaptic and postsynaptic
level. For example, >2 agonists and antagonists act at the level of
the somatodendritic noradrenergic neurons of the locus coer-
uleus; 5-HT1A partial agonists and antagonists act at the level of
the serotonergic neurons of the dorsal raphe, and D2 agonists and
antagonists act at the level of the dopaminergic neurons of the
ventral tegmental area. However, the final action of these pre-
synaptic drugs is to enhance monoaminergic transmission at the
postsynaptic level.
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Comai et al Journal of Clinical Psychopharmacology
The most important areas involved in the control of ag-
gression are the PFC, in particular the orbitoprefrontal cortex
and the anterior cingulate cortex, as well as the amygdala, hy-
pothalamus, hippocampus, septal nuclei, and periaqueductal
gray of the midbrain.13,134
The idea that the PFC is involved in the control of aggres-
sive behavior was first reported over 100 years ago. In the land-
mark case of Phineas Gage, severe damage to the frontal cortex
due to a tamping iron accident resulted in a profound personality
change, including a predisposition to aggression and violence.
Since then, much research has investigated the role of the PFC
in the genesis of aggression (for a detailed review, see Bufkin
and Luttrell135). Davidson et al136 suggest that aggression and
violence derive from a deregulation of the emotional circuit in
which the PFC and, in particular, the medial and orbitofron-
tal portions play a major role in suppressing negative emotions.
Although the case of Phineas Gage is over a century old, a
PubMed search for aggression and PFC reveals that of 182
indexed articles, 80% have been published in the last 10 years,
and 50% just in the last 5 years. Remarkably, the PFC repre-
sents the area not only where the main neurotransmitters impli-
cated in aggression are released (5-HT, DA, NE, and glutamate),
but also it is the area where the main receptors are located (ie,
5-HT1A, 5-HT2A, NMDA, AMPA, D1, and D2).137
Recently, advances in neuroimaging technology have en-
abled researchers to better explore this mechanism, but the role
of the PFC and its relationship to aggression remain to be fully
elucidated. A detailed description of our current understanding
of their relationship is beyond the scope of this review but is
covered extensively in recent reviews.7,134,138
Klüver and Bucy,139,140 in a milestone article, demonstrated
that bilateral temporal lobectomy in rhesus monkey reduced
aggression. However, because the amygdala is anatomically
subdivided into a number of subnuclei that have numerous ex-
trinsic and intrinsic connections (ie, to the hypothalamus), ab-
lation or stimulation of a given region of the amygdala can cause
different or opposite effects on the aggressive level of the ani-
mal.141 In particular, regions of the amygdala that facilitate de-
fensive rage include the basal complex, which projects to the
periaqueductal gray and uses excitatory amino acids as a neu-
rotransmitter, and the medial nucleus, which projects to the
medial hypothalamus and uses substance P as a neurotrans-
mitter.142 Similarly the electrical stimulation in cats of areas
connected to the amygdala such as the medial and lateral/
perifornical hypothalamus induces defensive rage and predatory
attacks, respectively.14 However, it is worthy to say that these
studies were performed in cats, and studies in rats led to con-
trasting results. Amygdala in humans consists of 23 distinct
subnuclei, and similarly to animals, the amygdalectomy was
shown to produce a cessation of aggressive behavior,143 but as
recently reviewed, the electrical stimulation of the certain spe-
cific amygdaloid nuclei (ie, the lateral or the anteromedial
group) may lead to control the behavior of highly aggressive,
treatment-refractory individuals,144 even though this approach
needs a large-scale validation. Some of these data have been
confirmed using brain imaging techniques. In particular, func-
tional and structural neuroimaging has revealed that decreased
prefrontal activity and increased subcortical activity may pre-
dispose individuals to antisocial behaviors, regardless of factors
in the psychosocial environment.135
CONCLUSIONS AND NOVEL PERSPECTIVES
Further studies are necessary to establish not only how the
emotional circuit works, and which cortical and subcortical areas
are involved, but also the role of the different neurotransmitter
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& Volume 32, Number 1, February 2012
systems in this circuit. For example, an aggression locus within
the ventrolateral subdivision of the ventromedial hypothalamus
has been recently identified in mice,145 but the neural circuits
controlling this small subdivision of the ventromedial hypo-
thalamus remain to be investigated. Research is also needed to
examine the epigenetic regulation of the expression of genes
related to aggression and the intracellular events following cell
activation/deactivation. In this review, we have presented the
impact of the different neurotransmitters on aggressive behav-
ior, but how they interact with each other at the level of the PFC
and other postsynaptic areas is still poorly understood. For ex-
ample, a recent report demonstrates that a specific interrelation
exists between sex hormones, aggression, and 5-HT1A receptor
distribution in the dorsolateral and ventromedial PFC, orbito-
frontal cortex, and anterior cingulate cortex.146 In addition,
several drugs clinically used in the treatment of aggressive be-
havior produce specific neurochemical effects in the PFC, in-
cluding clozapine,147,148 olanzapine,149,150 and quetiapine.151
Valproate, for example, not only does act at the level of GABA,
NMDA, and non-NMDA glutamatergic receptors in the PFC,152 but
is also a histone deacetylase inhibitor and facilitates chromatin
remodeling in the PFC when it is associated with clozapine or
sulpiride, mediating the epigenetic down-regulation of reelin and
GAD67 expression detected in cortical GABAergic interneurons of
schizophrenic patients.153
Further studies should focus on the neuroplastic processes
induced by antiaggressive drugs, including changes in receptor
expression in the PFC and, most importantly, the epigenetic
changes resulting from pharmacotherapy.
At present, the receptorial profile of psychotropic drugs used
to treat aggression is quite well known, but the ultimate molec-
ular mechanisms responsible for their therapeutic effects and
their relationships to disease etiology are still poorly understood.
Recently, independent lines of research, reviewed by Beaulieu
et al,154 have shown evidence for an involvement of the signaling
molecules Akt and glycogen synthase kinase 3 (GSK3) in the
regulation of DA and 5-HT receptors. These signaling molecules
may play a role in the actions of psychoactive drugs such as
antipsychotics, lithium, and other mood stabilizers. Moreover,
investigations of the mechanism by which D2 DA receptors reg-
ulate Akt/GSK3 signaling support the physiological relevance of a
new modality of G proteinYcoupled receptor signaling involving
the multifunctional scaffolding protein A-arrestin 2.
More research is needed to clarify the common pathways
of these drugs to have not only a better comprehension of
the clinical psychopharmacology, but also a better understanding
of aggression as a common denominator of many psychiatric
disorders. Indeed, discovering a common molecular pathway
for drugs will help to understand why many psychiatric patients
with different disorders share aggression as a symptom.
AUTHOR DISCLOSURE INFORMATION
Dr Gobbi has been a speaker for Eli Lilly and has re-
ceived grants/honoraria from GlaxoSmithKline, Merck, and
AstraZeneca in the past. Dr Comai and Mr Tau have no
conflicts of interest to declare.
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