Research in Autism Spectrum Disorders 8 (2014) 803813

Contents lists available at ScienceDirect

Research in Autism Spectrum Disorders

Journal homepage: http://ees.elsevier.com/RASD/default.asp

Review

Psychopharmacological treatment of challenging behaviours

in adults with autism and intellectual disabilities:
A systematic review
Amanda Sawyer a,b, Johanna K. Lake a,b, Yona Lunsky a,b, Shi-Kai Liu a,b,
Pushpal Desarkar a,b,*
a
b

Centre for Addiction and Mental Health, Canada

Department of Psychiatry, University of Toronto, Canada

A R T I C L E I N F O

A B S T R A C T

Article history:
Received 24 October 2013
Received in revised form 24 March 2014
Accepted 26 March 2014
Available online 25 April 2014

Introduction: Autism is a neurodevelopmental disorder with a high co-occurrence with

intellectual disability. Adults with Autism and intellectual disability have a high incidence
of challenging behaviour, dened as repetitive self injurious or aggressive behaviour. We
underwent a systemic review of the evidence for treating challenging behaviours in adults
with Autism and intellectual disability.
Methods: A literature search was conducted using three large databases to extract studies
on the treatment of challenging behaviour among adults with Autism and intellectual
disability. Papers, which met this criterion, were reviewed and analysed to assess study
evidence and quality.
Results: Seven articles were selected which included ve agents: uvoxamine, sertraline,
clomipramine, risperidone, and ziprasidone. Randomized control studies of uvoxamine
and risperidone, provided efcacy for the treatment of challenging behaviour in adults
with Autism and intellectual disability. Open label trials of sertraline, clomipramine and
ziprasidone were also effective in treating challenging behaviours for this population.
Discussion: Risperidone and uvoxamine provided the best evidence for treating
challenging behaviour, and risperidone was the only medication with multiple trials
showing its efcacy. Further studies are required to demonstrate the efcacy of
psychopharmacology in treating challenging behaviours among adults with Autism
and intellectual disability.
2014 Elsevier Ltd. All rights reserved.

Keywords:
Autism
Adults
Challenging behaviours
Psychopharmacology
Intellectual disability

Contents
1.
2.

Introduction . . . . . . . . . .
Methods . . . . . . . . . . . . .
Literature search.
2.1.
Study selection . .
2.2.
2.3.
Data extraction . .

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804
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* Corresponding author at: Centre for Addiction and Mental Health, University of Toronto, 1001 Queen Street West, Toronto, ON M6J 1H4, Canada.
Tel.: +1 416 535 8501x32726.
E-mail addresses: pushpal.desarkar@utoronto.ca, pushpal.desarkar@camh.ca (P. Desarkar).
http://dx.doi.org/10.1016/j.rasd.2014.03.021
1750-9467/ 2014 Elsevier Ltd. All rights reserved.

804

3.

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5.
6.

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

2.4.
Study quality assessment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Data synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Efcacy: repetitive behaviour . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Efcacy: self-injurious behaviour . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Efcacy: aggressive behaviour . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Tolerability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.4.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Main ndings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Methodological issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Experimental design . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.1.
Recruitment of subjects with intellectual disability .
4.2.2.
Insight into the aetiology of challenging behaviours .
4.2.3.
Assessment of challenging behaviours . . . . . . . . . . . .
4.2.4.
Future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction
Autism is a neurodevelopmental disorder characterized by decits in communication and social interactions, as well as
patterns of repetitive or restrictive behaviours and interests (5th ed., DSM-5, American Psychiatric Association, 2013).
Intellectual disability (ID) and Autism co-occur at high rates, with rates of ID estimated to affect between 38% and 70% of
individuals with Autism (Autism and Developmental Disabilities Monitoring Network Surveillance Year 2008 Principal
Investigators, 2012; Bryson, Bradley, Thompson, & Wainwright, 2008; Edelson, 2006; Matson & Shoemaker, 2009).
Challenging behaviour occurs at very high rates among individuals with Autism (Matson, Sipes, Fodstad, & Fitzgerald, 2011;
McCarthy et al., 2010), and is broadly dened as behaviour that jeopardizes an individual or excludes them from community
involvement (Matson et al., 2011; McCarthy et al., 2010). Since such a broad denition can encompass a range of behaviours, a
more specic denition commonly used by other researchers is aggressive, self injurious or repetitive/stereotyped behaviour
that is not caused by a major mental illness (Beherec et al., 2011; Emerson & Bromley, 1995; Matson et al., 2011). Aggression, self
injury and repetitive or stereotyped behaviour are common causes of referrals to mental health services in adults with Autism
and ID (Cohn & Sernyak, 2006; Hassiotis, Parkes, Jones, Fitzgerald, & Romeo, 2008; Tsakanikos, Sturmey, Costello, Holt, & Bouras,
2007), and are also common target symptoms for psychopharmacology (Lake, Balogh, & Lunsky, 2012; Myers, 2007). Some
researchers have suggested that challenging behaviour is more common among individuals with Autism and ID compared to
those with Autism and average to above average IQ, and that more severe challenging behaviour is associated with greater
cognitive impairment (Matson & Rivet, 2008; OBrien & Pearson, 2004). For example, rates of challenging behaviour in one study
were as high as 87.9% among adults with Autism and ID (McCarthy et al., 2010).
Challenging behaviour can also have a signicant negative impact on the lives of individuals with Autism and their
caregivers. In one study, challenging behaviour, not a primary psychiatric diagnosis, was the most common reason for
individuals with Autism and ID to present to a mental health clinic (Tsakanikos et al., 2007). Several studies demonstrate that
challenging behaviour is a barrier to employment, residence, and access to community-based services among adults with
Autism (Graetz, 2010; Matson & Rivet, 2008; McGill & Poynter, 2012). Further, challenging behaviour impedes learning,
social and adaptive skill acquisition (Herzinger & Campbell, 2007), and may lead to extended hospital admissions (Beherec
et al., 2011) or the use of physical or chemical restraints (Sturmey, Lott, Laud, & Matson, 2005). Financially, there are also
signicant costs and resources associated with caring for individuals with Autism and challenging behaviour (Hassiotis et al.,
2008). In adulthood, these consequences may be further magnied simply because of the individuals physical size. Thus,
adults with Autism, ID, and challenging behaviour, represent a unique and particularly difcult population to serve.
A number of studies provide evidence for the use of behavioural and psychosocial interventions as a rst line treatment
for the core symptoms of Autism in children (Ospina et al., 2008), however, behavioural interventions in adults with Autism
and ID are not well studied. Clinically, we know that challenging behaviour can represent communication of an unmet need,
and when communication is the aetiology of the challenging behaviour non-pharmacological approaches are often effective
(Kevan, 2003). Further, the National Institute for Health and Clinical Excellence, UK (NICE) guidelines suggest that
psychopharmacological treatment of challenging behaviours in individuals with Autism should only be used in conjunction
with non-pharmacological approaches when challenging behaviours persist in the presence of psychosocial interventions
alone (NICE, 2012). Despite this, psychopharmacology is often the rst treatment approach for challenging behaviour
(Myers, 2007; Tsakanikos et al., 2007), and once an individual in placed on psychotropic medication, they are likely to have
medications added rather than removed (Esbensen, Greenberg, Seltzer, & Aman, 2009; Myers, 2007).
Despite our knowledge that adults with Autism are often prescribed multiple psychotropic medications (Aman, Van
Bourgondien, Wolford, & Sarphare, 1995; Aman, Lam, & Collier-Crespin, 2003; Aman, Lam, & Van Bourgondien, 2005; Dove
et al., 2012; Esbensen et al., 2009; Lake et al., 2012; Lunsky & Elsera, 2012), and that psychotropic medications are often the

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

805

standard of care for the treatment of challenging behaviour (Ratey et al., 1987; Theoharides & Asadi, 2012), literature on
pharmacological treatment for adults with Autism and ID, particularly evidence based interventions targeting
challenging behaviour, are limited. A number of systematic reviews and meta-analyses have been conducted on
pharmacotherapy for challenging behaviour in children with Autism (Homer, Carr, & Strain, 2002; Matson & Dempsey,
2008; Matson et al., 2011), but research for the treatment of challenging behaviour in the adult population has been
largely ignored. Randomized controlled trials of risperidone, aripiprazole, haloperidol, methylphenidate, divalproex, and
naltrexone have been conducted and shown efcacy for the treatment of challenging behaviour among children with
Autism (Kaplan & McCracken, 2012), leading the US Food and Drug Association to approve risperidone and aripiprazole
for the treatment of Autism in children (Polittle & McDougle, 2014). Randomized controlled trials of SSRIs to treat
challenging behaviour in children with Autism have been conducted, but have yet to demonstrate efcacy (Kaplan &
McCracken, 2012). However, few randomized controlled trials of treating challenging behaviours in adults with autism
have been conducted. Further, of the few randomized controlled trials conducted on Autism and challenging behaviour
in adults, subjects with ID are often underrepresented or excluded (Alexander, Michael, & Gangadharan, 2004; Jordan,
Robertson, Catani, Craig, & Murphy, 2012).
To address these gaps, this systematic review aims to evaluate and synthesize the existing literature on pharmacological
interventions for the treatment of challenging behaviour among adults with Autism and ID. Results of this review describe
the efcacy of pharmacological treatments, as well as assess the quality of evidence and methods employed to study specic
medications. Given the signicant clinical, familial and systemic challenges associated with providing care for adults with
Autism, ID, and challenging behaviour, there is a clear need to obtain a richer understanding of effective pharmacological
interventions for this population.
2. Methods
2.1. Literature search
A systematic search strategy was conducted to identify relevant literature from the following bibliographic databases:
Embase, PubMed, and Cochrane. Searches were limited to English publications from 1980 to February 2012. The start date for
this review was chosen to coincide with the publication of the third edition of the Diagnostic and Statistical Manual of Mental
Disorders (DSM-III), at which time the diagnostic criteria for Autism became more consistent. Only English articles published
in peer reviewed journals were considered. At the time of study selection, the authors of this review were interested in
studies where all participants had ID and Autism. However, no studies were identied which met this criterion as well as the
criteria outlined below. To manage this, we included studies where all participants had Autism, at least some participants
had ID, and where the authors statistically addressed outcomes in the ID population.
2.2. Study selection
Inclusion and exclusion criteria for this review were:
(i) Study population. Adults (18 years and older) with Autism (autistic disorder; pervasive developmental disorder) and
intellectual disability (mental retardation in DSM IV-TR). Studies were included so long as all participants were
identied as having a diagnosis of Autism, at least one participant had a diagnosis of ID, and outcome with regards to
individuals with ID was addressed statistically. Studies which included participants with co-occurring major psychoses
(e.g., schizophrenia, bipolar disorder) were not included, as we wanted to ensure the focus of treatment was challenging
behaviour.
(ii) Interventions. Interventions targeting challenging behaviour (dened as targeting any one or combination of aggressive,
self-injurious, or repetitive/stereotyped behaviour (Beherec et al., 2011; Emerson & Bromley, 1995; Matson et al., 2011).
(iii) Study design. Considering the signicant dearth of randomized controlled trials in this area, and to generate a list of
potentially useful pharmacological agents, we decided to include open-label trials, case series, and chart reviews with
two or more charts reviewed. However, only controlled trials were included for quality assessment.
(iv) Study setting. Inpatient, outpatient, group home or institution settings.
(v) Outcomes. Inclusion of at least one symptomatic outcome measure for challenging behaviour.

2.3. Data extraction

All titles and abstracts were independently extracted by two of the authors (A.S., J.K.L.) and relevant articles were
selected and reviewed by all authors. Additional articles were identied by searching the references of retrieved articles
and systematic reviews. Seven studies met inclusion criteria for the current review (see Fig. 1). Data were extracted
according to study design (e.g., RCT, open-label trial, etc.); study population (e.g., number of participants, number of
dropouts, age, diagnosis, etc.); outcomes (aggression, self-injurious behaviour, etc.); interventions; and information on
adverse events.

806

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

Articles identified
through literature
search (n= 1,376)

Articles screened by
title and abstract

Articles excluded due to

irrelevance (n=1,343)

Additional articles
identified through retrieved
articles and systematic
reviews (n=2)
Full text articles
assessed for
eligibility (n=35)

Articles excluded (n= 28)

Irrelevant population
(n=12)
Invalidated outcome
measure
(n=8)
Could not obtain article
(n=2)
Different target behaviour
(n=6)
Articles included
(n=7)
Fig. 1. Flowchart of study selection.

2.4. Study quality assessment

Study quality was assessed using The Cochranes Collaboration Tool for assessing risk of bias in randomized trials (Higgins
et al., 2011). The Cochranes Collaboration Tool assesses studies based on high risk of bias, low risk of bias or unclear risk of
bias according to standardized criteria. Two reviewers independently (A.S., P.D.) assessed each studys risk of bias. Results
were compared and a consensus of bias was determined (see Table 2). Case series were not included in quality assessment.
2.5. Data synthesis
Conducting a meta-analysis was not possible due to heterogeneity of the population studied, as well as variations in the
outcome and intervention measures employed. Results were summarized according to characteristics, outcomes, and
interventions of the population studied.
3. Results
Seven articles met inclusion criteria for this review. Details of these publications are summarized in Table 1. Two of the
studies reviewed were double-blind randomized controlled trials (McDougle et al., 1996; McDougle, Holmes, et al., 1998),
three were open label trials (Brodkin, McDougle, Naylor, Cohen, & Price, 1997; Cohen, Fitzgerald, Kahn & Kahn, 2004;
McDougle, Brodkin, & Naylor, 1998), and one was a case series (McDougle et al., 1995). Five agents were studied:
uvoxamine, sertraline (SSRIs), clomipramine (TCAs), risperidone and ziprasidone (atypical antipsychotics).
The studies reviewed varied in terms of the proportion of individuals with ID, ranging from 3390% of the sample. Five of
the studies included individuals with mild to severe ID (Brodkin et al., 1997; McDougle et al., 1995, 1996; McDougle, Brodkin,
et al., 1998; McDougle, Holmes, et al., 1998), and one included individuals with profound ID (Cohen et al., 2004). All studies
examined statistical differences in medication response according to ID, and addressed whether there was a correlation
between IQ and response to treatment. ID status did not signicantly inuence medication response in all of the studies
reviewed.

Table 1
Studies examining the effects of medication use on challenging behaviour.
Medication
(n), dosage

Study design

Sample

Treatment setting

Target symptoms

Outcome
measure

Outcome

Side effects

Length
of study

McDougle et al. (1996)

Fluvoxamine
(15) vs
placebo (15).
Dose range
50100 mg/
day, mean
endpoint dose
276.7 mg/day

Double blind
placebo controlled

15 adults with Autism,

IQ 32114. Five had ID

Nine inpatient, 21
outpatient

Aggressive
behaviour,
repetitive
behaviour

CGI,
Y-BOCS,
BAS

Efcacy:
signicantly
greater
reduction in
Y-BOCS
(p = 0.001), BAS
(p = 0.03) in the
uvoxamine
group
Response rates
(CGI): 53%
Fluvoxamine,
0% placebo

Mild to moderate,
mainly including
nausea (n = 3) and
sedation (n = 2)

12 weeks

McDougle, Brodkin,
et al. (1998), McDougle,
Holmes, et al. (1998)

Sertaline
50200 mg,
mean
endpoint dose
122.0 mg/day

Prospective open
label trial

42 adults with Autism,

28/42 with ID

Two inpatients, 42
outpatients

Repetitive
behaviour,
aggressive
behaviour,
self injurious
behaviour

CGI,
Y-BOCS,
SIB-Q

Efcacy:
signicant
reduction in
Y-BOCS
(p = 0.005) and
SIB-Q
(p = 0.0001) in
responders
Response rates
(CGI): 57.1%
(p = 0.003)

Anorexia (n = 1),
headache (n = 1),
tinnitus (n = 1),
alopecia (n = 1),
weight gain (n = 3),
sedation (n = 1),
and anxiety/
agitation (n = 2)

12 weeks

Brodkin et al. (1997)

Clomipramine
75250 mg/
day, mean
endpoint dose
139.4 mg/day

Prospective open
label trial

33 adults with Autism,

21/33 with ID

outpatient

Repetitive
behaviour,
aggressive
behaviour,

CGI,
Y-BOCS,
BAS

Efcacy:
signicant
reduction in
Y-BOCS
(p < 0.001), BAS
(p < 0.001) in
responders
Response rates
(CGI): 55%

Seizures (n = 3),
sedation (n = 2),
constipation (n = 3),
agitation (n = 1),
weight gain (n = 3),
anorganosmia
(n = 1)

12 weeks

McDougle et al. (1995)

Risperidone
28 mg/day

Case report

Three adults with

Autism, 2/3 with ID

Two inpatient, one

group home

Aggressive
behaviour,
repetitive
behaviour,
self injurious
behaviour

CGI,
Y-BOCS,
SIB-Q,

Efcacy:
signicant
reduction in
Y-BOCS, SIB-Q,
Response rates
(CGI): 100%

Mild sedation
(n = 1)

1 year

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

Author(s) and year

807

808

Table 1 (Continued )
Medication
(n), dosage

Study design

Sample

Treatment setting

Target symptoms

Outcome
measure

Outcome

Side effects

Length
of study

McDougle, Brodkin,
et al. (1998), McDougle,
Holmes, et al. (1998)
Phase one of trial

Risperidone
16 mg/day,
mean
endpoint dose
2.9 mg/day

Double blind
placebo controlled

31 adults with Autism,

24/31 with ID

24 outpatient,
seven inpatient

Repetitive
behaviour,
aggressive
behaviour,
self injurious
behaviour

CGI,
Y-BOCS,
SIB-Q

Efcacy:
signicant
reduction in
SIB-Q (p < 0.01)
and Y-BOCS
(p < 0.02)
Response rates
(CGI): 57%
risperidone vs 0
in placebo

Sedation (n = 8),
weight gain (n = 2),
enuresis (n = 2), GI
(n = 1), dry mouth
(n = 1), abnormal
gait (n = 1),
sialorrhea (n = 1)

12 weeks

McDougle, Brodkin,
et al. (1998), McDougle,
Holmes, et al. (1998)
Phase two of trial

Risperidone
16 mg/day,
mean
endpoint dose
2.9 mg/day

Open label trial

19 adults with Autism,

13/16 with ID

From sample of 24
outpatient and
seven inpatient

Repetitive
behaviour,
aggressive
behaviour,
self injurious
behaviour

CGI,
Y-BOCS,
SIB-Q

Efcacy:
Signicant
reduction in
SIB-Q (p < 0.05)
and Y-BOCS
(O.03)
Response rates
(CGI): 60%
risperidone

None noted

12 weeks

Cohen et al. (2004)

Ziprasidone,
mean dose
128  4 mg/
day

Chart review
naturalistic open
label

None
6 months
Efcacy: no
change or
decrease in MBS
in 7/10
(p = 0.587)
ID, intellectual disability; CGI, clinical global impression scale, Y-BOCs, Yale Brown Obsessive Compulsive Scale; BAS, Brown Aggression Scale; SIB-Q, self injurious behaviour questionnaire; MBS, maladaptive
behaviour scale; n, number of participants.
10 adults with Autism,
9/10 with ID

Institution

Aggressive
behaviour, self
injurious
behaviour,

MBS

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

Author(s) and year

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

809

Table 2
Assessment of risk of bias in papers examining psychotropic treatment of challenging behaviour in adults with Autism and intellectual disability.
Paper

Random
sequence
generation

Allocation
concealment

Blinding of
participants
and personnel

Blinding of
outcome
assessment

Incomplete
outcome date

Selective
reporting
bias

McDougle et al. (1996)

McDougle, Brodkin, et al. (1998),
McDougle, Holmes, et al. (1998)
Brodkin et al. (1997)
McDougle, Brodkin, et al. (1998),
McDougle, Holmes, et al. (1998) 1st phase
McDougle, Brodkin, et al. (1998),
McDougle, Holmes, et al. (1998) 2nd phase
Cohen et al. (2004)

+
+

+
+

+
+

+
+

+ = low risk bias;

+
+

= high risk bias; ? = unknown risk of bias.

3.1. Efcacy: repetitive behaviour

(See Table 1 for more details on trials studying the treatment of repetitive behaviour in adults with Autism and ID).
Randomized control trials of uvoxamine and risperidone provided the least biased evidence for the treatment of
repetitive behaviour in adults with Autism and ID (McDougle et al., 1996, 2008a). The efcacy of risperidone in treating
repetitive behaviour was replicated in an open label study, thus providing further evidence for its use (McDougle et al.,
2008a). Furthermore, risperidone was effective in both short-term (12 weeks) and long-term (up to 1 year) treatment of
repetitive behaviour.
Sertraline and clomipramine were also effective in treating repetitive behaviour in participants with Autism and ID
(McDougle et al., 2008a; Brodkin et al., 1997), however, these studies were open label trials.
3.2. Efcacy: self-injurious behaviour
(See Table 1 for more details on trials studying the treatment of self-injurious behaviour in adults with Autism and ID).
One randomized control trial of risperidone provided the least biased evidence for the treatment of self-injurious
behaviour among adults with Autism and ID (McDougle et al., 2008a). Again risperidone was effective in both short-term (12
weeks) and long-term (up to 1 year) treatment of self-injurious behaviour, however, some adults appeared to have
worsening agitation when using this drug (McDougle et al., 2008a). A second phase open label trial (McDougle et al., 2008a)
and one case series (McDougle et al., 1995) provided further evidence for its efcacy.
An open label trial of ziprasidone demonstrated that it had comparable effects with lower metabolic side effects
compared to previous treatment over a 6-month period (Cohen et al., 2004); however, no randomized control studies have
been conducted. Similar effects were observed in an open label trial of sertraline over a 12-week period, but again, a lack of
randomized control trial and secondary side effects limited the strength of evidence.
3.3. Efcacy: aggressive behaviour
(See Table 1 for more details on trials examining the treatment of aggressive behaviour in adults with Autism and ID).
Randomized control trials of risperidone and uvoxamine provided the least biased evidence for the treatment of
aggressive behaviour among adults with Autism and ID. Risperidone provided additional evidence through one case series
(McDougle et al., 1995) and one open label trial (McDougle et al., 2008a). Risperidone was effective in both short-term (12
weeks) and long-term (up to 1 year) treatment of aggression.
Results of an open label trial of ziprasidone identied that it may serve as a weight neutral alternative (Cohen et al., 2004),
but a randomized control study has yet to be conducted. Open label trials of sertraline (McDougle et al., 2008b) and
clomipramine (Brodkin et al., 1997) provided evidence for the treatment of aggression in adults with Autism and ID (Brodkin
et al., 1997; McDougle et al., 2008b), however, sertraline was noted to increase aggression.
No studies were identied which examined the use of mood stabilizers/anticonvulsants, stimulants, rst generation
antipsychotics or opioid receptor antagonists in the treatment of challenging behaviour among individuals with Autism and ID.
3.4. Tolerability
(See Table 1 for more details of the tolerability of each medication.)
In terms of adverse effects, differences in tolerability were noted in the agents and studies reviewed. No participants
dropped out of the uvoxamine study (McDougle et al., 1996), however, ve participants dropped out of the sertraline study
due to increased agitation/anxiety, and it is not known whether those subjects had ID (McDougle et al., 1996). In the
clomipramine study, two participants, both of whom had ID, had pre-existing seizure disorders and reported increased
seizure frequency during treatment. Two participants, one of whom had ID dropped out due to secondary agitations and

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abdominal pain. One patient with ID in the clomipramine study developed a new onset seizure (Brodkin et al., 1997). Of the
11 participants who exhibited side effects on clomipramine, eight of them had ID. In one of the risperidone studies, a total of
seven participants, four of whom had ID dropped out; ve due to agitation, one because of abnormal gait, and one due to lack
of treatment change (McDougle et al., 2008a). Five of eight participants who experienced sedation in the risperidone study
had ID, and both participants who experienced weight gain on risperidone had ID (McDougle, 1998). Sertraline and
ziprasidone reported no adverse effects.
4. Discussion
To the best of our knowledge, this is the rst systematic review on the treatment of challenging behaviour specic to
adults with Autism and ID. Previous reviews focused on participants under the age of 18 (Ching & Pringsheim, 2012; Doyle &
McDougle, 2012; Jesner, Aref-Adib, & Coren, 2007) or targeted individuals with either ID (Brylewski & Duggan, 2004; Deb &
Unwin, 2007; Gormez, Rana, & Varghese, 2011) or Autism (Ching & Pringsheim, 2012; Jesner et al., 2007), but not both. One
review focused on individuals with Autism across the lifespan, but this was not specic to those with ID (Doyle & McDougle,
2012).
4.1. Main ndings
This review demonstrates that research on the pharmacological treatment of challenging behaviour in adults with Autism
and ID is limited. All of the medications studied, including uvoxamine, sertraline, clomipramine, risperidone, and
ziprasidone, showed reductions in challenging behaviour (Table 1); however, risperidone provided the best evidence for
effective short and long-term treatment in all three domains of challenging behaviour. This nding is consistent with
approval from the US Food and Drug Administration for the use of risperidone in the treatment of challenging behaviour
among children with Autism (Theoharides & Asadi, 2012).
4.2. Methodological issues
4.2.1. Experimental design
Randomized control trials specic to adults with Autism and ID are necessary in order to identify effective evidence-based
treatments for challenging behaviour in this population. To date, only two agents, risperidone and uvoxamine, have
undergone a randomized control trial. Studies of sertraline, clomipramine, and ziprasidone all had high risk of bias, as they
were open label studies. Thus, lack of randomization and high risk of bias have limited the generalizability of these ndings.
4.2.2. Recruitment of subjects with intellectual disability
Individuals with Autism and ID represent a difcult population to conduct clinical trials on because of ethical and
logistical complexities inherent to studying individuals with ID (Myers, 2007; Oliver-Africano et al., 2010). Because of this,
adults with Autism and ID are frequently underrepresented or excluded in the clinical trial literature (Table 1). This is
particularly concerning given that this is a population with a high frequency of challenging behaviour (Matson & Rivet, 2008;
OBrien & Pearson, 2004). All of the studies reviewed had fewer than 50 participants, a limitation consistent with previous
studies on medication use and ID (Oliver-Africano et al., 2010).
4.2.3. Insight into the aetiology of challenging behaviours
The studies reviewed do not explain the mechanism by which these medications work, or the aetiology of challenging
behaviour, and it is unclear whether they were treating challenging behaviour, anxiety, or beneting from the medications
sedating effects. Clinical experience shows that treating challenging behaviour is best guided by understanding the aetiology
of the challenging behaviour in adults with Autism and ID through a biological, psychological, and social perspective.
Physical factors, such as gastroesophageal reux disease, constipation, adverse reactions to medications, pain and seizures
can be the aetiology of challenging behaviour, and guidelines on the treatment of adults with ID state that nding and
treating medical causes of challenging behaviours should be the rst intervention in evaluating challenging behaviour
(Rubin, Fahs, & Beasley, 2007; Sullivan, Berg, Bradley, & Cheetam, 2011). An inference that medication is ineffective for
challenging behaviour when that behaviour is caused by an underlying physical factor could be inaccurate. Therefore, there
is a need to rene the methodology of case selection for adults with Autism and ID, to ensure that variables confounding the
aetiology of challenging behaviour, such as underlying medical illness, are not present.
4.2.4. Assessment of challenging behaviours
In terms of documenting the impact of medication use and monitoring its effects, it is worth noting that it is often difcult for
individuals with Autism who have signicant intellectual and communicative impairments, to communicate their internal
experience. Thus, measures assessing symptoms may not be accurate as they are reliant on clinician and caregiver ratings or
reports. In some instances, for example studies using the Y-BOCS, this meant that repetitive thoughts could not be measured. In
other instances, questionnaires had to be modied. It is important to use validated observer measures and creatively identify
how best to capture the patients subjective experience of medication use when communication is impaired.

A. Sawyer et al. / Research in Autism Spectrum Disorders 8 (2014) 803813

811

The other important point is that there is a need for researchers to ensure that measurement tools, such as the Y-BOCS or
Brown Aggression Scale, are valid measurements of challenging behaviour in adults with Autism and ID. For example, six out
of seven studies utilized Y-BOCS to measure repetitive behaviours, however, it is a well-known fact that, although
repetitive behaviours in Autism and OCD supercially resemble each other, they are in fact two distinct clinical constructs.
5. Future directions
There is a critical need for research on commonly prescribed medications for challenging behaviour in this population,
including antipsychotic medications, anticonvulsants/mood stabilizers, opioid antagonists and anxiolytics. As well as
randomized controlled studies are needed to provide further evidence for agents that show efcacy in open label studies,
such as sertraline, clomipramine and ziprasidone with efcacy and tolerability measurements specically adapted to adults
with Autism and ID. No studies have been published looking at haloperidol, aripiprazole, naltrexone, methylphenidate or
divaloproex, all medications that have shown efcacy in randomized controlled studies in children with Autism and
challenging behaviour (Kaplan & McCracken, 2012), and which are frequently used in adult patients with Autism and ID.
Efcacy of novel agents studied in children with Autism, such as intranasal oxytocin (Bakermans-Kranenburg & van
Ijzendoorn, 2013) need to be studied in adults with ID as well. Having a diagnosis of Autism, ID, and being an adult are all
independent risk factors for more severe challenging behaviour. Therefore, extrapolating results from studies of children
with Autism or adults with normal IQ and Autism may not provide sufcient evidence for efcacy in treating challenging
behaviour in adults with Autism and ID.
Further, all of the agents reviewed should be examined in terms of short- and long-term efcacy as well as adverse effects,
since these agents are often used longitudinally. In this regard, consideration of both inpatient and outpatient settings is
necessary as these groups may differ in terms of symptom severity which may impact effect size.
Finally, given that response patterns and tolerability of psychotropic medication for the treatment of challenging
behaviour in adults with Autism and ID remains unclear, future studies should consider the creation of tools for monitoring
treatment efcacy and adverse effects, particularly for those with ID or of limited verbal ability. In this regard, inclusion of
longitudinal behavioural assessment data as one of the indicators of the efcacy of pharmacological treatment may improve
overall quality of assessment.
These future studies are necessary in order to develop guidelines for the treatment of challenging behaviour in adults
with Autism and ID, for which there are currently none. Although in the UK, NICE has recently published guidelines for the
treatment of Autism (NICE, 2012), and will be publishing guidelines for the treatment of challenging behaviour among
individuals with ID in 2015 (NICE, 2014), these guidelines highlight the paucity of evidence for the treatment of challenging
behaviour in adults with Autism and ID, both in terms of pharmacological and psychosocial interventions.
6. Conclusion
This systematic review examined the evidence for pharmacological treatment of challenging behaviour among adults
with Autism and ID, a particularly difcult and unique population to serve. In doing so, we highlight the considerable scarcity
of level one evidence on this topic. It is imperative that randomized controlled studies specically study the treatment of
challenging behaviour in adults with Autism and ID, as they represent a distinctive clinical presentation.
Funding
No funding was received for this paper.
Conict of Interest
None to declare.
Acknowledgement
We would like to thank Dr. Robert Balogh for assistance with our systematic review methodology.
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