Neurobiology and Treatment of Aggression: A Translational Approach

Neurobiology and Treatment
of Aggression
A Translational Approach
Zoran M Pavlovic MD
Medical Director Psychiatry
Medical Affairs
5-Apr-2013.

Definitions
• Aggression
• Violence
• Agitation
• Hostility
• Impulsivity

• The World Health Organization 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
• It divides violence into 3 broad categories:
self-directed, interpersonal, and collective

Psychiatric disorders
and aggression
in the printed media

• 39% of all articles covering topics of psychiatric disorders
focused on dangerousness and criminal activities
• A vast majority of these articles presented mentally ill
individuals as perpetrators, 71.8%
• Persons with psychotic disorders were most frequently
presented as perpetrators (50.0%)
• Self-directed aggression behavior was reported 5.1% articles
mentioning completed suicide, (7.2%) with attempted
suicide, and in 2.1% articles selfharm was addressed

• homicide was associated mostly with psychotic (5.1%) and
affective disorders (3.5%),
• cases of physical assault were most frequently mentioned in
articles dealing with subjects with psychotic (4.0%), and
organic disorders (N = 4, 1.1%).
• schizophrenia was most frequently mentioned in the context
of homicide (40% of the articles).
• suicides and suicide attempts were most frequently reported
in the context of affective disorders, depression and bipolar
disorder poses the highest risk for suicide
• subjects with bipolar affective disorder and substance abuse
comorbidity are reported to commit more violent crimes
than the general population

Aggression and Violence
in Schizophrenia

• psychopathological symptoms such as delusions or
hallucinations
• comorbid substance use
• social deterioration
• neurobiological mechanisms
• cognitive deficits
• structural abnormalities

Magnetic Resonance Imaging Studies
• Structural abnormalities repeatedly have been shown in
violent and aggressive schizophrenia patients
• Reduced whole-brain and hippocampus volumes
• Indications of disturbed connectivity between the
orbitofrontal cortex and the amygdala,
• Impulsiveness correlated negatively with reduced
orbitofrontal gray
• The propensity for repetitive violence appeared to be
associated with reduced volumes of both the orbitofrontal
gray matter and the hippocampus.

• Larger volumes of the right orbitofrontal cortex
were associated with worse neuropsychological
performance
• Schizophrenia patients with violence were found to
have reduced gray matter volumes
• Significant disturbances were found in the
cerebellum, which may be of relevance for input
from ventrolateral prefrontal cortex and parietal
regions

Positron Emission Tomography/Single-Photon
Computed Tomography Studies
• Patients with a history of one act of violence showed
reduced absorption of radioactively labeled glucose
in the inferior, anterior, and temporal cortex of both
hemispheres
• Patients with a history of multiple acts of violence
showed decreased FDG absorption in the anterior
inferior, and temporal cortex of the left hemisphere
• Under neuropsychological stress (Wisconsin Card
Sorting test), prefrontal function was significantly
reduced in the violent patients

Functional MRI
• The group of violent schizophrenia patients showed a
bilateral activation deficit in the frontal cortex and precuneus
when compared with the healthy controls and deficits in the
area of the right inferior parietal region when compared with
the nonviolent schizophrenia patients
• Frontal (bilateral) and right-sided inferior parietal activity
was negatively associated with the degree of violent
behavior, whereby the right parietal region showed the
strongest association, so that possible disturbances in
executive functions may be part of the explanation for
violence in schizophrenia patients

Other parameters that may induce
Violence and Aggression in Schizophrenia
• Clinical symptoms („Command hallucinations’’ may lead to
aggressive behavior, although the risk may be small. Positive
symptoms of schizophrenia, such as delusions and
hallucinations.
• ‘‘Neurocognitive impairments’’
• Acute pharmacological effects of alcohol and
certain drugs
• Substance use disorders (also associated with
treatment nonadherence)
• historical (past violence, juvenile detention, physical abuse,
and parental arrest record and perceived threats)

• Dispositional (age, sex, and income)
• Contextual factors
(recent divorce, unemployment, and victimization)
• Confusion, impulsiveness, or psychopathic features
• Nonadherence
• Stress

Aggression and Violence in
Borderline Personality Disorder(BPD)

Impulsiveness and Impulsive aggression
• Impulsivity is a multifaceted construct that can include
concepts as varied as sensation seeking, lack of planning, lack
of persistence, inability to delay gratification, insensitivity to
delayed consequences, alteration in the perception of time,
urgency, and risk taking
• Most major theories of impulsivity include dimensions of
motor impulsivity (the inability to delay or inhibit a
proponent motor response) and cognitive impulsivity
(impulsive decision making such as the inability to shift sets
or delay gratification despite negative or less than optimal
consequences)

• Behavioral measures of both motor impulsivity (e.g.,
the Immediate Memory Task in which you have to
inhibit a prepotent motor response) as well as
cognitive impulsivity (e.g., the Passive Avoidance
Task in which subjects have to discriminate
numbers associated with monetary reward from
those associated with monetary loss) are shown to
discriminate between impulsive and nonimpulsive
groups

• Borderline Personality Disorder as a Prototype of Emotion
Dysregulation
• Disinhibited anger, which often leads to aggressive behavior
• Model of altered prefrontal–amygdala connectivity provides
a model for the primary symptom in BPD, disinhibition of
emotion
• This reciprocal interaction predicts that if cortical control of
the thalamoamygdala pathway is reduced, emotional
responses will be dysregulated

• Response to serotonergic challenge, specifically impulsive-
aggressive BPD patients demonstrate decreased metabolism
in anterior cingulate
• Impulsive aggression has been shown to respond the
treatment with SSRIs
• IED-BPD have hypometabolism widely across the frontal lobe
compared to healthy men, healthy women and women with
BPD
• An early study of amygdala volume in BPD showed that total
amygdala volume tended to be reduced in female BPD
subjects compared to controls showed that BPD patients had
greater cerebral blood flow signal in the amygdala bilaterally
during unpleasant pictures compared with neutral pictures
than healthy controls

Aggression and Violence in
Major Depression and
Bipolar Disorder

• Suicide risk in depression and bipolar disorder:
Do impulsiveness-aggressiveness and
pharmacotherapy predict suicidal intent

• Nearly one million lives are lost each year to suicide, and
between 3%–5% of adults make at least one suicide attempt
at some point in their life
• More than two-thirds of suicide completers and suicide
attempters have (mostly untreated) major depressive
episodes at the time of the suicidal act
• Major affective disorders (MAD), that is, unipolar major
depressive disorder (MDD) and bipolar disorder type I and
type II (BPD-I, BPD-II) patients are highly vulnerable to
suicidal behavior. It is estimated that individuals with BPD
are 30 times more likely to attempt suicide than those with
no psychiatric disorder

• Short-term risk factors for suicidal behavior
such as suicidal ideation and recent suicide
attempt, the major precursors and the most
powerful predictors of attempted and completed
suicide
• Impulsivity/aggression has been reported to be
related to suicidal behavior in several studies

In bipolar disorder, impulsivity has components that
are dependent on not only the
• ‘‘state’’ (manic or depressive episode)
• ‘‘trait’’(continued pattern)
• impulse control disorders and bipolar disorders
have some features in common, such as risk seeking,
sensation seeking, and seeking pleasurable activities
• The patients were euthymic at the time the
questionnaires were completed and bipolar II
patients had statistically significant higher scores on
the Barratt scale

• Sensation seeking and aggressiveness that should be
taken into account when studying the correlation
between bipolar disorders and impulsivity.
• Sensation seeking scale: There are situations linked
to impulsivity, such as sensation seeking, novelty
seeking, and boredom susceptibility

• Barratt scale, impulsivity is noted to increase
interepisodically in bipolar disorder, independent of
manic episodes
• Biological factors: there are differences between
patients who are impulsive-aggressive and those
who are not
• Increased impulsivity would be associated with the
prodrome of maniform states
• Depressive episodes are also associated with
impulsivity especially if suicidal behaviour is
present

• The scale most frequently used for evaluating
aggressiveness is the Buss-Durkee Hostility
Inventory
• Bipolar II patients score high on the violence
subscale of the Buss-Durkee Hostility Inventory in
the euthymic phase
• Patients whose predominant polarity was
depressive had higher global scores on the Buss-
Durkee Hostility Inventory as well as on the
irritability subscale and the distrust subscale

• Prefrontal cortex (PFC)
• Orbital frontal cortex (OFC)
• Amygdala: basolateral complex (BLC) and the dorsal
amygdala nucleus of the Central Nucleus (CN)

Neurobiology
of Aggressive Behavior

A translational approach, spanning basic
and clinical science, may offer a superior tool and
scientific framework for examining the treatment of
aggression

• A link between aggression and 5-HT was hypothesized was
issued by Bourgault in 1963.
• In general, low levels of 5-HT appear to be associated with
aggressive behavior, although the relationship might be
more complex than previously believed
• 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
• 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.
• It has been hypothesized that the link between aggression
and low 5-HIAA is specific to impulsive behavior

• Experimental evidence suggests that modulating the
serotonergic system by administering selective serotonin
reuptake inhibitors such as paroxetine and fluoxetine, which
increase postsynaptic availability of 5-HTby blocking reuptake,
can attenuate aggression
• 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.
• In addition, using positron 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 subjects, confirming
that this receptor is implicated in impulsive aggression

• First indexed article regarding this issue was published by
Karczmar and Scudder in 1967.
• aggression was highly correlated with changes in hypothalamic
DA levels, and D2 receptors were the DA receptor subtype
mediating the behavioral changes.
• 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 in animal models
• At mesolimbic level, electrophysiological in vivo recordings
in freely moving rats demonstrated that an increase in
dopaminergic activity takes place during a highly aversive
condition such as defeat stress

• A rise in DA levels was also reported in nucleus accumbens
during and after a single aggressive episode and when
aggression was enhanced by alcohol administration
• Cerebrospinal fluid levels of homovanillic acid, a DA
metabolite,are lower in impulsively aggressive violent
offenders with antisocial personality disorder than in non -
impulsively aggressive offenders with paranoid or passive-
aggressive personality disorder
• Dopamine antagonists, particularly typical antipsychotics
such as haloperidol, have been used effectively for decades
to treat aggression in psychotic patients

• The first evidence of a relationship between the GABAergic system and
aggressive behavior was reported by Brody et al. in 1969, several years
after the first studies on aggression
• The role of GABA receptors in aggression may appear counterintuitive and
paradoxical. Indeed, in clinical practice, benzodiazepines, which are
positive allosteric modulators of GABA-A 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 antianxiety and
soporific-hypnotic properties, benzodiazepines can be used as
antiaggressive agents
• The sedative and antiaggressive properties of benzodiazepine seem to be
linked to their agonistic effect on the GABA-A/Alpha1 subunit.
Benzodiazepines alter aggressive behavior in a biphasic manner, with low
doses increasing attacks and threats and high doses decreasing these
behaviors

• Pharmacotherapies using anticonvulsants, which indirectly
activate GABAergic transmission through GABA synthetic
enzymes, are commonly used to treat aggressive patients.
Examples include valproate, phenytoin, and carbamazepine
These drugs may attenuate impulsive aggressive acts
specifically.
• In one study, for example, phenytoin significantly reduced
the number and severity of aggressive acts in a group of
impulsively aggressive prison inmates, but not in a group of
non-impulsively aggressive inmates
• In male mice that GABA-B receptors modulate serotonergic
neural activity in the dorsal raphe nucleus and, in
particular, that the presynaptic GABA-B receptors on non-
5-HT neurons are responsible for the escalation of
aggressive behavior.

• Of the various glutamate receptors, NMDA receptors appear to be the
most promising targets for pharmacological intervention in treating
aggression, although emerging evidence suggests that other receptors,
including both ionotropic and metabotropic receptors, may play a role
in aggression.
• 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 selectively affect aggression
• GPI-5232, an inhibitor of the enzyme N-acetylated-alpha-linked 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, extinguishes or attenuates aggression
at several doses

• 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
• Recently, it has also been demonstrated that antiaggressive
drugs such as valproate and topiramate act on NMDA and
AMPA receptors

• 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
• In one experiment, 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 correlation 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
• Pharmacological interventions targeting the noradrenergic
system have also been shown to modify aggressive behavior. For
example, maprotiline, an NE reuptake inhibitor, stimulates
aggression during dyadic social interactions in male mice

• The effects of noradrenergic manipulations on aggression
may be partly due to actions on alpha-2-receptors. For example,
desipramine, an NE reuptake blocker, increases isolation-induced
aggression in mice in a dose-dependent manner. The alpha2-
receptor blocker yohimbine, but not the alpha1-receptor blocker
prazosin, dose dependently counters this desipramine-induced
enhancement in aggression. Treatment with clonidine, an alpha2-
receptor agonist, also blocks the desipramine-induced
enhancement of isolation-induced aggression
• Activation of the adrenergic autoreceptor decreases the
firing activity and release of NE at the postsynaptic level
• In addition, alpha2C-knockout mice attack faster than
wild-type mice, whereas tissue-specific overexpression of alpha-2-
C receptors results in an increased latency to attack

• Treatment with noradrenergic blockers, including
propranolol, appears to attenuate levels of aggressive
behavior
• Propranolol, which blocks postsynaptic beta-adrenergic
receptors, effectively controlled belligerence in all cases
• Pindolol, which blocks beta- adrenergic receptors as well
as 5-HT1A receptors, has also been shown to decrease
aggressive incidents when augmenting antipsychotic
treatment in schizophrenic inpatients
• In line with animal research, the alpha-2-receptor agonist
clonidine has been extensively used in the treatment of
agitated and aggressive patients

Site of action of
antiaggressive drugs

• Drugs for aggression can indeed act at the presynaptic and
postsynaptic level
• For example, Alpha-2 agonists and antagonists act at the
level of the somatodendritic noradrenergic neurons of the
locus coeruleus
• 5-HT1A partial agonists and antagonists act at the level
ofthe serotonergic neurons of the dorsal raphe, and D2
agonists and antagonists act at the level of the
dopaminergic neurons of the ventral tegmental area
• The final action of these presynaptic drugs is to enhance
monoaminergic transmission at the postsynaptic level

• The most important areas involved in the control of aggression are the
PFC, in particular the orbitoprefrontal cortex and the anterior cingulate
cortex, as well as the amygdala, hypothalamus , hippocampus, septal
nuclei, and periaqueductal gray of the midbrain
• The PFC represents the area not only where the main
neurotransmitters implicated 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)
• In addition, several drugs clinically used in the treatment of aggressive
behavior produce specific neurochemical effects in the PFC, including
clozapine, olanzapine, and quetiapine
• Valproate, for example, not only does act at the level of GABA, NMDA,
and non-NMDA glutamatergic receptors in the PFC, 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

The Psychopharmacology of Aggressive
Behavior:
Clinical Studies Using Atypical Antipsychotics,
Anticonvulsants, and Lithium

Aripiprazole
• A quinolinone derivative, is a unique atypical
antipsychotic
• Partial agonist at the D2 and 5-HT1A receptors
• 5-HT2A antagonist, a 5-HT2C partial agonist, a 5-
HT2B inverse agonist, a 5-HT6 weak antagonist, and
a 5-HT7 weak partial agonist
• Modest affinity for the alpha-1 and H1 receptors
and does not bind to muscarinic receptors

• Regions of the amygdala that facilitate defensive rage include
the basal complex, which projects to the periaqueductal gray
and uses excitatory amino acids as a neurotransmitter, and
the medial nucleus, which projects to the medial
hypothalamus and uses substance P as a neurotransmitter
• The electrical stimulation of the certain specific amygdaloid
nuclei (ie, the lateral or the anteromedial group) may lead to
control the behavior of highly aggressive, treatment-
refractory individuals

• The major metabolite of aripiprazole is a pure
dopamine D2 receptor antagonist.
• Recently, it has been reported that aripiprazole
interacts with the N-methyl-D-aspartate (NMDA)
system by reversing MK-801Y induced prepulse
inhibition deficits through regulation of the
mitogen-activated protein kinases pathway, a
downstream signal transduction system that is
common to both the dopaminergic and the NMDA
systems.

• These diverse effects on neurotransmission suggest
several possible mechanisms through which
aripiprazole therapy might modulate aggression.
• For example, the dense population of 5-HT1A and 5-
HT2A receptors in the prefrontal cortex may partly
account for aripiprazole’s antiaggressive properties
because 5-HT1A activation in the prefrontal cortex
produces inhibitory effects and 5-HT2A activation
produces excitatory effects

Clozapine
• Dibenzodiazepine derivative
• Exhibits a much stronger affinity for 5-HT2
receptors than it does for D2 receptors
• It also binds with higher affinity to D4 receptors
than it does to D2 receptors
• It binds with high affinity to the M1-M5, >1, H1,
H3,5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7
receptors.
• Affinity for the F-aminobutyric acid (GABA),
sigma,NMDA, D3, and neuropeptide receptors, as
well as the alpha-2- and A-adrenoreceptors

• Clozapine differentially modulates cholinergic transmission
through the M4 receptors depending on the tissue, increases
expression of several immediate-early genes in different
brain areas such as the prefrontal cortex, alters GABAA levels
and phosphorylation via the protein kinase C pathway, and
enhances frontal NMDA receptor density in chronically
treated rodents reared in isolation
• Clozapine further improves aggressive behavior over time,
and progressive positive effects of clozapine can indeed be
observed even 6 to 12 months after initiating treatment

Olanzapine
• Thienobenzodiazepine derivative, is a bioisostere of
clozapine that possesses potent antagonist properties
toward 5-HT2A, D2, >1, and H1 receptors
• It also acts as a low-affinity antagonist on D1 receptors.
• Olanzapine exhibits a lower D2 occupancy than clozapine,
with values similar to those of typical antipsychotic drugs
• It also has a high affinity for all muscarinic receptors,
particularly the M1 and M4 receptors, although it is unclear
whether it acts as an agonist or antagonist on the muscarinic
system because in vivo and in vitro studies have produced
conflicting results

• Evidence also suggests that olanzapine acts directly
on the GABAergic system by influencing the total
density of GABA-A receptors in the prefrontal
cortex, as well as indirectly by activating the
neurosteroid system

• Because serotonergic, dopaminergic, adrenergic,
and GABAergic mechanisms are posited to play a
role in aggression, olanzapine’s antiaggressive
effects may be related to one or more of these
nurotransmitter systems
• More recently, it has been shown that olanzapine
induces the expression of retinoic acid and trophic
factor signaling genes in the prefrontal cortex.
Because the prefrontal cortex is implicated in the
control of aggressive behavior, it may be worthwhile
to investigate these mechanisms in the context of
aggression

Quetiapine
• Dibenzothiazepine derivative with 5-HT2A and D2
antagonist properties and one of the lowest D2 affinities
among the atypical antipsychotics.
• Moreover, it acts as a very high-affinity antagonist to alpha-1-
adrenoreceptors compared with other atypical
antipsychotics and also acts at H1 receptors and alpha-2-
adrenoreceptors.
• Remarkably, quetiapine also exerts partial agonist activity at
5-HT1A receptors,and this property, along with its antagonist
action at 5-HT2A receptors, is believed to be the
neurobiological mechanism accounting for quetiapine’s
antidepressant properties.

• Its serotonergic, dopaminergic, and adrenergic effects may
partly account for quetiapine’s antiaggressive effects because
all 3 neurotransmitter systems are implicated in aggression.
• A recent study suggests that quetiapine might modify gene
expression, an effect that could also be responsible for its
antipsychotic or antiaggressive effects. In this experiment,
chronically stressed rats treated with quetiapine exhibited
modified gene expression in the prefrontal cortex, an area
implicated in aggression.

Risperidone
• Benzisoxazole derivative, is an atypical antipsychotic agent that acts
mainly as a 5-HT2A antagonist because its binding affinity for 5-HT2A
receptors is 20 times higher than that for D2 receptors
• Its potency as a dopaminergic antagonist is comparable to that of the
typical antipsychotic haloperidol
• Risperidone is metabolized by cytochrome P4502D6 and 3A4 to
9-hydroxyrisperidone, known also as paliperidone
• Paliperidone largely retains risperidone’s antipsychotic effects and has
recently been approved by the Food and Drug Administration for the
treatment of schizophrenia
• In additiont o its actions on the serotonergic and dopaminergic systems,
• Risperidone also exhibits nanomolar affinity for the alpha-1 and alpha-
adrenergic receptors and the H1 receptor

Ziprasidone
• 3-benzisothiazolylpiperazine derivative
• Very high affinity for 5-HT2A and D2 receptors, with a high 5-HT2A/D2
affinity antagonist ratio
• Ziprasidone also rapidly blocks the D3 and D4 receptors but expresses
very low affinity for the D1 receptor.
• It is likely that this receptor profile is at least partly responsible for
ziprasidone’s antiaggressive properties because its effects on aggression
are similar to those of other atypical antipsychotic compounds
• Its actions on serotonergic receptors are somewhat unique; it acts as an
agonist to the 5-HT1A receptor, but is a 5-HT1D, 5-HT2A, and 5-HT2C
antagonist, and a low-potency alpha-1 and H1 antagonist, and does not
seem to bind to the alpha2-adrenoreceptor
• Elevated affinity for the serotonin, dopamine, and noradrenergic
transporters, although the nature of its effects on these transporters in
vivo is still poorly understood

Amisulpride
• Benzamide derivative
• Highly selective D2 and D3 receptor antagonist
properties. Its affinity for D3 is slightly higher than
for D2
• Unlike other antipsychotics, it does not bind to other
dopamine receptor subtypes nor alpha-
adrenergic,H1, or cholinergic receptors
• At low doses, amisulpride acts primarily by blocking
the presynaptic dopamine receptor, while its actions
at postsynaptic receptors only occur at high doses

• These dose-dependent effects must be considered when
evaluating amisulpride’s mechanism of action on aggressive
behavior
• Low doses of amisulpride block D2 and D3 autoreceptors,
producing an increase in dopamine firing activity and
release, which elicits an antidepressive effect; at higher
doses, amisulpride also blocks postsynaptic receptors,
producing antipsychotic and antiaggressive effects.
• More recently, it was reported that amisulpride acts as a
potent antagonist at the 5-HT7A and 5-HT2B receptors. It
was demonstrated that the drug’s antidepressant properties
derived from its action on 5-HT7A receptors; whether these
mechanisms play a role in aggressive behavior remains to be
elucidated.

Topiramate
• Sulfamate-substituted monosaccharide, related to fructose
• Positive modulatory effect on the activity of GABA at GABAA
receptors and a negative modulatory effect on the activity of
glutamate at kainate/alpha-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid (AMPA) receptors. Remarkably,
these electrophysiological and pharmacological properties
belong even to valproate , a drug used for several years in the
treatment of aggression.
• These pharmacological characteristics may account for
topiramate’s efficacy as a treatment for aggression in
psychiatric patients.

Valproate
• Valproic acid (2-propylpentanoic acid)
• Increases GABAergic activity by inhibiting the enzymes responsible for its
metabolism, such as succinate semialdehydedehydrogenase, GABA
transaminase, and alpha-ketoglutarate dehydrogenase
• Antagonizes glutamatergic neurotransmission by blocking the excitatory
responses of NMDA, AMPA, and kainate receptors at the prefrontal cortex
• Modulates Voltage-gated Na+ channels,and evidence also suggests an
effect on the regulation of the Akt/GSK-3 signaling pathway
• These properties could explain its effect in aggression treatment

Lamotrigine
• Phenyltriazine derivative
• Its antiaggressive effects may be due to its action on several
different neurotransmitter systems
• Lamotrigine acts by blocking voltage-gated Na+ channels
and A-type K+ channels as well as by inhibiting excitatory
postsynaptic currents via voltage-gated sodium and calcium
channelblockade
• It also acts on excitatory neurotransmitters, especially the
glutamatergic system, by inhibiting overexcited neuronal
activities without significantly altering basal rates. Other
reports suggest lamotrigine attenuates neuronal excitability
on presynaptic sites, inhibits the postsynaptic AMPA
receptor, and reduces glutamate release

• Lamotrigine’s activity on the GABAergic remains
poorly understood, and current results are
somewhat contradictory; for example, one report
suggests that lamotrigine acts presynaptically to
enhance GABA release, whereas another study
demonstrated that it attenuates GABA release
• A regulation of GSK-3 signaling pathway by
lamotrigine has been also reported

Gabapentin
• 1-[Aminomethyl]cyclohexaneacetic acid) is derivate of GABA
• Modulates GABA transporter function (GAT1), increases GABA levels by
inhibiting GABA-transaminase, and directly acts on GABA-B receptors
• Gabapentin is not a direct ligand to either the GABAA or the GABAB
receptor or is it converted to GABA
• Gabapentin acts also at the levels of NMDA autoreceptors and affects the
glutamate release
• These combined effects of gabapentin on both GABA and glutamate may
account for its antiaggressive effect
• Moreover, gabapentin acts on the alpha-2C subunit of L-type voltage
regulated calcium channels, which might also play a role in its
antiaggressive properties

Lithium
• Monovalent cation belonging to the group of alkali metals, has been used
in psychiatry for more than 60 years in the treatment of bipolar disorders
• It has been largely demonstrated that lithium reduces suicidality even
more than antidepressants and decreases the recurrences of depressive
and manic episodes in bipolar patients.
• Remarkably, the first translational studies in the psychopharmacology of
aggression were carried out by M. Sheard in the early seventies.
• After publishing evidence that lithium enhances the metabolism of
serotonin and prolongs the latency to defensive reactions to foot shock in
• A rat model, he carried out the first clinical single blind trial in 12 male
aggressive prisoners. Using an on-off trial (lithium weeks 1-4, placebo
weeks 4-8, and lithium weeks 8Y12), he noticed that the episodes of
anger disappeared during the treatment with lithium (0.6-1.2 mEq/L).

• The mechanism of action in decreasing aggression has been not yet clarified.
Electrophysiological studies report that lithium does not change the presynaptic
electrical activity of serotonin neurons located in the dorsal raphe nuclei but
enhances the effect of the electrical activation of the ascending 5-HT pathways on
the firing activity of hyppocampal pyramidal neurons, thus potentiating the
postsynaptic effect of 5-HT in CA3 hippocampus.
• However, it is reported that lithium interacts with neurotransmitters such as
glutamate; in particular, chronic lithium treatment protects neurons in the
central nervous system against excitotoxicity by inhibiting NMDA receptor-
mediated calcium influx.
• Acts on D2 receptors and ion channels,
• Upregulates neurotrophins such as brain-derived neurotrophic factor, nerve
growth factor, and neurotrophin-3
• Lithium is also a synthase kinase 3 (GSK-3) inhibitor that, together with
valproate, presents synergistic neuroprotective effects
• Causes changes in the levels of several genes in rat frontal cortex a brain area also
involved in the control of aggression

Clinical Trials for the treatment of
Aggression

• Acute agitation, represented by a state of motor restlessness and accompanying
mental tension, is a serious medical problem that can present in a number of
psychiatric diso
• Characterised by symptoms that include pacing, hand wringing, fist clenching,
pressured speech, yelling and threatening other people, agitation may escalate
and necessitate physical restraint or seclusion to protect the individual, care
providers and others in the immediate environment
• Rapid, effective, and safe intervention that does not produce excessive sedation is
important in returning the agitated person to a less aroused and less potentially
dangerous state, thereby facilitating further assessment of the individual and
their treatment options.
• Antipsychotic drugs administered with or without supplemental benzodiazepines
are the current standard of care in the acute treatment of agitation
• Speed of onset is one of the most important factors in choosing a route of
medication administration. Intravenous administration of antipsychotic drugs
affords a rapid onset of action, it is often impractical unless intravenous access is
already established

• intramuscular administrations are more commonly used, but these routes can
entail a notably delayed onset of action. For example, controlled studies of
intramuscular antipsychotics demonstrate a statistically significant difference
from placebo in agitation from 15 to 60 min.12–15 During such a delay,
symptoms can escalate. Intramuscular administration is often resisted by
individuals, further increasing the risk of escalating symptoms.
• there is a clear need for novel anti-agitation treatments that are rapid in onset,
well tolerated, easy to administer and accepted by individuals and staff.
• Staccato system (product also known as AZ–004), a proprietary, breath-actuated
delivery system that delivers loxapine with intravenous-like pharmacokinetics
• inhaled loxapine was well tolerated and, in participants with schizophrenia, had
dose-related anti-agitation effects without evidence of excessive sedation.

Methodology
• At screening, agitation was evaluated by the Positive and Negative Syndrome
Scale–Excited Component (PANSS–EC).
• Individuals were eligible if they had a total score of >14 (out of 35) and a score 54
(out of 7) on at least one of the five items.
• Key exclusion criteria were agitation primarily because of acute intoxication; a
urine drug screen positive for psychostimulants; a history of drug or alcohol
dependence in the previous 2 months; a serious risk of suicide; use of
benzodiazepines or other hypnotics or oral or short-acting intramuscular
antipsychotic drugs in the 4 h before study treatment; use of injectable depot
antipsychotics within a one-dose interval before study treatment;

Study drug
• Inhaled loxapine was delivered by the Staccato system, a singledose, single-use,
hand-held drug-device combination
• The rapid absorption of the drug provides peak plasma levels in the systemic
circulation with a median Tmax (25, 75 percentiles) of 2 min after administration
of the product

Assessments
• Baseline assessments, which were conducted in the 30 min before study
treatment, were the PANSS–EC scale, the Clinical Global Impression–Severity
scale (CGI–S, a pre-treatment assessment of agitation), the Agitation–Calmness
Evaluation Scale (ACES, a scale developed Eli Lilly and Company) and vital signs
measurements.
• After randomisation, dose one was administered and the 24 h evaluation period
began. If necessary, a maximum of three doses of the study drug were allowed
during that 24 h period: if agitation did not subside sufficiently after dose one or
it recurred, dose two could be given 42 h after dose one (after completion of
• the 2 h assessments); if necessary, dose three could be given 54h after dose two.

Efficacy measures
• the PANSS–EC scale and the CGI–Improvement (CGI–I) scale.31 The PANSS–EC
scale measures the following five symptoms associated with agitation: poor
impulse control, tension, hostility, uncooperativeness and excitement. Each
symptom is rated on a scale of one (absent) to seven (extreme) and scores are
summed. Therefore, total scores can range from 5 (all symptoms absent) to 35
(all symptoms extreme).
• Participants were evaluated with the PANSS–EC scale at 10, 20, 30 and 45 min
and 1, 1.5, 2, 4 and 24 h after dose one. The CGI–I scale was used to assess the
change from baseline agitation. Scores range from one (very much improved) to
seven (very much worse).Participants were evaluated using the CGI–I scale at 2 h
after dose one.
• The primary end-point was the change from baseline in the PANSS–EC score 2 h
after dose one of inhaled loxapine compared with the change from baseline after
inhaled placebo. The key secondary efficacy end-point was the absolute CGI–I
score 2 h after dose one of inhaled loxapine compared with inhaled placebo.

Safety and Tolerability
• Sedation was assessed using the ACES, which rates the participant on an agitated–
calm–sleeping continuum. Scores range from one (marked agitation) to nine
(unarousable), with a score of four indicating ‘normal’. Participants were
evaluated using the ACES at 2 h after dose one.

Neurobiology and Treatment of Aggression: A Translational Approach

Side effects
• Inhaled loxapine was well tolerated. The percentage of participants who had at
least one adverse event was similar in the placebo and loxapine groups (placebo
group: 44/115; 5mg group: 40/116; 10 mg group: 43/113), and most events
were judged to be of mild or moderate severity and resolved without
intervention.
• The most common adverse events in participants receiving inhaled loxapine were
sedation, dysgeusia and dizziness. Wheezing or bronchospasm was reported in
three participants treated with inhaled loxapine: one participant receiving the 10
mg dose had moderate bronchospasm that resolved with use of an inhaled
bronchodilator (albuterol, two puffs by metered-dose inhaler) and led to
withdrawal from the study; two participants receiving the 5mg dose had mild
wheezing that resolved without treatment. Only one participant reported cough
(10 mg group), which was judged to be mild and possibly treatment related and it
resolved without intervention.

Trial recommendations
• Pharmaceutical manufacturers of antipsychotic drugs should be encouraged to
collaborate with research leaders to review the data from the 17 trials to see if
the rating instruments used were sensitive to change in agitation
• Pilot studies are needed to test newly proposed methods for assessment. These
should not be used as the basis for power calculations for larger trials as sampling
errors for the effect size from these small trials are often unreasonably large.
Instead, these should be used to check the feasibility of sampling, measurement,
treatment delivery, and outcome assessment proposals.
• Participation in trials should be offered to those most likely to benefit from
pharmacologic therapy and for whom there is minimal reason to expect serious
side effects. Although it is not always feasible, a nonpharmacologic intervention
should be attempted before enrolling a patient in a clinical trial. This may be
facilitated by encouraging a standardized nonpharmacologic intervention for all
patients at all sites.The intervention should be long enough to identify patients
who respond to nonpharmacologic intervention and not so long as to make it
difficult for patients with more severe symptom levels to be enrolled in the trial

• Patients enrolled in clinical trials should have severe and persistent or recurrent
symptoms of agitation and/or aggression that are unresponsive to
nonpharmacologic interventions. Enrollment should follow a central eligibility
process to verify that the patient meets enrollment criteria. By establishing these
entry criteria, early dropouts will be reduced.
• The trajectory of response is superior to an endpoint analysis as a measure of
treatment efficacy. This requires a repeated measures design and contrasting the
course of the response to drug or placebo over time. This design not only
increases power to detect treatment effects, it facilitates intention to treat
analysis and uses a measure more sensitive to change than any endpoint or
change score using the same instrument
• A meaningful effect size should be pre-specified prior to trial initiation. This
should be the area under the curve (AUC), which equals the probability that a
patient in the treatment group has a response clinically preferable to one in the
control group. With AUC one can incorporate consideration of multiple benefits
and multiple harms into one clinically interpretable index.

• Multivariate analysis of effectiveness expressed as the numbers needed to treat
(NNT) analyses may be the most readily interpretable type of data for clinicians,
but further assessment with this approach is recommended
• Since deaths from atypical antipsychotics involved cardiovascular and infectious
causes, it is prudent to monitor the medical status of patients very closely during
clinical trials and for the protocol to explicitly state criteria for termination of a
subject’s participation in the study.
• Sedation may contribute to adverse events as well as treatment success and
should be measured in clinical trials for agitation and aggression.
• Additional scientifically sound, adequately powered studies designed to assess
the effectiveness of nonpharmacologic interventions should be initiated. The
clinical trial methodology for essential multi-site trials remains to be established.
Initial support should be provided by governmental agencies (e.g. NIH) and
private sources. Pharmaceutical companies should pay increased attention to the
appropriate combination/integration of pharmacologic and nonpharmacologic
interventions insafety and efficacy studies of the treatment of agitation and
aggression in patients with dementia.

• Consensus could not be reached on the question of on-going non-pharmacological
treatments across all treatment arms over the course of medication trials in this
population of patients with dementia and serious symptoms of agitation and/or
aggression. Some conference participants did not recommend that on-going
standardized non-pharmacologic treatment should be continued over the course
of the trial in all treatment arms because of the absence of more definitive data on
the efficacy of non-pharmacologic interventions,. These participants felt that
ongoing standardized non-pharmacologic treatment continued over the course of
the trial in all treatment arms, may well confound pharmacologic effects. They
also argued that if standardized non-pharmacologic intervention is necessary in
the interest of patient and/or caregiver welfare, then these clinical trials need to
be clearly identified as studies of combined pharmacological and non-
pharmacological treatment with bothmodalities clearly specified
• To advance drug trials in elderly individuals with dementia, better definitions of
acute and chronic agitation and/or aggression are needed. The definition should
provide specific diagnostic criteria for a syndrome of agitation and aggression
associated with dementia.

• Reliable and valid rating scales are necessary to quantify the severity of agitation
and aggression and changes with treatment in registration trials. Other worthy
outcomes that may be secondary or primary in clinical trials include quality of
life, mobility, drowsiness, mood, and independence in addition to emotional
stability. A specific level of severity may be required for trial enrollment.
Repeated measurement analyses are essential. Selection of scales will vary by
trial, population, venue, and proposed analytic strategy. Commonly used scales for
agitation and aggression include the CMAI and NPI, including family or nursing
home versions. Measurement accuracy can be improved by the use of
standardized raters, better training of raters and observers, and advances in
measurement methods. In some cases, technological advances may augment
clinical measures, e.g., actigraph recording of activities levels. Variability is
characteristic of the phenomenon being measured (agitation and/or aggression)
and must be anticipated in trials.
• Stratifying the sample for severity of agitation and aggression may insure an
adequate number of more severely agitated patients, but stratification is to be
avoided unless there is prior evidence that a baseline variable moderates
treatment response

• Many classes of drugs may reduce agitation and may warrant testing in clinical
trials, including antipsychotics, selective serotonin reuptake inhibitors, mood
stabilizers, anxiolytics, cholinesterase inhibitors, memantine, and analgesics, as
well as novel pharmacologic agents.
• Biological markers for drug response and adverse event susceptibility should be
sought in clinical trials in order to determine if response (or failure) can be
predicted and to determine whether side effect patterns can also be predicted.
• Time to emergence of behavioral events is an important measure of treatment
success in trials of both symptomatic and disease-modifying agents for
neurodegenerative disorders.
• Most studies in this population will require a Data and Safety Monitoring Board
(DSMB), not only for review of adverse events and serious adverse events, but
also to evaluate the research protocol and monitor fidelity to the clinical trial
design and to help investigators deal with unexpected problems that often arise
in large randomized placebo controlled trials.

Neurobiology and Treatment of Aggression: A Translational Approach

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