Journal of Intellectual Disability Research doi: 10.1111/j.1365-2788.2009.01232.

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volume 54 part 1 pp 116 january 2010

Pharmacotherapy for aggressive behaviours in persons

with intellectual disabilities: treatment or mistreatment?
J. A. Tsiouris
NYS Institute for Basic Research, George A. Jervis Clinic, Staten Island, New York, USA

Abstract jir_1232 1..16 the literature on basic research regarding the brain
receptors implicated in aggressive behaviours and
Background Antipsychotic medications have been
the basic research and clinical studies on the anti-
used extensively to treat aggressive behaviours in
aggressive properties of antipsychotics was
persons with intellectual disabilities (ID) when the
reviewed.
main psychiatric diagnoses given to them in the
Results Aggressive behaviours in persons with ID
past were schizophrenia, childhood psychoses and
serve different functions and many factors contri-
ID with behaviour problems. Today, antipsychotics
bute to their initiation, maintenance and exacerba-
are still estimated to comprise 3050% of all the
tions or attenuation including most of the
psychotropics prescribed for persons with ID,
psychiatric and personality disorders. Genetic disor-
although the prevalence of psychotic disorders is
ders, early victimisation, non-enriched and restric-
only 3% in this population. The overuse of antipsy-
tive environments during childhood or later on and
chotics in persons with ID could be justified if their
traumatic brain injury, which are common in
aggressive behaviours were associated with mostly
persons with ID, have been associated with aggres-
psychotic disorders and not other psychiatric dis-
sive behaviours and with mostly non-psychotic dis-
orders or factors and if the anti-aggressive proper-
orders in persons with and without ID. If the
ties of the antipsychotics have been supported by
factors above and the knowledge derived from
basic research or reviews of clinical studies. Is that
studies of domestic violence and premeditated
so? This article explores these questions.
aggression in persons without ID are considered
Methods The literature on aggressive behaviours,
and applied during the evaluation of the most
their associations with psychiatric disorders and
severe aggressive behaviours in persons with ID,
other contributing factors and the past and current
more appropriate and effective treatment than
treatment options for aggressive behaviours in
antipsychotics can be implemented. Basic research
persons with and without ID was reviewed. Also,
implicates mostly the GABA and the serotonin pre
Correspondence: Dr John Tsiouris, NYS Institute for Basic post synaptic brain receptors influence the initia-
Research, George A. Jervis Clinic, 1050 Forest Hill Road, Staten tion, modulation or inhibition of aggression in
Island, New York, USA. Tel.: 718 4945237, Fax: 718 4942258
animals. The anti-aggressive properties of the anti-
(e-mail: john.tsiouris@omr.state.ny.us).
This article is an updated and elaborated version of The Blake
psychotics have not been supported by reviews of
Marsh Lecture delivered on June 19, 2007, at the Annual Meeting clinical studies and basic research is absent. Anti-
of the Royal College of Psychiatrists, Edinburgh. psychotics are the indicated treatment only for

2009 The Author. Journal Compilation 2009 Blackwell Publishing Ltd

 Journal of Intellectual Disability Research
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
psychiatric disorders and for aggressive behaviours
associated with psychotic disorders and psychotic
features as activation of dopamine receptor leads to
defensive aggression.
Conclusions Most of the persons with ID and
aggressive behaviours do not have a diagnosis of
psychotic disorder and there is lack of strong evi-
dence supporting the anti-aggressive properties of
the antipsychotics. The overuse of antipsychotics in
this population may be explained by the old, faulty
notion that aggressive behaviour in persons with ID
is mostly associated with psychotic disorders. Given
the discrediting of this notion, the use of antipsy-
chotics in persons with ID may, in some cases, be
considered mistreatment rather than proper treat-
ment. In order to reverse the practice of over-
prescribing antipsychotics for aggressive behaviours
in persons with ID, basic research information on
aggression must be disseminated, the search for the
quick fix must be abandoned and the promotion
of antipsychotics as anti-aggressive drugs must be
discouraged. Matching the treatment with the vari-
ables contributing to the aggressive behaviours,
seeking a long-term rather than a short-term solu-
tion and avoiding the promotion of only one type of
treatment for all types of aggression might change
the current practice and improve the quality of life
for many persons with ID.
Keywords aggressive behaviours, anti-aggressive
medication, antipsychotics, contributing factors,
intellectual disabilities, pharmacotherapy
Introduction
The two main psychiatric diagnoses in the medical
files of the many persons with ID who were resi-
dents of Willowbrook State School, Staten Island
and were re-evaluated in our tertiary clinic over the
last 25 years were: (1) ID with behaviour problems;
and (2) psychotic disorder (childhood psychosis for
children and schizophrenia for adults). We now
know that the point and lifetime prevalence and the
distribution of different psychiatric disorders in
persons with mild/moderate ID are estimated to be
similar to those in the general population if behav-
ioural problems are excluded as a diagnosis (Deb
2001; Whitaker & Read 2006; Cooper et al. 2007a),
with the exception of special syndromes (Harris
2009 The Author. Journal Compilation 2009 Blackwell Publishing Ltd
volume 54 part 1 january 2010
1992; Chow et al. 1998; Dykens & Hodapp 2001;
Gothelf et al. 2007). Also, adults with challenging
behaviours who reside in developmental centres, a
special cohort, have a threefold increase in psychiat-
ric disorders compared with those without challeng-
ing behaviours who reside in centres (Rojahn et al.
2004).
The typical, or classic, antipsychotic medications
(i.e. major tranquilizers or neuroleptics) were intro-
duced in 1950, and the atypical ones in 1990 have
improved the treatment conditions and quality of
life for people diagnosed with psychotic disorders.
Although antipsychotics lack effectiveness as the
first line of treatment for most non-psychotic disor-
ders and although the prevalence of psychotic disor-
ders is about 3% in the ID population (Deb 2001;
Cooper et al. 2007a), 3050% of all the psychotro-
pics prescribed to individuals with ID between 1970
and 1996 were antipsychotics (Rinck 1998; Robert-
son et al. 2000). What have the antipsychotics been
prescribed for?
It appears that since their introduction, antipsy-
chotics have been used mostly for control of aggres-
sive and other challenging behaviours in the ID
population, independently of the underlying psychi-
atric diagnoses (Clarke et al. 1990; Deb & Fraser
1994). Since the introduction of the atypical antip-
sychotics, which also have mood-stabilizing quali-
ties, antipsychotics may represent more than 30%
of all the psychotropics prescribed for children with
autism (Mandell et al. 2008) and more than 50%
of all the psychotropics prescribed for adults with
ID.
Psychiatrists without any training in providing
care to persons with ID, according to Beasley
(2004), treat aggressive behaviours in persons with
ID in the same way as when the two main diag-
noses are ID with behaviour problems or with psy-
chosis. This practice persists in spite of published
articles (Sovner & Hurley 1983; King et al. 1994;
Smalley et al. 1995; Szymanski et al. 1998; Lainhart
1999; Deb et al. 2001; Tsiouris 2001), treatment
guidelines (Deb & Fraser 1994; Kalachnik et al.
1998; Bhaumik & Branford 2005) and review
articles or book chapters regarding psychiatric diag-
nosis in persons with ID (McDougle & Posey 2002;
Dinca et al. 2005; King 2007). The practice of treat-
ing behaviour problems in persons with ID is
similar to how behaviour problems have been
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
treated in persons with traumatic brain injury (TBI)
and dementia through the years. The use of atypical
antipsychotics in the geriatric population has been
curtailed because of associated adverse events,
including higher mortality due to vascular events
(Ballard & Waite 2006). Work is under way to
improve treatment and rely less on antipsychotics
for persons with TBI and behaviour problems (Kile
et al. 2007).
Aggressive behaviour/its different variables
and functions
Maladaptive behaviours and inappropriate behav-
iours are the terms that have been used through
the years for problem behaviours. Currently,
the accepted term in the USA is challenging
behaviours and includes behaviours such as: physi-
cal aggression against others (assaultive behaviour),
aggression towards objects (destructive behaviour),
aggression toward self (self-injurious behaviour, or
SIB) and also verbal aggression, screaming and
tantrums.
The estimated prevalence of challenging behav-
iours in the ID population has ranged from 10%
(Emerson et al. 2001b; Lowe et al. 2007) to 15%
(Holden & Gitlesen 2006) and up to 60% (Smith
et al. 1996). The 12-month prevalence was reported
to be 51.8% (Crocker et al. 2006). The point preva-
lence for aggressive behaviours towards others or
objects, using the Diagnostic Criteria for Psychiatric
Disorders for Use with Adults with Learning
Disabilities/ID (Royal College of Psychiatrists
2001), was reported to be 9.8% (Cooper et al.
2009a) and for SIB, 4.9% (Cooper et al. 2009b).
Aggression has an important survival function for
living organisms and every human being may
express it in a different form within the appropriate
context (Connor 2002), but aggressive behaviour is
one of the reasons that individuals with ID are
excluded from many social and educational activi-
ties and are placed in restrictive environments
(Qureshi & Alborz 1992).
Aggressive behaviours can be normal for the
chronological or mental age and sex; they can be
proactive (offensive) or reactive (defensive), and
planned (premeditated) or impulsive (affective or
disinhibited) (Vitiello & Stoff 1997; Connor 2002;
Barratt & Felthous 2003). They can be character-
2009 The Author. Journal Compilation 2009 Blackwell Publishing Ltd
volume 54 part 1 january 2010
ised as cyclical or constant, setting-dependent or
setting-independent, and transient or chronic, and
their patterns can change depending on the vari-
ables initiating, maintaining or blocking them
(Lowe et al. 2007). Aggressive behaviours can serve
the function of establishing dominance, defending a
territory, getting attention, retaining isolation, com-
municating needs, satisfying wishes and needs or
avoiding tasks/demands/places (Iwata et al. 1982;
Mace & Mauk 1995; Sprague & Horner 1995;
Tsiouris et al. 2006).
Antipsychotics for the treatment of all
aggressive behaviours
In the past, the US Federal Drug Administration
issued specific disclaimers for the use of all antipsy-
chotics in the ID population. Mesoridazine was an
exception. It was labelled as indicated for children
with ID exhibiting hyperactivity and uncooperative-
ness (Schroeder et al. 1998). Haloperidol replaced
thioridazine and mesoridazine as the drug of choice
for autistic children with stereotypies and behaviour
problems, after a few studies were conducted with
small numbers of autistic children, but sound
methods were published (Cohen et al. 1980; Ander-
son et al. 1984). It remained the primary anti-
aggressive drug for the ID population in spite of the
many side effects that were observed in follow-up
studies (Campbell et al. 1997).
Risperidone has gradually replaced haloperidol as
the drug of choice in the USA after a double-blind
study by McDougle et al. (1998) for adults with
autism spectrum disorder and a multicentre study
by McCracken et al. (2002). Both studies showed
that risperidone controls irritability and aggressive
behaviour in young adolescents and adults with
autistic disorder. As in the past when the typical
antipsychotics entered the market, all the new atypi-
cal antipsychotics have been studied for their anti-
aggressive effects in children and adults with ID
(see reviews by Findling et al. 2005; Posey et al.
2008). A reduction mainly in the irritability/
hyperactivity items of the irritability sub-scale score
of the Aberrant Behaviour Checklist (Aman et al.
1985) in children (McCracken et al. 2002; Shea
et al. 2004) and an improvement measured by the
Global ImpressionImprovement scale in adults
with autistic disorder treated with risperidone
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
(McDougle et al. 1998) or with olanzapine, quetia-
pine, ziprasidone and aripiprazole in open-label
prospective studies (see Posey et al. 2008 for a
review) do not prove their anti-aggressive proper-
ties. Levitas and Hurley (2006a,b) discussed the
history of the use of antipsychotics in persons with
ID, and although the short-term side effects of the
atypical antipsychotics are known (Fedorowicz &
Fombonne 2005), their long-term side effects are
gradually being confirmed (Cheng-Shannon et al.
2004; Anderson et al. 2007).
Are antipsychotics anti-aggressive drugs?
Research in animals suggests that post-synaptic
5-HT1B receptors modulate aggression, and pre-
synaptic 5-HT1A and 5-HT1B autoreceptors influ-
ence aggression under certain conditions, while
GABA receptors act as modulators (Olivier & Van
Oorschot 2005). Activation of 5-HT2A receptors
increases aggressive behaviour in mice (Sakaue et al.
2002), and 5-HT2A and 5-HT2C receptor antago-
nists have opposing effects on a measure of impul-
sivity in animal models ( Winstanley 2004). Drugs
that function only as D2-receptor blockers, which
include the typical antipsychotics, do not act as
anti-aggressive drugs (Goedhard et al. 2006; Siever
2008), although the atypical antipsychotics with
prominent 5-HT2A-receptor blockade have shown
anti-aggressive properties in clinical populations
(Krakowski et al. 2006). The anti-aggressive proper-
ties of risperidone in Syrian hamsters in which
aggressivity was induced by cocaine hydrochloride
injections at puberty were attributed more to ris-
peridones blockage of 5-HT2A receptors than to
blockage of D2 receptors (Ricci et al. 2007). In this
study, a decrease by 6575% in the intensity, but
not the initiation, of aggression was noted. In recent
reviews (Singh et al. 2005), the effectiveness of ris-
peridone for challenging behaviours was question-
able, and there was not enough evidence for
targeting specific behavioural problems with specific
antipsychotics (Deb et al. 2007) Also, haloperidol, a
D2-receptor blocker, and risperidone, a D2- and
5-HT2A-receptor blocker, did not show better anti-
aggressive properties than placebo when prescribed
in a randomised controlled study of adults with ID
and aggressive behaviour (Tyrer et al. 2008). The
authors interpretation of the study finding was that
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antipsychotic drugs should no longer be regarded
as an acceptable routine treatment for aggressive
challenging behaviours in people with ID. Matson
and Wilkins (2008), commenting on this study,
echoed their conclusion, but pointed out the diffi-
culties in changing treatment practices.
Self-injurious behaviour in persons with ID and
self-mutilation (cutting or self-harm) in the general
population ( Jacobson & Gould 2007) has attracted
attention from clinicians and researchers. Various
hypotheses have been postulated regarding the aeti-
ology and treatment of SIB, but treatment with the
dopamine D1 D2 blocker fluphenazine (Breese et al.
1984a,b) and experiences with naltrexone
(Sandman et al. 1983) did not produce the expected
results to support these hypotheses.
The elimination or substantial decrease of SIB in
people with ID from various age groups and with
different aetiologies of ID, after recognition and
appropriate treatment of their underlying depres-
sive, anxiety- or impulse-control disorders and
tapering or discontinuation of the prescribed antip-
sychotics, has been reported (Tsiouris et al. 2003a).
The selective serotonin reuptake inhibitors (SSRIs)
improved aggressive behaviours in 50% of the
persons with ID in the limited studies reviewed by
Sohanpal et al. (2007) and the most pronounced
effect was in persons with an underlying anxiety
disorder including obsessivecompulsive disorder.
Are any changes in the treatment of aggressive
behaviour forthcoming?
The pharmacotherapy of aggressive behaviours in
the ID population is far from evidence-based
(Dinca et al. 2005; Bramble 2007; Leskovec et al.
2008). Literature review on the use of psychotropics
in the ID population through the years (Schroeder
et al. 1998; Handen & Gilchrist 2006) indicates that
nothing has changed in the pharmacotherapy of
aggressive behaviours except in certain specialised
centres. The field of psychiatry is still in search of
the magic anti-aggressive pill.
Today, the practice of pharmacotherapy of
aggressive behaviours in persons with and without
ID is like the practice of medicine years ago, when
medications were given for relief of pain or fever
because the underlying aetiology was unknown
( Jensen et al. 2007).
 Journal of Intellectual Disability Research
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
It must be emphasised that antipsychotics in oral
or injectable form are still the indicated treatment
for psychiatric emergencies and acute-onset aggres-
sive behaviours that are uncontrolled with other
interventions (Steiner et al. 2003). The use of antip-
sychotics in persons with ID as a maintenance
treatment for the control of aggressive behaviours is
justified only when there are clear signs of a psy-
chotic process with signs of perceived threat (para-
noid ideation). Also, psychotropics must be
reinstated if psychotic features re-emerge while
antipsychotics are being discontinued. It has been
noted that activation of dopamine receptor D2
increases anxiety, social fearfulness and defensive
aggression in cats (Sweidan et al. 1991) and mice
(Gendreau et al. 2000).
Behaviour modification in the treatment of
aggressive behaviours
The environments influence on aggressive behav-
iours has been confirmed by published cases of suc-
cessful treatment of aggressive behaviours with
various types of behaviour modification techniques
after a complete applied behaviour analysis
(Gardner & Cole 1987; Carr & Smith 1995; Mace &
Mauk 1995; Carr et al. 1996; Foxx 2003). Aggres-
sive behaviours are often treated unsuccessfully with
different behaviour modification techniques, includ-
ing aversive ones such as contingent electric shock
(Carr & Lovaas 1983), without considering the con-
tribution of the untreated non-psychotic disorders
in initiating, maintaining, changing or exacerbating
these behaviours (Tsiouris et al. 2003a).
Case A
Recently, small doses of citalopram and divalproex
eliminated SIB in a 22-year-old woman with autis-
tic disorder and severe ID after the diagnoses of
anxiety disorder and bipolar II disorder were made.
Ten years of special education and behaviour modi-
fication in a special school for children with ID
were ineffective in reducing her SIB.
Case B
In another case, reported by Pfadt and Wheeler
(2006), a 25-year-old man with autistic disorder,
profound ID secondary to congenital rubella syn-
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drome and seizures controlled with carbamazepine
received behaviour modification treatment and aver-
sive treatments, including contingent electric shock,
but his chronic and severe SIB did not respond to
these treatments, and only special restraints on his
hands prevented it. A trial with naltrexone was inef-
fective in reducing his SIB. Extensive observation
determined that an underlying mood disorder (not
well controlled with carbamazepine only) contrib-
uted to the cyclical patterns and the severity of his
SIB. The addition of lithium resulted in a dramatic
decline in the frequency and severity of his SIB,
freedom from restraints and his placement in a
much less restrictive environment.
Most often, the opposite is true. Without applied
behaviour analysis and fully implemented behaviour
modification plans, prescribers of psychotropics
have been asked to treat challenging behaviours
with a particular psychotropic, which has been
advertised as an anti-aggressive drug.
Improving the diagnostic and treatment
process of aggressive behaviours in persons
with ID: research and empirical suggestions
I. Psychiatric model (treating the psychiatric
disorder or syndromes instead of the aggressive
behaviours)
Aggressive behaviours in persons with ID have been
reported to be: (1) atypical (Bodfish et al. 1995) and
secondary features (Meins 1995; Marston et al.
1997) of psychiatric disorders, but not depressive
equivalents (Tsiouris et al. 2003b); (2) products of a
psychiatric disorder maintained by an operant
behavioural process (Emerson & Bromley 1995);
and (3) emerging because of a reduced threshold of
tolerance to environmental stimuli because of psy-
chiatric disorder (Lowry 1993), which act as setting
events for aggressive behaviours (Tsiouris et al.
2003a; Rojahn et al. 2004; Hemmings et al. 2006),
contributing to their exacerbation or attenuation
(Cooper et al. 2003).
Similar associations were reported by Belden
et al. (2008) in preschoolers without ID. The fre-
quency and severity of aggressive and SIB were
much higher in the group with depressive and dis-
ruptive characteristics than the control group.
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
Establishing a correct psychiatric diagnosis in
persons with ID and aggressive behaviours has
been a major, disputed issue regarding the psychi-
atric model for the treatment of aggressive behav-
iours. The Diagnostic and Statistical Manual
(DSM IV) (American Psychiatric Association
2000) and the International Classification of Dis-
orders ( World Health Organization 1992) are the
major and the most conservative frameworks
(Cooper et al. 2007a) that must be utilised by any
practising psychiatrist or professional prescriber of
psychotropics to diagnose and treat psychiatric
disorders in persons with ID (Szymanski et al.
1998). To help with the difficult task of making a
psychiatric diagnosis, clinicians and researchers
have developed: (1) questionnaires (Matson et al.
1984, 1991), assessment schedules (Moss et al.
1993) and screening instruments (Prosser
et al. 1996); (2) diagnostic guidelines (Deb et al.
2001); and (3) a parallel to DSM IV-TR guide-
lines for persons with ID (Fletcher et al. 2007)
and modified diagnostic scales for the ID popula-
tion (Clarke and Gomez 1999; Tsiouris et al.
2006) or added behaviour equivalent to
anxiety and mood disorders (Charlot et al.
2007).
Most often, anxiety, fear, hyperarousal, impulsiv-
ity, mood dysregulation and impaired cortical
control of an amygdala hypersensitive to stimuli
appear to be associated with the initiation, mainte-
nance or exacerbation of aggressive behaviours in
persons with ID, as in the general population
(Siever 2008). In a recent major study, no link
between major psychiatric disorders and violence
was reported in adults without ID. Factors such as
substance abuse, family history of violence, family
disruption, perceived threats, victimisation and lack
of education were reported to be directly and
independently associated with aggression and pre-
cipitation of mental illness (Elbogen & Johnson
2009).
All of these findings were taken into consider-
ation in the following six models, which have
proven useful in enhancing the diagnostic process
when the input of psychiatric disorders and other
neurobiological variables is evaluated in persons
with ID and aggressive behaviours. Mostly, non-
psychotic disorders are associated with aggressive
behaviours in these models.
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II. Aetiological models
A. The genotype model
Aggressive behaviours have been associated with
genetic syndromes such as Lesch Nyhan, fragile X,
Down, Prader Willi, Smith Magenis, velocardiofacial
and 5p-(Cri-du-chat) and other syndromes (Harris
1992; Chow et al. 1998; Dykens & Hodapp 2001;
Murphy 2004; Hodapp & Dykens 2007). An asso-
ciation of the severity of SIB and gene polymor-
phism variants was noted in Lesch Nyhan
syndrome (Schretlen et al. 2005) and the maternal
disomy subtype of PraderWilli syndrome (Zarcone
et al. 2007). Anxiety, depressive disorders and anti-
social behaviours are associated with the serotonin
transporter (5-HTT) short-allele gene, according to
the time and level of environmental stressors (Caspi
et al. 2002; 2003), and carriers of this genotype
show strong amygdala reactivity to stimuli (Heinz
et al. 2007).
A clinical phenotype characterised by borderline
intellectual functioning and stress-induced aggres-
sive behaviour was associated with selective MAO-A
deficiency (Brunner et al. 1993). Since then,
research has proven that, although important, the
role of the polymorphism in the monoamine
oxidase gene (MAO-A) in aggressive behaviours in
the general population has not been fully elucidated
(Caspi et al. 2002; Manuck et al. 2002; Widom &
Brzustowicz 2006). Studies in persons without ID
suggest that the low expression allele (MAO-A-L) is
associated with higher sensitivity to social rejection
(measured by the activation of dorsal anterior cin-
gulate cortex), and predisposition to aggression
(Eisenberger et al. 2007), especially in a situation of
high provocation (McDermott et al. 2009).
A recent study found that 43% of adults with ID
and problem behaviour had the short-allele MAO-A
polymorphism, vs. 20% of matched adults with and
without ID and no behaviour problems. It appears
that other genes, except MAO-A, and factors not
yet identified contribute to the problem behaviours
in persons with and without ID (May et al. 2009).
B. The early life victimisation model
Widoms work indicates that being victimised as a
child increases a persons risk for becoming the per-
petrator of violence in the future ( Widom 1989;
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
McGloin & Widom 2001). It has been found that
reactive and impulsive aggression in the general
population starts at the age of 34.5 years and is
associated with low IQ, poor peer relationships,
deficits in problem-solving patterns, history of
physical abuse (Dodge 1991; Dodge et al. 1997;
Vitaro et al. 2002) and negative emotions (remorse,
guilt, fear) towards the aggressive act (Donovan
et al. 2003).
It is known that many adolescents and adults
with ID have been victimised as children or have
perceived being victimised and rejected (Gil 1970;
Elvik et al. 1990). Although the diagnosis of post-
traumatic stress disorder and its contribution to
aggressive behaviour have entered the field of
persons with ID, the real problem and its influence
on the aggressive behaviours are waiting to unfold
(Ryan 1994).
History of a chronic course of aggressive behav-
iours in the ID population, starting with tantrums
at the age of 35 years and continuing with fluctua-
tions and varying degrees of severity and forms in a
large proportion of this population (Green et al.
2005), suggests that victimisation further contrib-
utes to the predisposition for aggressive acts and
psychopathology in persons with ID and must be
investigated further (Emerson et al. 1994, 2001a &
b, 2005; Horner-Johnson & Drum 2006).
C. The restricted and un-enriched environment model
Studies of animals and non-human primates raised
in captivity and in different environments (deprived
or enriched) have documented that self-injurious
and aggressive behaviours are associated with
restricted, crowded and un-enriched environments
(Honess & Marin, 2006). Restrictive environments
or changes in the living environments play a major
role in the psychopathology and the type, frequency
and severity of aggressive behaviour in people with
ID (Emerson 2003). It has been found that
unstructured or overly rigid, noisy, crowded,
demanding or competitive environments can initiate
or exacerbate aggressive behaviour (Emerson &
Bromley 1995; Emerson et al. 1996, 2005).
Case C. A man with ID was initially aggressive at
his programme and later on while on the bus going
to his programme or before entering the bus.
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However, he was not aggressive at his residence. He
was a middle-aged man with autistic disorder and
severe ID, who had resided at the former Willow-
brook State School at a young age. He has
responded well to a combination of quetiapine,
Pindolol and divalproex for his schizoaffective and
impulse-control disorders. When I refused to change
or increase his psychotropics and suggested a
change in programme, a solution was found. He
was changed to a quieter room, and since then, he
has been attending the programme without any
signs of aggressive behaviour.
D. The sequelae of the traumatic brain injury model
Depression and anxiety disorders including post-
traumatic stress disorder and bipolar disorders are
common in persons with TBI and correlate with
temporal lobe and amygdala injury ( Jorge et al.
1993; Murai & Fujimoto 2003). Psychotic features
rarely emerge during the acute phase of TBI and
are possibly associated with prefrontal and/or tem-
poral lobe injury (Zhang & Sachdev, 2003). Orbito-
frontal injury is strongly correlated with impulsive
aggression and personality changes (Koponen et al.
2002).
A large percentage of individuals with severe ID,
with known or unknown aetiology, have a history
suggesting TBI. Prenatal, perinatal or postnatal
insults, protracted and recurrent anesthesia for cor-
rective surgeries, encephalitis and meningitis at
early age, protracted seizures, falls, accidents and
physical abuse are common findings in their psy-
chosocial histories.
In the guidelines for the treatment of TBI
sequelae (Kile et al. 2007), antipsychotic drugs are
suggested only when psychotic features are present.
Other psychiatric diagnoses are treated with the
corresponding psychotropics, especially SSRIs and
mood stabilisers. The beta-blockers have been
tested and found to be the most effective medica-
tion for aggressive behaviours associated with TBI
(Fleminger et al. 2003) and are the most effective
drugs for certain impulsive aggression in persons
with ID (Ruedrich et al. 1990; Tsiouris et al.
2003a). Benzodiazepines increase disinhibition in
persons with TBI and must be prescribed for
persons with ID with caution and close monitoring
because of the reported higher incidence of
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J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
behavioural side effects including aggression
(Kalachnik et al. 2002).
III. Behavioural models
A. The domestic violence model
George et al. (2006) observed that perpetrators of
domestic violence in persons without ID exhibit the
following psychobiological characteristics.
Heightened sensitivity to environmental stimuli, anxiety,
conditioned fear and behaviours resulting in fear
avoidance. Hyperarousal, excitation, agitation and
pacing with changes in posture, breathing pattern
and facial expression are described by the staff as
the characteristic status of many persons with ID
before they exhibit aggressive behaviours. They
attack (fight response), run (flight response) and
push people out of the way or attack themselves
(SIB) if fight-and-flight response is being blocked.
They often engage in SIB without attacking others
or running away as a way of reducing anxiety and
fear (fear avoidance). Apologies in the form of
saying sorry, feeling bad or crying and repeating I
will be good follow these behaviours, as they try to
re-establish good relations with the staff around
them. Usually, these individuals, especially the
younger ones, respond better in the presence of a
male staff and one-on-one supervision, which offers
protection from others and enhances their sense of
security. This sense of security obtained through
different means prevents reactive/impulsive aggres-
sion in the adults without ID (George et al. 2006)
and in children and adults with fragile X syndrome
(Tsiouris & Brown 2004).
Impaired cortical input to a sensitive amygdale, resulting
in a reflexive fight/flight response or shutdown in response
to aversive stimuli (external or internal). Hyper-
responsiveness (increased amplitude of electroder-
mal response to stimuli) has been seen in
individuals with fragile X syndrome (Miller et al.
1999), various types of anxiety disorders (Boucsein
1992) and certain individuals with autistic disorder
(van Engeland 1984). These findings offer an expla-
nation for the reactive, impulsive and affective
aggression common in children and adults with
autistic disorder, in whom similar findings have
2009 The Author. Journal Compilation 2009 Blackwell Publishing Ltd
volume 54 part 1 january 2010
been reported (van Engeland 1984; Smalley et al.
1995; Baron-Cohen et al. 2000). Depression,
common in persons with ID (Meyers 1998; Moss
et al. 2000; Tsiouris 2001), is postulated as a shut-
down or a withdrawal response (Tsiouris 2005).
Low levels of serotonin and high levels of testosterone in
the cerebrospinal fluid (CSF) (subjects were male
perpetrators of domestic violence without ID). Low
cerebrospinal fluid (CSF) serotonin levels are a
known factor associated with impulsivity and
aggression (Olivier & van Oorschot 2005). High
testosterone levels in animal studies (Archer 2006;
Soma 2006) are associated with aggressive behav-
iour around mating season. Studies measuring the
CSF, serotonin or testosterone levels in aggressive
young men with ID have not been performed.
Perpetrators of domestic violence have been diagnosed
with anxiety, depressive, impulse control disorders and
borderline personality disorders, but not psychotic dis-
orders. Anxiety and depressive disorders (unipolar
and bipolar) and impulse control or intermittent
explosive disorders are associated with aggressive,
destructive and/or SIBs (Tsiouris et al. 2003a,b;
Tsiouris & Brown 2004). Hypomanic/manic epi-
sodes of bipolar II or I type or psychotic disorder
are associated more with destructive, aggressive and
sexually inappropriate behaviours (Lowry & Sovner
1992). Psychotic disorders have a higher prevalence
in the ID population than in the general popula-
tion, but they are still not the most common disor-
ders (Deb 2001; Emerson 2003; Cooper et al.
2007a,b,c; Mantry et al. 2008), except in special
syndromes such as velocardiofacial syndrome
(Gothelf et al. 2007).
B. Planned or premeditated aggression model
Planned or premeditated aggression starts at the age
of 6.5 years and is associated with aggressive role
models in the family and positive attitudes towards
aggression (Dodge 1991; Dodge et al. 1997).
Few adults with mild ID or borderline intellec-
tual functioning exhibit planned aggression in order
to gain dominance, instil fear in others, satisfy their
wishes, avoid unwanted tasks, change placements or
get back at staff who have mistreated them. These
individuals do not feel remorse, guilt or fear after
 Journal of Intellectual Disability Research
9
J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
the attack and they enjoy exercising their power
through instilling fear in others. Adults with border-
line intellectual functioning have treatable psychiat-
ric disorders (neurotic disorders, substance abuse)
and personality disorders including borderline per-
sonality disorder features (Hassiotis et al. 2008), but
if they do not have any underlying Axis I psychiatric
diagnoses, their aggressive behaviour does not
respond well to behaviour modification or psycho-
tropic trials.
The psychobiological finding of borderline per-
sonality disorders in adults with borderline intellec-
tual functioning bears similarities to the finding in
studies of many perpetrators of domestic violence
(Mauchnik et al. 2005; George et al. 2006). Dialec-
tical therapy, role-playing, SSRIs, mood stabilisers
and small doses of atypical antipsychotics in a
symptom-targeted manner are suggested for this
group of violent persons (Mauchnik et al. 2005).
Foxx (2003) has suggested aversive punitive treat-
ment in certain cases with similar behaviours, espe-
cially of the premeditated type.
Conclusion
Review of the literature on aggressive behaviours
strongly suggests that: (1) aggressive behaviours are
not directly associated with the major psychiatric
disorders; (2) the prevalence of psychotic disorders
in persons with ID is only 3%; and (3) antipsy-
chotic medications (typical and atypical) do not
have anti-aggressive properties and must not be
over-prescribed for control of aggressive behaviours
in children, adolescents and adults with ID. Every
reviewer of psychopharmacology in the ID popula-
tion recommends that practitioners analyse the
behaviours, make a psychiatric diagnosis first, and
treat the psychiatric disorders by initially using
lower doses, monitoring and increasing the doses
slowly (Kalachnik et al. 1998; Tsiouris et al. 2003a;
Tsiouris & Brown 2004; Bhaumik & Branford
2005; Handen & Gilchrist 2006). The same
approach has been reached by consensus for the
treatment of impulsive aggression as a symptom
across diagnostic categories in child psychiatry
( Jensen et al. 2007), for treatment of the sequelae of
TBI (Kile et al. 2007) and the behaviours associ-
ated with the onset of dementia in persons without
ID (Ballard & Waite 2006).
2009 The Author. Journal Compilation 2009 Blackwell Publishing Ltd
volume 54 part 1 january 2010
In the absence of any medical, neurological or
easily diagnosable psychiatric disorder acting as
setting events for aggressive behaviours (Carr &
Smith 1995), the different models outlined can
guide the treating professional to choose the appro-
priate psychotropics and treat the different syn-
dromes, symptoms and behavioural characteristics.
When other known variables trigger and maintain
the aggressive behaviours for which psychotropics
are not indicated or will be harmful to the person
with ID, psychotropics must not be prescribed. In
spite of the negative repercussions when physicians
refuse to prescribe unnecessary psychotropics,
doing so is in accordance with the first, do no
harm part of the Hippocratic oath. Saying no to
the staff, parents and other professionals who
request psychotropics that are not indicated will
force them to use their creativity to develop the
appropriate intervention for their consumers
aggressive behaviours.
Case E
A middle-aged adult with mild ID was treated with
different psychotropics for agitation and aggressive
behaviour. This behaviour emerged after he was
told that he could not fly from New York to his
sister in California, a trip that he had been making
yearly. Rejection by his sister and his fear of losing
her were the staffs explanation for his aggressive
behaviours. In-depth questioning of the consumer
during our evaluation revealed that not flying was
the source of his agitation. He calmed down and his
behaviour returned to baseline when a flight to
another destination was suggested to be arranged.
The findings from an epidemiological study of a
large catchment area that is based less on informant
questionnaires/checklists and more on personal
interviews with the informants and the consumers
by trained clinicians have already been reported
(Cooper et al. 2007a,b,c, 2009a,b; Mantry et al.
2008). Such studies will clarify the overall preva-
lence of the different psychiatric disorders in people
with ID and the association of aggressive behav-
iours with the psychiatric disorder, the aetiological
syndromes of ID and the severity of the ID or other
factors.
Studies are needed to assess the tolerance and
sensitivity of persons with ID and special
 Journal of Intellectual Disability Research
10
J. A. Tsiouris Pharmacotherapy for aggressive behaviours in ID
syndromes to psychotropics, not their efficacy, as
has been proposed by Sturmey & Ghaziuddin
(2005). Other studies are needed to further investi-
gate the best treatment modalities for aggressive
behaviour, according to their associations, type and
functions. Also, pharmaceutical companies should
test the anti-aggressive properties of their antipsy-
chotics and other drugs on persons with ID and
aggressive behaviours only after having clear evi-
dence of their anti-aggressive properties from repli-
cated studies of basic research in animals and
clinical studies in the general population.
If dissemination of information to professionals
regarding the appropriate treatment of aggressive
behaviours in persons with ID is improved, the
current practice of over-reliance on antipsychotic
medication may change for the better.
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Accepted 11 November 2009