2016 - Psychiatric Symptoms

Psychiatric Symptoms
and Comorbidities
in Autism Spectrum
Disorder
Luigi Mazzone
Benedetto Vitiello
Editors
123
Psychiatric Symptoms and Comorbidities in
Autism Spectrum Disorder
Luigi Mazzone • Benedetto Vitiello
Editors
Psychiatric Symptoms and

Comorbidities in Autism
Spectrum Disorder
Editors
Luigi Mazzone Benedetto Vitiello
I.R.C.C.S. Bambino Gesù Children’s Hospital National Institute of Mental Health
Rome Bethesda, Maryland
Italy USA
ISBN 978-3-319-29693-7 ISBN 978-3-319-29695-1 (eBook)

DOI 10.1007/978-3-319-29695-1
Library of Congress Control Number: 2016940095
© Springer International Publishing Switzerland 2016

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The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
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Printed on acid-free paper
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The registered company is Springer International Publishing AG Switzerland
This book is dedicated to my love Lia, sweet
woman and excellent researcher
(Luigi Mazzone)
Contents
1 Mood Disorders and Autism Spectrum Disorder. . . . . . . . . . . . . . . . . . . 1

Valentina Postorino, Stefano Vicari, and Luigi Mazzone
2 Anxiety in Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Mirko Uljarevic, Heather Nuske, and Giacomo Vivanti
3 Repetitive Behavior in Children with Autism Spectrum Disorder:
Similarities and Differences with Obsessive-Compulsive Disorder . . . . . 39
Lawrence Scahill, and Saankari A. Challa
4 Schizophrenia Spectrum Disorders and Autism
Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Katharine Chisholm, Ashleigh Lin, and Marco Armando
5 Feeding and Eating Disorders and Autism Spectrum Disorder . . . . . . 67
Valentina Postorino, and Luigi Mazzone
6 Attention-Deficit Hyperactivity Disorder and Autism
Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 79
Samuele Cortese
7 Tics and Tourette Syndrome in Autism Spectrum Disorder . . . . . . . . . 93
Alessandro Capuano, and Giovanni Valeri
8 Sleep Disorders and Autism Spectrum Disorder . . . . . . . . . . . . . . . . . 111
Silvia Miano, Flavia Giannotti, and Flavia Cortesi
9 Personality Disorders and Autism Spectrum Disorder:
What Is Similar and What Is Different? . . . . . . . . . . . . . . . . . . . . . . . . 129
Kathrin Sevecke, Luise Poustka, and Christian Popow
10 “Gender Is Not on My Agenda!”: Gender Dysphoria
and Autism Spectrum Disorder . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Rita George, and Mark Stokes
Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
vii
Introduction
One of the most remarkable phenomena of the past twenty years has been the
dramatic increase in the rate of the diagnosis of autism spectrum disorder (ASD) in
our society. It is estimated that 1 in 68 children had been diagnosed with this disor-
der in 2010 in the USA (Department of Health and Human Services. Centers for
Disease Control and Prevention, March 28, 2014).
This is a major increase over the 1 in 150 rate in 2000 and even the 1 in 88 rate
in 2008. It is unclear how much of this phenomenon is accounted by the broader
diagnostic criteria and the greater awareness for the condition among families,
teachers, and clinicians, rather than by a true rise of the disorder (APA 2013).
Regardless of the relative weight of the various possible causes, it is a fact that psy-
chiatrists, pediatricians, neurologists, and primary care physicians are now much
more likely to treat children with autism spectrum disorder in their daily practice
than just a few years ago.
The management of autism spectrum disorder is typically complex and multidis-
ciplinary. The core symptoms, consisting in deficits in social communication and
language, and a pattern of restricted interests and repetitive behaviors, are best
addressed with intensive psychoeducational programs that have been shown, on
average, to ameliorate functioning (Dawson et al. 2010; Reichow et al. 2012).
Treatment of associated medical problems, such as seizure disorders and gastroin-
testinal symptoms, is often needed. The management of behavioral problems in
persons with autism spectrum disorder is an important challenge for clinicians and
families, and the psychiatric symptoms in comorbidities could even exacerbate the
behavioral dyscontrol.
Moreover, the symptoms of psychopathological conditions may be masked by
those typical of ASD, and the threshold between autism spectrum core symptoms
and comorbid symptoms can be blurred (Mazzone et al. 2012). Another common
challenge for clinicians is to determine if psychiatric symptoms observed in ASD
are part of the same dimension of autism spectrum itself or rather represent different
categorical factors such as a psychiatric disorder in comorbidity. This happens
because, as mentioned above, the core symptoms of ASD often mask the symptoms
of the comorbid condition. A helpful strategy to disentangle this issue could be to
look prospectively at the overall clinical outcome through longitudinal studies.
Longitudinal studies allow researchers to closely follow the developmental trajecto-
ries of ASD and to detect subtle changes in behavior at different stages of
ix
x Introduction
development in terms of progressive appearance of clinical symptoms and impact of

life experiences. Unfortunately, most of the clinical studies on ASD conducted so
far typically have been cross-sectional, comparing one particular clinical measure at
a single time point across samples. The interpretation of these cross-sectional find-
ings is mostly focused on the abnormalities in the patient group as compared to
healthy controls and on the contributions that these abnormal clinical abnormalities
may have on disease evolution. If the need for longitudinal, prospective research is
common to the study of all developmental psychopathology, it is especially crucial
for ASD in order to understand the lifetime history of the disorder and the role of
comorbid disorders. Indeed, children suffering from ASD have a different pattern of
development compared to normal children, and their life experiences influence their
cognitive and emotional status beginning within their first years of life.
An additional concern regards the suitability of the psychometric tools used in
clinical practice to assess comorbid conditions in ASD. Of course, the psychiatric
diagnosis of comorbidity relies on the competence of clinicians, but adequate tools
such as scales or questionnaires adapted for ASD could be helpful to somehow stan-
dardize the recognition of psychiatric symptoms in this clinical sample. So far, most
of the studies have used questionnaires, checklists, and scales designed for individuals
with a normal awareness of their own and other’s mental status. These instruments
were not specifically adapted to take into account the neuropsychological characteris-
tics of ASD in terms of deficits in mind reading, impairments in processing, and
reporting their own feelings, emotions, and communication problems. Hence, new
psychometric instruments, developed or adapted specifically to ASD, are needed.
These psychiatric symptoms substantially contribute to the burden of autism on
patients and families. Even if not curative of the autism core deficits, successful
management of associated psychiatric symptoms can lead to a significant improve-
ment in functioning and quality of life (Arnold et al. 2003; Aman et al. 2009).
Indeed the proper recognition and diagnosis of psychiatric comorbidities in ASD is
also a crucial point for the pharmacological treatment of these individuals. The cor-
rect identification and attribution of overlapping symptoms either to the comorbid
disorder or to the ASD itself may contribute to the choice of the most appropriate
treatment for each one (Mazzone et al. 2012).
Psychiatric medications are commonly used in patients with autism spectrum
disorder, with some studies showing use in up to one-third of children and two-
thirds of adolescents (Coury et al. 2012). For years, this use has been based on
anecdotal reports and expert opinion rather than on controlled investigations, thus
raising concerns about both the efficacy and safety of these practices. More recently,
research on the treatment of psychiatric symptoms in autism spectrum disorder has
increased, and a number of controlled clinical trials have been conducted to test
benefit and tolerability of several pharmacological and psychosocial interventions
for the management of aggression, attention-deficit/hyperactivity disorder, and
associated disruptive symptoms in children and adolescents with autism spectrum
disorder (RUPP 2002; RUPP 2005; King et al. 2009; Scahill et al. 2015). This body
of research data provides an evidence base for assessing the balance between poten-
tial benefits and risk, which is necessary for any rational use of interventions.
Introduction xi
For example, we now know that certain agents, such as risperidone and aripipra-
zole, are highly effective in decreasing aggression and irritability, but their use can
be accompanied by important metabolic adverse effects (Martin et al. 2004), or that
methylphenidate is less effective and more likely to cause adverse effects when used
for the management of ADHD in children with autism spectrum disorder as com-
pared to ADHD without autism (RUPP 2005). And we also know that selective
serotonin reuptake inhibitor medication is generally not effective in the manage-
ment of repetitive behaviors in autism (King et al. 2009).
The integration of pharmacological treatment with psychosocial, educational,
and rehabilitative interventions is a critical aspect of the management of autism
spectrum disorder (Volkmar et al. 2014). Combining medication with behavioral
intervention can be more effective in improving the level of functioning (Aman
et al. 2009). As always in medicine, the treatment of the individual with autism
spectrum disorder is an art that requires integration of the state-of-science data with
the specific needs and characteristics of the patient. The purpose of this book is to
provide clinicians with the most updated information on the diagnosis and treatment
of common psychiatric symptoms associated with autism spectrum disorder, and it
is meant to offer clinicians with the best scientific evidence on which to build suc-
cessful therapeutic strategies for their patients.
The opinions and assertions here presented are the private views of the author,
and are not to be construed as official statement of the National Institute of Mental
Health, the National Institutes of Health, or the U.S. Department of Health and
Human Services.
Rome, Italy Luigi Mazzone

Bethesda, Maryland, USA Benedetto Vitiello
References
1. Aman MG, McDougle CJ, Scahill L, Handen B, Arnold LE, Johnson C, Stigler KA, Karen
Bearss K, Butter E, Swiezy NB, Sukhodolsky DD, Yaser Ramadan Y, Stacie L, Pozdol SL,
Roumen Nikolov R, Lecavalier L, Arlene E. Kohn AE, Koenig K, Hollway JA, Korzekwa P,
Gavaletz A, Mulick JA, Kristy L. Hall, Dziura J, Louise Ritz L, Trollinger S, Yu S, Vitiello B,
Wagner A (2009) Medication and parent training in children with pervasive developmental
disorders and serious behavior problems. J Am Acad Child Adolesc Psychiatry
48:1143–1154
2. American Psychiatric Association (2013) Diagnostic and Statistical Manual of Mental
Disorders, 5th edn (DSM-5). American Psychiatric Association, Washington, DC
3. Arnold LE, Vitiello B, McDougle C, Scahill L, Shah B, Gonzalez NM, Chuang S, Davies M,
Hollway J, Aman MG, Cronin P, Koenig K., Kohn AE, McMahon DJ, Tierney E (2003)
Parent-defined target symptoms respond to risperidone in RUPP autism study: customer
approach to clinical trials. J Am Acad Child Adolesc Psychiatry 42:1443–1450
4. Coury DL, Anagnostou E, Manning-Courtney P, Reynolds A, Cole L, McCoy R, Whitaker A,
Perrin JM (2012) Use of psychotropic medication in children and adolescents with autism
spectrum disorders. Pediatrics 130(Suppl 2):S69–S76
xii Introduction
5. Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J

(2010) Randomized, controlled trial of an intervention for toddlers with autism: the Early Start
Denver Model. Pediatrics 125(1):e17–23
6. King BH, Hollander E, Sikich L, McCracken JT, Scahill L, Bregman JD, Donnelly CL,
Anagnostou E, Dukes K, Sullivan L, Hirtz D, Wagner A, Ritz L (2009) STAART
Psychopharmacology Network. Lack of efficacy of citalopram in children with autism spec-
trum disorders and high levels of repetitive behavior: citalopram ineffective in children with
autism. Arch Gen Psychiatry 66:583–590
7. Martin A, Scahill L, Anderson GM, Aman M, Arnold LE, McCracken J, McDougle CM,
Tierney E, Chuang S, Vitiello B, and the Research Units on Pediatric Psychopharmaco-logy
Autism Network (2004) Weight and leptin changes among risperidone-treated youths with
autism: six-month prospective data. Am J Psychiatry 161:1125–1127
8. Mazzone L, Ruta L, Reale L (2012) Psychiatric comorbidities in asperger syndrome and high
functioning autism: diagnostic challenges. Ann Gen Psychiatry 11:16
9. Reichow B, Barton EE, Boyd BA, Hume K (2012) Early intensive behavioral intervention
(EIBI) for young children with autism spectrum disorders (ASD). Cochrane Database Syst
Rev 10:CD009260.
10. Research Units on Pediatric Psychopharmacology Autism Network (2002) Risperidone in
children with autism and serious behavioral problems. N Engl J Med 347:314–321
11. Research Units on Pediatric Psychopharmacology (RUPP) Autism Network (2005) A random-
ized controlled crossover trial of methylphenidate in pervasive developmental disorders with
hyperactivity. Arch Gen Psychiatry 62:1266–12174
12. Scahill L, McCracken JT, King BH, Rockhill C, Shah B, Politte L, Sanders R, Minjarez M,
Cowen J, Mullett J, Page C, Ward D, Deng Y, Loo S, Dziura J, McDougle CJ (2015) Research
Units on Pediatric Psychopharmacology Autism Network. Extended-release guanfacine for
hyperactivity in children with autism spectrum disorder. Am J Psychiatry Aug 28:appi-
ajp201515010055. [Epub ahead of print]
13. U.S. Department of Health and Human Services. Centers for Disease Control and Prevention.
Prevalence of autism spectrum disorder among children aged 8 years—autism and develop-
mental disabilities monitoring network, 11 Sites, United States, 2010. Morbidity and Mortality
Weekly Report. Surveillance Summaries/Vol. 63/No. 2, 28 Mar 2014 (Available at Website
http://www.cdc.gov/mmwr/pdf/ss/ss6302.pdf)
14. Volkmar F, Siegel M, Woodbury-Smith M, King B, McCracken J, State M, American Academy
of Child and Adolescent Psychiatry (AACAP) Committee on Quality Issues (CQI) (2014)
Practice parameter for the assessment and treatment of children and adolescents with autism
spectrum disorder. J Am Acad Child Adolesc Psychiatry. 53:237–257
Mood Disorders and Autism
Spectrum Disorder 1
Valentina Postorino, Stefano Vicari, and Luigi Mazzone
1 Introduction
Behavioral problems, which are often linked to psychiatric disorders in comorbidity

in individuals with autism spectrum disorder (ASD), make the management of these
patients even more difficult either for clinicians or families (Mazzone et al. 2012,
2013). Several studies documented high rates of psychiatric comorbidities in indi-
viduals with ASD, especially with regard to internalizing disorders. An association
has been frequently reported with mood disorders, including depression and bipolar
disorders (Hedley and Young 2006; Munesue et al. 2008; Simonoff et al. 2008,
2012). Internalizing symptoms are difficult to recognize in this clinical population
because they can be misinterpret as features of autism. However, their identification
represents a crucial point for both diagnosis and treatment (Mazzone et al. 2012,
2013). Therefore, understanding how mood symptoms (i.e., depression and mania)
appear in individuals with ASD can help clinicians to delineate a correct distinction
between these two conditions in order to develop adequate treatment strategies,
either psychological or pharmacological. In this chapter we will describe the preva-
lence, the phenomenology and clinical features, the diagnostic process, neurobio-
logical and genetic bases, and treatment of mood disorders in ASD.
V. Postorino (*)
Department of Pediatrics, Marcus Autism Center, Emory University School of Medicine,
Atlanta, GA, USA
Child Neuropsychiatry Unit, Department of Neuroscience, I.R.C.C.S. Bambino Gesù
Children’s Hospital, Rome, Italy
e-mail: [email protected]
S. Vicari • L. Mazzone
Child Neuropsychiatry Unit, Department of Neuroscience, I.R.C.C.S. Bambino Gesù
Children’s Hospital, Rome, Italy
e-mail: [email protected]; [email protected]
© Springer International Publishing Switzerland 2016 1

L. Mazzone, B. Vitiello (eds.), Psychiatric Symptoms and Comorbidities in
Autism Spectrum Disorder, DOI 10.1007/978-3-319-29695-1_1
2 V. Postorino et al.
2 Prevalence
Studies published so far on the co-occurrence of ASD and mood disorders have
reported variable prevalence rates ranging from 1.4 % to 70 % (Amr et al. 2012;
Barnhill and Smith 2001; Brereton et al. 2006; Cassidy et al. 2014; De Bruin et al.
2007; Ghaziuddin and Greden 1998; Green et al. 2000; Gotham et al. 2014; Hedley
and Young 2006; Henry et al. 2014; Hofvander et al. 2009; Joshi et al. 2013; Kim
et al. 2000; Lainhart and Folstein 1994; Leyfer et al. 2006; Lugnegãrd et al. 2011;
Mazefsky et al. 2011; Mazzone et al. 2013; Mattila et al. 2010; Munesue et al. 2008;
Pouw et al. 2013; Rosenberg et al. 2011; Simonoff et al. 2008, 2012; Stahlberg et al.
2004; Sterling et al. 2008; Strang et al. 2012; Vickerstaff et al. 2007; Whitehouse
et al. 2009; Williamson et al. 2008; Wozniak et al. 1997). However, all these studies
used different diagnostic criteria, reasons for referral, and age ranges; thus these
issues could account for these wide rates. Indeed, these discrepancies could be
explained by the level of intellectual ability of the patients enrolled. In fact, studies
involving individuals with ASD and intellectual disability (ID) generally report
slightly lower rate of co-occurring mood disorders in this population (De Bruin
et al. 2007; Hofvander et al. 2009; Rosenberg et al. 2011). For instance, De Bruin
et al. (2007) in a sample of 94 children with Pervasive Developmental Disorder-Not
Otherwise Specified (PDD-NOS) reported that 13.8 % of them had at least one
mood disorder of which major depression occurred most frequently (10.6 %).
However, patients enrolled in this study reported a highly variable intellectual abil-
ity (intelligence quotient (IQ) ranging from 55 to 120). Similarly, a recent study
examining variation in cumulative prevalence of community diagnosis of psychiat-
ric comorbidity in 4,343 children with ASD, and including 1,170 individuals with
an ID, found that 11 % of them showed a comorbid depression and 5.2 % a bipolar
disorder (Rosenberg et al. 2011). On the other hand, individuals with high-
functioning autism (HFA) seem to be particularly affected by mood disorders
(Ghaziuddin and Greden 1998; Kim et al. 2000; Mazzone et al. 2013; Munesue
et al. 2008; Stewart et al. 2006; Vickerstaff et al. 2007; Whitehouse et al. 2009). For
instance, two recent studies investigating depressive symptoms in HFA samples
through self-report questionnaires found that these patients reported severe depres-
sive symptoms (Mazzone et al. 2013; Whitehouse et al. 2009). Moreover, Ghaziuddin
and Greden (1998) reported a rate of mood disorders of 34 % in a sample of 35
patients with a diagnosis of Asperger Syndrome (AS). In line with these results, a
recent study found that 16 out of 44 outpatients with HFA (36.4 %) had a comorbid
mood disorder (Munesue et al. 2008). Higher rates of co-occurrence of bipolar I
disorder and ASD were obtained in a large controlled analysis of phenotypic and
familiar correlates in a referred population of youth with bipolar I disorder assessed
for the comorbidity with ASD (Joshi et al. 2013). Specifically, these authors reported
that 30.3 % of the bipolar I probands met criteria for ASD (Joshi et al. 2013).
Generally, in adolescent and adult patients with HFA, the rates of comorbid mood
disorders seem to be even higher (Cassidy et al. 2014; Hofvander et al. 2009;
Lugnegãrd et al. 2011; Stahlberg et al. 2004; Sterling et al. 2008). In more detail,
Hofvander et al. (2009) reported that the most common lifetime comorbid condition
1 Mood Disorders and Autism Spectrum Disorder 3
was mood disorders (53 %) in a sample of adolescents and adults with ASD without
ID. Moreover, Lugnegãrd et al. (2011) investigating psychiatric comorbidity in
young adults with a clinical diagnosis of AS reported that 70 % of adults with ASD
had experienced at least one major episode of depression and 50 % of them had suf-
fered from recurrent depressive episodes. Indeed, a recent clinical cohort study on
374 adults with AS found that 32 % of the sample reported a history of depression
(Cassidy et al. 2014).
3 Phenomenology and Clinical Issues
Autistic symptoms can mask psychiatric disorders in comorbidity, and thereby

shedding light on the phenomenology of mood symptoms in ASD is a clinical issue
(Frazier et al. 2002; Lainhart and Folstein 1994; Magnuson and Constantino 2011;
Mazzone et al. 2012, 2013, 2014; Simonoff et al. 2008). Depressive symptoms (e.g.,
social withdrawal and blunt affect) can be easily covered by some of the core autis-
tic symptoms if not specifically investigated. During the diagnostic process, clini-
cians have to keep in mind that the clinical manifestation of depressive symptoms in
patients with ASD may involve generic depressive clinical signs (e.g., increase in
crying, self-injury, decrease in activity with a loss of interest in the daily living,
apathy, anhedonia, feelings of guilt, low self-esteem, and recurrent thought of death)
(Ghaziuddin et al. 2002; Mazzone et al. 2012; Vannucchi et al. 2014). Furthermore,
as in other patients with depressive symptoms, the neurovegetative symptoms can
be present (e.g., changes in appetite and weight or sleep disturbance, including
hypersomnia, insomnia, or reversal of day and night). On the other hand, there are
some possible depressive symptoms which could be more specific in ASD. These
might include irritability, a change in repetitive and stereotyped behavior, or an
increase in compulsive behaviors (Ghaziuddin et al. 2002; Gotham et al. 2014). For
instance, clinicians has to consider that a temporary decrease of repetitive and ste-
reotyped behaviors in individuals with ASD can be either an improvement of autis-
tic symptoms or a manifestation of depressive symptoms (Lainhart and Folstein
1994; O’Brien et al. 2001; Stewart et al. 2006; Tantam 2000; Weissman and Bates
2010; Wing 1996). Age of onset of a co-occurring depression is predominantly
around pre-adolescence and adolescence, probably because during this period of
transition these patients become more aware of their own social skills (Ghaziuddin
et al. 2002; Mazzone et al. 2012; Williamson et al. 2008). Indeed, several studies
suggest that the rate of depression in individuals with ASD increases with age, as
well as the lower self-perceived social competence (Brereton et al. 2006; Ghaziuddin
et al. 2002; Vickerstaff et al. 2007). Another clinical symptom of depression pecu-
liar of individuals with ASD is the regression often observed in this clinical popula-
tion during lifespan. It is particularly observed in individuals with low functioning
autism and might be characterized by loss of language, social withdrawal, loss of
eye contact, moodiness, tantrums, fearfulness, obsessiveness, stereotypies, hyperac-
tivity, and occasionally self-injurious behaviors (Ghaziuddin et al. 2002; Myers and
Winters 2002).
Other factors that can play an important role in the onset of mood disorders in
ASD are environmental factors: stressors and negative life events (i.e., family sick-
ness, change of house, or bereavement) may contribute to the occurrence of depres-
sion in individuals with ASD (Ghaziuddin et al. 1995). It is well known that patients
with depression have experience of increasing stressors before illness onset (Brown
and Harris 1989; Hammen 2005). Therefore, the experience of these negative life
events could play a role in the occurrence of this disorder also in people with autism.
According to this, Ghaziuddin et al. (1995) have investigated the presence of inde-
pendent negative life events in two groups of children with pervasive developmen-
tal disorder (PDD) (11 patients with PDD and 11 patients with PDD and depression)
for a period of 12 months prior to onset of depression. Findings indicated that 82 %
of children with PDD and a comorbid depression had a history of recent unpleasant
life events as compared to 45 % of the group with PDD without depression.
Regarding bipolar disorders the symptoms that could strongly suggest their
occurrence in individuals with autism are manic and hypomanic signs (e.g., irrita-
ble, instable and dysphoric mood, excessive reactivity, hyperarousal, agitation,
flight of ideas, pressured speech, increase distractibility, poor judgment, intrusive-
ness, laughing, aggression, and noncompliance) (Lainhart and Folstein 1994; Joshi
et al. 2013; Skeppar et al. 2013; Vannucchi et al. 2014). In clinical practice it is
common to misinterpret affective signs as features of schizophrenia in patients with
ASD (Skeppar et al. 2013). Generally, it has to be considered that bizarre thoughts
are different from odd thinking and stereotypic ideas and feelings which are com-
mon in this clinical population. Even though in individuals with ASD these bizarre
ideas may become more pronounced and intense during manic episodes, these are
stable and preexisting since childhood (Vannucchi et al. 2014).
In order to make a correct distinction between these conditions, clinicians has to
consider that manic symptoms in autism (e.g., hyperarousal or excessive reactivity)
may simply be caused by impairments in social understanding, instead of being
clinical signs of co-occurring mood disorders (Mazzone et al. 2012). A recent study
has investigated the phenotypic and familial correlates of bipolar disorder when it
occurs with and without ASD in order to understand if these correlates of bipolar
disorder could be comparable despite the comorbidity with autism (Joshi et al.
2013). Results revealed that the phenotypic features of bipolar disorder were similar
in youth with and without ASD comorbidity, with an age of onset of bipolar disor-
der significantly earlier when there was a comorbidity with autism (Joshi et al.
2013). Thus, this study suggested that the phenotypic and familial correlates are
typical and specific of the bipolar disorder despite the presence of ASD comorbid-
ity. Similarly, Wozniak et al. (1997) investigating the overlap between mania and
PDD in a consecutive sample of referred youths found that 21 % of these children
reported both disorders. Moreover, supporting the independence of the two syn-
dromes, the autistic symptoms were identical in children with autism irrespective of
the comorbidity with mania (Wozniak et al. 1997). In addition, the clinical features
and the course of mania, such as irritable mood and chronic course, were similar in
manic children with and without autism (Wozniak et al. 1997). These results pro-
vide preliminary evidence of a peculiar clinical profile in children with both
conditions. However, further studies better characterizing the different clinical and
neurocognitive impairments experienced by youth with ASD with and without
bipolar disorder are needed in order to shed light on the different clinical character-
istics of these conditions and help clinicians in the diagnostic process.
4 Peculiar Features of Mood Disorders in ASD
4.1 Relation Between Cognitive Ability and Mood Symptoms

in Patients with ASD
Cognitive ability is a factor that seems to account the occurrence of a mood disorder
in autism. HFA are more likely to develop mood symptoms (Cassidy et al. 2014;
Ghaziuddin et al. 2002; Ghaziuddin and Greden 1998; Hofvander et al. 2009; Kim
et al. 2000; Lugnegãrd et al. 2011; Mazzone et al. 2013; Munesue et al. 2008;
Stahlberg et al. 2004; Sterling et al. 2008; Stewart et al. 2006; Vickerstaff et al.
2007; Whitehouse et al. 2009). A factor that can contribute to this higher rate is that
even if these individuals could be interested in social interaction, they may not have
the appropriate skills to successfully develop social relationships (Barnhill and
Smith 2001). Generally they report difficulties in social functioning, including
make friends and maintain peer relationship, thus experiencing loneliness (Brunstein
Klomek et al. 2007; Little 2002; Humphrey and Lewis 2008; Mazurek 2014;
Whitehouse et al. 2009). A recent study on the relationship between social function-
ing and depressive symptoms in children with HFA compared to a group of typi-
cally developing children reported that the former showed more maladaptive coping
strategies and poorer social functioning which were uniquely associated with more
symptoms of depression (Pouw et al. 2013). Therefore, a person with ASD and an
average or above-average cognitive ability probably experiences multiple failures in
different social contests (e.g., school, family, etc.). The experience of these social
failures can lead to a lower self-esteem, which, in turn, increases the risk for depres-
sion (Ozonoff et al. 2002).
A possible explanation of the lower occurrence of depression in individuals with
autism and ID is that the abilities to process and perceive these social failures as
negative experiences could be compromised in this clinical population; thereby the
risk to develop depressive symptoms is decreased.
Another possible hypothesis for the higher association of depressive symptoms
in HFA is that these individuals can misinterpret social situation since they are not
able to make inferences regarding own and others’ state of mind. These difficulties
seem to be particularly pronounced during adolescence, a developmental period in
which the social identification becomes essential (Simonoff et al. 2008; Sterling
et al. 2008). For instance, Strang et al. (2012) examining the relationship between
age, IQ, autism, and depressive symptoms in school-age children and adolescents
with ASD and an average IQ, through a parent-report questionnaire that investigates
behavioral problems (i.e., Child Behavior Checklist (CBCL)), reported that 30 % of
the sample was in the clinical range for depression.
4.2 Co-occurrence of Catatonia as an Exacerbation of Mood

Symptoms in ASD
Catatonia is a disorder of movement that can occur in the context of several psychi-
atric disorders and other medical conditions (American Psychiatric Association
2013). In the Diagnostic and Statistical Manual-5th edition (DSM-5), catatonia is
defined by the presence of 3 or more of 12 psychomotor features and is not consid-
ered as an independent disorder, but as a specifier for a mental disorder (i.e., neuro-
developmental disorder, psychotic disorder, depressive disorder, bipolar disorder, or
other mental disorders) or due to another medical condition (APA 2013). Currently,
literature studies suggest an increased recognition of catatonia as a comorbid disor-
der of ASD (Billstedt et al. 2005; Fink et al. 2006; Fink and Taylor 2003; Mazzone
et al. 2014; Takaoka and Takata 2007; Wing and Shah 2000). However, given the
overlap of symptoms between these conditions, such as mutism, stereotypic speech,
repetitive behaviors, echolalia, posturing, mannerisms, purposeless agitation, and
rigidity, in clinical practice it is difficult to make a correct distinction between cata-
tonia and ASD (Dhossche et al. 2006; Dhossche 2004; Mazzone et al. 2014). The
broad clinical presentation of catatonia symptoms, ranging from marked unrespon-
siveness to marked agitation, leads the recognition of this comorbidity in ASD even
more challenging. Generally, it should be taken into account that catatonia appears
at a later age than autistic symptoms, and an assessment of a comorbid catatonia in
patients with autism should be considered only if a change in type and pattern of
preexisting symptoms is observed (Mazzone et al. 2013; Wing and Shah 2000).
Although historically catatonia has been linked to schizophrenia, recent studies
have highlighted that in the majority of cases this syndrome involves individual with
mood disorders (i.e., depression and bipolar disorders) (Fink 2013; Fink et al. 2006;
Fink and Taylor 2003). Therefore, as in this clinical population, even in patients
with autism, catatonia could be an exacerbation of mood symptoms already present
(Mazzone et al. 2014). For instance, Fink et al. (2006) in a series of six case reports
with a history of autism and a comorbid catatonia suggested that catatonia in patients
with ASD can be thought of as the comorbidity with a mood disorder instead of a
separate disorder. Moreover, given that mood symptoms are difficult to recognize in
patients with ASD, the marked clinical presentation of catatonic presentation is
sometimes an easier and only way to identify previous mood alteration already pres-
ent in this clinical population.
5 Diagnosis and Evaluation: Assessment Tools
The assessment of mood symptoms in this clinical population is particularly com-

plex because of the reduced ability of these patients for introspection and problems
in communicating their personal state (Ghaziuddin et al. 2002; Lainhart 1999).
Regarding this last point, the recognition of comorbid mood disorders in individu-
als with ASD and ID is even more difficult because in this clinical population the
impairment of these abilities might be even higher. Currently, to our knowledge,
only four tools were specifically developed to assess comorbid psychopathology in

autism and tested in this clinical population: (1) Autism Comorbidity Interview-
Present and Lifetime Version (ACI-PL), a modification of the Kiddie-Schedule for
Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADS-PL)
to make it more appropriate for use in autism; (2) the Autism Spectrum Disorders-
Comorbidity for Children (ASD-CC), a 49-item rating scale designed to assess
symptoms of emotional difficulties which commonly occur in children with ASD;
(3) the Autism Spectrum Disorders-Comorbidity for Adults (ASD-CA), 84-item
scale designed to look at comorbid psychopathology in adults with ASD and ID;
and (4) the Psychopathology in Autism Checklist (PAC), a checklist discriminating
between autism and four major psychiatric disorders (i.e., psychosis, depression,
anxiety, and obsessive-compulsive disorder) (Helverschou et al. 2009; Kaufman
et al. 1997; Leyfer et al. 2006; Matson et al. 2009, Matson and Wilkins 2008;
Matson and Boisjoli 2003; Thorson and Matson 2012). However, these instruments
investigate psychiatric comorbidities in general, and to date diagnostic tools spe-
cifically created and validated to investigate the presence of mood disorders in
patients with ASD are still lacking. In fact, the instruments usually used are struc-
tured or semi-structured clinical interviews based on the DSM criteria, which
investigate multiple domains of psychopathology, including mood symptoms
(Kaufman et al. 1997; Mazzone et al. 2012, 2013; Shaffer et al. 2000; Spitzer et al.
1994; Welner et al. 1987). Furthermore, these diagnostic tools have been designed
and standardized referring to the general population and as such likely not appro-
priate for ASD (Mazzone et al. 2012, 2013). Parent-report questionnaires are also
often used, but these instruments only inquire about current symptoms (Achenbach
1991; Gracious et al. 2002). Self-report questionnaires have been widely used
(Allgaier et al. 2014; Beck et al. 1961; Brink et al. 1982; Esbensen et al. 2003;
Frühe et al. 2012; Hamilton 1960; Kovacs 1982; Radloff 1977; Young et al. 1978;
Zigmond and Snaith 1983). However, many items of these scales require metacog-
nitive abilities (e.g., such as awareness, self-awareness, and auto-consciousness)
which may be problematic for patients with ASD. Therefore, this issue makes these
tools not appropriate for this clinical population. For instance, the Children’s
Depression Inventory (CDI) is a self-report scale in which the child or the adoles-
cent has to choose among three options indicating increasing severity of depressive
symptoms, including the presence of negative mood, interpersonal difficulties,
negative self-esteem, and ineffectiveness (Kovacs 1982). Noticeable is that, in
order to rate the presence of these symptoms, the abilities to understand and report
own and others’ feeling and emotions should be unimpaired. However, even in
presence of average language and cognitive skills, autistic patients might have a
deficit in these competencies. Indeed, even clinician-rated instruments, such as the
Children’s Depression Rating Scale-Revised (CDRS-R), a 17-item clinical inter-
view for child, parent, and teacher investigating the severity of depressive symp-
toms, require intact metacognitive skills, including the ability to describe their
mental states, mental experiences, and daily life experiences (Leyfer et al. 2006;
Poznanski and Mokros 1996). Hence, this issue affects the sensitivity of these
instruments (Mazzone et al. 2012).
In fact, literature studies report a lack of correspondence between self-report

screeners and parent-reported psychiatric diagnosis that could be explained by the
metacognitive difficulties of autistic patients (Mazefsky et al. 2011).
In order to reduce the discrepancy created by these diagnostic issues, it is recom-
mended a deep evaluation of the history and development. Moreover, it is funda-
mental that the clinician gathers information from multiple sources (e.g., patents,
parents, teachers, etc.) and settings in order to have a complete picture of the patient
and distinguish between these conditions (Jepsen et al. 2012; Magnuson and
Constantino 2011; Mazzone et al. 2012, 2013).
6 Neurobiological Bases for the Relation Between ASD

and Mood Disorders
Shedding light on the neurobiological bases and defining the mechanisms underlying
autism and mood disorders is a crucial issue in order to delineate the distinct features
of these conditions. Analyzing the neurobiological systems can contribute to illustrate
which are the relations between these disorders. Even though abnormalities in brain
functioning and structures have been described either in autistic or mood disorder
patients, to our knowledge only one study compared brain structures (i.e., caudate
volume) in these clinical populations (Kerestes et al. 2013; Mazzone and Curatolo
2010; Voelbel et al. 2006; Wiggins et al. 2012; Zhang et al. 2014). Therefore, we
decided to focus this section on the genetic and biological basis of these disorders.
6.1 Genetic Overlap Between ASD and Mood Disorders
A growing body of evidences supports that both ASD and mood disorders are high
heritable genetic pathologies. Broad rates of association between these disorders
suggest that their genetic and biological basis could be partially shared or that a
common etiological pathway may exist (Magnuson and Constantino 2011; Munesue
et al. 2008; Ragunath et al. 2011; Scherff et al. 2014). However, to date, little is
known about the causes of the occurrence of mood disorders in autism. Several
researches have tried to clarify the relationship between ASD and mood disorders,
but only a few studies assessed the etiological factors associated between these dis-
orders within a genetic model and the available findings have shown contrasting
results (Ghaziuddin et al. 2002; Mazzone et al. 2012, 2013; Ragunath et al. 2011).
A recent study has identified common pathways and genes involved in ASD and
bipolar disorder using independently two different tools: consensus path database (a
molecular functional interaction database that integrates information from different
manually curated pathway on protein interaction, metabolism, genetic interaction
signaling, and gene regulation) and GeneGO pathway maps (an integrated func-
tional software suite for functional analysis of genetic data) were employed for the
analysis (Kamburov et al. 2009; Ragunath et al. 2011). These tools identified four
pathways common to both disorders: the synaptic transmission pathway, the
neuroactive ligand receptor interaction pathway, the circadian rhythm pathway, and
the catecholamine biosynthesis pathway. All these pathways are involved in several
functions, such as regulating stress or maintaining mood, implicated in both ASD
and bipolar disorder. Therefore, it has been suggested that the comorbidity of these
disorders can be correlated to the genes involved in the pathways shared by the two
disorders (Ragunath et al. 2011). Moreover, a recent genome-wide analysis for five
psychiatric disorders (i.e., ASD, major depressive disorder, bipolar disorder, atten-
tion deficit-hyperactivity disorder (ADHD), and schizophrenia) conducted by the
Psychiatric Genomics Consortium with the aim of identifying specific variants
underlying genetic effects shared between these disorders showed a reduced, but
still significant, overlap between aggregate genetic risk for ASD with schizophrenia
and bipolar disorder (Cross-Disorder Group of the Psychiatric Genomics Consortium
2013a). However, no significant polygenetic overlap was detected between ASD
and major depressive disorder or ADHD. On the other hand, another study per-
formed by the same research group and examining the genetic relationship between
these five psychiatric disorders estimated from genome-wide single-nucleotide
polymorphisms (SNPs) reported a low genetic correlation between ASD and schizo-
phrenia but nonsignificant correlations for ASD and the other three disorders
(Cross-Disorder Group of the Psychiatric Genomics Consortium 2013b).
Nonetheless, as stated by the authors of this study, it should be pointed out that the
sample sizes varied widely across the five psychiatric disorders; thus the nonsignifi-
cant associations could reflect a lack power to detect common associated variants of
small effect instead of the actual absence of this association.
Indeed, some studies have hypothesized a bidirectional influence between
autistic-like traits and internalizing symptoms (Hallett et al. 2010, 2012; Pine et al.
2008; Scherff et al. 2014; Towbin et al. 2005). For instance, Hallett et al. (2012) in
a community-based twin study investigated both phenotypic and etiological asso-
ciations between autistic-like traits and internalizing traits, in 7.311 twin pairs aged
7 and 8 years. Results showed a phenotypic correlation and a genetic association
between autistic-like traits (i.e., social difficulties, communication problems, and
repetitive/restricted behaviors) and internalizing traits (i.e., social anxiety, fears,
generalized anxiety, and negative affect). Considering that the majority of studies
suggest a genetic overlap between ASD and mood disorders, but the available find-
ings are still unclear, further researches are needed in order to identify specific
genes that can contribute to comorbidity. Shedding light on this issue could help to
develop novel management strategies and therapeutics techniques.
6.2 The Role of Serotonin in Autism and Mood Disorders
A pivotal role in the relationship between autism and mood disorders could be played
by serotonin (5-HT). This neurotransmitter influences many functions in the central
nervous system (CNS) and periphery system (e.g., regulating mood, sleep, food
intake, body temperature, arousal, moderating pain sensitivity, sleep, aggression,
affective, sexual behavior, and hormone release) and, during early stages, plays an
important role in brain development (Chugani 2002; Meyer 2013). Research studies
have reported that 5-HT is involved in the development of psychiatric disorders, and
in many of these disorders, including autism, depression, and bipolar disorders, a
dysregulation of the serotoninergic system has been described (Blier and El Mansari
2013; Chugani 2002; Jiang et al. 2013; Kepser and Homberg 2015). The role of the
5-HT system in the development of major depressive disorder has been widely
described through the studies on the therapeutic efficacy of antidepressant treatments
(Blier and El Mansari 2013). However, only little is known about the mechanism
underlying autism. Hyperserotonemia, that is, the increase of 5-HT in blood, is gen-
erally the most widely described change in individuals with autism, observed in one
third of this clinical population (Cook and Leventhal 1996; Coutinho et al. 2007;
Janusonis 2005; Kepser and Homberg 2015; Meyer 2013; Ramoz et al. 2006;
Veenstra-vanderweele et al. 2001). A recent review investigating the potential causes
of ASD suggests that elevated cortisol levels during pregnancy increase the expres-
sion of the serotonin reuptake transporter (SERT), consequently altering the sero-
tonin levels during gestation and modifying prenatal neuronal development in
children with ASD. Prenatal conditions that elevate cortisol levels, thus increasing
the risk for ASD, include hypertension, gestational diabetes, and depression (Meyer
2013). Thus, a possible prevention for autism could be the establishment of a stan-
dard protocol to measure cortisol levels during pregnancy. Indeed, given that depres-
sion can negatively influence the neurodevelopment of unborns and newborns,
treatment of this disorder is crucial. Selective serotonin reuptake inhibitors (SSRIs)
are the most frequently prescribed medication for the treatment of depression, even
for depressed pregnant and postpartum women (Nonacs and Cohen 2003).
Nonetheless, SSRIs increase 5-HT levels by inhibiting its reuptake, and prenatal and
postnatal SSRI exposures are indicated as risk factors for autism. For this reason non-
drug treatments, such as cognitive-behavioral therapy (CBT), could be a possible
strategy in order to prevent the risk of newborn affected by autism (Cuijpers et al.
2013; Strauss et al. 2014). Consequently, further studies on the efficacy of these
treatments in depressed pregnant women are essential in order to help clinicians to
choose the optimal treatment. Finally, a recent study supporting the important role of
5-HT in human affect and sociality in disorders like depression and autism proposed
an interaction between 5-HT and oxytocin (OXT) in areas of the brain important for
the regulation of emotion-based behaviors (Mottolese et al. 2014). Specifically, these
authors highlighted the role of OXT in the inhibitory regulation of 5-HT signaling,
thus suggesting that these neuromodulators should be considered in order to imple-
ment novel therapeutic strategies for these disorders.
7 Treatments
7.1 Non-medical Treatments
Some evidence is reported on the psychotherapy treatments for mood disorders in

ASD. Non-medical treatments for mood symptoms in autism have been focused on
the application of CBT interventions, implemented through individual- or group-

based settings (Brosnan and Healy 2011; Cardaciotto and Herbert 2004; Dawson
and Burner 2011; Kuroda et al. 2013; Reichow et al. 2012; Sofronoff et al. 2007;
Weiss and Lunsky 2010). However, its efficacy in treating depressive symptoms in
autistic individuals has only been studied to a limited extent.
The majority of interventions have been developed for the treatment of associ-
ated symptoms in individual with autism (i.e., aggression, impaired social skills,
theory of mind, or the improvement of emotion recognition and regulation) thus not
focused on mood symptoms (Brosnan and Healy 2011; Cardaciotto and Herbert
2004; Dawson and Burner 2011; Kuroda et al. 2013; Reichow et al. 2012; Sofronoff
et al. 2007). For instance, Kuroda et al. (2013) in a randomized control trial (RCT)
of CBT for emotion regulation in adults with ASD examined 60 adults with autism
and demonstrated the efficacy of CBT for improving the ability of these patients to
identify their own and others’ mental states. In line with these results, Sofronoff
et al. (2007) in a RCT on anger management in children with AS revealed the effi-
cacy of a small group CBT intervention to help children with autism with anger
control. Notice that recent researches have also described limitation of this therapy
for this clinical population. In fact, cognitive restructuring, which is one of the tech-
niques used in CBT interventions, is useful for understanding unhappy feelings and
moods and for challenging the sometimes-wrong “automatic beliefs” that can lie
behind them. However, the concept of cognitive restructuring could be very difficult
to learn for individuals with autism for their impairment in understand their own
mental states. Moreover, generalization to real-life situations of cognitive-behavioral
techniques is arduous. Mindfulness-based therapy (MBT) may also prove to be a
useful therapeutic technique to reduce depression in ASD populations (Hofmann
et al. 2010; Spek et al. 2013; Teasdale et al. 1995). Mindfulness has been defined as
paying attention to experiences in the present moment in a nonjudgmental and
accepting way, and its efficacy has been proved in treating patients with mood dis-
orders (Hofmann et al. 2010; Kabat-Zinn 1990; Teasdale et al. 1995). This method
encourages individuals to identify feelings or thoughts in the present moment and
accept them, as they appear without analysis or discussion, an approach that may be
well suited to those with theory of mind and communication deficits. Recently,
Spek et al. (2013) carried out a first RCT aimed at investigating the beneficial effect
of a MBT intervention in adults with ASD in treating comorbid affective symptoms.
The results of this study showed a reduction in depression and rumination and an
increase in positive affect in the intervention group as opposed to the control group,
thus supporting the importance to examine this technique in the treatment of comor-
bid depression in patients with ASD.
7.2 Pharmacological Interventions
Data on the pharmacological intervention in individuals with ASD and comorbid

mood disorders is scarce and consists only of case reports and open-label trials
(RCTs are lacking) (Frazier et al. 2002; Joshi et al. 2012; King 2000; Siegel et al.
2014; Vannucchi et al. 2014). Moreover, the majority of these studies have investi-
gated the effectiveness and tolerability of pharmacological treatments in treating
target symptoms frequently associated with autism and highly suggestive of a
comorbid mood disorder (i.e., irritability, self-injurious behaviors, severe tantrum,
and aggression) (Hellings et al. 2005; Hollander et al. 2010; Kimberly 2014; Kirino
2014). Currently, risperidone and aripiprazole are the only two medications
approved for these symptoms in autism (Findling et al. 2014; Marcus et al. 2009;
McDougle et al. 1997; Kimberly 2014; Politte et al. 2014; Stachnik and Nunn-
Thompson 2007). Regarding the effectiveness of other second-generation antipsy-
chotics (SGA) (i.e., quetiapine, olanzapine, and ziprasidone) for the treatment of
irritability associated with autism, the studies report inconsistent results (Kimberly
2014; Politte et al. 2014).
Lithium has been widely used as a mood stabilizer in autistic individuals, and
studies have supported the efficacy of this drug, especially, for manic symptoms
(Epperson et al. 1994; Frazier et al. 2002; Siegel et al. 2014). However, it has to be
noticed that the available findings on lithium in this clinical population are based
only on the limited literature data reported in case reports and case series.
Furthermore, among the mood-stabilizing anticonvulsants, the effects of divalproex
sodium have been widely examined and it has been suggested the efficacy of this
medication for the treatment of irritability and aggression in patients with autism
(Hollander et al. 2010; Kimberly 2014). Concerning tricyclic antidepressant (TCA)
and SSRI for treating depression in patients with ASD, the evidences are limited
and conflicting (Hurwitz et al. 2012; Vannucchi et al. 2014). Generally, when these
treatment options are used, the clinicians should be aware of their relevant side
effects, such as an increment of hyperactivity, aggression, and suicidal thoughts,
especially in children and adolescents, and a continuous monitoring of these medi-
cations is recommended.
Summarizing, when a patient with ASD and a comorbid mood disorder is unrespon-
sive or insufficiently responsive to non-medical treatments, a pharmacological interven-
tions can be explored. However, caution is warranted given that RCTs on medication in
this clinical population are lacking, and further research is needed on this topic.
8 Discussion and Future Directions
Further studies are needed on the prevalence rate of the co-occurrence of these
disorders. Indeed, shedding light on the phenomenology of mood symptoms in
this clinical population is a crucial issue given that the presence of comorbid dis-
orders seems to be a negative prognostic factor on outcome of patients with ASD
(Fein et al. 2013; Orinstein et al. 2014; Troyb et al. 2014). Indeed, the need of
proper screening tools specifically designed for this population and the study of
the mechanisms underlying these disorders have been described. Finally, given
the lack of RCT on medical and psychological treatments, longitudinal controlled
studies are essential in order to provide evidence-based guidelines for clinicians
and therapists.
References
Achenbach TM (1991) Child behavior checklist. Psychological Corporation, San Antonio
Allgaier AK, Krick K, Opitz A, Saravo B, Romanos M, Schulte-Körne G (2014) Improving early
detection of childhood depression in mental health care: the children’s depression screener
(ChilD-S). Psychiatry Res 217(3):248–252
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders,
5th edn. American Psychiatric Association, Washington, DC
Amr M, Raddad D, El-Mehesh F, Bakr A, Sallam K, Amin T (2012) Comorbid psychiatric disor-
ders in Arab children with autism spectrum disorders. Res Aut Spectrum Disord 6:240–248
Barnhill GP, Smith MB (2001) Attributional style and depression in adolescents with Asperger
syndrome. J Posit Behav Interv 3:175–182
Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J (1961) An inventory for measuring depres-
sion. Arch Gen Psychiatry 4:561–571
Billstedt E, Gilberg C, Gilberg C (2005) Autism after adolescence: population-based 13- to 22-year
follow-up study of 120 individuals with autism diagnosed in childhood. J Autism Dev Disord
35:351–360
Blier P, El Mansari M (2013) Serotonin and beyond: therapeutics for major depression. Philos
Trans R Soc Lond B Biol Sci 25(1615):368
Brereton AV, Tonge BJ, Einfeld SL (2006) Psychopathology in children and adolescents with
autism compared to young people with intellectual disability. J Autism Dev Disord
36(7):863–870
Brink TL, Yesavage JA, Lum O, Heersema PH, Adey M, Rose TL (1982) Screening tests for geri-
atric depression. Clin Gerontol 1:37–43
Brosnan J, Healy O (2011) A review of behavioral interventions for the treatment of aggression in
individuals with developmental disabilities. Res Dev Disabil 32:437–446
Brown GW, Harris TO (1989) Life events and illness. Guilford, New York
Brunstein Klomek A, Marrocco F, Kleinman M, Schonfeld IS, Gould MS (2007) Bullying, depres-
sion, and suicidality in adolescents. J Am Acad Child Adolesc Psychiatry 46(1):40–49
Cardaciotto L, Herbert JD (2004) Cognitive behavior therapy for social anxiety disorder in the
context of Asperger’s syndrome: a single-subject report. Cogn Behav Pract 11:75–81
Cassidy S, Bradley P, Robinson J, Allison C, McHugh M, Baron-Cohen S (2014) Suicidal ideation
and suicide plans or attempts in adults with Asperger’s syndrome attending a specialist diag-
nostic clinic: a clinical cohort study. Lancet Psychiatry 1:142–147
Chugani DC (2002) Role of altered brain serotonin mechanisms in autism. Mol Psychiatry 7(Suppl
2):S16–S17
Cook EH, Leventhal BL (1996) The serotonin system in autism. Curr Opin Pediatr
8(4):348–354
Coutinho AM, Sousa I, Martins M, Correia C, Morgadinho T, Bento C, Marques C, Ataíde A,
Miguel TS, Moore JH, Oliveira G, Vicente AM (2007) Evidence for epistasis between SLC6A4
and ITGB3 in autism etiology and in the determination of platelet serotonin levels. Hum Genet
121(2):243–256
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013a) Identification of risk loci
with shared effects on five major psychiatric disorders: a genome-wide analysis. Lancet
381:1371–1379
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013b) Genetic relationship
between five psychiatric disorders estimated from genome-wide SNPs. Nat Genet
45(9):984–994
Cuijpers P, Berking M, Andersson G, Quigley L, Kleiboer A, Dobson KS (2013) A meta-analysis
of cognitive-behavioural therapy for adult depression, alone and in comparison with other
treatments. Can J Psychiatry 58(7):376–385
Dawson G, Burner K (2011) Behavioral interventions in children and adolescents with autism
spectrum disorder: a review of recent findings. Curr Opin Pediatr 23:616–620
De Bruin EI, Ferdinand RF, Meester S, de Nijs PF, Verheij F (2007) High rates of psychiatric co-
morbidity in PDD-NOS. J Autism Dev Disord 37(5):877–886
Dhossche DM (2004) Autism as early expression of catatonia. Med Sci Monit 10(3):RA 31–RA 39
Dhossche D, Shah A, Wing L (2006) Blueprints for the assessment, treatment, and future study of
catatonia in autism spectrum disorders. Int Rev Neurobiol 72:267–284
Epperson CN, McDougle CJ, Anand A, Marek GJ, Naylor ST, Volkmar FR, Donald JC, Lawrence
HP (1994) Lithium augmentation of fluvoxamine in autistic disorder: a case report. J Child
Adolesc Psychopharmacol 4(3):201–207
Esbensen AJ, Rojahn J, Aman MJ, Ruedrich S (2003) Reliability and validity of an assessment
instrument for anxiety, depression, and mood among individuals with mental retardation.
J Autism Dev Disord 33(6):617–629
Fein D, Barton M, Eigsti IM, Kelley E, Naigles L, Schultz RT, Stevens M, Helt M, Orinstein A,
Rosenthal M, Troyb E, Tyson K (2013) Optimal outcome in individuals with a history of
autism. Child Psychol Psychiatry 54(2):195–205
Findling R, Mankoski R, Timko K, Lears K, McCartney T, McQuade RD, Eudicone JM, Amatniek
J, Marcus RN, Sheehan JJ (2014) A randomized controlled trial investigating the safety and
efficacy of aripiprazole in the long-term maintenance treatment of pediatric patients with irri-
tability associated with autistic disorder. J Clin Psychiatry 75(1):22–30
Fink M (2013) Rediscovering catatonia: the biography of a treatable syndrome. Acta Psych Scand
127(suppl 441):1–47
Fink M, Taylor M (2003) Catatonia: a clinician’s guide to diagnosis and treatment. Cambridge
University Press, Cambridge
Fink M, Taylor MA, Ghaziuddin N (2006) Catatonia in autistic spectrum disorders: a medical
treatment algorithm. Int Rev Neurobiol 72:233–244
Frazier JA, Doyle R, Chiu S, Coyle JT (2002) Treating a child with Asperger’s disorder and comor-
bid bipolar disorder. Am J Psychiatry 159(1):13–21
Frühe B, Allgaier AK, Pietsch K, Baethmann M, Peters J, Kellnar S, Heep A, Burdach S, von
Schweinitz D, Schulte-Körne G (2012) Children’s depression screener (ChilD-S): develop-
ment and validation of a depression screening instrument for children in pediatric care. Child
Psychiatry Hum Dev 43:137–151
Ghaziuddin M, Greden J (1998) Depression in children with autism/pervasive developmental dis-
order: a case-control family history study. J Autism Dev Disord 28(2):111–115
Ghaziuddin M, Alessi N, Greden JF (1995) Life events and depression in children with pervasive
developmental disorders. J Autism Dev Disord 25(5):495–502
Ghaziuddin M, Ghaziuddin N, Greden J (2002) Depression in persons with autism: implications
for research and clinical care. J Autism Dev Disord 32(4):299–306
Gotham K, Unruh K, Lord C (2014) Depression and its measurement in verbal adolescents and
adults with autism spectrum disorder. Autism 10.
Gracious BL, Youngstrom EA, Findling RL, Calabrese JR (2002) Discriminative validity of a parent
version of the young mania rating scale. J Am Acad Child Adolesc Psychiatry 41:1350–1359
Green J, Gilchrist A, Burton D, Cox A (2000) Social and psychiatric functioning in adolescents
with Asperger Syndrome compared with conduct disorder. J Autism Dev Disord
30(4):279–293
Hallett V, Ronald A, Rijsdijk F, Happé F (2010) Association of autistic-like and internalizing traits
during childhood: a longitudinal twin study. Am J Psychiatry 167(7):809–817
Hallett V, Ronald A, Rijsdijk F, Happé F (2012) Disentangling the associations between autistic-
like and internalizing traits: a community based twin study. J Abnorm Child Psychol
40(5):815–827
Hamilton M (1960) A rating scale for depression. J Neurol Neurosurg Psychiatry 23:56–62
Hammen C (2005) Stress and depression. Ann Rev Clin Psychol 1:293–319
Hedley D, Young R (2006) Social comparison processes and depressive symptoms in children and
adolescents with Asperger syndrome. Autism 10:139–153
Hellings JA, Weckbaugh M, Nickel EJ, Cain SE, Zarcone JR, Reese RM, Hall S, Ermer DJ, Tsai
LY, Schroeder SR, Cook EH (2005) A double-blind, placebo-controlled study of valproate for
aggression in youth with pervasive developmental disorders. J Child Adolesc Psychopharmacol

15(4):682–692
Helverschou SB, Bakken TL, Martinsen H (2009) The psychopathology in autism checklist (PAC):
a pilot study. Res Aut Spectrum Disord 3:179–195
Henry CA, Nowinski L, Koesterer K, Ferrone C, Spybrook J, Bauman M (2014) Low rates of
depressed mood and depression diagnoses in a clinic review of children and adolescents with
autistic disorder. J Child Adolesc Psychopharmacol 24(7):403–406
Hofmann SG, Sawyer AT, Witt AA, Oh D (2010) The effect of mindfulness-based therapy on anxi-
ety and depression: a meta-analytic review. J Consult Clin Psychol 78:169–183
Hofvander B, Delorme R, Chaste P, Nydén A, Wentz E, Ståhlberg O, Herbrecht E, Stopin A,
Anckarsäter H, Gillberg C, Råstam M, Leboyer M (2009) Psychiatric and psychosocial prob-
lems in adults with normal-intelligence autism spectrum disorders. BMC Psychiatry 10:9–35
Hollander E, Chaplin W, Soorya L, Wasserman S, Novotny S, Rusoff J, Feirsen N, Pepa L,
Anagnostou E (2010) Divalproex sodium vs placebo for the treatment of irritability in children
and adolescents with autism spectrum disorders. Neuropsychopharmacology 35(4):990–998
Humphrey N, Lewis S (2008) ‘Make me normal’: the views and experiences of pupils on the autis-
tic spectrum in mainstream secondary schools. Autism 12(1):23–46
Hurwitz R, Blackmore R, Hazell P, Williams K, Woolfenden S (2012) Tricyclic antidepressants for
autism spectrum disorders (ASD) in children and adolescents. Cochrane Database Syst Rev 3,
CD008372
Janusonis S (2005) Statistical distribution of blood serotonin as a predictor of early autistic brain
abnormalities. Theor Biol Med Model 19:2–27
Jepsen MJ, Gray KM, Taffe JR (2012) Agreement in multi-informant assessment of behaviour and
emotional problems and social functioning in adolescents with Autistic and Asperger’s
Disorder. Res Aut Spectrum Disord 6:1091–1098
Jiang HY, Qiao F, Xu XF, Yang Y, Bai Y, Jiang LL (2013) Meta-analysis confirms a functional
polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disor-
der in European populations. Neurosci Lett 549:191–196
Joshi G, Biederman J, Wozniak J, Doyle R, Hammerness P, Galdo M, Sullivan N, Williams C,
Brethel K, Woodworth KY, Mick E (2012) Response to second generation antipsychotics in
youth with comorbid bipolar disorder and autism spectrum disorder. CNS Neurosci Ther
18(1):28–33
Joshi G, Biederman J, Petty C, Goldin RL, Furtak SL, Wozniak J (2013) Examining the comorbid-
ity of bipolar disorder and autism spectrum disorders: a large controlled analysis of phenotypic
and familial correlates in a referred population of youth with bipolar I disorder with and with-
out autism spectrum disorders. J Clin Psychiatry 74(6):578–586
Kabat-Zinn J (1990) Full catastrophe living: using the wisdom of your body and mind to face
stress, pain, and illness. Delacourt, New York
Kamburov A, Wierling C, Lehrach H, Herwig R (2009) ConsensusPathDB-a database for integrat-
ing human functional interaction networks. Nucleic Acids Res 37(Database issue):D623–D628
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997)
Schedule for affective disorders and schizophrenia for school-age children-present and lifetime
version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry
36(7):980–988
Kepser LJ, Homberg JR (2015) The neurodevelopmental effects of serotonin: A behavioural per-
spective. Behav Brain Res 277:3–13
Kerestes R, Davey CG, Stephanou K, Whittle S, Harrison BJ (2013) Functional brain imaging
studies of youth depression: a systematic review. Neuroimage Clin 4:209–231
Kim J, Szatmari P, Bryson S, Streiner DL, Wilson FJ (2000) The prevalence of anxiety and mood
problems among children with autism and Asperger syndrome. Autism 4:117–132
Kimberly A (2014) Stigler psychopharmacologic management of serious behavioral disturbance
in ASD. Child Adolesc Psychiatr Clin N Am 23:73–82
King BH (2000) Pharmacological treatment of mood disturbances, aggression, and self-injury in
persons with pervasive developmental disorders. J Autism Dev Disord 30(5):439–445
Kirino E (2014) Efficacy and tolerability of pharmacotherapy options for the treatment of irritabil-
ity in autistic children. Clin Med Insights Paediatr 8:17–30
Kovacs M (1982) The children’s depression inventory: a self-rated depression scale of school-aged
youngsters. University of Pittsburgh School of Medicine, Pittsburgh
Kuroda M, Kawakubo Y, Kuwabara H, Yokoyama K, Kano Y, Kamio Y (2013) A cognitive-
behavioral intervention for emotion regulation in adults with high-functioning autism spectrum
disorders: study protocol for a randomized controlled trial. Trials 23(14):231
Lainhart JE (1999) Psychiatric problems in individuals with autism, their parents and siblings. Int
Rev Psychiatry 11:278–298
Lainhart JE, Folstein S (1994) Affective disorders in people with autism: a review of published
cases. J Autism Dev Disord 24:587–601
Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, Tager-Flusberg H, Lainhart JE
(2006) Comorbid psychiatric disorders in children with autism: interview development and
rates of disorders. J Autism Dev Disord 36:849–861
Little L (2002) Middle-class mothers’ perceptions of peer and sibling victimization among chil-
dren with Asperger’s syndrome and nonverbal learning disorders. Issues Compr Pediatr Nurs
25(1):43–57
Lugnegãrd T, Unenge Hallerbäck M, Gillberg C (2011) Psychiatric comorbidity in young adults
with a clinical diagnosis of Asperger syndrome. Res Dev Disabil 32(5):1910–1917
Magnuson KM, Constantino JN (2011) Characterization of depression in children with autism
spectrum disorders. J Dev Behav Pediatr 32(4):332–340
Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH, Aman MG (2009) A
placebo-controlled, fixed-dose study of aripiprazole in children and adolescents with irritabil-
ity associated with autistic disorder. J Am Acad Child Adolesc Psychiatry 48(11):1110–1119
Matson JL, Boisjoli JA (2003) Autism spectrum disorders in adults with intellectual disability and
comorbid psychopathology: scale development and reliability of the ASD-CA. Res Aut
Spectrum Disord 2:276–287
Matson JL, Wilkins J (2008) Reliability of the autism spectrum disorders-comorbidity for children
(ASD-CC). J Dev Phys Disabil 20:155–165
Matson JL, LoVullo SV, Rivet TT, Boisjoli JA (2009) Validity of the autism spectrum disorder-
comorbid for children (ASD-CC). Res Aut Spectrum Disord 3:345–357
Mattila ML, Hurtig T, Haapsamo H, Jussila K, Kuusikko-Gauffin S, Kielinen M, Linna SL,
Ebeling H, Bloigu R, Joskitt L, Pauls DL, Moilanen I (2010) Comorbid psychiatric disorders
associated with Asperger syndrome/high-functioning autism: a community and clinic-based
study. J Autism Dev Disord 40(9):1080–1093
Mazefsky CA, Kao J, Oswald DP (2011) Preliminary evidence suggesting caution in the use of
psychiatric self-report measures with adolescents with high-functioning autism spectrum dis-
orders. Res Aut Spectrum Disord 5(1):164–174
Mazurek MO (2014) Loneliness, friendship, and well-being in adults with autism spectrum disor-
ders. Autism 18(3):223–232
Mazzone L, Curatolo P (2010) Conceptual and methodological challenges for neuroimaging stud-
ies of autistic spectrum disorders. Behav Brain Funct 9:6–17
Mazzone L, Ruta L, Reale L (2012) Psychiatric comorbidities in Asperger syndrome and high
functioning autism: diagnostic challenges. Ann Gen Psychiatry 11(1):16
Mazzone L, Postorino V, De Peppo L, Fatta L, Lucarelli V, Reale L, Giovagnoli G, Vicari S (2013)
Mood symptoms in children and adolescents with autism spectrum disorders. Res Dev Disabil
34(11):3699–3708
Mazzone L, Postorino V, Valeri G, Vicari S (2014) Catatonia in patients with autism: prevalence
and management. CNS Drugs 28(3):205–215
McDougle CJ, Holmes JP, Bronson MR, Anderson GM, Volkmar FR, Price LH, Cohen DJ (1997)
Risperidone treatment of children and adolescents with pervasive developmental disorders: a
prospective open label study. J Am Acad Child Adolesc Psychiatry 36(5):685–693
Meyer RR (2013) A review of the serotonin transporter and prenatal cortisol in the development of
autism spectrum disorders. Mol Autism 4(1):37
Mottolese R, Redouté J, Costes N, Le Bars D, Sirigu A (2014) Switching brain serotonin with
oxytocin. Proc Natl Acad Sci U S A 111(23):8637–8642
Munesue T, Ono Y, Mutoh K, Shimoda K, Nakatani H, Kikuchi M (2008) High prevalence of
bipolar disorder comorbidity in adolescents and young adults with high-functioning autism
spectrum disorder: a preliminary study of 44 outpatients. J Affect Disord 111(2–3):
170–175
Myers K, Winters NC (2002) Ten-year review of rating scales. II: scales for internalizing disorders.
J Am Acad Child Adolesc Psychiatry 41:634–659
Nonacs R, Cohen LS (2003) Assessment and treatment of depression during pregnancy: an update.
Psychiatr Clin North Am 26(3):547–562
O’Brien G, Pearson J, Berney T, Barnard L (2001) Measuring behaviour in developmental dis-
ability: a review of existing schedules. Dev Med Child Neurol Suppl 87:1–72
Orinstein AJ, Helt M, Troyb E, Tyson KE, Barton ML, Eigsti IM, Naigles L, Fein DA (2014)
Intervention for optimal outcome in children and adolescents with a history of autism. J Dev
Behav Pediatr 35(4):247–256
Ozonoff S, Dawson G, McPartland J (2002) A parent’s guide to Asperger syndrome and high-
functioning autism. Guilford Press, New York
Pine DS, Guyer AE, Goldwin M, Towbin KA, Leibenluft E (2008) Autism spectrum disorder scale
scores in pediatric mood and anxiety disorders. J Am Acad Child Adolesc Psychiatry
47(6):652–661
Politte LC, Henry CA, McDougle CJ (2014) Psychopharmacological interventions in autism spec-
trum disorder. Harv Rev Psychiatry 22(2):76–92
Pouw L, Rieffe C, Stockmann L, Gadow KD (2013) The link between emotion regulation, social
functioning, and depression in boys with ASD. Res Aut Spectrum Disord 7:549–556
Poznanski EO, Mokros HB (1996) Children’s depression rating scale, revised (CDRS-R) manual.
Western Psychological Services Publishers and Distributors, Los Angeles
Radloff LS (1977) The CES-D scale: a self-report depression scale for research in the general
population. Appl Psychol Meas 1:385–401
Ragunath P, Chitra R, Mohammad S, Abhinand P (2011) A systems biological study on the comor-
bidity of autism spectrum disorders and bipolar disorder. Bioinformation 7(3):102–106
Ramoz N, Cai G, Reichert JG, Corwin TE, Kryzak L, Smith CJ, Silverman JM, Hollander E,
Buxbaum JD (2006) Family-based association study of TPH1 andTPH2 polymorphisms in
autism. Am J Med Genet B Neuropsychiatr Genet 141 B(8):861–7
Reichow B, Steiner AM, Volkmar F (2012) Social skills groups for people aged 6 to 21 with autism
spectrum disorders (ASD). Evid-Based Child Health 7:266–315
Rosenberg RE, Kaufmann WE, Law JK, Law PA (2011) Parent report of community psychiatric
comorbid diagnoses in autism spectrum disorders. Autism Res Treat. 405849
Scherff A, Taylor M, Eley TC, Happé F, Charman T, Ronald A (2014) What causes internalising
traits and autistic traits to co-occur in adolescence? A Community-Based Twin Study. J Abnorm
Child Psychol 42:601–610
Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000) NIMH diagnostic interview
schedule for children version IV (NIMH DISC-IV): description, differences from previous ver-
sions, and reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry
39(1):28–38
Siegel M, Beresford CA, Bunker M, Verdi M, Vishnevetsky D, Karlsson C, Teer O, Stedman A,
Smith KA (2014) Preliminary investigation of lithium for mood disorder symptoms in
children and adolescents with autism spectrum disorder. J Child Adol Psychopharmacol
24(7):399–402
Simonoff E, Pickles A, Charman T, Chandler S, Loucas T, Baird G (2008) Psychiatric disorders in
children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a
population-derived sample. J Am Acad Child Adolesc Psychiatry 47(8):921–929
Simonoff E, Jones CR, Pickles A, Happé F, Baird G, Charman T (2012) Severe mood problems
in adolescents with autism spectrum disorder. J Child Psychol Psychiatry 53(11):
1157–1166
Skeppar P, Thoor R, Sture A, Isakson A, Skeppar I, Persson B, Fitzgerald M (2013)

Neurodevelopmental disorders with comorbid affective disorders sometimes produce psychiat-
ric conditions traditionally diagnosed as schizophrenia. Clin Neuropsychiatr 10(3–4):
123–133
Sofronoff K, Attwood T, Hinton S, Levin I (2007) A randomized controlled trial of a cognitive
behavioural intervention for anger management in children diagnosed with Asperger syn-
drome. J Autism Dev Disord 37:1203–1214
Spek AA, van Hama NC, Nyklıcek I (2013) Mindfulness-based therapy in adults with an autism
spectrum disorder: a randomized controlled trial. Res Dev Dis 34:246–253
Spitzer RL, Williams JBW, Kroenke K, Linzer M, deGruy FVIII, Hahn SR et al (1994) Utility of
a new procedure for diagnosing mental disorders in primary care: the PRIME-MD 1000 study.
JAMA 272:1749–1756
Stachnik JM, Nunn-Thompson C (2007) Use of atypical antipsychotics in the treatment of autistic
disorder. Ann Pharmacother 41(4):626–634
Stahlberg O, Soderstrom H, Rastam M, Gillberg C (2004) Bipolar disorder, schizophrenia, and
other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disor-
ders. J Neural Transm 111(7):891–902
Sterling L, Dawson G, Estes A, Greenson J (2008) Characteristics associated with presence of
depressive symptoms in adults with autism spectrum disorder. J Autism Dev Disord
38(6):1011–1018
Stewart ME, Barnard L, Pearson J, Hasan R, O’Brien G (2006) Presentation of depression in
autism and Asperger syndrome: a review. Autism 10:103–116
Strang JF, Kenworthy L, Daniolos P, Case L, Wills MC, Martin A, Wallace GL (2012) Depression
and anxiety symptoms in children and adolescents with autism spectrum disorders without
intellectual disability. Res Autism Spectr Disord 6(1):406–412
Strauss C, Cavanagh K, Oliver A, Pettman D (2014) Mindfulness-based interventions for people
diagnosed with a current episode of an anxiety or depressive disorder: a meta-analysis of ran-
domized controlled trials. PLoS One 9(4), e96110
Takaoka K, Takata T (2007) Catatonia in high-functioning autism spectrum disorders: case report
and review of literature. Psychol Rep 101:961–969
Tantam D (2000) Psychological disorder in adolescents and adults with Asperger syndrome.
Autism 4:47–62
Teasdale JD, Segal ZV, Williams MG (1995) How does cognitive therapy prevent depressive
relapse and why should attentional control (mindfulness training) help? Behav Res Ther
33:25–39
Thorson RT, Matson J (2012) Cutoff scores for the autism spectrum disorder – comorbid for chil-
dren (ASD-CC). Res Aut Spectrum Disord 6:556–559
Towbin KE, Pradella A, Gorrindo T, Pine DS, Leibenluft E (2005) Autism spectrum traits in chil-
dren with mood and anxiety disorders. J Child Adol Psychopharmacol 15(3):452–464
Troyb E, Orinstein A, Tyson K, Helt M, Eigsti IE, Stevens M, Fein D (2014) Academic abilities in
children and adolescents with a history of autism spectrum disorders who have achieved opti-
mal outcomes. Autism 18:233–243
Vannucchi G, Masi G, Toni C, Dell’Osso L, Erfurth A, Perugi G (2014) Bipolar disorder in adults
with Asperger’s syndrome: a systematic review. J Affect Disord 168:151–160
Veenstra-vanderweele J, Kim S, Lord C, Courchesne R, Akshoomoff N, Leventhal BL, Courchesne
E, Cook EH Jr (2001) Transmission disequilibrium studies of the serotonin 5-HT 2A receptor
gene (HTR2A) in autism. Am J Med Genet 114(3):277–283
Vickerstaff S, Heriot S, Wong M, Lopes A, Dossetor D (2007) Intellectual ability, self-perceived
social competence and depressive symptomatology in children with high-functioning autistic
spectrum disorders. J Autism Dev Disord 37(9):1647–1664
Voelbel GT, Bates ME, Buckman JF, Pandina G, Hendren RL (2006) Caudate nucleus volume and
cognitive performance: are they related in childhood psychopathology? Biol Psychiatry
60(9):942–950
Weiss JA, Lunsky Y (2010) Group cognitive behaviour therapy for adults with Asperger syndrome
and anxiety or mood disorder: a case series. Clin Psychol Psychother 17(5):438–446
Weissman A, Bates ME (2010) Increased clinical and neurocognitive impairment in children with
autism spectrum disorders and comorbid bipolar disorder. Res Aut Spectrum Disord
4:670–680
Welner Z, Reich W, Herjanic B, Jung KG, Amado H (1987) Reliability, validity, and parent-child
agreement studies of the diagnostic interview for children and adolescents (DICA). J Am Acad
Child Adolesc Psychiatry 26(5):649–653
Whitehouse AJ, Durkin K, Jacquet E, Ziatas K (2009) Friendship, loneliness and depression in
adolescents with Asperger’s syndrome. J Adolesc 32(2):309–322
Wiggins JL, Peltier SJ, Bedoyan JK, Carrasco M, Welsh RC, Martinet DM, Lord C, Monk CS
(2012) The impact of serotonin transporter genotype on default network connectivity in chil-
dren and adolescents with autism spectrum disorders. Neuroimage Clin 2:17–24
Williamson S, Craig J, Slinger R (2008) Exploring the relationship between measures of self-
esteem and psychological adjustment among adolescents with Asperger syndrome. Autism
12(4):391–402
Wing L (1996) The autistic spectrum: a guide for parents and professionals. Constable, London
Wing L, Shah A (2000) Catatonia in autistic spectrum disorders. Br J Psychiatry 176:357–362
Wozniak J, Biederman J, Faraone S, Frazier J, Kim J, Millstein R, Gershon J, Thornell A, Cha K,
Snyder JB (1997) Mania in children with pervasive developmental disorder, revisited. J Am
Acad Child Adolesc Psychiatry 36(11):1552–1559
Young RC, Biggs JT, Ziegler VE, Meyer DA (1978) A rating scale for mania: reliability, validity
and sensitivity. Br J Psychiatry 133:429–435
Zhang H, Chen Z, Jia Z, Gong Q (2014) Dysfunction of neural circuitry in depressive patients with
suicidal behaviors: a review of structural and functional neuroimaging studies. Prog
Neuropsychopharmacol Biol Psychiatry 53:61–66
Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand
67:361–370
Anxiety in Autism Spectrum
Disorder 2
Mirko Uljarevic, Heather Nuske, and Giacomo Vivanti
1 Introduction
Anxiety has been linked to autism spectrum disorder (ASD) since Leo Kanner and
Hans Asperger first described this condition seven decades ago. Kanner (1943)
provides a detailed report on a child whose behavior was “governed by an anx-
iously obsessive desire for the maintenance of sameness.” For example, he would
get very anxious if furniture was moved around, but then his anxiety would sud-
denly disappear when things were rearranged as they were previously. Other chil-
dren described by Kanner would experience anxiety in response to loud sounds or
mechanical noises. Asperger (1944) mentions anxiety in a different context, report-
ing that some of his patients would feel anxious as a consequence of being merci-
lessly bullied at school.
Clarifying the nature of the link between autism and anxiety is currently consid-
ered to be a priority in the field, as anxiety issues can interfere drastically with the
ability to participate in home, school, and community activities, and might impact
on the child and family well-being and quality of life above and beyond the core
symptoms of ASD (Davis III et al. 2014; Pellecchia et al. 2015).
M. Uljarevic
La Trobe University, Melbourne, Australia
H. Nuske
University of Pennsylvania, Philadelphia, USA
G. Vivanti (*)
AJ Drexel Autism Institute, Drexel University, Philadelphia, USA

22 M. Uljarevic et al.
2 Prevalence
The existing research shows that individuals with ASD exhibit higher levels of anxi-
ety compared to both typically developing individuals (Kim et al. 2000; Bellini
2004; Gadow et al. 2005; Lopata et al. 2010) and individuals from other clinical
groups, including Down syndrome (Evans et al. 2005), conduct disorder (Green
et al. 2000), specific language impairment (Gillott et al. 2001), Williams syndrome
(Rodgers et al. 2012a), and learning disabilities (Gadow et al. 2005; Gillot and
Standen 2007). Additionally, there is evidence that individuals with ASD experi-
ence anxiety levels that are comparable to those of clinically anxious non-ASD
individuals (Russell and Sofronoff 2005; Farrugia and Hudson 2006).
Reported prevalence of anxiety in ASD has varied widely, with estimates rang-
ing from 13.6 to 84.1 % (Bellini 2004; Bradley et al. 2004; Kim et al. 2000; Muris
et al. 1998; Lidstone et al. 2014). A recent systematic review (van Steensel et al.
2011) has identified that clinically significant levels of anxiety were present in
39.6 % of a pooled sample of 2,121 individuals with ASD obtained from 31 studies.
Although findings are inconsistent, the most frequent anxiety disorders in ASD
appear to be specific phobias, generalized anxiety disorder, separation anxiety dis-
order, obsessive-compulsive disorder, and social phobia (Muris et al. 1998; Evans
et al. 2005; Gadow et al. 2005; Weisbrot et al. 2005; de Bruin et al. 2007; Gillot and
Standen 2007; Sukhodolsky et al. 2008).
In conclusion, anxiety appears to be more common in ASD than in both the gen-
eral population and various clinical groups, with possibly up to 40 % of individuals
in the autism spectrum presenting elevated levels of at least on anxiety subtype.
In many autobiographical accounts of individuals with ASD, the experience of

feeling anxious is described with reference to symptoms and feelings that resem-
ble those occurring in the typical population. For example, Temple Grandin
(1992) reports, “The feeling [of anxiety] was like a constant feeling of stage
fright all the time. I had a pounding heart, sweaty palms, and restless movements.
(…) For weeks I had horrible bouts of colitis. (…) I started waking up in the
middle of the night with my heart pounding.” Nevertheless, the manifestation of
anxiety in ASD might present differently from its expression in individuals with-
out an ASD or might be less apparent. Several factors might underlie these
differences.
First, manifestations of the core features of ASD and anxiety symptoms overlap
frequently, and this can make anxiety symptoms “invisible” (Kerns and Kendall
2014; Renno and Wood 2013). For example, social avoidance/withdrawal can be an
expression of anxiety as well as a manifestation of the social communication impair-
ment that characterizes ASD. Similarly, ritualistic behaviors are a known manifesta-
tion of anxiety but also an expression of the restricted and repetitive features that are
pathognomonic of ASD. Therefore, an anxiety disorder that manifest with social
2 Anxiety in Autism Spectrum Disorder 23
avoidance and ritualistic behaviors, while easily identifiable in a child without ASD,
can easily pass unnoticed in a child with ASD.
Additionally, even when manifestations of anxiety do not overlap with ASD
symptoms, they can be less noticeable in the context of the clinical variability
observed in ASD. As the range of behavioral manifestations associated with ASD is
extremely large and heterogeneous, any atypical behavior in this population can be
mistakenly interpreted as being a consequence of having ASD (for an example of
diagnostic overshadowing, see Kanne 2013). For example, the presence of restless-
ness and phobias (two symptoms of anxiety that do not overlap with the character-
istic features of ASD) in a child who has severe ASD might be seen as a behavioral
manifestation of ASD, rather than anxiety (Helverschou and Martinsen 2011; Kerns
et al. 2015).
Furthermore, individuals with ASD might present with idiosyncratic anxiety
symptoms. For example, recent research (Mayes et al. 2013; Kerns and Kendall
2014) documented a high proportion of atypical anxiety symptoms, including
unusual specific phobias (e.g., vacuum cleaners, toilets) and fears of change/nov-
elty. However, it is unclear whether such symptoms are manifestations of anxiety or
reflect aspects of the core symptoms of ASD.
Communication difficulties further complicate the picture, as many individuals
with ASD do not have the communication skills necessary to express their experi-
ence of distress or discomfort verbally. This both affects the overt manifestations of
anxiety and limits the possibility to ascertain the presence of anxiety symptoms, in
particular in minimally verbal children.
In summary, despite the high prevalence of anxiety in the ASD population, there
is still uncertainty in the field on how to best define the clinical presentation of anxi-
ety in individuals with ASD. This reflects the clinical issues discussed above (over-
lap between core symptoms of the two conditions, diagnostic overshadowing,
atypical symptoms that encompass elements of both conditions, and impact of core
ASD impairments in symptom expression), as well as current lack of knowledge on
the causal relationship between ASD and anxiety. The increased risk for anxiety in
individuals with ASD might reflect a number of different scenarios (Mazefsky and
Herrington 2014; Weisbrot et al. 2005; Wood and Gadow 2010). First, it is possible
that individuals with ASD are anxious as the inevitable consequence of having to
cope with social demands that are beyond their level of understanding. The difficul-
ties in core social cognition processes such as mindreading (Baron-Cohen 1997)
and action understanding (Vivanti et al. 2011), as well as in social-affiliative behav-
iors such as establishing and maintaining social relationships, might result in per-
ceiving the social world as unpredictable, confusing, and ultimately
anxiety-provoking. Other factors that might lead to increased risk for anxiety in
ASD include restrictions to self-determination that are often experienced especially
in lower functioning individuals (Carter et al. 2013) and peer rejection encountered
by higher functioning individuals who are motivated by the desire of friendships
and relationships. Moreover, hypersensitivity to sensory stimuli (e.g., loud noises)
might lead to the development of aversion and subsequent phobic responses to situ-
ations (e.g., dogs barking, balloons popping, vacuum cleaners) that would not
normally trigger such reactions in typical peers. While there is evidence supporting
this scenario (Wood and Gadow 2010; Hollocks et al. 2014) if anxiety is the inevi-
table consequence of having ASD, then is not clear why not all individuals with
ASD have anxiety.
An alternative explanation is that features that are not specific or pathognomonic
of ASD, but co-occur frequently in this population, confer the increased risk of
anxiety in ASD. For example, intellectual disability, depression, tic disorders, and
obsessive-compulsive disorder are frequently associated both with ASD and anxi-
ety. Issues in emotional regulation, which are very frequent in ASD, might also play
a relevant role (Mazefsky et al. 2013). Thus the occurrence of anxiety in this popu-
lation is likely to reflect the interplay between different, co-occurring risk factors.
Finally, it is possible that ASD and anxiety share a common etiology (see section
on Neurobiological Bases (Sect. 6)).
4 Correlates of Anxiety in ASD
In the typical population, the presentation of anxious symptoms is tied to normative

developmental periods and the challenges they bring (Warren and Sroufe 2004). It is
therefore expected that separation anxiety and phobias of animals should be pre-
dominant in children aged 6–9 years, generalized anxiety symptoms and phobias
regarding danger and death in children aged 10–13 years, and social anxiety in ado-
lescents around ages 14–17 years. Several studies have supported this model. For
example, Kashani and Orvaschel (1990) looked at the fear of social situations across
three age groups. In a group of 8-year-old children, fear of social situations was
reported in approximately 21.4 %; this rate increased to 45.75 % of 12 year olds and
to 55.7 % of 17 year olds. Furthermore, “worrying about what others think about me”
was reported by 38.6 % of 8 year olds and increased to 67.1 % in 12 and 17 year olds.
Following these findings, several studies have examined the role of age and
developmental level in the expression of anxiety in autism, with some studies
reporting that higher levels of anxiety are associated with cognitive ability (Weisbrot
et al. 2005; Lecavalier et al. 2006; Mazurek and Kanne 2010) and increased age
(Kuusikko et al. 2008; Davis III et al. 2010; Green et al. 2012). However, other stud-
ies have failed to find associations between anxiety, cognitive level (Mazefsky et al.
2011; Strang et al. 2012), and chronological age (e.g., Strang et al. 2012). It is
important to emphasize that existing literature has predominantly focused on
school-aged children and adolescents, with only few studies examining anxiety in
very young children (Davis III et al. 2011a; Matson et al. 2010; Green et al. 2012)
and adult populations (Bejerot et al. 2014; Gillott and Standen 2007). A recent study
by Davis III et al. (2011a) compared the levels of anxiety in 131 toddlers (aged
17–36 months), children (aged 3–16 years), and adults (aged 20–65 years) diag-
nosed with ASD and found that anxiety increases from toddlerhood to childhood,
decreases from childhood to young adulthood, but again increases from young
adulthood into older adulthood. Although the study by Davis and colleagues pro-
vides an initial insight into how anxiety might change over the lifespan in
individuals with ASD, it is necessarily limited by the use of different anxiety mea-
sures for different age groups and more importantly by its cross-sectional design.
Studies examining the relationship between overall autism severity and anxiety
have yielded mixed results, with Mazurek and Keane (2010) finding a significant
negative association between autism severity and anxiety levels and Lopata et al.
(2010) reporting no significant association.
Although research on anxiety in non-ASD populations has consistently shown a
link between impairments in language and communication and levels of anxiety
(Beitchman et al. 2001; Bornstein et al. 2013), only a handful of studies have exam-
ined the relationship between the social communication impairments and anxiety in
ASD, consistently reporting that anxiety symptoms are more common in children
with stronger communication abilities (Davis III et al. 2011b, 2012; Sukhodolsky
et al. 2008; Kerns et al. 2015). However, several authors (e.g., Strang et al. 2012;
Sukhodolsky et al. 2008; Tsai 1996) have suggested that lower levels of anxiety in
minimally verbal children with ASD might be a consequence of difficulties in com-
municating anxious symptoms rather than a true reflection of lower levels of anxiety
in this subgroup.
In a recent study, Kerns et al. (2015) reported that individuals with ASD and co-
occurring anxiety displayed more self-injury and depression than those with ASD
alone. In the same study, co-occurring anxiety was associated with high levels of
parental stress. Finally, studies in this field have consistently reported that elevated
levels of anxiety are associated with both increased sensory modulation problems
(Ben-Sasson et al. 2008; Green et al. 2012; Lidstone et al. 2014; Mazurek et al.
2013) and higher levels of repetitive behaviors (Sukhodolsky et al. 2008; Rodgers
et al. 2012a, b; Gotham et al. 2013).
The diagnosis of anxiety disorders in people with ASD is complicated by a number

of factors. Firstly, as approximately 30 % of individuals with autism remain mini-
mally verbal throughout their lifespan (Tager-Flusberg and Kasari 2013), ascertain-
ment of anxiety symptoms in this subgroup must rely on information provided by
parents, teachers, or other caregivers. Since secondhand accounts of anxious
thoughts or behavior can be problematic due to common misconceptions or biases
of the reporter, diagnosticians should exercise a healthy level of caution when inter-
preting this information. For example, repetitive patterns of play in a child with
ASD may appear to their parent as a symptom of obsessive-compulsive disorder
(OCD), though children with ASD usually enjoy engaging in these behaviors,
whereas those with OCD do not (Turner-Brown et al. 2011).
Challenges exist also with respect to self-reports from verbally fluent people
with autism, due to difficulties in interoception (the sense of one’s own physiologi-
cal state) as well as difficulties in verbal expression of emotional states, one aspect
of alexithymia, which is present in 40–65 % of individuals with ASD (Berthoz and
Hill 2005; Hill et al. 2004). Nevertheless, self-reports from the individual affected
are an important source of information in assessing symptoms and tailoring treat-

ment strategies on individual needs.
Use of behavioral monitoring and, where possible, direct observation is recom-
mended to supplement self- or other reports of anxiety. Behavioral monitoring has
the advantage of tracking the triggers of anxiety for a particular individual in natural
settings and has been used in children without ASD (e.g., Hagopian et al. 1990).
Where a specific trigger is known, direct observation may include a behavioral
avoidance test (Dadds et al. 1994), a method which involves systematically assess-
ing avoidant behavior associated with a particular phobia-inducing stimulus.
Therefore, as with any diagnosis, diagnoses of anxiety in ASD are likely to be more
accurate when information is integrated across multiple sources.
A second source of complexity in assessing anxiety in people with ASD is the
already mentioned degree of overlap in behavioral symptoms between the two dis-
orders, despite the distinction in their function and phenomenology.
Due to this apparent overlap in symptoms, there has been an effort over the last
decade to design ASD-specific diagnostic and evaluation tools for anxiety disorders
which examine the particular way in which these symptoms arise, manifest, and are
maintained in ASD, including potentially unique contributions of sensory sensitivi-
ties, inherent difficulties in negotiating social interactions, and difficulties regulat-
ing emotions and behavior. For example, the Autism Comorbidity Interview (ACI;
Leyfer et al. 2006) includes questions to establish the child’s emotions and behavior
at his/her best in order to establish a baseline. Another approach is to use diagnostic
and evaluation protocols for anxiety disorders designed for other populations to
diagnose anxiety in individuals with ASD. However, large-scale studies on the psy-
chometric properties of such measures when applied to ASD populations are lack-
ing and the overlap in symptoms may cause a clinician to make incorrect inferences
on the person with ASD’s scores on such measures. Tools that are currently used to
assess anxiety symptoms in ASD are listed in Table 2.1. As only few of these instru-
ments are designed specifically for use in ASD, and for some the reliability and
validity is yet to be established in the full range of anxiety disorders, more research
in this area is needed to establish best practices in evaluating the presence and sever-
ity of anxiety features occurring in ASD.
This reinforces the need for a multi-method analysis of anxiety in ASD, includ-
ing parental, caregiver, and/or teacher report and direct observation. Future research
should investigate the feasibility of adding physiological measures such as heart
rate and skin conductance response as an additional source of information in diag-
nostic and assessment protocols.
6 Neurobiological Bases of Anxiety in ASD
The very few studies that have directly explored neural correlates of anxiety in
ASD have exclusively focused on the potential role of amygdala dysregulation.
Kleinhans et al. (2010) found that increased levels of social anxiety were associated
with increased activation of right amygdala during an emotion recognition task.
2
Table 2.1 Anxiety Assessment Tools

Name (reference) Reporter Sub-scales Designed for ASD? Age group
Autism Comorbidity Interview- Parent version Panic disorders, separation Yes and has been used in some 5–17 years
Present and Lifetime Version anxiety, social phobia, specific studies (e.g., Leyfer et al. 2006;
(ACI-PL; Leyfer et al. 2006) phobia, generalized anxiety, and Mazefsky et al. 2011; Mazefsky
OCD et al. 2012)
Anxiety Disorder Interview Parent and child DSM-IV referenced scales No, but studies on ASD have been 6–17 years
Schedule for DSM-IV-Child versions available conducted (e.g., Storch et al. 2012;
and Parent Versions (ADIS; Chalfant et al. 2007; Drahota et al.
Silverman and Albano 1996) 2011; Sze and Wood 2007, 2008;
White et al. 2009; Wood et al. 2009)
Diagnostic Interview Schedule Parent version Simple phobia, social phobia, No, but studies on ASD have been Parent: 6–17 years
for Children IV (DISC IV; agoraphobia, panic disorder, conducted (e.g., Leyfer et al. 2006; Child: 11–17 years
Anxiety in Autism Spectrum Disorder
Shaffer et al. 2000) separation anxiety disorder, Muris et al. 1998)

avoidant disorder of childhood or
adolescence, overanxious disorder,
and obsessive-compulsive disorder
Baby and Infant Screen for Parent version Part 1 and part 3 evaluate the Yes and has been used in some 17–37 months
Children with Autistic Traits symptoms of ASD and studies (e.g., Davis et al. 2010,
(BISCUIT; Matson, Boisjoli, externalizing symptoms, 2011a; Matson et al. 2010)
and Wilkins 2007) respectively. Part 2 assesses
comorbid psychopathology
including an anxiety/repetitive
scale, among others
Autism Spectrum Disorders- Parent version Worry/depressed, among other Yes and has been used in some 3–16 years
Comorbid for Children scales studies (e.g., Davis et al. 2011a, b;
(ASD-CC; Matson and Hess et al. 2010; Worley and Matson
Gonzalez 2007; 2010)
Matson and
Wilkins 2008)
27
(continued)
Table 2.1 (continued)
28

Behavioral Assessment System Parent, teacher, Anxiety, somatization, and No, but ASD norms included and Preschool, 2–5 years;
for Children-2 (BASC-2; and self-report internalizing, among other scales studies on ASD have been conducted child, 6–11 years; and
Reynolds and Kamphaus 2004) (e.g., Bellini 2004; Burnette et al. adolescent,
2005; Meyer et al. 2006; Solomon 12–21 years
et al. 2008; Lopata et al. 2010)
Spence Children’s Anxiety Parent and child Generalized anxiety, social No, but studies on ASD have been 7–19 years/3–6 years
Scale (SCAS)/Spence versions available anxiety, obsessive-compulsive conducted (e.g., Murris et al. 1998;
Preschool Anxiety Scale disorder, physical injury fears, and Gillott et al. 2001; Russell and
(Spence 1998) separation anxiety Sofronoff 2005; Chalfant et al. 2007;
Greenway and Howlin 2010)
Screening for Childhood Parent and child Somatic/panic, generalized No, but a study on ASD has been 8–18 years
Anxiety and Related Emotional versions available anxiety, separation anxiety, and conducted (e.g., Reaven et al. 2012)
Disorders (SCARED; Birmaher social phobia
et al. 1997, 1999)
Early Child Inventory-5 Parent and teacher Generalized anxiety disorder, No, but studies on ASD have been 3–5 years
(ECI-5; Gadow and Sprafkin versions available separation anxiety disorder, social conducted (e.g., Weisbrot et al.
1997) phobia, posttraumatic stress 2005)
disorder, simple phobia, OCD
Multidimensional Anxiety Parent and child Somatic/panic, general anxiety, No, but studies on ASD have been 4–19 years
Scale for Children (MASC; versions available separation anxiety, social phobia, conducted (e.g., Bellini 2004, 2006;
March et al. 1997) and school phobia Sze and Wood 2008; White et al.
2009; Wood et al. 2009)
Child Behavior Checklist Parent, teacher, Internalizing, anxious/depressed, No, but studies on ASD have been 1.5–5 years, 6–18 years
(CBCL; Achenbach and and child versions somatic complaints, anxiety conducted (e.g., Juranek et al. 2006;
Rescorla 2001): available problems, somatic problems, Kuusikko et al. 2008; Sze and Wood
among other scales 2008)
M. Uljarevic et al.
2

Diagnostic Assessment for the Parent version Overall anxiety scale, among other 33–80 years
Severely Handicapped-II scales
(DASH-II; Matson 1996)
Revised Children’s Anxiety Self-report Major depressive disorder, panic No, but studies on ASD have been 6–18 years
and Depression Scale disorder, social phobia, separation conducted (e.g., Hallet et al. 2013;
(RCADS; Chorpita et al. 2005) anxiety disorder, generalized Sterling et al. 2015)
anxiety disorder, and obsessive-
compulsive disorder
Psychopathology in Autism Staff/caregiver Overall anxiety scale, among other Yes 17–56 years
Checklist (PAC; Helvershou scales
et al. 2009)
Anxiety in Autism Spectrum Disorder
29
Juranek et al. (2006) reported that increased total and right (but not left) amygdala
volume was associated with higher levels of anxiety (as measured by the Anxious/
Depressed subscale of the Child Behavior Checklist) in a sample of 49 individuals
with ASD (mean chronological age, 7 years and 11 months; range, 3 years and
8 months to 14 years and 8 months).
As the neurobiology of ASD is still poorly understood, it is informative to turn
to the large body of work that has explored the role of certain brain structures in the
development and maintenance of anxiety in non-ASD populations. A large network
of brain structures are involved in fear and anxiety (see Paulus and Stein 2006; Shin
and Liberzon 2010 for excellent overviews). Among these, the amygdala, ventro-
medial prefrontal cortex, hippocampus, and insula play a critical role, both sepa-
rately and through their complex set of mutual connections, in the processes of
threat detection, emotional learning, interceptive awareness, and monitoring that
have been suggested to be impaired in anxiety disorders.
Dysregulation of these brain structures might be linked to anxiety in ASD, as
structural and functional abnormalities in the amygdala, hippocampus, ventrome-
dial prefrontal cortex, and insula have been reported in ASD across a number of
research studies and investigation techniques, including postmortem exploration
(Bauman and Kempler 1985), structural neuroimaging (Aylward et al. 1999; Sparks
et al. 2002), and functional neuroimaging (Dalton et al. 2005). Inconsistencies exist
with respect to the nature of such abnormalities, with some studies finding enlarged
amygdala volume (Howard et al. 2000; Sparks et al. 2002) and overactivity (Dalton
et al. 2005) and other reduced volume (Aylward et al. 1999; Pierce et al. 2001) and
hypo-activity (Green et al. 2000; Muris et al. 1998). Furthermore, studies have sug-
gested structural and functional abnormalities of prefrontal cortical areas (see
Kaiser et al. 2010) and insula (Menon and Udin 2010) in ASD. Despite this sugges-
tive evidence, the role of these regions, individually and especially in terms of pat-
terns of connectivity, has not been fully explored, and our understanding of the
neurobiology of anxiety in ASD is currently indirect and limited.
7 Treatment of Anxiety in ASD
The most commonly used nonmedical treatments for anxiety disorders in ASD are
those rooted in cognitive behavioral therapy (CBT). The Coping Cat series of inter-
ventions for children, adolescents, and adults with anxiety has been shown to be
effective (Kendall 1994), with results maintained at 1 and 7 years post treatment
(Kendall et al. 2008). An adapted version of this program has recently been applied
to high-functioning youth with ASD with comparable efficacy (McNally Keehn
et al. 2013), showing the promise of CBT-based strategies for treatment of anxiety
in ASD. However, as the treatment procedures in this program place many demands
on the child’s cognitive skills and language comprehension, applicability of this
program might be limited to the higher functioning end of the autism spectrum.
Emerging evidence suggests that behavioral strategies, such as the use of gradu-
ated exposure and positive reinforcement for approach behavior, could be effective
for treating phobic avoidance in individuals in the spectrum, including those who
are more severely affected (Jennett and Hagopian 2008). Importantly, a number of
intervention programs for ASD, such as TEACCH (Treatment and Education of
Autistic and Communication Handicapped Children; Mesibov et al. 2004) and
SCERTS (Social Communication, Emotional Regulation, and Transactional
Support; Prizant et al. 2006), include targeted procedures to address anxiety issues,
such as the use of highly predictable routines to decrease stress and uncertainty and
strategies to prevent and recover from emotion dysregulation.
Research on the effectiveness of comprehensive intervention and specific strate-
gies to improve anxiety symptoms in individuals with ASD, especially those with
associated learning impairments, is still at its infancy.
7.2 Pharmacological Treatments
Current guidelines suggest the use of the selective serotonin reuptake inhibitors
(SSRIs) and the serotonin and noradrenaline reuptake inhibitors (SNRIs) as the agents
of choice for the first-line pharmacotherapy on anxiety disorders due to relatively
good efficacy and relatively low incidence of adverse effects (Baldwin et al. 2011).
Only a few studies have explored potential efficacy of pharmacological agents in
treating anxiety in ASD. Namerow et al. (2003) and Couturier and Nicolson (2002)
have reported some evidence for treatment efficacy of SSRIs on anxiety in ASD
population, while the study by Martin et al. (2003) found no evidence of improve-
ment in anxiety symptoms. Furthermore, all three studies have noted significant
adverse effects. For example, in the Martin et al. study, 13 individuals (72 %) had at
least 1 adverse effect during the course of the trial, and treatment for 3 participants
had to be terminated due to the behavioral activation. Similarly Namerow et al.
(2003) reported adverse effects such as headache, sedation, aggression, and agita-
tion in five individuals.
Finally, Buitelaar et al. (1998) found that 16 of 22 individuals with ASD aged
6–17 years experienced a reduction of anxiety (on the Clinical Global Impressions
Scale) after being treated with buspirone for a period of 6–8 weeks. Unlike with
SSRIs, side effects of buspirone were relatively mild.
7.3 Novel Treatment Strategies
One novel approach to the treatment of anxiety in children involves the use of
computer-based CBT interventions. Khanna and Kendall (2010) adapted the Coping
Cat program into a computer program, Camp Cope-A-Lot, and found no differences
in effectiveness between the computer program and individualized CBT in young
children (without ASD). This implementation method has not yet been used in peo-
ple with ASD who have clinical levels of anxiety.
Another somewhat promising avenue for novel treatments of anxiety in ASD is

the use of biofeedback devices to increase emotional awareness and support devel-
opment in interoception in this population. Bio-monitoring systems measure,
amplify, and feedback information primarily from nervous system processes such as
respiration, heart rate, muscle tension, skin temperature, blood flow, and blood pres-
sure to the individual being monitored, thus promoting awareness of these processes
to facilitate voluntary control over body and mind. Recent reviews on the use of
biofeedback to treat anxiety have shown some positive effects, particularly when
multiple channels of biofeedback are used (Wells et al. 2012). However, the findings
on bio- or neuro-feedback in ASD have not shown any specific effects on anxiety,
but rather on cognitive processes such as executive functioning (Kouijzer et al.
2009). Larger scale studies are needed to confirm these findings and establish effec-
tive protocols for individuals in the autism spectrum presenting with co-occurring
anxiety symptoms.
8 Conclusions and Future Directions
While anxiety is very prevalent and causes significant impairments in the ASD pop-
ulation, research in this area is still in its infancy. A critical challenge for researchers
and clinicians alike is the issue of whether anxiety is a manifestation of core autistic
symptoms, a causally unrelated co-occurring condition, a consequence of the chal-
lenges faced by individuals with ASD in their social environment, or a combination
of different factors. Dedicated research programs investigating typical and atypical
anxiety symptom presentation, causal links between ASD and anxiety features, sta-
bility, and developmental changes in anxiety symptoms are needed to (1) reach a
consensus around the concept of anxiety in ASD; (2) develop gold standard, multi-
axial, developmentally sensitive assessment protocols for anxiety in ASD to com-
plement standard evaluation procedures, and (3) identify treatment targets and
develop individualized intervention programs to address this profoundly disabling
comorbidity.
References
Achenbach TM, Rescorla LA (2001) Manual for the ASEBA School-Age Forms and Profiles.
Burlington, VT: University of Vermont, Research Center for Children, Youth, and Families
Asperger H (1944) Die autistischen psychopathen in Kindersalten. Arch Psychiatr
Nervenkrankenheiten 117:76–136
Aylward EH, Minshew NJ, Goldstein G, Honeycutt NA, Augustine AM, Yates KO, Barta PE,
Pearlson GD (1999) MRI volumes of amygdala and hippocampus in non- mentally retarded
autistic adolescents and adults. Neurology 53(9):2145–2150
Baldwin DS, Waldman S, Allgulander C (2011) Evidence-based pharmacological treatment of
generalized anxiety disorder. Int J Neuropsychopharmacol 14(5):697–710
Baron-Cohen S (1997) Mindblindness: an essay on autism and theory of mind. MIT Press,
Boston
Bauman M, Kemper TL (1985) Histoanatomic observations of the brain in early infantile autism.
Neurology 35:866–874
Beitchman JH, Wilson B, Johnson CJ, Atkinson L, Young A, Adlaf E, Escobar M, Douglas L
(2001) Fourteen-year follow-up of speech/language-impaired and control children: psychiatric
outcome. J Am Acad Child Adolesc Psychiatry 40(1):75–82
Bejerot S, Eriksson JM, Mörtberg E (2014) Social anxiety in adult autism spectrum disorder.
Psychiatry Res 220:705–707
Bellini S (2004) Social skill deficits and anxiety in high-functioning adolescents with autism spec-
trum disorders. Focus Autism Other Dev Disabil 19(2):78–86
Bellini S (2006) The development of social anxiety in adolescents with autism spectrum disorders.
Focus on Autism and Other Developmental Disabilities, 21(3):138–145
Ben-Sasson A, Cermak SA, Orsmond GI, Tager-Flusberg H, Carter AS, Kadlec MB (2008)
Sensory subgroups of toddlers with autism spectrum disorders: differences in internalizing
symptoms. J Child Psychol Psychiatry 49(8):817–825
Berthoz S, Hill EL (2005) The validity of using self-reports to assess emotion regulation abilities
in adults with autism spectrum disorder. Eur Psychiatry 20(3):291–298
Birmaher B, Brent DA, Chiappetta L, Bridge J, Monga S, Baugher M (1999) Psychometric proper-
ties of the Screen for Child Anxiety Related Emotional Disorders (SCARED): a replication
study. J Am Acad Child Adolesc Psychiatry 38:1230–1236
Birmaher B, Khetarpal S, Brent D, Cully M, Balach L, Kaufman J, Neer MS (1997) The Screen
for Child Anxiety Related Emotional Disorders (SCARED): scale construction and psycho-
metric characteristics. J Am Acad Child Adolesc Psychiatry 36:545–553
Bornstein MH, Hahn CS, Suwalsky JT (2013) Language and internalizing and externalizing
behavioral adjustment: developmental pathways from childhood to adolescence. Dev
Psychopathol 25(3):857–878
Bradley EA, Summers JA, Wood HL, Bryson SE (2004) Comparing rates of psychiatric and
behavior disorders in adolescents and young adults with severe intellectual disability with and
without autism. J Autism Dev Disord 34:151–161
Buitelaar JK, van der Gaag RJ, van der Hoeven J (1998) Buspirone in the management of anxiety
and irritability in children with pervasive developmental disorders: results of an open-label
study. J Clin Psychiatry 59(2):56–59
Burnette CP, Mundy PC, Meyer JA, Sutton SK, Vaughan AE, Charak D (2005) Weak central coher-
ence and its relations to theory of mind and anxiety in autism. J Autism Dev Disord 35:63–73
Carter EW, Lane KL, Cooney M, Weir K, Moss CK, Machalicek W (2013) Parent assessments of
self-determination importance and performance for students with autism or intellectual dis-
ability. Am J Intellect Dev Disabil 118(1):16–31
Chalfant AM, Rapee R, Carroll L (2007) Treating anxiety disorders in children with high function-
ing autism spectrum disorders: a controlled trial. J Autism Dev Disord 37:1842–1857
Chorpita BF, Moffitt CE, Gray J (2005) Psychometric properties of the revised child anxiety and
depression scale in a clinical sample. Behav Res Ther 43(3):309–322
Couturier JL, Nicholson R (2002) A retrospective assessment of citalopram in children and adoles-
cents with pervasive developmental disorders. J Child Adolesc Psychopharmacol 12:243–248
Dadds MR, Rapee RM, Barrett PM (1994) Behavioral observation. In: Ollendick TH, King NJ,
Yule W (eds) International handbook of phobic and anxiety disorders in children and adoles-
cents. Plenum, New York, pp 349–364
Dalton KM, Nacewicz BM, Johnstone T, Schaefer HS, Gernsbacher MA, Goldsmith HH,
Alexander AL, Davidson RJ (2005) Gaze fixation and the neural circuitry of face processing in
autism. Nat Neurosci 8(4):519–526
Davis III TE, Fodstad JC, Jenkins WS, Hess JA, Moree BN, Dempsey T, … Matson JL (2010)
Anxiety and avoidance in infants and toddlers with autism spectrum disorders: evidence for
differing symptom severity and presentation. Res Autism Spectr Disord 4:305–313
Davis III TE, Hess JA, Moree BN, Fodstad JC, Dempsey T, Jenskins WS,… Matson J (2011a)
Anxiety symptoms across the lifespan in people diagnosed with autistic disorder. Res Autism
Spectr Disord 5:112–118
Davis III TE, Moree BN, Dempsey T, Reuther ET, Fodstad JC, Hess JA, … Matson JL (2011b) The
relationship between autism spectrum disorders and anxiety: The moderating effect of com-
munication. Res Autism Spectr Disord 5:324–329
Davis TE III (2012) Where to from here for ASD and anxiety? Lessons learned from child anxiety
and the issue of DSM-5. Clin Psychol Sci Pract 19:358–363
Davis TE III, White SW, Ollendick TH (2014) Handbook of autism and anxiety. Springer, New York
de Bruin EI, Ferdinand RF, Meester S, De Nijs PFA, Verheij F (2007) High rates of psychiatric
co-morbidity in PDD-NOS. J Autism Dev Disord 37:877–886
Drahota A, Wood JJ, Sze KM, Van Dyke M (2011) Effects of cognitive behavioral therapy on daily
living skills in children with high-functioning autism and concurrent anxiety disorders. J
Autism Dev Disord 41(3):257–265
Evans DW, Canavera K, Klinepeter FL, Taga K, Maccubbin E (2005) The fears, phobias and anxi-
eties of children with autism spectrum disorders and Down syndrome: comparisons with devel-
opmentally and chronologically age matched children. Child Psychiatry Hum Dev 36:3–26
Farrugia S, Hudson J (2006) Anxiety in adolescents with Asperger syndrome: negative thoughts,
behavioral problems, and life interference. Focus Autism Other Dev Disabil 21(1):25–35
Gadow KD, Sprafkin J (1997) Early Childhood Inventory-4 norms manual. Stony Brook,
NY: Checkmate Plus
Gadow KD, DeVincent CJ, Pomeroy J, Azizian A (2005) Comparison of DSM-IV symptoms in
elementary school-age children with PDD versus clinic and community samples. Autism
9:392–415
Gillot A, Furniss F, Walter A (2001) Anxiety in high-functioning children with autism. Autism
5:277–286
Gillott A, Standen PJ (2007) Levels of anxiety and sources of stress in adults with autism. J Intellect
Disabil 11:359–370
Gotham K, Bishop SL, Hus V, Huerta M, Lund S, Buja A, Krieger A, Lord C (2013) Exploring the
relationship between anxiety and insistence on sameness in autism spectrum disorders. Autism
Res 6(1):33–41
Grandin, T (1992) An Inside View of Autism. In E. Schopler and G.B. Mesibov (eds), High-
Functioning Individuals with Autism. New York: Plenum Press 105–26
Green SA, Ben-Sasson A, Soto TW, Carter AS (2012) Anxiety and sensory over-responsivity in
toddlers with autism spectrum disorders: bidirectional effects across time. J Autism Dev Disord
42(6):1112–1119
Green J, Gilchrist A, Cox A (2000) Social and psychiatric functioning in adolescents with Asperger
syndrome compared with conduct disorder. J Autism Dev Disord 30:279–293
Greenway R, Howlin P (2010) Dysfunctional attitudes and perfectionism and their relationship to
anxious and depressive symptoms in boys with autism spectrum disorders. J Autism Dev
Disord 40(10):1179–1187
Hagopian LP, Weist MD, Ollendick TH (1990) Cognitive-behavior therapy with an 11-year-old
girl fearful of AIDS infection, other diseases, and poisoning: a case study. J Anxiety Disord
4:257–265
Hallett V, Ronald A, Colvert E, Ames C, Woodhouse E, Lietz S, Bolton P (2013) Exploring anxiety
symptoms in a large-scale twin study of children with autism spectrum disorders, their co-twins
and controls. Journal of Child Psychology and Psychiatry, 54(11), 1176–1185
Helverschou SB, Martinsen H (2011) Anxiety in people diagnosed with autism and intellectual
disability: recognition and phenomenology. Res Autism Spectr Disord 5(1):377–387
Helvershou SB, Bakken TL, Martinsen H (2009) The psychopathology in autism (PAC): a pilot
study. Res Autism Spectr Disord 3:179–195
Hess JA, Matson JL, Dixon DR (2010) Psychiatric symptom endorsements in children and adoles-
cents diagnosed with autism spectrum disorders: a comparison to typically developing children
and adolescents. J Dev Phys Disabil 22:485–496
Hill EL, Berthoz S, Frith U (2004) Brief report: cognitive processing of own emotions in indi-
viduals with autistic spectrum disorder and in their relatives. J Autism Dev Disord 34(2):
229–235
Hollocks MJ, Jones CR, Pickles A, Baird G, Happé F, Charman T, Simonoff E (2014) The associa-
tion between social cognition and executive functioning and symptoms of anxiety and depres-
sion in adolescents with autism spectrum disorders. Autism Res 7(2):216–228
Howard MA, Cowell PE, Boucher J, Broks P, Mayes A, Farrant A, … Roberts N (2000) Convergent
neuroanatomical and behavioral evidence of an amygdala hypothesis of autism. Neuroreport
11:2931–2935
Jennett HK, Hagopian LP (2008) Identifying empirically supported treatments for phobic avoid-
ance in individuals with intellectual disabilities. Behav Ther 39:151–161
Juranek J, Filipek PA, Berenji GR, Modahl C, Osann K, Spence MA (2006) Association between
amygdala volume and anxiety level: magnetic resonance imaging (MRI) study in autistic chil-
dren. J Child Neurol 21(12):1051–1058
Kaiser MD, Hudac CM, Shultz S, Lee SM, Cheung C, Berken AM, Deen B, Pitskel NB, Sugrue
DR, Voos AC, Saulnier CA, Ventola P, Wolf JM, Klin A, Vander Wyk BC, Pelphrey KA (2010)
Neural signatures of autism. Proc Natl Acad Sci 107(49):21223–21228
Kanne S (2013) Diagnostic overshadowing. In: Encyclopedia of autism spectrum disorders.
Springer, New York, pp 938–940
Kanner L (1943) Autistic disturbances of affective contact. Nerv Child 2:217–250
Kashani JH, Orvaschel H (1990) A community study of anxiety in children and adolescents. Am
J Psychol 147:313–318
Kendall PC (1994) Treating anxiety disorders in children: results of a randomized clinical trial.
J Consult Clin Psychol 62:100–110
Kendall PC, Hudson JL, Gosch E, Flannery-Schroeder E, Suveg C (2008) Cognitive-behavioral
therapy for anxiety disordered youth: a randomized clinical trial evaluating child and family
modalities. J Consult Clin Psychol 76:282–297
Kerns CM, Kendall PC (2014) Autism and anxiety: overlap, similarities, and differences. In: Handbook
of autism and anxiety. Springer Cham Heidelberg New York Dordrecht London, pp 75–89
Kerns CM, Kendall PC, Zickgraf H, Franklin ME, Miller J, Herrington J (2015) Not to be over-
shadowed or overlooked: functional impairments associated with comorbid anxiety disorders
in youth with ASD. Behav Ther 46(1):29–39
Khanna M, Kendall P (2010) Computer-assisted cognitive behavioral therapy for child anxiety:
results of a randomized clinical trial. J Consult Clin Psychol 78(5):737–745
Kim JA, Szatmari P, Bryson SE, Streiner DL, Wilson FJ (2000) The prevalence of anxiety and
mood problems among children with Autism and Asperger syndrome. Autism 4:117–132
Kleinhans NM, Richards T, Weaver K, Johnson LC, Greenson J, Dawson G, … Alyward E (2010)
Association between amygdala response to emotional faces and social anxiety in autism spec-
trum disorders. Neuropsychologia 48(12):3665–3670
Kouijzer MEJ, de Moor JMH, Gerrits BJL, Buitelaar JK, van Schie HT (2009) Long-term effects
of neurofeedback treatment in autism. Res Autism Spectr Disord 3(2):496–501
Kuusikko S, Pollock-Wurman R, Jussila K, Carter AS, Mattila ML, Ebeling H, Pauls DL,
Moilanen I (2008) Social anxiety in high-functioning children and adolescents with autism and
Asperger syndrome. J Autism Dev Disord 38(9):1697–1709
Lecavalier L, Leone S, Wiltz J (2006) The impact of behaviour problems on caregiver stress in
young people with autism spectrum disorders. J Intellect Disabil Res 50(3):172–183
Leyfer OT, Folstein SE, Bacalman S, Davis NO, Dinh E, Morgan J, Tager-Flusberg H, Lainhart JE
(2006) Comorbid psychiatric disorders in children with autism: interview development and
rates of disorders. J Autism Dev Disord 36:849–861
Lidstone J, Uljarević M, Sullivan J, Rodgers J, McConachie H, Freeston M, … Leekam SR (2014)
Relations among restricted and repetitive behaviors, anxiety and sensory features in children
with autism spectrum disorders. Res Autism Spectr Disord 8(2):82–92
Lopata C, Toomey JA, Fox JD, Volker MA, Chow SY, Thomeer ML, Lee GK, Rodgers JD,
McDonald CA, Smerbeck AM (2010) Anxiety and depression in children with HFASDs:
symptom levels and source differences. J Abnorm Child Psychol 38(6):765–776
March JS (1997). Manual for multidimensional anxiety scale for children. Tonawanda,
NY: Multi-Health System Inc
Martin A, Koenig K, Anderson G, Scahill L (2003) Low dose fluvoxamine treatment of children
and adolescents with pervasive developmental disorders: A prospective, open-label study.
Matson JL, Benavidez DA, Compton LS, Paclawskyj T, Baglio C (1996) Characteristics of autism
as assessed by the diagnostic assessment for the severely handicappated-II (DASH-II). Res
Dev Disab 17, 135–143
Matson JL, Boisjoli JA, Wilkins J (2007) The Baby and Infant Screen for Children with aUtIsm
Traits (BISCUIT). Disability Consultants, Baton Rouge
Matson JL, Gonzalez ML (2007) Autism spectrum disorders – comorbidity – child version.
Disability Consultants, Baton Rouge
Matson JL, Hess JA, Boisjoli JA (2010) Comorbid psychopathology in infants and toddlers with
autism and pervasive developmental disorders – not otherwise specified (PDD-NOS). Res
Autism Spectr Disord 4(2):300–304
Matson JL, Wilkins J (2008) Reliability of the Autism Spectrum Disorders-Comorbid for Children
(ASD-CC). J Dev Phys Disabil 20(4):327–336. doi:10.1007/s10882-008-9100-1
Mayes SD, Calhoun SL, Aggarwal R, Baker C, Mathapati S, Molitoris S, Mayes RD (2013)
Unusual fears in children with autism. Res Autism Spectr Disord 7(1):151–158
Mazefsky CA, Herrington J (2014) Autism and anxiety: etiologic factors and transdiagnostic pro-
cesses. In: Handbook of autism and anxiety. Springer International Publishing, pp 91–103
Mazefsky CA, Kao J, Oswald DP (2011) Preliminary evidence suggesting caution in the use of
psychiatric self-report measures with adolescents with high-functioning autism spectrum dis-
orders. Res Autism Spectr Disord 5:164–174
Mazefsky CA, Herrington J, Siegel M, Scarpa A, Maddox BB et al (2013) The role of emotion
regulation in autism spectrum disorder. J Am Acad Child Adolesc Psychiatry 52:679–688
Mazefsky CA, Oswald DP, Day TN, Eack SM, Minshew NJ, Lainhart JE (2012) ASD, a psychiat-
ric disorder, or both? Psychiatric diagnoses in adolescents with high-functioning ASD. J Clin
Child Adolesc Psychol 41(4):516–523
Mazurek MO, Kanne SM (2010) Friendship and internalizing symptoms among children and ado-
lescents with ASD. J Autism Dev Disabil 40(12):1512–1520
Mazurek MO, Vasa RA, Kalb LG, Kanne SM, Rosenberg D, Keefer A, Murray DS, Freedman B,
Lowery LA (2013) Anxiety, sensory over-responsivity, and gastrointestinal problems in chil-
dren with autism spectrum disorders. J Abnorm Child Psychol 41(1):165–176
McNally Keehn RH, Lincoln AJ, Brown MZ, Chavira DA (2013) The coping cat program for
children with anxiety and autism spectrum disorder: a pilot randomized controlled trial.
Menon V, Udin LQ (2010) Saliency, switching, attention and control: a network model of insula
function. Brain Struct Funct 214(5–6):655–667
Mesibov GB, Shea V, Schopler E (2004) The TEACCH approach to autism spectrum disorders.
New York: Springer Science & Business Media
Meyer JA, Mundy PC, van Hecke AV, Durocher JS (2006) Social attribution processes and comor-
bid psychiatric symptoms in children with Asperger syndrome. Autism 10(4):383–402
Muris P, Steerneman P, Merckelbach H, Holdrinet I, Meesters C (1998) Comorbid anxiety symp-
toms in children with pervasive developmental disorders. J Anxiety Disord 12:387–393
Namerow LB, Prakash T, Bostic JQ, Prince J, Monuteaux MC (2003) Use of citalopram in perva-
sive developmental disorders. J Dev Behav Pediatr 24:104–108
Paulus MP, Stein MB (2006) An insular view of anxiety. Biol Psychiatry 60:383–387
Pellecchia M, Connell JE, Kerns CM, Xie M, Marcus SC, Mandell DS (2015) Child characteristics
associated with outcome for children with autism in a school-based behavioral intervention.
Autism 1362361315577518
Pierce K, Muller RA, Ambrose J, Allen G, Courchesne E (2001) Face processing occurs outside
the fusiform ‘face area’ in autism: evidence from functional MRI. Brain 124:2059–2073
Prizant B, Wetherby A, Rubin E, Laurent A, Rydell P (2006) The SCERTS® model: a comprehen-
sive educational approach for children with autism spectrum disorders, vol 1 and 2. Paul
H. Brookes, Baltimore
Reaven J, Blakeley-Smith A, Leuthe E, Moody E, Hepburn S (2012) Facing your fears in
adolescence: cognitive-behavioral therapy for high-functioning autism spectrum disorders and
anxiety. Autism Res Treat. doi: 10.1155/2012/423905
Renno P, Wood JJ (2013) Discriminant and convergent validity of the anxiety construct in children
with autism spectrum disorders. J Autism Dev Disord 43(9):2135–2146
Reynolds CR, Kamphaus RW (2004) Manual: behavior assessment system for children, 2nd edn.
American Guidance Service, Circle Pines
Rodgers J, Riby DM, Janes E, Connolly B, McConachie H (2012a) Anxiety and repetitive behav-
iours in autism spectrum disorders and Williams syndrome: a cross-syndrome comparison.
Rodgers J, Glod M, Connolly B, McConachie H (2012b) The relationship between anxiety and
repetitive behaviours in autism spectrum disorders. J Autism Dev Disord 42(11):2404–2409
Russell E, Sofronoff K (2005) Anxiety and social worries in children with Asperger syndrome.
Aust N Z J Psychiatry 39:633–638
Shaffer D, Fisher P, Lucas CP, Dulcan MK, Schwab-Stone ME (2000) Diagnostic interview sched-
ule for children version IV (DISC-IV): description, differences from previous versions, and
reliability of some common diagnoses. J Am Acad Child Adolesc Psychiatry 39(1):28–38
Shin LM, Liberzon I (2010) The neurocircuitry of fear, stress, and anxiety disorders.
Neuropsychopharmacology 35(1):169–191
Silverman W, Albano AM (1996) Manual for the anxiety disorders interview schedule for DSM-IV:
child and parent versions. Psychological Corporation, San Antonio
Solomon M, Ozonoff S, Carter C, Caplan R (2008) Formal thought disorder and the autism spec-
trum: relationship between symptoms, executive control, and anxiety. J Autism Dev Disord
38:1474–1484
Sparks BF, Friedman SD, Shaw DW, Aylward EH, Echelard D, Artru AA, Maravilla KR, Giedd
JN, Munson J, Dawson G, Dager SR (2002) Brain structural abnormalities in young children
with autism spectrum disorder. Neurology 59:184–192
Spence SH (1998) A measure of anxiety symptoms among children. Behav Res Ther
36(5):545–566
Sterling L, Renno P, Storch EA, Ehrenreich-May J, Lewin AB, Arnold E, Lin E, Wood J (2015)
Validity of the Revised Children’s Anxiety and Depression Scale for youth with autism
spectrum disorders. Autism. 2015 Jan;19(1):113–7. doi: 10.1177/1362361313510066
Storch EA, May JE, Wood JJ, Jones AM, De Nadai AS, Lewin AB, Arnold EB, Murpy TK (2012)
Multiple informant agreement on the anxiety disorders interview schedule in youth with autism
spectrum disorders. J Child Adolesc Psychopharmacol 22(4):292–299
Strang JF, Kentworthy L, Daniolos P, Case L, Willis MC, Martin A, Wallace GL (2012) Depression
and anxiety symptoms in children and adolescents with autism spectrum disorders without
intellectual disability. Res Autism Spectr Disord 6:406–412
Sukhodolsky DG, Scahill L, Gadow KD, Arnold LE, Aman MG, McDougle CJ, Tierney E,
Williams White S, Lecavalier L, Vitiello B (2008) Parent-rated anxiety symptoms in children
with pervasive developmental disorders: frequency and association with core autism symptoms
and cognitive functioning. J Abnorm Child Psychol 36(1):117–128
Sze KM, Wood JJ (2007) Cognitive behavioral treatment of comorbid anxiety disorders and social
difficulties in children with high functioning autism: a case report. J Contemp Psychother
37:133–143
Sze KM, Wood JJ (2008) Enhancing CBT for the treatment autism spectrum disorders and concur-
rent anxiety. Behav Cogn Psychother 36:403–409
Tager-Flusberg H, Kasari C (2013) Minimally verbal school-aged children with autism spectrum
disorder: the neglected end of the spectrum. Autism Res 6(6):468–478
Tsai LY (1996) Brief report: comorbid psychiatric disorders of autistic disorder. J Autism Dev
Disord 26:159–164
Turner-Brown LM, Lam KS, Holtzclaw TN, Dichter GS, Bodfish JW (2011) Phenomenology and
measurement of circumscribed interests in autism spectrum disorders. Autism 15(4):437–456
van Steensel FJ, Bogels SM, Perrin S (2011) Anxiety disorders in children and adolescents with
autistic spectrum disorders: a meta-analysis. Clin Child Fam Psychol Rev 14:302–317
Vivanti G, McCormick C, Young GS, Abucayan F, Hatt N, Nadig A, Ozonoff S, Rogers SJ (2011)
Intact and impaired mechanisms of action understanding in autism. Dev Psychol 47(3):841
Warren SL, Sroufe LA (2004) Developmental issues. In: Ollendick TH, March JS (eds) Phobic and
anxiety disorders in children and adolescents: a clinicians guide to effective psychosocial and
pharmacological interventions. Oxford University Press, New York, pp 92–115
Weisbrot DM, Gadow KD, DeVincent CJ, Pomeroy J (2005) The presentation of anxiety in chil-
dren with pervasive developmental disorders. J Child Adolesc Psychopharmacol 15:477–496
Wells R, Outhred T, Heathers JAJ, Quintana DS, Kemp AH (2012) Matter over mind: a randomised-
controlled trial of single-session biofeedback training on performance anxiety and heart rate
variability in musicians. PLoS One 7(10):e46597
White SW, Oswald D, Ollendick T, Scahill L (2009) Anxiety in children and adolescents with
autism spectrum disorders. Clin Psychol Rev 29:216–229
Wood JJ, Gadow KD (2010) Exploring the nature and function of anxiety in youth with autism
spectrum disorders. Clin Psychol Sci Pract 17(4):281–292
Wood JJ, Drahota A, Sze K, Har K, Chiu K, Langer DA (2009) Cognitive behavioral therapy for
anxiety in children with autism spectrum disorders: a randomized, controlled trial. J Child
Psychol Psychiatry 50(3):224–234
Worley JA, Matson JL, Sipes M, Koziowski AM (2010) Prevalence of autism spectrum disorders
in toddlers receiving early intervention services. Res Autism Spectr Disord 5:920–925
Repetitive Behavior in Children
with Autism Spectrum Disorder: 3
Similarities and Differences
with Obsessive-Compulsive Disorder
Lawrence Scahill and Saankari A. Challa
1 Introduction
Restrictive interests and repetitive behavior are defining features of autism spectrum
disorder (ASD) (American Psychiatric Association 2013). The types of repetitive
behaviors and restrictive interests vary widely in children with ASD from motor
stereotypy to intense interests in unusual topics such as fans, air conditions, or televi-
sion court shows (Bodfish et al. 2000; Lam and Aman 2007; Turner-Brown et al.
2011; Honey et al. 2012a; Bishop et al. 2013; Scahill et al. 2014). Although essential
for the diagnosis of ASD, restricted interests and repetitive behavior (RRBs) may not
be pressing problems in all cases. Heterogeneity of symptom types and severity of
RRBs in ASD raise several challenges for diagnosis and treatment planning (Honey
et al. 2012b; Scahill et al. 2015a). For example, bedtime rituals and favorite objects
(special blankets or a favorite nightgown) are common in typically developing young
children (Leekam et al. 2007; Arnott et al. 2009). In clinical practice, depending on
the age of the child, it may be difficult to distinguish normal ritualistic behavior from
abnormal RRBs. Repetitive behaviors are also central characteristics of obsessive-
compulsive disorder (OCD) and Tourette syndrome. In addition, repetitive behaviors
are often observed in children with developmental disabilities due to genetic syn-
dromes, adults with schizophrenia, and adults with dementia (Moss et al. 2009;
Morrens et al. 2006; Cipriani et al. 2013). These observations serve as a reminder
that repetitive behavior in humans has an extraordinary range and is unlikely to have
a single explanation (Lewis and Kim 2009; John et al. 2010).
Our understanding of repetitive and stereotypic behaviors in neurodevelopmen-
tal and psychiatric disorders has been informed by animal models on habit learning
L. Scahill (*) • S.A. Challa

Atlanta, GA, USA

40 L. Scahill and S.A. Challa
(Berridge et al. 2005; de Wit and Dickinson 2009). A large body of preclinical data
provides insight on the transition from goal-directed, reward-based behavior to
automatic behavior (habit). When the reward-based behavior becomes habitual, it
will persist even in the absence of reward (reward devaluation). Animal models sug-
gest that the transition from goal-directed behavior to “automatic” behavior involves
a shift in specific cortico-basal ganglia neural pathways (Alexander et al. 1986;
Graybiel 2008). Given the wide range of RRBs in children with ASD and the poten-
tially overlapping repetitive behaviors in children with OCD and Tourette syn-
drome, however, habit learning from preclinical models may not provide sufficient
explanation for the phenomenon.
This chapter examines the similarities and differences of repetitive behavior in
children with ASD and OCD. Examination of similarities and differences may help
clinicians disentangle the repetitive behaviors attributable to OCD from those attrib-
utable to ASD, plan treatment and monitor progress. We begin with a brief decon-
struction of comorbidity as it applies to ASD and OCD.
2 Comorbidity
Morbidity is a departure from a healthy state and is roughly equivalent to the dis-
ability caused by a symptom, syndrome, or disease. The term comorbidity implies
the presence of two (or more) distinct conditions that are separately contributing to
overall impairment. The boundaries between psychiatric conditions can be impre-
cise. This imprecision raises several questions about simple co-occurrence versus
symptom overlap or the presence of a combined syndrome. For example, the co-
occurrence of attention-deficit hyperactivity disorder (ADHD) and conduct disor-
der has long been proposed to represent an etiologically separate subgroup of
ADHD (Banaschewski et al. 2003). If so, it would be inaccurate to consider con-
duct disorder as a comorbid condition with ADHD. Hyperactivity, impulsiveness,
and distractibility are common in children with ASD (Gadow et al. 2006; Simonoff
et al. 2008). In Diagnostic and statistical manual of mental disorders-text revised
(DSM-IV-TR) however, clinicians were advised against giving a separate diagno-
sis of ADHD in line with the notion that the symptoms of ADHD could be explained
by ASD (American Psychiatric Association 2000). Diagnostic and Statistical
Manual of Mental Disorders, 5th edition, (DSM-5) has dropped this convention.
Based on DSM-5, the presence of hyperactivity, impulsiveness, and distractibility
in a child with ASD would be considered comorbid ADHD (American Psychiatric
Association 2013). Here again, there is evidence that ADHD and ASD may have
shared underlying genetic risk (Reiersen et al. 2007). There is also ongoing debate
about whether anxiety disorders are separate from ASD or directly or indirectly
caused by ASD or whether anxiety disorders are somehow blended with ASD
(Kerns and Kendall 2012; Lecavalier et al. 2014). Discussion on co-occurrence
versus overlap of OCD and ASD is not new and is not resolved (Baron-Cohen
1989; McDougle et al. 1995; Scahill et al. 2014). Among the phenomenological
and conceptual problems inherent in this longstanding discussion is the simple fact
that repetitive behaviors are central to the definition of both disorders.
3 Repetitive Behavior in Children with Autism Spectrum Disorder 41
3 Prevalence of OCD in ASD
The prevalence of OCD in the general population of children and adolescent is esti-
mated to be between 2 % and 4 % with most studies leaning toward the lower end
of this range (Geller 2006). Reports on the prevalence of OCD in children with ASD
provide a stunning range of estimates from 2.6 % to 37.2 % (van Steensel et al.
2011). This wide range of estimates is due to differences in the source and size of
the sample as well as the assessment methods used. For example, several studies
included only higher functioning children. Sample sizes ranged from 20 to 300.
Some studies used structured interviews; others used parent report on rating scales.
Using a fixed-effect model in their meta-analysis, van Steensel and colleagues
(2011) reported a 12.5 % prevalence of OCD in children with ASD. This estimate is
clearly higher than the prevalence of OCD in the general population of children, but
is substantially lower than the estimated co-occurrence of ADHD or other anxiety
disorders in children with ASD (Simonoff et al. 2008).
4 Repetitive Behavior in OCD
Obsessive-compulsive disorder is defined by the presence of recurrent intrusive

thoughts or worries, repetitive behaviors, or both. In order to meet the current
diagnostic criteria for OCD in DSM-5, the obsessions and/or compulsions must
be time consuming and cause marked distress or impairment. Intrusive thoughts
or images (obsessions) are often accompanied by anxiety that may be temporarily
relieved by performing intentional repetitive behaviors (compulsions). The
sequence of obsessional worry (e.g., harm coming to the self or family) and rising
anxiety, followed by anxiety reduction and by the compulsive behavior (e.g.,
checking), is the historical basis for classifying OCD as an anxiety disorder. In
addition to anxiety caused by obsessions, compulsive behavior in children with
OCD may be driven by a need to achieve a sense of completion rather than a clear-
cut obsession (Geller 2006; Scahill et al. 2003). In DSM-5, OCD has been
removed from anxiety disorders and placed with body dysmorphic disorder,
trichotillomania, excoriation (skin-picking) disorder, and hoarding disorder under
the rubric of obsessive-compulsive and related disorders. There is incomplete
consensus on this new category in DSM-5 and findings from a large twin study do
not fully support the position that these disorders are etiologically related
(Monzani et al. 2014). In that study, Monzani and colleagues (2014) proposed that
trichotillomania and skin-picking disorder appear to share genetic influences that
are separate from OCD. Thus, the model of rising anxiety and temporary anxiety
reduction should not be dismissed in favor of lumping disorders by virtue of
repetitive behavior alone.
Common obsessions in children include recurring worries about contamination,
harm coming to the self or family members, and abnormal need for symmetry.
Common compulsions include handwashing, other cleaning rituals, touching in
complex patterns, and repeating routine activities such as moving back and forth
across a doorway (Rettew et al. 1992; Scahill et al. 2003; Geller 2006). Children
with OCD usually describe their worries as nagging, unpredictable, unpleasant, and
unwanted. Similarly, compulsions are unwelcomed behaviors that the child feels
obliged to perform. Given the unwanted nature of obsessions and compulsions in
OCD, affected children describe them as distressing and difficult to resist despite
effort.
The connection between obsession and compulsion is often clear. The child who
fears germ contamination may engage in compulsive handwashing. In other cases,
the connection is remote. The child may describe the need to repeat a motor sequence
such as bending down and touching the ground three times to prevent harm to a fam-
ily member. Younger children may be unable to articulate that the behavior is unre-
lated to protect the family member. By contrast, adolescents may clearly state that
the compulsive habit is unrelated and likely ineffective, yet they will perform the
ritual “just in case.” In still other cases of youth with OCD, repetitive behaviors are
not connected to harm reduction. The child may describe touching in complex pat-
terns or repeating a routine behavior (putting a key in and out of a lock several times
before turning it) in order to avert a deep sense of physical discomfort. Even with the
recognition that the behavior is unnecessary, the child may report that it is easier to
perform the ritual than wrestle with the internal discomfort. Each of these examples
reflects a negative reinforcement model in that the behavior is followed by decreased
anxiety, doubt, or discomfort. For example, the child with compulsive handwashing
may describe that the handwashing as necessary to reduce contamination, but it is the
reduction in anxiety that reinforces the repetitive behavior. The child who touches
the floor three times, six times, or nine times may do so to relieve feelings of doubt
about an unrelated threat (for discussion of OCD phenomenology in children, see
Rettew et al. 1992; Scahill et al. 2003; Geller 2006; Piacentini 2008).
To break down the apparent heterogeneity of OCD, several investigators have
used factor analysis to build a basis for a dimensional approach that would clas-
sify OCD subtypes (Leckman et al. 1997; Rosario-Campos et al. 2006; Mataix-
Coles et al. 2005; Miguel et al. 2005). Replicated symptom clusters include: (1)
aggression and checking, (2) symmetry and ordering/arranging, (3) contamina-
tion and cleaning, and (4) hoarding. The replication of these factors across dif-
ferent samples supports the dimensional model of OCD rather than the broad
categories of obsessions and compulsions. For example, contamination worries
and washing rituals may provide a coherent clinical picture for establishing
baseline severity and change with treatment – rather than considering obses-
sional worry as separate from the compulsive behavior. The dimensional schema
may also be influenced by age (Diniz et al. 2004). In children, the onset of com-
pulsions may precede the onset of obsessions or, perhaps, the child’s ability to
describe the obsession (Scahill et al. 2003). Children may engage in “tic-like”
compulsion such as touching, tapping, blinking in patterns, and repeating rou-
tine activities such as opening and closing cupboard doors. These tic-like com-
pulsions are more common in children with OCD with a history of tics and, in
some cases, may be difficult to distinguish from complex tics (Leckman et al.
2001). The application of the dimensional approach to phenotypic characteriza-
tion of subjects with OCD may be useful in neuroimaging studies, family
history, and gene association studies and studies on moderators of treatment

(Nestadt et al. 2002; Rauch and Jeike 1993; Monzani et al. 2014; Miguel et al.
2005; Rosario-Campos et al. 2006).
In summary, OCD in its paradigmatic form is characterized by the intrusion of
unwanted thoughts that increase anxiety. The compulsive ritual reduces anxiety and,
consequently, the behavior is reinforced. There is growing evidence that OCD is man-
ifested by symptom clusters that may represent subtypes. The category of obsessive-
compulsive and related disorders (including OCD, body dysmorphic disorder,
hoarding, trichotillomania, excoriation) proposed in DSM-5 is not uniformly accepted
and may not stand the test of time (American Psychiatric Association 2013).
5 Repetitive Behavior in ASD
As noted above, RRBs in children with ASD vary in type and severity. Repetitive
behaviors range from stereotyped motor behaviors such as hand flapping, spinning,
rocking, shaking fingers in front of the eyes, and repetitive self-injury. Repetitive
behaviors may also involve more complex behaviors such as repeating phrases from
movies, watching the same video segment over and over, lining up toys, and insis-
tence on following routines in everyday living (e.g., eating, getting dressed or ready
for bed in ritualized sequence) (Bodfish et al. 2000; Lam et al. 2008; Mirenda et al.
2010; Bishop et al. 2013; Scahill et al. 2014). Restricted interests may include fans,
leaf blowers, car models, train schedules, or historical facts and figures (Turner-
Brown et al. 2011). These restricted interests may meet the dictionary definition of
obsession – but are not the same as unwanted and bothersome thoughts in OCD. In
addition to time spent with such preoccupations, children with ASD may engage
repeated questioning of others about the topic or expounding on it far beyond the
listener’s interest. This range of RRBs has been classified as higher and lower order
behaviors. Lower order behaviors include motor stereotypy and other seemingly
involuntary behaviors (Turner 1999). By contrast, higher order behaviors include
what appear to be more deliberate activities. This broad categorization has been
examined and reevaluated resulting in three to five categories. A factor analysis of
the Autism Diagnostic Interview-Revised identified three subtypes: repetitive motor
behaviors, insistence on sameness, and circumscribed interests (Lam et al. 2008).
Based on expert opinion, the World Health Organization (WHO 2007) designated
four subtypes: (a) preoccupations with part objects or nonfunctional elements of
materials, (b) stereotyped and repetitive motor mannerisms, (c) preoccupations or
circumscribed patterns of interest, and (d) adherence to specific nonfunctional rou-
tines or rituals (WHO 2007; Honey et al. 2012a, b). Factor analysis of the 43-item
Repetitive Behavior Scale-Revised has yielded five factors: stereotyped behavior,
self-injurious behavior (skin picking, biting self), compulsive behavior (ordering
and arranging objects, counting, touching, and tapping), ritualistic/sameness behav-
ior (insisting on certain order to eating or sleeping, insisting on arrangement of
furniture or objects), and restricted interests (Lam and Aman 2007; Mirenda et al.
2010; Bishop et al. 2013).
In contrast to obsessive-compulsive symptoms in children with OCD, repetitive

behaviors may not cause distress for children with ASD. Although the purpose of
RRBs in children with ASD is not always clear, many children appear to have a
strong drive to perform these behaviors (Honey et al. 2012a; Scahill et al. 2014). In
some children, repetitive behavior such as hand flapping may increase during peri-
ods of anxiety or excitement (Bearss et al. 2015). In other cases, repetitive rocking
may be used to reduce high levels of arousal or serve as a form of self-soothing.
Although children with ASD may not be distressed during the performance of
repetitive behaviors, these behaviors can be impairing due to the time spent as well
as the child’s distress, noncompliance, and protest when repetitive behaviors are
interrupted (Scahill et al. 2006). Some children with ASD perform repetitive behav-
iors in public places that stand out and contribute to social disability (Turner-Brown
et al. 2011; Scahill et al. 2014).
In a sample of 272 children with ASD (age 4–17 years), we used principal compo-
nents analysis to evaluate the symptom checklist on the Children’s Yale-Brown
Obsessive-Compulsive Scales for ASD (CYBOCS-ASD) (Scahill et al. 2014). The
study sample consisted of participants in one of three clinical trials conducted by the
Research Units on Pediatric Psychopharmacology (RUPP) Autism Network. The symp-
tom checklist included 39 items, most of which were from the original list of compul-
sions on the CYBOCS. This measure was designed to assess severity of obsessions and
compulsions in children with OCD (Scahill et al. 1997). When applied to the ASD
sample, 15 checklist items were endorsed by less than 5 % of the sample (e.g., checking
related to harm reduction, excessive cleaning, excessive list making, repetitive behavior
to prevent harm, superstitious behavior) and were dropped from further analysis. As
noted above, checking and other repetitive behavior to protect against harm and exces-
sive cleaning are common in children with OCD – but were clearly uncommon in this
sample of well-characterized children with ASD. The principal components analysis
identified five categories: ritualistic behavior, ordering and arranging behavior, same-
ness and self-injurious behavior, and restricted interest (see Table 3.1 for examples).
Although many children exhibited behaviors from more than one category, some behav-
iors were associated with cognitive ability. Children in the normal intelligence quotient
(IQ) range were more likely to perform complex ritualistic behavior (Scahill et al. 2014).
Consistent with other reports, children with intellectual disability were more likely to
exhibit motor stereotypy and self-injurious behavior (Bishop et al. 2006).
Self-injurious behavior in children with ASD is a potentially serious problem
that warrants separate discussion. In some children, self-injurious behavior is inad-
vertently reinforced by social reward such escape from a routine demand, obtaining
a preferred object (a food or a toy) or obtaining caregiver attention. Alternatively,
self-injurious behavior appears to be a repetitive, automatic behavior that is some-
how self-reinforcing. These different types of self-injurious behavior (socially
maintained vs automatic) may reflect of different underlying neural pathways
(Oliver et al. 2012; Hagopian et al. 2015).
Given the wide range of cognitive functioning and language skills in children with
ASD, distinguishing between the repetitive behaviors of ASD and behaviors that
reflect the co-occurrence of OCD may be difficult (Bishop et al. 2013; Scahill et al.
Table 3.1 Product of principal component analysisa of CYBOCS-ASD checklist in 272 children
with ASD
Sameness and
Sensory motor self-injurious Restricted
Ritualistic behavior and arranging behavior Stereotypy interest
Difficulty Lining up Re-reading same Hand flapping, Touching in
throwing things objects (toys, book shaking fingers patterns
away furniture) in front of eyes
Counting objects, Echolalia Insisting on Repeating Preoccupations
repeating certain routines (driving routine activities (e.g., trains,
numbers directions, (e.g., opening specific videos,
morning routine) and closing fans)
doors)
Checking locks, Rocking, Head banging, Object
checking that spinning, biting own hand, stereotypy
objects are in the pacing hitting self (spinning object,
right place shaking a pen or
piece of string,
etc.)
Ritualized eating Repetitive Masturbation,
behavior (food water play crotch grabbing
prepared in (flushing and
specific way) re-flushing
toilet)
Hair pulling, skin
picking, nail
biting
a
Principal component analysis was used to explore the dimensionality of the CYBOCS checklist
2014). Some children with ASD may be able to report why they perform repetitive
behaviors; others may not. The inability to describe the purpose of the repetitive
behavior is obvious for nonverbal children with ASD. Even children with language,
however, may not be able to describe the link between an obsession (e.g., worry
about harm) and the compulsion (complex touching behavior to reduce harm). Thus,
clinicians may need to focus on observable behavior. Results of the meta-analysis,
however, suggest that some children with ASD have a clinical picture that warrants a
separate diagnosis of OCD (van Steensel et al. 2011). Lewin and colleagues (2011)
compared OCD symptom picture in 35 children with high-functioning ASD and
OCD to a group of 35 children with OCD (without ASD). In this study, the investiga-
tors used the original CYBOCS checklist and found some differences in symptom
type and no difference in severity across the two groups. In the OCD plus ASD
group, however, common OCD symptoms such as checking and washing were not
endorsed.
In summary, some children with ASD present a clinical picture that warrants a
separate diagnosis of OCD. The clinical picture of children with ASD accompanied
by OCD appears similar to OCD in children without ASD. In clinical practice,
therefore, the possible co-occurrence of OCD warrants careful consideration. The
Table 3.2 Repetitive behavior, obsessions, and preoccupations in ASD and OCD
Diagnosis Behaviors Obsessions/preoccupation Impairment/distress
ASD Flapping, rocking, Fans, air conditioners; Wastes time, interferes with
flipping objects, fireman and fire trucks, daily living and social
watching the same insistence on routines (turn interaction, hinders
video, lining up right at the corner) constructive activities,
objects, upsets if behavior is
interrupted (drawn to do it)
OCD Washing, checking, Contamination, harm to self Wastes time, interferes with
repetitive touching or others, need for daily living and social
or repeating routine symmetry interaction, leads to
behavior to prevent avoidance. Unwanted
harm, ordering and thoughts repetitive
arranging, behavior cause ↓ anxiety
contamination (has to do it)
worries
12.5 % prevalence estimate of OCD in children with ASD is higher than the preva-
lence in the general pediatric population. If this estimate is accurate, it is clear that
most children with ASD do not have OCD. Indeed, the repetitive behaviors for most
children with ASD are not the same as the compulsions of OCD (see Table 3.2).
Children with ASD may not be distressed about repetitive behavior. Indeed, protest
and disruptive behavior may occur when the child is interrupted or blocked from
performing the preferred repetitive behavior. Preoccupations with restricted inter-
ests in children with ASD are not the same as the nagging and unwanted obsessional
thoughts in children with OCD.
6 Response to Selective Serotonin Reuptake Inhibitors
Alterations in serotonin neurotransmission have long been proposed as having a role

in the pathophysiology of ASD. Medications such as selective serotonin reuptake
inhibitors (SSRIs) are commonly used in children with ASD (Oswald and Sonenklar
2007; Coury et al. 2012; Romanelli et al. 2014). This frequent use of the SSRIs in
treatment of children with ASD is due, at least in part, to the success of this medica-
tion class for the treatment of children with OCD (King et al. 2009). Findings from
randomized clinical trials on the efficacy of the SSRIs for the treatment of repetitive
behavior in ASD have been inconsistent. In adults with ASD, fluvoxamine (McDougle
et al. 1996) and fluoxetine (Hollander et al. 2012) each showed superiority to placebo
for reducing repetitive behavior. Hollander and colleagues conducted a placebo-
controlled study of fluoxetine in 39 children and reported modest but statistically
greater reductions in repetitive behaviors versus placebo (Hollander et al. 2005). In
stark contrast, two large-scale randomized trials used the Children’s Yale-Brown
Obsessive-Compulsive Scales (CYBOCS-ASD) to measure repetitive behavior
before and after treatment (Scahill et al. 2015b). In a sample of 149 children with
ASD, liquid citalopram was no better than placebo (King et al. 2009). Similarly, in a
sample of 158 children with ASD, an oral disintegrating formulation of fluoxetine

(Neuropharm, clinicaltrials.gov 2011) was not superior to placebo for reducing
repetitive behaviors. The seeming difference in response to SSRIs in adults with
ASD compared to children with ASD is difficult to explain (Esbensen et al. 2009).
The failure of SSRIs for reducing repetitive behavior in two separate, large-scale tri-
als in children with ASD compared to the demonstrated benefit in children with
OCD, however, implies differences in underlying neurobiology for the repetitive
behavior in ASD versus OCD.
References
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated
circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381
American Psychiatric Association (APA) (2000) Diagnostic and statistical manual of mental
disorders-text revised (DSM-IV-TR), 4th edn. American Psychiatric Association (APA),
Washington, DC
American Psychiatric Association (APA) (2013) Diagnostic and statistical manual of mental
disorders-fifth edition (DSM 5). American Psychiatric Association (APA), Washington, DC
Arnott B, McConachie H, Meins E, Fernyhough C, Le Couteur A, Turner M, Parkinson K, Vittorini
L, Leekam S (2009) The frequency of restricted and repetitive behaviours in 15 month-old typi-
cally developing infants. J Dev Behav Pediatr: JDBP 31(3):223–229
Banaschewski T, Brandeis D, Heinrich H, Albrecht B, Brunner E, Rothenberger A (2003)
Association of ADHD and conduct disorder – brain electrical evidence for the existence of a
distinct subtype. J Child Psychol Psychiatry 44(3):356–376
Baron-Cohen S (1989) Do autistic children have obsessions and compulsions? Br J Clin Psychol
28:193–200
Bearss K, Taylor CA, Aman MG, Whittemore R, Lecavalier L, Miller J, Pritchett J, Green B,
Scahill L (2015) Using qualitative methods to guide scale development for anxiety in youth
with autism spectrum disorder. Autism. Online ahead of print
Berridge KC, Aldridge JW, Houchard KR, Zhuang X (2005) Sequential superstereotypy of anin-
stinctive fixed action pattern in hyperdopaminergic mutant mice: a model of obsessive compul-
sive disorder and Tourette’s. BMC Biol 3:4
Bishop SL, Richler J, Lord C (2006) Association between restricted and repetitive behaviors and
nonverbal IQ in children with autism spectrum disorders. Child Neuropsychol: J Norm Abnorm
Dev Child Adolesc 12(4–5):247–267
Bishop SL, Hus V, Duncan A, Huerta M, Gotham K, Pickles A, Kreiger A, Buja A, Lund S, Lord
C (2013) Subcategories of restricted and repetitive behaviors in children with autism spectrum
disorders. J Autism Dev Disord 43(6):1287–1297
Bodfish JW, Symons FJ, Parker D, Lewis MH (2000) Varieties of repetitive behavior in autism:
comparisons to mental retardation. J Autism Dev Disord 30:237–243
Cipriani G, Vedovello M, Ulivi M, Nuti A, Lucetti C (2013) Repetitive and stereotypic phenomena
and dementia. Am J Alzheimers Dis Other Demen 28(3):223–227
Coury DL, Anagnostou E, Manning-Courtney P, Reynolds A, Cole L, McCoy R, Whitaker A,
Perrin JM (2012) Use of psychotropic medication in children and adolescents with autism
spectrum disorders. Pediatrics 130(Suppl 2):S69–S76
de Wit S, Dickinson A (2009) Associative theories of goal-directed behaviour: a case for animal-
human translational models. Psychol Res 73:463–476
Diniz JB, Rosario-Campos MC, Shavitt RG, Curi M, Hounie AG, Brotto SA, Miguel EC (2004)
Impact of age at onset and duration of illness on the expression of comorbidities in obsessive-
compulsive disorder. J Clin Psychiatry 65(1):22–27
Esbensen AJ, Seltzer MM, Lam KSL, Bodfish JW (2009) Age-related differences in restricted
repetitive behaviors in autism spectrum disorders. J Autism Dev Disord 39:57–66
Gadow KD, DeVincent CJ, Pomeroy J (2006) ADHD symptom subtypes in children with perva-
sive developmental disorder. J Autism Dev Disord 36(2):271–283
Geller DA (2006) Obsessive-compulsive and spectrum disorders in children and adolescents.
Psychiatr Clin North Am 29(2):353–370
Graybiel AM (2008) Habits, rituals, and the evaluative brain. Annu Rev Neurosci 31:359–387
Hagopian LP, Rooker G R, Zarcone JR (2015). Toward the identification of subtypes of self-inju-
rious behavior maintained by automatic reinforcement. Journal of Applied Behavior Analysis,
48:523–543.
Hollander E, Phillips A, Chaplin W, Zagursky K, Novotny S, Wasserman S, Iyengar R (2005) A
placebo controlled crossover trial of liquid fluoxetine on repetitive behaviors in childhood and
adolescent autism. Neuropsychopharmacology 30(3):582–589
Hollander E, Soorya L, Chaplin W, Anagnostou E, Taylor BP, Ferretti CJ, Wasserman S, Swanson
E, Settipani C (2012) A double-blind placebo-controlled trial of fluoxetine for repetitive behav-
iors and global severity in adult autism spectrum disorders. Am J Psychiatry 169(3):292–299
Honey E, McConachie H, Turner M, Rodgers J (2012a) Validation of the repetitive behaviour
questionnaire for use with children with autism spectrum disorder. Res Autism Spectr Dis
6:355–362
Honey E, Rodgers J, McConachie H (2012b) Measurement of restricted and repetitive behaviour
in children with autism spectrum disorder: selecting a questionnaire or interview. Res Autism
Spectr Dis 6(2):757–776
John CE, McCracken CB, Haber SN (2010) Motivation on the Mediterranean: reward, compul-
sions and habit formation. Neurosci Biobehav Rev 34(1):2–6
Kerns CM, Kendall PC (2012) The presentation and classification of anxiety in autism spectrum
disorder. Clin Psychol: Sci Pract 19(4):323–347
King BH, Hollander E, Sikich L, McCracken JT, Scahill L, Bregman JD, Donnelly CL, Anagnostou
E, Dukes K, Sullivan L, Hirtz D, Wagner A, Ritz L, STAART Psychopharmacology Network
(2009) Lack of efficacy of citalopram in children with autism spectrum disorders and high
levels of repetitive behavior: citalopram ineffective in children with autism. Arch Gen
Psychiatry 66(6):583–590
Lam KS, Aman MG (2007) The repetitive behavior scale–revised: independent validation in indi-
viduals with autism spectrum disorders. J Autism Dev Disord 37(5):855–866
Lam KSL, Bodfish JW, Piven J (2008) Evidence for three subtypes of repetitive behavior in autism
that differ in familiality and association with other symptoms. J Child Psychol Psychiatry
49(11):1193–1200
Lecavalier L, Wood JJ, Halladay AK, Jones NE, Aman MG, Cook EH, Handen BL, King BH,
Pearson DA, Hallett V, Sullivan KA, Grondhuis S, Bishop SL, Horrigan JP, Dawson G, Scahill
L (2014) Measuring anxiety as a treatment endpoint in youth with autism spectrum disorder.
Leckman JF, Grice DE, Boardman J, Zhang H, Vitale A, Bondi C, Alsobrook J, Peterson BS,
Cohen DJ, Rasmussen SA, Goodman WK, McDougle CJ, Pauls DL (1997) Symptoms of
obsessive–compulsive disorder. Am J Psychiatry 154:911–917
Leckman JF, Peterson BS, King RA, Scahill L, Cohen DJ (2001) Phenomenology of tics and natu-
ral history of tic disorders. Adv Neurol 85:1–14
Leekam S, Tandos J, McConachie H, Meins E, Parkinson K, Wright C, Turner M, Arnott B,
Vittorini L, Le Couteur A (2007) Repetitive behaviours in typically developing 2-year-olds.
J Child Psychol Psychiatry 48(11):1131–1138
Lewin AB, Wood JJ, Gunderson S, Murphy TK, Storch EA (2011) Phenomenology of comorbid
autism spectrum and obsessive-compulsive disorders among children. J Dev Phys Disabil
23:543–553
Lewis M, Kim SJ (2009) The pathophysiology of restricted repetitive behavior. J Neurodevelopmental
Dis 1(2):114–132
Mataix-Cols D, do Rosario-Campos MC, Leckman JF (2005) A multidimensional model of obses-

sive–compulsive disorder. Am J Psychiatry 162:228–238
McDougle CJ, Kresch LE, Goodman WK, Naylor ST, Volkmar FR, Cohen DJ, Price LH (1995) A
case-controlled study of repetitive thoughts and behavior in adults with autistic disorder and
obsessive-compulsive disorder. Am J Psychiatry 152(5):772–777
McDougle CJ, Naylor ST, Cohen DJ, Volkmar FR, Heninger GR, Price LH (1996) A double-blind,
placebo-controlled study of fluvoxamine in adults with autistic disorder. Arch Gen Psychiatry
53(11):1001–1008
Miguel EC, Leckman JF, Rauch S, do Rosario-Campos MC, Hounie AG, Mercadante MT, Chacon
P, Pauls DL (2005) Obsessive–compulsive disorder phenotypes: implications for genetic stud-
ies. Mol Psychiatry 10:258–275
Mirenda P, Smith IM, Vaillancourt T, Georgiades S, Duku E, Szatmari P et al (2010) Validating the
repetitive behavior scale-revised in young children with autism spectrum disorder. J Autism
Dev Disord 40(12):1521–1530
Monzani B, Rijsdijk F, Harris J, Mataix-Cols D (2014) The structure of genetic and environmental
risk factors for dimensional representations of DSM-5 obsessive-compulsive spectrum disor-
ders. JAMA Psychiatry 71(2):182–189
Morrens M, Hulstijn W, Lewi PJ, De Hert M, Sabbe BG (2006) Stereotypy in schizophrenia.
Schizophr Res 84:397–404
Moss J, Oliver C, Arron K, Burbidge C, Berg K (2009) The prevalence and phenomenology of
repetitive behavior in genetic syndromes. J Autism Dev Dis 39:572–588
Nestadt G, Samuels JF, Riddle MA, Bienvenu OJ, Liang KY, Grados MA, Cullen B (2002)
Obsessive-compulsive disorder: defining the phenotype. J Clin Psychiatry 63(Suppl 6):5–7
Neuropharm. Study of fluoxetine in autism (SOFIA). Available at: http://clinicaltrials.ov/ct2/show/
NCT00515320. Accessed 23 Apr 2011
Oliver C, Petty J, Ruddick L, Bacarese-Hamilton M (2012) The association between repetitive,
self-injurious and aggressive behavior in children with severe intellectual disability. J Autism
Dev Dis 42:910–919
Oswald DP, Sonenklar NA (2007) Medication use among children with autism spectrum disorders.
J Child Adolesc Psychopharmacol 17(3):348–355
Piacentini J (2008) Optimizing cognitive-behavioral therapy for childhood psychiatric disorders.
J Am Acad Child Adolesc Psychiatry 47(5):481–482
Rauch SL, Jenike MA (1993) Neurobiological models of obsessive-compulsive disorder.
Psychosomatics 34(1):20–32
Reiersen AM, Constantino JN, Volk HE, Todd RD (2007) Autistic traits in a population-based
ADHD twin sample. J Child Psychol Psychiatry 48(5):464–472
Rettew DC, Swedo SE, Leonard HL, Lenane MC, Rapoport JL (1992) Obsessions and compul-
sions across time in 79 children and adolescents with obsessive-compulsive disorder. J Am
Acad Child Adolesc Psychiatry 31(6):1050–1056
Romanelli RJ, Wu FM, Gamba R, Mojtabai R, Segal JB (2014) Behavioral therapy and serotonin
reuptake inhibitor pharmacotherapy in the treatment of obsessive-compulsive disorder: a sys-
tematic review and meta-analysis of head-to-head randomized controlled trials. Depression
Anxiety 31(8):641–652
Rosario-Campos MC, Miguel EC, Quatrano S, Chacon P, Ferrao Y, Findley D, Katsovich L,
Scahill L, King RA, Woody SR, Tolin D, Hollander E, Kano Y, Leckman JF (2006) The
dimensional Yale-Brown obsessive-compulsive scale (DY-BOCS): an instrument for assessing
obsessive-compulsive symptom dimensions. J Mol Psychiatry 11(5):495–504
Scahill L, Riddle MA, McSwiggin-Hardin M, Ort SI, King RA, Goodman WK, Cicchetti D,
Leckman JF (1997) Children’s Yale-Brown obsessive compulsive scale: reliability and validity.
Scahill L, Kano Y, King RA, Carlson A, Peller A, LeBrun U, do Rosario-Campos MC, Leckman
JF (2003) Influence of age and tic disorders on obsessive-compulsive disorder in a pediatric
sample. J Child Adolesc Psychopharmacol 13(Suppl 1):S7–S17
Scahill L, McDougle CJ, Williams SK, Dimitropoulos A, Aman MG, McCracken JT, Tierney E,
Arnold LE, Cronin P, Grados M, Ghuman J, Koenig K, Lam KS, McGough J, Posey DJ, Ritz
L, Swiezy NB, Vitiello B, Research Units on Pediatric Psychopharmacology Autism Network
(2006) The Children’s Yale-Brown obsessive compulsive scales modified for pervasive devel-
opmental disorders. J Am Acad Child Adolesc Psychiatry 45(9):1114–1123
Scahill L, Dimitropoulos A, McDougle CJ, Aman MG, Feurer ID, McCracken JT, Tierney E, Pu J,
White S, Lecavalier L, Hallett V, Bearss K, King B, Arnold LE, Vitiello B (2014) Children’s
Yale-Brown obsessive compulsive scale in autism spectrum disorder: component structure of
symptom checklist and distribution of severity scales. J Am Acad Child Adolesc Psychiatry
53(1):97–107
Scahill L, Aman MG, Lecavalier L, Halladay AK, Bishop SL, Bodfish JW, Grondhuis S, Jones N,
Horrigan JP, Cook EH, Handen BL, King BH, Pearson DA, McCracken JT, Sullivan KA,
Dawson G (2015a) Measuring repetitive behaviors as a treatment endpoint in youth with autism
spectrum disorder. Autism 19(1):38–52
Scahill L, Sukhodolsky DG, Anderberg E, Dimitropoulos A, Dziura J, Aman MG, McCracken J,
Tierney E, Hallett V, Katz K, Vitiello B, McDougle C (2015b) Sensitivity of the modified chil-
dren’s Yale-Brown obsessive compulsive scale to detect change: results from two multi-site
trials. Autism 19(1):38–52
population-derived sample. J Am Acad Child Adolesc Psychiatry 47(8):921–929
Turner M (1999) Annotation: repetitive behaviour in autism: a review of psychological research.
Turner-Brown LM, Lam KSL, Holtzclaw TN, Dichter GS, Bodfish JW (2011) Phenomenology
and measurement of circumscribed interests in autism spectrum disorders. Autism
15(4):437–456
van Steensel FJ, Bögels SM, Perrin S (2011) Anxiety disorders in children and adolescents with
autistic spectrum disorders: a meta-analysis. Clin Child Fam Psychol Rev 14(3):302–317
World Health Organization (WHO) (2007) The ICD-10 classification of mental and behavioural
disorders: diagnostic criteria. WHO, Geneva
Schizophrenia Spectrum Disorders
and Autism Spectrum Disorder 4
Katharine Chisholm, Ashleigh Lin, and Marco Armando
1 Introduction
Schizophrenia spectrum disorders (SSD) and autism spectrum disorder (ASD) are
currently conceptualised as separate illnesses. SSD, as defined by the DSM-5,
include schizophrenia, other psychotic disorders, and schizotypal personality disor-
der. This group of disorders involves delusions, hallucinations, disorganised think-
ing, disorganised behaviour, and negative symptoms. Definitions of ASD and SSD
have undergone many revisions. Bleuler (1950) believed that autism was a central
feature of schizophrenia, whilst others viewed it as the childhood onset of the disor-
der (Bender 1947). In fact, the term autism was used interchangeably with schizo-
phrenia until the 1970s, when Rutter (1972) and Kolvin (1971) proposed that they
were distinct disorders. The nosologic separation between ASD and SSD may ini-
tially appear justified given the distinct differences in age of onset and many differ-
ences in presentation. Yet, despite apparent differences, SSD and ASD share
multiple phenotypic similarities and risk factors (Hamlyn et al. 2013; Spek and
Wouters 2010), have both been conceptualised as neurodevelopmental rather than
neurodegenerative disorders (Goldstein et al. 2002), and have been reported to
K. Chisholm (*)
School of Psychology, University of Birmingham, Birmingham, UK
A. Lin
Telethon Kids Institute, The University of Western Australia, Perth, Australia
M. Armando
Child and Adolescence Neuropsychiatry Unit, Department of Neuroscience,
I.R.C.C.S. Bambino Gesù Children’s Hospital, Rome, Italy
Office Médico-Pédagogique Research Unit, Department of Psychiatry, University of Geneva
School of Medicine, Geneva, Switzerland

52 K. Chisholm et al.
co-occur at elevated rates (Mouridsen et al. 2008a, b; Rapoport et al. 2009; Solomon
et al. 2011; Stahlberg et al. 2004). Systematic research on their co-occurrence has
been limited, although emerging genetic and neuroanatomical evidence has led to
increasing recognition of the overlap between the conditions (Carroll and Owen
2009; Cheung et al. 2010).
In this chapter, we describe prevalence rates of overlap between the ASD and
SSD at a clinical and trait level and discuss difficulties in the diagnosis and evalua-
tion of the disorders. We then discuss genetic and neurobiological evidence, high-
lighting similarities and areas of distinction between the disorders. Finally, we
briefly present treatment options, including non-medical and novel treatment strate-
gies as well as pharmacological interventions.
2 Prevalence
Although there have been reports that SSD and ASD do not co-occur at elevated
rates (Volkmar and Cohen 1991), the majority of research suggests that the disor-
ders co-occur at a higher rate than would be expected in the general population. As
ASD and SSD both occur in around 1 % of the population (Brugha et al. 2011;
Kendler et al. 1996; Baio 2012; van Os et al. 2001), studies with fewer than 100
participants are unlikely to be truly representative. We have identified 14 papers that
showed overlapping prevalence of ASD and SSD published since 2004 (Table 4.1).
Of these, nine investigate rates of SSD in ASD populations (Bakken et al. 2010;
Billstedt et al. 2005; Eaves and Ho 2008; Hofvander et al. 2009; Joshi et al. 2010;
Lugnegard et al. 2011; Mouridsen et al. 2008a, b; Stahlberg et al. 2004), and five
examined rates of ASD in those diagnosed with SSD (Davidson et al. 2014;
Hallerback et al. 2012; Solomon et al. 2011; Sporn et al. 2004; Waris et al. 2013).
Only six had samples >100 (Billstedt et al. 2005; Davidson et al. 2014; Hofvander
et al. 2009; Joshi et al. 2010; Mouridsen et al. 2008a, b). These papers found a mean
incidence of 12.8 % of SSD in ASD populations, with only one study reporting on
ASD in SSD with a sample of over 100 (Davidson et al. 2014) and finding an inci-
dence rate of 3.6 %. Large population studies are needed to ascertain true diagnostic
comorbidities in ASD and SSD.
As well as the high prevalence of comorbidity between ASD and SSD, there is
also an overlap in terms of symptoms, at both clinical (Waris et al. 2013) and
subclinical (Bevan Jones et al. 2012) levels. Moreover, neurodevelopmental
abnormalities frequently found in children with ASD, such as a delay in motor
development and impaired receptive language, and relationship and adjustment
difficulties are frequently found as prodromal features of SSD (Owen et al. 2011).
Likewise, childhood deficits documented in those who later develop SSD mimic
ASD traits (Dickson et al. 2011). Whilst in neurotypical adults with well-described
4 Schizophrenia Spectrum Disorders and Autism Spectrum Disorder 53
Table 4.1 Rates of co-occurrence between ASD and SSD

Authors n % co-occurrence
SSD in ASD populations
Eaves and Ho (2008) 48 young adults with ASD 0%
Lugnegard et al. (2011) 54 young adults with Asperger syndrome 3.7 %
Mouridsen et al. (2008a, b) 118 individuals diagnosed as children with 6.6 %
infantile autism
Billstedt et al. (2005) 120 individuals with autism diagnosed in 7%
childhood
Hofvander et al. (2009) 122 adults with normal intelligence ASD 12 %
Stahlberg et al. (2004) 129 adults diagnosed with ASD 14.8 %
Joshi et al. (2010) 217 children and adolescents meeting 20 %
diagnostic criteria for an ASD
Bakken et al. (2010) 62 adults with autism and intellectual 25.1 %
disability
Mouridsen et al. (2008a, b) 89 individuals with atypical autism 34.8 %
ASD in SSD populations
Davidson et al. (2014) 197 adults attending an early intervention in 3.6 %
psychosis service
Sporn et al. (2004) 75 children with COS 3.9 %
Solomon et al. (2011) 16 individuals with first episode of psychosis 19 %
Waris et al. (2013) 18 adolescents with early-onset 44 %
schizophrenia
Hallerback et al. (2012) 46 adults with a diagnoses of schizophrenic 50–60 %
psychotic disorders
symptoms differentiating between psychotic and autistic symptoms is not particu-

larly challenging, diagnostic difficulties are more common in the early phase of
these disorders, when symptoms are less clear cut, or in individuals who lack the
receptive or expressive language skills to describe their symptoms (Dossetor
2007). Hallucinatory experiences, for example, are often reported in individuals
with ASD, although differentiating between an external voice and an internal dia-
logue may be difficult. In this regard, sensory abnormalities are reported in as
many as 90 % of children with ASD and can be misinterpreted as hallucinations
(Leekam et al. 2007). Conversely, some symptoms, which are core feature of
ASD, are frequently seen and often misinterpreted in individuals with SSD. For
example, a deficit in emotion recognition, leading to misinterpretations of the
actions of others as paranoid delusions, is a core feature of ASD and also common
in SSD (Kaland et al. 2008).
Given the arbitrary nature of diagnostic thresholds and the heterogeneity of pre-
sentations of individuals with ASD and SSD, it is important to consider the co-
occurrence at the trait level. A descriptive overlap exists in the traits that make up
the diagnostic criteria for ASD and SSD. Both disorders include deficits in social
interaction and communication as primary symptoms; the lack of emotional reci-
procity in ASD can be compared to blunted affect (a lack of emotional response) in
SSD; the delay or lack of speech development in ASD parallels alogia (poverty of
speech) in SSD; and catatonic features are observed in both diagnoses. It is perhaps
unsurprising that much research has found co-occurrence of traits such as these (e.g.
Brüne 2005; Spek and Wouters 2010). Similarities are also found in traits that relate
to, but are not part of, the diagnostic criteria. Theory of mind and mentalising
impairments are hypothesised to be central to both disorders (Baron-Cohen et al.
1985; Bora et al. 2009; Brüne 2005; Chung et al. 2013). Similarly, Eack et al. (2013)
report that those with ASD and SSD experience similar deficits in their neurocogni-
tive and social cognitive functioning.
Conversely, other authors report traits that do differentiate between the disor-
ders. Intellectual disability, for example, is more common in ASD than SSD
(Baio 2010; Cooper 1997; Morgan and Jorm 2008). Although both disorders
show a higher male to female ratio in individuals diagnosed, the male-female
ratio appears to be considerably higher in ASD than SSD (Ochoa et al. 2012;
Wing 1981b). Level of communication deficits may also differentiate between
ASD and SSD. In a study comparing individuals at risk for psychosis, those with
a first episode of psychosis, individuals with autism, and healthy controls,
Solomon and colleagues (2011) found that 20 % of those in the high risk or first-
episode psychosis groups met diagnostic criteria for ASD as assessed by parental
report. However, there were a number of traits which distinguished between the
different diagnostic categories. Atypical developmental trajectories in communi-
cation and social behaviours, as well as structural and pragmatic language, were
found to a much greater extent in the ASD group compared to the SSD and con-
trol groups. Similarly, when comparing individuals with ASD and SSD, Spek
and Wouters (2010) demonstrated that individuals with ASD reported more
impairment with social skills, attention switching, and communication than those
with SSD.
There is also longitudinal evidence for an overlap between ASD and SSD at
the trait level. Evidence from two large cohort studies has confirmed that the
presence of psychotic experiences at age 12 is associated with ASD traits earlier
in life (Bevan Jones et al. 2012; Sullivan et al. 2013). Similarly, meta-analysis
has recently confirmed that childhood deficits documented in those who later
develop SSD mimic ASD traits (Dickson et al. 2011). Whether these traits reflect
aspects of ASD which were undiagnosed or did not reach clinical significance or
instead reflect the status of SSD as a neurodevelopmental disorder remains to be
determined.
Other research suggests, however, that ASD traits may not be predictive of the
development of SSD. A study from Vorstman and colleagues (2013) investigated
childhood ASD traits in 78 patients with 22q11.2 deletion syndrome, 36 of whom
had developed psychotic disorder. High levels of ASD traits were reported to have
occurred during childhood in their population, but were not predictive of the devel-
opment of SSD. Higher rates of ASD traits had a stronger association with the non-
psychotic individuals with the deletion, suggesting that, in the case of 22q11.2
deletion syndrome, the disorders share a genetic vulnerability but are distinct in
their expression of this vulnerability.
4 Peculiar Features of the Disorder in Comorbidity with ASD
As can be seen in the section above, there are many shared traits or symptoms
between those diagnosed with ASD and those diagnosed with SSD. Despite this,
often symptoms can still be distinctive. For example, in ASD misinterpretations of
other’s behaviours/emotions, which lead to delusions, are mostly caused by a lack
of social cognition (Blackshaw et al. 2001). On the other hand, in people with SSD,
the process that leads to delusion formation is mostly driven by affective dysregula-
tion (Smeets et al. 2012), rather than a deficit in social cognition. Thus, whilst it can
be difficult to differentiate between individuals with ASD and SSD by focusing on
clinical presentation of the delusional symptom alone, a clearer differentiation can
be found at a phenomenological level. These differences in phenomenological char-
acterisation of the delusion have relevant consequences in the choice of and response
to treatments.
Beyond the peculiar features of psychotic symptoms in ASD and SSD, what is
interesting to note is that, among individuals with from SSD, some are characterised
by an evident autistic phenotype, whilst positive psychotic symptoms are less prom-
inent (King and Lord 2011). Retrospective research has identified two subgroups
within SSD populations: a larger group with relatively little behavioural impairment
throughout childhood and a smaller group which displays early behavioural abnor-
malities (Corcoran et al. 2003; Rossi et al. 2000). This latter subgroup of patients
can be characterised by difficulties in the metacognitive domain, emotion process-
ing, and motor abnormalities (Cheung et al. 2010) as well as an earlier onset of SSD
and a more chronic course of illness (Myin-Germeys and van Os 2007; Rossi et al.
2000). At the same time, this subgroup usually shows a prevalence of negative
symptoms and obtains high scores on the Autism Diagnostic Observation Schedule
(ADOS; Bastiaansen et al. 2011), leading some to suggest they may be a potential
subgroup with a stronger association to ASD (Konstantareas and Hewitt 2001).
Anecdotally, the diagnosis of ASD in SSD (and vice versa) poses problems. There
are currently no assessment tools for differentiating ASD and SSD despite their com-
mon co-occurrence, and diagnosis is usually made via clinical interview. Unless an
individual with SSD has been given a diagnosis with ASD as a child, the diagnosis
of ASD is clinically challenging. For example, the clinician must differentiate nega-
tive symptoms from stable traits of ASD. Researchers have investigated ASD in
populations with SSD and first-episode psychosis and individuals at ultra-high risk
(UHR) for psychosis (the criteria for which are based on a combination of state and
trait risk factors; the most common of these are attenuated positive psychotic symp-
toms below the threshold for a diagnosis of frank psychosis; Yung et al. 1996). Some
researchers have employed lengthy diagnostic interviews such as the Diagnostic
Interview for Social and Communication Disorders (DISCO; Wing 2006) to diag-
nose ASD in populations with SSD (Waris et al. 2013; Hallerback et al. 2012). Others
have used the Social Communication Questionnaire (Rutter et al. 2003), which is
based on the Autism Diagnostic Observation Schedule (ADOS), to approximate a
diagnosis of ASD (Soloman et al. 2011; Sprong et al. 2008). ASD screening tools
have also been used for this purpose (Davidson et al. 2014; Sporn et al. 2004), such
as the Autism Screening Questionnaire (Berument et al. 1999) or Autism Spectrum
Disorder in Adults Screening Questionnaire (Nylander and Gillberg 2001). However,
these instruments may lack validity in a person help-seeking for psychological dis-
tress, and differentiating state and trait symptoms is challenging. Indeed, if an indi-
vidual is floridly psychotic or psychologically very unwell, completing these
measures may not be possible. Thus the comorbid diagnosis of ASD in SSD is best
conducted after symptom stabilisation, with primary goal of diagnosis to be how
therapy (particularly psychological therapy) might be best delivered.
The diagnosis of SSD in a person with ASD can be even more difficult. No
assessment tools have been developed that account for many of the core features of
ASD, in particular deficits in communication. Establishing the functional impact of
psychosis is also a challenging task since individuals with ASD may to already have
deficits in everyday functioning, especially within the social domain. In verbal indi-
viduals with ASD, semi-structured interviews, such as the Positive and Negative
Symptom Scale (PANSS, Kay et al. 1987), may be useful for the determination of
positive symptomology. Scales used to assess the UHR state may also be valuable,
such as the Comprehensive Assessment of the At-Risk Mental State (CAARMS;
Yung et al. 2005) or the Structured Interview for Prodromal Symptoms (SIPS;
McGlashan et al. 2001). The advantage of these assessments is that subthreshold
symptoms are captured. If the individual does meet the UHR criteria, it is up to the
clinician to make the judgement on whether these symptoms represent the prodrome
of a psychotic disorder or whether they are more stably related to the individual’s
ASD. All of these tools can be used to assess negative and disorganised symptoms
in people with ASD, although determining if these types of symptoms are related to
psychosis and require treatment or are state traits of ASD is more complex. In sum-
mary, we suggest that the diagnosing psychotic symptoms in individuals with ASD
should be done by a multidisciplinary team via clinical interview and using the vali-
dated measures where possible. There is a clear need to develop improved means of
diagnosis of psychosis in individuals with ASD.
6 Neurobiological Bases and Genetic Overlap
6.1 Genetic Risk Factors
ASD and SSD rates of heritability are both estimated to be high at around 50–80 %
(Cardno and Gottesman 2000; Freitag 2006; Sandin et al. 2014). What is particu-
larly interesting is the fact that, as well as showing high levels of heritability
within each disorder, there is evidence of relatively high levels of heritability
between the disorders (Daniels et al. 2008; Larsson et al. 2005; Sporn et al. 2004;
Sullivan et al. 2012).
This is consistent with studies investigating copy number variants (CNVs; varia-
tions of DNA sequence in the genome) in SSD and ASD. Particular CNVs are
implicated in both ASD and SSD, and specific rare alleles have been found to occur
in both disorders (Lionel et al. 2013; McCarthy et al. 2009; Moreno-De-Luca et al.
2010; Weiss et al. 2008). The high number of shared CNV deletions and duplica-
tions, including NRXN1, CNTNAP2, 22q11.2, 1q21.1, and 15q13.3, led Carroll
and Owens (2009) to conclude in their review that genetic evidence challenges the
assumption that ASD and SSD are completely unrelated disorders.
A particularly compelling example of overlapping genetic vulnerability comes
from the high rates of ASD and SSD seen in individuals with 22q11.2 deletion syn-
drome. In the largest study to date, investigators examined psychiatric morbidity in
1,402 individuals with the syndrome (Schneider et al. 2014). SSD were found in
1.97 % of children aged 6–12, 10.12 % of adolescents aged 13–17, 23.53 % of
emerging adults aged 18–25, 41.33 % of young adults aged 26–35, and 41.73 % of
mature adults aged 36 or above. Similarly high rates of ASD were also found, with
rates varying across the life span of 12.77 % for children, to 26.54 % for adoles-
cents, and to 16.10 % for adults.
There is also evidence of genetic differentiation between the disorders. Whilst
CNVs appear to be enriched in individuals with ASD and SSD, common risk alleles
have not generally been found to be shared between the disorders. Using genome-
wide genotype data from the Cross-Disorder Group of the Psychiatric Genomics
Consortium (2013), only a low genetic correlation was found between ASD and
SSD. This suggests that common risk variants may play a limited role in ASD when
compared to SSD, particularly when considering the lack of confirmed genome-
wide association study results in ASD (Devlin et al. 2011).
6.2 Neurobiological Risk Factors
Neuroimaging evidence presents a similar picture to phenomenological and genetic

risk factor research, with many similarities apparent between the disorders, but also
some differences. In terms of similarities, both individuals with ASD and those with
SSD have been found via meta-analysis to show reduced grey matter volume in
limbic-striato-thalamic circuitry, predominantly on the right, including the insula,
posterior cingulate, and parahippocampal gyrus (Cheung et al. 2010).
Reduced fractional anisotropy values (reflecting altered white matter integrity)
have also been found in both disorders (Mueller et al. 2012). In ASD, implicated
areas include the corpus callosum, the right corticospinal tract, the internal capsule,
the left and right pedunculi cerebri, and the cingulate gyrus (Bloemen et al. 2010;
Brito et al. 2009). Within SSD, implicated areas are the left frontal deep white mat-
ter including the frontal lobe, thalamus, and cingulate gyrus and the left temporal
deep white matter including the frontal lobe, insula, hippocampus-amygdala com-
plex, and temporal and occipital lobes (Ellison-Wright and Bullmore 2009).
Functional imaging analyses have focused on social cognition as a primary
feature of both disorders. A meta-analysis has shown that brain regions thought
to be part of a social cognition network show hypoactivation in both ASD and

SSD in response to social stimuli, most consistently seen in the medial prefrontal
cortex and superior temporal sulcus (Sugranyes et al. 2011). Similarly, a review
from Abdi and Sharma (2004) found reductions in blood flow to the fusiform
gyrus and abnormal amygdala activation during emotional perception tasks in
both ASD and SSD.
Neurochemical abnormalities such as dopamine disruption have also been
observed in both disorders (Cartier et al. 2015; Hérault et al. 1993; Muck-Seler et al.
2004; Stone et al. 2007). Within SSD dopamine disruption has been identified as a
central feature of the disorder (Howes and Kapur 2009; Winton-Brown et al. 2014).
Research into the dopamine system in ASD is more limited. In a study which com-
pared eight adults with Asperger syndrome to five healthy controls using positron
emission tomography (PET), Nieminen-von Wendt et al. (2004) found increased
FDOPA influx (Ki) values in the striatum of the ASD group. Similarly, in another
PET study which compared 20 individuals with ASD with control participants, an
over-functioning of dopaminergic systems in the orbitofrontal cortex was suggested
by a higher level of dopamine transporter bindings in the ASD group when com-
pared to controls (Nakamura et al. 2010).
There are also potential areas of distinction between the disorders. These include
increased cerebral ventricle volume and a reduction in overall brain volume found
in individuals with SSD but not ASD (Shenton et al. 2001; Toal et al. 2009), as well
as decreased white matter integrity, again found in individuals diagnosed with SSD
but not ASD (Davis et al. 2003; Hao et al. 2006; Toal et al. 2009). A meta-analysis
from Cheung et al. (2010), which aimed to quantify structural similarities between
ASD and SSD, found that abnormalities in the right and left superior and medial
frontal gyrus, right and left cingulate, left insula, caudate, temporal gyrus, and
amygdala were specific to SSD and abnormalities in the left putamen appeared
specific to ASD.
Other research, particularly studies investigating social deficits, has found
opposing patterns of activation during functional magnetic resonance imaging
(fMRI). A recent study from Ciaramidaro et al. (2014), which directly compared
individuals with ASD and SSD on different types of intentionality, found that acti-
vation between the right posterior superior temporal sulcus and the ventral medial
prefrontal cortex was abnormal in both groups, with an increased connectivity
found in those with SSD and a decreased connectivity in those with ASD. The
increased connectivity in SSD was found during the control condition (‘physical
intentionality’, e.g. a balloon is blown by a gust of wind), and the decreased con-
nectivity in ASD was found during the experimental intention condition. The
authors argue that this is consistent with the hypo-hyper-intentionality hypothesis
(Abu-Akel and Bailey 2000; Crespi and Badcock 2008) that individuals with SSD
over-attribute intentions to others and physical events, whereas those with ASD
often fail to attribute intentions to others. This hypothesis parallels evidence from
EEG studies which find reduced Mu suppression (used as marker for mirror neuron
activity) in ASD participants taking part in socio-emotional tasks (Oberman et al.
2005) and increased Mu suppression in those with SSD (McCormick et al. 2012).
A particularly interesting investigation of brain anatomy in individuals with ASD

compared to those with comorbid ASD and SSD found that the primary differences
in those with comorbid ASD and SSD (compared to those with ASD alone) related
to reductions in grey matter in the right insular cortex, the cerebellum, the fusiform
gyrus and the lingual gyri (Toal et al. 2009). Toal et al. (2009) note that their partici-
pants with comorbid ASD and SSD did not display the same changes usually found
in populations who have developed SSD such as an increased volume of cerebral
ventricles with a reduction in total brain volume (Shenton et al. 2001). They suggest
that their comorbid population appear to share more anatomical similarities with
individuals in UHR for psychosis groups rather than those with frank SSD and points
out that the cerebellum and fusiform gyrus (which showed reductions in their comor-
bid population) have been implicated in UHR individuals (alongside left parahippo-
campal gyrus and the orbitofrontal and cingulate cortex, e.g. Job et al. 2005; Pantelis
et al. 2003). Toal et al. suggest that these anatomical differences may hint that, for
some individuals, ASD represent a different pathway into SSD.
7 Treatment
Whilst there is a robust literature on pharmacological and psychosocial treatments

for ASD and SSD as separate disorders, there is a strong lack of evidence on the
treatment of psychotic symptoms and SSD in comorbidity with ASD (Na Young
and Findling 2015; Starling and Dossetor 2009). There is an established evidence
base for early intervention in psychosis (Hollis 2013; Marshall and Rathbone 2011),
which includes symptom-targeted interventions, low starting doses of atypical anti-
psychotics, psychoeducation for patients and families, other psychosocial interven-
tions as needed, and assertive community treatment. Very limited data exist on the
treatment of SSD in ASD, and to the best of our knowledge, no randomised con-
trolled trials have been conducted to date.
Antipsychotic drugs (APD) have had a long association with ASD (Cohen et al.
1978). Nevertheless, most of the studies are focused on the effectiveness of APD for
the treatment of behavioural disorders in ASD. In this regard, the Research Units on
Pediatric Psychopharmacology (RUPP) study (Arnold et al. 2003, 2005) showed
their efficacy for treating disruptive behaviour in ASD (tantrums, aggression, and
hyperactivity). However, a rapid return of disruptive and aggressive behaviour after
discontinuation emerged. Second-generation antipsychotics (SGAs) in general
(particularly risperidone and aripiprazole) appear to be more effective in controlling
positive and disorganised symptoms (Ching and Pringsheim 2012; Na Young and
Findling 2015). The side effects such as metabolic adverse events, including weight
gain and dyslipidaemia, appear to be more common than in SSD without ASD
(Arnold et al. 2005; Ching and Pringsheim 2012; Na Young and Findling 2015).
Overall, efficacy and tolerability of APD in patients with ASD and psychotic
symptoms are less favourable than in patients with SSD alone (Ameis et al. 2013).
Similarly, limited data exist for non-medical treatment of psychotic symptoms in

ASD. Psychosocial interventions are now recognised as important components of a
comprehensive therapeutic approach in schizophrenia, improving outcomes, reduc-
ing negative symptoms, and increasing functional recovery. Moreover, pharmaco-
logical treatment alone has limited efficacy on negative symptoms and functional
recovery (Hollis 2003). Consequently, there is a growing interest in psychosocial
interventions, which are now recognised as an important component of a compre-
hensive therapeutic approach in schizophrenia (Armando et al. 2015). Indeed, there
are relatively large numbers of randomised studies on the efficacy of psychosocial
interventions such as cognitive-behavioural therapy, cognitive remediation, psycho-
education, and family intervention (Morrison et al. 2012; Puig et al. 2014; Wykes
and Reeder 2005), and several systematic reviews have been conducted on this topic
(Pilling et al. 2002; Tarrier et al. 2002). Nevertheless, there is a distinct lack of evi-
dence regarding the efficacy of psychosocial interventions for psychotic symptoms
in ASD. To date, no randomised controlled trial, systematic review, or meta-analysis
has been conducted on this topic.
The relative success of APD in treating positive symptoms in SSD is limited by their
lack of efficacy for negative and cognitive symptoms, which often determine the
level of functional impairment. In addition, whilst SGAs produce fewer motor side
effects, safety and tolerability concerns about metabolic syndrome have emerged.
Consequently, there is an urgent need for more effective and better-tolerated APD
and to identify new molecular targets. Following this evidence, a variety of new
experimental pharmacological approaches have emerged in SSD recently, including
molecules acting on targets other than the dopamine D2 receptor. In this context,
future drug development strategies can fall into three categories: (1) improvement
of precedent mechanisms of action to provide drugs of comparable or superior effi-
cacy and side effect profiles to existing APD, (2) development of non-D2 mecha-
nism APD, and (3) development of interventions as adjuncts to APD to augment
efficacy by targeting specific symptom dimensions of SSD (Miyamoto et al. 2012).
In this regard, newer agents, including glutamatergic agents, oxytocin, tolcapone,
and entacapone, appear promising albeit with mixed results (Apud and Weinberger
2007; Gupta et al. 2011; Na Young and Findling 2015). Nevertheless, none of these
novel treatment strategies, as well as previous well-consolidated pharmacological
and non-pharmacological intervention for SSD, have been tested, validated, and
replicated for psychotic symptoms in ASD. To date only few open-label studies
exist on the efficacy of those interventions in this group of patients.
It is becoming increasingly evident that it is necessary to prospectively investigate

the co-occurrence of, and commonalities between, SSD and ASD at the trait level
using multifactorial data from large samples. Undiagnosed co-occurring disorders
may result in individuals not receiving appropriate services, benefits, or treat-
ment, and given the similarities between disorders, misdiagnosis is possible
(Davidson et al. 2014; Wing 1981a). There is clearly a need for the development
of appropriate diagnostic tools to differentiate between ASD and SSD and for
research investigating optimal pharmacological treatments of patients presenting
with both disorders. It is important that future research accounts for the heteroge-
neity of both disorders and examines evidence on multiple levels to identify endo-
phenotypic markers, as well as taking the dimensional nature of the disorders into
consideration. Together, these approaches can provide an important conceptual
framework for understanding the association between ASD and SSD. This in turn
may lead towards the development of a fundamental understanding of the two
disorders.
References
Abdi Z, Sharma T (2004) Social cognition and its neural correlates in schizophrenia and autism.
CNS Spectr 9:335–343
Abu-Akel A, Bailey AL (2000) Letter. Psychol Med 30(03):735–738
Ameis SH, Corbett-Dick P, Cole L, Correll CU (2013) Decision making and antipsychotic medica-
tion treatment for youth with autism spectrum disorders: applying guidelines in the real world.
J Clin Psychiatry 74(10):1022–1024
Apud JA, Weinberger DR (2007) Treatment of cognitive deficits associated with schizophrenia.
CNS Drugs 21(7):535–557
Armando M, Pontillo M, Vicari S (2015) Psychosocial interventions for very early and early-onset
schizophrenia: a review of treatment efficacy. Curr Opin Psychiatry 28:312–323
Arnold LE, Vitiello B, McDougle C et al (2003) Parent defined target symptoms respond to risperi-
done in RUPP autism study: customer approach to clinical trials. J Am Acad Child Adolesc
Psychiatry 42:1143–1450
Arnold LE, Vitiello B, McDougle C et al (2005) Risperidone treatment of autistic disorder: longer-
term benefits and blinded discontinuation after 6 months. Am J Psychiatry 162(7):1361–1369
Baio J (2010) Prevalence of autism spectrum disorder among children aged 8 years – autism and
developmental disabilities monitoring network, 11 Sites, United States. Centers for Disease
Control and Prevention
Baio J (2012) Prevalence of autism spectrum disorders: autism and developmental disabilities
monitoring network, 14 sites, United States, 2008. Morbidity and mortality weekly report.
Surveillance Summaries. Vol. 61(3). Centers for Disease Control and Prevention
Bakken TL, Helverschou SB, Eilertsen DE, Heggelund T, Myrbakk E, Martinsen H (2010)
Psychiatric disorders in adolescents and adults with autism and intellectual disability: a repre-
sentative study in one county in Norway. Res Dev Disabil 31(6):1669–1677
Baron-Cohen S, Leslie AM, Frith U (1985) Does the autistic child have a “theory of mind”?
Cognition 21(1):37–46
Bastiaansen JA, Meffert H, Hein S, Huizinga P, Ketelaars C, Pijnenborg M, de Bildt A (2011)
Diagnosing autism spectrum disorders in adults: the use of Autism Diagnostic Observation
Schedule (ADOS) module 4. J Autism Dev Disord 41(9):1256–1266
Bender L (1947) Childhood schizophrenia. Am J Orthopsychiatry 17(1):40–56
Berument SK, Rutter M, Lord C, Pickles A, Bailey A (1999) Autism screening questionnaire:
diagnostic validity. Br J Psychiatry 175(5):444–451
Bevan Jones R, Thapar A, Lewis G, Zammit S (2012) The association between early autistic traits
and psychotic experiences in adolescence. Schizophr Res 135:164–169
Billstedt E, Gillberg C, Gillberg C (2005) Autism after adolescence: population-based 13-to
22-year follow-up study of 120 individuals with autism diagnosed in childhood. J Autism Dev
Disord 35(3):351–360
Blackshaw AJ, Kinderman P, Hare DJ, Hatton C (2001) Theory of mind, causal attribution and
paranoia in Asperger syndrome. Autism 5(2):147–163
Bleuler E (1950) Dementia Praecox or the Group of Schizophrenias, 1911 (English translation: J.
Zinkin). International Universities Press, New York
Bloemen OJ, Deeley Q, Sundram F, Daly EM, Barker GJ, Jones DK, Murphy KC (2010) White
matter integrity in Asperger syndrome: a preliminary diffusion tensor magnetic resonance
imaging study in adults. Autism Res 3(5):203–213
Bora E, Yucel M, Pantelis C (2009) Theory of mind impairment in schizophrenia: meta-analysis.
Schizophr Res 109(1):1–9
Brito AR, Vasconcelos MM, Domingues RC, da Cruz Jr H, Celso L, Rodrigues LDS, Calçada
CABP (2009) Diffusion tensor imaging findings in school‐aged autistic children.
J Neuroimaging 19(4):337–343
Brugha TS, McManus S, Bankart J, Scott F, Purdon S, Smith J, Meltzer H (2011) Epidemiology of
autism spectrum disorders in adults in the community in England. Arch Gen Psychiatry
68(5):459–465
Brüne M (2005) “Theory of mind” in schizophrenia: a review of the literature. Schizophr Bull
31(1):21–42
Cardno AG, Gottesman II (2000) Twin studies of schizophrenia: from bow‐and‐arrow concor-
dances to star wars Mx and functional genomics. Am J Med Genet 97(1):12–17
Carroll LS, Owen MJ (2009) Genetic overlap between autism, schizophrenia and bipolar disorder.
Genome Med 1(10):102
Cartier E, Hamilton PJ, Belovich AN, Shekar A, Campbell NG et al. 2015. Rareautism-associated
variants implicate syntaxin 1 (STX1 R26Q) phosphorylation and the dopamine transporter
(hDAT R51W) in dopamine neurotransmission and behaviors. EBioMedicine 2:135–146
Cheung C, Yu K, Fung G, Leung M, Wong C, Li Q, McAlonan G (2010) Autistic disorders and
schizophrenia: related or remote? An anatomical likelihood estimation. PLoS One 5(8):e12233
Ching H, Pringsheim T (2012) Aripiprazole for autism spectrum disorders (ASD). Cochrane
Database Syst Rev 5
Chung YS, Barch D, Strube M (2014) A meta-analysis of mentalizing impairments in adults with
schizophrenia and autism spectrum disorder. Schizophr Bull 40(3):602–616
Ciaramidaro A, Bölte S, Schlitt S, Hainz D, Poustka F, Weber B, Walter H (2015) Schizophrenia
and autism as contrasting minds: neural evidence for the hypo-hyper-intentionality hypothesis.
Schizophr Bull 41(1):171–179
Cohen IL, Anderson LT, Campbell M (1978) Measurement of drug effects in autistic children.
Psychopharmacol Bull 14(4):68–70
Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Genetic relationship between
five psychiatric disorders estimated from genome-wide SNPs. Nat Genet 45(9):984–994
Cooper SA (1997) Psychiatry of elderly compared to younger adults with intellectual disabilities.
J Appl Res Intellect Disabil 10(4):303–311
Corcoran C, Davidson L, Sills-Shahar R, Nickou C, Malaspina D, Miller T, McGlashan T (2003)
A qualitative research study of the evolution of symptoms in individuals identified as prodro-
mal to psychosis. Psychiatr Q 74(4):313–332
Crespi B, Badcock C (2008) Psychosis and autism as diametrical disorders of the social brain.
Behav Brain Sci 31(03):241–261
Daniels JL, Forssen U, Hultman CM, Cnattingius S, Savitz DA, Feychting M, Sparen P (2008)
Parental psychiatric disorders associated with autism spectrum disorders in the offspring.
Pediatrics 121(5):E1357–E1362. doi:10.1542/peds.2007-2296
Davidson C, Greenwood N, Stansfield A, Wright S (2014) Prevalence of Asperger syndrome

among patients of an early intervention in psychosis team. Early Interv Psychiatry 8(2):138–
146. doi:10.1111/eip.12039
Davis KL, Stewart DG, Friedman JI, Buchsbaum M, Harvey PD, Hof PR, Haroutunian V (2003)
White matter changes in schizophrenia: evidence for myelin-related dysfunction. Arch Gen
Psychiatry 60(5):443
Devlin B, Melhem N, Roeder K (2011) Do common variants play a role in risk for autism?
Evidence and theoretical musings. Brain Res 1380:78–84
Dickson H, Laurens K, Cullen A, Hodgins S (2011) Meta-analyses of cognitive and motor function
in youth aged 16 years and younger who subsequently develop schizophrenia. Psychol Med
1(1):1–13
Dossetor DR (2007) ‘All that glitters is not gold’: misdiagnosis of psychosis in pervasive develop-
mental disorders – a case series. Clin Child Psychol Psychiatry 12(4):537–548
Eack SM, Bahorik AL, McKnight SA, Hogarty SS, Greenwald DP, Newhill CE, Minshew NJ
(2013) Commonalities in social and non-social cognitive impairments in adults with autism
spectrum disorder and schizophrenia. Schizophr Res 148(1):24–28
Eaves LC, Ho HH (2008) Young adult outcome of autism spectrum disorders. J Autism Dev
Disord 38(4):739–747
Ellison-Wright I, Bullmore E (2009) Meta-analysis of diffusion tensor imaging studies in schizo-
phrenia. Schizophr Res 108(1):3–10
Freitag CM (2006) The genetics of autistic disorders and its clinical relevance: a review of the lit-
erature. Mol Psychiatry 12(1):2–22
Goldstein G, Minshew NJ, Allen DN, Seaton BE (2002) High-functioning autism and schizophre-
nia: a comparison of an early and late onset neurodevelopmental disorder. Arch Clin
Neuropsychol 17(5):461–475
Gupta M, Kaur H, Jajodia A, Jain S, Satyamoorthy K, Mukerji M, Kukreti R (2011) Diverse facets
of COMT: from a plausible predictive marker to a potential drug target for schizophrenia. Curr
Mol Med 11(9):732–743
Hallerback MU, Lugnegard T, Gillberg C (2012) Is autism spectrum disorder common in schizo-
phrenia? Psychiatry Res 198(1):12–17
Hamlyn J, Duhig M, McGrath J, Scott J (2013) Modifiable risk factors for schizophrenia and
autism – shared risk factors impacting on brain development. Neurobiol Dis 53:3–9.
doi:10.1016/j.nbd.2012.10.023
Hao Y, Liu Z, Jiang T, Gong G, Liu H, Tan L, Zhang Z (2006) White matter integrity of the whole
brain is disrupted in first-episode schizophrenia. Neuro Rep 17(1):23–26
Hérault J, Martineau J, Perrot-Beaugerie A, Jouve J, Tournade H, Barthelemy C, Muh J-P (1993)
Investigation of whole blood and urine monoamines in autism. Eur Child Adolesc Psychiatry
2(4):211–220
Hofvander B, Delorme R, Chaste P, Nydén A, Wentz E, Ståhlberg O, Gillberg C (2009) Psychiatric
and psychosocial problems in adults with normal-intelligence autism spectrum disorders. BMC
Psychiatry 9(1):35
Hollis C (2003) Developmental precursors of child-and adolescent-onset schizophrenia and affec-
tive psychoses: diagnostic specificity and continuity with symptom dimensions. The Br J
Hollis C, Kendall T, Birchwood M et al (2013) Psychosis and schizophrenia in children and young
people, vol 155, Clinical Guideline. National Institute for Health and Clinical Excellence,
London, pp 1–51
Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III – the final
common pathway. Schizophr Bull 35(3):549–562
Job DE, Whalley HC, Johnstone EC, Lawrie SM (2005) Grey matter changes over time in high risk
subjects developing schizophrenia. Neuroimage 25(4):1023–1030
Joshi G, Petty C, Wozniak J, Henin A, Fried R, Galdo M, Biederman J (2010) The heavy burden
of psychiatric comorbidity in youth with autism spectrum disorders: a large comparative study
of a psychiatrically referred population. J Autism Dev Disord 40(11):1361–1370
Kaland N, Callesen K, Møller-Nielsen A, Mortensen EL, Smith L (2008) Performance of children

and adolescents with Asperger syndrome or high-functioning autism on advanced theory of
mind tasks. J Autism Dev Disord 38(6):1112–1123
Kay SR, Flszbein A, Opfer LA (1987) The positive and negative syndrome scale (PANSS) for
schizophrenia. Schizophr Bull 13(2):261
Kendler KS, Gallagher TJ, Abelson JM, Kessler RC (1996) Lifetime prevalence, demographic risk
factors, and diagnostic validity of nonaffective psychosis as assessed in a US community sam-
ple: the national comorbidity survey. Arch Gen Psychiatry 53(11):1022–1031
King BH, Lord C (2011) Is schizophrenia on the autism spectrum? Brain Res 1380:34–41
Kolvin I (1971) Studies in the childhood psychoses: I. Diagnostic criteria and classification. Br
J Psychiatry 118(545):381–384
Konstantareas MM, Hewitt T (2001) Autistic disorder and schizophrenia: diagnostic overlaps.
Larsson HJ, Eaton WW, Madsen KM, Vestergaard M, Olesen AV, Agerbo E, Mortensen PB (2005)
Risk factors for autism: perinatal factors, parental psychiatric history, and socioeconomic sta-
tus. Am J Epidemiol 161(10):916–925. doi:10.1093/aje/kwi123
Leekam SR, Nieto C, Libby SJ, Wing L, Gould J (2007) Describing the sensory abnormalities of
children and adults with autism. J Autism Dev Disord 37(5):894–910
Lionel AC, Vaags AK, Sato D, Gazzellone MJ, Mitchell EB, Chen HY, Thiruvahindrapuram B
(2013) Rare exonic deletions implicate the synaptic organizer Gephyrin (GPHN) in risk for
autism, schizophrenia and seizures. Hum Mol Genet 22(10):2055–2066
Lugnegard T, Hallerback MU, Gillberg C (2011) Psychiatric comorbidity in young adults with a
clinical diagnosis of Asperger syndrome. Res Dev Disabil 32(5):1910–1917. doi:10.1016/j.
ridd.2011.03.025
Marshall M, Rathbone J (2011) Early intervention for psychosis. Schizophr Bull 37(6):1111–1114
McCarthy SE, Makarov V, Kirov G, Addington AM, McClellan J, Yoon S, Krastoshevsky O
(2009) Microduplications of 16p11. 2 are associated with schizophrenia. Nat Genet
41(11):1223–1227
McCormick LM, Brumm MC, Beadle JN, Paradiso S, Yamada T, Andreasen N (2012) Mirror
neuron function, psychosis, and empathy in schizophrenia. Psychiatry Res Neuroimaging
201(3):233–239
McGlashan TH, Miller TJ, Woods SW (2001) Structured interview for prodromal syndromes (ver-
sion 3.0). PRIME Research Clinic, Yale School of Medicine, New Haven
Miyamoto S, Miyake N, Jarskog L, Fleischhacker W, Lieberman J (2012) Pharmacological treat-
ment of schizophrenia: a critical review of the pharmacology and clinical effects of current and
future therapeutic agents. Mol Psychiatry 17(12):1206–1227
Moreno-De-Luca D, Mulle JG, Kaminsky EB, Sanders SJ, Myers SM, Adam MP, Weik L (2010)
Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizo-
phrenia. Am J Hum Genet 87(5):618–630
Morgan AJ, Jorm AF (2008) Self-help interventions for depressive disorders and depressive symp-
toms: a systematic review. Ann Gen Psychiatry 7:13
Morrison A, Hutton P, Wardle M, Spencer H, Barratt S, Brabban A, French P (2012) Cognitive
therapy for people with a schizophrenia spectrum diagnosis not taking antipsychotic medica-
tion: an exploratory trial. Psychol Med 42(05):1049–1056
Mouridsen S, Rich B, Isager T (2008a) Psychiatric disorders in adults diagnosed as children with
atypical autism. A case control study. J Neural Transm 115(1):135–138
Mouridsen SE, Rich B, Isager T (2008b) Epilepsy and other neurological diseases in the parents of
children with infantile autism. A case control study. Child Psychiatry Hum Dev 39(1):1–8.
doi:10.1007/s10578-007-0062-9
Muck-Seler D, Pivac N, Mustapic M, Crncevic Z, Jakovljevic M, Sagud M (2004) Platelet sero-
tonin and plasma prolactin and cortisol in healthy, depressed and schizophrenic women.
Psychiatry Res 127(3):217–226
Mueller S, Keeser D, Reiser M, Teipel S, Meindl T (2012) Functional and structural MR imaging
in neuropsychiatric disorders, part 2: application in schizophrenia and autism. Am J Neuroradiol
33(11):2033–2037
Myin-Germeys I, van Os J (2007) Stress-reactivity in psychosis: evidence for an affective pathway

to psychosis. Clin Psychol Rev 27(4):409–424
Na Young J, Findling RL (2015) An update on pharmacotherapy for autism spectrum disorder in
children and adolescents. Curr Opin Psychiatry 28(2):91–101
Nakamura K, Sekine Y, Ouchi Y, Tsujii M, Yoshikawa E, Futatsubashi M, Suzuki K (2010) Brain
serotonin and dopamine transporter bindings in adults with high-functioning autism. Arch Gen
Nieminen-von Wendt TS, Metsähonkala L, Kulomäki TA, Aalto S, Autti TH, Vanhala R, von
Wendt LO (2004) Increased presynaptic dopamine function in Asperger syndrome. Neuro Rep
15(5):757–760
Nylander L, Gillberg C (2001) Screening for autism spectrum disorders in adult psychiatric out‐
patients: a preliminary report. Acta Psychiatr Scand 103(6):428–434
Oberman LM, Hubbard EM, McCleery JP, Altschuler EL, Ramachandran VS, Pineda JA (2005)
EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Cogn Brain Res
24(2):190–198
Ochoa S, Usall J, Cobo J, Labad X, Kulkarni J (2012) Gender differences in schizophrenia and
first-episode psychosis: a comprehensive literature review. Schizophr Res Treat 2012, Article
ID 916198
Owen MJ, O’Donovan MC, Thapar A, Craddock N (2011) Neurodevelopmental hypothesis of
schizophrenia. Br J Psychiatry 198(3):173–175
Pantelis C, Velakoulis D, McGorry P, Wood S, Suckling J, Phillips L, McGuire P (2003)
Neuroanatomical abnormalities before and after onset of psychosis: a cross-sectional and lon-
gitudinal MRI comparison. Lancet 361(9354):281
Pilling S, Bebbington P, Kuipers E, Garety P, Geddes J, Orbach G, Morgan C (2002) Psychological
treatments in schizophrenia: I. Meta-analysis of family intervention and cognitive behaviour
therapy. Psychol Med 32(05):763–782
Puig O, Penadés R, Baeza I, De la Serna E, Sánchez-Gistau V, Bernardo M, Castro-Fornieles
J (2014) Cognitive remediation therapy in adolescents with early-onset schizophrenia: a ran-
domized controlled trial. J Am Acad Child Adolesc Psychiatry 53(8):859–868
Rapoport J, Chavez A, Greenstein D, Addington A, Gogtay N (2009) Autism spectrum disorders
and childhood-onset schizophrenia: clinical and biological contributions to a relation revisited.
Rossi A, Pollice R, Daneluzzo E, Marinangeli M, Stratta P (2000) Behavioral neurodevelopment
abnormalities and schizophrenic disorder: a retrospective evaluation with the Childhood
Behavior Checklist (CBCL). Schizophr Res 44(2):121–128
Rutter M (1972) Childhood schizophrenia reconsidered. J Autism Dev Disord 2(3):315–337
Rutter M, Bailey A, Lord C (2003) SCQ: social communication questionnaire. Western
Psychological Services, Los Angeles
Sandin S, Lichtenstein P, Kuja-Halkola R, Larsson H, Hultman CM, Reichenberg A (2014) The
familial risk of autism. JAMA 311(17):1770–1777
Schneider M, Debbané M, Bassett AS, Chow EW, Fung WLA, van den Bree MB, Kates WR
(2014) Psychiatric disorders from childhood to adulthood in 22q11. 2 Deletion Syndrome:
results from the international consortium on brain and behavior in 22q11. 2 Deletion Syndrome.
Am J Psychiatry 171(6):627–639
Shenton ME, Dickey CC, Frumin M, McCarley RW (2001) A review of MRI findings in schizo-
phrenia. Schizophr Res 49(1):1–52
Smeets F, Lataster T, Hommes J, Lieb R, Wittchen H-U, van Os J (2012) Evidence that onset of psy-
chosis in the population reflects early hallucinatory experiences that through environmental risks
and affective dysregulation become complicated by delusions. Schizophr Bull 38(3):531–542
Solomon M, Olsen E, Niendam T, Ragland JD, Yoon J, Minzenberg M, Carter CS (2011) From
lumping to splitting and back again: atypical social and language development in individuals
with clinical-high-risk for psychosis, first episode schizophrenia, and autism spectrum disor-
ders. Schizophr Res 131(1–3):146–151
Spek AA, Wouters SGM (2010) Autism and schizophrenia in high functioning adults: behavioral
differences and overlap. Res Autism Spectr Dis 4(4):709–717. doi:10.1016/j.rasd.2010.01.009
Sporn AL, Addington AM, Gogtay N, Ordoñez AE, Gornick M, Clasen L, Lenane M (2004)
Pervasive developmental disorder and childhood-onset schizophrenia: comorbid disorder or a
phenotypic variant of a very early onset illness? Biol Psychiatry 55(10):989–994
Sprong M, Becker HE, Schothorst PF, Swaab H, Ziermans TB, Dingemans PM, Van Engeland H
(2008) Pathways to psychosis: a comparison of the pervasive developmental disorder subtype
Multiple Complex Developmental Disorder and the “At Risk Mental State”. Schizophrenia
research 99(1):38–47
Stahlberg O, Soderstrom H, Rastam M, Gillberg C (2004) Bipolar disorder, schizophrenia, and
other psychotic disorders in adults with childhood onset AD/HD and/or autism spectrum disor-
ders. J Neural Transm 111(7):891–902
Starling J, Dossetor D (2009) Pervasive developmental disorders and psychosis. Curr Psychiatry
Rep 11(3):190–196
Stone JM, Morrison PD, Pilowsky LS (2007) Review: glutamate and dopamine dysregulation in
schizophrenia – a synthesis and selective review. J Psychopharmacol 21(4):440–452
Sugranyes G, Kyriakopoulos M, Corrigall R, Taylor E, Frangou S (2011) Autism spectrum disor-
ders and schizophrenia: meta-analysis of the neural correlates of social cognition. PLoS One
6(10):e25322
Sullivan PF, Magnusson C, Reichenberg A, Boman M, Dalman C, Davidson M, Långström N
(2012) Family history of schizophrenia and bipolar disorder as risk factors for autism family
history of psychosis as risk factor for ASD. Arch Gen Psychiatry 69(11):1099–1103
Sullivan S, Rai D, Golding J, Zammit S, Steer C (2013) The association between autism spectrum
disorder and psychotic experiences in the Avon longitudinal study of parents and children
(ALSPAC) birth cohort. J Am Acad Child Adolesc Psychiatry 52(8):806–814. e802
Tarrier N, Haddock G, Barrowclough C, Wykes T (2002) Are all psychological treatments for
psychosis equal? The need for CBT in the treatment of psychosis and not for psychodynamic
psychotherapy. Psychol Psychother Theory Res Pract 75(4):365–374
Toal F, Bloemen OJN, Deeley Q, Tunstall N, Daly EM, Page L, Murphy DGM (2009) Psychosis
and autism: magnetic resonance imaging study of brain anatomy. Br J Psychiatry
194(5):418–425
van Os J, Hanssen M, Bijl RV, Vollebergh W (2001) Prevalence of psychotic disorder and com-
munity level of psychotic symptoms: an urban–rural comparison. Arch Gen Psychiatry
58:663–668
Volkmar FR, Cohen DJ (1991) Comorbid association of autism and schizophrenia. Am J Psychiatry
148(12):1705
Vorstman JAS, Breetvelt EJ, Thode KI, Chow EWC, Bassett AS (2013) Expression of autism
spectrum and schizophrenia in patients with a 22q11.2 deletion. Schizophr Res 143(1):55–59.
doi:10.1016/j.schres.2012.10.010
Waris P, Lindberg N, Kettunen K, Tani P (2013) The relationship between Asperger’s syndrome
and schizophrenia in adolescence. Eur Child Adolesc Psychiatry 22(4):217–223
Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Green T (2008) Association between
microdeletion and microduplication at 16p11. 2 and autism. N Engl J Med 358(7):667–675
Wing L (1981a) Asperger’s syndrome: a clinical account. Psychol Med 11(1):115–129
Wing L (1981b) Sex ratios in early childhood autism and related conditions. Psychiatry Res
5(2):129–37
Wing L (2006) Diagnostic interview for social and communication disorders, 11th edn. Centre for
Social and Communication Disorders, Bromley
Winton-Brown TT, Fusar-Poli P, Ungless MA, Howes OD (2014) Dopaminergic basis of salience
dysregulation in psychosis. Trends Neurosci 37(2):85–94
Wykes T, Reeder C (2005) Cognitive remediation therapy for schizophrenia. Routledge, London
Yung A, McGorry PD (1996) The prodromal phase of first episode psychosis: past and current
phase of first episode psychosis: past and current conceptualisations. Schizophrenia Bulletin
Schizophrenia Bulletin 22:353–370
Yung A, Yuen H, McGorry P, Phillips L, Kelly D, Dell’Olio M, Buckby J (2005) Mapping the
onset of psychosis: the comprehensive assessment of at-risk mental states. Aust N Z J Psychiatry
39:964–971
Feeding and Eating Disorders and
Autism Spectrum Disorder 5
Valentina Postorino and Luigi Mazzone
1 Introduction
Feeding and eating disorders (FEDs) are characterized by a markedly abnormal

attitude to eating which result in altered pattern of behavior. These include pica,
rumination disorder, avoidant/restrictive food intake disorder, anorexia nervosa
(AN), bulimia nervosa (BN), and binge-eating disorder (APA 2013). Among FEDs,
AN and BN are the most common. AN is an eating disorder diagnosed when an
individual body weight is below a minimally normal level (body mass index (BMI)
is used for adults, and BMI-for-age percentile is used for children and adolescents)
due to a persistent energy intake restriction caused by an intense fear of gaining
weight and a disturbance in self-perceived body image (APA 2013). BN is described
as recurrent episodes of binge eating generally followed by inappropriate compen-
satory behaviors in order to prevent weight gain (APA 2013). At first glance, FEDs
and autism spectrum disorder (ASD) would appear completely different. However,
it is well known that feeding and eating problems, such as atypical eating behaviors
at mealtime, are common in individuals with ASD (Cermack et al. 2010; Postorino
et al. 2015a). In particular, food selectivity is described as the most frequent one
(Cermack et al. 2010; Postorino et al. 2015a). Furthermore, food selectivity is often
associated with inadequate nutrient intake, suggesting that a limited diet may put
V. Postorino (*)
Atlanta, GA, USA
Department of Neuroscience, I.R.C.C.S. Bambino Gesù Children’s Hospital, Child
Neuropsychiatry Unit, Rome, Italy
L. Mazzone
Department of Neuroscience, I.R.C.C.S. Bambino Gesù Children’s Hospital,
Child Neuropsychiatry Unit, Rome, Italy

68 V. Postorino and L. Mazzone
any child at risk for nutritional deficiency (Bandini et al. 2010; Bicer and Alsaffar
2013; Schmitt et al. 2008). Literature studies describe that girls with a diagnosis of
ASD are at greater risk of developing a FED and males with autism are also at
increased risk for low body weight (Kalvya 2009; Oldershaw et al. 2011a, b;
Sobanski et al. 1999). Currently, a recent line of research has focused on the hypoth-
esis that there may be an association between FEDs and ASD (Anckarsater et al.
2012; Baron-Cohen et al. 2013; Carton and Smith 2014; Coombs et al. 2011; Courty
et al. 2013; Huke et al. 2013, 2014; Mandy and Tchanturia 2015; Rhind et al. 2014;
Tchanturia et al. 2013). Specifically, these works have supported the assumption of
similar behavioral and cognitive features in FEDs and ASD. For instance, deficits in
theory of mind and difficulty in expressing emotions and recognizing emotional
stimuli have been reported in individuals with ASD, as well as in patients with AN
(APA 2013; Davies et al.,2010; Oldershaw et al. 2010, 2011; Tchanturia et al. 2013).
However, given that atypical eating behaviors are common in individuals with ASD,
recognizing when these symptoms are reported within the clinical eating disorder
range is a challenge for clinicians. Nevertheless, the distinction between these dis-
orders is of crucial importance for the diagnostic and treatment processes. For this
reason, practical information for clinicians on the prevalence, phenomenology and
clinical features, diagnostic process, neurobiological and genetic bases, and treat-
ment of FEDs in ASD will be described in the present chapter.
2 Prevalence of FEDs in ASD
2.1 Atypical Eating Behaviors and Food Selectivity in ASD
Atypical eating behaviors, and more precisely food selectivity, are often present
in children with ASD. Literature studies have shown that this atypical eating
behavior is more prevalent in children with ASD than in typically developing
children. With these considerations, researches exploring the prevalence of food
selectivity in children with ASD have reported highly variable rates, ranging from
13 to 87 % (Ahearn et al. 2001; Bandini et al. 2010; Collins et al. 2003; Cornish
1998; Dominick et al. 2007; Field et al. 2003; Kalvya 2009; Klein and Nowak
1999; Nadon et al. 2011; Schmitt et al. 2008; Schreck and Williams 2006; Schreck
et al. 2004; Suarez et al. 2013; Whiteley et al. 2000; Williams et al. 2000, 2005).
For instance, Whiteley et al. (2000) reported that 83 % of parents indicated that
their children ate a restrictive repertoire of foods as their core diet. Similarly,
Williams et al. (2000) found that 67 % of parents reported that their child was a
“picky eater.” However, 73 % reported that their child had a good appetite for
foods that they liked, suggesting that picky eating is not associated with a lack of
appetite. On the other hand, Bandini et al. (2010), comparing food selectivity
between children with ASD and typically developing children, indicated a lower
rate (41.7 %) of this atypical eating behavior in their sample of children with
ASD. Of note is that these studies used different definitions of food selectivity;
distinct methodologies, including rating scales, checklists, and interviews; as well
5 Feeding and Eating Disorders and Autism Spectrum Disorder 69
as daily food record diaries, and this issue may represent a possible explanation
for these discrepancies. It’s only recent that Bandini et al. (2010) have operation-
alized the definition of food selectivity to comprise three separate domains: food
refusal, limited food repertoire, and high-frequency single food intake (Bandini
et al. 2010).
2.2 FEDs in ASD
Studies report highly variable prevalence rates of co-occurring FEDs and ASD
ranging from 4 % to 37 % (Anckarsäter et al. 2012; Huke et al. 2013, 2014; Gillberg
et al. 1995; Råstam 1992; Råstam et al. 2003; Rhind et al. 2014; Wentz Nilsson
et al. 1998, 1999, 2005). It is to note that only two studies evaluated patients with
current AN and BN, whereas the remaining were based only on AN samples.
Moreover, the majority of studies have investigated retrospectively the presence of
an ASD during and following AN (Anckarsäter et al. 2012; Gillberg et al. 1995;
Råstam 1992; Råstam et al. 2003; Wentz Nilsson et al. 1998, 2005). For instance,
Rastam et al. (2003) evaluating premorbid conditions, including ASD, compared
51 individuals with AN with a group of 51 comparison subjects. These investiga-
tors found that 20 % of the sample met the ASD criteria. Moreover, all the
researches investigating the comorbidity between these disorders used different
screening measures for investigating ASD symptoms; therefore, there is a lack of
consistency in terms of methodology that make comparisons between studies
difficult.
A recent line of research investigates the presence of autistic traits in AN sam-
ples reporting that patients with AN possess high level of autistic-like behaviors
(Baron-Cohen et al. 2013; Calderoni et al. 2015; Courty et al. 2013; Hambrook et al
2008; Huke et al. 2013, 2014; Rhind et al. 2014; Tchanturia et al. 2013). For
instance, Tchanturia et al. (2013) exploring the association between autistic traits
and eating disorder symptoms in a group of 66 participants with AN compared to a
group of 66 typical controls found that women with anorexia reported a greater
number of autistic traits than typical women. However, it is worth mentioning that
all these studies explored the presence of autistic traits in anorexia through a self-
report measure (the Autism Spectrum Quotient-AQ); thereby an accurate assess-
ment of autistic traits through gold-standard diagnostic measures for ASD is
recommended in future researches (Baron-Cohen et al. 2001).
To our knowledge so far, only one case series investigated the co-occurrence of
ASD and AN through the Autism Diagnostic Observation Schedule (ADOS),
which is the gold-standard measure for the diagnosis of ASD (Lord et al. 2000;
Mandy and Tchanturia 2015). In more detail, Mandy and Tchanturia (2015) eval-
uating through the ADOS ten women receiving treatment for an eating disorder
estimated that seven of them had an ASD. However, it is worth to note that the
level of autistic symptoms found in this case series could be overestimated by the
fact that one of the participants’ inclusion criteria was that an ASD had to be
suspected.
3 Phenomenology and Clinical Issues of FEDs in ASD
It is not easy to make a comorbid diagnosis of FED in the context of ASD. In fact,
at first glance, these conditions appear to be completely different. FEDs are more
common in females than in males, with a female-to-male (F:M) ratio of 10:1 (Smink
et al. 2014). Generally, eating disorders begin during adolescence, and the lifetime
course and outcomes are highly variable among affected individuals (Anderluh
et al. 2009). Indeed, literature studies report that most people with FEDs have an
above-average intelligence (Lopez et al. 2010). By contrast, ASD is a lifelong con-
dition with an early onset (12–24 months of age). This condition is more prevalent
in males than females, with a M:F ratio of 4:1 (CDC 2014). Moreover, intellectual
functioning is one of the factors that contribute to the clinical heterogeneity of this
disorder, and literature studies have shown an association between ASD and intel-
lectual disability ranging from 16.4 to 84 % (de Bildt et al. 2004; Miller et al. 2012).
Besides these differences, these disorders share some behavioral traits, and several
clinical issues make difficult the distinction between these conditions. First, ASD is
challenging to identify in females, especially in higher functioning individuals,
probably due to a different behavioral phenotype between genders, and it is there-
fore possible that girls either go undiagnosed or are misdiagnosed (Postorino et al.
2015b). Thus, it could be that behaviors and symptoms used to make a diagnosis are
gender specific. A direct consequence of this first diagnostic issue is the fact that the
majority of eating disorders can have a later onset compared to autism; thereby,
individuals present to adult psychiatrist who may not be able to make the diagnosis.
Another issue concerns the fact that starvation itself has a deep impact on brain
functioning and can produce a condition that can be misinterpreted as autism, char-
acterized by social retirement, rigidity, and repetitive behaviors (Treasure 2013).
Third, children with autism have strong preferences and enjoy repetition (e.g., eat-
ing the same foods), as well as sensory sensitivities that may interfere with eating
and cause food selectivity. Therefore, distinguishing restricted and repetitive behav-
iors that are diagnostic features of autism from a more structured eating disorder can
be difficult. Indeed, it has to be noticed that when an individual with a FED presents
for diagnosis and/or treatment, clinicians often do not investigate the developmental
history, which is fundamental in order to make an ASD diagnosis. In fact, generally
the first clinical focus is to manage the physical and acute risk of an eating disorder
patient. During the diagnostic process, in order to make a clear distinction between
these disorders, clinicians have to keep in mind the common behavioral traits of
these disorders. For instance, repetitive and rigid behaviors are also present in FEDs
and frequently precede the onset of an eating disorder. Obsessive-compulsive fea-
tures characterized by rigid attitudes and behaviors and problems in set shifting and
attention to details have been described in both conditions (Solomon et al. 2008;
Tchanturia et al. 2011, 2012). Regarding this last point, it has to be pointed out that
in FEDs these features are focused on food and weight, whereas in autism, these are
given by repetitive behaviors and narrow interests, which include a range of mani-
festations according to age and ability (APA 2013). Several studies have described
that patients with FEDs have difficulty in recognizing emotional stimuli and
expressing emotions, and deficit in theory of mind has been reported in AN and BN
samples (Oldershaw et al. 2010, 2011a, b; Davies et al. 2010). As a reminder,
although all the features described above are common for both disorders, FEDs are
accentuated in the acute illness state and became less pronounced after treatment,
whereas in autism these remain stable over time. Social impairments, such as loneli-
ness, shyness, and solitary activities, are often described by clinicians in individuals
with a FED, especially in the state that precedes the onset of the disorder (Kim et al.
2009; Krug 2012). It is important to take into account that in order to make a diag-
nosis of ASD, these impairments in the social abilities must be clearly present since
childhood, whereas in case of eating disorders, these are usually circumscribed and
time limited and disappear after the management of the acute phase of illness. Thus,
a deep assessment of the history and development is necessary in order to distin-
guish between these disorders and eventually make a comorbid diagnosis.
The detection of eating disorders in ASD is particularly challenging for clinicians.

Some of the autistic features, such as repetitive behaviors and sensory sensitivity
that may interfere with eating, can make the distinction of these disorders even
more difficult. Moreover, the diagnostic process is complicated by the fact that
adequate tools that might support clinicians in the distinction between these disor-
ders are still lacking. Several studies have investigated food selectivity in autism
through different measures (Ahearn et al. 2001; Bandini et al. 2010; Collins et al.
2003; Cornish 1998; Dominick et al. 2007; Field et al. 2003; Kalvya 2009; Klein
and Nowak 1999; Nadon et al. 2011; Postorino et al. 2015a; Schmitt et al. 2008;
Schreck and Williams 2006; Schreck et al. 2004; Suarez et al. 2013; Whiteley et al.
2000; Williams et al. 2000, 2005). The majority of these studies have used food
diaries, parental interviews, nutritional adequacy, and parental standard question-
naires. One of the most commonly used dietary assessment tools is the Food
Frequency Questionnaire (FFQ) (Field et al. 1999). It is a self-administered ques-
tionnaire that asks participants to report the frequency of consumption and portion
size of a series of foods over a defined period of time (e.g., the last month; the last
3 months). However, all these instruments were not specifically created to investi-
gate food selectivity in autistic individuals, thus are probably not appropriate to
evaluate these problematic behaviors in ASD. In line with this issue, the measures
that are often used to evaluate FEDs are self and parent-report questionnaires not
designed for this clinical population. It is important to note that in order to fill these
questionnaires, the skills to understand own feelings and problems must be unim-
paired. For instance, the most widely self-report questionnaire used to detect FEDs
is the Eating Disorder Inventory-3 (EDI-3) (Garner 2004; Giannini et al. 2008). It
provides a standardized clinical evaluation of symptomatology associated with eat-
ing disorders and consists of 91 items organized into three subscales measuring
eating disorder symptoms and nine more general psychological trait subscales.
However, even in the presence of average language and cognitive skills, many
items of this questionnaire require intact metacognitive abilities. In the same way,
parent-report questionnaires or interviews (e.g., the Kiddie–Schedule for Affective
Disorders and Schizophrenia–Present and Lifetime version- K-SADS-PL) require
the parent to have the ability to discern between the repetitive behaviors typical of
autism that may interfere with eating and more structured problems concerning
feeding and eating (Kaufman et al. 1997). During the diagnostic process, clinicians
have to be aware that since one feature of individuals with ASD is the need to per-
form ritualistic behaviors, repetitive actions, and routine and structured activities,
changes in these routine actions or the discrepancy between social context expecta-
tions and autistic functioning can cause in these individuals, especially in high-
functioning subjects, stress that may be involved in the development of eating
disorders. Therefore, it is possible that FEDs are a consequence of stressful life
events (e.g., bereavement, pressure at school, or lack of occupation) in autistic
patients showing a predisposition to develop these symptoms. Furthermore, an
exacerbation of certain autistic behavioral features related to feeding and eating
(i.e., a worsening of food selectivity), as well as changes in the type and pattern of
preexisting symptoms, or the onset of new symptoms, in a patient affected by ASD,
should warn clinicians and lead them to conduct a more in-depth assessment. In
these cases, a complete diagnostic evaluation of FEDs in individuals with ASD
should include psychological, physical, and medication management investiga-
tions. An initial assessment, in order to collect information on case history, current
clinical picture, skills, disabilities, and motor competencies, is important for the
diagnostic process of children and adolescents with ASD who develop feeding
problems. A broad psychological evaluation on the possible exposure to traumatic
or stressful life events should be also undertaken. Moreover, given that girls with
autism could be undiagnosed and that feeding and eating problems are sometimes
the only and easier clinical signs that bring these patients to a psychiatric service,
a good clinical practice is to complete the assessment on all the information
described above in patients with FEDs who present severe rigidness and social
retirement in order to evaluate the presence of an ASD.
Whether these conditions share neural networks and genes is an important area of
research in order to shed light on the mechanisms underlying symptoms and delin-
eate different features of these disorders. Several studies have investigated the neu-
ral networks in these two conditions, but to our knowledge, none of these studies
have compared brain structures in these clinical populations (Treasure 2013; Zucker
et al. 2007). The majority of studies on functional imaging in FEDs have investi-
gated the response to food and body images cues (Van den and Treasure 2009).
Recently some functional magnetic resonance imaging researches have provided
support that patients with AN, similar to individuals with ASD, report altered acti-
vation in brain networks underlying theory of mind, cognitive and behavioral flexi-
bility, and central coherence compared to healthy controls (Fonville et al. 2013;
Schulte-Rüther et al. 2012; Zastrow et al. 2009). Other studies have investigated the
biological overlap between these disorders. In particular, some reports have shown
a disturbed processing of oxytocin in both AN and ASD (Rastam 1992; Rastam
et al. 2003; Tchanturia et al. 2004). Moreover, AN and ASD appear to co-exist
within families indicating that these observed similarities may reflect a direct
genetic link (Comings and Comings 1991; Gillberg 1985; Steffenburg 1991).
However, further studies are needed in order to identify genes that can contribute to
the development of these conditions.
6 Treatment
The presence of a comorbid eating disorder in individuals with ASD has direct
implication for clinical work. Given that studies describe that patients with FEDs
report more autistic traits, shedding light on the social cognitive processing of
these patients might be useful in order to predict outcomes and to develop adequate
interventions (Baldock and Tchanturia 2007). In fact, difficulties in social func-
tioning may decrease the efficacy of psychological interventions and affect the
course of the illness (Treasure et al. 2005). Therefore, a modified psychological
therapy for ASD processing styles may improve treatment effectiveness in patients
with ASD and a comorbid FED. In the same way, these interventions could be also
beneficial for patients with eating disorders and high traits of autism. Programs
focusing on promoting social skills in autism have been implemented and have
been applied to eating disorders patients. These interventions are based on cogni-
tive behavioral strategies, and even if there is a paucity of randomized control trials
(RCT), studies published so far have shown the effectiveness of these psychologi-
cal therapies in this clinical population (Lock et al. 2013; Galsworthy-Francis and
Allan 2014; Tchanturia et al. 2014, 2015). A novel intervention who has shown a
growing evidence in the treatment of AN is the cognitive remediation therapy
(CRT) (Lock et al. 2013; Tchanturia et al. 2014, 2015). This is a brief manualized
intervention (ten sessions) which targets cognitive processes, such as increasing
the cognitive flexibility and the ability to switch between mental tasks (set shift-
ing). The literature on this intervention in AN samples consists of single case stud-
ies, case series, and four RCTs, which report improvements in all target symptoms
and low dropout rates (around 10–15 %) (Brockmeyer et al. 2014; Courty et al
2005; Davies and Tchanturia 2005; Dingemans et al. 2014; Lock et al. 2013;
Tchanturia et al. 2007, 2008, 2014). For instance, Dingemans et al. (2014)ran-
domly assigned 82 patients with AN to CRT and treatment as usual or to treatment
as usual only. Results showed that patients who received CRT reported a signifi-
cant improvement in eating disorder symptoms, in quality of life as well as set
shifting and central coherence abilities (Dingemans et al. 2014). Although all these
studies concur on the efficacy of this intervention in patients with AN, to our
knowledge, none of these has investigated the feasibility of the CRT on patients
with ASD and co-occurring FEDs. Therefore, further RCTs are needed in order to
examine the efficacy of CRT on this clinical population.
Another important topic for the treatment concerns the intervention programs for
children with ASD and atypical eating behaviors. Overall, previous studies have
demonstrated that trials on behavioral interventions represent a well-supported
treatment for children with ASD and food selectivity (Marı’-Bauset et al. 2014;
Sharp et al. 2011). In particular, these interventions have shown significant improve-
ments in terms of calorie intake, weight gain, and the variety and volume of food
consumed during meals in children with ASD. Recently, a pilot study has investi-
gated the feasibility of a behaviorally based parent training intervention called the
“Autism MEAL Plan” to address feeding problems in children with ASD, providing
support regarding the utility of the program (Sharp et al. 2014). Given these results,
as a good clinical practice, the behavior at meal times should be monitored as part
of routine assessments of children with ASD in order to implement the right
intervention.
Finally, studies on drug therapy in patients with ASD and a comorbid FED are
lacking. Moreover, evidence for drug therapy alone in FEDs is weak (Hay and
Claudino 2012). Some trials have reported that low dose of antipsychotic medica-
tion can improve symptoms. However, all the studies concur that the intervention
for FED patients needs to target both physical (i.e., promotion of weight gain,
reducing risk of physical complications) and psychological aspects of the disorder
(e.g., working with disordered cognitions, harmful behaviors, body image issues,
and associated emotional disturbances) (Galsworthy-Francis and Allan 2014).
Therefore, cautions are warranted in the use of pharmacological interventions, and
clinicians should explore this possibility only when all the other treatments were
worthless.
Recent studies have highlighted that FEDs can occur in the context of an ASD and
that patients with eating disorders report higher degree of autistic traits when com-
pared to healthy controls. However, further researches examining the presence of
ASD in FED patients through an in-depth assessment performed by a multidisci-
plinary team and using gold-standard diagnostic measures for autism (e.g., ADOS)
are needed in order to shed light on the prevalence of this comorbidity. Given that in
clinical practice the characteristics of the female autistic phenotype are difficult to
be recognized, future studies have to address the need of developing proper screen-
ing tools for eating disorders specifically designed for the ASD population.
Furthermore, whether these two conditions share common cerebral mechanism or
genes is still an open issue. In the same way, controlled studies on the medical and
psychological treatments of eating disorders in ASD are still lacking. Therefore, we
think that it will be important to analyze whether individuals with ASD and FEDs
have a distinct etiology, treatment needs, and prognosis compared to people with
ASD who do not have FEDs or people with FEDs who do not have ASD. Longitudinal
studies might be essential to fill this gap.
References
Ahearn WH, Castine T, Nault K, Green G (2001) An assessment of food acceptance in children
with autism or pervasive developmental disorder-not otherwise specified. J Autism Dev Disord
31:505–511
5th edn. American Psychiatric Association, Washington, DC
Anckarsater B, Hofvander E, Billstedt IC, Gillberg C, Gillberg E, Wentz M, Rastam M (2012) The
sociocommunicative deficit subgroup in anorexia nervosa: autism spectrum disorders and neu-
rocognition in a community-based, longitudinal study. Psychol Med 42:1957–1967
Anderluh M, Tchanturia K, Rabe-Hesketh S, Collier D, Treasure J (2009) Lifetime course of eat-
ing disorders: design and validity testing of a new strategy to define the eating disorders phe-
notype. Psychol Med 39:105–114
Baldock E, Tchanturia K (2007) Translating laboratory research into practice: foundations, functions
and future of cognitive remediation therapy for anorexia nervosa. Future Med 4(3):285–292
Bandini LG, Anderson SE, Curtin C, Cermak S, Evans EW, Scampini R et al (2010) Food selectiv-
ity in children with autism spectrum disorders and typically developing children. J Pediatr
157:259–264
Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E (2001) The autism spectrum quo-
tient (AQ): evidence from Asperger syndrome/high-functioning autism, males and females,
scientists and mathematicians. J Autism Dev Disord 31:5–17
Baron-Cohen S, Jaffa T, Davies S, Auyeung B, Allison C, Wheelwright S (2013) Do girls with
anorexia nervosa have elevated autistic traits? Mol Autism 4:24
Bicer AH, Alsaffar AA (2013) Body mass index, dietary intake and feeding problems of Turkish
children with autism spectrum disorder (ASD). Res Dev Disabil 34:3978–3987
Brockmeyer T, Ingenerf K, Walther S, Wild B, Hartmann M, Herzog W et al (2014) Training cog-
nitive flexibility in patients with anorexia nervosa: a pilot randomized controlled trial of cogni-
tive remediation therapy. Int J Eat Disord 47:24–31
Calderoni S, Fantozzi P, Balboni G, Pagni V, Franzoni E, Apicella F, Narzisi A, Maestro S,
Muratori F (2015) The impact of internalizing symptoms on autistic traits in adolescents with
restrictive anorexia nervosa. Neuropsychiatr Dis Treat 11:75–85
Carton AM, Smith AD (2014) Assessing the relationship between eating disorder psychopathol-
ogy and autistic traits in a non-clinical adult population. Eat Weith Disord 19(3):285–293
Cermack SA, Curtin C, Bandini LG (2010) Food selectivity and sensory sensitivity in children
with autism spectrum disorders. J Am Diet Assoc 110(2):238–246
Collins MSR, Kyle R, Smith S, Laverty A, Roberts S, Eaton-Evans J (2003) Coping with the usual
family diet. Eating behavior and food choices of children with Down’s syndrome, autistic spec-
trum disorders, or Cri du chat syndrome and comparison groups of siblings. J Learn Disabil
7:137–155
Comings DE, Comings BG (1991) Clinical and genetic relationships between autism-pervasive
developmental disorder and tourette syndrome: a study of 19 cases. Am J Med Genet
39:180–191
Coombs MS, Bryant-Waugh R, Skevington SM (2011) An investigation into the relationship
between eating disorder psychopathology and autistic symptomatology in a non-clinical sam-
ple. Br J Clin Psychol 50:326–338
Cornish E (1998) A balanced approach towards healthy eating in autism. J Hum Nutr Diet
11:501–509
Courty ASM, Lalanne C, Ringuenet D, Vindreau C, Chevallier C, Pouga L, Pinabel F, Philippe A,
Adrien J, Davies C, Tchanturia K (2005) Cognitive remediation therapy as an intervention for
acute anorexia nervosa: a case report. Eur Eat Disord Rev 13:311–316
Courty ASM, Lalanne C, Ringuenet D, Vindreau C, Chevallier C, Pouga L, Pinabel F, Philippe A,
Adrien J, Barry C, Berthoz S (2013) Levels of autistic traits in anorexia nervosa: a comparative
psychometric study. BMC Psychiatry 13:222
Davies H, Schmidt U, Stahl D, Tchanturia K (2010) Evoked facial emotional expression and emo-
tional experience in people with anorexia nervosa. Int J Eat Disord 44:531–539
De Bildt A, Systema S, Kraijer D, Minderaa R (2004) Prevalence of pervasive developmental
disorders in children and adolescents with mental retardation. J Child Psychol Psychiatry
46:275–286
Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal Investigators;
Centers for Disease Control and Prevention (CDC) (2014) Prevalence of autism spectrum dis-
order among children aged 8 years – autism and developmental disabilities monitoring net-
work, 11 sites, United States, 2010. Morbidity and mortality weekly report. Surveill Summ
63(2):1–21
Dingemans AE, Danner UN, Donker JM, Aardoom JJ, van Meer F, Tobias K et al (2014) The
effectiveness of cognitive remediation therapy in patients with a severe or enduring eating
disorder: a randomized controlled trial. Psychother Psychosom 83:29–36
Dominick KC, Davis NO, Lainhart J, Tager-Flusberg H, Folstein S (2007) Atypical behaviors in
children with autism and children with a history of language impairment. Res Dev Disabil
28:145–162
Field AE, Camargo CA, Taylor CB, Berkey CS, Frazier AL, Gillman MW et al (1999) Overweight,
weight concerns, and bulimic behaviors among girls and boys. J Am Acad Child Adolesc
Field D, Garland M, Williams K (2003) Correlates of specific childhood feeding problems.
J Pediatr Child Health 39:299–304
Fonville L, Lao-Kaim NP, Giampietro V et al (2013) Evaluation of enhanced attention to local
detail in anorexia nervosa using the embedded figure test; an fMRI study. PLoS One 8(5):e63964
Galsworthy-Francis L, Allan S (2014) Cognitive behavioral therapy for anorexia nervosa: a sys-
tematic review. Clin Psychol Rev 34:54–72
Garner DM (2004) Eating disorder inventory-3. Professional manual. Psychological Assessment
Resources, Lutz
Giannini M, Pannocchia L, Dalle Grave R, Muratori F, Viglione V (2008) Eating disorder inven-
tory-3. Giunti OS, Firenze
Gillberg C (1985) Autism and anorexia nervosa: related conditions? Nord J Psychiatry
39:307–312
Gillberg C, Råstam M, Gillberg C (1995) Anorexia nervosa 6 years after onset: part I. Personality
disorders. Compr Psychiatry 36:61–69
Hambrook D, Tchanturia K, Schmidt U, Russell T, Treasure J (2008) Empathy, systemizing, and
autistic traits in anorexia nervosa: a pilot study. Br J Clin Psychol 47:335–339
Hay PJ, Claudino AM (2012) Clinical psychopharmacology of eating disorders: a research update.
Int J Neuropsychopharmacol 15:209–222
Huke V, Turk J, Saeidi S, Kent A, Morgan JF (2013) Autism spectrum disorders in eating disorder
populations: a systematic review. Eur J Eating Disord Rev 21(5):345–351
Huke V, Turk J, Saeidi S, Kent A, Morgan JF (2014) The clinical implications of high levels of
Autism spectrum disorder features in Anorexia Nervosa: a pilot study. Eur J Eat Disord Rev
22(2):116–121
Kalvya E (2009) Comparison of eating attitudes between adolescent girls with and without
asperger syndrome. Daughters’ and mothers’ report. J Autism Disord 39:480–486
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, Williamson D, Ryan N (1997)
Schedule for affective disorders and schizophrenia for school-age children-present and lifetime
version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry
36(7):980–988
Kim YR, Heo SY, Kang H, Song KJ, Treasure J (2009) Childhood risk factors in Korean women
with anorexia nervosa: two sets of case – control studies with retrospective comparisons. Int
J Eat Disord 43:598–595
Klein U, Nowak AJ (1999) Characteristics of patients with autistic disorder (AD) presenting for
dental treatment. A survey and chart review. Spec Care Dent Off Publ Am Assoc Hosp Dent
Acad Dent 19:200–207
Krug I (2012) Low social interactions in eating disorder patients in childhood and adulthood: a
multicentre European case control study. J Health Psychol 18:26–37
Lock J, Agras WS, Fitzpatrick KK, Bryson SW, Jo B, Tchanturia K (2013) Is outpatient cognitive
remediation therapy feasible to use in randomized clinical trials for anorexia nervosa? Int J Eat
Disord 46(6):567–575
Lopez C, Stahl D, Tchanturia K (2010) Estimated intelligence quotient in anorexia nervosa: a
systematic review and meta-analysis of the literature. Ann Gen Psychiatry 9:40
Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC et al (2000) The Autism
diagnostic observation schedule—generic: a standard measure of social and communication
deficits associated with the spectrum of Autism. J Autism Dev Disord 30:205–223
Mandy W, Tchanturia K (2015) Do women with eating disorders who have social and flexibility
difficulties really have autism? Acase series. Mol Autism 6:6
Marı’-Bauset S, Zazpe I, Mari-Sanchis A, Llopis-Gonza’lez A, Morales-Sua’rez-Varela M (2014)
Food selectivity in autism spectrum disorders: a systematic review. J Child Neurol
29(11):1554–1561
Miller JS, Bilder D, Farley M, Coon H, Pinborough-Zimmerman J, Jenson W et al (2012) Autism
spectrum disorder reclassified: a second look at the 1980s Utah/UCLA autism epidemiologic
study. J Autism Dev Disord 43:200–210
Nadon G, Feldman DE, Dunn W, Gisel E (2011) Mealtime problems in children with autism spec-
trum disorder and their typically developing siblings. A comparison study. Autism Int J Res
Pract 15:98–113
Oldershaw A, Hambrook D, Tchanturia K, Treasure J, Schmidt U (2010) Emotional theory of
mind and emotional awareness in recovered anorexia nervosa patients. Psychosom Med
72(1):73–79
Oldershaw A, Hambrook D, Stahl D, Tchanturia K, Treasure J, Schmidt U (2011a) The socio-
emotional processing stream in anorexia nervosa. Neurosci Biobehav Rev 35(3):970–988
Oldershaw A, Treasure J, Hambrook D, Tchanturia K, Schmidt U (2011b) Is anorexia nervosa a
version of autism spectrum disorders? Eur J Eat Disord Rev 19:462–474
Postorino V, Sanges V, Giovagnoli G, Fatta LM, De Peppo L, Armando M, Vicari S, Mazzone L
(2015a) Clinical differences in children with autism spectrum disorder with and without food
selectivity. Appetite 1(92):126–132
Postorino V, Fatta LM, De Peppo L, Giovagnoli G, Armando M, Vicari S, Mazzone L
(2015b) Longitudinal comparison between male and female preschool children with autism
spectrum disorder. J Autism Dev Disord 45(7):2046–2055
Råstam M (1992) Anorexia nervosa in 51 Swedish adolescents: premorbid problems and comor-
bidity. J Am Acad Child Adolesc Psychiatry 31:5
Råstam M, Gillberg C, Wentz E (2003) Outcome of teenage onset anorexia nervosa in a Swedish-
community based sample. Eur Child Adolesc Psychiatry 12:78–90
Rhind C, Bonfioli E, Hibbs R, Goddard E, Macdonald P, Gowers S, Schmidt U, Tchanturia K,
Micali N, Treasure J (2014) An examination of autism spectrum traits in adolescents with
anorexia nervosa and their parents. Mol Autism 5:56
Schmitt L, Heiss C, Campbell E (2008) A comparison of nutrient intake and eating behaviors of
boys with and without autism. Top Clin Nutr 23:23–31
Schreck KA, Williams K (2006) Food preferences and factors influencing food selectivity for
children with autism spectrum disorders. Res Dev Disabil 27:353–363
Schreck KA, Williams K, Smith AF (2004) A comparison of eating behaviors between children
with and without autism. J Autism Dev Disord 34:433–438
Schulte-Rüther M, Mainz V, Fink GR, Herpertz-Dahlmann B, Konrad K (2012) Theory of mind
and the brain in anorexia nervosa: relation to treatment outcome. J Am Acad Child Adolesc
Sharp WG, Jaquess DL, Morton JF et al (2011) Pediatric feeding disorders: a quantitative synthe-
sis of treatment outcomes. Clin Child Fam Psychol Rev 13:348–365
Sharp WG, Burrell L, Jaquess DL (2014) The autism MEAL plan: a parent-training curriculum to
manage eating aversions and low intake among children with autism. Autism 18(6):712–722
Smink FR, van Hoeken D, Oldehinkel AJ, Hoek HW (2014) Prevalence and severity of DSM-5
eating disorders in a community cohort of adolescents. Int J Eat Disord 47(6):610–619
Sobanski E, Marcus A, Henninghausen K, Hebebrand J, Schmidt MH (1999) Further evidence for
a low body weight in male children and adolescents with Asperger’s disorder. Eur Child
Adolesc Psychiatry 8:312–314
Solomon M, Ozonoff SJ, Cummings N, Carter CS (2008) Cognitive control in autism spectrum
disorders. Int J Dev Neurosci 26:239–247
Steffenburg S (1991) Neuropsychiatric assessment of children with autism: a population-based
study. Dev Med Child Neurol 33:495–511
Suarez MA, Nelson NW, Curtis AB (2013) Longitudinal follow-up of factors associated with food
selectivity in children with autism spectrum. The International Journal of Research and
Practice, Autism
Tchanturia K, Morris RG, Anderluh MB, Collier DA, Nikolaou V, Treasure J (2004) Set shifting
in anorexia nervosa: an examination before and after weight gain, in full recovery and relation-
ship to childhood and adult OCPD traits. J Psychiatr Res 38:545–552
Tchanturia K, Davies H, Campbell IC (2007) Cognitive remediation therapy for patients with
anorexia nervosa: preliminary findings. Ann Gen Psychiatry 6:14
Tchanturia K, Davies H, Lopez C, Schmidt U, Treasure J, Wykes T (2008) Letter to the editor:
neuropsychological task performance before and after cognitive remediation in anorexia ner-
vosa: a pilot case-series. Psychol Med 38:1371–1373
Tchanturia K, Harrison A, Davies H, Roberts M, Oldershaw A, Nakazato M, Treasure J (2011)
Cognitive flexibility and clinical severity in eating disorders. PLoS ONE 6(6):e20462
Tchanturia K, Davies H, Harrison A, Roberts M, Nakazato M, Schmidt U, Treasure J, Morris R
(2012) Poor cognitive flexibility in eating disorders: examining the evidence using the
Wisconsin cart sorting task. PLoS ONE 7(1):e28331
Tchanturia K, Weineck F, Fidanboylu E, Kern N, Treasure J, Baron Cohen S (2013) Exploring
autistic traits in anorexia: a clinical study. Mol Autism 4:44
Tchanturia K, Lounes N, Holttum S (2014) Cognitive remediation in anorexia nervosa and related
conditions: a systematic review. Eur J Eat Disord Rev 22:454–462
Tchanturia K, Doris E, Mountfor V, Fleming C (2015) Cognitive Remediation and Emotion Skills
Training (CREST) for anorexia nervosa in individual format: self-reported outcomes. BMC
Psychiatry 15:53
Treasure J (2013) Coherence and other autistic spectrum traits and eating disorders: building from
mechanism to treatment. The Birgit Olsson lecture. Nord J Psychiatry 67:38–42
Treasure J, Tchanturia K, Schmidt U (2005) Research to examine the how rather than the what of
change. Couns Psychother Res 5(3):191–202
Van den EF, Treasure J (2009) Neuroimaging in eating disorders and obesity: implications for
research. Child Adolesc Psychiatry Clin Am 18:95–115
Wentz Nilsson E, Gillberg C, Råstam M (1998) Familial factors in anorexia nervosa: a community-
based study. Compr Psychiatry 39:392–399
Wentz Nilsson E, Gillberg IC, Gillberg C, Råstam M (1999) Ten-year follow-up of adolescent-onset
anorexia nervosa: personality disorders. J Am Acad Child Adolesc Psychiatry 38:1389–1395
Wentz Nisson E, Lacey JH, Waller G, Rastam M, Turk J, Gillberg C (2005) Childhood onset neu-
ropsychiatric disorders in adults eating disorder patients. A pilot study. Eur Child Adolesc
Whiteley P, Rodgers J, Shattock P (2000) Feeding patterns in autism. Autism Int J Res Pract
4:207–211
Williams PG, Dalrymple N, Neal J (2000) Eating habits of children with autism. Pediatr Nurs
26:259–264
Williams K, Gibbons BG, Schreck KA (2005) Comparing selective eaters with and without devel-
opmental disabilities. J Dev Phys Disabil 17:299–309
Zastrow A, Kaiser S, Stippich C et al (2009) Neural correlates of impaired cognitive-behavioral
flexibility in anorexia nervosa. Am J Psychiatry 166(5):608–616
Zucker NL1, Losh M, Bulik CM, LaBar KS, Piven J, Pelphrey KA (2007) Anorexia nervosa and
autism spectrum disorders: guided investigation of social cognitive endophenotypes. Psychol
Bull 133(6):976–1006
Attention-Deficit Hyperactivity Disorder
and Autism Spectrum Disorder 6
Samuele Cortese
1 Introduction
Attention-deficit/hyperactivity disorder (ADHD) is the most common neurodevel-

opmental disorder (Polanczyk et al. 2014). According to the Diagnostic and
Statistical Manual of Mental Disorders, 5th edition, DSM-5 (American Psychiatric
Association 2013), ADHD is characterized by a persistent and impairing pattern of
inattention and/or hyperactivity/impulsivity. Hyperkinetic disorder (HKD), defined
in the International Classification of Diseases, 10th Edition (WHO 1992), is a nar-
rower diagnostic category, requiring both symptoms of inattention and hyperactiv-
ity/impulsivity and including individuals diagnosed with the combined presentation
of ADHD as per DSM-5 (American Psychiatric Association 2013). A large body of
evidence shows that ADHD is often comorbid with other psychiatric conditions,
such as oppositional defiant disorder/conduct disorder, specific learning disorders,
mood and anxiety disorders, and sleep disturbances (Biederman and Faraone 2005;
Cortese et al. 2013). Over the past years, the relationship between attention-deficit/
hyperactivity disorder (ADHD), or ADHD symptoms, and autism spectrum disor-
der (ASD) has been the focus of increasing interest, both from a clinical and research
standpoint (Antshel et al. 2013). Criterion E of the previous version of the DSM
(DSM-IV-TR) did not allow the comorbid diagnosis of ADHD in individuals with
ASD. The underlying rationale was that, since ASD was considered the most severe
disorder within the diagnostic hierarchy, any symptoms of inattention and/or hyper-
activity/impulsivity were deemed to be an expression of the primary diagnosis of
S. Cortese
Department of Psychology, Developmental Brain-Behaviour Laboratory,
University of Southampton, Southampton, UK
IRCCS Stella Maris, Scientific Institute of Child Neurology and Psychiatry,
Calambrone, Pisa, Italy
The Child Study Center at NYU Langone Medical Center, New York, NY, USA

80 S. Cortese
ASD. However, some individuals with ASD do meet full criteria for ADHD, which
contributes to a more severe impairment. Moreover, for a subset of individuals with
mild ASD (in particular, the condition previously referred to as Asperger’s syn-
drome), the primary reason for clinical referral is ADHD symptoms rather than
impairment due to ASD core symptoms. Therefore, it is possible that DSM-IV-TR
ADHD criterion E contributed to the undertreatment of impairing ADHD-like
symptoms in individuals with ASD. Acknowledging this issue, the most recent ver-
sion of the DSM (DSM-5) does allow a dual diagnosis of ADHD and ADD, thus
highlighting the importance of addressing inattention, hyperactivity, and/or impul-
sivity in individuals with ASD.
2 Prevalence
ADHD is a major public health issue (Feldman and Reiff 2014). Its worldwide-
pooled prevalence is estimated at about 5 % in school-age children (Polanczyk et al.
2007, 2014). Impairing symptoms of ADHD persist in adulthood in up to 65 % of
cases (Faraone et al. 2006), with a pooled prevalence of adulthood ADHD around
2.5 % (Simon et al. 2009).
Currently, there are no available meta-analyses on the prevalence of ADHD in
individuals with ASD. Across studies, the prevalence of ADHD symptoms in indi-
viduals with a primary clinical diagnosis of ASD has been reported to be between
13 and 50 % in the general population and in community-based studies and between
20 and 85 % in clinical samples (Grzadzinski et al. 2011).
The main clinical issue when dealing with the recognition and diagnosis of ADHD
arguably pertains to the differential diagnosis. Indeed, the core symptoms of ADHD
(i.e., inattention, hyperactivity/impulsivity) are highly specific and can characterize
several, if not the majority, developmental psychopathological disorders. While the
differential diagnosis between ADHD and disorders such as mood and anxiety dis-
orders has been addressed in a large body of research (suggesting that the early
onset and chronicity of ADHD should be differentiated from the episodic manifes-
tation of depression/bipolarity and anxiety), the relationships between ADHD and
other disorders (such as attachment disorders) need to be better elucidated. Another
issue relates to the dimension of “mood dysregulation” that is found in many,
although not all, individuals with ADHD. It is currently debated if this dimension
should be considered among the defining criteria for ADHD. To complicate the
matter, many disorders that can be considered in differential diagnosis with ADHD
are claimed to be present also as comorbidity. Arguably, the current atheoretical and
descriptive approach of the DSM does not allow to fully disentangle issues pertain-
ing to comorbidity/differential diagnosis in the light of the etiopathophysiology and
developmental psychopathology of the symptoms.
6 Attention-Deficit Hyperactivity Disorder and Autism Spectrum Disorder 81
4 Peculiar Features of the Disorder in Comorbidity

with ASD
4.1 Diagnosis and Evaluation: Assessment Tools
The history/intake interview focusing on the chief complaints about inattention,

impulsivity, distractibility, and hyperactivity at school and at home and specifically
addressing the DSM-IV criteria for ADHD is the cornerstone of the diagnostic
assessment for ADHD (Pliszka 2007). The clinician should perform a detailed
interview with the parent(s) about each of the ADHD symptoms listed in DSM-5.
For each symptom, the clinician should determine whether it is present as well as its
duration, severity, and frequency. Age at onset of the symptoms (<12 years) should
be assessed. The patient must have the required number of symptoms, a chronic
course, and onset of symptoms during childhood. After reviewing the ADHD symp-
toms, the clinician should interview the parent(s) regarding other common psychi-
atric disorders of childhood. Formal structured and semi-structured interviews, such
as the Schedule for Affective Disorders and Schizophrenia for School-Age Children
(Kaufman et al. 1997), are available. Questionnaires, such as the Conners Parent
(Conners et al. 1998b) and Teacher (Conners et al. 1998a) Rating Scales-Revised
(CRS-R), are an important and efficient part of the diagnostic assessment but cannot
be used in isolation to make a diagnosis of ADHD.
Teachers, parents, and older children can/should all report on symptoms to assess
for agreement/validity of diagnosis, to document that the ADHD symptoms occur
in multiple settings, and to take advantage of the special information that each can
provide. Multiple informants (parents, teachers, youths, and healthcare profession-
als) do not necessarily agree on diagnosis. If the teacher cannot provide such a rat-
ing scale or the parent declines permission to contact the school, then materials
from school, such as work samples or report cards, should be reviewed or inquired
about. Care must be taken to determine the best interpretation of the data if dis-
agreements occur.
A thorough medical history is part of the initial evaluation. For example, prema-
turity and frequent episodes of otitis with hearing loss may be risk factors of
ADHD. A complete family history for ADHD and its common comorbidities should
be taken. ADHD is a highly heritable disorder, and, although a positive family his-
tory does not confirm the diagnosis, it can be supportive. After interviewing the
parents, the clinician should interview the child or adolescent. Young children are
often unaware of their symptoms of ADHD, and older children and adolescents may
be aware of symptoms but will minimize their significance. The interview with the
child or adolescent allows the clinician to identify signs or symptoms inconsistent
with ADHD or suggestive of other serious comorbid disorders. This is achieved by
means of a mental status examination, assessing appearance, sensorium, mood,
affect, and thought processes. This step is particularly relevant in case of the comor-
bidity between ADHD and ASD.
Since several medical problems can be associated with ADHD, as previously
discussed, the general medical examination is indispensable to corroborate some of
82 S. Cortese
these conditions (Nass 2005). The neurologic examination is part of any complete
diagnostic evaluation. In addition to the traditional neurologic examination, a num-
ber of standardized office examinations that tap developmental neurologic functions
are available. Furthermore, the neurologic examination provides an opportunity to
evaluate for commonly comorbid neurologic problems of coordination like dys-
praxia and dysgraphia (Nass 2005).
Neuropsychological testing is not a necessary part of the diagnostic assessment
of ADHD, unless specific comorbid or associated learning issues need to be evalu-
ated. Results of neuropsychological testing, however, may lend support to the diag-
nosis and are useful to detect possible neuropsychological subtypes that need a
targeted management. Intelligence should be assessed. Higher IQ ADHD children
may compensate for their attention difficulties sufficiently to mask executive dys-
function on traditional measures.
If the patient’s medical history is unremarkable, laboratory or neurological testing
is not indicated. The measurement of thyroid levels and thyroid-stimulating hormone
should be considered only if symptoms of hyperthyroidism other than increased
activity level are present. Exposure to lead, either prenatally or during development,
is associated with a number of neurocognitive impairments, including ADHD. If a
patient has been raised in environment where exposure to lead paint or plumbing is
probable, then serum lead levels should be considered. Serum lead levels, such as
measurement of other metals, should not be part of routine screening.
Neuroimaging or genetic studies are not currently indicated in the daily clinical
practice (Pliszka 2007).
Increasing evidence from neuroimaging and genetic studies points both to overlap
and specificity across the two disorders. A recent review of the literature of struc-
tural brain imaging studies [both anatomical magnetic resonance imaging (aMRI)
and diffusion tensor imaging (DTI)] concluded that total brain volume (increased in
ASD and decreased in ADHD), volume of amygdala (larger in ASD and normal in
ADHD), and fractional anisotropy (FA, a DTI proxy of white matter integrity) in the
internal capsule (ASD: unclear, ADHD: reduced FA in DTI) differed between the
two disorders. By contrast, overlap was reported in the corpus callosum and cere-
bellum (lower volume in aMRI and decreased FA in DTI) and superior longitudinal
fasciculus (reduced FA) (Dougherty et al. 2015). A meta-analysis of from functional
magnetic resonance imaging (fMRI) has shown similarities across the two disorders
in abnormal activation of regions in the attentional dorsal, executive functions,
visual, somatomotor circuits and the default activation circuit and specific deficits in
the reward circuit in ADHD and abnormalities in the circuits social cognition and
language processes specific to ASD (Proal et al. 2013).
From a genetic standpoint, literature on possible overlaps/differences is still in its
infancy. A twin study using twin-based structural equation modeling suggested a
moderate phenotypic correlation between autistic and ADHD symptoms. In a bivar-
iate model, genetic correlation (r(g)) between autistic and ADHD traits was 0.72
(Reiersen et al. 2008). The authors concluded that in young adults, a substantial
proportion of the genetic influences on self-reported autistic and ADHD symptoms
may be shared between the two disorders. Only a few candidate gene studies, link-
age studies, and GWAS studies have focused on this co-occurrence, pointing to
some promising pleiotropic genes, loci, and single nucleotide polymorphisms
(SNPs). For example, a seminal study suggested that 15q QTL has possible pleio-
tropic effects for ADHD and ASD (Nijmeijer et al. 2010).
6 Treatment
Available treatments for ADHD include pharmacological and non-pharmacological

strategies. Pharmacological treatments are an important element of therapeutic
strategies for ADHD and are recommended as the first-choice option in several
guidelines/practice parameters (e.g., Pliszka 2007), at least for severe cases or as a
treatment strategy for patients who have not responded to non-pharmacological
interventions (Taylor et al. 2004).
6.1 Pharmacological Treatment
Medications for ADHD include psychostimulant (e.g., methylphenidate and

amphetamines) and non-psychostimulant drugs (e.g., atomoxetine or guanfacine).
A large body of evidence from randomized controlled trials (RCTs), summarized in
several meta-analyses in children and/or adults, shows that psychostimulants [e.g.,
methylphenidate (Castells et al. 2011; Koesters et al. 2009; Schachter et al. 2001;
Van der Oord et al. 2008) or mixed amphetamine salts (Faraone and Biederman
2002) and other amphetamine derivatives (Castells et al. 2011)] are significantly
more effective than placebo to control ADHD symptoms, at least in the short term.
Indeed, the effect sizes expressing the efficacy of psychostimulants on ADHD core
symptoms found in the meta-analysis by Faraone and Buitelaar (2010) (0.72 for
methylphenidate and 0.99 for amphetamines) are among the highest ones consider-
ing all available pharmacological treatments in psychiatry. Psychostimulants have
been found efficacious also when pooling results from studies at longer term
(>12 months) (Maia et al. 2014).
Non-psychostimulant treatments, such as atomoxetine (Cheng et al. 2007; Cunill
et al. 2013; Kratochvil et al. 2008; Tanaka et al. 2013), are also significantly more
efficacious than placebo, at least in the short term, albeit with smaller effect sizes
than psychostimulants in terms of efficacy on ADHD core symptoms in the short
term (ES: 0.6) (Schwartz and Correll 2014). A meta-analysis (Hanwella et al. 2011)
of randomized controlled trials concluded that, overall, methylphenidate and atom-
oxetine have similar profiles in terms of all-cause discontinuation and incidence of
adverse events. However, a recent naturalistic study (Cortese et al. 2015b) showed a
better safety profile for methylphenidate than atomoxetine.
There is meta-analytic evidence that when used for ADHD symptoms in children
with comorbid ASD, psychostimulants are somewhat less efficacious and less well
84 S. Cortese
tolerated than in children with ADHD without ASD. A meta-analysis of four RCTs of
methylphenidate for ADHD symptoms in children with ASD found an ES = 0.6
(Reichow et al. 2013). The rates of adverse events, including, in particular social with-
drawal and irritability, were higher than those typically reported in preschoolers with
ADHD without ASD. As for non-psychostimulants, the most recent systematic review
of trials of atomoxetine concluded that although clinical practice suggests potential
efficacy of atomoxetine for ADHD symptoms in children with ASD, there are not
enough controlled clinical trial to corroborate such statement (Ghanizadeh 2013).
6.2 Non-pharmacological Treatments
While medications for ADHD are efficacious in randomized controlled trials (RCT)
in the short/medium term and are indicated as the first-line treatment (at least for
severe cases, Taylor et al. 2004), they have a number of potential limitations – each
affecting some patients. These include (i) partial or nonresponse (Faraone et al. 2006),
(ii) possible adverse effects (Cortese et al. 2013), (iii) uncertainty about long-term
costs and benefits (Molina et al. 2009), (iv) poor adherence (Adler and Nierenberg
2010), and (v) negative medication-related attitudes from patients, parents, or clini-
cians (Kovshoff et al. 2012). Therefore, in the past years, there has been an increasing
interest to non-pharmacological treatments for ADHD. The most recent and arguably
rigorous synthesis of such literature has been carried out in the past 3 years by the
European ADHD Guidelines Group (EAGG) in a series of meta-analyses addressing
the efficacy of a different number of non-pharmacological treatments for ADHD,
including dietary interventions (restricted elimination diets, artificial food color exclu-
sions, and free fatty acid supplementation), behavioral interventions, cognitive train-
ing, and neurofeedback. Overall, this series of meta-analyses showed that while all
these interventions are efficacious on ADHD core symptoms when considering rat-
ings from assessors probably not blinded, the efficacy of such interventions (with the
possible exception for a small effect for free fatty acid supplementation) drops to
nonsignificant when relying on rating from blinded assessors (Cortese et al. 2015a;
Daley et al. 2014; Sonuga-Barke et al. 2013). However, non-pharmacological inter-
ventions have been found efficacious on conditions associated with ADHD. For
instance, behavioral interventions had a significant effect on positive parenting, reduc-
tion of negative parenting, and on conduct disorders associated with ADHD, also
when considering probably blinded ratings (Daley et al. 2014). In addition, cognitive
training significantly improved working memory deficits that are impaired in a sub-
sample of children with ADHD (Cortese et al. 2015a).
Current available treatment approaches for ADHD are symptomatic rather than
being grounded on the pathophysiology of the disorder. The search for
pathophysiology-based treatments such as transcranial magnetic stimulation (TMS)

is ongoing (Zaman 2015), along with the advance in our knowledge on the patho-
physiology of the disorder, although at present these therapeutic approaches cannot
be recommended as standard and evidence-based treatments for ADHD.
There are many important questions that should be addressed in future studies. First,
further investigation is needed to better understand the reasons underlying the
comorbidity between ADHD and ASD. Indeed, since the DSM is conceived as an
atheoretical classification, the notion of comorbidity between two disorders is
purely meant to be descriptive in order to facilitate the communication among clini-
cians but does not provide any clue on the possible explanations for this association.
Second, genetic and environmental factors and their interaction, underlying the
association between ADHD and ASD, deserve further attention. Third, since cur-
rently available assessment tools for ADHD do not include items specifically
adapted for children with ASD, future research should focus on the evaluation of
more specific tools that take into account how the semiology of ADHD is impacted
by the co-occurrence of ASD. Finally, specific and, possibly, pathophysiologically
based intervention strategies to manage ADHD symptoms in individuals with
ADHD are needed, given that standard pharmacological treatments for ADHD are
less effective and less well tolerated in individuals with ASD and non-
pharmacological therapies for ADHD have been poorly evaluated in this clinical
population.
Appendix. Management of Disruptive Behaviors (Other

Than ADHD) in Children and Adolescents with ASD
In a sizable portion of patients with ASD referred to child and adolescent mental
health services, the main concerns include not only typical ADHD core symptoms
(i.e., hyperactivity, inattention, and impulsivity) but also related disruptive behav-
iors such as physical aggressiveness, temper outbursts, or irritability, the latter being
defined as an abnormal disposition to uncontrolled anger or aggression (Elbe and
Lalani 2012). Although the prevalence of such maladaptive behaviors has not sys-
tematically been evaluated in children/adolescents with ASD, individual studies
show that they are frequent and impairing in this population. For example, a study
in a sample of 487 young people with pervasive developmental disorder (PDD)
showed that up to 30 % of them presented with symptoms of irritability, including
aggression (24.5 %), severe tantrums (30.2 %), and deliberate self-injurious behav-
ior (16 %) (Lecavalier 2006).
Empirical evidence is available for both pharmacological and non-pharmacological
strategies aimed to manage such impairing behaviors. Non-pharmacological
86 S. Cortese
interventions are grounded on behavioral techniques such as stimulus-based proce-

dures (e.g., altering antecedent events), instruction-based procedures (e.g., instruc-
tion of appropriate behaviors), extinction-based procedures (e.g., withholding or
minimizing presumed reinforcers), reinforcement-based procedures (e.g., increasing
desired behaviors), punishment-based procedures (e.g., reducing behavior by deliv-
ering a contingent event), and systems change procedures (e.g., altering structural
features of environment) (Horner et al. 2002). Although no formal meta-analyses
have been published on the efficacy (and safety) of these behavioral interventions, a
comprehensive research synthesis concluded that (1) disruption/tantrum was the
most likely behavior targeted by such interventions, with aggression being the sec-
ond most likely; (2) early use of behavioral interventions results in reductions of
problem behaviors by 80–90 %; (3) interventions based on functional assessment are
more likely to reduce the severity and frequency of disruptive behaviors (Horner
et al. 2002).
Another promising and relatively novel intervention is based on Social Stories,
originally developed to teach children with autistic spectrum disorders how to play
games while increasing their ability to interact with others in a socially appropriate
way (Gray 1993). Such stories are written to reflect a situation that the child with
ASD finds difficult and provide information on what is happening, why, and which
are the desirable responses in that specific social situation. A systematic review of
case series reported so far concluded that across all seven research articles retrieved,
13 of 15 participants demonstrated a decrease in the frequency of disruptive behav-
ior, with only two participants recording no change in behavior following the
Social Story intervention (Rhodes 2014). It is worthy to point out that a rigorous
meta-analysis of the efficacy/effectiveness of non-pharmacological interventions
for disruptive behaviors in children with ASD, taking into account the level of
blinding of raters, for example, a recent meta-analysis on non-pharmacological
interventions for ADHD (Sonuga-Barke et al. 2013), is currently lacking in the
field.
With regard to pharmacological treatments, although, as pointed out in the main
chapter, no medication is currently approved to treat the core symptoms of ASD,
there is an extensive practice, and an increasing evidence base, for the use of several
agents to reduce the intensity and frequency of disruptive behaviors associated with
ASD. Most of the evidence pertains to antipsychotics, in particular risperidone. The
body of research on risperidone for disruptive behaviors has been recently meta-
analytically reviewed pooling data from 16 open-label studies and 6 placebo-
controlled trials (Sharma and Shaw 2012). This meta-analysis concluded that the
sample weighted mean effect size for risperidone was 1.13 for open-label studies
and 1.21 for placebo-controlled studies, thus indicating, in both cases, high efficacy
of risperidone on ASD-related disruptive behavioral, according to the Cohen’s clas-
sification of effect size (Cohen 1992). In terms of tolerability and safety, the most
common adverse events (AEs) reported in trials of risperidone for ASD included
excessive weight gain [e.g., in the Research Units on Pediatric Psychopharmacology
(RUPP) study (McDougle et al. 2005): 2.7 ± 2.9 kg vs. 0.8 ± 2.2 kg in the control
group], increased appetite, fatigue, drowsiness, dizziness, and drooling. Follow-up

data indicate that after 6 months of treatment, risperidone leads to a mean weight
gain of about 5 kg, which exceeds developmentally expected norms (Martin et al.
2004). Prolactin levels tend to increase significantly: for instance, after 8 weeks, a
fourfold increase has been observed, with a slight decrease after 6 months. Of note,
prolactin levels were not associated with any adverse events (Anderson et al. 2007).
Another agent that has been increasingly investigated over the past years is
aripiprazole. Two published placebo-controlled randomized trials (Owen et al.
2009; Marcus et al. 2009) assessing the effects of this drug for disruptive behaviors
in children with ASD reported a statistically significant reduction of disruptive
symptoms favoring aripiprazole (dose: 5–15 mg/day). In the first trial (Owen et al.
2009), discontinuation rates due to adverse events (AEs) were 10.6 % for aripipra-
zole and 5.9 % for placebo. Extrapyramidal symptom-related AE rates were 14.9 %
for aripiprazole and 8.0 % for placebo. Mean weight gain was 2.0 kg with aripipra-
zole and 0.8 kg with placebo at week 8. No serious AEs were reported. In the second
study (Marcus et al. 2009), sedation was the most common AE leading to discon-
tinuation. Presyncope (at the dose of 5 mg/day) and aggression (at 10 mg/day) were
the two severe AEs reported during the study. At week 8, mean weight change was
+0.3 kg on placebo, +1.3 kg on aripiprazole 5 mg/day, +1.3 kg on aripiprazole
10 mg/day, and 1.5 kg on aripiprazole 15 mg/day.
This body of evidence has led the Food and Drug Administration to approve first
risperidone (www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/
ucm108759.htm) and, more recently, aripiprazole (www.online.lexi.com) for the
treatment of irritability associated with autism spectrum disorder in children aged
6–17 years, and by contrast, in Europe, the European Medicines Agency has
approved risperidone for the short-term treatment of aggressive or disruptive behav-
iors in children with subaverage intellectual level and disruptive behavior from the
age of 5 years (www.medicines.org.uk/emc/medicine/12818/SPC/).
Other agents that have been assessed for the management of ASD-related disrup-
tive behaviors include typical antipsychotic such as haloperidol [e.g., (Cohen et al.
1980)], although their possible side effects, including sedation, acute dystonia, and
withdrawal dyskinesias, do not make this class as first-line option. Research on
other drugs, such as antiepileptic (lamotrigine and levetiracetam), amantadine, and
carnitine, has not shown so far clear beneficial effects of these agents on disruptive
behaviors in children with ASD (Kirino 2014).
With regard to the sequencing of treatments (pharmacological and non-
pharmacological), the National Institute for Health and Care Excellence (NICE)
guidelines recommended using medication for behavioral problems in ASD only if
environmental, psychosocial, or other interventions have been insufficient or cannot
be delivered because of the severity of the behavior (https://www.nice.org.uk/guid-
ance/qs51). Many experts in the field [e.g., (Dinnissen et al. 2015; Scahill et al.
2009)] concur with the view that pharmacological treatments should be considered
only as short-term option when there is a history of behavioral symptoms that occur
in multiple settings and that do not respond to behavioral interventions.
88 S. Cortese
References
Adler LD, Nierenberg AA (2010) Review of medication adherence in children and adults with
ADHD. Postgrad Med 122:184–191
5th edn, DSM-5. American Psychiatric Publishing, Washington, DC
Anderson GM, Scahill L, McCracken JT, McDougle CJ, Aman MG, Tierney E et al (2007) Effects
of short- and long-term risperidone treatment on prolactin levels in children with autism. Biol
Antshel KM, Zhang-James Y, Faraone SV (2013) The comorbidity of ADHD and autism spectrum
disorder. Expert Rev Neurother 13:1117–1128
Biederman J, Faraone SV (2005) Attention-deficit hyperactivity disorder. Lancet 366:237–248
Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M (2011a) Amphetamines for
Attention Deficit Hyperactivity Disorder (ADHD) in adults. Cochrane Database Syst Rev
(6):CD007813
Castells X, Ramos-Quiroga JA, Rigau D, Bosch R, Nogueira M, Vidal X et al (2011a) Efficacy of
methylphenidate for adults with attention-deficit hyperactivity disorder: a meta-regression
analysis. CNS Drugs 25:157–169
Cheng JY, Chen RY, Ko JS, Ng EM (2007) Efficacy and safety of atomoxetine for attention-deficit/
hyperactivity disorder in children and adolescents-meta-analysis and meta-regression analysis.
Psychopharmacology (Berl) 194:197–209
Cohen J (1992) A power primer. Psychol Bull 112:155–159
Cohen IL, Campbell M, Posner D, Small AM, Triebel D, Anderson LT (1980) Behavioral effects
of haloperidol in young autistic children. An objective analysis using a within-subjects reversal
design. J Am Acad Child Psychiatry 19:665–677
Conners CK, Sitarenios G, Parker JD, Epstein JN (1998a) Revision and restandardization of the
Conners Teacher Rating Scale (CTRS-R): factor structure, reliability, and criterion validity.
J Abnorm Child Psychol 26:279–291
Conners CK, Sitarenios G, Parker JD, Epstein JN (1998b) The revised Conners’ Parent Rating
Scale (CPRS-R): factor structure, reliability, and criterion validity. J Abnorm Child Psychol
26:257–268
Cortese S, Holtmann M, Banaschewski T, Buitelaar J, Coghill D, Danckaerts M et al (2013)
Practitioner review: current best practice in the management of adverse events during treatment
with ADHD medications in children and adolescents. J Child Psychol Psychiatry 54:227–246
Cortese S, Ferrin M, Brandeis D, Buitelaar J, Daley D, Dittmann RW et al (2015a) Cognitive train-
ing for attention-deficit/hyperactivity disorder: meta-analysis of clinical and neuropsychologi-
cal outcomes from randomized controlled trials. J Am Acad Child Adolesc Psychiatry
54:164–174
Cortese S, Panei P, Arcieri R, Germinario EA, Capuano A, Margari L et al (2015b) Safety of meth-
ylphenidate and atomoxetine in children with Attention-Deficit/Hyperactivity Disorder
(ADHD): data from the Italian National ADHD Registry. CNS Drugs 29(10):865–77
Cunill R, Castells X, Tobias A, Capella D (2013) Atomoxetine for attention deficit hyperactivity
disorder in the adulthood: a meta-analysis and meta-regression. Pharmacoepidemiol Drug Saf
22:961–969
Daley D, Van der Oord S, Ferrin M, Danckaerts M, Doepfner M, Cortese S et al (2014) Behavioral
interventions in attention-deficit/hyperactivity disorder: a meta-analysis of randomized controlled
trials across multiple outcome domains. J Am Acad Child Adolesc Psychiatry 53:835–847
Dinnissen M, Dietrich A, van den Hoofdakker BJ, Hoekstra PJ (2015) Clinical and pharmacoki-
netic evaluation of risperidone for the management of autism spectrum disorder. Expert Opin
Drug Metab Toxicol 11:111–124
Dougherty CC, Evans DW, Myers SM, Moore GJ, Michael AM (2015) A comparison of structural
brain imaging findings in autism spectrum disorder and Attention-Deficit Hyperactivity
Disorder. Neuropsychol Rev 26(1):25–43
Elbe D, Lalani Z (2012) Review of the pharmacotherapy of irritability of autism. J Can Acad Child
Faraone SV, Biederman J (2002) Efficacy of Adderall for attention-deficit/hyperactivity disorder:
a meta-analysis. J Atten Disord 6:69–75
Faraone SV, Buitelaar J (2010) Comparing the efficacy of stimulants for ADHD in children and
adolescents using meta-analysis. Eur Child Adolesc Psychiatry 19:353–364
Faraone SV, Biederman J, Mick E (2006a) The age-dependent decline of attention deficit hyperac-
tivity disorder: a meta-analysis of follow-up studies. Psychol Med 36:159–165
Faraone SV, Biederman J, Spencer TJ, Aleardi M (2006b) Comparing the efficacy of medications
for ADHD using meta-analysis. Med Gen Med 8:4
Feldman HM, Reiff MI (2014) Clinical practice. Attention deficit-hyperactivity disorder in chil-
dren and adolescents. N Engl J Med 370:838–846
Ghanizadeh A (2013) Atomoxetine for treating ADHD symptoms in autism: a systematic review.
J Atten Disord 17:635–640
Gray CA (1993) The original social stories book. Future Horizons, Arlington
Grzadzinski R, Di MA, Brady E, Mairena MA, O’Neale M, Petkova E et al (2011) Examining
autistic traits in children with ADHD: does the autism spectrum extend to ADHD? J Autism
Dev Disord 41:1178–1191
Hanwella R, Senanayake M, de Silva V (2011) Comparative efficacy and acceptability of methyl-
phenidate and atomoxetine in treatment of attention deficit hyperactivity disorder in children
and adolescents: a meta-analysis. BMC Psychiatry 11:176
Horner RH, Carr EG, Strain PS, Todd AW, Reed HK (2002) Problem behavior interventions for
young children with autism: a research synthesis. J Autism Dev Disord 32:423–446
Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P et al (1997) Schedule for affective
disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL):
initial reliability and validity data. J Am Acad Child Adolesc Psychiatry 36:980–988
Kirino E (2014) Efficacy and tolerability of pharmacotherapy options for the treatment of irritabil-
ity in autistic children. Clin Med Insights Pediatr 8:17–30
Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S (2009) Limits of meta-analysis: methyl-
phenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol
23:733–744
Kovshoff H, Williams S, Vrijens M, Danckaerts M, Thompson M, Yardley L et al (2012) The deci-
sions regarding ADHD management (DRAMa) study: uncertainties and complexities in assess-
ment, diagnosis and treatment, from the clinician’s point of view. Eur Child Adolesc Psychiatry
21:87–99
Kratochvil CJ, Milton DR, Vaughan BS, Greenhill LL (2008) Acute atomoxetine treatment of
younger and older children with ADHD: a meta-analysis of tolerability and efficacy. Child
Adolesc Psychiatry Ment Health 2:25
Lecavalier L (2006) Behavioral and emotional problems in young people with pervasive develop-
mental disorders: relative prevalence, effects of subject characteristics, and empirical classifi-
cation. J Autism Dev Disord 36:1101–1114
Maia CR, Cortese S, Caye A, Deakin TK, Polanczyk GV, Polanczyk CA et al (2014) Long-Term
efficacy of methylphenidate immediate-release for the treatment of childhood ADHD: a sys-
tematic review and meta-analysis. J Atten Disord, in press
Marcus RN, Owen R, Kamen L, Manos G, McQuade RD, Carson WH et al (2009) A placebo-
controlled, fixed-dose study of aripiprazole in children and adolescents with irritability associ-
ated with autistic disorder. J Am Acad Child Adolesc Psychiatry 48:1110–1119
Martin A, Scahill L, Anderson GM, Aman M, Arnold LE, McCracken J et al (2004) Weight and
leptin changes among risperidone-treated youths with autism: 6-month prospective data. Am
J Psychiatry 161:1125–1127
McDougle CJ, Scahill L, Aman MG, McCracken JT, Tierney E, Davies M et al (2005) Risperidone
for the core symptom domains of autism: results from the study by the autism network of the
research units on pediatric psychopharmacology. Am J Psychiatry 162:1142–1148
90 S. Cortese
Molina BS, Hinshaw SP, Swanson JM, Arnold LE, Vitiello B, Jensen PS et al (2009) MTA at 8
years: prospective follow-up of children treated for combined-type ADHD in a multisite study.
Nass RD (2005) Evaluation and assessment issues in the diagnosis of attention deficit hyperactiv-
ity disorder. Semin Pediatr Neurol 12:200–216
Nijmeijer JS, Arias-Vasquez A, Rommelse NN, Altink ME, Anney RJ, Asherson P et al (2010)
Identifying loci for the overlap between attention-deficit/hyperactivity disorder and autism
spectrum disorder using a genome-wide QTL linkage approach. J Am Acad Child Adolesc
Owen R, Sikich L, Marcus RN, Corey-Lisle P, Manos G, McQuade RD et al (2009) Aripiprazole
in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics
124:1533–1540
Pliszka S (2007) Practice parameter for the assessment and treatment of children and adolescents
with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry
46:894–921
Polanczyk G, de Lima MS, Horta BL, Biederman J, Rohde LA (2007) The worldwide prevalence
of ADHD: a systematic review and metaregression analysis. Am J Psychiatry 164:942–948
Polanczyk GV, Willcutt EG, Salum GA, Kieling C, Rohde LA (2014) ADHD prevalence estimates
across three decades: an updated systematic review and meta-regression analysis. Int J
Epidemiol 43(2):434–42
Proal E, Gonzalez-Olvera J, Blancas AS, Chalita PJ, Castellanos FX (2013) Neurobiology of
autism and attention deficit hyperactivity disorder by means of neuroimaging techniques: con-
vergences and divergences. Rev Neurol 57(Suppl 1):S163–S175
Reichow B, Volkmar FR, Bloch MH (2013) Systematic review and meta-analysis of pharmaco-
logical treatment of the symptoms of attention-deficit/hyperactivity disorder in children with
pervasive developmental disorders. J Autism Dev Disord 43:2435–2441
Reiersen AM, Constantino JN, Grimmer M, Martin NG, Todd RD (2008) Evidence for shared
genetic influences on self-reported ADHD and autistic symptoms in young adult Australian
twins. Twin Res Hum Genet 11:579–585
Rhodes C (2014) Do Social Stories help to decrease disruptive behaviour in children with autistic
spectrum disorders? A review of the published literature. J Intellect Disabil 18:35–50
Scahill L, Aman MG, McDougle CJ, Arnold LE, McCracken JT, Handen B et al (2009) Trial
design challenges when combining medication and parent training in children with pervasive
developmental disorders. J Autism Dev Disord 39:720–729
Schachter HM, Pham B, King J, Langford S, Moher D (2001) How efficacious and safe is short-
acting methylphenidate for the treatment of attention-deficit disorder in children and adoles-
cents? A meta-analysis. CMAJ 165:1475–1488
Schwartz S, Correll CU (2014) Efficacy and safety of atomoxetine in children and adolescents with
attention-deficit/hyperactivity disorder: results from a comprehensive meta-analysis and
metaregression. J Am Acad Child Adolesc Psychiatry 53:174–187
Sharma A, Shaw SR (2012) Efficacy of risperidone in managing maladaptive behaviors for chil-
dren with autistic spectrum disorder: a meta-analysis. J Pediatr Health Care 26:291–299
Simon V, Czobor P, Balint S, Meszaros A, Bitter I (2009) Prevalence and correlates of adult
attention-deficit hyperactivity disorder: meta-analysis. Br J Psychiatry 194:204–211
Sonuga-Barke EJ, Brandeis D, Cortese S, Daley D, Ferrin M, Holtmann M et al (2013)
Nonpharmacological interventions for ADHD: systematic review and meta-analyses of ran-
domized controlled trials of dietary and psychological treatments. Am J Psychiatry
170:275–289
Tanaka Y, Rohde LA, Jin L, Feldman PD, Upadhyaya HP (2013) A meta-analysis of the consis-
tency of atomoxetine treatment effects in pediatric patients with attention-deficit/hyperactivity
disorder from 15 clinical trials across four geographic regions. J Child Adolesc Psychopharmacol
23:262–270
Taylor E, Dopfner M, Sergeant J, Asherson P, Banaschewski T, Buitelaar J et al (2004) European

clinical guidelines for hyperkinetic disorder – first upgrade. Eur Child Adolesc Psychiatry
13(Suppl 1):I7–I30
Van der Oord S, Prins PJ, Oosterlaan J, Emmelkamp PM (2008) Efficacy of methylphenidate,
psychosocial treatments and their combination in school-aged children with ADHD: a meta-
analysis. Clin Psychol Rev 28:783–800
WHO (1992) The ICD-10 classification of mental and behavioral disorders: clinical descriptions
and diagnostic guidelines 1992; diagnostic criteria for research 1993. Geneva 1992
Zaman R (2015) Transcranial magnetic stimulation (TMS) in Attention Deficit Hyperactivity
Disorder (ADHD). Psychiatr Danub 27(Suppl 1):530–532
Tics and Tourette Syndrome in Autism
Spectrum Disorder 7
Alessandro Capuano and Giovanni Valeri
1 Introduction
Autism spectrum disorder (ASD) and Tourette syndrome (TS) are neurodevelop-
mental disorders that typically begin in childhood and are considered chronic condi-
tions in the lifetime. Even if ASD and TS are apparently different disorders, these
two conditions share some epidemiological, phenomenological, and pathophysio-
logical features, and several researchers have considered overlap between ASD and
TS. There is an increasing interest in the clinical characteristics and biological
underpinnings of TS and common co-occurring psychopathology, including ASD.
Although there is no enough evidence to support a unified theory, recent research
has focused on both genetic and neuropathological etiologies of TS and ASD.
ASD is are neurodevelopmental disorder characterized by the presence of
impaired social interaction and communication, typically accompanied by restricted
interests and/or stereotyped behaviors (American Psychiatric Association, DSM-5
2013). A recent epidemiological study estimated the global prevalence of ASD to be
between 1 % and 2 % (Elsabbagh et al. 2012). Comorbid psychiatric disorders are
present in 70 % of individuals with ASD (Simonoff et al. 2008): attention deficit
hyperactivity disorder (ADHD), obsessive compulsive behaviors/disorder (OCB/D),
tics and TS, mood disorders, anxiety, oppositional defiant disorder (ODD), conduct
disorder (CD), and personality disorders (PDs).
Tourette syndrome (TS) is the primary tic disorder with an estimated prevalence
close to 1 % between 5 and 18 years of age (Burd et al. 2009). Core features of TS
are motor and phonic tics (DSM-5). In addition to their well-characterized
A. Capuano
Neurology Unit, Department of Neuroscience,
G. Valeri (*)
Child Neuropsychiatry Unit, Department of Neuroscience,
94 A. Capuano and G. Valeri
phenomenology, tics display a peculiar variability over time, which is strongly

influenced by a variety of contextual factors. A relevant proportion of patients with
TS display complex, tic-like, repetitive behaviors that include echophenomena,
coprophenomena, and nonobscene socially inappropriate behaviors (NOSIBs).
Comorbid conditions are ADHD, OCB/D, and ASD; coexistent psychopatholo-
gies include depression, anxiety, ODD, CD, and PDs.
The complexity of the Tourette spectrum has been confirmed by cluster and factor
analytical approaches (Cavanna et al. 2011). It is suggested that TS is not a unitary
condition and that one phenotype (“pure TS” [tics only]) occurs in about 10–14 %.
The presence of comorbid ADHD is the main determinant of cognitive dysfunction
in TS patients and influences heavily also the risk of developing disruptive behaviors
(Müller-Vahl et al. 2010). The burden of behavioral comorbidities is very important in
determining significant impairment, poor self-esteem, and a low quality of life.
2 Prevalence
Epidemiologically, more recent studies have highlighted that ASD is overrepresented in

TS, occurring in about 4–5 % of TS population (Burd et al. 2009; Freeman et al. 2000).
Burd et al. (2009) examined 7,288 participants from the Tourette Syndrome
International Database Consortium and found that TS substantially increased the risk
of ASD/pervasive developmental disorders by 13-fold across the reporting sites.
Furthermore, Kadesjo and Gillberg (2000) found that about 5 % of patients with
TS also had a diagnosis of Asperger’s syndrome, 17 % showed three or more autis-
tic symptoms, and 65 % had deficits relating to the autism spectrum. Thus, TS and
ASD are more frequently associated than expected by chance.
Other common epidemiological features are constituted by (1) gender preva-
lence, in fact males are considerably more likely to be diagnosed with ASD or TS
than females, and (2) age of onset, in fact both disorders often manifest during
childhood with the median ages of diagnosis of 4.7 and 6.0 years for ASD and TS,
respectively (Centers for Disease Control and Prevention (CDC) Developmental
Disabilities Monitoring Network Surveillance Year 2010).
Numerous reports have examined the relationship between ASD and TS
(Canitano and Vivanti 2007; Kerbeshian and Larry 2003; Burd et al. 2009; Zappella
2002; Rapin 2001; Baron-Cohen et al. 1999) including several population-based
studies identifying a significant relationship between TS and ASD above and
beyond what would be expected by chance.
However, highly variable rates of comorbidity between tic disorders and ASD
have been reported, ranging from 2.9 to 30 %. This range of incidence rates may be
attributed to variable clinical samples and/or differences in research methodology.
The association between ASD and tic disorders was initially described in single
case reports, followed by several case series presenting an elevated concurrence of
ASD and TS as well as examples of tic development positively impacting autistic
symptoms in several young children (mostly males). Collectively, these early reports
spurred a growing interest and discussion in regard to the potential clinical and
genetic overlap between the two disorders.
7 Tics and Tourette Syndrome in Autism Spectrum Disorder 95
A consistent limitation in studies reporting overlap between ASD and TS has been
capturing large cohorts of TS and/or ASD subjects. In 1999, Baron-Cohen and col-
leagues identified 8.1 % of 37 school-aged children with autism presenting with
comorbid TS (Yang et al. 2012). Later, Canitano et al. evaluated a clinical sample of
105 children with ASD, observing 22 % with a tic disorder (11 % with TS and 11 %
with chronic motor tics). These findings suggested that the rate of comorbidity was
higher than what would have been expected by chance; however, in both reports, the
small sample size limited the generalizability of findings. Recently, the Tourette
Syndrome International Consortium was initiated to more accurately describe the
comorbidity patterns of TS using a large cohort of individuals. Using these data,
(Burd et al. 2009) observed that 4.6 % of the 7,288 participants with TS presented with
a comorbid pervasive development disorder (PDD), providing significant support that
TS increases the risk for PDD/ASD 13-fold. Further, the presence of TS and comorbid
PDD/ASD significantly increased the risk of additional comorbid psychopathology
(not including PDD/ASD), with nearly 98 % presenting with one or more comorbidity
versus 13.2 % in the group with TS only (Burd et al. 2009). These findings suggest that
patients with TS and PDD/ASD may present with a more complex diagnostic picture,
likely demanding more comprehensive and intensive managed care.
2.1 Familial and Genetic Findings
Several studies have identified a positive family history of TS and/or ASD in indi-
viduals presenting with both disorders concurrently (Mandell et al. 2005;
Karagiannidis et al. 2012). In a clinical sample of 105 youth with ASD, Canitano
et al. observed a positive family history for tic disorders in 59.5 % of youth present-
ing with ASD and comorbid TS. Burd et al. also identified an association between
neuropsychiatric symptoms (including TS and ASD) and a deletion involving exons
4, 5, and 6 of the gene neuroligin 4 (NLGN4) in a family study.
To further delineate potential genetic associations between TS and ASD,
Fernandez et al. (2012) examined gene copy number variants (CNVs) in individuals
with TS (n = 460) compared to control subjects (n = 1,131). While no significant
increases in the number of de novo or transmitted rare CNVs were identified in TS
subjects compared to controls, gene mapping within rare CNVs in TS subjects
showed significant overlap with CNVs previously identified in individuals with
ASD. Taken together, these findings reinforce the idea of a common pathogenetic
mechanism and shared genetic risk between the two disorders.
3.1 Tourette Syndrome
As defined and widely described, TS is characterized by motor and vocal tics, with a
waxing and waning course, often accompanied by compulsive behavior (Cohen et al.
2013). From a phenomenological point of view, tics are classified into “hyperkinetic
movement disorders” and they are defined as nonvoluntary body movements or

vocal sounds that are made repeatedly, rapidly, and suddenly. Tics are stereotyped
but no rhythmic movement. The child or adolescent with a tic experiences it as irre-
sistible but can suppress the movement or noise for a period of time. Both kinds of
tics, motor and vocal, can be simple or complex. Simple tics involve only a few
muscles or sounds that are not yet words. Examples of simple motor tics include
nose wrinkling, facial grimaces, eye blinking, jerking the neck, shrugging the shoul-
ders, or tensing the muscles of the abdomen. Simple vocal tics include grunting,
clucking, sniffing, chirping, or throat-clearing noises. Simple tics rarely last longer
than a few hundred milliseconds. Complex tics involve multiple groups or muscles
or complete words or sentences. Examples of complex motor tics include such ges-
tures as jumping, squatting, making motions with the hands, twirling around when
walking, touching or smelling an object repeatedly, and holding the body in an
unusual position. Complex motor tics last longer than simple motor tics, usually
several seconds or longer. Two specific types of complex motor tics that often cause
parents concern are copropraxia, in which the tic involves a vulgar or obscene ges-
ture, and echopraxia, in which the tic is a spontaneous imitation of someone else’s
movements. Similarly, complex vocal tics involve full speech and language, which
may range from the spontaneous utterance of individual words or phrases, such as
“Stop,” or “Oh boy,” to speech blocking or meaningless changes in the pitch, vol-
ume, or rhythm of the child’s voice. Specific types of complex vocal tics include
palilalia, which refers to the child’s repetition of his or her own words; coprolalia,
which refers to the use of obscene words or abusive terms for certain racial or reli-
gious groups; and echolalia, in which the child repeats someone else’s last word or
phrase. Other features of tics are that they typically occur in bouts or episodes alter-
nating with periods of tic-free behavior lasting from several seconds to several
hours. They generally diminish in severity when the child is involved in an absorb-
ing activity such as reading or doing homework and increase in frequency and
severity when the child is tired, ill, or stressed. Some children have tics during the
lighter stages of sleep or wake up during the night with a tic. Severe complex motor
tics carry the risk of physical injury, as the child may damage muscles or joints,
fracture bones, or fall down during an episode of these tics. Some children harm
themselves deliberately by self-cutting or self-hitting, while others hurt themselves
unintentionally by touching or handling lighted matches, razor blades, or other dan-
gerous objects. Severe complex vocal tics may interfere with breathing or
swallowing.
3.2 ASD
ASD is defined by qualitative impairments in both communication and social inter-

action and in restricted and repetitive patterns of behavior, interests, and activities
(American Psychiatric Association 2013). Commonly ASD patients present “move-
ment disorders” resembling tics but phenomenologically different called stereoty-
pies. As defined by the Taskforce on Childhood Movement Disorders (Sanger et al.
2010), stereotypies are repetitive, simple movements that can be voluntarily
suppressed. Examples include repetitive chewing, rocking, twirling, or touching.

These movements can occur also in children with intellectual disability (mental
retardation) or other developmental disorders such as Rett syndrome as well as in
normal children during neurodevelopment.
Stereotyped and repetitive motor mannerisms or complex whole-body move-
ments (e.g., hand or finger flapping or twisting, rocking, swaying, dipping, walking
on tiptoe [toe walking]) are another feature of ASD (Ming et al. 2007; Mandell et al.
2005). Children with ASD may line up an exact number of playthings in the same
manner in a stereotyped ritual, without apparent awareness of what the toys repre-
sent. Other stereotyped behaviors may include echolalia and idiosyncratic phrases.
Motor mannerisms are reported in 37–95 % of individuals with ASD (Filipek
et al. 2000). Motor mannerisms often manifest during the preschool years.
Stereotyped motor mannerisms appear to be self-stimulating and may also be self-
injurious (Teplin 1999).
Self-injurious behaviors are more common among ASD patients with cognitive
disability and include headbanging, face or body slapping, self-biting, or self-
pinching. The triggers for these behaviors may be predictable (frustration, anxiety,
excitement) or seemingly random.
Sensory processing abilities are aberrant in 42–99 % of individuals with ASD
(Filipek et al. 2000). Aberrant responses may include overresponsiveness, underre-
sponsiveness, and paradoxical responses to environmental stimuli (Kientz and Dunn
1997). Examples are (1) visual inspection of objects out of the corner of the eyes;
(2) preoccupation with edges, spinning objects, or shiny surfaces, lights, or odors;
(3) preoccupation with sniffing or licking nonfood objects; (4) resistance to being
touched or increased sensitivity to certain kinds of touch; (5) apparent indifference
to pain; (6) strong preferences for and/or compulsive touching of certain textures
and strong aversions to others; and (7) hypersensitivity to certain frequencies or
types of sound (e.g., distant fire engines) with lack of response to sounds close-by
or sounds that would startle other children.
4 Peculiar Features of the Disorder in Comorbidity

with ASD
4.1 Similarities in Symptomatology
Beyond potential etiological similarities, phenotypic overlap exists between TS and

ASD.
First, there is a significant male predominance in both disorders (approximately
60–80 %).
Second, these disorders have many overlapping clinical symptoms, including
social deficits, speech abnormalities (e.g., echolalia or palilalia), sensory abnormali-
ties, obsessive-compulsive symptoms, and repetitive motor behaviors.
However, there are also significant differences between the two disorders, for
example, speech abnormalities such as coprolalia may present in TS but are not char-
acteristic of ASD symptoms. In TS, disordered movements present as motor and
Table 7.1 Comparison of motor and nonmotor features of TS and ASD

TS ASD
Motor symptoms Tics Stereotypies
Simple and complex motor tics Simple and complex
stereotypies
Simple and complex vocal tics Vocalizations, echolalia
Compulsion, repetitive patterns Frequently reported (especially Core feature
of behavior in OCD comorbidity)
Impaired socialization Frequently reported Core feature
Impaired communication Frequently reported Core feature
Impaired attention Associated symptom Associated symptom
Hyperactivity Associated symptom Associated symptom
Obsessive-compulsive Associated symptom Frequently reported
behavior
Sensory processing issues Frequently reported Associated symptom
Sleep disturbance Frequently reported Frequently reported
vocal tics (i.e., repetitive, sudden, brief, irregular, involuntary), while ASD patients
often present with stereotypies (i.e., repetitive, ritualistic, rhythmical, purposeful).
Further, rigidity and resistance to change, common features of ASD, are somewhat
distinct from the classic obsessive symptoms that frequently co-occur with TS.
Specific differences between tics and stereotypies can usually be differentiated
by a thorough and comprehensive clinical evaluation, providing an accurate differ-
ential diagnosis. A summary of overlapped clinical features of ASD and TS is
showed in Table 7.1.
The American Psychiatric Association (APA) defined three tic disorders in the 5th
edition of the Diagnostic and Statistical Manual of Mental Disorders, or DSM-5: (1)
provisional tic disorder, (2) persistent (chronic) motor or vocal tic disorder, and (3)
Tourette syndrome. The disorders are distinguished from one another according to
three criteria: the child’s age at onset, the duration of the disorder, and the number
and variety of tics. The diagnosis is based on a set of clinical diagnostic criteria. A
classification of tics is shown in Table 7.2.
In particular, TS is defined by the following clinical criteria:
• Both multiple motor tics and one or more phonic tics must be present at some
time during the illness, although not necessarily concurrently tics must occur
many times a day, nearly every day, or intermittently throughout a period of more
than 1 year.
• Onset of tics before the age of 18 years.
• Involuntary movements and noises must not be explained by another medical
condition or by the physiological effects of substance.
Table 7.2 Classification of tics

Primary pathological
Physiologic tics tics Secondary pathological tics (“Tourettism”)
Mannerisms Sporadic Inherited
Transient motor or Huntington disease
phonic tics (<1 year)
Chronic motor or Primary dystonia
phonic tics (>1 year)
Adult-onset Neuroacanthocytosis
(recurrent) tics
Tourette syndrome Neurodegeneration with brain iron accumulation
Tuberous sclerosis
Wilson disease
Infections: encephalitis, Creutzfeldt-Jakob disease,
Sydenham chorea
Drugs: stimulants, levodopa, carbamazepine,
phenytoin, phenobarbital, antipsychotics (tardive
dyscinesia)
Toxins: carbon monoxide
Developmental: static encephalopathy, mental
retardation syndromes, chromosomal
abnormalities
Other: head trauma, stroke, neurocutaneous
syndromes, schizophrenia, neurodegenerative
disorders
5.1 An Integrated Approach to Diagnosis and Evaluation

of Tourette and Comorbid Conditions
Based on description made previously in this chapter, it is clear that the diagnosis
of TS is based on clinical features of the symptoms. Thus, a detailed medical his-
tory and a complete psychosocial and family history to detect psychiatric and/or
neurological conditions in relatives are often enough to clarify the clinical frame-
work of the disorder. However, a small minority of patients with TS presents a pure
tic disorder, while a psychopathology and comorbidity occur in about 80–90 %
(Martino et al. 2013).
A series of scales and other instruments have been developed to completely
assess TS and comorbid conditions. An algorithm is shown in Fig. 7.1.
6.1 Neuropathological Similarities
Given the growing evidence suggesting an etiological overlap between TS and

ASD, this relationship has been investigated by several researchers via psycho-
pathological, neuropsychological, brain imaging, genetic, and clinical studies.
General evaluation Yale Global Tics Severity Scale

Medical interview, history, Tic severity: number, frequency,
familial history intensity, complexity, interference
Motor and vocal scores
Overall impairment
Specific Interview on Shapiro Tourette Syndrome Severity
tics Scale
Agr of onset motor/vocal, five items including the noticeability to
premonitory urge, sensory others, and interference of daily life
tics, stressors due to tics
Hopkins motor and vocal tic
scale
focuses both on tics and their
Parent- and patient rating impairment, using visual analogue
scales to support the CBCL scales on which physicians and
general evaluation parents seperately rank motor and
vocal tics
CGI
support to general
evaluation Psychosocial functioning
GTS-QOL
OCD symptoms (past/present) CY-BOCS
ADHD SNAP/CAARS
comorbid
conditions Autism symptoms SCQ / SRS
Impulsive behavior BIS 11
Fig. 7.1 Assessment tool algorithm for TS and its comorbid conditions
A recent review by Kern et al. (2015) observed several neuropsychological simi-

larities between TS, ASD, and ADHD, highlighting that these disorders may be part
of a broader neurodevelopmental illness spectrum (termed abnormal connectivity
spectrum disorder [ACSD]), resulting from neural processes that cause long-range
underconnectivity and short-range overconnectivity. These connectivity abnormali-
ties may be related to neurotoxicity, neuroinflammation, excitotoxicity, sustained
microglial activation, proinflammatory cytokines, toxic exposure, and oxidative
stress. Evidence also suggests that the severity of connectivity deficits is associated
with symptom severity in TS, ASD, and ADHD. Collectively, these data further
support the hypothesis that these disorders, though separate, may share common
risk factors or possibly etiology.
6.2 Neurobiology of TS and ASD: Common Features

and Mechanisms
6.2.1 The Role of Basal Ganglia in TS and ASD

Currently, it is recognized that dysfunctions of basal ganglia (BG) lead to cognitive
and behavioral disorders other than purely motor symptoms. Historically, most of
reattach attention has been focused on abnormal moments, considering BG as struc-
tures purely involved in motor control. It is only since the end of 1990s that cogni-
tive, behavioral, and motivational aspects have been considered as another role of
BG. The implication of BG in behavioral disorders arises from (1) anatomical and
functional studies on organization of circuitry into BG, which revealed functional
compartmentalization in close relation to different cortical territories; (2) animal
models, especially in nonhuman primates that allowed to establish a causal link
between dysfunctions in BG and specific motor and nonmotor symptoms; and (3)
clinical studies on dopamine therapy or deep brain stimulation (DBS).
As described above, many features of ASD patients represented by gait abnor-
malities, impairment in dexterity, abnormal/stereotyped movements, and repetitive
pattern of behavior suggest an involvement of BG. Moreover, recent experimental
and functional studies confirm BG dysfunction in ASD (Shepherd 2013). Thus, BG
could be considered the anatomical and functional link between TS and ASD.
6.2.2 BG Anatomy and Recent Theory of Functional Circuitry

and Projections
The BG are a complex of deep nuclei that consist of the corpus striatum, globus
pallidus (GP), and substantia nigra. The corpus striatum, which includes the cau-
date nucleus and the putamen, receives input from the cerebral cortex and the
thalamus and, in turn, projects to the GP, which projects via the thalamus to the
premotor and motor cortex. Thus, in this very simplified view of BG connectivity,
we distinguish main input information arising from cortical areas and projected to
striatum and a main output pathway arising from GP and directed to cortical areas
(primary motor cortex) to facilitate goal-directed movement. Substantia nigra via
its dopaminergic pathway modulates GP output. So, one of first model of BG
functionality considered different cortical (mainly motor) inputs that converge
into only one output pathway controlling the execution of movement (Parent and
Hazrati 1995). In 1986, Alexander et al. presented an alternative hypothesis of BG
organization with functional parallel loops rather than a unique functional conver-
gence. According to this model, BG are divided into functional territories in close
relation to different territories of frontal cortex. The so called cortico-BG circuitry
defines a complex pathway in which at least three parallel functional loops can be
distinguished: (1) orbitofrontal/anterior cingulate projections to ventral striatum,
(2) dorsolateral prefrontal cortex projections to caudate nucleus, and (3) premo-
tor/motor cortex projections to putamen. Projections from BG (output via GPi and
substantia nigra) to cortex, mainly through thalamic nuclei constitute a feed-for-
ward circuitry.
Therefore, these three loops process three different domains of movement control.
The recognition of relationship between the ventral striatum and the orbitofrontal
and cingulate cortices and the return projections to these areas processes the motiva-
tional information, the expected outcome and reward (Tremblay et al. 2009). The
caudate nucleus and its projection from and to dorsofrontal cortex are related to
cognitive aspects regarding the selection of conditioned stimuli that guide action
toward the goal (Middleton and Strick 1997). The third loop, the putamen, and motor
and premotor cortex related to motor pattern selection and execution. The interaction
between these different BG loops could arise from hierarchical corticocortical pro-
jections from prefrontal areas to the motor and premotor cortex, providing the link
between the three closed parallel loops. In addition, thalamic relay that transmits BG
output provides not only a feedback closed-loop but initiates feed-forward open-loop
projections to other cortical areas (McFarland and Haber 2002).
On the basis of these anatomical results, these circuits have been divided in sev-
eral circuits dedicated to more specific cognitive and motor activities, whereas
behavioral studies have identified specialized circuits, treating opposite motivational
domains according to pleasant or unpleasant stimuli, or processing the motivation for
a food reward versus the hedonic value of this reward (Berridge and Kringelbach
2013). The impact of this model is in the view that BG could be implicated in many
psychiatric disorders: cognitive aspects of schizophrenia, OCD, ADHD, and phobia
and anxiety (Simpson et al. 2010; Yang et al. 2012). TS is a unique model to study
BG involvement in motor and nonmotor aspects: a dysfunction of sensory motor ter-
ritories of BG can be responsible of motor (tics) symptoms, while associative and
limbic domains of BG play a role in behavioral (OCD, ADHD) aspects.
Based on the knowledge of BG organization, it has been postulated that in TS
patients, a primary dysfunction of striatum leads to an impairment of inhibitory
control in BG. Experimental works (Kataoka et al. 2010; Kalanithi et al. 2005) have
shown in the brain of TS patients a fewer inhibitory parvalbumin interneurons and
cholinergic interneurons in the anterior part of the striatum compared to healthy
controls. These interneurons are normally about 1 % of striatal neuronal population
but exert a powerful inhibitory control in the striatum. Thus, a hypothesis is that
during the neurodevelopment, an impaired migration of these interneurons into the
striatum could occur. The final result is a lack of inhibitory control of GP output on
cortex. Most of these inhibitory controls inside the striatum allow the selection of
relevant information while blocking noise or competitive informations that induce
abnormal movement (i.e., tics) or actions inappropriate to context or behaviors.
A systematic review of anatomic imaging studies found that caudate volumes
were reduced in children and adults with TS (Plessen et al. 2009). In addition, tic
severity in children with TS correlated with sensorimotor cortex volume reduction.
Positron emission tomography (PET) scanning has shown variable rates of glucose
utilization in basal ganglia as compared with controls. One study, utilizing [18F]
fluorodeoxyglucose PET scans, identified a TS-related pattern characterized by
increased premotor cortex and cerebellum activity and reduced resting activity of
the striatum and orbitofrontal cortex (Pourfar et al. 2011).
6.2.3 The Burden of Genetics in Shared Mechanisms of TS and ASD

Pathology
Mainly, five genes have been reported directly disrupted in TS by independent
genomic rearrangements and copy number variants with unique breakpoints,
namely, IMMPL2, NRNX1, CTNNA3, NLGN4X, and CNTNAP2 (Clarke et al.
2012). Taken into account each isolated gene, it is difficult to interpret genomic
disruption related to complex disorders as TS. For example, IMMPL2 is localized
into mitochondrial membrane and regulates reactive oxygen levels. However, three
of these genes (IMMPL2, NRNX1, and CTNNA3) had undergone recurrent disrup-
tion in unrelated TS individuals and other two genes (NLGN4X and CNTNAP2)
co-segregate with the disorder within families, which greatly strengthens their
pathogenicity. Moreover, the disruption of these genes is associated with comorbid
conditions described in TS; in particular, NLGN4X was associated with ASD

(Wang et al. 2009). Conversely, all five genes have all shown independent associa-
tion with ASD (without tics), suggesting their pathogenicity in overlapping phe-
nomenology and epidemiology of TS and ASD.
Polymorphism in two additional structurally related genes LRRN3 and LRRTM3
have shown strong association with ASD susceptibility (Sousa et al. 2010). LRRN3
and LRRTM3 are both neuronal leucine-rich repeat transmembrane protein genes
and both interestingly are nested genes. Nested gene is defined as a gene wholly
located within another gene, usually in intronic region. LRRN3 and LRRTM3 are
nested within two of genes disrupted in TS, i.e., IMMPL2 and CTNNA3, respec-
tively. LRRN3-IMMPL2 and LRRTM3-CTNNA3 may constitute transcriptional
complexes in neurodevelopment linking TS and ASD. Both LRR gene-associated
proteins are transmembrane proteins involved in synaptic development through pro-
tein-protein interactions. They share similar structural domains, particularly the
extracellular domain, the LRR domain. LRR domain of LRRTM3 represents a
ligand-binding site for the formation of transsynaptic complexes with neurexins
(NRXNs). NRXNs are presynaptic proteins that bind neuroligin (NLGNs) and
LRRTMs in brain development. NRXN1 gene is disrupted in TS as well as NLGN4X,
depicting a complex synaptic interaction in which genetic disruption leads to an
imbalance of synaptic formation in TS and ASD (Gauthier et al. 2011). Another gene
named CBLN2 has been found associated to TS. CBLN proteins play a role in cell
adhesion and synaptogenesis; these proteins bind NRXs and glutamate receptor delta
(GRID) competing with NLG-mediated synaptogenesis. Once again, genetic break-
down leads to an imbalance of developmental synaptogenesis (Turrigiano 2012). A
summary of genetic findings and their functional implications is reported in Table 7.3.
Table 7.3 Summary of genes involved in TS and ASD and their functional implications
Gene Locus Protein encoded Function
IMMPL2 7q31 Mitochondrial Radicals of oxygen
transmembrane protein regulation
LRRN3 (nested into 7q31 Leucine-rich repeat Postsynaptic protein for
IMMPL2) neuronal proteins protein-protein interaction
in synaptogenesis
CTNNA3 10q21 Alpha2-catenin Transmembrane synaptic
ligand
LRRTM3 (nested gene 10q21 Leucine-rich repeat Postsynaptic protein
into CTNNA2) transmembrane neurexins ligand
proteins
NRXN1 2p21 Neurexin proteins Presynaptic
transmembrane protein
NRXN4/CNTNAP2 7q35 Neurexin family Presynaptic
transmembrane protein
NLGN4X Xp22.23 Neuroligin protein Postsynaptic neurexin
family ligand
CBLN2 18q22.2 CBLN superfamily of Neurexin ligand
C1q/tumor necrosis (CBLN2-NRX-GRID
factor superfamily complex)
Evidence suggests that neuropathological findings in striatum, the loss of inhibi-

tory interneurons (parvalbumin positive cells) as mentioned above, can be explained
by dysfunction of synaptogenesis due to genetic predisposition.
However, phenotypic variability can also be caused by nongenetic factors or sec-
ond hits such as prematurity, perinatal trauma, hypoxia, infections, autoimmunity,
and other modulators such as gender (Herbert 2010).
While the evidence for a genetic contribution is strong, several genes, including
SLITRK1, LIM homeobox (LHX6, LHX8), and HDC, have been suggested to be
responsible for the different clinical phenotypes (Karagiannidis et al. 2012; Paschou
et al. 2012). However, its exact nature has yet to be clarified fully. Etiological factors
include genetic vulnerability pre- and perinatal difficulties (PNDs) and probably
neuroimmunological factors.
7 Treatment
Treatment of TS and tic disorders includes psychoeducation and reassurance, medi-

cations, target-specific botulinum toxin injections, and, in a few severe refractory
adult cases, deep brain stimulation life (Müller-Vahl et al. 2011).
General consensus on TS treatment indicates that watch-and-wait strategy works
well for many patients with tics. This strategy coupled with psychoeducation
improves symptoms tolerance and supports stress reduction. However, a minority of
patients needs pharmacological intervention (Roessner et al. 2011). General indica-
tions of drug treatment of motor and vocal tics in TS patients include:
1. Subjective discomfort
2. Social isolation or bullying problems
3. Social and emotional problems
4. Functional interference
Thus, the burden of global impairment in daily life is the major indication for
medical treatment option. Furthermore, the frequent comorbid conditions associ-
ated to TS have to be taken into account for a specific choice of drug.
7.1 Nonmedical Treatments
7.1.1 Behavioral and Psychosocial Intervention

The guidelines from ESSTS Group (Verdellen et al. 2011) were the first European
overview describing the state-of-the-art of non-pharmacological evidence-based
treatment for tics. The group details two behavioral treatment approaches of differ-
ent methodology, with most evidence pointing to the effectiveness of habit reversal
training (HRT) and exposure with response prevention (ERP), the latter being sup-
ported by slightly less evidence in systematic studies. Both interventions are consid-
ered first-line behavioral treatments for tics for both children and adults and should
be offered to patients. The choice of one or the other therapy will depend on the
accessibility of the treatment and the patient’s preference.
The rationale behind both therapies is the notion that external and internal physi-
ological factors influence the expression of tics and that tics thus should be regarded
as semi-voluntary movements. Along the same lines, tics often are preceded by
premonitory urges, and these unpleasant bodily sensations often act as a trigger for
tics. Hence, behavioral approaches employ the ability of individuals with TS to
actively suppress tics and habituate to the premonitory urges.
HRT comprises a functional analysis of tics and relaxation techniques and psy-
chosocial support activities. This structured and manual-based treatment consists of
6–8 weekly treatment hours over a period of 8–10 weeks. Briefly, the two behav-
ioral approaches follow similar principles, but HRT targets one tic at a time and the
method is practiced at specific times of the day, whereas in ERP, the patient is asked
to suppress all occurring tics during several times of the day. Although more sys-
tematic studies have examined the effectiveness of HRT in clinical settings, effect
sizes were larger for ERP than for HRT. In view of the limited benefit of pharmaco-
logical treatment and good evidence for the efficacy of HRT, it is worth it to try this
form of therapy in children and families who are motivated to start training.
Other treatments that are considered second-line or add-on behavioral treatments
mentioned in the review are contingency management, function-based interven-
tions, and relaxation training, whereas neurofeedback in tic disorders is still consid-
ered in an experimental stage.
Pharmacotherapy has probably the fastest onset when compared with behavioral
treatment options, but few randomized clinical trials exist on pharmacological
choices in TS.
The recent guidelines from ESSTS Group (Roessner et al. 2011) reviewed the
existing Cochrane reviews and provided the first comprehensive review of medical
options through a MEDLINE, Pubmed, and EMBASE search between 1970 and
2010. Based on these guidelines, pharmacological options include antipsychotic
agents, noradrenergic agents, and miscellaneous drugs as alternatives. Table 7.4
shows a review of drug classes used in TS and ASD.
Haloperidol, pimozide, and risperidone show the highest level of evidence
(receiving a grade A), with several randomized controlled trials (RCTs) showing
efficacy for treating tics. First-generation antipsychotics have been associated with
adverse effects, including parkinsonism, dystonia, dyskinesia, akathisia, and tardive
dyskinesia; thus, the other medications to treat tics are necessary.
Among new (atypical) antipsychotic agents, aripriprazole shows a good profile
of tolerability and efficacy. Several nonantipsychotic medications were also recom-
mended for the treatment of tics although most have not been as extensively or as
rigorously studied. Among noradrenergic agents, clonidine is used in particular in
TS patients with comorbid ADHD. Clonidine resulted efficaciously in reducing tic
frequency in randomized controlled trial also in a patch transdermal formulation.
Cardiovascular side effects have to be taken into account along with more common
side effects as dry mouth, headache, and irritability. Among other drugs used in TS
patients, tetrabenazine, a vesicular monoamine transporter type 2 inhibitor, might
Table 7.4 Principal pharmacological treatments for TS and ASD

Drug TS ASD Side effects
Typical neuroleptics
Haloperidol Level of evidence Useful in reducing EPS, sedation, increased
A mannerisms and appetite
stereotypies
Pimozide Level of evidence – EPS, sedation, increased
A appetite
Atypical neuroleptics
Aripriprazole Level of evidence Useful in reducing Sedation, akathisia, EPS,
C stereotypies headache, increased appetite
(lesser than other
antipsychotics)
Risperidone Level of evidence Useful in reducing EPS, sedation, increased
A stereotypies appetite, orthostatic
hypotension
Alpha-adrenergic agonists
Clonidine Level of evidence – Sedation, increased appetite,
A (ADHD/TS) orthostatic hypotension,
sleepiness
be an alternative to antipsychotic agents. No tardive dyskinesia or other dystonic

side effects have been reported with tetrabenazine.
Recent evidence indicates topiramate as useful alternative for tic reduction,
while levetiracetam has not reached enough evidence for its choice in TS treatment.
Finally, sertraline should be used in TS/OCD patients.
For the treatment of stereotypies in children with ASD, risperidone has been shown
in both a Cochrane review in 2006 and two subsequent randomized control trials to be
effective. The addition of pentoxifylline to risperidone may have added benefit.
Haloperidol did not improve stereotypy and was poorly tolerated. There is good
evidence that aripiprazole is effective in the treatment of stereotypies in children
with ASD.
A large randomized trial of citalopram did not show any improvement in stereo-
typies. Single trials of levetiracetam, guanfacine, and atomoxetine suggest they are
not useful in the reduction of stereotypies in children with ASD.
Originally described over a century ago, Tourette syndrome is now recognized as a

relatively common neurodevelopmental disorder, with a privileged position at the
border between neurology and psychiatry. The clinical and epidemiological studies
suggest that associated social and emotional/behavioral problems are common in
individuals with Tourette syndrome, and it seems likely that the investigation of the
neurobiological bases of Tourette syndrome will shed light on the common brain
mechanisms underlying movement, social, and behavior regulation.
Overall, ADHD, OCD, depression, personality disorders, and ASD are the most
common neuropsychiatric conditions encountered in patients with Tourette syndrome.
Existing research suggests an increased prevalence of comorbid ASD (and/or
disturbances in social functioning) among individuals with TS. While the precise
nature of these relationships is uncertain, both genetic factors, putative common
neurobiological features and co-occurring psychopathology, have been implicated
in the etiology and/or maintenance of these difficulties.
Over the last few decades, researchers have identified several factors that may
contribute to these social and behavioral disturbances, highlighting the negative
impact of comorbid psychiatric diagnoses, disruptive behaviors, and/or increased
tic severity. Evidence also suggests that peer victimization experienced by youth
with TS is associated with increased tic symptom severity, strength of premonitory
urge, loneliness, internalizing symptoms (e.g., anxiety and/or depression), explo-
sive outbursts, and deficits in quality of life.
Although several studies postulate that reducing these disabling social and
behavioral aspects of symptom presentations beyond tics will reduce the overall
burden of TS, most are cross-sectional or preliminary in nature. As such, interven-
tions for TS, and for TS associated with ASD, should aim to address not only tic
severity but also the multifaceted reasons for social and behavioral impairments
within this population.
References
Alexander GE, DeLong MR, Strick PL (1986) Parallel organization of functionally segregated
circuits linking basal ganglia and cortex. Annu Rev Neurosci 9:357–381
fifth edition (DSM-5). American Psychiatric Association, Arlington
Baron-Cohen S, Mortimore C, Moriarty J, Izaguirre J, Robertson M (1999) The prevalence of
Gilles de la Tourette’s syndrome in children and adolescents with autism. J Child Psychol
Berridge KC, Kringelbach ML (2013) Neuroscience of affect: brain mechanisms of pleasure and
displeasure. Curr Opin Neurobiol 23:294–303
Burd L, Li Q, Kerbeshian J, Klug MG, Freeman RD (2009) Tourette syndrome and comorbid
pervasive developmental disorders. J Child Neurol 24:170–175
Canitano R, Vivanti G (2007) Tics and Tourette syndrome in autism spectrum disorders. Autism
11:19–28
Cavanna AE, Critchley HD, Orth M, Stern JS, Young MB, Robertson MM (2011) Dissecting the
Gilles de la Tourette spectrum: a factor analytic study on 639 patients. J Neurol Neurosurg
Clarke RA, Lee S, Eapen V (2012) Pathogenetic model for Tourette syndrome delineates overlap
with related neurodevelopmental disorders including Autism. Transl Psychiatry 2:e163
Cohen SC, Leckman JF, Bloch MH (2013) Clinical assessment of Tourette syndrome and tic dis-
orders. Neurosci Biobehav Rev 37:997–1007
Elsabbagh M, Divan G, Koh YJ, Kim YS, Kauchali S, Marcín C, Montiel-Nava C, Patel V, Paula
CS, Wang C, Yasamy MT, Fombonne E (2012) Global prevalence of autism and other perva-
sive developmental disorders. Autism Res 5:160–179
Fernandez TV, Sanders SJ, Yurkiewicz IR, Ercan-Sencicek AG, Kim YS, Fishman DO, Raubeson
MJ, Song Y, Yasuno K, Ho WS, Bilguvar K, Glessner J, Chu SH, Leckman JF, King RA,
Gilbert DL, Heiman GA, Tischfield JA, Hoekstra PJ, Devlin B, Hakonarson H, Mane SM,
Günel M, State MW (2012) Rare copy number variants in Tourette syndrome disrupt genes in
histaminergic pathways and overlap with autism. Biol Psychiatry 1(71):392–402
Filipek PA, Accardo PJ, Ashwal S et al (2000) Practice parameter: screening and diagnosis of
autism: report of the Quality Standards Subcommittee of the American Academy of Neurology
and the Child Neurology Society. Neurology 55:468–479
Freeman RD, Fast DK, Burd L, Kerbeshian J, Robertson MM, Sandor P (2000) An international
perspective on Tourette syndrome: selected findings from 3,500 individuals in 22 countries.
Dev Med Child Neurol 2:436–447
Gauthier J, Siddiqui TJ, Huashan P, Yokomaku D, Hamdan FF, Champagne N et al (2011)
Truncating mutations in NRXN2 and NRXN1 in autism spectrum disorders and schizophrenia.
Hum Genet 130:563–573
Herbert MR (2010) Contributions of the environment and environmentally vulnerable physiology
to autism spectrum disorders. Curr Opin Neurol 23:103–110
Kadesjö B, Gillberg C (2000) Tourette’s disorder: epidemiology and comorbidity in primary
school children. J Am Acad Child Adolesc Psychiatry 39:548–555
Kalanithi PS, Zheng W, Kataoka Y, DiFiglia M, Grantz H, Saper CB, Schwartz ML, Leckman JF,
Vaccarino FM (2005) Altered parvalbumin-positive neuron distribution in basal ganglia of
individuals with Tourette syndrome. Proc Natl Acad Sci U S A 102:13307–13312
Karagiannidis R, Rizzo Z, Tarnok Z, Wolanczyk T, Hebebrand J, Nöthen MM, Lehmkuhl G,
Farkas L, Nagy P, Barta C, Szymanska U, Panteloglou G, Miranda DM, Feng Y, Sandor P, Barr
C, TSGeneSEE, Paschou P (2012) Replication of association between a SLITRK1 haplotype
and Tourette syndrome in a large sample of families. Mol Psychiatry 17:665–668
Kataoka Y, Kalanithi PS, Grantz H, Schwartz ML, Saper C, Leckman JF, Vaccarino FM (2010)
Decreased number of parvalbumin and cholinergic interneurons in the striatum of individuals
with Tourette syndrome. J Comp Neurol 518:277–291
Kerbeshian J, Larry B (2003) Tourette syndrome and prognosis in autism. Eur Child Adolesc
Psychiatry 12:103
Kern JK, Geier DA, King PG, Sykes LK, Mehta JA, Geier MR (2015) Shared brain connectivity
issues, symptoms, and comorbidities in autism spectrum disorder, attention deficit/hyperactiv-
ity disorder, and Tourette syndrome. Brain Connect 5:321–335
Kientz MA, Dunn W (1997) A comparison of the performance of children with and without autism
on the Sensory Profile. Am J Occup Ther 51:530
Mandell DS, Novak MM, Zubritsky CD (2005) Factors associated with age of diagnosis among
children with autism spectrum disorders. Pediatrics 116:1480–1486
Martino D, Madhusudan N, Zis P, Cavanna AE (2013) An introduction to the clinical phenomenol-
ogy of Tourette syndrome. Int Rev Neurobiol 112:1–33
McFarland NR, Haber SN (2002) Thalamic relay nuclei of the basal ganglia form both reciprocal
and nonreciprocal cortical connections, linking multiple frontal cortical areas. J Neurosci
22:8117–8132
Middleton FA, Strick PL (1997) New concepts about the organization of basal ganglia output. Adv
Neurol 74:57–68
Ming X, Brimacombe M, Wagner GC (2007) Prevalence of motor impairment in autism spectrum
disorders. Brain Dev 29:565–570
Müller-Vahl K, Dodel I, Müller N, Münchau A, Reese JP, Balzer-Geldsetzer M, Dodel R, Oertel
WH (2010) Health-related quality of life in patients with Gilles de la Tourette’s syndrome. Mov
Disord 25:309–314
Müller-Vahl KR, Cath DC, Cavanna AE, Dehning S, Porta M, Robertson MM, Visser-Vandewalle
V, ESSTS Guidelines Group (2011) European clinical guidelines for Tourette syndrome and
other tic disorders. Part IV: deep brain stimulation. Eur Child Adolesc Psychiatry 20:377
Parent A, Hazrati LN (1995) Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-
thalamo-cortical loop. Brain Res Brain Res Rev 20:91–127
Paschou P, Stylianopoulou E, Karagiannidis I, Rizzo R, Tarnok Z, Wolancyzk T, Hebebrand J,

Nöthen MM, Lehmkuhl G, Farkas L, Nagy P, Szymanska U, Lykidis D, Androutsos C,
Szymanska U, Tsironi V, Koumoula A, Barta C, Klidonas C, Ypsilantis P, Simopoulos P,
Skavdis G, Grigoriou M (2012) TSGeneSEE: evaluation of the LIM homeobox genes LHX6
and LHX8 as candidates for Tourette syndrome. Genes Brain Behav 11:444–451
Plessen KJ, Bansal R, Peterson BS (2009) Imaging evidence for anatomical disturbances and neu-
roplastic compensation in persons with Tourette syndrome. J Psychosom Res 67:559–573
Pourfar M, Feigin A, Tang CC et al (2011) Abnormal metabolic brain networks in Tourette syn-
drome. Neurology 76:944–952
Rapin I (2001) Autism spectrum disorders: relevance to Tourette syndrome. Adv Neurol
85:89–101
Roessner V, Plessen KJ, Rothenberger A, Ludolph AG, Rizzo R, Skov L, Strand G, Stern JS,
Termine C, Hoekstra PJ, ESSTS Guidelines Group (2011) European clinical guidelines for
Tourette syndrome and other tic disorders. Part II: pharmacological treatment. Eur Child
Sanger TD, Chen D, Fehlings DL, Hallett M, Lang AE, Mink JW, Singer HS, Alter K, Ben Pazi H,
Butler EE, Chen R, Collins A, Dayanidhi S, Forssberg H, Fowler E, Gilbert DL, Gorman SL,
Gormley ME Jr, Jinnah HA, Kornblau B, Krosschell KJ, Lehman RK, MacKinnon C, Malanga
CJ, Mesterman R, Michaels MB, Pearson TS, Rose J, Russman BS, Sternad D, Swoboda KJ,
Valero-Cuevas F (2010) Definition and classification of hyperkinetic movements in childhood.
Mov Disord 25(11):1538–1549
Shepherd GM (2013) Corticostriatal connectivity and its role in disease. Nat Rev Neurosci
14:278–291
population-derived sample. J Am Acad Child Adolesc Psychiatry 47:921–929
Simpson EH, Kellendonk C, Kandel E (2010) A possible role for the striatum in the pathogenesis
of the cognitive symptoms of schizophrenia. Neuron 65:585–596
Sousa I, Clark TG, Holt R, Pagnamenta AT, Mulder EJ, Minderaa RB et al (2010) Polymorphisms
in leucine-rich repeat genes are associated with autism spectrum disorder susceptibility in
populations of European ancestry. Mol Autism 1:7
Teplin SW (1999) Autism and related disorders. In: Levine MD, Carey WB, Crocker AC (eds)
Developmental-behavioral pediatrics, 3rd edn. WB Saunders, Philadelphia
Tremblay L, Worbe Y, Hollerman R (2009) The ventral striatum: a heterogeneous structure
involved in reward processing, motivation and decision-making. In: Dr. Dreher JC, Tremblay L
(eds) Handbook of reward and decision making. Academic, Oxford, pp 51–77
Turrigiano G (2012) Homeostatic synaptic plasticity: local and global mechanisms for stabilizing
neuronal function. Cold Spring Harb Perspect Biol 4:a005736
Verdellen C, van de Griendt J, Hartmann A, Murphy T, ESSTS Guidelines Group (2011) European
clinical guidelines for Tourette syndrome and other tic disorders. Part III: behavioural and
psychosocial interventions. Eur Child Adolesc Psychiatry 20:197–207
Wang K, Zhang H, Ma D, Bucan M, Glessner JT, Abrahams BS et al (2009) Common genetic vari-
ants on 5p14.1 associate with autism spectrum disorders. Nature 459:528–533
Yang H, Spence JS, Devous MD Sr et al (2012) Striatal-limbic activation is associated with inten-
sity of anticipatory anxiety. Psychiatry Res 204:123–131
Zappella M (2002) Early-onset Tourette syndrome with reversible autistic behaviour: a dysmatu-
rational disorder. Eur Child Adolesc Psychiatry 11:18–23
Sleep Disorders and Autism
Spectrum Disorder 8
Silvia Miano, Flavia Giannotti, and Flavia Cortesi
1 Introduction
Sleep disorders affect approximately 30 % of typically developing children and

decrease to 3–12 % during adolescence (ICSD-3 2014). Sleep disorders may have
multidimensional consequences such as poor growth, behavioral and learning prob-
lems, and poor quality of family life (ICSD-3 2014). Notwithstanding the signifi-
cant impact of pediatric sleep disorders, most of them remained worldwide
unrecognized, and unresolved. The most common sleep disorders reported by care-
givers is chronic insomnia (disorder of initiating and maintaining sleep), behavioral
insomnia in most cases, and secondary insomnia due to major sleep problems or
other medical issues in the remaining cases (ICSD-3 2014).
The majority of the studies about sleep problems in children with mental dis-
abilities reported unspecific sleep problems such as insomnia, sleep-wake deregula-
tion, or sleepiness. Chronic insomnia (lasting more than 3 months, with sleep onset
problems and multiple night awakenings) occurs in about 30–50 % of school-aged
children with intellectual disabilities. In addition, epilepsy and other neurological
impairments increase the risk and the severity of insomnia and of sleep-wake rhythm
disorders (Miano and Peraita-Adrados 2014).
All these considerations are valid also for children with autism spectrum disor-
der (ASD), considering that in one-quarter of them sleep disorders start from birth
(Miano and Ferri 2010). In addition, together with mental delay and epilepsy, sleep
disorders are considered early indicators of neurological impairment in ASD (Miano
S. Miano (*)
Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Civic Hospital of Lugano,
Lugano, Switzerland
F. Giannotti • F. Cortesi
Department of Pediatrics and Developmental Neuropsychiatry,
Center of Pediatric Sleep Disorders, University of Rome La Sapienza, Rome, Italy

112 S. Miano et al.
and Ferri 2010). Sleep disorders may exacerbate social interactions, repetitive
behaviors, affective problems, and inattention/hyperactivity (Malow et al. 2006a).
The relationship between sleep disorders and ASD is complex because circadian
abnormalities and epilepsy are strong contributors and have a bidirectional influ-
ence on sleep of ASD (Accardo and Malow 2014; Goldman et al. 2014). The impor-
tance of these comorbidities with sleep disorders is demonstrated by the significant
increasing numbers of papers published during the last two decades, about ASD and
sleep. One of the main topic is the role of melatonin in sleep disorders of ASD: It
has been reported a disruption and/or reduction of melatonin concentration in urine,
plasma, and serum sample both during daytime and nighttime, moreover genes
whose products regulate endogenous melatonin and modify sleep patterns have
been implicated in the pathogenesis of ASD, and supplemental melatonin has been
successfully used to treat sleep onset problems, as evidenced by recent randomized
trials in ASD (Veatch et al. 2015; Goldman et al. 2014; Tordjman et al. 2015; Cortesi
et al. 2012).
It is desirable in the next future an early management of sleep disorders in ASD,
which may influence the prognosis of cognitive and behavioral disabilities. For this
reason practical information for clinicians about prevalence, genetic implications,
clinical features, diagnostic assessment, and treatment of sleep disorders will be
helpful.
2 Prevalence of Sleep Problems in ASD
Sleep problems are particularly common in children with ASD with prevalence
rates ranging from 50 % to 80 % compared with a 9–50 % prevalence rates in age-
matched typically developing (TD) children (Schreck and Mulick 2000; Wiggs
2001; Polimeni et al. 2005; Doo and Wing 2006; Liu et al. 2006; Malow et al. 2006a,
b; Malow and Mc Grew 2008; Richdale and Schreck 2009; Hollway et al. 2011;
Kotagal and Broomall 2012). As stated by Ming et al. (2008), they rank as one of
the most common concurrent clinical disorders and also one of the most burden-
some complaints among parents of children with ASD (Cohen et al. 2014).
It should be noted that some reports revealed an increased proportion of sleep
problems in more severely developmentally delayed children (Miano et al. 2007;
Giannotti et al. 2008, 2011). However, in a study of highly functioning children with
ASD, sleep problems appeared to be relatively specific to them compared with both
typically developing and children with intellectual disabilities without autism
(Richdale and Prior 1995; Bradley et al. 2004; Couturier et al. 2005). Based on the
parental reports, Krakowiak and colleagues (2008) found that 53 % of children
(2–5 years in age) with autism had at least one frequently experienced sleep problem
compared to 46 % of children with non-ASD developmental delays and 32 % of typi-
cally developing children. Moreover, studies comparing children with autism and a
history of regression with no developmentally regressed children showed more sleep
problems in the regressed than in non-regressed group (Giannotti et al. 2008, 2011).
8 Sleep Disorders and Autism Spectrum Disorder 113
Sleep disturbances are also persistent in ASD. According to parental reports, up

to 63 % of children with ASD and sleep problems reported persistence of their sleep
difficulties over a long period of time (Robinson and Richdale 2004). Recently,
Hodgle et al. (2014) compared age-related changes in the sleep of children with
ASD with those of TD children. Unlike TD children, in which the rate of parental
reported sleep disorders dropped significantly with age, in ASD the rate increased
from 84 % at 3–5 years to 87 % at 10–17 year of age, with a peak in the middle age
group. Interestingly, the type of sleep problems changed with age: while bedtime
resistance improved, sleep anxiety worsened significantly with age. Conversely, in
May (2015) a 1 year longitudinal study conducted in high-functioning ASD chil-
dren aged 7–12 years found a slight decrease of sleep disturbances over time (from
78 % to 65 %). Anders et al. (2011) in a longitudinal study on sleep-wake patterns
in preschool children with autism, developmental delayed (DD) compared with TD
children, reported persistent shorten sleep duration and night-to-night variability in
the ASD and DD groups.
Despite variability in definitions of sleep disorders and heterogeneity of ASD
patient samples, there is compelling evidence for the high prevalence of sleep dis-
turbances in children with ASD.
Children with ASD showed a wide range of sleep problems and many of them expe-
riencing multiple problems concurrently (Delahaye et al. 2014). Interestingly, simi-
lar sleep problems occur in all the ASD subgroups, and the only factor associated
with a higher risk of sleep problems was the occurrence of them before the age of
2 years (Doo and Wing 2006). The most common sleep problem experienced by
children with ASD is insomnia. According to parental reports, sleep onset problems
and night wakings commonly occur in children with ASD (Liu et al. 2006; Malow
and Mc Grew 2008; Johnson and Malow 2008; Richdale and Schreck 2009; Cortesi
et al. 2010). Recently, Engelhartdt et al. (2013) demonstrated that bedroom access
to a television or a computer was more strongly associated with reduced sleep in
children with ASD compared to TD children. Moreover, compared to TD, ASD
children spend more time playing video games and watching TV, having more trou-
bles disengaging from screen-based media (Nally et al. 2000). This increased media
use coupled with the potential influence of bright screens on melatonin production
and circadian rhythms (Engelhardt et al. 2013). A recent meta-analysis study based
on objective measures confirm a prolonged sleep latency, shortened sleep duration,
and less sleep efficiency in children with autism, even though these alterations are
more common in those with concurrent intellectual disability (Elrod and Hoods
2015). Lengthy periods of nocturnal awakening lasting for up to 2–3 h have been
reported when the child may simply laugh, talk, scream, or get up and play with toys
or various objects in the room (Robinson and Richdale 2004; Malow et al. 2006b;
Miano et al. 2007; Goodlin-Jones et al. 2008; Giannotti et al. 2011). As noted by
114 S. Miano et al.
Richdale and Schreck 2009, these types and duration of night wakings seem typical
for children with autism.
The etiology of insomnia in children with autism is thought to be multifactorial,
including potential disruption in circadian rhythms and melatonin dysregulation
besides poor sleep hygiene practices (Richdale and Schreck 2009; Johnson and
Malow 2008). Particularly, fragmented irregular sleep-wake patterns, including
inconsistent sleep onset and rise time, free-running sleep-wake rhythm, sleep onset
delay, and early morning awakening have been reported (Wiggs and Stores 2004;
Goodlin-Jones et al. 2008; Richdale and Schreck 2009; Giannotti et al. 2011).
Furthermore, children with autism showed a marked night-to-night variability in
their sleep-wake cycle (Anders et al. 2011). Moreover, Matsuura and colleagues
(2008) experimentally reproduced sleep patterns of autistic children and suggested
a bifurcation of the sleep-wake cycle with increased sensitivity to external noise and
short sleep duration.
A recent study showed that insomnia in children with autism may be due to
arousal dysregulation and sensory over-responsivity (Mazurek et al. 2015). An
over-responsivity to sensory input within the sleep environment, including noise,
light, and temperature, was significantly associated with sleep onset delay, sleep
duration, and night waking in these children. As reported by Richdale et al. (2014)
in ASD children, pre-sleep cognitive arousal was associated with insomnia by
increasing physiological arousal and emotional distress which interfere with sleep.
Moreover, Tordjman et al. (2014) found a flattened circadian rhythm of cortisol,
suggesting also alterations in circadian time structure in children with autism.
Furthermore, children with ASD may be more prone to insomnia due to the neu-
robiologic overlap with other concurrent medical and psychiatric problems.
Epilepsy, which occurs in a significant minority of patients with ASD, may nega-
tively impact sleep (Giannotti et al. 2008; Accardo and Malow 2014).
4 Peculiar Features of Sleep Disorders in Comorbidity

with ASD and Impact of Other Comorbidities to Sleep
Problems
Psychiatric comorbidity and epilepsy may worsen the management and prognosis
of sleep disorders in ASD. In addition, the differential diagnosis between primary
insomnia and sleep major disorders remains a challenging diagnosis for clinicians,
especially in children with mental disabilities and ASD. Major sleep disorders (such
as restless legs syndrome, nocturnal epilepsy, sleep disordered breathing) should
always be suspected in ASD children with insomnia not respondent to standard
treatment and who display multiple awakenings during sleep and hypersomnia dur-
ing daytime (although normal hours of bedtime have been demonstrated).
The aim of this paragraph is not reporting in details the pathogenesis and impli-
cations of psychiatric comorbidity of ASD, but clinicians should take in mind that
psychiatric disorders may worsen insomnia and that specific sleep problems may
anticipate the onset of psychiatric disorders (such as attention-deficit hyperactivity
disorders, bipolar disorders, anxiety, depression, and psychosis). A brief summary

of sleep problems in these specific psychiatric disorders will be helpful for better
management of both disorders (ASD and psychiatric comorbidity). Anxiety and
depression are recognized as major co-occurring problems in children and young
people with ASD. The state of hypervigilance or hyperarousal, which represents the
main sign of anxiety, strongly and negatively influence sleep, as it has been also
widely describe in psychophysiological insomnia (Ivanenko and Johnson 2008).
Children with anxiety disorders may complain of severe sleep onset and mainte-
nance problems, frequent nocturnal awakenings, bedtime refusal, cosleeping, night-
mares, and nocturnal fears. Anxiety is strongly associated with specific sleep habits:
sleeping with the lights on, requiring a toy/object for sleep onset, sensitivity to
noises, fear of the dark or of being alone, and requiring bedtime rituals (Ivanenko
and Johnson 2008). On the contrary, early final awakening is a strong indicator of
the onset of a major depressive disorder, especially during prepubertal and pubertal
age (Ivanenko and Johnson 2008). Recent studies showed that children with autism
and co-occurring anxiety may be particularly predisposed to sleep problems
(Nadeau et al. 2014; Mazurek et al. 2015). As stated by Nadeau et al. (2014), anxi-
ety symptoms may impact children’s sleep in multiple ways. First, it may signifi-
cantly impact bedtime routine, especially if anxiety is centered around bedtime with
fear of dark and separation. Second, physiological symptoms of anxiety such as
heart palpitation, sweating, etc. could contribute to exacerbate sleep insomnia
(Nadeau et al. 2014). As hypothesized by Mazurek et al. (2015), children with ASD
and anxiety may have trouble falling asleep due to increased physiological arousal
and autonomic activity. Sedative antidepressant, such as trazodone, may be war-
ranted in cases of depressive symptoms or anxiety disorder associated with insom-
nia, resistant to cognitive-behavioral therapy (Owens et al. 2010), and this may be
also valid in children with ASD.
About 30 % of ASD patients have comorbid attention-deficit hyperactivity disor-
ders (ADHD), with clinically significant levels of ADHD symptoms, particularly
hyperactivity. However, there are also comorbid children with a primary ADHD
diagnosis and significant social interaction problems (Chantiluke et al. 2014). This
bidirectional interaction between ASD and ADHD is also reflected in the allowance
for co-diagnosis in the Association AP (2013). While it is well recognized that
ADHD and ASD share common deficits in executive functions (EF) (Rommelse
et al. 2011), children with ASD may also share the same sleep phenotype described
in children with ADHD (Miano et al. 2013). About 25–50 % of children and adoles-
cents with attention-deficit hyperactivity disorder (ADHD) experience sleep prob-
lems. According to literature data, five sleep phenotypes may be identified: a sleep
phenotype characterized mainly by a hypo-arousal state, resembling narcolepsy, a
phenotype associated with delayed sleep onset latency and with a higher risk of
bipolar disorder, a phenotype associated with sleep disordered breathing (SDB),
another phenotype related to restless legs syndrome (RLS) and/or periodic limb
movements (PLMDs), lastly, a phenotype related to epilepsy/or EEG interictal dis-
charges. These major sleep disorders described in children with ADHD have been
poorly reported in children with ASD and/or with intellectual disabilities (Miano
116 S. Miano et al.
et al. 2007, 2013), although sleep fragmentations caused by sleep disorders induce
early in life and in some cases irreversible frontal and prefrontal deficits (Miano
et al. 2013). It is strongly suggested to explore and exclude the presence of major
sleep disorders or of nocturnal epilepsy in children with ASD, especially with
comorbid ADHD and referred sleep problems. Although is a very rare condition,
some children with narcolepsy and cataplexy, especially after the H1N1 pandemic
influenza or vaccination, may have florid psychotic symptoms due to signs and
symptoms of cataplexy and to many hypnagogic hallucinations during daytime,
inducing both ADHD and ASD symptoms and misleading diagnosis (Rocca et al.
2015).
Furthermore, an association between sleep problems and gastrointestinal dys-
function has been described in children with ASD (Johnson 2005; Ming et al. 2008).
While children with ASD do not appear to be particularly at an increased risk for
obstructive sleep apnea, other sleep problems, such as parasomnias, may be likely
underdiagnosed. Research regarding the prevalence of parasomnias in the autistic
population is mixed with some studies suggesting an increased prevalence and oth-
ers demonstrating no increase (Richdale and Prior 1995; Patzold et al. 1998; Schreck
and Mulick 2000; Liu et al. 2006; Wiggs and Stores 2004). There are mixed reports
regarding the association of REM sleep behavior disorder (RBD) with autism too.
RBD was reported to occur in a number of children with ASD described in a case
series (Thirumalai et al. 2002). Additionally, a relatively high percentage of peri-
odic leg movements during sleep has been reported in children with autism (Dosman
et al. 2007).
The report of frequent multiple awakening, sleepiness, nocturnal hyperkinesia,
and/or stereotyped and clinic movements during sleep may be suspected of noctur-
nal seizures. Epilepsy is more common in ASD patients than in the general pediatric
population, with the prevalence rates estimated at 2–3 % among all children com-
pared with 30 % in ASD, even in children with ASD without other risks for epilepsy
(normal intelligence; no family history; no other risk factors, such as cerebral palsy
and perinatal disorders; or other medical disorders) (Malow 2006). In the absence
of a history of clinical seizures, interictal epileptiform discharges (IEDs) also are
more prevalent in ASD patients (Malow 2006). It has been demonstrated that
approximately 32 % of children with epilepsy evaluated using validated autism
screening questionnaires fit the criteria for having ASD. Most of these children had
not been previously diagnosed and have the worst behavior, early occurrence sei-
zures (approximately 2 years), more difficulty falling back to sleep after arousals,
early morning wakings, and daytime sleepiness (Clarke 2005). Therefore children
with ASD and epilepsy should particularly be evaluated for sleep disturbances
(Accardo and Malow 2014). It has been reported a higher percentage of regression
and of sleep problems in ASD children with epilepsy and in those with frequent
EEG epileptiform activity compared with those with rare or no abnormalities
(Giannotti et al. 2008). The coexistence of disrupted sleep patterns and epilepsy in
regressed children suggests a disruption of the neuronal circuitry, since the peak age
at onset of sleep problems coincides with that of regression, during the second year
of life. In ASD, prolonged EEG recording including sleep showed increased
prevalence of IEDs (up to 60 % of cases), especially over temporal regions, only

seen during sleep (Chez et al. 2006), or over frontal regions (Valdizán-Usón et al.
2002). Interestingly, magnetoelectroencephalography identified more frequently
epileptiform activity (82 % of cases) compared to the EEG recording (68 % of
cases) (Lewine et al. 1999). The same intra-/perisylvian epileptiform regions of
Landau-Kleffner syndrome were active in the majority of cases but also additional
nonsylvian zones of independent epileptiform activity were recorded (Lewine et al.
1999).
Sleep problems in children with ASD have been widely investigated by sleep ques-
tionnaires, and actigraphic recording (usually associated with sleep diaries), more
rarely with polysomnographic recording. The detection of plasma, urine, or salivary
melatonin secretion is warranted to diagnose sleep-wake rhythm disorders in this
specific population, but still remains a diagnostic tool used for research purpose. A
diagnostic algorithm to asses sleep problems has been already described in children
with ASD (Miano and Ferri 2010). After a detailed animalistic interview about sleep
problems (sleep onset problems, many awakenings during sleep, presence of sleep
hyperkinesias, myoclonic movements or stereotyped movements during sleep,
many naps during daytime, daytime sleepiness, maturation of the sleep-wake
rhythm, time of bedtime, and of final awakening in the morning), caregivers may fill
sleep questionnaire, already used in children with ASD, such as the Children’s Sleep
Habits questionnaire or other validated sleep questionnaire (Bruni et al. 1997;
Owens et al. 2000). In most of cases a behavioral insomnia and or circadian rhythm
disorder is suspected. Sleep diaries and actigraphic recording of at least 1 week are
warranted to confirm the diagnosis and assess sleep-wake behavior. Actigraphy pro-
vides useful information about sleep in the natural sleep environment variables.
Collecting data representing body movement over time, actigraphy paints a picture
of daily sleep-wake cycles, which can be useful in the diagnosis and evaluation of
several clinical sleep disorders and treatment outcomes (Morgenthaler et al. 2007;
Martin and Hakim 2011). Actigraphy is a simple device similar to a watch, usually
worn in the nondominant wrist. The software calculates many sleep parameters
such as total sleep time, sleep efficiency (defined as the percentage of time sleeping
while in bed and lights off), and sleep latency (defined by time from lights off to
sleep onset) and offers an overview of daytime activity, indirectly assessing daytime
sleepiness and the number of naps (see Fig. 8.1, example of a sleep onset delayed
insomnia recorded by actigraphy of a week). The sleep diary usually serves to
ensure the functioning of actigraphy. On the contrary, when major sleep disorders
are suspected, a video-polysomnographic recording (video PSG) with extensive
EEG channels is warranted. Despite the sanitary cost, including the necessity of a
sleep expert medical doctor for diagnosis, laboratory-attended video PSG-recording
remains the gold standard for the pediatric diagnosis of nocturnal epilepsy, sleep
disordered breathing, and sleep movements disorders (Aurora et al. 2011, 2012).
118 S. Miano et al.
12:00 20:00 00:00 06:00 12:00
12:00 18:00 00:00 06:00 12:00
Fig. 8.1 An actigraphic recording of a week, showing a sleep onset delay with sleep onset after
midnight (sleep period in blue)
The standard variables recorded during an overnight PSG recordings were at least
eight EEG channels (frontal, central, temporal, and occipital monopolar montages
referred to the contralateral mastoid or bilateral montages), according to the
International “10–20” system to place electrodes in standardized scalp locations; an
electrooculogram (electrodes placed 1 cm above the right outer cantus and 1 cm
below the left outer cantus and referred to A1); and a submental electromyogram
and an electrocardiogram (one derivation). Chest and abdominal movements and
efforts and oronasal airflow are recorded with a thermocouple (or nasal pressure
monitor when children tolerated a nasal cannula). Arterial oxygen saturation was
monitored by means of a pulse oximeter. Recording usually starts at the patients’
usual bedtime and continued until spontaneous awakening.
The following PSG variables are usually scored manually and automatically cal-
culated, according to standard criteria (Berry et al. 2012a, b): time in bed (TIB),
sleep period time (SPT; time from sleep onset to sleep end), total sleep time (TST;
SPT minus time spent in wakefulness after sleep onset), sleep efficiency index
(TST/TIB*100), sleep onset latency (SOL; time from lights out to sleep onset,
defined as the first of two consecutive epochs of stage 1 sleep or one epoch of any
other stage, in minutes), first rapid eye movement (REM) latency (FRL; time from
sleep onset to the first REM epoch), minutes spent in each stage and percentage
relative to SPT, number of stage shifts/hour, number of REM periods, number of
awakenings/hour, percentage of each sleep stages (stage N1, N2, N3, REM sleep);
central, obstructive, and mixed apnea events and the apnea hypopnea index (number
of respiratory events during sleep), overnight oxygen saturation and desaturation
index, leg movements (LMs), and periodic leg movements (PLMs) during sleep.
Alterations of hormone secretion and neurotransmitters have been hypothesized for

the pathogenesis of sleep disorders in ASD, such as abnormal dopaminergic activity
in the low medial prefrontal cortex; high level of catecholamines in blood, urine,
and CSF (Ernst et al. 1997); as well as abnormalities in the circadian secretion of
melatonin. Recently mutations in circadian-relevant genes affecting gene function
in ASD children have been reported, particularly two kinds of mutations that were
detected only in individuals with ASD and sleep disorders (Yang et al. 2015).
Melatonin is the “darkness hormone,” involved in signaling the appropriate timing
of the sleep and wake cycle. Melatonin regulates vigilance states: MT2 receptors are
mainly involved in non-rapid eye movement sleep, whereas MT receptors are
mainly involved in REM sleep. Melatonin has been shown to influence basal metab-
olism, oxidative stress, inflammation, and apoptosis and to prevent premature aging
and tumorigenesis, and it seems to be critically involved in early development
through its direct effects on placenta, developing neurons and glia, and its role in the
ontogenetic establishment of diurnal rhythms (Tordjman et al. 2013).
Several studies have demonstrated abnormal melatonin regulation in individuals
with autism compared with controls, including elevated daytime melatonin and sig-
nificantly lower nocturnal melatonin (Ritvo et al. 1993; Nir et al. 1995; Kulman
et al. 2000; Tordjman et al. 2005, 2012). More specifically abnormally low daytime
and nighttime melatonin secretion was associated with an absence of melatonin
circadian variation in some individuals with autism (Tordjman et al. 2012). Melke
et al. (2008) found lower level of acetylserotonin O-methyltransferase (ASMT)
120 S. Miano et al.
activity, an enzyme which converts serotonin to melatonin, as well as genetic varia-

tion in the promoter of ASMT in children with ASD. Even though other studies
failed to show a direct association of the promoter variants in ASMT with autism
(Toma et al. 2007; Wang et al. 2013), genetic variation in ASMT has been reported
to be more common in children with autism (Cai et al. 2008). More recently Veatch
et al. (2015) demonstrated the alteration of two melatonin pathway genes in a subset
of children with autism and sleep onset delay. A disruption of the serotonin-
melatonin pathway with elevated whole-blood serotonin and decreased plasma
melatonin has been also reported in 278 ASD patients and deficit of melatonin
which is significantly associated with insomnia (Pagan et al. 2014). In contrast, a
recent research showed relatively normal patterns of endogenous melatonin secre-
tion during sleep (Goldman et al. 2014).
7 Treatment
The diagnosis of a sleep disorder is the first and the most important step in success-
ful intervention. The identification and treatment of possible underlying medical,
neurological, or psychiatric conditions should be part of a comprehensive, multidis-
ciplinary approach to the treatment of children with ASD.
7.1 Nonmedical Treatment: Sleep Hygiene and Behavioral

Interventions
Sleep hygiene and behavioral therapy are shown to be effective interventions for
both typically developing children and for ASD children. Several studies have dem-
onstrated effectiveness of behavioral interventions for bedtime problems, sleep
onset, and sleep maintenance problems in children with ASD (Wiggs 2000;
Thackeray 2002; Richdale and Wiggs 2005; Weiskop et al. 2005; Kuhn and Floress
2008). Thus, the first line of treatment in children with neurodevelopmental disabili-
ties is to improve sleep hygiene, a set of sleep related behaviors which can promote
a better sleep (Jan et al. 2008).
Basic principles of sleep hygiene include the selection of an appropriate bedtime,
establishment of a positive consistent bedtime routine, and reduction of emotional
and/or behavioral stimulation at night. As above stated, the association between
media exposure, bedtime resistance, and sleep onset delay is strongly pronounced in
ASD children; thus, minimizing television watching and playing computer or video
games may represent an important intervention target for improving sleep
(Engelhardt et al. 2013). Taking into consideration the night-to-night variability of
sleep-wake patterns in children with ASD (Anders et al. 2011), it is equally impor-
tant to pay attention to the consistency of the bedtime and risetime in the morning
in order to enhance a regular sleep-wake cycle.
Furthermore, as previously stated, children with ASD frequently have hypersen-
sitivity to environmental stimuli, including noises or tactile sensitivity to bedclothes
or blankets. A parental survey conducted by Williams et al. (2006) indicated that

wrapping a child in weighted blankets may be helpful in children with tactile sensi-
tivities with sleep onset problems. More recently, Gringas et al. (2014) in a random-
ized placebo-controlled crossover design on 67 children with ASD reported that
even though the use of a weighted blanket did not help for a longer period of time
or to fall asleep faster or wake less often, as actigraphically demonstrated, it was
favored by children and parents and was tolerated over the period.
The behavioral interventions used to treat insomnia in children with ASD are
essentially the same as those used in typically developing children. Behavioral
interventions can be utilized to set appropriate behavioral limits at bedtime and to
promote the development of the more adaptive self-soothing skills (Williams et al.
2006). Among behavioral interventions, graduated extinction, where new behavior
is taught in small steps, appears more appropriate when treating children with ASD
(Wiggs 2000).
Despite promising evidence regarding the effectiveness of behavioral treatment in
reducing settling problems and awakenings in children with ASD (Wiggs 2000;
Thackeray 2002, Weiskop et al. 2005; Vriend et al. 2011), these interventions might be
time intensive and expensive, particularly to support parents with face-to-face meeting
(Montgomery et al. 2004). To partially overcome these problems, recently, Austin et al.
(2013) evaluated the positive effect of a parent group program for children with ASD
and sleep disturbances, which included workshop session as well as individualized
treatment plans. More recently Malow (2014) evaluated the effect of individualized
compared to group education sleep intervention on a large sample of 80 ASD children.
Interestingly, mode of education did not differ in the positive effects of treatment.
Moreover, Stuttard et al. (2015a) confirmed the efficacy of a group-delivered sleep
management intervention for parents of children with intellectual disabilities including
autism. In addition Stuttard et al. (2015b) in another pilot study demonstrated that it
may be acceptable to support parents implementing a behavioral sleep intervention via
telephone call. Even though this new approach seems to be effective, authors recom-
mended flexibility when further face-to face contacts may be beneficial.
In ASD children with comorbid anxiety, family-based-cognitive-behavioral ther-
apy displayed a significant reduction in frequency of sleep problems (Nadeau et al.
2014). In addition Papadopoulos et al. (2015) reported the efficacy of a brief sleep
intervention in 28 school-aged children with ASD and comorbid ADHD. Children
with ASD-ADHD reported not only a moderate to large improvement in sleep prob-
lems but also moderate improvement in quality of life.
7.2 Pharmacological Intervention
If a child fails to respond to sleep hygiene and behavioral intervention or has only
partial response, pharmacological treatment options should be considered in con-
junction with the ongoing behavioral therapy for sleep disorders.
There is growing evidence in particular for the use of melatonin. Melatonin is
considered a nutritional supplement and is not regulated by the Food and Drug
122 S. Miano et al.
Administration (FDA). Given this labeling, melatonin is readily available over the
counter and relatively inexpensive. Several studies showed that exogenous melato-
nin is efficient in promoting sleep and is well tolerated, and no serious long-term
adverse effects have been described (Jan et al. 1994; Dodge and Wilson 2001; Ross
et al. 2002; Phillips and Appleton 2004; Gringas et al. 2012).
There have been relatively few trials utilizing melatonin exclusively in children
with ASD. In an open-label trial, 15 children with Asperger’s syndrome were
administered 3 mg of immediate-release melatonin 30 min prior to bedtime for
2 weeks (Paavonen et al. 2003). Sleep latency decreased significantly from 40 to
21 min during treatment as measured by actigraphy. A second open-label study of
children with autism utilized combined immediate- and controlled-release melato-
nin in a dose range of 3–6 mg (Giannotti et al. 2006). All of the children improved
according to sleep diaries and questionnaires. A randomized, placebo-controlled
trial of melatonin 5 mg was found effective in children with ASD and insomnia
(Garstang and Wallis 2006). A larger retrospective study of over 100 children with
ASD treated with melatonin documented minimal adverse effects, with improved
sleep in 85 % of children treated (Andersen et al. 2008). A study on 24 ASD chil-
dren with sleep onset delay using dose escalation of controlled-release melatonin,
from 2 to 9 mg when clinically required, reported significant improvement in sleep
latency within the first week of treatment (Malow et al. 2011). Furthermore, in a
randomized double-blind crossover trial on 22 ASD children with sleep insomnia,
Wright et al. (2011) reported significant improvement in sleep latency and total
sleep time, as reported by parents in the melatonin group. Moreover, a randomized
placebo-controlled study demonstrated the superior efficacy of the combination of
controlled-release melatonin treatment with behavioral interventions in 134 chil-
dren with autism and long-lasting sleep problems (Cortesi et al. 2012). In addition,
four meta-analysis studies confirmed the beneficial effects of melatonin on sleep in
ASD children with no or minus side effects (Guénolé et al. 2011; Doyen et al. 2011;
Rossignol et al. 2011; Reading 2012).
There are likely several mechanisms by which melatonin may promote sleep in
people with ASD. Melatonin may simply act as a hypnotic to promote sleep espe-
cially at higher than physiologic doses (Heuvel et al. 2005). When used as a hypnotic
for sleep onset insomnia, melatonin should be given approximately 30 min prior to
the desired bedtime. Melatonin also has a chronobiotic (phase-shifting) effect and
therefore may be more effective in individuals with a delayed sleep phase when
given several hours before bedtime. A dosage range of 1–3 mg is usually adequate,
but on occasion, doses of 6 mg or higher are needed. Recently, Ayyash et al. (2015)
demonstrated that increasing melatonin above 6 mg/night adds further benefit only in
a small percentage of children with neurodevelopmental disabilities including
autism. Liquid formulations are available and useful in children who have difficulty
swallowing tablets. Extended-release melatonin may be helpful for the child with
sleep maintenance difficulties (Jan et al. 2000; Giannotti et al. 2006; Cortesi et al.
2012). Once the sleep schedule stabilizes over several months, attempts should be
made to discontinue melatonin.
Recently a positive effect of ramelteon, a selective melatonin receptor agonist,

has been reported in three ASD children with circadian sleep disorders (Kawabe
et al. 2014). Ramelteon is a relative new drug with high selectivity for the melatonin
MT1 and MT2 receptors, which are located in the suprachiasmatic nucleus and have
been implicated in the regulation of sleep-wake cycle. Authors reported that ramelt-
eon reduce not only sleep disorders but autistic behavior as well.
There is limited research on the use of prescription medications with sedative
properties for children with autism. One study demonstrated effectiveness of
Niaprazine, a histamine H1-receptor antagonist with sedative properties which were
available in Europe in treating insomnia in this population (Rossi et al. 1999). A
recent retrospective study found that clonidine, an alpha-2 adrenergic receptor ago-
nist, was effective in reducing sleep initiation latency and night awakening (Ming
et al. 2008).
Successful pharmacological treatment of comorbid psychiatric disorders like
ADHD, mood, and/or anxiety disorders as well as neurological conditions like epi-
lepsy and movement disorders may help to alleviate symptoms of insomnia and
markedly improve outcome.
Providing safety is the priority when treating parasomnias. Arousal disorders
such as sleep terrors and sleep walking may be severe enough in children or adoles-
cents to warrant pharmacotherapy. Clonazepam or tript-oh is the treatment of choice
when a medication is indicated. Clonazepam is also effective in treating rhythmic
movement disorder when the potential for injury is present as well as REM sleep
behavior disorder also responds to clonazepam, although dopaminergic agents and
melatonin have also been tried (Diomedi et al. 1999).
The restoration of some basic regular physiological rhythms such as circadian

rhythms may open new therapeutic perspectives in ASD. Both pharmacologic and
behavioral interventions have demonstrated to be effective for the treatment of sleep
problems in autistic children.
The most common types of behavioral interventions are unmodified extinction
and various forms of graduated extinction, while melatonin has shown promising
results restoring the impaired circadian melatonin rhythm in ASD. The synchroni-
zation of internal biological clocks may directly impact and improve social com-
munication, stereotyped behaviors, and adaptation to environmental changes. Even
though the results of controlled studies are limited, there are more data demonstrat-
ing the safety and effectiveness of melatonin in ASD than for other sedative/hyp-
notic drugs. We firmly suggest dual treatment for insomnia in ASD consisting of
melatonin administration associated with behavioral intervention. Randomized
clinical trials in ASD are warranted to establish potential therapeutic efficacy of
melatonin for social communication impairments and stereotyped behaviors or
interests (Tordjman et al. 2013).
124 S. Miano et al.
References
International classification of sleep disorders (2014) 3rd edn. American Academy of Sleep
Medicine, Darien
Accardo JA, Malow BA (2014) Sleep, epilepsy, and autism. Epilepsy Behav. pii:
S1525-5050(14)00533-2
Anders TF et al (2011) Six month sleep-wake organization in pre-school-age children with devel-
opmental delay and typical development. Behav Sleep Med 829:92–106
Andersen IM et al (2008) Melatonin for insomnia in children with autism spectrum disorders.
J Child Neurol 23:482–485
Association AP (1980) Diagnostic and statistical manual of mental disorders, 5th edn. American
Psychiatric Association, Washington, DC, p 2013
Aurora RN, American Academy of Sleep Medicine et al (2011) Practice parameters for the respi-
ratory indications for polysomnography in children. Sleep 34:379–388
Aurora RN et al (2012) Practice parameters for the non-respiratory indications for polysomnogra-
phy and multiple sleep latency testing for children. Sleep 35:1467–1473
Austin et al (2013) Preliminary evaluation of stepwise program for children with sleep disturbance
and developmental delay. Child Fam Behav Ther 35:195–211
Ayyash HF et al (2015) Melatonin for sleep disturbance in children with neurodevelopmental dis-
orders: prospective observational naturalistic study. Expert Rev Neurother 4:1–7
Berry R, et al. for the American Academy of Sleep Medicine (2012a) The AASM manual for the
scoring of sleep and associated events: rules, terminology and technical specifications. Darien:
American Academy of Sleep Medicine. Version 2.0. www.aasmnet.org.
Berry RB, et al (2012b) Rules for scoring respiratory events in sleep: update of the 2007 AASM
manual for the scoring of sleep and associated Events. Deliberations of the sleep apnea defini-
tions task force of the American Academy of Sleep Medicine. J Clin Sleep Med 8:597–619
Bradley EA et al (2004) Comparing rates of psychiatric and behavior disorders in adolescents and
young adults with severe intellectual disability with and without autism. J Autism Dev Disord
34:151–161
Bruni O et al (1997) Prevalence of sleep disorders in childhood and adolescence with headache: a
case-control study. Cephalalgia 17:492–498
Cai G et al (2008) Multiplex ligation-dependent probe amplification for genetic screening in
autism spectrum disorders: efficient identification of known microduplications and identifica-
tion of a novel microduplication in ASMT. BMC Med Genomics I:50
Chantiluke K et al (2014) Disorder-specific functional abnormalities during temporal discounting
in youth with Attention Deficit Hyperactivity Disorder (ADHD), autism and comorbid ADHD
and autism. Psychiatry Res 223:113–120
Chez MG et al (2006) Frequency of epileptiform EEG abnormalities in a sequential screening of
autistic patients with no known clinical epilepsy from 1996 to 2005. Epilepsy Behav
8:267–271
Clarke DF, Roberts W (2005) The prevalence of autistic spectrum disorder in children surveyed in
a tertiary care epilepsy clinic. Epilepsia 46:1970–1977
Cohen S et al (2014) The relationship between sleep and behavior in autism spectrum disorder
ASD: a review. J Neurodev Disord 6:44
Cortesi F et al (2010) Sleep in children with autism spectrum disorders. Sleep Med 11:659–664
Cortesi F et al (2012) Controlled-release melatonin, singly and combined with cognitive behav-
ioral therapy for persistent insomnia in children with autism spectrum disorders: a randomized
placebo-controlled trial. Sleep Res 21:700–709
Couturier JL et al (2005) Parental perception of sleep problems in children of normal intelligence
with pervasive developmental disorders: prevalence, severity, and pattern. J Am Acad Child
Delahaye J et al (2014) The relationship between health-related quality of life and sleep problems
in children with autism spectrum disorders. Res Autism Spectr Disord 8:292–303
Diomedi M, Curatolo P, Scalise A, Placidi F, Caretto F, Gigli GL (1999) Sleep abnormalities in

mentally retarded autistic subjects: Down’s syndrome with mental retardation and normal sub-
jects. Brain Dev 21(8):548–53
Dodge NN, Wilson GA (2001) Melatonin for treatment of sleep disorders in children with devel-
opmental disabilities. J Child Neurol 16:581–584
Doo S, Wing YK (2006) Sleep problems of children with pervasive developmental disorder: cor-
relation with parental stress. Dev Med Child Neurol 48:650–655
Dosman CF et al (2007) Children with autism: effect of iron supplementation on sleep and ferritin.
Pediatr Neurol 36:152–158
Doyen C et al (2011) Melatonin in children with autism spectrum disorders: recent and practical
data. Eur Child Adolesc Psychiatry 20:231–239
Elrod MG, Hoods BS (2015) Sleep differences among children with autism spectrum disorders
and typically developing peers: a meta-analysis. J Dev Behav Pediatr 36:166–177
Engelhardt CR et al (2013) Media use and sleep among boys with autism spectrum disorders,
ADHD, or typical development. Pediatrics 132:1081–1089
Ernst M et al (1997) Low medial prefrontal dopaminergic activity in autistic children. Lancet 350,
Erratum in: Lancet 1998; 351:454
Garstang J, Wallis M (2006) Randomized controlled trial of melatonin for children with autistic
spectrum disorders and sleep problems. Child Care Health Dev 32:585–589
Giannotti F, Cortesi F, Cerquiglini A, Bernabei P (2006) An open-label study of controlled-release
melatonin in treatment of sleep disorders in children with autism. J Autism Dev Disord
36(6):741–752
Giannotti F et al (2008) An investigation of sleep characteristics, EEG abnormalities and epilepsy
of developmentally regressed and non-regressed autistic children. J Autism Dev Disord
38:1888–1897
Giannotti F et al (2011) Sleep in children with autism with and without developmental regression.
J Sleep Res 20:338–347
Goldman SE et al (2014) Melatonin in children with autism spectrum disorders: endogenous and
pharmacokinetic profiles in relation to sleep. J Autism Dev Disord 44:2525–2535
Goodlin-Jones BL et al (2008) Sleep patterns in preschool-age children with autism, developmen-
tal delay and typical development. J Am Acad Child Adolesc Psychiatry 47:930–938
Gringas P et al (2012) Melatonin for sleep problems in children with neurodevelopmental disor-
ders: randomized double masked placebo controlled trial. Br Med J 345:1–16
Gringas P et al (2014) Weighted blankets and Sleep in Autistic children – a randomized controlled
trial. Pediatrics 134:298–306
Guénolé F et al (2011) Melatonin for disordered sleep in individual with autism spectrum disor-
ders: a systematic review and discussion. Sleep Med Rev 15:379–387
Heuvel CJ et al (2005) Melatonin as a hypnotic: con. Sleep Med Rev 9:71–80
Hodge D et al (2014) Sleep patterns in children with and without autism spectrum disorders: devel-
opmental comparisons. Res Dev Disabil 35:1631–1638
Hollway AJ et al (2011) Sleep correlates of pervasive developmental disorders: a review of the
literature. Res Dev Disabil 32:1399–1421
Ivanenko A, Johnson K (2008) Sleep disturbances in children with psychiatric disorders. Semin
Pediatr Neurol 15:70–78
Jan JE et al (1994) The treatment of sleep disorders with melatonin. Dev Med Child Neurol
36:97–107
Jan JE et al (2000) Clinical trials of controlled-release melatonin in children with sleep-wake cycle
disorders. J Pineal Res 29:34–39
Jan JE et al (2008) Sleep hygiene for children with neurodevelopmental disabilities. Pediatrics
122:1343–1350
Johnson DA (2005) Gastroesophageal reflux disease and sleep disorders: a wake-up call for physi-
cians and their patients. Rev Gastroenterol Disord 5(suppl 2):S3–S11
Johnson KP, Malow BA (2008) Sleep in children with autism spectrum disorders. Curr Neurol
Neurosci Rep 8:155–161
126 S. Miano et al.
Kawabe K et al (2014) The melatonin receptor agonist ramelteon effectively treats insomnia and
behavioral symptoms in autistic disorders. Case Rep Psychiatry 2014:561071
Kotagal S, Broomall E (2012) Sleep in children with autism spectrum disorders. Pediatr Neurol
47:242–251
Krakowiak P et al (2008) Sleep problems in children with autism spectrum disorders, developmen-
tal delays, and typical development: a population-based study. J Sleep Res 17:197–206
Kuhn BR, Floress MT (2008) Nonpharmacological interventions for sleep disorders in children.
In: Ivanenko A (ed) Sleep and psychiatric disorders in children and adolescents. Informa
Healthcare, New York, pp 261–278
Kulman G et al (2000) Evidence of pineal endocrine hypofunction in autistic children.
Neuroendocrinol Lett 20:31–34
Lewine JD et al (1999) Magnetoencephalographic patterns of epileptiform activity in children with
regressive autism spectrum disorders. Pediatrics 104(3 Pt 1):405–418
Liu X et al (2006) Sleep disturbances and correlates of children with autism spectrum disorders.
Child Psychiatry Hum Dev 37:179–191
Malow BA (2006) Searching for autism symptomatology in children with epilepsy – a new
approach to an established comorbidity. Epilepsy Curr 6:150–152
Malow B (2014) A parent-based sleep education for children with autism spectrum disorders.
J Autism Dev Disord 44:216–228
Malow BA, Mc Grew SG (2008) Sleep disturbance and autism. Sleep Med Clin 3:479–488
Malow BA et al (2006a) Characterizing sleep in children with autism spectrum disorders: a multi-
dimensional approach. Sleep 29:1563–1571
Malow BA et al (2006b) Sleep and autism spectrum disorders. In: Tuchman R, Rapin I (eds)
Autism: a neurological disorders of early brain development. Mac Keith Press, London,
pp 188–201
Malow B et al (2011) Melatonin for sleep in children with autism: a controlled trial examining
dose, tolerability and outcomes. J Autism Dev Disord 42:1729–1732
Martin JL, Hakim AD (2011) Wrist actigraphy. Chest 139:1514–1527
Matsuura H et al (2008) Dynamical properties of the two-process model for sleep-wake cycles in
infantile autism. Cogn Neurodyn 2:221–228
May T et al (2015) Sleep in high functioning children with autism: Longitudinal developmental
change and associations with behavior problems. Sleep Med 13:2–18
Mazurek MO et al (2015) Sleep problems in children with autism spectrum disorder: examining
the contributions of sensory over-responsivity and anxiety. Sleep Med 16:270–279
Melke J et al (2008) Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry
13:90–98
Miano S, Ferri R (2010) Epidemiology and management of insomnia in children with autistic
spectrum disorders. Paediatr Drugs 12:75–84
Miano S, Peraita-Adrados R (2014) Pediatric insomnia: clinical, diagnosis, and treatment. Rev
Neurol 58:35–42
Miano S et al (2007) Sleep in children with autistic spectrum disorder: a questionnaire and poly-
somnographic study. Sleep Med 9:64–70
Miano S et al (2013) Case reports of sleep phenotypes of ADHD: from hypothesis to clinical prac-
tice. J Atten Disord 17:565–573
Ming X et al (2008) Autism spectrum disorders: concurrent clinical disorders. J Child Neurol 23:6–13
Montgomery P et al (2004) The relative efficacy of two brief treatments for sleep problems in
young learning disabled children: a randomized controlled trial. Arch Dis Child 89:125–130
Morgenthaler T, Standards of Practice Committee, American Academy of Sleep Medicine et al
(2007) Practice parameters for the use of actigraphy in the assessment of sleep and sleep disor-
ders: an update for 2007. Sleep 30:519–529
Nadeau JM et al (2014) Frequency and clinical correlates of sleep-related problems among anxi-
uos youth with autism spectrum disorders. Child Psychiatry Hum Dev 46:558–566
Nally B et al (2000) Researchers in brief: the management of television and video by parents of
children with autism. Autism 4:331–337
Nir I et al (1995) Brief report: circadian melatonin, thyroid-stimulating hormone, prolactin, and
cortisol levels in serum of young adults with autism. J Autism Dev Disord 25:641–654
Owens JA et al (2000) The Children’s Sleep Habits Questionnaire (CSHQ): psychometric proper-
ties of a survey instrument for school-aged children. Sleep 23:1043–1051
Owens JA et al (2010) Use of pharmacotherapy for insomnia in child psychiatry practice: a national
survey. Sleep Med 11:692–700
Paavonen EJ et al (2003) Effectiveness of melatonin in the treatment of sleep disturbances in chil-
dren with Asperger disorder. J Child Adolesc Psychopharmacol 13:83–95
Pagan C et al (2014) The serotonin-N acetylserotonin-melatonin pathway as a biomarker for
autism spectrum disorders. Transl Psychiatry 4, e479, 1–8
Papadopoulos N et al (2015) The efficacy of a brief behavioral sleep intervention in school-aged
children with ADHD and comorbid autism spectrum disorders. J Atten Disord. pii:
1087054714568565
Patzold LM et al (1998) An investigation into sleep characteristics of children with autism and
Asperger’s disorder. J Paediatr Child Health 34:528–533
Phillips L, Appleton R (2004) Systematic review of melatonin treatment in children with neurode-
velopmental disabilities and sleep impairment. Dev Med Child Neurol 46:771–775
Polimeni MA et al (2005) A survey of sleep problems in autism, Asperger’s disorder and typically
developing children. J Intellect Dis Res 49:260–268
Reading R (2012) Melatonin in autism spectrum disorders: a systematic review and metanalysis.
Child Care Health Dev 38:301–302
Richdale AL, Prior MR (1995) The sleep/wake rhythm in children with autism. Eur Child Adolesc
Richdale AL, Schreck KA (2009) Sleep problems in autism spectrum disorders: prevalence, nature
and possible biopsychosocial etiologies. Sleep Med Rev. doi:10.1016/j.smrv.2009.02.003
Richdale A, Wiggs L (2005) Behavioral approaches to the treatment of sleep problems in children
with developmental disorders. What is the state of the art? Int J Behav Consult Ther
1:165–189
Richdale AL et al (2014) The role of insomnia, pre-sleep arousal and psychopathology symptoms
in daytime impairment in adolescents with high-functioning autism spectrum disorder. Sleep
Med 15:1082–1088
Ritvo ER et al (1993) Elevated daytime melatonin concentrations in autism: a pilot study. Eur
Child ASDolesc Psychiatry 2:75–78
Robinson AM, Richdale AL (2004) Sleep problems in children with an intellectual disabilities:
parental perception of sleep problems and views of treatment effectiveness. Child Care, Health
Dev 30:139–150
Rocca FL et al (2015) Narcolepsy during childhood: an update. Neuropediatrics 46:181–198
Rommelse NNJ et al (2011) A review on cognitive and brain endophenotypes that may be common
in autism spectrum disorder and attention-deficit/hyperactivity disorder and facilitate the
search for pleiotropic genes. Neurosci Biobehav Rev 35:1363–1396
Ross C et al (2002) Melatonin treatment for sleep disorders in children with neurodevelopmental
disorders: an observational study. Dev Med Child Neurol 44:339–344
Rossi PG et al (1999) Niaprazine in the treatment of autistic disorder. J Child Neurol 14:547–550
Rossignol DA et al (2011) Melatonin in autism spectrum disorders: a systematic review and meta-
nalysis. Dev Med Child Neurol 53:783–792
Schreck KA, Mulick JA (2000) Parental report of sleep problems in children with autism. J Autism
Dev Disord 30:127–135
Stuttard L et al (2015a) Replacing home visits with telephone calls to support parents implement-
ing a sleep management intervention: findings from a pilot study and implications for future
research. Child Care Health Dev 41:1074–1081
Stuttard L et al (2015b) A preliminary investigation into the effectiveness of a group-delivered
sleep management for parents of children with intellectual disabilities. J Int Dis 19:342–355
Thackeray EJ, Richdale AL (2002) The behavioural treatment of sleep difficulties in children with
intellectual disabilities. Behav Interv 17:211–231
128 S. Miano et al.
Thirumalai SS et al (2002) Rapid eye movement sleep behavior disorder in children with autism.
J Child Neurol 17:173–178
Toma CF et al (2007) Is ASMT a susceptibility gene for autism spectrum disorders? A replication
study in European populations. Mol Psychiatry 12:977–979
Tordjman S et al (2005) Nocturnal excretion of 6-sulphatoxymelatonin in children and adolescents
with autistic disorder. Biol Psychiatry 57:134–138
Tordjman S et al (2012) Day and nighttime excretion of 6-sulphatoxymelatonin in adolescents and
young adults with autistic disorder. Psychoneurocrinology 37:1990–1997
Tordjman S et al (2013) Advances in the research of melatonin in autism spectrum disorders: lit-
erature review and new perspectives. Int J Mol Sci 14:20508–20542
Tordjman S et al (2014) Altered circadian patterns of salivary cortisol in low-functioning children
and adolescents with autism. Psychoneurocrinology 50:227–245
Tordjman S et al (2015) Autism as a disorder of biological and behavioral rhythms: toward new
therapeutic perspectives. Front Pediatr 3:1
Valdizán-Usón JR et al (2002) Nocturnal polysomnogram in childhood autism without epilepsy.
Rev Neurol 34:1101–1105
Veatch OJ et al (2015) Genetic variation in melatonin pathway enzymes in children with autism
spectrum disorder and comorbid sleep onset delay. J Autism Dev Disord 45:100–110
Vriend JL et al (2011) Behavioral interventions for sleep problems in children with autism spec-
trum disorders: current findings and future directions. J Pediatr Psychol 36:1017–1029
Wang L et al (2013) Sequencing ASMT identifies rare mutations in Chinese Han patients with
autism. PLoS One 8:e 53727
Weiskop S et al (2005) Behavioral treatment to reduce sleep problems in children with autism or
fragile X syndrome. Dev Med Child Neurol 47:94–104
Wiggs L (2001) Sleep problems in children with developmental disorders. J R Soc Med
94:177–179
Wiggs L, France K (2000) Behavioural treatments for sleep problems in children and adolescents
with physical illness, psychological problems or intellectual disabilities. Sleep Med Rev
4:299–314
Wiggs L, Stores G (2004) Sleep patterns and sleep disorders in children with autistic spectrum
disorders: insights using parent report and actigraphy. Dev Med Child Neurol 46:372–380
Williams G et al (2006) Parent perceptions of efficacy for strategies used to facilitate sleep in chil-
dren with autism. J Dev Phys Disabil 18:25–33
Wright B et al (2011) Melatonin versus placebo in children with autism spectrum conditions and
severe sleep problems not amenable to behavior, management strategies: a randomized con-
trolled crossover trial. J Autism Dev Disord 41:175–184
Yang et al (2015) Circadian-relevant genes are highly polymorphic in autism spectrum disorder
patients Brain Dev (in press)
Personality Disorders and Autism
Spectrum Disorder: What Is Similar 9
and What Is Different?
Kathrin Sevecke, Luise Poustka, and Christian Popow
1 Introduction
Personality disorders (PDs) are mental disorders characterized by enduring mal-

adaptive patterns of cognition and behavior, causing difficulties in personal and
social functioning (American Psychiatric Association 2013). The origins of PDs are
poorly understood; recent pathogenic models are based on traumatic negative
(early) childhood experiences and on genetic background (Ballard et al. 2015;
Chanen and Kaess 2012). In contrast to personality, i.e., mental traits that character-
ize human beings, PDs are associated with significant dysfunctional experience and
behavior, a number of comorbid conditions, and severe personal disadvantages.
These endanger personal well-being, education, social and occupational integration,
and relationships (Biskin 2015).
Autism spectrum disorder (ASD) is a heterogeneous group of pervasive disorders
characterized by problems of social communication and interaction, restrictive inter-
ests, and repetitive behaviors (American Psychiatric Association 2013). Caused by
genetic deficiencies that impair brain networking, ASD shows a broad range of
severity of impaired intellectual functioning, inflexibility, and personal and social
dysfunction. There are multiple comorbid conditions, e.g., concerning sensory inte-
gration, attention, neurology, anxiety, and PDs. ASD are not curable, but improve-
ments of development and personal and social functioning may be attained through
K. Sevecke (*)
Department of Child and Adolescent Psychiatry, Innsbruck Medical University,
Innsbruck, Austria
L. Poustka • C. Popow
Department of Child and Adolescent Psychiatry, Vienna Medical University, Vienna, Austria

130 K. Sevecke et al.
structured therapy for low-functioning children and through appropriate psychologi-

cal and pharmacological therapy for higher-functioning children and adolescents. In
this paper, we will focus on ASD patients with normal intellectual capacity; the rela-
tionships between low-functioning ASD patients and PDs have not yet been explored.
The relationships and overlapping psychopathology between ASD and PDs,
although evident (especially for clusters A and C), are only poorly described and
understood. These areas of overlap include pervasive impairment, abnormal develop-
ment, stable patterns, long duration, onset in childhood to adolescence or early adult-
hood, and social impairment (Miller and Ozonoff 1997). However, a PD should be
excluded “if the enduring pattern is not better accounted for as a manifestation or
consequence of any other mental disorder” (American Psychiatric Association 2013).
In this article, we will focus on these complex relationships, drawing upon available
literature and aiming to contribute to the knowledge and (medical) handling of both
disorders. We will especially focus on prevalence, phenomenology and clinical issues,
common and uncommon features of PDs and ASD, and assessment and treatment.
2 Prevalence
PDs are among the most prevalent disorders in adulthood, reaching rates of 10 % in
community samples (Coid et al. 2006) and up to 50 % in clinical samples (American
Psychiatric Association 2000; Sevecke and Krischer 2008). Longitudinal studies
suggest that prevalence rates of PDs are higher in adolescence and decline linearly
up to the age of 27 (Chanen and Kaess 2012). Differences in prevalence rates may
be explained by nonuniform interpretation of diagnostic criteria and the various
classification systems.
The diagnosis of a PD is less stable than formerly expected (Biskin 2015; Skodol
et al. 2005; Stepp 2012) and differs among the various types. PD traits such as “self-
injurious behavior” are less stable than states such as “affective instability” and
“impulsivity.” Symptom stability is relatively stable over time for borderline (BPD),
histrionic, and schizotypal PD and less stable for other categorical diagnoses.
3 Phenomenology, Comorbidity, and Clinical Issues
PD types are differently described by the various diagnostic systems: ICD-10 lists
eight categories and a number of “others”; DSM-IV defined three clusters (A: odd,
B: dramatic, C: anxious) and ten PDs in a separate diagnostic axis; and DSM-5 cre-
ated a hybrid model, defining six categories of core impairments (antisocial, avoid-
ant, borderline, narcissistic, obsessive-compulsive, and schizotypal PD, Criterion
A) and five high-order traits (negative emotionality, detachment, antagonism, disin-
hibition, psychoticism, Criterion B). This new model reflects the complexity of
PDs, improves discriminant validity and stability of the diagnosis, reduces comor-
bidity, and allows for assessing personal (identity and self-directedness) and
9 Personality Disorders and Autism Spectrum Disorder 131
interpersonal (empathy and intimacy) functioning. Although personality traits may

be present in early childhood, a definite PD diagnosis is now permitted in adoles-
cence, respecting that early intervention and adequate psychological and pharmaco-
logical therapy may result in significant functional improvement and even cure. In
so doing, therapeutic nihilism and the mischaracterization of PDs as lifelong condi-
tions should be avoided.
Patients with an increased symptom level are more severely affected in their
psychosocial functioning. A high level of cluster A symptoms has been related to
lower educational levels and job performance (Cohen et al. 2005).
Diagnostic and statistical manual of mental disorders- Fifth edition (DSM-5) has
also introduced revised specifications for ASD: ASD is now a spectrum disorder, with
two main symptoms – (1) deficits in social communication and interaction and (2)
restricted interests and repetitive behavior. The previous categories no longer exist.
Moreover, DSM-5 has introduced specifiers, intellectual and language impairment,
association with a known medical or genetic condition, and three severity levels.
PDs and ASD share many comorbid conditions that aggravate the severity of the
disorders. Comorbidities of BPD mainly relate to attention deficit (ADHD), mood,
anxiety, posttraumatic stress disorder (PTSD), and eating disorders (EDs). The
close relationship between antisocial PD (ASPD) and ADHD remains stable into
adulthood (Mannuzza et al. 1998; Nigg et al. 2002; Rösler et al. 2008; Sevecke and
Krischer 2008). In addition, characteristics of ASPD, BPD, and early complex
PTSD and problems of interaction may overlap (Brunner et al. 2001; Schmid et al.
2010), and there are close similarities between PTSD and BPD (Jucksch et al. 2009;
Krischer and Sevecke 2008). Comorbidities of ASD mainly relate to ADHD and
sensory integration problems and mood, tic, and anxiety disorders.
There are only a few studies relating PS and ASD. Generally, adolescents and
adults with PDs and ASD face problems in social interaction, mentalizing abilities,
and building and maintaining stable relationships. Cluster A and C PDs seem to be
more prevalent in ASD patients (Lugnegård et al. 2012), whereas ASD psychopa-
thology seems to protect patients from cluster B PDs. This could be related to early
difficulties and less interest in social interaction in ASD, limiting the effects of poor
parenting and inconsistent parent-child interaction on the developing personality.
Subjectively experienced excessive emotional demands leading to temper tantrums
could be a link between ASD and cluster B PDs, but the backgrounds seem to be
different: children with ASD are overburdened because of their limited cognitive
flexibility, whereas BPD patients are overburdened by their difficulties in express-
ing and regulating their emotions (Jarnecke et al. 2015). Moreover, although BPD
and ASD patients exhibit social problem-solving deficits, the former have intense
but unstable social relationships and strive to avoid abandonment, whereas ASD
patients seem to be socially more independent and to display less interest in social
interactions (King-Casas and Chiu 2012). There is also a sex difference: ASD
patients are predominantly male, while PDs show a female predominance.
Tantam (1988) and Esterberg et al. (2008) have described more severe current
and past autistic features, such as social impairment and unusual interests and
behavior in adolescents with schizotypal PD (SPD) compared to normal and other

PD controls. Hurst et al. (2006), studying patients with Asperger’s syndrome and
SPD, found overlapping diagnostic criteria and correlations between social-
interpersonal and communication-disorganized areas between the two disorders.
Personality traits that are similar but less severe than in ASD are seen in the “broader
autism phenotype” (BAP), comprising the traits “rigid,” “impulsive,” “aloof,” “shy,”
“tactless,” “reserved/schizoid,” “irritable,” “hypersensitive to criticism,” “neurotic,”
“undemonstrative,” and “anxious” (Sucksmith et al. 2011; Vannucchi et al. 2014).
Lugnegård et al. (2012), investigating 54 young adults with the clinical diagnosis
of Asperger’s syndrome (DSM-IV criteria, SKID-II interview), found marked PD
symptoms in one-half of the autistic patients, two-thirds of the male, and one-third
of the female population. The PD criteria were fulfilled for only four PDs, schizoid,
schizotypal, avoidant, and obsessive-compulsive PD, and there were no cluster B
diagnoses.
According to Hare and Neumann (2009), psychopathy as a specific PD sub-
type and ASD are both associated with strong deficits in empathy. Empathy defi-
cits differed, however, in both groups of patients in genetic, cognitive, and
neurologic aspects (Wallace et al. 2012). Specifically, individuals with psycho-
pathic personality traits had problems in processing emotional stimuli, had
reduced levels of anxiety, and had deficits in ethical reasoning, whereas patients
with ASD had difficulties with the cognitive processing of emotional cues
(Rogers et al. 2006). Roberz et al. (2013) discuss the differential diagnosis in
regard to a case report about a 17-year-old boy. ASD patients perceive the suffer-
ing of others as aversive (Blair 1999; Sigman et al. 2003). ASD patients also have
difficulties understanding the reasoning and feeling of others and seem to act
insensitively. Yet when information is presented in such a way that enables them
to emotionally understand the problems of others, they feel and care empathi-
cally normal (Jones et al. 2010).
Anckarsater (2006) reviewed brain imaging similarities between ASD and
aggressive PD or psychopathy, especially in regard to hypoactivity and structural
reduction of the prefrontal cortex and the limbic circuitry. Patients with ASPD show
smaller prefrontal and cingulate cortices (Yang et al. 2009), while ASD patients
show volume reductions in the temporal and parietal areas (Scheel et al. 2011;
Wallace et al. 2010, 2012).
Diagnostic evaluation for PDs includes semi-structured instruments such as
SCID-II (Structured Clinical Interview for DSM-IV (First et al. 1997)) and IPDE
(International Personality Disorder Examination (Loranger 1994)). The diagnosis
of ASD relies on ADOS 2 (Autism Diagnostic Observation Schedule (Poustka et al.
2015)) and ADI-R (Autism Diagnostic Interview – Revised (Bölte et al. 2006)),
both of which assess autistic symptoms in a semi-structured way. Patients with PD
or ASD are not always aware of their clinical problems, and this leads to interper-
sonal difficulties. As patients may not report their problems, it is essential to also
rely on external sources of information, such as parents, relatives, and teachers.
Furthermore, experienced clinicians will detect interpersonal dysfunctions by ana-
lyzing transference and countertransference phenomena.
4 Treatment
4.1 Nonmedical Interventions
A number of effective psychotherapeutic programs and manuals for treating (B)PDs

are available for adults. For adolescents, these therapies – with the exception of
DBT-A – have not yet been fully evaluated:
• Specific psychodynamic therapies: Transference-Focused Psychotherapy (TFP

(Clarkin et al. 2004)) and Mentalization-Based Treatment (MbT (Bateman and
Fonagy 2006)) and Adolescent Identity Treatment (AIT (Foelsch et al. 2013))
• Specific cognitive behavioral therapies: Dialectical Behavior Therapy (DBT and
DBT-A (Linehan 1993)) and Schema Therapy (Young et al. 2003)
Ongoing clinical trials for the treatment of adolescents with PDs aim to respect
the specific needs of this age group (see overviews: Krischer et al. 2006; Krischer
and Sevecke 2010). Examples of modified adult treatment protocols are Adolescent
Identity Treatment (AIT (Foelsch et al. 2008)), Transference-Focused Psychotherapy
for Adolescents (TFP-A (Fleischhaker et al. 2011)), and Dialectic Behavioral
Therapy for Adolescents (DBT-A (Miller et al. 1997)). These therapies focus more
on identity diffusion than on identity crisis (Foelsch et al. 2010). Identity diffusion
entails the lack of an integrative self-concept, similarly lacking in regard to signifi-
cant persons. Identity diffusion is a prerequisite for developing adolescent PDs. The
patient describes himself or herself and others in a highly chaotic way, unable to
detect or integrate contradictions (Clarkin et al. 2004). Adolescent PD therapy aims
at improving interpersonal relationships with friends, parents, and teachers. It fur-
ther aims at defining lifetime goals, developing a sense of self-worth, and achieving
a stable identity.
Pharmacological interventions for ASD and PDs are only symptomatic and sup-
portive. The main target symptoms are aggressive behavior/temper tantrums,
depression, sleep problems, and ADHD; in ASD patients with seizures, anticonvul-
sive medication is indicated. A recent field study on psychopharmacological treat-
ment in Germany (Bachmann et al. 2013) included 1,124 patients, 0.5 % having the
diagnosis of ASD. One-third of the ASD patients received medication, with methyl-
phenidate and risperidone the most frequently prescribed substances.
Pharmacological studies on treating PDs mainly focus on BPD (Paris 2011), with
low evidence (Klar and Siever 1984). Treatment guidelines, e.g., for BPD (Oldham
et al. 2001), are poorly evidence supported and are no longer up to date.
Neuroleptics are widely used to decrease intrapersonal stress levels, enabling a
distancing from environmental stressors and a reduction of impulsivity and reactive
aggressive behavior. Although widely used, neuroleptic treatment shows poor
evidence of efficacy because large RCTs are lacking, especially for second-
generation antipsychotics.
Anticonvulsants – aside from their use in epilepsy and bipolar disorder – are
commonly used to reduce impulsivity and aggressive behavior. The evidence of
such treatment is, however, poor (Huband et al. 2010).
Antidepressants are generally less effective in ASD (Williams et al. 2013) and
PD (Paris 2011). This may be caused by the background and unchanging intraper-
sonal strain (due to flexibility problems) or by neuro-functional differences that are
poorly understood.
The efficacy of ADHD medication, specifically methylphenidate and atomox-
etine, has been proven in several prospective trials in ASD patients. Both medica-
tions seem to be less effective in ASD and PD patients than in normotypic and
non-PD ADHD patients. However, methylphenidate (Simonoff et al. 2013) and ato-
moxetine (Handen et al. 2015) are effective in children with ASD, with atomoxetine
showing a slightly better side effect profile. (B)PD patients with comorbid ADHD
also benefit from these two medications (Newcorn et al. 2007). In addition, aggres-
sive behavior (Blader et al. 2013) and the occurrence of SUD (Steinhausen and
Bisgaard 2014) are reduced, and psychotherapeutic adherence improved with long-
term medication (Prada et al. 2015).
Clinical diagnosis and treatment of adolescents with PDs and ASD are sensitive,
complex tasks that require specific knowledge and experience. The available diag-
nostic tools, mainly structured interviews and clinical observation, are relatively
sensitive, specific, and reliable.
The findings to date and the abandoned age limitation for the assessment of PD
(DSM-5) clearly justify the diagnosis of PDs in adolescence, but more work is nec-
essary to better identify and understand age-specific processes and characteristics.
Early, careful diagnosis of adolescents with PS, followed by specific treatment, is
certainly indicated. It is noteworthy that large numbers of patients, when treated
appropriately, are able to go into remission, rendering therapeutic nihilism as a con-
sequence of presumed “incurability” unwarranted.
The new DSM-5 criteria for both groups of disorders provide a courageous
approach, enhancing the quality of dimensional diagnosis. For PDs, abandoning
the age limit of 18 and introducing a hybrid disorder model, keeping “old” catego-
ries and adding five high-order traits and 25 trait facets, will help characterizing
the clinical picture more precisely. In ASD patients, emphasizing common prob-
lems, adding specifiers and severity levels, and abandoning categorization will
likely increase diagnostic precision. Nevertheless, longitudinal studies for both
groups of disorders are needed to better characterize the stability of the diagnostic
criteria and the effects of specific therapies. For both groups of disorders, access
to specific therapy and early, accurate diagnosis are essential to providing appro-
priate support.
As in all disorders, comorbidity is crucial for clinical severity, vocational suc-

cess, and quality of life. The two disorders share multi-comorbid conditions, includ-
ing ADHD and mood, anxiety, dysexecutive, and other disorders that further impair
social functioning. Treatment must therefore consider the part of impairment caused
by comorbid conditions.
The relationship between PDs and ASD is complex and not clearly defined.
There are similarities, e.g., social ostracism, poor emotional control, comorbid con-
ditions, unknown stability of symptoms, and therapy-related alleviation, as well as
differences, e.g., age at onset, intellectual performance, social skills, and fears of
abandonment. Some PDs and ASD and schizotypal PD show significant overlap.
One of the main differences, besides age at onset, is etiology: ASD is primarily
related to genetic problems of brain networks, with less parental impact, whereas
PDs usually have a family and social background but are predominantly acquired
disorders, related, for example, to poor parental functioning and repeated
traumatization.
Nevertheless, PDs, especially those with schizotypal personality traits, and ASD
share impaired social functioning due to emotional dysfunction. They appear to be
of different etiology, however, which is apparent in their differing genetic, cogni-
tive, and neuronal characteristics. The key point for differential diagnosis between
PD and ASD thus appears to lie in the precise assessment of patients’ empathy
deficit.
Future work will likely focus on long-term epidemiology, etiology (genetics,
inborn and acquired problems), and therapy. Precise diagnostics will influence spe-
cific therapies. The introduction of the dimensional-categorical hybrid model of the
DSM-5, with its assessment of traits and trait facets, now allows for a better differ-
entiation and characterization within personality pathology profiles. It may indeed
also be helpful to create such profiles for patients with ASD.
Other questions concern social integration and specific vocational training as
well as tailor-made and cost-effective psychotherapies for specific clinical entities.
Similarly, the long-term effect of psychotherapies remains to be explored.
References
fourth edition, text revision (DSM-IV-TR). American Psychiatric Association, Washington,
DC
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders.
Fifth edition (DSM-5). American Psychiatric Association, Arlington
Anckarsater H (2006) Central nervous changes in social dysfunction: autism, aggression, and psy-
chopathy. Brain Res Bull 69(3):259–265. doi:10.1016/j.brainresbull.2006.01.008
Bachmann CJ, Manthey T, Kamp-Becker I, Glaeske G, Hoffmann F (2013) Psychopharmacological
treatment in children and adolescents with autism spectrum disorders in Germany. Res Dev
Disabil 34:2551–2563
Ballard ED, Van Eck K, Hart SR, Storr CL, Breslau N, Wilcox HC (2015) Latent classes of child-
hood trauma exposure predict the development of behavioral health outcomes in adolescence
and young adulthood. Psychol Med 45(15):3305–3316
Bateman A, Fonagy P (2006) Mentalization-based treatment for borderline personality disorder.

Oxford University Press, Oxford
Biskin RS (2015) The lifetime course of borderline personality disorder. Can J Psychiatry
60(7):303–308
Blader JC, Pliszka SR, Kafantaris V, Foley CA, Crowell JA, Carlson GA, . . . Daviss WB (2013)
Callous-unemotional traits, proactive aggression, and treatment outcomes of aggressive chil-
dren with attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 52(12):
1281–1293. doi:10.1016/j.jaac.2013.08.024
Blair RJR (1999) Psychophysiological responsiveness to the distress of others in children with
autism. Personal Individ Differ 26(3):477–485. doi:10.1016/s0191-8869(98)00154-8
Bölte S, Rühl D, Schmötzer G, Poustka F (2006) ADI-R Diagnostisches Interview für Autismus -
Revidiert Deutsche Fassung des Autism diagnostic interview – revised von Michael Rutter,
Ann Le Couteur und Catherine Lord (1st ed). Huber/Hogrefe, Bern
Brunner R, Parzer P, Resch F (2001) Dissoziative Symptome und traumatische Lebensereignisse
bei Jugendlichen mit einer Borderline-Störung. Persönlichkeitsstörungen 5:4–12
Chanen AM, Kaess M (2012) Developmental pathways to borderline personality disorder. Curr
Psychiatry Rep 14(1):45–53. doi:10.1007/s11920-011-0242-y
Clarkin JF, Levy KN, Lenzenweger MF, Kernberg OF (2004) The Personality Disorders Institute/
Borderline Personality Disorder Research Foundation randomized control trial for borderline
personality disorder: rationale, methods, and patient characteristics. J Personal Disord
18(1):52–72. doi:10.1521/pedi.18.1.52.32769
Cohen P, Crawford TN, Johnson JG, Kasen S (2005) The children in the community study of
developmental course of personality disorder. J Personal Disord 19(5):131–140. doi:10.1521/
pedi.2005.19.5.466
Coid J, Yang M, Tyrer P, Roberts A, Ullrich S (2006) Prevalence and correlates of personality
disorder in Great Britain. Br J Psychiatry 188:423–431
Deutschsprachige Fassung der Autism Diagnostic Observation Schedule – 2 von C. Lord,
M. Rutter, P.C. DiLavore, S. Risi, K. Gotham und S.L. Bishop (Module 1-4) und C. Lord,
R.J. Luyster, K. Gotham und W. Guthrie (Kleinkind-Modul) (1st ed). Hogrefe, Bern
Esterberg ML, Trotman HD, Brasfield JL, Compton MT, Walker EF (2008) Childhood and current
autistic features in adolescents with schizotypal personality disorder. Schizophr Res 104(1–
3):265–273. doi:10.1016/j.schres.2008.04.029
First MB, Gibbon M, Spitzer RL, Williams JB (1997) Structured clinical interview for DSM-IV
(SCID-I/SCID-II). American Psychiatric Publishers, Arlington
Fleischhaker C, Sixt B, Schulz E (2011) DBT-A Dialektisch-behaviorale Therapie für Jugendliche.
Springer Science + Business Media, Berlin
Foelsch PA, Kernberg OF, Krischer MK (2008) Übertragungsfokussierte Psychotherapie für
Jugendliche. Prax Kinderpsychol Kinderpsychiatr 57(8–9):662–692
Foelsch PA, Odom A, Arena H, Krischer MK, Sevecke K, Schlüter-Müller S (2010) Differenzierung
zwischen Identitätskrise und Identitätsdiffusion und ihre Bedeutung für die Behandlung – am
Beispiel einer Kasuistik. Praxis Kinderpsychologie Kinderpsychiatrie 59:418–434.
doi:10.13109/prkk.2008.57.89.662
Foelsch P, Schlüter-Müller S, Odom A, Arena H, Borzutzky A, Schmeck K (2013) Behandlung
von Jugendlichen mit Identitätsstörungen (AIT). Springer, Berlin
Handen BL, Aman MG, Arnold LE, Hyman SL, Tumuluru RV, Lecavalier L, . . . Smith T (2015)
Atomoxetine, parent training, and their combination in children with autism spectrum disorder
and attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Psychiatry 54(11):905–
915. doi:10.1016/j.jaac.2015.08.013
Hare RD, Neumann CS (2009) Psychopathy: assessment and forensic implications. Can
J Psychiatry 54(12):791–802. doi:10.1093/med/9780199551637.003.0007
Huband N, Ferriter M, Nathan R, Jones H (2010) Antiepileptics for aggression and associated impul-
sivity. Cochrane Database Syst Rev (2):CD003499. doi:10.1002/14651858.CD003499.pub3
Hurst RM, Nelson-Gray RO, Mitchell JT, Kwapil TR (2006) The relationship of Asperger’s char-
acteristics and Schizotypal personality traits in a non-clinical adult sample. J Autism Dev
Disord 37(9):1711–1720. doi:10.1007/s10803-006-0302-z
Jarnecke AM, Miller ML, South SC (2015) Daily diary study of personality disorder traits:
momentary affect and cognitive appraisals in response to stressful events. Personal Disord.
doi:10.1037/per0000157
Jones AP, Happé FGE, Gilbert F, Burnett S, Viding E (2010) Feeling, caring, knowing: different
types of empathy deficit in boys with psychopathic tendencies and autism spectrum disorder.
J Child Psychol Psychiatry 51(11):1188–1197. doi:10.1111/j.1469-7610.2010.02280.x
Jucksch V, Salbach-Andrae H, Lehmkuhl U (2009) Persönlichkeitsentwicklung im Kindes- und
Jugendalter. Nervenarzt 80(11):1322–1326. doi:10.1007/s00115-009-2805-2
King-Casas B, Chiu PH (2012) Understanding interpersonal function in psychiatric illness through
multiplayer economic games. Biol Psychiatry 72(2):119–125. doi:10.1016/j.
biopsych.2012.03.033
Klar H, Siever LJ (1984) The psychopharmacologic treatment of personality disorders. Psychiatr
Clin North Am 7(4):791–801
Krischer MK, Sevecke K (2008) Early traumatization and psychopathy in female and male juve-
nile offenders. Int J Law Psychiatry 31(3):253–262. doi:10.1016/j.ijlp.2008.04.008
Krischer MK, Sevecke K (2010, July 1–3) The prevalence of personality disorders in adolescent
in-patients. Paper presented at the 1st International Congress on Borderline Personality
Disorders, Berlin
Krischer M, Sevecke K, Döpfner M, Lehmkuhl G (2006) Persönlichkeitsstörungsmerkmale im
Kindes- und Jugendalter: Konzepte, methodische Ansätze und empirische Ergebnisse. Z
Kinder Jugendpsychiatr 34(2):87–100. doi:10.1024/1422-4917.34.2.87
Linehan M (1993) Cognitive-behavioral treatment of borderline personality disorder, 1st edn. The
Guilford Press, New York
Loranger AW (1994) The international personality disorder examination. Arch Gen Psychiatry
51(3):215–224. doi:10.1001/archpsyc.1994.03950030051005
Lugnegård T, Hallerbäck MU, Gillberg C (2012) Personality disorders and autism spectrum disor-
ders: what are the connections? Compr Psychiatry 53(4):333–340. doi:10.1016/j.
comppsych.2011.05.014
Mannuzza S, Klein RG, Bessler A, Malloy P, LaPadula M (1998) Adult psychiatric status of
hyperactive boys grown up. Am J Psychiatry 155(4):493–498. doi:10.1176/ajp.155.4.493
Miller JN, Ozonoff S (1997) Did Asperger’s cases have Asperger disorder? A research note.
Miller AL, Rathus JH, Linehan MM, Wetzler S, Leigh E (1997) Dialectical behavior therapy adapted
for suicidal adolescents. J Psychiatr Pract 3(2):78–86. doi:10.1097/00131746-199703000-
00002
Newcorn JH, Weiss M, Stein MA (2007) The complexity of ADHD: diagnosis and treatment of the
adult patient with comorbidities. CNS Spectr 12(8 Suppl 12):1–14, quiz 15–16
Nigg JT, John OP, Blaskey LG, Huang-Pollock CL, Willicut EG, Hinshaw SP, Pennington B
(2002) Big five dimensions and ADHD symptoms: links between personality traits and clinical
symptoms. J Personal Soc Psychol 83(2):451–469. doi:10.1037/0022-3514.83.2.451
Oldham JM, Gabbard GO, Goin MK, Gunderson J, Soloff P, Spiegel D, . . . Phillips KA (2001)
Practice guideline for the treatment of patients with borderline personality disorder. J Psychiatry
1–82
Paris J (2011) Pharmacological treatments for personality disorders. Int Rev Psychiatry 23(3):303–
309. doi:10.3109/09540261.2011.586993
Poustka L, Rühl D, Feineis-Matthews S, Bölte S, Poustka F, Hartung M (2015) Diagnostische
Beobachtungsskala für Autistische Störungen – 2
Prada P, Nicastro R, Zimmermann J, Hasler R, Aubry JM, Perroud N (2015) Addition of methyl-
phenidate to intensive dialectical behaviour therapy for patients suffering from comorbid
borderline personality disorder and ADHD: a naturalistic study. Atten Defic Hyperact Disord
7(3):199–209. doi:10.1007/s12402-015-0165-2
Roberz J, Lehmkuhl G, Sevecke K (2013) Autismus oder “Psychopathy”? Forensische Psychiatrie,
Psychologie. Kriminologie 7(4):282–289
Rogers K, Dziobek I, Hassenstab J, Wolf OT, Convit A (2006) Who Cares? Revisiting empathy in
Asperger syndrome. J Autism Dev Disord 37(4):709–715. doi:10.1007/s10803-006-0197-8
Rösler M, Retz W, Yaqoobi K, Burg E, Retz-Junginger P (2008) Attention deficit/hyperactivity

disorder in female offenders: prevalence, psychiatric comorbidity and psychosocial implica-
tions. Eur Arch Psychiatry 259(2):98–105. doi:10.1007/s00406-008-0841-8
Scheel C, Rotarska-Jagiela A, Schilbach L, Lehnhardt FG, Krug B, Vogeley K, Tepest R (2011)
Imaging derived cortical thickness reduction in high-functioning autism: key regions and tem-
poral slope. Neuroimage 58(2):391–400. doi:10.1016/j.neuroimage.2011.06.040
Schmid M, Fegert JM, Petermann F (2010) Traumaentwicklungsstörung: Pro und Contra. Kindheit
Entwicklung 19(1):47–63. doi:10.1026/0942-5403/a000008
Sevecke K, Krischer M (2008) ADHS und Persönlichkeitsstörungen bei klinisch behandelten und
inhaftierten Jugendlichen. Prax Kinderpsychol Kinderpsychiatr 57:641–661
Sigman M, Dissanayake C, Corona R, Espinosa M (2003) Social and cardiac responses of young
children with autism. Autism 7(2):205–216. doi:10.1177/1362361303007002007
Simonoff E, Jones CR, Baird G, Pickles A, Happe F, Charman T (2013) The persistence and stabil-
ity of psychiatric problems in adolescents with autism spectrum disorders. J Child Psychol
Skodol AE, Gunderson JG, Shea MT, McGlashan TH, Morey LC, Sanislow CA, . . . Stout RL
(2005) The Collaborative Longitudinal Personality Disorders Study (CLPS): overview and
implications. J Personality Disord 19(5):487–504. doi:10.1521/pedi.2005.19.5.487
Steinhausen HC, Bisgaard C (2014) Substance use disorders in association with attention-deficit/
hyperactivity disorder, co-morbid mental disorders, and medication in a nationwide sample.
Eur Neuropsychopharmacol 24(2):232–241. doi:10.1016/j.euroneuro.2013.11.003
Stepp SD (2012) Development of borderline personality disorder in adolescence and young adult-
hood: introduction to the special section. J Abnorm Child Psychol 40(1):1–5. doi:10.1007/
s10802-011-9594-3
Sucksmith E, Roth I, Hoekstra RA (2011) Autistic traits below the clinical threshold: re-examining
the broader autism phenotype in the 21st century. Neuropsychol Rev 21(4):360–389
Tantam D (1988) Lifelong eccentricity and social isolation. II. Br J Psychiatry 153(6):783–791
Vannucchi G, Masi G, Toni C, Dell’Osso L, Marazziti D, Perugi G (2014) Clinical features, devel-
opmental course, and psychiatric comorbidity of adult autism spectrum disorders. CNS Spectr
19(2):157–164. doi:10.1017/s1092852913000941
Wallace GL, Dankner N, Kenworthy L, Giedd JN, Martin A (2010) Age-related temporal and
parietal cortical thinning in autism spectrum disorders. Brain 133(12):3745–3754. doi:10.1093/
brain/awq279
Wallace GL, Shaw P, Lee NR, Clasen LS, Raznahan A, Lenroot RK, . . . Giedd JN (2012) Distinct
cortical correlates of autistic versus antisocial traits in a longitudinal sample of typically devel-
oping youth. J Neurosci 32(14):4856–4860. doi:10.1523/jneurosci.6214-11.2012
Williams K, Brignell A, Randall M, Silove N, Hazell P (2013) Selective serotonin reuptake inhibi-
tors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev (8):1-49.
doi:10.1002/14651858.CD004677.pub3
Yang Y, Raine A, Colletti P, Toga AW, Narr KL (2009) Abnormal temporal and prefrontal cortical
gray matter thinning in psychopaths. Mol Psychiatry 14(6):561–562. doi:10.1038/mp.2009.12
Young JE, Klosko JS, Weishaar M (2003) Schema therapy: a practitioner’s guide. The Guilford
Press, New York
“Gender Is Not on My Agenda!”:
Gender Dysphoria and Autism 10
Spectrum Disorder
Rita George and Mark Stokes
1 Gender Dysphoria: A Disconnection Between Gender

Identity and Birth Sex
Many people treat the terms “sex” and “gender” as though they were synonymous.
Biological sex comprises physical attributes such as external genitalia and internal
reproductive structures such as gonads, sex chromosomes, and sex hormones.
Gender, on the other hand, can be a little less straightforward and is not inherently
or exclusively associated to one’s physical anatomy. Gender is a product of the
complex interrelationship between an individual’s biological sex and one’s gender
identity, which is an internal sense of self as male, female, both, or neither.
Most youngsters are cognizant of their gender between the ages 18 months and
3 years, and by the beginning of school years, most children will have achieved a
sense of their gender identity and a certain degree of gender constancy, at which
time children begin to realize that gender is a permanent state that cannot be altered
by a change of clothing or activity (Paikoff and Brooks-Gunn 1991). By the age of
4 years, children typically outline preferences for the company of their same-sex
peers, and by this time, boys and girls differ in interests and types of group activities
and behaviors (Rosenfield and Wasserman 1993).
Gender identity can be the same or different from one’s birth-assigned sex.
Generally, an individual’s gender identity correlates with the gender roles or attributes
that a given society considers appropriate for males and females. Occasionally how-
ever, for some individuals, this is not the case. Gender dysphoria (GD) is a clinical
condition where the individual experiences a persistent sense of discontentment over
the incongruence between their experienced or expressed gender and their birth sex
leading to significant distress to the person, an impairment of social or occupational
functioning, and a desire to live a cross-gender life (Diagnostic and Statistical Manual
R. George • M. Stokes (*)

Department of Psychology, School of Psychology, Deakin University, Geelong, Australia

140 R. George and M. Stokes
of Mental Disorders [DSM-5] (American Psychiatric Association 2013)). It is esti-

mated that between 0.005 % and 0.014 % of natal males and 0.002–0.003 % of natal
females would be diagnosed with GD, based on current diagnostic criteria (Zucker
and Lawrence 2009). Expressions of GD include a preference for cross-dressing
(dressing up in clothes typically worn by the opposite sex as defined by the person’s
cultural norms) and for stereotypical cross-gender roles and, additionally in children,
make-believe play and a strong inclination for playmates of the opposite sex.
2 Gender Dysphoria (GD) and Autism Spectrum

Disorder (ASD)
Interestingly, a handful of case studies (Landen and Rasmusen 1997; Tateno et al.
2008; Mukaddes 2002; Gallucci et al. 2005; Kraemer et al. 2005) attest to a comor-
bid presentation of ASD with GD (see Table 10.1), while empirical reports (De
Vries et al. 2010; Jones et al. 2012; Pasterski et al. 2014) indicate elevated GD rates
within the ASD population.
Table 10.1 Summary of case studies on the comorbid presentation of ASD and GD
Case and study Findings
Kraemer et al. Emotionally nonreciprocating and unapproachable as a child; obstinate
(2005) fascination with geometric patterns; preferred the company of male
35-year-old playmates, described as being tomboyish, enjoyed male stereotypical
biological female play; insisted she was a boy had an aversion to her body and secondary
with AS and GD sex characteristics; insisted she always felt like a boy and refused girl’s
clothing
Galluci et al. Early developmental history remarkable for headbanging, rocking,
(2005) socio-communicative impairments; preoccupation with soft fabrics,
41-year-old actively seeking these out; artistically talented; history of cross-dressing
biological male with women’s clothing; strong desire to have the body of a woman; has
with AS and GD fantasies of himself as a woman; expresses extreme distress with natal
sex; pervasive preoccupation with physical appearance; dislikes having a
penis and has confessed to wanting to use a “butcher knife to whack it
off”; strongly desires sexual reassignment; obsessive need for order and
predictability; passive death wish and paranoid thoughts
Tateno et al. The individual presented with preoccupation with colors and figures;
(2008) difficulty developing peer relationships; avoided socializing; given to
5-year-old male temper tantrums and strict adherence to own self-made rules; strong
with AS and GD preference for female playmates; marked preoccupation with female
activities abhorrence to male stereotypical toys and play; cross-dressing;
disliked male body; insisted that he would grow up to be a woman;
symptoms were present on follow-up for 2 years
Landen and The subject displayed echopraxia and echolalia; selective mutism;
Rasmusen (1997) obsessive compulsions with handwashing; claimed she was a boy; refused
14-year-old female girl’s clothing or using the girl’s toilet; insisted on being addressed as
with AS and GD “he”; treatment with clomipramine helped with OCD-related symptoms
but gender dysphoria persisted
10 “Gender Is Not on My Agenda!”: Gender Dysphoria and Autism Spectrum Disorder 141
Table 10.1 (continued)

Case and study Findings
Williams et al. Presentation included symptoms of hyperactivity, impulsivity, loneliness,
(1996) and moodiness; perseverative motor activities; echolalic and echopraxic
5-year-old male patterns; female stereotypical play and strong rejection of male pursuits;
and 3-year- and interested in Barbie dolls, related paraphernalia and female cartoon
7-month-old males characters; ripped the heads off the dolls to play with their hair; fascinated
with ASD and GD with bright objects; preoccupation with cross-dressing, fashioned long
hair from scarves; playing with dolls by shaking their hair. Described as a
loner; perseverative play such as opening and closing doors; running hand
repeatedly through water; prone to temper tantrums; stubbornness;
favorite toys are Minnie mouse doll and Barbie doll; cross-dresses with
mother’s and sister’s clothing and high-heeled shoes; bras and underwear;
wraps shirts overhead and pretends like it is long hair
Mukaddes (2002) Subject demonstrated autistic behaviors such as restricted eye contact,
10-year-old male unresponsiveness to verbal stimuli, echolalia, perseveration, and
and 7-year-old neologisms; developed attachment to feminine objects such as cosmetics
male, respectively at age 3 years; at age 6, started to cross-dress with mother’s dresses,
pretend to wear high heels, and express his disappointment with his
gender; prayed to God to “make his penis disappear”; had fantasies about
becoming a bride and being married to a man; complete disinterest in
rough-tumble play typical of males; preferred the company of girls
Subject presented with a history of delayed language; difficulties with
social-affective development and eye contact; stereotypical behaviors,
toe walking, and a low frustration tolerance; at the age of 4–5 years
started some make-believe play, such as “playing house” and “playing
mother roles”; avoided rough-tumble male-oriented play and preferred
the company of his mother and female classmates; persistently expressed
his desire to grow up to be a woman like his mother and enjoyed making
skirts with his mother’s scarves
Perera et al. The case presented with socially awkward behavior; rejection of all
(2003) peer-group activities; classroom disruptive behavior; indiscriminate and
20-year-old female frequent aggression; recurrent compulsion; parents distressed about her
with AS, GD, and strange obsession with licking public floors; confession to irrational
OCD compulsive fears about parents dying; high achiever in school and
artistically talented; at age of 14 years, started to experience gender-
dysphoric symptoms; voiced deep resentment to her gender and insisted
on being a male; physically violent to those who resisted her thinking
insisted on sexual reassignment surgery and hormonal treatments after
menarche; patient was diagnosed with OCD and AS; medication with
clomipramine alleviated some of the OCD symptoms, with less overt GD
symptoms
When using the Diagnostic Interview for Social and Communication Disorders
(Leekam et al. 2002), a group of Dutch researchers found an incidence of 7.8 % of
ASD among a sample of children and adolescents referred to a gender identity clinic
for management of their GD (N = 204, Mage = 10.8 years, SD = 3.58). This rate is
much higher than the prevalence rate of ASD in the general population which ranges
from 0.6 % to 2 % (Fombonne 2005; Blumberg et al. 2013). Similarly, employing
the Autism Spectrum Quotient (AQ, Baron-Cohen et al. 2003), a standardized test
to measure autistic characteristics, Jones et al. (2012) demonstrated that 14.8 % of
female adults with GD (N = 61) and 3 % of male adults with GD (N = 198) met the
criteria for a potential diagnosis of ASD, while Pasterski et al. (2014) also testified
to the ASD-GD association among adults in their sample, where 7.1 % of the
females with GD (N = 28) and 4.7 % of males with GD (N = 63) met diagnostic cri-
teria according to the recommended cutoff scores on the AQ.
While some research has assessed for ASD traits in a population referred for GD,
newer research by Strang et al. (2014) measured gender variance, defined as the
desire to be the opposite gender, in a population of children with ASD (N = 147). On
analyzing parental responses to the item “Wishes to be the opposite sex” on the
Child Behavior Checklist (CBCL), gender variance was 7.59 times higher in the
ASD group than in the non-ASD participants, which comprised of a community
sample (N = 165) and normative data from the non-referred standardization sample
of the CBCL (N = 1,605). Bejerot and Eriksson (2014) similarly demonstrated a
gender-atypical pattern (males were less masculine and females were less feminine)
in their sample of 50 adults with ASD when compared to 53 typically developing
individuals.
George and Stokes (submitted) measured gender-dysphoric symptomology in an
international population of adults diagnosed with ASD (N = 220), using a mixed
methods approach. In their quantitative study, using the Gender Dysphoria and
Gender Identity Questionnaire (GIDQ-AA, Deogracias et al. 2007), results demon-
strated that individuals with ASD were significantly more likely to report experienc-
ing gender-dysphoric symptoms than were typically developing individuals
(Cohen’s d = 0.63). In a subsequent qualitative analysis investigating gender-related
attitudes among 94 adults with ASD, female participants reported that it was easier
to identify with males and that they were not like other women in that “vulnerabil-
ity, nurturing and intimacy is not natural to me” and that men were more “straight-
forward, easier to understand,” “blunt,” and “did not bother with emotional stuff.”
Male participants also conceded to feeling “sensitive, shy and introverted,” “not
fitting the typical male stereotype,” and not enjoying sports and “stereotypical male
socializing activities” but divulged that their disconnection from other men was not
primarily due to gender issues, but due to ASD-related issues. Taken together, an
androgynous self-concept, gender ambivalence, and dissatisfaction with culturally
dictated gender roles emerged as dominant themes in the discourse.
3 Why Would Gender Dysphoria Be More Prevalent

in ASD?
3.1 Hormonal Factors and GD
The coexistence of ASD and GD is worth noting as the prevalence of both condi-
tions is reasonably low. Reasons for this comorbidity have been a topic of emerging
interest, and several plausible speculations have been proposed to account for this
association. Some researchers have hypothesized that perhaps ASD is the driver that
predisposes some individuals to GD (Kraemer et al. 2005). A neurobiological
mechanism might provide some explanation. The “extreme male brain” theory of
ASD (Baron-Cohen 2002) argues that fetal testosterone or fT is a strong candidate
for contributing to sexually dimorphic cognition and behavior and may present a
risk factor for conditions characterized by social impairments, such as ASD
(Knickmeyer and Baron-Cohen 2006), where individuals with ASD may demon-
strate characteristics generally associated with masculinity, such as an overdevelop-
ment of logical thinking, low emotionality, and high level of perseverance. Elevated
levels of fT are positively correlated with autistic traits and with masculinizing neu-
ral development (Auyeung et al. 2009). The hypothesis that fT levels influence
human sexual behavior derives from a large body of research on the neural and
behavioral effects of early hormone manipulations among rodents and nonhuman
primates (Hines et al. 2004). Castrated males show feminized cognition and behav-
iors, while conversely females treated with testosterone show corresponding mascu-
linization (Knickmeyer et al. 2005; Berenbaum et al. 2009).
Information on the influence of fT on neural and behavior development in
humans may be derived from clinical literature where the amount or activity of
fT is disrupted, such as among women with congenital adrenal hyperplasia
(CAH) and men with complete androgen insensitivity syndrome (CAIS). The
prenatal exposure to unusually high levels of fT among girls with CAH is hypoth-
esized to influence sexual development. Girls with CAH show increased male-
typical play behaviors (Hines et al. 2004), masculinized gender identities
(Dessens et al. 2005), and homosexual and bisexual orientations (Meyer-
Bahlburg et al. 2008). Interestingly, an increased number of autistic traits as
measured on the AQ were also noted in this group (Knickmeyer et al. 2006). The
opposite pattern of a female-typical psychosexual development is demonstrated
by men with CAIS, an X-linked disorder characterized by a complete absence of
functional androgen receptors (Hines et al. 2004). These pathways provide an
explanation for GD among females with ASD; the predisposing dual role of ele-
vated levels of fT in ASD and in male gender identity development (Gooren
2006) points to one possible neurohormonal explanatory pathway for the co-
occurrence of GD and ASD among females, where a primarily masculine cogni-
tion and self-perception in ASD may be lead females with ASD to interpret
themselves as masculine relative to their same-sex peers, and this then could
pave the way to the development of GD.
However, when viewed through the same theoretical lens, elevated fT levels do
not provide a very forthright explanation for increased rates of GD among males
within ASD. Higher levels of fT would be expected to hypermasculinize the male
brain and thus allow for a pronounced male gender identity. Given the association
between elevated levels of fT in ASD, why then would males with ASD demon-
strate higher rates of GD, when the converse would be expected or, at the least, simi-
lar rates of GD among ASD and TD males?
MacCulloch and Waddington (1981) and Pillard and Weinrich (1987) have sug-
gested that human sexual orientation depends on, among other factors, differences
in the degree of in utero masculinization and behavioral defeminization of the brain,

where the “default brain” is believed to be female. Support for such a model comes
from observations on gender-dependent cognitive abilities that are mostly female-
like in homosexual males (Robinson and Manning 2000). Research into the exis-
tence of neuroendocrinological differences between homosexual and heterosexual
men may be reflective of a partially female-differentiated neural circuitry in homo-
sexual males (Dorner et al. 1975; Gladue et al. 1984). While this finding has
prompted the assumption that homosexual males have been exposed to low levels of
fT, a number of researchers have challenged this idea (McFadden and Champlin
2000; Rahman and Wilson 2003; Williams et al. 2000; Jenkins 2010). Studies look-
ing into somatic features such as finger length ratios (Robinson and Manning 2000)
and male genitalia proportions (Bogaert and Hershberger 1999) tend to support the
conclusion that elevated levels of prenatal testosterone might predispose the male
fetus to homosexuality.
More recent literature has found a relationship between another sexually dimor-
phic sex hormone, the anti-Müllerian hormone (AMH), and ASD, where lower lev-
els of AMH have been associated with increased ASD symptoms in males (Pankhurst
and McLennan 2012). AMH is believed to play a role in the masculinization of or
the defeminization of the male fetus (Behringer et al. 1994), and whether lower
levels of AMH contribute in any way to a less masculinized brain, which could then
lend itself to a higher risk for gender dysphoria, has not yet been researched, but
provides a promising avenue for future research.
Given the shared pathways between elevated fT and ASD, elevated fT and
male homosexuality, the predilection for a higher rate of female-type cogni-
tion, and behaviors among male homosexuals, together with the higher preva-
lence rates of male homosexuality in ASD (George and Stokes submitted),
perhaps the correlations between the different variables in this biological
model could provide one possible instructive pathway for the high rates of GD
among ASD males.
To limit a construct as complex as gender identity to biological factors would be
overly reductionistic. While there is no consensus in the scientific community on
why a person develops a particular gender identity (American Psychological
Association, 2013), an individual’s gender identity would most likely be an interac-
tion of their physiology with their social environment. Specifically, certain features
characteristic to ASD may increase the risk for GD (VanderLaan et al. 2015).
3.2 ASD-Specific Features and GD
The general consensus among researchers looking into the ASD-GD association
was that “autistic-like” traits were possibly driving GD. It is speculated that sensory
issues characteristic of ASD may hinder what is perceived as normative gendered
behavior. Categorizing individuals into a binary gender system on the conjecture of
clothing may not be of much relevance to many individuals with ASD, where the
primary focus may sometimes be on a preference for specific sensory input, featural
details, or tactile sensation (Tateno et al. 2008; de Vries et al. 2010) and not social
norms. Consistently, in George and Stokes’s (submitted) study, male responses indi-
cated that they preferred softer, glittery, and silkier fabrics, not because they were
“girly” clothes, but because “of my autism.” Female responses similarly suggested
that “girly clothes were tight and itchy,” “makeup felt terrible,” and “men’s clothes
were comfortable, straightforward, and practical.”
Communication difficulties are characteristic of ASD, and some individuals with
ASD may have challenges recognizing gender due to linguistics. Since gender relies
on semantic factors (Eckert and McConnell-Ginet 2003; Labov 2011), language
delays during childhood may also interfere with a developing sense of gender-
related discourse, where, without words for “boy-girl,” “pink-blue,” or “trucks-
dolls,” for example, or without employing these words in appropriate contexts, one
may not develop a clear understanding of gendered behavior.
It has been suggested that another ASD-specific feature that may play a role
in the ASD-GD association is the frequent presence of obsessive compulsive
behaviors in ASD (Gallucci et al. 2005). The DSM-5 includes intense/obses-
sional interests and repetitive behaviors as part of the diagnostic criteria for ASD,
and pharmacological studies have created a compelling argument for the associa-
tion between ASD and obsessive compulsive disorder (Hollander et al. 2006).
Thus, a rather intriguing speculation is that in some individuals with ASD, GD
may develop as a sequel to ASD, where one’s unusual preoccupations with cross-
gender activities and objects may not be related to gender identity confusion in
the truest sense, but may just be part of the symptomology of ASD. Findings
reported by the VanderLaan et al. (2015) study are consistent with this argument.
They found that a sample of 534 children clinically referred for GD showed an
elevation in intense and obsessional interests on responses to an item on the
CBCL which measures obsessions and compulsions, when compared to CBCL
clinic-referred and non-referred standardization samples. The pervasive preoc-
cupations and distress with cross-gender roles, restricted related interests, and
sometimes ritualized behavior seen in clients with GD could be one manifesta-
tion of obsessive behaviors inherent to ASD, and other researchers have agreed
to this (Landén and Rasmussen 1997; Perera and Gadambanathan 2003; Gallucci
et al. 2005).
3.3 Gender Is Socio-Rhetorical
Gender identity typically forms around 3–4 years of age and is considered a social
developmental marker (Robinow 2009). Literature has reliably demonstrated that
early positive social interactions are critical to the development of a fund of higher-
order social skills (Parker and Asher 1993), which in turn is pivotal to the develop-
ment and healthy expression of gender and sexuality (Gagnon and Simon 2011;
Rees et al. 2006). Given that impaired social functioning is a hallmark feature of
ASD, the establishment of a gender identity could become complex. Additionally,
drawing on the theory of mind in relation to autism, deficits with empathy and
imagination may further hinder the development of a view of oneself as belonging

to a gender group (Happé and Frith 1995).
Abelson (1981) indicated that the establishment of gender identity in children
with autism appeared to be a function of their social communication. He went on
to stress that achieving gender identity is a critical milestone for children as this
would then go on to facilitate forming effective emotional bonds with their identi-
fied gender group, which would then help forge meaningful and appropriate social
relationships. A rather vicious circle is speculated here, where deficiencies in
their social skills raise challenges for the child with ASD to come to a clear under-
standing of their gender identity, and then a fragmented or dysfunctional gender
identity interferes with the child’s integration into their own gender group, plac-
ing them at a disadvantage to develop healthy social bonds with their peers.
However, it must be stressed that, clearly, not all children with ASD struggle with
their gender identity and many go on to have a clear understanding of their gender
(Abelson 1981).
Accordingly, on investigating attitudes of individuals with ASD to gender iden-
tity, George and Stokes (submitted) found that 83 % of the responses from males
and 94 % of responses from females indicated that gender was conceptualized as a
socio-rhetorical system. Participants shared that the system was not always straight-
forward to negotiate for the individual with ASD and that gender would best be
described as “fluid, a socially restrictive label, confusing, outdated, and irrelevant to
their personal identity.” Furthermore, many participants shared sentiments on being
more content with a “genderless society.” Other authors diagnosed with ASD shared
similar sentiments and confessed that their “nervous system is configured differ-
ently” (Golubock 2003) and that their wiring just would not “understand, interpret,
and perform gender-typing” effortlessly and without conflict and conceded to
“gender-blindness” (Meyerding 2003). Perhaps then, examining gender from the
perspective of someone with ASD licenses a denaturalization of social norms and
expectations.
4 Management of GD
While for many individuals with ASD, a gender-fluid lifestyle may not hinder
social, mental, and occupational functioning, for some the incongruence between
their perceived gender identity and their birth sex could develop into a GD, as was
evident in the increased number of ASD diagnoses among clients referred to gender
clinics for clinical management (Jones et al. 2012; Pasterski et al. 2014). This is
understandable, given that the rigid thinking styles characteristic of ASD would not
lend itself to a dissonance between one’s thoughts and their behavior. George and
Stokes (submitted) similarly found significantly higher scores on their GD survey
among ASD participants; three individuals scored over the cutoff point, warranting
a diagnosis of GD. This rate of 1.4 % was much higher than found in the general
population, approximately 560 times higher than the prevalence rates in the wider
population.
Living with GD can be extremely distressing to the individual, and treatment is

generally aimed at alleviating this distress by helping the individuals with GD live
their lives the way they would like to, in their preferred gender identity. What this
means would vary from person to person and thus management of GD is undertaken
on a case to case basis. For individuals under the age of 18 years of age, a multidis-
ciplinary team, comprising specialists from the mental health profession and pedi-
atric endocrinologists, is called upon to provide assistance to the child and the
family. For children under the age of 12, support provided is mostly psychological,
rather than medical or surgical. This is because in most gender-dysphoric children,
GD will cease when they reach puberty (Wallien and Cohen-Kettenis 2008).
Psychological support offers children and their families a chance to discuss their
thoughts and receive support to help them emotionally cope with their distress,
without rushing into more drastic treatments.
However, if GD persists into adolescence, hormonal treatment is commenced
sometimes with gonadotropin-releasing hormone (GnRH) analogs, which suppress
pubertal hormones responsible for bringing about physical changes to the body
related to one’s biological sex (Hembree et al. 2009). GnRH can aid with the delay
of these potentially distressing physical changes until the individual with GD is old
enough for more radical treatment options. Treatment with GnRH is reversible and
gives the young person time to consider their choices and make informed decisions
regarding their future course.
Once the young person reaches the age of 18, management will be transferred to
gender identity clinics that specialize in support and treatment of adults with GD
(Hembree et al. 2008). At this stage, both the individual and the medical team are
more confident in their course of action, and permanent pharmacological treatment
such as masculinizing or feminizing hormones and surgical treatment through sex-
ual reassignment are available to alter the individual’s physical appearance to fur-
ther line up with their gender identity.
However, when an individual with GD presents with co-occurring ASD, the
level of complexity in terms of clinical management increases, owing to the comor-
bid presence of symptoms of both GD and ASD. In treating the GD, the ASD will
need to be taken into account, and disentangling whether the GD is indeed a sepa-
rate condition and not related to ASD-related symptoms remains a challenge to
provide individuals with comorbid ASD and GD with proper care (De Vries et al.
2010). Having a diagnosis of ASD need not affect whether the individual continues
on their chosen path for sexual reassignment surgery but, considering the diagno-
sis, may assist the individual in examining the motives behind their choices and
accordingly make better informed decisions about treatment and physical
mediations.
Conclusions
Possibly the most fundamental characteristic of a person’s identity is their gender,
which conceivably deeply influences every part of one’s life. In a society where this
crucial aspect of self has been so narrowly defined and rigidly enforced, individuals
who exist outside its norms likely face innumerable challenges and can become
targets of disapproval. An individual diagnosed with ASD and experiencing GD

would understandably bear a significant burden of distress, and George and Stokes
(submitted) found levels of depression, anxiety, and stress positively correlated with
the levels of GD symptomology reported by individuals with ASD.
Gender is possibly the one most intensively socialized construct, with many
“rules” that are not explicit, and while these gendered norms are typically reflex-
ively embodied by most persons, it is reasonable that gender may be somewhat
challenging for some individuals with ASD. The confusion of navigating within this
milieu may manifest as GD in some cases of individuals with ASD, when it might
be an ASD identity versus a neurotypical identity that may be at the core of their
identity issue, rather than a clear desire for a cross-gendered lifestyle. Indeed, this
tension could contribute to the development of a true GD. Equally tenable is the
possibility that ASD may share a common pathway with the pathophysiology of
GD, an avenue that requires careful empirical clarification.
GD is overrepresented in ASD when compared to the general population. While
we cannot say with any certainty that gender identity is impervious to biological
influences or that gender identity is free of social influences, we suggest that the
relative balance of biological and social influences may be more variant and syner-
gistic, on average, for individuals with ASD than for TD individuals.
References
Abelson AG (1981) The development of gender identity in the autistic child. Child Care Health
Dev 7(6):347–356
American Psychiatric Association (2013) Diagnostic and statistical manual of mental disorders
(5th ed.).
Auyeung B, Baron‐Cohen S, Ashwin E, Knickmeyer R, Taylor K, Hackett G (2009) Fetal testos-
terone and autistic traits. Br J Psychol 100(1):1–22
Baron-Cohen S (2002) The extreme male brain theory of autism. Trends Cogn Sci 6(6):248–254
Baron-Cohen S, Richler J, Bisarya D, Gurunathan N, Wheelwright S (2003) The systemizing
quotient: an investigation of adults with Asperger syndrome or high–functioning autism, and
normal sex differences. Philos Trans R Soc Lond B: Biol Sci 358(1430):361–374
Behringer RR, Finegold MJ, Cate RL (1994) Müllerian-inhibiting substance function during mam-
malian sexual development. Cell 79(3):415–425
Bejerot S, Eriksson JM (2014) Sexuality and gender role in autism spectrum disorder: a case con-
trol study. PLoS One 9(1):e87961
Berenbaum SA, Bryk KK, Nowak N, Quigley CA, Moffat S (2009) Fingers as a marker of prenatal
androgen exposure. Endocrinology 150(11):5119–5124
Blumberg SJ, Bramlett MD, Kogan MD, Schieve LA, Jones JR, Lu MC (2013) Changes in preva-
lence of parent-reported autism spectrum disorder in school-aged US children: 2007 to 2011–
2012. Natl Health Stat Rep 65(20):1–7
Bogaert AF, Hershberger S (1999) The relation between sexual orientation and penile size. Arch
Sex Behav 28(3):213–221
De Vries AL, Noens IL, Cohen-Kettenis PT, van Berckelaer-Onnes IA, Doreleijers TA (2010)
Autism spectrum disorders in gender dysphoric children and adolescents. J Autism Dev Disord
40(8):930–936
Deogracias JJ, Johnson LL, Meyer-Bahlburg HF, Kessler SJ, Schober JM, Zucker KJ (2007) The
gender identity/gender dysphoria questionnaire for adolescents and adults. J Sex Res
44(4):370–379
Dessens AB, Slijper FM, Drop SL (2005) Gender dysphoria and gender change in chromosomal
females with congenital adrenal hyperplasia. Arch Sex Behav 34(4):389–397
Dörner G, Rohde W, Stahl F, Krell L, Masius WG (1975) A neuroendocrine predisposition for
homosexuality in men. Arch Sex Behav 4(1):1–8
Eckert P, McConnell-Ginet S (2003) Language and gender. Cambridge University Press
Fombonne E (2005) The changing epidemiology of autism. J Appl Res Intellect Disabil
18(4):281–294
Gagnon JH, Simon W (2011) Sexual conduct: The social sources of human sexuality. Transaction
Publishers, Piscataway
Gallucci G, Hackerman F, Schmidt CW Jr (2005) Gender identity disorder in an adult male with
Asperger’s syndrome. Sex Disabil 23(1):35–40
George R, Stokes MA (submitted) Sexual orientation and gender-identity among high functioning
individuals with autism spectrum disorder
Gladue BA, Green R, Hellman RE (1984) Neuroendocrine response to estrogen and sexual orien-
tation. Science 225(4669):1496–1499
Golubock S (2003) Different on the inside. In: Miller JK (ed) Women from another planet? Our
lives in the universe of autism. 1st Books Library, Fairfield, pp 157–70, Print
Gooren L (2006) The biology of human psychosexual differentiation. Horm Behav 50(4):589–601
Happé F, Frith U (1995) Theory of mind in autism. In: Learning and cognition in autism. Springer
US, pp 177–97
Hembree WC, Cohen-Kettenis P, Delemarre-van de Waal HA, Gooren LJ, Meyer III WJ,
Spack NP, Tangpricha V, Montori VM (2009) Endocrine treatment of transsexual persons:
an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 94(9):
3132–3154
Hines M, Brook C, Conway GS (2004) Androgen and psychosexual development: core gender
identity, sexual orientation, and recalled childhood gender role behavior in women and men
with congenital adrenal hyperplasia (CAH). J Sex Res 41(1):75–81
Hollander E, Soorya L, Wasserman S, Esposito K, Chaplin W, Anagnostou E (2006) Divalproex
sodium vs. placebo in the treatment of repetitive behaviours in autism spectrum disorder. Int
J Neuropsychopharmacol 9(02):209–213
Jenkins WJ (2010) Can anyone tell me why I’m gay? What research suggests regarding the origins
of sexual orientation. N Am J Psychol 12(2):279
Jones RM, Wheelwright S, Farrell K, Martin E, Green R, Di Ceglie D, Baron-Cohen S (2012)
Brief report: female-to-male transsexual people and autistic traits. J Autism Dev Disord
42(2):301–306
Knickmeyer RC, Baron-Cohen S (2006) Topical review: fetal testosterone and sex differences in
typical social development and in autism. J Child Neurol 21(10):825–845
Knickmeyer RC, Wheelwright S, Taylor K, Raggatt P, Hackett G, Baron-Cohen S (2005) Gender-
typed play and amniotic testosterone. Dev Psychol 41(3):517
Knickmeyer R, Baron-Cohen S, Fane BA, Wheelwright S, Mathews GA, Conway GS, Brook CG,
Hines M (2006) Androgens and autistic traits: A study of individuals with congenital adrenal
hyperplasia. Horm Behav 50(1):148–53. Epub 2006 Apr 19
Kraemer B, Delsignore A, Gundelfinger R, Schnyder U, Hepp U (2005) Comorbidity of Asperger
syndrome and gender identity disorder. Eur Child Adolesc Psychiatry 14(5):292–296
Labov W (2011) Principles of linguistic change, cognitive and cultural factors, (Vol. 3). John
Wiley & Sons
Landén M, Rasmussen P (1997) Gender identity disorder in a girl with autism—a case report. Eur
Child Adolesc Psychiatry 6(3):170–173
Leekam SR, Libby SJ, Wing L, Gould J, Taylor C (2002) The diagnostic interview for social and
communication disorders: algorithms for ICD‐10 childhood autism and wing and Gould autis-
tic spectrum disorder. J Child Psychol Psychiatry 43(3):327–342
MacCulloch MJ, Waddington JL (1981) Neuroendocrine mechanisms and the aetiology of male
and female homosexuality. Br J Psychiatry 139(4):341–345
McFadden D, Champlin CA (2000) Comparison of auditory evoked potentials in heterosexual,
homosexual, and bisexual males and females. J Assoc Res Otolaryngol 1(1):89–99
Meyer-Bahlburg HF, Dolezal C, Baker SW, New MI (2008) Sexual orientation in women with
classical or non-classical congenital adrenal hyperplasia as a function of degree of prenatal
androgen excess. Arch Sex Behav 37(1):85–99
Meyerding J (2003) Growing up genderless. In: Miller JK (ed) Women from another planet? Our
lives in the universe of autism. 1st Books Library, Fairfield, pp 157–70, Print
Mukaddes NM (2002) Gender identity problems in autistic children. Child Care Health Dev
28(6):529–532
Paikoff RL, Brooks-Gunn J (1991) Do parent-child relationships change during puberty? Psychol
Bull 110(1):47
Pankhurst MW, McLennan IS (2012) Inhibin B and anti-Müllerian hormone/Müllerian-inhibiting
substance may contribute to the male bias in autism. Transl Psychiatry 2(8):e148
Parker JG, Asher SR (1993) Friendship and friendship quality in middle childhood: links with peer
group acceptance and feelings of loneliness and social dissatisfaction. Dev Psychol 29(4):611
Pasterski V, Gilligan L, Curtis R (2014) Traits of autism spectrum disorders in adults with gender
dysphoria. Arch Sex Behav, 43(2):387–393
Perera H, Gadambanathan T, Weerasiri S (2003) Gender identity disorder presenting in a girl with
Asperger’s disorder and obsessive compulsive disorder. Ceylon Med J 48(2):57–58
Pillard RC, Weinrich JD (1987) The periodic table model of the gender transpositions: part I. A
theory based on masculinization and defeminization of the brain. J Sex Res 23(4):425–454
Rahman Q, Wilson GD (2003) Sexual orientation and the 2nd to 4th finger length ratio: evidence
for organising effects of sex hormones or developmental instability? Psychoneuroendocrinology
28(3):288–303
Rees AM, Doyle C, Miesch J. Sexual orientation, gender role expression, and stereotyping: the
intersection between sexism and sexual prejudice (homophobia). Vistas 2006 Online
Robinow O (2009) Paraphilia and transgenderism: a connection with Asperger’s disorder? Sex
Relatsh Ther 24(2):143–151
Robinson SJ, Manning JT (2000) The ratio of 2nd to 4th digit length and male homosexuality. Evol
Hum Behav 21(5):333–345
Rosenfield A, Wasserman S (1993) Sexual development in the early school-aged child. Child
Adolesc Psychiatr Clin N Am 2:393–406
Strang JF, Kenworthy L, Dominska A, Sokoloff J, Kenealy LE, Berl M, … Wallace GL (2014)
Increased gender variance in autism spectrum disorders and attention deficit hyperactivity dis-
order. Arch Sex Behav 43(8):1525–1533
Tateno M, Tateno Y, Saito T (2008) Comorbid childhood gender identity disorder in a boy with
Asperger syndrome. Psychiatry Clin Neurosci 62(2):238–238
VanderLaan DP, Postema L, Wood H, Singh D, Fantus S, Hyun J, … Zucker KJ (2015) Do children
with gender dysphoria have intense/obsessional interests?. J Sex R 52(2):213–219
Wallien MS, Cohen-Kettenis PT (2008) Psychosexual outcome of gender-dysphoric children.
Williams PG, Allard AM, Sears L (1996) Case study: cross-gender preoccupations with two male
children with autism. J Autism Dev Disord 26(6):635–642
Williams TJ, Pepitone ME, Christensen SE, Cooke BM, Huberman AD, Breedlove NJ, …
Breedlove SM (2000) Finger-length ratios and sexual orientation. Nature 404(6777):455–456
Zucker KJ, Lawrence AA (2009) Epidemiology of gender identity disorder: recommendations for
the standards of care of the world professional association for transgender health. Int
J Transgenderism 11(1):8–18
Index
A diagnosis and evaluation, 81–82

Acetylserotonin O-methyltransferase neurobiological bases and genetic
(ASMT), 119–120 overlap, 82–83
Anti-Müllerian hormone (AMH), 144 non-pharmacological treatments, 84
Antipsychotic drugs (APD), 59 novel treatment strategies, 84–85
Anxiety, 7, 115, 121, 131 pharmacological treatment, 83–84
assessment tools, 25–29 prevalence, 80
child and family well-being, 21 Autism Comorbidity Interview-Present and
fear of social situations, 24 Lifetime Version (ACI-PL), 27
loud sounds/mechanical noises, 21 Autism Diagnostic Observation Schedule
neurobiological bases, 26, 30 (ADOS), 69
non-ASD populations, 25 “Autism MEAL Plan,” 74
non-medical treatments, 30–31 Autism spectrum disorder (ASD)
novel treatment strategies, 31–32 ADHD (see Attention-deficit
pharmacological treatments, 31 hyperactivity disorder (ADHD))
phenomenology and clinical issues anxiety (see Anxiety)
clinical variability, 23 FEDs (see Feeding and eating disorders
communication difficulties, 23 (FEDs))
emotional regulation, 25 mood disorders (see Mood disorders)
fears of change/novelty, 23 repetitive behavior
hypersensitivity, sensory stimuli, 23 cognitive functioning and language
restlessness and phobias, 23 skills, 44
ritualistic behaviors, 22 CYBOCS-ASD, 44, 45
social avoidance/withdrawal, 22 factor analysis, 43
social cognition processes, 23 lower order behaviors, 43
prevalence, 22 obsessions/preoccupation, 46
quality of life, 21 Repetitive Behavior Scale-Revised, 43
repetitive behaviors, 25 self-injurious behavior, 44
school-aged children and adolescents, 24 selective serotonin reuptake inhibitors,
self-injury and depression, 25 46–47
sensory modulation problems, 25 self-injurious behaviors, 97
social communication impairments, 25 sensory processing abilities, 97
Anxiety Disorder Interview Schedule for SSD (see Schizophrenia spectrum
DSM-IV-Child and Parent disorders)
Versions (ADIS), 27 stereotyped behaviors, 97
Asperger syndrome (AS), TS (see Tourette syndrome (TS))
2, 58, 80, 94, 122, 132 Autism Spectrum Disorders-Comorbid
Attention-deficit hyperactivity disorder for Children (ASD-CC), 27
(ADHD), 9, 40, 115, 116 Autism Spectrum Quotient (AQ), 69

Autism Spectrum Disorder, DOI 10.1007/978-3-319-29695-1
152 Index
B phenomenology and clinical issues,

Baby and Infant Screen for Children with 70–71
Autistic Traits (BISCUIT), 27 treatment, 73–74
BAP. See Broader autism phenotype (BAP) Food Frequency Questionnaire (FFQ), 71
Behavioral Assessment System for
Children-2 (BASC-2), 28
Broader autism phenotype (BAP), 132 G
GD. See Gender dysphoria (GD)
Gender dysphoria (GD)
C ASD-specific features, 144–145
Catatonia, 6 and autism spectrum disorder, 140–142
Child Behavior Checklist (CBCL), 28, 142 clinical management, 146–147
Children’s Depression Inventory (CDI), 7 gender identity, 145–146
Children’s Depression Rating Scale-Revised hormonal factors, 142–144
(CDRS-R), 7 “sex” and “gender,” 139–140
Children’s Yale-Brown Obsessive-Compulsive Gonadotropin-releasing hormone
Scales for ASD (CYBOCS-ASD), (GnRH), 147
44, 45
Cognitive-behavioral therapy (CBT), 10
Cognitive remediation therapy (CRT), 73 H
Complete androgen insensitivity syndrome High-functioning autism (HFA), 2
(CAIS), 143 Hyperserotonemia, 10
Comprehensive Assessment of the At-Risk
Mental State (CAARMS), 56
Congenital adrenal hyperplasia (CAH), 143 I
Intellectual disability (ID),
2, 24, 70, 97, 112, 113, 115, 121
D Intelligence quotient (IQ), 2
Diagnostic and Statistical Manual-5th edition Interictal epileptiform discharges (IEDs),
(DSM-5), 6 116, 117
Diagnostic Assessment for the Severely
Handicapped-II (DASH-II), 29
Diagnostic Interview for Social and M
Communication Disorders Melatonin, 112–114, 117, 119–122
(DISCO), 55 Mindfulness-based therapy (MBT), 11
Diagnostic Interview Schedule for Mood disorders
Children IV (DISC IV), 27 catatonia, 6
cognitive ability, 5
diagnosis and evaluation, 6–8
E genetic overlap, 8–9
Early Child Inventory-5 (ECI-5), 28 non-medical treatments, 10–11
European ADHD Guidelines Group pharmacological interventions, 11–12
(EAGG), 84 phenomenology and clinical issues
“Extreme male brain” theory, 143 age of onset, 3
bipolar disorders, 4
in children, 4
F clinical symptom, 3
Feeding and eating disorders (FEDs) depressive symptoms, 3
atypical eating behaviors and food stressors and negative life events, 4
selectivity, 68–69 in youth, 5
autistic traits, 69 prevalence, 2–3
diagnosis and evaluation, 71–72 serotonin, role of, 9–10
neurobiological bases and genetic Multidimensional Anxiety Scale for
overlap, 72–73 Children (MASC), 28
Index 153
O neurobiological risk factors

Obsessive-compulsive disorder (OCD) dopamine disruption, 58
in children, 40 Mu suppression, 58
comorbidity, 40 social cognition, 57
obsessions/preoccupation, 46 social deficits, 58
prevalence, 41 socio-emotional tasks, 58
repetitive behavior non-medical treatments, 60
compulsive handwashing, 42 novel treatment strategies, 60–61
DSM-5, 41 pharmacological interventions, 59–60
germ contamination fears, 42 phenomenology and clinical issues
intrusive thoughts/images, 41 atypical developmental
motor sequence, 42 trajectories, 54
negative reinforcement model, 42 communication deficits, 54
symptom clusters, 43 hallucinatory experiences, 53
tic-like compulsions, 42 neurodevelopmental abnormalities, 52
trichotillomania and skin-picking psychotic experiences, 54
disorder, 41 rates of co-occurrence, 53
Oxytocin (OXT), 10, 60, 73 social interaction and communication,
53
theory of mind and mentalising
P impairments, 54
Personality disorders (PDs) prevalence, 52
clinical issues, 130–132 Schizotypal PD (SPD), 132, 135
comorbidity, 130–132 Screening for Childhood Anxiety and
definition, 129 Related Emotional Disorders
phenomenology, 130–132 (SCARED), 28
prevalence, 130 Second-generation antipsychotics
treatment (SGAs), 12, 59
nonmedical interventions, 133 Selective serotonin reuptake inhibitors
pharmacological interventions, (SSRIs), 10, 46–47
133–134 Sleep disorders
Psychiatric comorbidity, 2, 3 ASMT, 119–120
ADHD, 115, 116 chronic insomnia, 111
hypervigilance/hyperarousal, 115 diagnosis and evaluation, 117–119
IEDs, 116, 117 melatonin, 119
pathogenesis and implications, phenomenology and clinical issues,
114–115 113–114
RBD, 116 prevalence, 112–113
Psychopathology in Autism Checklist psychiatric comorbidity
(PAC), 7, 29 ADHD, 115, 116
hypervigilance/hyperarousal, 115
IEDs, 116, 117
R pathogenesis and implications,
Randomized control trial (RCT), 11, 83 114–115
REM sleep behavior disorder (RBD), 116 RBD, 116
Revised Children’s Anxiety and treatment
Depression Scale (RCADS), 29 pharmacological intervention,
121–123
sleep hygiene and behavioral
S therapy, 120–121
Schizophrenia spectrum disorders (SSD) vs.ASD, 112
comorbidity, 55 Spence Children’s Anxiety Scale
diagnosis and evaluation, 55–56 (SCAS)/Spence Preschool
genetic risk factors, 56–57 Anxiety Scale, 28
154 Index
T pharmacological interventions, 105–106

Tourette syndrome (TS), 40 phenomenology and clinical issues, 95–96
basal ganglia, role of, 100–101 prevalence
BG anatomy and functional circuitry epidemiological features, 94
and projections, 101–102 familial and genetic findings, 95
diagnosis and evaluation, 98–99 incidence rates, 94
genetics, 102–104 symptomatology, 97–98
motor and phonic tics, 93
neuropathological similarities,
99–100 V
nonmedical treatments, 104–105 Video-polysomnographic recording, 117

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Psychiatric Symptoms

Psychiatric Symptoms and

ISBN 978-3-319-29693-7 ISBN 978-3-319-29695-1 (eBook)

Library of Congress Control Number: 2016940095

© Springer International Publishing Switzerland 2016

Printed on acid-free paper

This Springer imprint is published by Springer Nature

1 Mood Disorders and Autism Spectrum Disorder. . . . . . . . . . . . . . . . . . . 1

development in terms of progressive appearance of clinical symptoms and impact of

Rome, Italy Luigi Mazzone

5. Dawson G, Rogers S, Munson J, Smith M, Winter J, Greenson J, Donaldson A, Varley J

Behavioral problems, which are often linked to psychiatric disorders in comorbidity

© Springer International Publishing Switzerland 2016 1

3 Phenomenology and Clinical Issues

Autistic symptoms can mask psychiatric disorders in comorbidity, and thereby

4 Peculiar Features of Mood Disorders in ASD

4.1 Relation Between Cognitive Ability and Mood Symptoms

4.2 Co-occurrence of Catatonia as an Exacerbation of Mood

5 Diagnosis and Evaluation: Assessment Tools

The assessment of mood symptoms in this clinical population is particularly com-

only four tools were specifically developed to assess comorbid psychopathology in

In fact, literature studies report a lack of correspondence between self-report

6 Neurobiological Bases for the Relation Between ASD

6.1 Genetic Overlap Between ASD and Mood Disorders

6.2 The Role of Serotonin in Autism and Mood Disorders

7.1 Non-medical Treatments

Some evidence is reported on the psychotherapy treatments for mood disorders in

the application of CBT interventions, implemented through individual- or group-

7.2 Pharmacological Interventions

Data on the pharmacological intervention in individuals with ASD and comorbid

8 Discussion and Future Directions

aggression in youth with pervasive developmental disorders. J Child Adolesc Psychopharmacol

Skeppar P, Thoor R, Sture A, Isakson A, Skeppar I, Persson B, Fitzgerald M (2013)

© Springer International Publishing Switzerland 2016 21

3 Phenomenology and Clinical Issues

In many autobiographical accounts of individuals with ASD, the experience of

4 Correlates of Anxiety in ASD

In the typical population, the presentation of anxious symptoms is tied to normative

5 Diagnosis and Evaluation: Assessment Tools

The diagnosis of anxiety disorders in people with ASD is complicated by a number

are an important source of information in assessing symptoms and tailoring treat-

6 Neurobiological Bases of Anxiety in ASD

Table 2.1 Anxiety Assessment Tools

Shaffer et al. 2000) separation anxiety disorder, Muris et al. 1998)

Name (reference) Reporter Sub-scales Designed for ASD? Age group

Name (reference) Reporter Sub-scales Designed for ASD? Age group

7 Treatment of Anxiety in ASD

7.1 Non-medical Treatments

7.2 Pharmacological Treatments

7.3 Novel Treatment Strategies

Another somewhat promising avenue for novel treatments of anxiety in ASD is

8 Conclusions and Future Directions

Lawrence Scahill and Saankari A. Challa

L. Scahill (*) • S.A. Challa

© Springer International Publishing Switzerland 2016 39

3 Prevalence of OCD in ASD

4 Repetitive Behavior in OCD

Obsessive-compulsive disorder is defined by the presence of recurrent intrusive

history, and gene association studies and studies on moderators of treatment