Review article 95
Neurodevelopmental and psychiatric issues in Down’s
syndrome: assessment and intervention
Stefano Vicaria, Maria Pontilloa and Marco Armandoa,b,c
Down’s syndrome (DS) is the most frequent genetic cause
of intellectual disability and patients with DS show
significant psychopathology (18–23%). Moreover,
individuals with DS often show a cognitive decline
associated with ageing characterized by a deterioration in
memory, language and cognitive functioning. According
to these relevant findings, an overview is presented
of state-of-the-art knowledge of the neurocognitive,
neurobiological and psychopathological profile,
c 2013 Wolters Kluwer Health | Lippincott
assessment and treatment of patients with DS.
The linguistic characteristics of DS develop differently
along distinct developmental trajectories. Thus, for
example, morphosyntax deficit, especially in production,
is more evident in adolescence than in early childhood and
lexicon is usually better preserved in all ages (at least in
comprehension). So far, rehabilitation is the only effective
approach for improving cognitive and linguistic abilities.
However, ongoing preliminary reports on other approaches
such as transmagnetic stimulation or drugs suggest
alternative or integrative treatment for the future.
Individuals with DS show typical organization of brain
structures related to some cognitive abilities, such as
reduced volume in frontal and prefrontal areas, which is
related to poor executive and linguistic abilities.
Introduction
Down’s syndrome (DS), or trisomy 21, is caused by the
presence of an extra chromosome 21. Standard trisomy 21,
characterized by the presence of a free-standing extra
chromosome 21, occurs in about 95% of cases. Approxi-
mately 1% of individuals with DS have a mosaicism with
both normal and trisomic cells. In the remaining 5% of
cases, the trisomy is related to a chromosome translocation.
The clinical phenotype of individuals with DS includes
unique facial characteristics: a flat occiput, round cheeks,
epicanthal folds and upslanting palpebral fissures, low
nasal bridge and a thick and a protruding tongue, which
allows the diagnosis of the syndrome in newborns.
The incidence of DS is about one child in 1000 live births
(Cocchi et al., 2010); indeed, it is the most frequent
genetic cause of intellectual disability (ID).
Although a few individuals with DS have been reported to
have an intelligence quotient (IQ) in the normal range
(Epstein, 1989), IQ is usually in the moderately to severely
retarded range (IQ = 25–55) and mental age is rarely above
8 years (Gibson, 1978). It should also be noted that in
individuals with DS, differently from typically developing
0955-8829
c 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins
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They also frequently show psychiatric disorders such
as externalizing disorders as well as depression, anxiety
and obsessive-compulsive disorder. Nevertheless,
as for other genetic syndrome with intellectual disability,
there is a significant lack of research specifically
focused on treatments of psychiatric and behavioural
problems in DS. This is true both for psychosocial
and for pharmacological interventions. Psychiatr Genet
23:95–107
Williams & Wilkins.
Psychiatric Genetics 2013, 23:95–107
Keywords: assessment, Down’s syndrome, intellectual disability,
neurodevelopment, psychiatric disorders, treatment
a
Department of Neuroscience, Child and Adolescence Psychiatry Unit,
Children Hospital Bambino Gesù, bDepartment of Psychiatry,
PhD School ‘Early Intervention in Psychosis’, ‘Sapienza’ University, Rome,
Italy and cDepartment of Environmental Science, School of Psychology,
University of Birmingham, Edgbaston, Birmingham, UK
Correspondence to Marco Armando, MD, Department of Neuroscience,
Child and Adolescence Psychiatry Unit, Children Hospital Bambino Gesù,
Piazza Sant’Onofrio 4, I-00165 Roma, Italy
Tel: + 390 06 68592475; fax: + 390 06 68592450;
e-mail: marco.armando@opbg.net
Received 2 March 2012 Revised 8 October 2012 Accepted 27 October 2012
children, IQ is not constant across the lifespan, but
decreases progressively with age (Pennington et al., 2003).
Moreover, in adults with DS, IQ can be influenced by the
increased risk of early-onset dementia of the Alzheimer
type, which is often reported in this syndrome (Bush and
Beail, 2004; Lott and Dierssen, 2010).
Compared with other groups of children and adolescents
with ID, children with DS are at a lower risk for
significant psychopathology (Dykens and Kasari,
1997; Stores et al., 1998; Dykens, 2000). In fact, 30–40%
of children with ID show significant psychopathology
(Reiss, 1990; Einfeld and Tonge, 1996; Coe et al., 1999)
compared with 18–23% of children with DS (Gath and
Gumley, 1986; Myers and Pueschel, 1991; Dykens, 2000).
Nevertheless, this prevalence is higher than that in the
general population of children and adolescents, which
ranges between 8 and 18% (Patel et al., 2007). Therefore,
psychopathology in this special population should be
considered a major topic in psychiatry.
In summary, DS, compared with other genetic syndromes
with ID and the general population, shows specific
neurodevelopmental, neurocognitive and psychopathological
DOI: 10.1097/YPG.0b013e32835fe426
96 Psychiatric Genetics 2013, Vol 23 No 3
patterns that should be well understood and taken into
account in clinical practice.
Therefore, the purpose of this review is to provide an
overview of the recent literature aiming: (a) to describe
the similarities and differences in the cognitive and
functional developmental trajectory and age-related
comorbidities over the lifespan of individuals with DS
compared with those with other genetically determined
neurodevelopmental syndromes and the general popula-
tion; (b) to consider mechanisms for, and the implications
of, such differences and to identify gaps in knowledge;
and (c) to evaluate the role of, and evidence for,
educative, rehabilitative, behavioural and pharmacological
interventions.
For clarity, the paper is divided into three main
paragraphs. The first will attempt to address the
previously stated aims of the neurocognitive and neuro-
developmental profiles of DS, whereas the second will
be focused on psychiatric issues. The main gaps in
knowledge and the future directions in terms of research
and clinical practice will be highlighted in the third
paragraph.
Neurocognitive profiles
Cognitive deficits asymmetry and ageing
DS is characterized by an uneven cognitive profile that
consists of clear weaknesses in language, verbal short-
term memory and explicit long-term memory but
relatively preserved in visuospatial abilities, associative
learning and implicit long-term memory (Vicari et al.,
2004; Lott and Dierssen, 2010).
Impaired language development of children with DS is
evident when their performances are compared with
those of typically developing (TD) peers of the same
mental age but also with those of individuals with ID of
different aetiologies, such as Williams syndrome (Wang
and Bellugi, 1994; Klein and Mervis, 1999; Mervis and
Robinson, 2000; Vicari et al., 2000). Studies investigating
the different components of linguistic abilities in DS
have pointed out marked difficulty in the area of verbal
production and comprehension (Rondal et al., 1988; Miller,
1992; Rondal, 1993; Chapman, 1995; Vicari et al.,
2000; Naess et al., 2012). However, early linguistic
development in DS infants presents some surprises and
a much less even pattern with production and lexical
comprehension abilities that are comparable to those of
TD children of the same mental age (Cromer, 1987;
Fowler, 1990). Thus, with increasing age, the split
between lexical and morphosyntactic abilities decreases
and a generalized picture of linguistic difficulty emerges
(Fowler, 1990; Miller, 1992; Fabbretti et al., 1997; Vicari
et al., 2004).
Finally, a more extensive use of communicative gestures
in DS infants than in TD infants at the same stage of
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communicative-linguistic development has been reported
extensively (Franco and Wishart, 1995; Singer Harris et al.,
1997; Caselli et al., 1998; Iverson et al., 2003), thus
suggesting preserved communicative capacities in DS
children in front of their generalized verbal linguistic
impairment.
All these findings seem to suggest that in children with
DS, linguistic characteristics may develop differently
along distinct developmental trajectories. In other words,
the linguistic skills of adolescents with DS cannot be
predicted directly by the pattern shown at younger ages.
Visual–spatial abilities are less impaired than language in
DS (Vicari, 2006; Frenkel et al., 2009). However, a
discrepancy within the visuospatial domain has been
reported. Indeed, individuals with DS performed
significantly worse than mental age TD matched in tasks
of visual perceptual and visual imagery, but the perfor-
mance of the two groups did not differ significantly
when the tasks involved the processing of spatial data
(Vicari et al., 2006). In other words, DS individuals
showed reduced visual but relatively preserved spatial
abilities.
Individuals with DS also show different levels of
impairment in learning and memory. Specifically, impair-
ment in verbal short-term and working memory has been
documented extensively (Wang and Bellugi, 1994; Jarrold
and Baddeley, 1997; Jarrold et al., 1999; Vicari and
Carlesimo, 2002; Brock and Jarrold, 2004; Lanfranchi
et al., 2004; Vicari et al., 2004, 2006).
Explicit and implicit long-term memory has been
investigated in DS (for a review, see Vicari and Carlesimo,
2002). Explicit memory involves the intentional recall or
recognition of experiences or information. Implicit
memory is manifested as facilitation (i.e. improvement
in performance) on perceptual, cognitive and motor tasks,
without any conscious reference to previous experiences.
Although explicit memory deficits have been documen-
ted extensively in both the verbal and the visual–spatial
domain, relative preservation of implicit memory has
been reported in individuals with DS (Carlesimo et al.,
1997; Vicari et al., 2000, 2001, 2007).
Individuals with DS often show a cognitive decline
associated with ageing characterized by a deterioration in
memory, language and cognitive functioning that resem-
bles Alzheimer’s disease (AD). Already in 1876, referring
to individuals with DS, Fraser and Michell noted that: ‘in
not a few instances, however, death was attributed
nothing more than general decay-sort of precipitated
senility’. There are well established and recognized
neuropathological and neurochemical links between DS
and AD, with both associated with chromosome 21
(Wisniewski et al., 1985). Several genes are implicated
in AD-like neurodegenerative mechanisms in individuals
with DS. These include Cu/Zn superoxide dismutase 1,

Ets-2 transcription factors, Down’s syndrome critical
region 1 stress-inducible factor and the amyloid precursor
protein (APP) gene (Tanzi et al., 1987; Lott et al., 2006).
Endoproteolytic cleavage of APP yields the pathogenic
amyloid-b (Ab) peptides that progressively accumulate in
the brain as the diffuse and neuritic plaques of AD as
confirmed recently in a PET study by Landt et al. (2011).
Overexpression of APP in the obligate region for DS is
associated with abundant Ab plaques and tangles
consistent with Braak stage V–VI. Intraneuronal Abeta
in DS appears to trigger a pathological cascade leading to
oxidative stress and a neurodegeneration typical of AD.
There are suggestions that an increase in subcellular
processing of APP and factors related to membrane APP
cleavage favours the secretion of Abeta with age in DS.
An imbalance between superoxide dismutase 1 and
glutathione perioxidase activity in DS has been linked
to free radical generation. Ets-2 and Down’s syndrome
critical region 1 overexpression in DS has been linked to
cell degeneration. Age-related accumulation of somatic
DNA mutations in both DS and AD contribute towards
oxidative stress that exacerbates the imbalance in gene
expression. This leads to enhanced Abeta deposition and
further neuronal vulnerability (Lott et al., 2006; Lockrow
et al., 2012).
Although anatomical degeneration characteristic of AD is
reported in most individuals with DS older than 35 years
(Wisniewski et al., 1985), only a low percentage of them
present clinical evidence of dementia (Oliver et al., 1998).
Indeed, AD is diagnosed in only 22–25% of individuals
with DS 40 years of age or older, compared with about
2–3% of individuals with other ID (Janicki and Dalton,
2000). However, the percentages of individuals with DS
with a diagnosis of AD increased with age and it ranges
between 9 and 22% at 40–49 years (Prasher, 1995;
Sekijima et al., 1998; Janicki and Dalton, 2000) and
between 36–66% for those aged 50–59 years (Prasher,
1995; Sekijima et al., 1998). Recently, Carr (2012), in a 40-
year follow-up study, found that a percentage varying
between 13 and 27% of the cohort followed showed a
cognitive decline, thus confirming previous reports
(Oliver et al., 1998; Janicki and Dalton, 2000; Prasher
et al., 2005).
Moreover, with increasing age, individuals with DS become
more susceptible to some age-related physical, neurological
and psychiatric conditions than individuals who do not have
DS probably because of many age-related changes; reduced
DNA repair, increased biological ageing and mortality occur
at an earlier age in individuals with DS than in those who
do not have the disorder (Lott and Dierssen, 2010).
However, sensory impairments as well as hypothyroidism
may mimic dementia and, therefore, the diagnosis of
ageing in DS requires evidence of a functional impair-
ment and change over time. This issue will be discussed
in the next paragraph.
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Neurodevelopmental and psychiatric issues in DS Vicari et al. 97
Assessment
Most of the neuropsychological assessments available for
the general populations have not been properly validated
in children with ID. Special challenges are associated
with testing individuals who have intellectual and
developmental disorders, including considerable floor
effects and the confounding effects of impaired language
and attention. Very recently, Edgin (2010) specifically
developed the Arizona Cognitive Test Battery (ACTB) to
assess the cognitive phenotype in DS. The ACTB
includes tasks with specific correlates with brain function
including tests of general cognitive ability and prefrontal,
hippocampal and cerebellar function. The neuropsycho-
logical assessments were chosen to assess a range of skills
nonverbally so as to not confound the assessment with
language demands and to be applicable to a wide age
range and across contexts. The tasks were drawn from the
Cambridge Neuropsychological Testing Automated Bat-
tery (CANTAB) eclipse battery or based on established
paradigms (e.g. NEPSY, c–g arena and the dots task)
already used in earlier studies of individuals with DS
(Pennington et al., 2003; Visu-Petra et al., 2007). These
studies have shown a consistent impairment on several
CANTAB tests, in particular the CANTAB Paired
Associates Learning task. Similar spatial associative
memory measures have been found to show age-related
decline in DS (Alexander et al., 1997). Many of these tests
are error-based, helping to limit floor effects, and are
applicable to children across a wide range of ages, with
alternate forms to decrease practice effects. Another
positive aspect of the CANTAB tests and the ACTB is
that there is evidence for their effective use across
languages and cultures (Luciana and Nelson, 2002).
In terms of ageing, cognitive decline in DS starts from a
lower baseline than in TD. Thus, it is crucial to establish
the premorbid level of functioning to assess whether, and
at what rate, dementia is progressing. Assessment of
history from the caregivers can provide information on
psychiatric, personal, past medical and family histories, as
well as an evaluation of mental state. To this end, specific
cognitive mental state examination tools for adults with
DS are required (CAMDEX-DS; Ball et al., 2004).
Reports by the American Association on Mental Retar-
dation-International Association for the Scientific Study
of Intellectual Disability (AAMR-IASSID), Aylward et al.,
1997 and by Burt and Aylward (2000) suggested tests for
the diagnosis of dementia applied to individuals with ID.
A more recent contribution is then reported in UK
guidance [National Institute for Health and Clinical
Excellence (NICE), 2006]. We report below some
examples of test batteries that may be administered.
The Dementia Scale for Down’s Syndrome (DSDS;
Huxley et al., 2000) can assess short-term and long-term
memory, orientation, speech, language, praxis, fine motor
skills, practical skills, mood, activity/interest, behavioural
98 Psychiatric Genetics 2013, Vol 23 No 3
disturbances and seizure onset, and is designed to
measure dementia in its early, middle and late stages.
The Dementia Questionnaire for Persons with Mental
Retardation (DMR) (revised edition: the Dementia
Questionnaire for People with Learning Disabilities;
Evenhuis et al., 2006) includes questions to assess the
sum of cognitive scores (which includes short-term and
long-term memory, spatial and temporal orientation)
and sum of social scores (which includes speech, practical
skills, mood, activity/interest and behavioural distur-
bance) to aid diagnosis and prognosis.
The Adaptive Behaviour Dementia Questionnaire
(ABDQ) is a short questionnaire used as a screening tool
to detect changes in adaptive behaviour (Prasher et al.,
2004).
Individuals with little or no speech may be tested by the
Test for Severe Impairment (modified) (Albert and
Cohen, 1992) and the Spatial Recognition Span (Moss
et al., 1986).
It is important to rule out treatable causes of dementia
such as depression, thyroid problems, etc., in addition to
motor slowness, sensory deficits and general physical ill
health, as these can all present with symptoms similar to
those of dementia (Aylward et al., 1997). Although various
tests are available, at this time, there is no definitive
mental status examination or neuropsychological instru-
ment that can aid the diagnosis of dementia in individuals
with DS. There is a need to focus on issues around ease of
use and interpretation by those administering such tests
(NICE, 2006). For example, neuroimaging results for
individuals with DS may appear to yield results that are
‘false positives’ for AD from an early age if the standards
for the general population are used.
Treatments
The last decade has witnessed considerable progress in
the understanding of the neurobiological bases of the
cognitive impairment in DS and recent findings high-
lighting promising avenues for pharmacological interven-
tion in DS (Fernandez et al., 2007; Roper et al., 2006).
Thus, it sounds very interesting to wait for systematic
data from this perspective in the next future.
However, trials of possible treatment in DS have been
based, so far, on the hypothesis that developmental delays
in children with DS may be related to neuronal damage
caused by biochemical factors such as increased oxidative
stress, abnormal folate metabolism or both. Indeed,
cultured neuronal cells from foetuses with DS undergo
apoptotic death more rapidly than those from unaffected
foetuses, and this is reversed by the addition of
antioxidants (Brooksbank and Balazs, 1984; Busciglio
and Yankner, 1995). Consistent with this hypothesis,
Lejeune (1990) suggested that folate treatment might
improve the psychomotor development of children with
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
DS. However, this study had methodological biases and the
finding was not consistent with other studies (Bennett
et al., 1983; Bidder et al., 1989). More recently, Ellis et al.
(2008) clearly documented that daily supplementation
with antioxidants, folinic acid or both did not alter
psychomotor or language development in children with
DS. Thus, there is no high-quality in-vivo evidence that
supplementation with folate, antioxidants or both amelio-
rates neurodevelopment in infants with DS.
On the basis of these findings, rehabilitation is the only
realistic approach to improve cognitive and linguistic
abilities in children with DS. However, there are many
different rehabilitative approaches and few studies have
investigated their efficacy.
Among those, early intervention programmes also invol-
ving family members have shown their validity in improv-
ing linguistic, communicative and social skills (Mahoney
et al., 2006).
Therefore, at present, only anecdotal results are available.
For example, Conners et al. (2008) documented that some
of the 16 children with DS they followed using a home-
based rehearsal training may have experienced a partial
improvement in their short-term memory capacities. In
addition, in a recent review, Lemons and Fuchs (2010)
suggested that treatment based on phonological aware-
ness seemed to improve the reading of words not taught
directly, comprehension and fluency in children with DS.
In any case, long-term, intensive interventions, possibly
delivered in a one-on-one format, are necessary to achieve
educational gains.
More longitudinal controlled studies on the effect of early
intervention programmes and rehabilitative strategies are
required to better clarify their real efficacy.
In terms of ageing, although DS has a high incidence of
AD, relatively little research has been carried out on its
treatment. The use of medication for AD in individuals
with DS is therefore more controversial than that in the
general population (Stanton and Coetzee, 2004).
The NICE has amended and reissued guidance following
the outcome of a judicial review, and only donepezil, a
reversible inhibitor of acetylcholinesterase, galantamine,
a reversible noncompetitive inhibitor of acetylcholines-
terases, and rivastigmine, an acetylcholinesterase and
butyryl-cholinesterase temporary inhibitor, were recom-
mended for the treatment of AD. However, there is little
research evidence that assesses whether any of the
available treatments are effective in this population
(Prasher et al., 2004; Mohan et al., 2009a, 2009b, 2009c).
Neurobiological characteristics
The cognitive and behavioural profile of individuals with
DS is a consequence of anomalous brain development
caused by trisomy 21. Autopsy reports indicate lower
brain weight with particularly small cerebellum, frontal

and temporal lobes (Wisniewski, 1990) in this population.
By contrast, subcortical areas, such as lenticular nuclei
and the posterior parietal and occipital cortical grey
matter (GM), have relatively normal brain volumes.
Consistently, volumetric MRI studies of individuals with
DS and healthy controls confirmed abnormal volumes of
many cerebral areas. In particular, smaller brain volume
was documented in the temporal areas and in the
cerebellum in a DS group (White et al., 2003).
The cerebellar morphometry might play a major role in
the motor dysfunction and hypotonia of individuals with
DS (Clark and Wilson, 2003; Vicari, 2006). Many studies
have suggested that the cerebellum plays a role in several
cognitive functions, such as language, abstract reasoning,
attention, working memory and executive functions,
which are usually impaired in DS populations (Wishart,
2007). More specifically, Menghini et al. (2011) docu-
mented abnormal GM density in the posterior part of the
cerebellum, a region believed to be mainly associated
with high-order cognitive functions such as attentional
abilities and executive functions (Strick et al., 2009).
Menghini et al. (2011) also reported a GM reduction of
the temporal lobe and the hippocampus, which may be
considered responsible for the explicit long-term memory
and linguistic deficits documented in individuals with DS
(Rondal et al., 1988; Fowler, 1990; Carlesimo et al.,
1997; Vicari et al., 2005).
By contrast, individuals with DS have increased GM
density in the right parahippocampus, the basal ganglia
and the insula bilaterally (Kesslak et al., 1994, Raz et al.,
1995, Aylward et al., 1997; Menghini et al., 2011). Relative
sparing of the putamen and caudate nucleus and, more
generally, of the basal ganglia could be related to
proficient performance on implicit and procedural learn-
ing tasks (Vicari et al., 2001, 2007). Instead, the GM
increase in the parahippocampal gyrus has been related to
relatively good performance on some recognition memory
tasks, including delayed nonmatch to sample and visual
paired comparison tasks (Kesslak et al., 1994).
In summary, MRI studies carried out with different
tasks show that a number of regions subserve the
performance of individuals with DS. Indeed, the organi-
zation of their brain structures is typical for some
cognitive abilities, such as visual and spatial memory,
but abnormal for others, such as linguistic and verbal
memory abilities.
Psychiatric issues
Epidemiology and general considerations
Children and adolescents with DS have more psychiatric
and behavioural disorders than typically developing
children (Gath and Gumley, 1986; Pueschel et al.,
1991; Des Noyers Hurley, 1996; Stores et al., 1998; Coe
et al., 1999; Nicham et al., 2003). Compared with TD
controls, 4-year-old to 18-year-old children with DS are
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Neurodevelopmental and psychiatric issues in DS Vicari et al. 99
more likely to show externalizing behaviours such as
stubbornness, oppositionality, inattention, speech prob-
lems, concentration difficulties, attention seeking and
impulsivity (Pueschel et al., 1991; Dykens et al., 2002), as
well as depression, anxiety and obsessive-compulsive
disorder (OCD). Not surprisingly, from 6 to 8% of
children with DS are diagnosed with attention deficit
hyperactivity disorder (ADHD) and from 10 to 15% of
children or young individuals are diagnosed with conduct
or oppositional disorders, which manifest in noncompli-
ant, disobedient or aggressive behaviours (Myers and
Pueschel, 1991; Coe et al., 1999).
Usually, a significant shift occurs in the psychiatric
symptomatology of children and adolescents with
DS. Stores et al. (1998) found that adolescents with DS
showed significantly lower hyperactivity than children
with DS. Dykens et al. (2002) documented a significant
reduction in externalizing behaviours in adolescents
compared with children. They also found that adoles-
cents showed a significant increase in internalizing
symptoms, (e.g. withdrawal and depression). Nicham
et al. (2003) showed that externalizing behaviour prob-
lems (dominance, opposition, hyperactivity, impulsivity,
inattention) were more common in children aged 5–10
years, whereas internalizing behaviour problems (shyness,
low confidence) were more common in adolescents and
adults.
In terms of resilience and sensitivity to mental disorders
(Collip et al., 2008), lower ability and lower independent
functioning level were predictive of severe problem
behaviours in adult life, as were childhood psychiatric
disorder, parental mental health, quality of parental
marriage and social class during childhood (McCarthy,
2008).
Assessment
Even today, many mental health professionals do not
recognize or appreciate the co-occurrence of psychiatric
problems and ID and this is also true for DS.
There are three reasons for this:
(1) The presence of diagnostic overshadowing (Reiss
et al., 1982), which is typical of dual diagnoses, creates
a veil that leads to attributing the presence of
psychiatric disorders to ID. Consequently, any
psychiatric disorder is perceived as a ‘reaction’ to,
not a comorbidity of, ID. In fact, the former are
downgraded to behavioural disturbances and treated
as such (Dykens, 2007; Mazzone et al., 2012).
(2) If psychiatric disorders are associated with ID, they
significantly alter the clinical expression of the
disorder, which ranges from aspecific behavioural
manifestations in cases of serious cognitive impair-
ment to psychiatric symptoms that can be correlated
with specific disorders in cases of slight ID.
100 Psychiatric Genetics 2013, Vol 23 No 3
This means that the phenomenology of the disorder
changes, not the disorder itself. In fact, even in cases
of more serious psychiatric disturbances, such as
schizophrenia, it has been observed that the nucle-
arity of the disturbance is not differentiated in the
two subgroups (Klosterkotter et al., 1996).
This proteiform symptomatology and aspecificity can
lead to a tendency in clinical practice to formulate
diagnoses and treatments by focusing on the
symptomatological aspect of behaviour and adopting
a therapeutic approach that is exclusively dimen-
sional rather than pathogenic and categorical.
Nevertheless, most psychiatrists, psychologists and
social workers do not receive specific training for
making ‘dual diagnoses’ or for recognizing specific
psychiatric symptom presentation in patients with
ID. Indeed, the need for specialization in this area
has been emphasized in recent years (Einfeld,
1992; Einfeld et al., 2007).
(3) Most studies on psychiatric disorders in the general
population typically exclude individuals with low IQ.
Furthermore, specific studies on ID and psychiatric
disorders are lacking. As a result, even though in-
dividuals with ID are at an increased risk for
psychiatric problems, we know much less about the
causes, courses and treatments of these problems in
this vulnerable population. Therefore, in recent
years, considerable efforts have been made to develop
specific psychiatric diagnostic criteria for patients
with dual diagnoses (Einfeld, 1992; Szymanski and
King, 1999).
One of the first attempts in this direction was the
development of the Diagnostic Criteria for Psychiatric
Disorders for Use with Adults with Learning Disabilities/
Mental Retardation (DC-LD) (Royal College of Psychia-
trists, 2001), which represent the first psychiatric
classificatory system devised specifically for use with
adults with intellectual disabilities.
The use of DC-LD is aimed at adults with moderate to
profound intellectual disabilities, although it may be useful
in some adults with mild or low average intelligence,
depending on the individual’s presentation and has a very
high diagnostic accuracy. Indeed, in a field trial (Cooper
et al., 2003) conducted to investigate the diagnostic
accuracy of the instrument, in 96.3% of the 709 recruited
patients, the DC-LD diagnosis was fully concordant with
that of the clinical opinion.
Subsequently, the National Association for the Dually
Diagnosed (NADD), in association with the American
Psychiatric Association (APA), developed a manual
(Fletcher et al., 2007) designed as an adaptation of the
Diagnostic and Statistical Manual of Mental Disorders, 4th ed. –
Text Revision (DSM-IV-TR). The Diagnostic Manual-Intellec-
tual Disability (DM-ID): a textbook of diagnosis of mental
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
disorders in persons with intellectual disability attempts
to provide a useful adaptation of the DSM-IV-TR for
individuals with ID. In a recent study (Fletcher et al.,
2009), professionals indicated that the manual was easy to
use, aided accurate diagnoses and reduced the use of the
not otherwise specified category.
Another psychiatric diagnostic tool developed especially
for dual diagnoses is the Diagnostic Assessment for
the Severely Handicapped, 2nd modified version (DASH
II) (Matson, 1995); its content validity was established
by deriving disorder subscales and individual items
from the DSM-III-R and previous studies of this
population. This instrument was found to have good
inter-rater and test–retest reliability both in populations
with ID (Matson and Smiroldo, 1997) and specifically
in DS.
To date, only few studies have focused psychiatric
disorders in DS using tools especially developed
for ID. Clark and Wilson (2003) assessed the behaviour
of 60 children with DS using a specific instrument
developed for dual diagnosis: the Reiss psychopathology
rating scale. Agreement between parent and teacher
raters was over 75% and the structure of the Reiss
instrument was useful for distinguishing behaviours
potentially related to medical problems from actual
psychopathology.
Recently, interesting preliminary findings were obtained
using the minor physical anomaly (MPA) that is believed
to reflect abnormal development of the CNS. Exploring
the incidence of MPA and its behavioural correlates in DS
and comparing these findings with the other causes of ID
and normal population, Bhattacharyya et al. (2010) found
that DS has significantly more MPA and that a pattern of
correlation between MPA and behavioural abnormalities
exists in DS. Nevertheless, even though most of the
studies were carried out using assessment instruments
developed for TD, to measure their validity, no compara-
tive studies in a DS population between these instruments
and others specifically developed for ID were carried
out. Moreover, only a few studies have focused on com-
parison between DS and other common genetic syndromes
of psychopathology and even fewer on their adaptive
profiles. A recent study (Di Nuovo and Buono, 2011)
comparing similarities and differences in the adaptive
profiles of the most frequent genetic syndromes using the
Vineland Adaptive Behavior Scale showed a specific
adaptive profile of DS with respect to psychiatric disorders
comorbidity.
Treatments
As for other genetic syndromes with ID, there is a
significant lack of research specifically focused on
treatments of psychiatric and behavioural problems in
DS. This is true both for psychosocial and for pharma-
cological interventions.

Psychosocial interventions for challenging behaviour
To date, the behavioural intervention most frequently
used in ID is the applied behaviour analysis (for more
details, see Carr et al., 2002). This methodology was found
to be effective across a wide range of populations, with
various disabilities. Recently, the technology of positive
behaviour support (Carr et al., 1999, 2002) has emerged as
an application of the principles of behaviour analysis to
not only address skill repertoires but also redesign
individuals’ living environments with the goal of achiev-
ing enhanced quality of life and decrease problem
behaviour (Carr et al., 1999).
Nevertheless, only a few studies have investigated the
effect of psychosocial and behavioural interventions in
this specific population. Feeley and Jones (2008), in an
extensive review of the literature, identified a small
number of studies utilizing behavioural assessment
strategies, as well as several intervention studies that
addressed severe challenging behaviour in individuals
with DS. Even though considerable empirical research
(Reichle and Wacker, 1993; Carr et al., 2002; Feeley and
Jones, 2006) has shown the effective use of behaviourally
based procedures to intervene on challenging behaviour
in individuals with ID, close examination of the
behavioural intervention literature shows relatively few
applications with children with DS and even fewer
applications targeting the specific and characteristic
challenges presented by these children. In the case
studies analysed by Feeley and Jones (2008), these
interventions show an effective decrease in challenging
behaviours in children with DS.
Pharmacological interventions
Most studies of psychotropic prescriptions in ID have not
specifically focused on DS and tended to be open trials,
case reports or controlled studies with small samples.
Reviews on this topic suggest that individuals with ID
respond similar to the TD population to various psycho-
tropic medications (Handen and Gilchrist, 2006; Ulzen
and Powers, 2008). However, rates of response tend to be
poorer and the occurrence of side effects tends to be more
frequent. The use of psychotropic medications in children
and adolescents with ID requires even greater monitoring
and the use of lower doses and slower dosage increases
than in the general population.
Consequently, considerable efforts have been made to
develop specific guidelines. For example, Aman et al.
(2004) published consensus guidelines for the treatment
of psychiatric illness and behavioural problems in
individuals with ID, which emphasizes the presence of
a diagnosis, consideration of alternatives and evaluation.
Individuals with ID tend to be overmedicated. Studies in
the last 20 years indicate that almost 50% of individuals
with ID who are under care take psychotropic medication
for the treatment of psychiatric disorders and/or problem
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Neurodevelopmental and psychiatric issues in DS Vicari et al. 101
behaviours (Holden and Gitlesen, 2004). Holden and
Gitlesen (2004) reported that prescriptions frequently
violate current guidelines, especially those given by
general practitioners. For example, many prescriptions
were given without a diagnosis, alternatives to medica-
tions had rarely been explored and evaluation of effects
and side effects was generally lacking. Instead, the
application of specific guidelines significantly improved
the reliability of prescriptions. Engel et al. (2010)
reported that medication with neuroleptics and anti-
depressive compounds has increased. Atypical and typical
neuroleptics do not differ significantly in terms of side
effects, but the number of side effects in selective
serotonin reuptake inhibitors compared with tricyclic
antidepressive compounds has been reduced significantly.
Psychotropic drugs can be divided into four general
categories: psychostimulants, antipsychotics, antidepres-
sants and mood stabilizers. Each category has specific
target symptoms and disorders. Table 1 provides a
summary of possible treatment indications for specific
disorders.
Specific disorders
Mood disorders
The incidence of depressive disorders is lower in children
and adolescents than in adults with DS (Dykens et al.,
2002; Nicham et al., 2003; Maatta et al., 2006). The
prevalence rates of depression in adults with DS range
from 5.2 to 11.4% (Collacott et al., 1992; Mantry et al.,
2008) compared with only 4% in adults with other ID
(Collacott et al., 1992). A recent longitudinal cohort study
of adolescents and adults (16 years) with DS (Mantry
et al., 2008) who received a detailed psychiatric assess-
ment showed that the incidence of depressive disorders
was 5.2% of the total sample. Lower rates of depression
are found in children with DS who are more prone to have
externalizing disorders (Capone et al., 2006).
Assessment: The ‘somatic’ spectrum of depressive disorders
is the most common DSM-IV criterion observed in
individuals with DS and depression. The spectrum
includes decreased interest, psychomotor slowing, fa-
tigue, appetite/weight change, sleep disturbance, poor
concentration and reduced speech. Feelings of worthless-
ness or guilt and agitation may also be present (Cooper
and Collacott, 1994; Myers and Pueschel, 1995). Self-care
routines may deteriorate, thus necessitating assistance or
frequent prompting. Psychosocial stressors often precede
the onset of mood disorders in adolescents and young
adults with DS (Dodd et al., 2005).
Primary sleep disorders are common in adolescents with
DS (Resta et al., 2003) and should not be confounded
with secondary sleep disturbances, which are typically
present in depressive disorders. Primary sleep disorder
can have a significant impact on mood, attention,
cognition and motivation level (Andreou et al., 2002),
102 Psychiatric Genetics 2013, Vol 23 No 3

Table 1 Treatment indications for specific disorders

Psychiatric disorders Target symptoms First-choice drug Clinical considerations

Depression Depressed mood SSRI SSRIs are chosen over TCAs. For depressive symptoms,
fluoxetine remains the only approved treatment for
children. As sertraline is approved for treatment of children
with anxiety, it is also a reasonable option. Citalopram/
escitalopram remain other good choices because of their
higher specificity and fewer side effects
Dysphoric mood SSRI + mood stabilizer
Anhedonia, apathy, insomnia, Dual reuptake inhibitor, SSRI
social withdrawal
Obsessive-compulsive Obsession, compulsion SSRI, TCA, atypical
disorder neuroleptics
Perseveration, tics Atypical/typical neuroleptics
Anxiety Anxiety, somatic symptoms, SSRI/BDZ
restlessness
Autism spectrum Social withdrawal, Atypical neuroleptics Risperidone is the treatment of choice in children and
disorder disorganization, stereotyping, adolescents with ID. For individuals who fail to respond or
physical aggression who experience side effects, quetiapine, aripiprazole and
ziprasidone may cause less weight gain. Because of
aripiprazole’s lack of effect on weight and QT length, it may
become the treatment of choice in the near future
Psychosis Delusions, hallucinations, Atypical neuroleptics
catatonia, agitation
Negative symptoms Lower dose of atypical
neuroleptics
Manic symptoms Mood stabilizer, lithium, atypical
neuroleptics
ADHD Distractibility, hyperactivity Metilphenidate, atomoxetine Bipolar disorders in the ID population are more likely to
impulsivity guanfacine respond to valproic acid and other antiepileptic drugs,
because individuals with ID are more often atypical, mixed
or rapid cycling. However, to achieve a better outcome,
combined treatments are often needed, such as two mood
stabilizers and a low dose of an antipsychotic drug.
Stimulants remain the first-choice treatment for ADHD in
ID. Atomoxetine is considered a second-choice treatment.
a-Agonists are probably a third option
Oppositional-defiant Physical aggression, Atypical neuroleptic/mood
disorder destructiveness stabilizer

ADHD, attention deficit hyperactivity disorder; BDZ, benzodiazepine; ID, intellectual disability; QT, quetiapine; TCA, tricyclic antidepressant; SSRI, selective serotonin
reuptake inhibitors.

but a full response to antidepressant medication may not
be achieved until the sleep abnormality is identified and
treated successfully (Means et al., 2003).
Obsessive-compulsive disorder
The prevalence of OCD in DS ranges from 0.8% (Myers
and Pueschel, 1991) to 4.5% (Prasher, 1995); indeed, it is
lower than in other psychiatric disorders and not higher
than in the general population. Obsessive thoughts may
be difficult to ascertain in individuals with cognitive
impairment. As for depression and other internalizing
disorders in DS, OCD increases in adolescents and
adults.
Assessment: Compulsions that require abstract thinking are
common in OCD in the general population but can be
rare or absent in OCD in individuals with ID. Clinicians
familiar with OCD in individuals of average intelligence
may believe that OCD is absent if an individual with ID
does not engage in ‘classic’ compulsions. Compulsions
that require counting skills or abstract concepts, such as
contamination or germs or safety, do not occur in
individuals with ID who are unable to think abstractly
or to count.
Not all repetitive behaviours in individuals with ID can
be defined as obsessive-compulsive phenomena (Gedye,
1996). Indeed, repetitive behaviours with physiologically
rewarding properties, namely, masturbation, stealing,
hyperventilation, overeating, polydipsia, smoking, hum-
ming and pacing, should not be considered in making
diagnoses.
The Compulsive Behavior Checklist for clients with ID
(Gedye, 1992, 1996) is a guide for collecting information
to help ascertain whether OCD criteria have been
fulfilled. The Obsessive Speech Checklist (Gedye,
1998) is a guide for collecting information on obsessive
speech patterns in individuals with ID. The OCD
Severity Scale (Vitiello et al., 1989) rates the severity of
OCD symptoms in individuals with ID.
When obsessive-compulsive symptoms appear abruptly
in prepubertal children, they may indicate the presence
of paediatric autoimmune neuropsychiatric disorders

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

associated with streptococcal infections or PANDAS
(Snider and Swedo, 2004).
Attention deficit hyperactivity disorder and externalizing
behaviours
ADHD is diagnosed when inattention, impulsivity and
hyperactivity are present and result in significant
academic or social impairment. In young children with
DS, hyperactivity and impulsivity are more frequent than
inattention (Green et al., 1989).
Compared with TD controls, 4-year-old to 18-year-old
individuals with DS are more likely to show externalizing
behaviours related to ADHD, OCD and conduct disorder
(Pueschel et al., 1991; Coe et al., 1999; Bhattacharyya et al.,
2009). Indeed, 6–8% of children with DS are diagnosed
with ADHD and 10–15% of children or adolescents are
diagnosed with conduct or oppositional disorders (Gath
and Gumley, 1986; Myers and Pueschel, 1991; Coe et al.,
1999). Moreover, in a recent study (Maatta et al., 2006) of
129 individuals with DS, 33% had manifested ADHD
symptoms during childhood and adolescence.
Assessment: Hyperactivity and impulsivity are the most
dangerous symptoms in children with DS + ADHD; in
fact, these children are at an especially high risk for
accidental injury, wandering, running away or getting lost.
During assessment, ID can overshadow inattention,
which should be treated as an important issue because
of its specific effect on academic impairment. Hyper-
thyroidism, hearing loss, sleep disturbance or sleep
apnoea (Levanon et al., 1999; Fallone et al., 2002;
Goday-Arno et al., 2009), and medication side effects
(stimulants, selective serotonin reuptake inhibitors,
antihistamines, adrenergic agonists and caffeine) should
be considered as possible aetiological factors when
evaluating children with DS + ADHD.
Anxiety disorders
To our knowledge, no specific studies have been carried
out on the incidence and prevalence of anxiety symptoms
in DS.
Evidence-based knowledge of the assessment and diag-
nosis of anxiety disorders in individuals with ID,
especially in DS, is weak. This may be because the
current diagnostic classification systems have been
validated in populations with typical intellectual func-
tioning. Because of the lack of insights, the subjective
elements of the diagnostic criteria may not be reported
and may not be applicable in this group (Einfeld, 1992).
However, objective features of anxiety present in the
general population, such as fear, trembling, flushing and
irritability, are readily observable in individuals with DS
(Fletcher et al., 2007). Often, objective features of anxiety
are present in children with DS in comorbidity with
ADHD symptoms (Green et al., 1989; Coe et al., 1999),
and they can easily be confounded with hyperactivity and
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Neurodevelopmental and psychiatric issues in DS Vicari et al. 103
impulsivity. Therefore, it is very important to carefully
explore the nature of this kind of symptom in patients
with DS (Dykens, 2007).
Psychotic disorders
There is a lower prevalence of schizophrenia and bipolar
disorder in individuals with DS than in adults with ID
related or not to genetic syndromes (Collacott et al.,
1992; Armando et al., 2012), and adolescents and young
adults without ID (Morgan et al., 2008).
Although positive symptoms, such as delusions and
hallucinations, may be present, negative symptoms, such
as cognitive and behavioural disorganization, social with-
drawal, apathy, psychomotor slowing, reduced speech and
affective blunting, are more frequent.
In one of the largest epidemiological studies
(n = 245 749) on the co-occurrence of ID with schizo-
phrenia and other psychiatric illnesses, Morgan et al.
(2008) found that schizophrenia, but not bipolar disorder,
was considerably over-represented in individuals with a
dual diagnosis: depending on birth cohort, 3.7–5.2% of
those with ID had co-occurring schizophrenia. Never-
theless, DS was much less prevalent among individuals
with a dual diagnosis, even though it was the most
predominant cause of ID. To our knowledge, no studies
have been published thus far on psychotic like experi-
ences (Armando et al., 2010) and at-risk mental states
(Yung et al., 2003) in DS populations.
In conclusion, there is some evidence that psychosis is
rare in individuals with DS (Sovner et al., 1985; Collacott
et al., 1992; Prasher, 1995; Morgan et al., 2008). Recent
data (Mantry et al., 2008) suggest that the effect of
unknown resilience factors associated with DS may play a
protective role in the development of psychosis and
mental illness in general. These resilience factors seem to
reduce the effect of environmental resilience factors such
as family circumstances, poor lifestyles and lack of social
support (McCarthy and Boyd, 2001).
As so few studies have investigated this relationship
directly, the question remains open as to whether the
observed difference in prevalence is real or because of
diagnostic underascertainment.
Autism spectrum disorders
The autistic spectrum disorder (ASD) is characterized by
qualitative impairment in reciprocal social and commu-
nication skills, as well as restricted interests and
repetitive play routines or movements; onset occurs
before 36 months.
Early studies relied on clinical patient records of existing
diagnoses. They were carried out with inconsistent
diagnostic criteria for ASD and found very low rates of
autism, that is, 1–2% (Gath and Gumley, 1986; Myers and
Pueschel, 1991; Collacott et al., 1992).
104 Psychiatric Genetics 2013, Vol 23 No 3
More recent studies (Kent et al., 1999; Pary and Hurley,
2002), which were carried out using more reliable
diagnostic criteria, suggested that 7–10% of children
and adolescents with DS may also have ASD.
The children with DS (compared with those with ASD in
general) were generally much older when they received
their ASD diagnosis (Rasmussen et al., 2001); in fact,
diagnosis ages across studies ranged from 6 to 16 years of
age. This was probably because of diagnostic overshadow-
ing rather than later ASD onset.
Recent clinical studies (Capone et al., 2005; Carter et al.,
2007) in which children with DS and ASD were
compared with children with DS without ASD showed
that the first group had lower IQs and more severe, odd
stereotypic behaviours, anxiety and social withdrawal.
Other studies (Howlin et al., 1995) reported that patients
with DS and ASD also manifested significant impulsivity,
more pronounced cognitive disorganization, disruptive
behaviour and self-injury. Some studies (Ghaziuddin,
2000; Rasmussen et al., 2001; Starr et al., 2005) reported
that risk factors associated with ASD in children with DS
included postcardiac surgery complications, hypothyroid-
ism, lower IQs and first-degree relatives with ASD.
Infantile spasms and myoclonic seizures were associated
with an increased risk of developing ASD in children with
DS (Goldberg-Stern et al., 2001; Eisermann et al., 2003).
Conclusion
DS is the most frequent genetic cause of ID. Never-
theless, even though many neuropsychological studies
have been carried out in children and adolescents with
DS, a significant gap that emerged in our review is that
very few have examined the effectiveness of rehabilita-
tion treatments.
At the same time, despite the high prevalence of
psychiatric comorbidity in DS, very few studies have
investigated the specific characteristics of psychiatric
disorders in DS and even fewer studies have investigated
the effectiveness of different treatments for these
disturbances in children and adolescents.
In conclusion, many research and treatment gaps remain
in the mental health arena, and these disparities are also
present in the larger field of ID. Future work on
psychopathology in DS is required to help close this
gap. In fact, research should aim to clarify specific
diagnostic criteria to enable identification of both risk and
protective factors across the biospsychosocial spectrum
and to document combinations of treatments that
ameliorate distressful symptoms and enhance positive
states.
Neurodevelopmental disorders with identified genetic
aetiologies present a unique opportunity to study gene–
brain–behaviour connections in child psychiatry.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Acknowledgements
Conflicts of interest
There are no conflicts of interest.
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